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Sample records for t-cell-mediated tumor control

  1. Tumor-necrosis factor impairs CD4(+) T cell-mediated immunological control in chronic viral infection.

    Science.gov (United States)

    Beyer, Marc; Abdullah, Zeinab; Chemnitz, Jens M; Maisel, Daniela; Sander, Jil; Lehmann, Clara; Thabet, Yasser; Shinde, Prashant V; Schmidleithner, Lisa; Köhne, Maren; Trebicka, Jonel; Schierwagen, Robert; Hofmann, Andrea; Popov, Alexey; Lang, Karl S; Oxenius, Annette; Buch, Thorsten; Kurts, Christian; Heikenwalder, Mathias; Fätkenheuer, Gerd; Lang, Philipp A; Hartmann, Pia; Knolle, Percy A; Schultze, Joachim L

    2016-05-01

    Persistent viral infections are characterized by the simultaneous presence of chronic inflammation and T cell dysfunction. In prototypic models of chronicity--infection with human immunodeficiency virus (HIV) or lymphocytic choriomeningitis virus (LCMV)--we used transcriptome-based modeling to reveal that CD4(+) T cells were co-exposed not only to multiple inhibitory signals but also to tumor-necrosis factor (TNF). Blockade of TNF during chronic infection with LCMV abrogated the inhibitory gene-expression signature in CD4(+) T cells, including reduced expression of the inhibitory receptor PD-1, and reconstituted virus-specific immunity, which led to control of infection. Preventing signaling via the TNF receptor selectively in T cells sufficed to induce these effects. Targeted immunological interventions to disrupt the TNF-mediated link between chronic inflammation and T cell dysfunction might therefore lead to therapies to overcome persistent viral infection.

  2. Vaccination with an adenoviral vector encoding the tumor antigen directly linked to invariant chain induces potent CD4(+) T-cell-independent CD8(+) T-cell-mediated tumor control

    DEFF Research Database (Denmark)

    Sorensen, Maria R; Holst, Peter J; Pircher, Hanspeter

    2009-01-01

    of the vaccine antigen to invariant chain (Ii). To evaluate this strategy we used a mouse model, in which an immunodominant epitope (GP33) of the LCMV glycoprotein (GP) represents the tumor-associated neoantigen. Prophylactic vaccination of C57BL/6 mice with a replication-deficient human adenovirus 5 vector...... vaccination with adenovirus expressing GP alone (Ad-GP), or GP and Ii unlinked (Ad-GP+Ii). Ad-Ii-GP- induced tumor control depended on an improved generation of the tumor-associated neoantigen-specific CD8(+) T-cell response and was independent of CD4(+) T cells. IFN-gamma was shown to be a key player during...

  3. Tumor sialylation impedes T cell mediated anti-tumor responses while promoting tumor associated-regulatory T cells

    NARCIS (Netherlands)

    Perdicchio, Maurizio; Cornelissen, Lenneke A. M.; Streng-Ouwehand, Ingeborg; Engels, Steef; Verstege, Marleen I.; Boon, Louis; Geerts, Dirk; van Kooyk, Yvette; Unger, Wendy W. J.

    2016-01-01

    The increased presence of sialylated glycans on the tumor surface has been linked to poor prognosis, yet the effects on tumor-specific T cell immunity are hardly studied. We here show that hypersialylation of B16 melanoma substantially influences tumor growth by preventing the formation of effector

  4. T-cell mediated anti-tumor immunity after photodynamic therapy: Why does it not always work and how can we improve it?

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    de Freitas, Lucas Freitas; Hamblin, Michael R

    2015-01-01

    Photodynamic therapy (PDT) uses the combination of non-toxic photosensitizers and harmless light to generate reactive oxygen species that destroy tumors by a combination of direct tumor cell killing, vascular shutdown, and activation of the immune system. It has been shown in some animal models that mice that have been cured of cancer by PDT, may exhibit resistance to rechallenge. The cured mice can also possess tumor specific T-cells that recognize defined tumor antigens, destroy tumor cells in vitro, and can be adoptively transferred to protect naïve mice from cancer. However, these beneficial outcomes are the exception rather than the rule. The reasons for this lack of consistency lie in the ability of many tumors to suppress the host immune system and to actively evade immune attack. The presence of an appropriate tumor rejection antigen in the particular tumor cell line is a requisite for T-cell mediated immunity. Regulatory T-cells (CD25+, Foxp3+) are potent inhibitors of anti-tumor immunity, and their removal by low dose cyclophosphamide can potentiate the PDT-induced immune response. Treatments that stimulate dendritic cells (DC) such as CpG oligonucleotide can overcome tumor-induced DC dysfunction and improve PDT outcome. Epigenetic reversal agents can increase tumor expression of MHC class I and also simultaneously increase expression of tumor antigens. A few clinical reports have shown that anti-tumor immunity can be generated by PDT in patients, and it is hoped that these combination approaches may increase tumor cures in patients. PMID:26062987

  5. The Escape of Cancer from T Cell-Mediated Immune Surveillance: HLA Class I Loss and Tumor Tissue Architecture

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    Federico Garrido

    2017-02-01

    Full Text Available Tumor immune escape is associated with the loss of tumor HLA class I (HLA-I expression commonly found in malignant cells. Accumulating evidence suggests that the efficacy of immunotherapy depends on the expression levels of HLA class I molecules on tumors cells. It also depends on the molecular mechanism underlying the loss of HLA expression, which could be reversible/“soft” or irreversible/“hard” due to genetic alterations in HLA, β2-microglobulin or IFN genes. Immune selection of HLA-I negative tumor cells harboring structural/irreversible alterations has been demonstrated after immunotherapy in cancer patients and in experimental cancer models. Here, we summarize recent findings indicating that tumor HLA-I loss also correlates with a reduced intra-tumor T cell infiltration and with a specific reorganization of tumor tissue. T cell immune selection of HLA-I negative tumors results in a clear separation between the stroma and the tumor parenchyma with leucocytes, macrophages and other mononuclear cells restrained outside the tumor mass. Better understanding of the structural and functional changes taking place in the tumor microenvironment may help to overcome cancer immune escape and improve the efficacy of different immunotherapeutic strategies. We also underline the urgent need for designing strategies to enhance tumor HLA class I expression that could improve tumor rejection by cytotoxic T-lymphocytes (CTL.

  6. Surgical Stress Abrogates Pre-Existing Protective T Cell Mediated Anti-Tumor Immunity Leading to Postoperative Cancer Recurrence.

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    Abhirami A Ananth

    Full Text Available Anti-tumor CD8+ T cells are a key determinant for overall survival in patients following surgical resection for solid malignancies. Using a mouse model of cancer vaccination (adenovirus expressing melanoma tumor-associated antigen (TAA-dopachrome tautomerase (AdDCT and resection resulting in major surgical stress (abdominal nephrectomy, we demonstrate that surgical stress results in a reduction in the number of CD8+ T cell that produce cytokines (IFNγ, TNFα, Granzyme B in response to TAA. This effect is secondary to both reduced proliferation and impaired T cell function following antigen binding. In a prophylactic model, surgical stress completely abrogates tumor protection conferred by vaccination in the immediate postoperative period. In a clinically relevant surgical resection model, vaccinated mice undergoing a positive margin resection with surgical stress had decreased survival compared to mice with positive margin resection alone. Preoperative immunotherapy with IFNα significantly extends survival in surgically stressed mice. Importantly, myeloid derived suppressor cell (MDSC population numbers and functional impairment of TAA-specific CD8+ T cell were altered in surgically stressed mice. Our observations suggest that cancer progression may result from surgery-induced suppression of tumor-specific CD8+ T cells. Preoperative immunotherapies aimed at targeting the prometastatic effects of cancer surgery will reduce recurrence and improve survival in cancer surgery patients.

  7. STAT3 expression by myeloid cells is detrimental for the T- cell-mediated control of infection with Mycobacterium tuberculosis.

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    Yu Gao

    2018-01-01

    Full Text Available STAT3 is a master regulator of the immune responses. Here we show that M. tuberculosis-infected stat3fl/fl lysm cre mice, defective for STAT3 in myeloid cells, contained lower bacterial load in lungs and spleens, reduced granuloma extension but higher levels of pulmonary neutrophils. STAT3-deficient macrophages showed no improved control of intracellular mycobacterial growth. Instead, protection associated to elevated ability of stat3fl/fl lysm cre antigen-presenting cells (APCs to release IL-6 and IL-23 and to stimulate IL-17 secretion by mycobacteria-specific T cells. The increased IL-17 secretion accounted for the improved control of infection since neutralization of IL-17 receptor A in stat3fl/fl lysm cre mice hampered bacterial control. APCs lacking SOCS3, which inhibits STAT3 activation via several cytokine receptors, were poor inducers of priming and of the IL-17 production by mycobacteria-specific T cells. In agreement, socs3fl/fl cd11c cre mice deficient of SOCS3 in DCs showed increased susceptibility to M. tuberculosis infection. While STAT3 in APCs hampered IL-17 responses, STAT3 in mycobacteria-specific T cells was critical for IL-17 secretion, while SOCS3 in T cells impeded IL-17 secretion. Altogether, STAT3 signalling in myeloid cells is deleterious in the control of infection with M. tuberculosis.

  8. A Critical Role of IL-21-Induced BATF in Sustaining CD8-T-Cell-Mediated Chronic Viral Control

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    Gang Xin

    2015-11-01

    Full Text Available Control of chronic viral infections by CD8 T cells is critically dependent on CD4 help. In particular, helper-derived IL-21 plays a key role in sustaining the CD8 T cell response; however, the molecular pathways by which IL-21 sustains CD8 T cell immunity remain unclear. We demonstrate that IL-21 causes a phenotypic switch of transcription factor expression in CD8 T cells during chronic viral infection characterized by sustained BATF expression. Importantly, BATF expression during chronic infection is both required for optimal CD8 T cell persistence and anti-viral effector function and sufficient to rescue “unhelped” CD8 T cells. Mechanistically, BATF sustains the response by cooperating with IRF4, an antigen-induced transcription factor that is also critically required for CD8 T cell maintenance, to preserve Blimp-1 expression and thereby sustain CD8 T cell effector function. Collectively, these data suggest that CD4 T cells “help” the CD8 response during chronic infection via IL-21-induced BATF expression.

  9. Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth.

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    Robbert G van der Most

    Full Text Available BACKGROUND: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinical models clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immune system can be mobilized to generate anti-tumor immune responses in the context of chemotherapy. METHODS AND FINDINGS: We used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependent tumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in a CD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-alpha/beta response and a profound negative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential for curative responses. The important effector molecules used by the anti-tumor immune response included IFN-gamma and TRAIL. The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could be compensated by agonistic anti-TRAIL-receptor (DR5 antibodies. CONCLUSION: The data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-, mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumor resolution and explains the paradox of successful CD8 T cell-dependent anti-tumor responses in the absence of CD8 T cell expansion.

  10. An oral Salmonella-based vaccine inhibits liver metastases by promoting tumor-specific T cell-mediated immunity in celiac & portal lymph nodes. A preclinical study.

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    Alejandrina eVendrell

    2016-03-01

    Full Text Available Primary tumor excision is one of the therapies of cancer most widely used. However, the risk of metastases development still exists following tumor resection. The liver is a common site of metastatic disease for numerous cancers. Breast cancer is one of the most frequent source of metastases to the liver. The aim of this work was to evaluate the efficacy of the orally-administered Salmonella Typhi vaccine strain CVD 915 on the development of liver metastases in a mouse model of breast cancer. To this end, one group of BALB/c mice was immunized with CVD 915 via o.g. while another received PBS as a control. After 24 h, mice were injected with LM3 mammary adenocarcinoma cells into the spleen and subjected to splenectomy. This oral Salmonella-based vaccine produced an antitumor effect, leading to a decrease in the number and volume of liver metastases. Immunization with Salmonella induced an early cellular immune response in mice. This innate stimulation rendered a large production of IFN-γ by intrahepatic immune cells (IHIC detected within 24 h. An antitumor adaptive immunity was found in the liver and celiac & portal lymph nodes (LDLN 21 days after oral bacterial inoculation. The antitumor immune response inside the liver was associated with increased CD4+ and DC cell populations as well as with an inflammatory infiltrate located around liver metastatic nodules. Enlarged levels of inflammatory cytokines (IFN-γ and TNF were also detected in IHIC. Furthermore, a tumor-specific production of IFN-γ and TNF as well as tumor-specific IFN-γ-producing CD8 T cells (CD8+IFN-γ+ were found in the celiac & portal lymph nodes of Salmonella-treated mice. This study provides first evidence for the involvement of LDLN in the development of an efficient cellular immune response against hepatic tumors, which resulted in the elimination of liver metastases after oral Salmonella-based vaccination.

  11. Mechanism of nuclear factor of activated T-cells mediated FasL expression in corticosterone -treated mouse Leydig tumor cells

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    Wang Qian

    2008-06-01

    Full Text Available Abstract Background Fas and FasL is important mediators of apoptosis. We have previously reported that the stress levels of corticosterone (CORT, glucocorticoid in rat increase expression of Fas/FasL and activate Fas/FasL signal pathway in rat Leydig cells, which consequently leads to apoptosis. Moreover, our another study showed that nuclear factor of activated T-cells (NFAT may play a potential role in up-regulation of FasL during CORT-treated rat Leydig cell. It is not clear yet how NFAT is involved in CORT-induced up-regulation of FasL. The aim of the present study is to investigate the molecular mechanisms of NFAT-mediated FasL expression in CORT-treated Leydig cells. Results Western blot analysis showed that NFAT2 expression is present in mouse Leydig tumor cell (mLTC-1. CORT-induced increase in FasL expression in mLTC-1 was ascertained by Western Blot analysis and CORT-induced increase in apoptotic frequency of mLTC-1 cells was detected by FACS with annexin-V labeling. Confocal imaging of NFAT2-GFP in mLTC-1 showed that high level of CORT stimulated NFAT translocation from the cytoplasm to the nucleus. RNA interference-mediated knockdown of NFAT2 significantly attenuated CORT-induced up-regulation of FasL expression in mLTC. These results corroborated our previous finding that NFAT2 is involved in CORT-induced FasL expression in rat Leydig cells and showed that mLTC-1 is a suitable model for investigating the mechanism of CORT-induced FasL expression. The analysis of reporter constructs revealed that the sequence between -201 and +71 of mouse FasL gene is essential for CORT-induced FasL expression. The mutation analysis demonstrated that CORT-induced FasL expression is mediated via an NFAT binding element located in the -201 to +71 region. Co-transfection studies with an NFAT2 expression vector and reporter construct containing -201 to +71 region of FasL gene showed that NFAT2 confer a strong inducible activity to the FasL promoter at its

  12. Role of macrophage inflammatory protein-1alpha in T-cell-mediated immunity to viral infection

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    Madsen, Andreas N; Nansen, Anneline; Christensen, Jan P

    2003-01-01

    The immune response to lymphocytic choriomeningitis virus in mice lacking macrophage inflammatory protein-1alpha (MIP-1alpha) was evaluated. Generation of virus-specific effector T cells is unimpaired in MIP-1alpha-deficient mice. Furthermore, MIP-1alpha is not required for T-cell-mediated virus...... control or virus-induced T-cell-dependent inflammation. Thus, MIP-1alpha is not mandatory for T-cell-mediated antiviral immunity....

  13. Impaired virus control and severe CD8+ T-cell-mediated immunopathology in chimeric mice deficient in gamma interferon receptor expression on both parenchymal and hematopoietic cells

    DEFF Research Database (Denmark)

    Henrichsen, Pernille; Bartholdy, Christina; Christensen, Jan Pravsgaard

    2005-01-01

    virus completely lack the ability to control the infection and develop severe wasting disease. Further, the study shows that IFN-gamma receptor expression on parenchymal cells in the viscera is more important for virus control than IFN-gamma receptor expression on bone marrow-derived cells.......Bone marrow chimeras were used to determine the cellular target(s) for the antiviral activity of gamma interferon (IFN-gamma). By transfusing such mice with high numbers of naive virus-specific CD8(+) T cells, a system was created in which the majority of virus-specific CD8(+) T cells would...... be capable of responding to IFN-gamma, but expression of the relevant receptor on non-T cells could be experimentally controlled. Only when the IFN-gamma receptor is absent on both radioresistant parenchymal and bone marrow-derived cells will chimeric mice challenged with a highly invasive, noncytolytic...

  14. Possible neuroimmunomodulation therapy in T-cell-mediated oral diseases

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    Tsuyoshi Sato

    2015-01-01

    Full Text Available Introduction: Recurrent aphthous stomatitis and oral lichen planus are local chronic inflammatory diseases which are implicated in T cell-mediated immunity. According to the systematic review, there is insufficient evidence to support any specific treatment for T-cell mediated oral diseases. The hypothesis: In this paper, we propose a hypothesis that recurrent aphthous stomatitis and oral lichen planus can be treated with selective α7 subunit of nicotinic acetylcholine receptor (α7 -nAChR agonists. Our hypothesis is supported by the following two facts. First, the pathophysiological conditions, T h 1/T h 17 cell activation and autonomic nervous system dysfunction, are observed in T-cell mediated oral diseases as well as in T-cell mediated systemic diseases such as rheumatoid arthritis. Second, the cholinergic anti-inflammatory pathway is inhibited in systemic T-cell mediated chronic inflammatory diseases. On the other hand, treatment with α7 -nAChR agonists which activate the cholinergic anti-inflammatory pathway suppresses neuroinflammation via inhibition of T h 1/T h 17 responses in animal model of systemic T-cell mediated chronic inflammatory diseases. We thus expect that selective α7 -nAChR agonists will be effective for the treatment of T-cell mediated oral diseases. Evaluation of the hypothesis: To test our hypothesis, we need to develop in vivo mouse model of T-cell mediated oral diseases. To evaluate the therapeutic effect of a selective α7 -nAChR agonist, we choose ABT-107 because of its safety and tolerability. We believe that the selective α7 -nAChR agonist, especially ABT-107, may be a therapeutic drug to treat T-cell mediated oral diseases.

  15. Membrane-bound Dickkopf-1 in Foxp3+ regulatory T cells suppresses T-cell-mediated autoimmune colitis.

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    Chae, Wook-Jin; Park, Jong-Hyun; Henegariu, Octavian; Yilmaz, Saliha; Hao, Liming; Bothwell, Alfred L M

    2017-10-01

    Induction of tolerance is a key mechanism to maintain or to restore immunological homeostasis. Here we show that Foxp3 + regulatory T (Treg) cells use Dickkopf-1 (DKK-1) to regulate T-cell-mediated tolerance in the T-cell-mediated autoimmune colitis model. Treg cells from DKK-1 hypomorphic doubleridge mice failed to control CD4 + T-cell proliferation, resulting in CD4 T-cell-mediated autoimmune colitis. Thymus-derived Treg cells showed a robust expression of DKK-1 but not in naive or effector CD4 T cells. DKK-1 expression in Foxp3 + Treg cells was further increased upon T-cell receptor stimulation in vitro and in vivo. Interestingly, Foxp3 + Treg cells expressed DKK-1 in the cell membrane and the functional inhibition of DKK-1 using DKK-1 monoclonal antibody abrogated the suppressor function of Foxp3 + Treg cells. DKK-1 expression was dependent on de novo protein synthesis and regulated by the mitogen-activated protein kinase pathway but not by the canonical Wnt pathway. Taken together, our results highlight membrane-bound DKK-1 as a novel Treg-derived mediator to maintain immunological tolerance in T-cell-mediated autoimmune colitis. © 2017 The Authors. Immunology Published by John Wiley & Sons Ltd.

  16. Cytotoxic T cells mediate pathology and metastasis in cutaneous leishmaniasis.

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    Fernanda O Novais

    Full Text Available Disease progression in response to infection can be strongly influenced by both pathogen burden and infection-induced immunopathology. While current therapeutics focus on augmenting protective immune responses, identifying therapeutics that reduce infection-induced immunopathology are clearly warranted. Despite the apparent protective role for murine CD8⁺ T cells following infection with the intracellular parasite Leishmania, CD8⁺ T cells have been paradoxically linked to immunopathological responses in human cutaneous leishmaniasis. Transcriptome analysis of lesions from Leishmania braziliensis patients revealed that genes associated with the cytolytic pathway are highly expressed and CD8⁺ T cells from lesions exhibited a cytolytic phenotype. To determine if CD8⁺ T cells play a causal role in disease, we turned to a murine model. These studies revealed that disease progression and metastasis in L. braziliensis infected mice was independent of parasite burden and was instead directly associated with the presence of CD8⁺ T cells. In mice with severe pathology, we visualized CD8⁺ T cell degranulation and lysis of L. braziliensis infected cells. Finally, in contrast to wild-type CD8⁺ T cells, perforin-deficient cells failed to induce disease. Thus, we show for the first time that cytolytic CD8⁺ T cells mediate immunopathology and drive the development of metastatic lesions in cutaneous leishmaniasis.

  17. The CD8⁺ T Cell-Mediated Immunity Induced by HPV-E6 Uploaded in Engineered Exosomes Is Improved by ISCOMATRIXTM Adjuvant.

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    Manfredi, Francesco; di Bonito, Paola; Ridolfi, Barbara; Anticoli, Simona; Arenaccio, Claudia; Chiozzini, Chiara; Baz Morelli, Adriana; Federico, Maurizio

    2016-11-09

    We recently described the induction of an efficient CD8⁺ T cell-mediated immune response against a tumor-associated antigen (TAA) uploaded in engineered exosomes used as an immunogen delivery tool. This immune response cleared tumor cells inoculated after immunization, and controlled the growth of tumors implanted before immunization. We looked for new protocols aimed at increasing the CD8⁺ T cell specific response to the antigen uploaded in engineered exosomes, assuming that an optimized CD8⁺ T cell immune response would correlate with a more effective depletion of tumor cells in the therapeutic setting. By considering HPV-E6 as a model of TAA, we found that the in vitro co-administration of engineered exosomes and ISCOMATRIX TM adjuvant, i.e., an adjuvant composed of purified ISCOPREP TM saponin, cholesterol, and phospholipids, led to a stronger antigen cross-presentation in both B- lymphoblastoid cell lines ( and monocyte-derived immature dendritic cells compared with that induced by the exosomes alone. Consistently, the co-inoculation in mice of ISCOMATRIX TM adjuvant and engineered exosomes induced a significant increase of TAA-specific CD8⁺ T cells compared to mice immunized with the exosomes alone. This result holds promise for effective usage of exosomes as well as alternative nanovesicles in anti-tumor therapeutic approaches.

  18. The CD8+ T Cell-Mediated Immunity Induced by HPV-E6 Uploaded in Engineered Exosomes Is Improved by ISCOMATRIXTM Adjuvant

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    Manfredi, Francesco; di Bonito, Paola; Ridolfi, Barbara; Anticoli, Simona; Arenaccio, Claudia; Chiozzini, Chiara; Baz Morelli, Adriana; Federico, Maurizio

    2016-01-01

    We recently described the induction of an efficient CD8+ T cell-mediated immune response against a tumor-associated antigen (TAA) uploaded in engineered exosomes used as an immunogen delivery tool. This immune response cleared tumor cells inoculated after immunization, and controlled the growth of tumors implanted before immunization. We looked for new protocols aimed at increasing the CD8+ T cell specific response to the antigen uploaded in engineered exosomes, assuming that an optimized CD8+ T cell immune response would correlate with a more effective depletion of tumor cells in the therapeutic setting. By considering HPV-E6 as a model of TAA, we found that the in vitro co-administration of engineered exosomes and ISCOMATRIXTM adjuvant, i.e., an adjuvant composed of purified ISCOPREPTM saponin, cholesterol, and phospholipids, led to a stronger antigen cross-presentation in both B- lymphoblastoid cell lines ( and monocyte-derived immature dendritic cells compared with that induced by the exosomes alone. Consistently, the co-inoculation in mice of ISCOMATRIXTM adjuvant and engineered exosomes induced a significant increase of TAA-specific CD8+ T cells compared to mice immunized with the exosomes alone. This result holds promise for effective usage of exosomes as well as alternative nanovesicles in anti-tumor therapeutic approaches. PMID:27834857

  19. Contribution of T cell-mediated immunity to the resistance to staphlococcal infection

    International Nuclear Information System (INIS)

    Tsuda, S.; Sasai, Y.; Minami, K.; Nomoto, K.

    1978-01-01

    Abscess formation in nude mice after subcutaneous inoculation of Staphylococcus aureus (S. aureus) was more extensive and prolonged as compared with that in phenotypically normal littermates. Abscess formation in nude mice was augmented markedly by whole-body irradiation. Not only T cell-mediated immunity but also radiosensitive, nonimmune phagocytosis appear to contribute to the resistance against staphylococcal infection

  20. Opposing effects of CXCR3 and CCR5 deficiency on CD8+ T cell-mediated inflammation in the central nervous system of virus-infected mice

    DEFF Research Database (Denmark)

    de Lemos, Carina; Christensen, Jeanette Erbo; Nansen, Anneline

    2005-01-01

    T cells play a key role in the control of viral infection in the CNS but may also contribute to immune-mediated cell damage. To study the redundancy of the chemokine receptors CXCR3 and CCR5 in regulating virus-induced CD8+ T cell-mediated inflammation in the brain, CXCR3/CCR5 double-deficient mice...... and therefore protect mice against the otherwise fatal CD8+ T cell-mediated immune attack. Contrary to expectations, the accumulation of mononuclear cells in cerebrospinal fluid was only slightly delayed compared with mice with normal expression of both receptors. Even more surprising, CXCR3/CCR5 double......-deficient mice were more susceptible to intracerebral infection than CXCR3-deficient mice. Analysis of effector T cell generation revealed an accelerated antiviral CD8+ T cell response in CXCR3/CCR5 double-deficient mice. Furthermore, while the accumulation of CD8+ T cells in the neural parenchyma...

  1. Challenges and opportunities for T cell-mediated strategies to eliminate HIV reservoirs

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    Mark Alan Brockman

    2015-10-01

    Full Text Available HIV’s ability to establish latent reservoirs of reactivation-competent virus is the major barrier to cure. Shock and kill methods consisting of latency reversing agents (LRAs followed by elimination of reactivating cells through cytopathic effects are under active development. However, the clinical efficacy of LRAs remains to be established. Moreover, recent studies indicate that reservoirs may not be reduced efficiently by either viral cytopathic or CD8+ T-cell-mediated mechanisms. In this perspective, we highlight challenges to T-cell-mediated elimination of HIV reservoirs, including characteristics of responding T-cells, aspects of the cellular reservoirs and properties of the latent virus itself. We also discuss potential strategies to overcome these challenges by targeting the antiviral activity of T-cells towards appropriate viral antigens following latency.

  2. Role of very late antigen-1 in T-cell-mediated immunity to systemic viral infection

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    Ørding Kauffmann, Susanne; Thomsen, Allan Randrup; Christensen, Jan Pravsgaard

    2006-01-01

    The T-cell response to lymphocytic choriomeningitis virus was studied in mice lacking very late antigen-1 (VLA-1). The generation of virus-specific effector T cells was unimpaired in VLA-1(-/-) mice. In the memory phase, VLA-1 deficiency did not influence the number of memory CD8(+) T cells or th......, the current findings indicate that the expression of VLA-1 is not pivotal for T-cell-mediated antiviral immunity to a systemic infection....... or their distribution between lymphoid and nonlymphoid organs. Regarding a functional role of VLA-1, we found that intracerebral infection of both VLA-1(-/-) and wild-type (wt) mice resulted in lethal T-cell-mediated meningitis, and quantitative and qualitative analyses of the cellular exudate did not reveal any...

  3. [T cell-mediated immune responses and the recognition of tuberculosis antigens].

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    Tsujimura, Kunio; Koide, Yukio

    2010-06-01

    T cell-mediated immune responses profoundly contribute to the protection against the re-activation of latently infected Mycobacterium tuberculosis. Th1 cells produce IFN-gamma to activate infected macrophages and promote the formation of granulomas around infected macrophages. CD8+, gamma delta and CD1-restricted T cells also produce IFN-gamma and participate the protective responses against bacterial growth. Th17 cells produce IL-17 to promote the mobilization of immunocompetent cells and contribute to the granuloma formation. On the contrary, Th2 cells and Tregs interfere these protective immune responses.

  4. Role of T-cell-mediated inflammation in psoriasis: pathogenesis and targeted therapy

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    Flatz L

    2013-02-01

    Full Text Available Lukas Flatz, Curdin ConradDepartment of Dermatology, University Hospital of Lausanne (CHUV, Lausanne, SwitzerlandAbstract: Psoriasis is one of the most common chronic, inflammatory, T-cell-mediated autoimmune diseases. Over the past decade, increased knowledge of disease pathogenesis has fundamentally changed psoriasis treatment, with the introduction of biologics, and this has led to a multitude of improved selective targets providing potential therapeutic options. Indeed, numerous pathogenesis-based treatments are currently in development, as psoriasis has also become increasingly relevant for proof-of-concept studies. The purpose of this review was to summarize current knowledge of psoriasis immunopathogenesis, focusing on the T-cell-mediated immune response and its initiation. The authors describe recent advances in psoriasis treatment and discuss pathogenesis-based therapies that are currently in development or which could be envisioned for the future. Although current biologics are well tolerated, several issues such as long-term efficacy, long-term safety, and high costs keep driving the search for new and better therapies. With further advances in understanding disease pathogenesis, more genomic data from psoriasis patients becoming available, and potentially the identification of autoantigens in psoriasis, current research should lead to the development of a growing arsenal of improved targeted treatments and to further breakthrough immunotherapies.Keywords: autoimmunity, autoimmune disease, immune response, immunopathogenesis

  5. Circumvention of regulatory CD4(+) T cell activity during cross-priming strongly enhances T cell-mediated immunity.

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    Heit, Antje; Gebhardt, Friedemann; Lahl, Katharina; Neuenhahn, Michael; Schmitz, Frank; Anderl, Florian; Wagner, Hermann; Sparwasser, Tim; Busch, Dirk H; Kastenmüller, Kathrin

    2008-06-01

    Immunization with purified antigens is a safe and practical vaccination strategy but is generally unable to induce sustained CD8(+) T cell-mediated protection against intracellular pathogens. Most efforts to improve the CD8(+) T cell immunogenicity of these vaccines have focused on co-administration of adjuvant to support cross-presentation and dendritic cell maturation. In addition, it has been shown that CD4(+) T cell help during the priming phase contributes to the generation of protective CD8(+) memory T cells. In this report we demonstrate that the depletion of CD4(+) T cells paradoxically enhances long-lasting CD8-mediated protective immunity upon protein vaccination. Functional and genetic in vivo inactivation experiments attribute this enhancement primarily to MHC class II-restricted CD4(+) regulatory T cells (Treg), which appear to physiologically suppress the differentiation process towards long-living effector memory T cells. Since, in functional terms, this suppression by Treg largely exceeds the positive effects of conventional CD4(+) T cell help, even the absence of all CD4(+) T cells or lack of MHC class II-mediated interactions on priming dendritic cells result in enhanced CD8(+) T cell immunogenicity. These findings have important implications for the improvement of vaccines against intracellular pathogens or tumors, especially in patients with highly active Treg.

  6. Inhibitors of histone deacetylase 1 reverse the immune evasion phenotype to enhance T-cell mediated lysis of prostate and breast carcinoma cells.

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    Gameiro, Sofia R; Malamas, Anthony S; Tsang, Kwong Y; Ferrone, Soldano; Hodge, James W

    2016-02-16

    The clinical promise of cancer immunotherapy relies on the premise that the immune system can recognize and eliminate tumor cells identified as non-self. However, tumors can evade host immune surveillance through multiple mechanisms, including epigenetic silencing of genes involved in antigen processing and immune recognition. Hence, there is an unmet clinical need to develop effective therapeutic strategies that can restore tumor immune recognition when combined with immunotherapy, such as immune checkpoint blockade and therapeutic cancer vaccines. We sought to examine the potential of clinically relevant exposure of prostate and breast human carcinoma cells to histone deacetylase (HDAC) inhibitors to reverse tumor immune escape to T-cell mediated lysis. Here we demonstrate that prostate (LNCAP) and breast (MDA-MB-231) carcinoma cells are more sensitive to T-cell mediated lysis in vitro after clinically relevant exposure to epigenetic therapy with either the pan-HDAC inhibitor vorinostat or the class I HDAC inhibitor entinostat. This pattern of immunogenic modulation was observed against a broad range of tumor-associated antigens, such as CEA, MUC1, PSA, and brachyury, and associated with augmented expression of multiple proteins involved in antigen processing and tumor immune recognition. Genetic and pharmacological inhibition studies identified HDAC1 as a key determinant in the reversal of carcinoma immune escape. Further, our findings suggest that the observed reversal of tumor immune evasion is driven by a response to cellular stress through activation of the unfolded protein response. This offers the rationale for combining HDAC inhibitors with immunotherapy, including therapeutic cancer vaccines.

  7. T Cell-Mediated Immunity towards Yellow Fever Virus and Useful Animal Models.

    Science.gov (United States)

    Watson, Alan M; Klimstra, William B

    2017-04-11

    The 17D line of yellow fever virus vaccines is among the most effective vaccines ever created. The humoral and cellular immunity elicited by 17D has been well characterized in humans. Neutralizing antibodies have long been known to provide protection against challenge with a wild-type virus. However, a well characterized T cell immune response that is robust, long-lived and polyfunctional is also elicited by 17D. It remains unclear whether this arm of immunity is protective following challenge with a wild-type virus. Here we introduce the 17D line of yellow fever virus vaccines, describe the current state of knowledge regarding the immunity directed towards the vaccines in humans and conclude with a discussion of animal models that are useful for evaluating T cell-mediated immune protection to yellow fever virus.

  8. Inhibition of CSF-1R supports T-cell mediated melanoma therapy.

    Directory of Open Access Journals (Sweden)

    Marjolein Sluijter

    Full Text Available Tumor associated macrophages (TAM can promote angiogenesis, invasiveness and immunosuppression. The cytokine CSF-1 (or M-CSF is an important factor of TAM recruitment and differentiation and several pharmacological agents targeting the CSF-1 receptor (CSF-1R have been developed to regulate TAM in solid cancers. We show that the kinase inhibitor PLX3397 strongly dampened the systemic and local accumulation of macrophages driven by B16F10 melanomas, without affecting Gr-1(+ myeloid derived suppressor cells. Removal of intratumoral macrophages was remarkably efficient and a modest, but statistically significant, delay in melanoma outgrowth was observed. Importantly, CSF-1R inhibition strongly enhanced tumor control by immunotherapy using tumor-specific CD8 T cells. Elevated IFNγ production by T cells was observed in mice treated with the combination of PLX3397 and immunotherapy. These results support the combined use of CSF-1R inhibition with CD8 T cell immunotherapy, especially for macrophage-stimulating tumors.

  9. TRESK channel as a potential target to treat T-cell mediated immune dysfunction

    Energy Technology Data Exchange (ETDEWEB)

    Han, Jaehee [Medical Research Center for Neural Dysfunction, Department of Physiology, Institute of Health Sciences, Gyeongsang National University, School of Medicine, Jinju 660-751 (Korea, Republic of); Kang, Dawon, E-mail: dawon@gnu.ac.kr [Medical Research Center for Neural Dysfunction, Department of Physiology, Institute of Health Sciences, Gyeongsang National University, School of Medicine, Jinju 660-751 (Korea, Republic of)

    2009-12-25

    In this review, we propose that TRESK background K{sup +} channel could serve as a potential therapeutic target for T-cell mediated immune dysfunction. TRESK has many immune function-related properties. TRESK is abundantly expressed in the thymus, the spleen, and human leukemic T-lymphocytes. TRESK is highly activated by Ca{sup 2+}, calcineurin, acetylcholine, and histamine which induce hypertrophy, whereas TRESK is inhibited by immunosuppressants, such as cyclosporin A and FK506. Cyclosporine A and FK506 target the binding site of nuclear factor of activated T-cells (NFAT) to inhibit calcineurin. Interestingly, TRESK possesses an NFAT-like docking site that is present at its intracellular loop. Calcineurin has been found to interact with TRESK via specific NFAT-like docking site. When the T-cell is activated, calcineurin can bind to the NFAT-docking site of TRESK. The activation of both TRESK and NFAT via Ca{sup 2+}-calcineurin-NFAT/TRESK pathway could modulate the transcription of new genes in addition to regulating several aspects of T-cell function.

  10. Bowman Capsulitis Predicts Poor Kidney Allograft Outcome in T Cell-Mediated Rejection.

    Science.gov (United States)

    Gallan, Alexander J; Chon, W James; Josephson, Michelle A; Cunningham, Patrick N; Henriksen, Kammi J; Chang, Anthony

    2018-02-28

    Acute T cell-mediated rejection (TCMR) is an important cause of renal allograft loss. The Banff classification for tubulointerstitial (type I) rejection is based on the extent of both interstitial inflammation and tubulitis. Lymphocytes may also be present between parietal epithelial cells and Bowman capsules in this setting, which we have termed "capsulitis." We conducted this study to determine the clinical significance of capsulitis. We identified 42 patients from the pathology archives at the University of Chicago with isolated Banff type I TCMR from 2010-2015. Patient demographic data, Banff classification, and graft outcome measurements were compared between capsulitis and non-capsulitis groups using Mann-Whitney U test. Capsulitis was present in 26 (62%), and was more frequently seen in Banff IB than IA TCMR (88% vs 44%, P=.01). Patients with capsulitis had a higher serum creatinine at biopsy (4.6 vs 2.9mg/dL, P=.04) and were more likely to progress to dialysis (42% vs 13%, P=.06) with fewer recovering their baseline serum creatinine (12% vs 38%, P=.08). Patients with both Banff IA TCMR and capsulitis have clinical outcomes similar or possibly worse than Banff IB TCMR compared to those with Banff IA and an absence of capsulitis. Capsulitis is an important pathologic parameter in the evaluation of kidney transplant biopsies with potential diagnostic, prognostic, and therapeutic implications in the setting of TCMR. Copyright © 2018. Published by Elsevier Inc.

  11. Mathematical modeling on T-cell mediated adaptive immunity in primary dengue infections.

    Science.gov (United States)

    Sasmal, Sourav Kumar; Dong, Yueping; Takeuchi, Yasuhiro

    2017-09-21

    At present, dengue is the most common mosquito-borne viral disease in the world, and the global dengue incidence is increasing day by day due to climate changing. Here, we present a mathematical model of dengue viruses (DENVs) dynamics in micro-environment (cellular level) consisting of healthy cells, infected cells, virus particles and T-cell mediated adaptive immunity. We have considered the explicit role of cytokines and antibody in our model. We find that the virus load goes down to zero within 6 days as it is common for DENV infection. From our analysis, we have identified the important model parameters and done the numerical simulation with respect to such important parameters. We have shown that the cytokine mediated virus clearance plays a very important role in dengue dynamics. It can change the dynamical behavior of the system and causes essential extinction of the virus. Finally, we have incorporated the antiviral treatment for dengue in our model and shown that the basic reproduction number is directly proportional to the antiviral treatment effects. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Endogenous n-3 polyunsaturated fatty acids attenuate T cell-mediated hepatitis via autophagy activation

    Directory of Open Access Journals (Sweden)

    Yanli Li

    2016-09-01

    Full Text Available Omega-3 polyunsaturated fatty acids (n-3 PUFAs exert anti-inflammatory effects in several liver disorders, including cirrhosis, acute liver failure, and fatty liver disease. To date, little is known about their role in immune-mediated liver diseases. In this study, we used fat-1 transgenic mice rich in endogenous n-3 PUFAs to examine the role of n-3 PUFAs in immune-mediated liver injury. Concanavalin A (Con A was administered intravenously to wild-type (WT and fat-1 transgenic mice to induce T cell-mediated hepatitis. Reduced liver damage was shown in Con A-administrated fat-1 transgenic mice, as evidenced by decreased mortality, attenuated hepatic necrosis, lessened serum alanine aminotransferase (ALT activity, and inhibited production of pro-inflammatory cytokines (e.g. TNF-α, IL-6, IL-17A and IFN-γ. In vivo and in vitro studies demonstrated that n-3 PUFAs significantly inhibited the activation of hepatic T cells and the differentiation of Th1 cells after Con A challenge. Further studies showed that n-3 PUFAs markedly increased autophagy level in Con A-treated fat-1 T cells compared with the WT counterparts. Blocking hepatic autophagy activity with chloroquine diminished the differences in T cell activation and liver injury between Con A-injected WT and fat-1 transgenic mice. We conclude that n-3 PUFAs limit Con A-induced hepatitis via an autophagy-dependent mechanism, and could be exploited as a new therapeutic approach for autoimmune hepatitis.

  13. Emerging Targets for Developing T Cell-Mediated Vaccines for Human Immunodeficiency Virus (HIV-1

    Directory of Open Access Journals (Sweden)

    Danushka K. Wijesundara

    2017-10-01

    Full Text Available Human immunodeficiency virus (HIV-1 has infected >75 million individuals globally, and, according to the UN, is responsible for ~2.1 million new infections and 1.1 million deaths each year. Currently, there are ~37 million individuals with HIV infection and the epidemic has already resulted in 35 million deaths. Despite the advances of anti-retroviral therapy (ART, a cost-effective vaccine remains the best long-term solution to end the HIV-1 epidemic especially given that the vast majority of infected individuals live in poor socio-economic regions of the world such as Sub-Saharan Africa which limits their accessibility to ART. The modest efficacy of the RV144 Thai trial provides hope that a vaccine for HIV-1 is possible, but as markers for sterilizing immunity are unknown, the design of an effective vaccine is empirical, although broadly cross-reactive neutralizing antibodies (bNAb that can neutralize various quasispecies of HIV-1 are considered crucial. Since HIV-1 transmission often occurs at the genito-rectal mucosa and is cell-associated, there is a need to develop vaccines that can elicit CD8+ T cell immunity with the capacity to kill virus infected cells at the genito-rectal mucosa and the gut. Here we discuss the recent progress made in developing T cell-mediated vaccines for HIV-1 and emphasize the need to elicit mucosal tissue-resident memory CD8+ T (CD8+ Trm cells. CD8+ Trm cells will likely form a robust front-line defense against HIV-1 and eliminate transmitter/founder virus-infected cells which are responsible for propagating HIV-1 infections following transmission in vast majority of cases.

  14. T-Cell Mediated Immune Responses Induced in ret Transgenic Mouse Model of Malignant Melanoma

    International Nuclear Information System (INIS)

    Abschuetz, Oliver; Osen, Wolfram; Frank, Kathrin; Kato, Masashi; Schadendorf, Dirk; Umansky, Viktor

    2012-01-01

    Poor response of human malignant melanoma to currently available treatments requires a development of innovative therapeutic strategies. Their evaluation should be based on animal models that resemble human melanoma with respect to genetics, histopathology and clinical features. Here we used a transgenic mouse model of spontaneous skin melanoma, in which the ret transgene is expressed in melanocytes under the control of metallothionein-I promoter. After a short latency, around 25% mice develop macroscopic skin melanoma metastasizing to lymph nodes, bone marrow, lungs and brain, whereas other transgenic mice showed only metastatic lesions without visible skin tumors. We found that tumor lesions expressed melanoma associated antigens (MAA) tyrosinase, tyrosinase related protein (TRP)-1, TRP-2 and gp100, which could be applied as targets for the immunotherapy. Upon peptide vaccination, ret transgenic mice without macroscopic melanomas were able to generate T cell responses not only against a strong model antigen ovalbumin but also against typical MAA TRP-2. Although mice bearing macroscopic primary tumors could also display an antigen-specific T cell reactivity, it was significantly down-regulated as compared to tumor-free transgenic mice or non-transgenic littermates. We suggest that ret transgenic mice could be used as a pre-clinical model for the evaluation of novel strategies of melanoma immunotherapy

  15. T-Cell Mediated Immune Responses Induced in ret Transgenic Mouse Model of Malignant Melanoma

    Directory of Open Access Journals (Sweden)

    Dirk Schadendorf

    2012-04-01

    Full Text Available Poor response of human malignant melanoma to currently available treatments requires a development of innovative therapeutic strategies. Their evaluation should be based on animal models that resemble human melanoma with respect to genetics, histopathology and clinical features. Here we used a transgenic mouse model of spontaneous skin melanoma, in which the ret transgene is expressed in melanocytes under the control of metallothionein-I promoter. After a short latency, around 25% mice develop macroscopic skin melanoma metastasizing to lymph nodes, bone marrow, lungs and brain, whereas other transgenic mice showed only metastatic lesions without visible skin tumors. We found that tumor lesions expressed melanoma associated antigens (MAA tyrosinase, tyrosinase related protein (TRP-1, TRP-2 and gp100, which could be applied as targets for the immunotherapy. Upon peptide vaccination, ret transgenic mice without macroscopic melanomas were able to generate T cell responses not only against a strong model antigen ovalbumin but also against typical MAA TRP-2. Although mice bearing macroscopic primary tumors could also display an antigen-specific T cell reactivity, it was significantly down-regulated as compared to tumor-free transgenic mice or non-transgenic littermates. We suggest that ret transgenic mice could be used as a pre-clinical model for the evaluation of novel strategies of melanoma immunotherapy.

  16. T-Cell Mediated Immune Responses Induced in ret Transgenic Mouse Model of Malignant Melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Abschuetz, Oliver [Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim , Heidelberg 69120 (Germany); Osen, Wolfram [Division of Translational Immunology, German Cancer Center, Heidelberg 69120 (Germany); Frank, Kathrin [Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim , Heidelberg 69120 (Germany); Kato, Masashi [Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Aichi 487-8501 (Japan); Schadendorf, Dirk [Department of Dermatology, University Hospital Essen, Essen 45122 (Germany); Umansky, Viktor, E-mail: v.umansky@dkfz.de [Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim , Heidelberg 69120 (Germany)

    2012-04-26

    Poor response of human malignant melanoma to currently available treatments requires a development of innovative therapeutic strategies. Their evaluation should be based on animal models that resemble human melanoma with respect to genetics, histopathology and clinical features. Here we used a transgenic mouse model of spontaneous skin melanoma, in which the ret transgene is expressed in melanocytes under the control of metallothionein-I promoter. After a short latency, around 25% mice develop macroscopic skin melanoma metastasizing to lymph nodes, bone marrow, lungs and brain, whereas other transgenic mice showed only metastatic lesions without visible skin tumors. We found that tumor lesions expressed melanoma associated antigens (MAA) tyrosinase, tyrosinase related protein (TRP)-1, TRP-2 and gp100, which could be applied as targets for the immunotherapy. Upon peptide vaccination, ret transgenic mice without macroscopic melanomas were able to generate T cell responses not only against a strong model antigen ovalbumin but also against typical MAA TRP-2. Although mice bearing macroscopic primary tumors could also display an antigen-specific T cell reactivity, it was significantly down-regulated as compared to tumor-free transgenic mice or non-transgenic littermates. We suggest that ret transgenic mice could be used as a pre-clinical model for the evaluation of novel strategies of melanoma immunotherapy.

  17. Opposing effects of CXCR3 and CCR5 deficiency on CD8+ T cell-mediated inflammation in the central nervous system of virus-infected mice

    DEFF Research Database (Denmark)

    de Lemos, Carina; Christensen, Jeanette Erbo; Nansen, Anneline

    2005-01-01

    T cells play a key role in the control of viral infection in the CNS but may also contribute to immune-mediated cell damage. To study the redundancy of the chemokine receptors CXCR3 and CCR5 in regulating virus-induced CD8+ T cell-mediated inflammation in the brain, CXCR3/CCR5 double-deficient mice......-deficient mice were more susceptible to intracerebral infection than CXCR3-deficient mice. Analysis of effector T cell generation revealed an accelerated antiviral CD8+ T cell response in CXCR3/CCR5 double-deficient mice. Furthermore, while the accumulation of CD8+ T cells in the neural parenchyma...... were generated and infected intracerebrally with noncytolytic lymphocytic choriomeningitis virus. Because these chemokine receptors are mostly expressed by overlapping subsets of activated CD8+ T cells, it was expected that absence of both receptors would synergistically impair effector T cell invasion...

  18. Enhancement Of The T Cell Mediated Hypersensitivity Reaction By Thymus Extract In GAMMA Irradiated BALB/C Mice

    International Nuclear Information System (INIS)

    EL-BEIH, N.M.; ESSAM, H.M.; MOHAMED, M.I.

    2009-01-01

    swelling response caused by gamma radiation. In conclusion, data of the present study showed a beneficial role of thymus extract in combating the negative effect of gamma irradiation on the T cell mediated hypersensitivity reaction.

  19. Depression of Complement Regulatory Factors in Rat and Human Renal Grafts Is Associated with the Progress of Acute T-Cell Mediated Rejection.

    Directory of Open Access Journals (Sweden)

    Kazuaki Yamanaka

    Full Text Available The association of complement with the progression of acute T cell mediated rejection (ATCMR is not well understood. We investigated the production of complement components and the expression of complement regulatory proteins (Cregs in acute T-cell mediated rejection using rat and human renal allografts.We prepared rat allograft and syngeneic graft models of renal transplantation. The expression of Complement components and Cregs was assessed in the rat grafts using quantitative real-time PCR (qRT-PCR and immunofluorescent staining. We also administered anti-Crry and anti-CD59 antibodies to the rat allograft model. Further, we assessed the relationship between the expression of membrane cofactor protein (MCP by immunohistochemical staining in human renal grafts and their clinical course.qRT-PCR results showed that the expression of Cregs, CD59 and rodent-specific complement regulator complement receptor 1-related gene/protein-y (Crry, was diminished in the rat allograft model especially on day 5 after transplantation in comparison with the syngeneic model. In contrast, the expression of complement components and receptors: C3, C3a receptor, C5a receptor, Factor B, C9, C1q, was increased, but not the expression of C4 and C5, indicating a possible activation of the alternative pathway. When anti-Crry and anti-CD59 mAbs were administered to the allograft, the survival period for each group was shortened. In the human ATCMR cases, the group with higher MCP expression in the grafts showed improved serum creatinine levels after the ATCMR treatment as well as a better 5-year graft survival rate.We conclude that the expression of Cregs in allografts is connected with ATCMR. Our results suggest that controlling complement activation in renal grafts can be a new strategy for the treatment of ATCMR.

  20. TNFα and IFNγ but not perforin are critical for CD8 T cell-mediated protection against pulmonary Yersinia pestis infection.

    Science.gov (United States)

    Szaba, Frank M; Kummer, Lawrence W; Duso, Debra K; Koroleva, Ekaterina P; Tumanov, Alexei V; Cooper, Andrea M; Bliska, James B; Smiley, Stephen T; Lin, Jr-Shiuan

    2014-05-01

    Septic pneumonias resulting from bacterial infections of the lung are a leading cause of human death worldwide. Little is known about the capacity of CD8 T cell-mediated immunity to combat these infections and the types of effector functions that may be most effective. Pneumonic plague is an acutely lethal septic pneumonia caused by the Gram-negative bacterium Yersinia pestis. We recently identified a dominant and protective Y. pestis antigen, YopE69-77, recognized by CD8 T cells in C57BL/6 mice. Here, we use gene-deficient mice, Ab-mediated depletion, cell transfers, and bone marrow chimeric mice to investigate the effector functions of YopE69-77-specific CD8 T cells and their relative contributions during pulmonary Y. pestis infection. We demonstrate that YopE69-77-specific CD8 T cells exhibit perforin-dependent cytotoxicity in vivo; however, perforin is dispensable for YopE69-77-mediated protection. In contrast, YopE69-77-mediated protection is severely impaired when production of TNFα and IFNγ by CD8 T cells is simultaneously ablated. Interestingly, TNFα is absolutely required at the time of challenge infection and can be provided by either T cells or non-T cells, whereas IFNγ provided by T cells prior to challenge appears to facilitate the differentiation of optimally protective CD8 T cells. We conclude that cytokine production, not cytotoxicity, is essential for CD8 T cell-mediated control of pulmonary Y. pestis infection and we suggest that assays detecting Ag-specific TNFα production in addition to antibody titers may be useful correlates of vaccine efficacy against plague and other acutely lethal septic bacterial pneumonias.

  1. Enhancement of T-cell-mediated antitumor response: angiostatic adjuvant to immunotherapy against cancer.

    Science.gov (United States)

    Dings, Ruud P M; Vang, Kieng B; Castermans, Karolien; Popescu, Flavia; Zhang, Yan; Oude Egbrink, Mirjam G A; Mescher, Matthew F; Farrar, Michael A; Griffioen, Arjan W; Mayo, Kevin H

    2011-05-15

    Tumor-released proangiogenic factors suppress endothelial adhesion molecule (EAM) expression and prevent leukocyte extravasation into the tumor. This is one reason why immunotherapy has met with limited success in the clinic. We hypothesized that overcoming EAM suppression with angiogenesis inhibitors would increase leukocyte extravasation and subsequently enhance the effectiveness of cellular immunotherapy. Intravital microscopy, multiple color flow cytometry, immunohistochemistry, and various tumor mouse (normal and T-cell deficient) models were used to investigate the temporal dynamics of cellular and molecular events that occur in the tumor microenvironment during tumor progression and angiostatic intervention. We report that while EAM levels and T-cell infiltration are highly attenuated early on in tumor growth, angiostatic therapy modulates these effects. In tumor models with normal and T-cell-deficient mice, we show the active involvement of the adaptive immune system in cancer and differentiate antiangiogenic effects from antiangiogenic mediated enhancement of immunoextravasation. Our results indicate that a compromised immune response in tumors can be obviated by the use of antiangiogenic agents. Finally, with adoptive transfer studies in mice, we show that a phased combination of angiostatic therapy and T-cell transfer significantly (P response within the tumor microenvironment, in particular as a consequence of the temporal dynamics of EAM levels. Moreover, our results suggest that adjuvant therapy with angiogenesis inhibitors holds promise for cellular immunotherapy in the clinic. ©2011 AACR.

  2. Inhibition of clone formation as an assay for T cell-mediated cytotoxicity: short-term kinetics and comparison with 51Cr release

    International Nuclear Information System (INIS)

    Lees, R.K.; MacDonald, H.R.; Sinclair, N.R.; University of Western Ontario London

    1977-01-01

    The short-term kinetics of T cell-mediated cytotoxicity was investigated using a cloning inhibition assay. Murine cytotoxic thymus-derived lymphocytes generated in vitro in mixed leukocyte cultures were incubated for various periods of time at 37degC with allogeneic mastocytoma target cells. The mixtures were then plated in soft agar, and mastocytoma clone formation was assessed after 5-7 days incubation. Using this technique, it was demonstrated that events leading to the loss of cloning ability could be detected after 1-3 min incubation at 37degC, and after 20-30 min, 95% of the clone forming cells had been inactivated. When these results were compared directly with those obtained using the conventional 51 Cr-release assay, it was found that the events leading to loss of cloning ability occurred more rapidly than indicated by the isotope assay. However, a modification of the 51 Cr-release assay involving EDTA addition gave comparable result to the cloning inhibition assay. These results raise the possibility that the events leading to 51 Cr-release of tumor target cells may be related in time to those leading to the loss of cloning ability

  3. Lactobacillus rhamnosus CRL1505 nasal administration improves recovery of T-cell mediated immunity against pneumococcal infection in malnourished mice.

    Science.gov (United States)

    Barbieri, N; Herrera, M; Salva, S; Villena, J; Alvarez, S

    2017-05-30

    Immunobiotic lactic acid bacteria have become an interesting alternative for the prevention of respiratory infections. Previously, we demonstrated that the nasal administration of Lactobacillus rhamnosus CRL1505, during repletion of malnourished mice, resulted in diminished susceptibility to the challenge with the respiratory pathogen Streptococcus pneumoniae. Considering the known alterations induced by malnutrition on T lymphocytes and the importance of this cell population on the protection against respiratory pathogens, we aimed to study the effect of L. rhamnosus CRL1505 nasal administration on the recovery of T cell-mediated defences against pneumococcal infection in malnourished mice under nutritional recovery. Malnourished mice received a balanced conventional diet (BCD) for seven days or BCD for seven days with nasal L. rhamnosus CRL1505 supplementation during last two days of the treatment. After the treatments mice were infected with S. pneumoniae. Flow cytometry studies were carried out in bone marrow, thymus, spleen and lung to study T cells, and Th 1 /Th 2 cytokine profiles were determined in broncho-alveolar lavages and serum. The administration of CRL1505 strain to malnourished mice under recovery reduced quantitative and qualitative alterations of CD4 + T cells in the bone marrow, thymus, spleen and lung induced by malnutrition. In addition, CRL1505 treatment augmented Th 2 -cytokines (interleukin 10 and 4) in respiratory and systemic compartments after pneumococcal infection. These results show that modulation of CD4 + T lymphocytes induced by L. rhamnosus CRL1505 has an important role in the beneficial effect induced by this strain on the recovery of malnourished mice. These data also indicate that nasally administered L. rhamnosus CRL1505 may represent a non-invasive alternative to modulate and improve the T cell-mediated immunity against respiratory pathogens in immunocompromised malnourished hosts.

  4. Inducible nitric-oxide synthase plays a minimal role in lymphocytic choriomeningitis virus-induced, T cell-mediated protective immunity and immunopathology

    DEFF Research Database (Denmark)

    Bartholdy, C; Nansen, A; Christensen, Jeanette Erbo

    1999-01-01

    By using mice with a targetted disruption in the gene encoding inducible nitric-oxide synthase (iNOS), we have studied the role of nitric oxide (NO) in lymphocytic choriomeningitis virus (LCMV)-induced, T cell-mediated protective immunity and immunopathology. The afferent phase of the T cell......-mediated immune response was found to be unaltered in iNOS-deficient mice compared with wild-type C57BL/6 mice, and LCMV- induced general immunosuppression was equally pronounced in both strains. In vivo analysis revealed identical kinetics of virus clearance, as well as unaltered clinical severity of systemic....... This might suggest a role of NO in regulating vascular reactivity in the context of T cell-mediated inflammation. In conclusion, these findings indicate a minimal role for iNOS/NO in the host response to LCMV. Except for a reduced local oedema in the knockout mice, iNOS/NO seems to be redundant...

  5. Epistasis between MicroRNAs 155 and 146a during T Cell-Mediated Antitumor Immunity

    Directory of Open Access Journals (Sweden)

    Thomas B. Huffaker

    2012-12-01

    Full Text Available An increased understanding of antitumor immunity is necessary for improving cell-based immunotherapies against human cancers. Here, we investigated the roles of two immune system-expressed microRNAs (miRNAs, miR-155 and miR-146a, in the regulation of antitumor immune responses. Our results indicate that miR-155 promotes and miR-146a inhibits interferon γ (IFNγ responses by T cells and reduces solid tumor growth in vivo. Using a double-knockout (DKO mouse strain deficient in both miR-155 and miR-146a, we have also identified an epistatic relationship between these two miRNAs. DKO mice had defective T cell responses and tumor growth phenotypes similar to miR-155−/− mice. Further analysis of the T cell compartment revealed that miR-155 modulates IFNγ expression through a mechanism involving repression of Ship1. Our work reveals critical roles for miRNAs in the reciprocal regulation of CD4+ and CD8+ T cell-mediated antitumor immunity and demonstrates the dominant nature of miR-155 during its promotion of immune responses.

  6. Genetic adjuvantation of recombinant MVA with CD40L potentiates CD8 T cell mediated immunity

    Directory of Open Access Journals (Sweden)

    Henning eLauterbach

    2013-08-01

    Full Text Available Modified vaccinia Ankara (MVA is a safe and promising viral vaccine vector that is currently investigated in several clinical and pre-clinical trials. In contrast to inactivated or sub-unit vaccines, MVA is able to induce strong humoral as well as cellular immune responses. In order to further improve its CD8 T cell inducing capacity, we genetically adjuvanted MVA with the coding sequence of murine CD40L, a member of the tumor necrosis factor (TNF superfamily. Immunization of mice with this new vector led to strongly enhanced primary and memory CD8 T cell responses. Concordant with the enhanced CD8 T cell response, we could detect stronger activation of dendritic cells and higher systemic levels of innate cytokines (including IL-12p70 early after immunization. Interestingly, acquisition of memory characteristics (i.e., IL-7R expression was accelerated after immunization with MVA-CD40L in comparison to non-adjuvanted MVA. Furthermore, the generated CTLs also showed improved functionality as demonstrated by intracellular cytokine staining and in vivo killing activity. Importantly, the superior CTL response after a single MVA-CD40L immunization was able to protect B cell deficient mice against a fatal infection with ectromelia virus. Taken together, we show that genetic adjuvantation of MVA can change strength, quality and functionality of innate and adaptive immune responses. These data should facilitate a rational vaccine design with a focus on rapid induction of large numbers of CD8 T cells able to protect against specific diseases.

  7. Vaccine-induced T cell-mediated immunity plays a critical role in early protection against pseudorabies virus (suid herpes virus type 1) infection in pigs

    NARCIS (Netherlands)

    Rooij, van E.M.A.; Bruin, de M.G.M.; Visser-Hendriksen, de Y.E.; Middel, W.G.; Boersma, W.J.A.; Bianchi, A.T.J.

    2004-01-01

    The aim of our study was to evaluate the relative importance of antibody and T cell-mediated immunity in protection against pseudorabies virus (suid herpes virus type 1) infection in pigs. We induced different levels of immune responses by using: (1) a modified live vaccine; (2) the same modified

  8. CD8+ T Cell-Mediated Immunity during Trypanosoma cruzi Infection: A Path for Vaccine Development?

    Science.gov (United States)

    dos Santos Virgilio, Fernando; Pontes, Camila; Dominguez, Mariana Ribeiro; Ersching, Jonatan; Rodrigues, Mauricio Martins; Vasconcelos, José Ronnie

    2014-01-01

    MHC-restricted CD8+ T cells are important during infection with the intracellular protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. Experimental studies performed in the past 25 years have elucidated a number of features related to the immune response mediated by these T cells, which are important for establishing the parasite/host equilibrium leading to chronic infection. CD8+ T cells are specific for highly immunodominant antigens expressed by members of the trans-sialidase family. After infection, their activation is delayed, and the cells display a high proliferative activity associated with high apoptotic rates. Although they participate in parasite control and elimination, they are unable to clear the infection due to their low fitness, allowing the parasite to establish the chronic phase when these cells then play an active role in the induction of heart immunopathology. Vaccination with a number of subunit recombinant vaccines aimed at eliciting specific CD8+ T cells can reverse this path, thereby generating a productive immune response that will lead to the control of infection, reduction of symptoms, and reduction of disease transmission. Due to these attributes, activation of CD8+ T lymphocytes may constitute a path for the development of a veterinarian or human vaccine. PMID:25104879

  9. CD8+ T Cell-Mediated Immunity during Trypanosoma cruzi Infection: A Path for Vaccine Development?

    Directory of Open Access Journals (Sweden)

    Fernando dos Santos Virgilio

    2014-01-01

    Full Text Available MHC-restricted CD8+ T cells are important during infection with the intracellular protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. Experimental studies performed in the past 25 years have elucidated a number of features related to the immune response mediated by these T cells, which are important for establishing the parasite/host equilibrium leading to chronic infection. CD8+ T cells are specific for highly immunodominant antigens expressed by members of the trans-sialidase family. After infection, their activation is delayed, and the cells display a high proliferative activity associated with high apoptotic rates. Although they participate in parasite control and elimination, they are unable to clear the infection due to their low fitness, allowing the parasite to establish the chronic phase when these cells then play an active role in the induction of heart immunopathology. Vaccination with a number of subunit recombinant vaccines aimed at eliciting specific CD8+ T cells can reverse this path, thereby generating a productive immune response that will lead to the control of infection, reduction of symptoms, and reduction of disease transmission. Due to these attributes, activation of CD8+ T lymphocytes may constitute a path for the development of a veterinarian or human vaccine.

  10. Possible Therapeutic Application of Targeting Type II Natural Killer T Cell-Mediated Suppression of Tumor Immunity

    Science.gov (United States)

    Kato, Shingo; Berzofsky, Jay A.; Terabe, Masaki

    2018-01-01

    Natural killer T (NKT) cells are a unique T cell subset that exhibits characteristics from both the innate immune cells and T cells. There are at least two subsets of NKT cells, type I and type II. These two subsets of NKT cells have opposite functions in antitumor immunity. Type I NKT cells usually enhance and type II NKT cells suppress antitumor immunity. In addition, these two subsets of NKT cells cross-regulate each other. In this review, we mainly focus on immunosuppressive NKT cells, type II NKT cells. After summarizing their definition, experimental tools to study them, and subsets of them, we will discuss possible therapeutic applications of type II NKT cell pathway targeted therapies. PMID:29520281

  11. Immunoregulatory mechanisms in Chagas disease: modulation of apoptosis in T-cell mediated immune responses.

    Science.gov (United States)

    Chaves, Ana Thereza; de Assis Silva Gomes Estanislau, Juliana; Fiuza, Jacqueline Araújo; Carvalho, Andréa Teixeira; Ferreira, Karine Silvestre; Fares, Rafaelle Christine Gomes; Guimarães, Pedro Henrique Gazzinelli; de Souza Fagundes, Elaine Maria; Morato, Maria José; Fujiwara, Ricardo Toshio; da Costa Rocha, Manoel Otávio; Correa-Oliveira, Rodrigo

    2016-04-30

    Chronic Chagas disease presents different clinical manifestations ranging from asymptomatic (namely indeterminate) to severe cardiac and/or digestive. Previous results have shown that the immune response plays an important role, although no all mechanisms are understood. Immunoregulatory mechanisms such as apoptosis are important for the control of Chagas disease, possibly affecting the morbidity in chronic clinical forms. Apoptosis has been suggested to be an important mechanism of cellular response during T. cruzi infection. We aimed to further understand the putative role of apoptosis in Chagas disease and its relation to the clinical forms of the disease. Apoptosis of lymphocytes, under antigenic stimuli (soluble T. cruzi antigens - TcAg) where compared to that of non-stimulated cells. Apoptosis was evaluated using the expression of annexin and caspase 3(+) by T cells and the percentage of cells positive evaluated by flow cytometry. In addition activation and T cell markers were used for the identification of TCD4(+) and TCD8(+) subpopulations. The presence of intracellular and plasma cytokines were also evaluated. Analysis of the activation status of the peripheral blood cells showed that patients with Chagas disease presented higher levels of activation determined by the expression of activation markers, after TcAg stimulation. PCR array were used to evaluate the contribution of this mechanism in specific cell populations from patients with different clinical forms of human Chagas disease. Our results showed a reduced proliferative response associated a high expression of T CD4(+)CD62L(-) cells in CARD patients when compared with IND group and NI individuals. We also observed that both groups of patients presented a significant increase of CD4(+) and CD8(+) T cell subsets in undergoing apoptosis after in vitro stimulation with T. cruzi antigens. In CARD patients, both CD4(+) and CD8(+) T cells expressing TNF-α were highly susceptible to undergo apoptosis

  12. IL-2/neuroantigen fusion proteins as antigen-specific tolerogens in experimental autoimmune encephalomyelitis (EAE): correlation of T cell-mediated antigen presentation and tolerance induction.

    Science.gov (United States)

    Mannie, Mark D; Clayson, Barbara A; Buskirk, Elizabeth J; DeVine, Jarret L; Hernandez, Jose J; Abbott, Derek J

    2007-03-01

    The purpose of this study was to assess whether the Ag-targeting activity of cytokine/neuroantigen (NAg) fusion proteins may be associated with mechanisms of tolerance induction. To assess this question, we expressed fusion proteins comprised of a N-terminal cytokine domain and a C-terminal NAg domain. The cytokine domain comprised either rat IL-2 or IL-4, and the NAg domain comprised the dominant encephalitogenic determinant of the guinea pig myelin basic protein. Subcutaneous administration of IL2NAg (IL-2/NAg fusion protein) into Lewis rats either before or after an encephalitogenic challenge resulted in an attenuated course of experimental autoimmune encephalomyelitis. In contrast, parallel treatment of rats with IL4NAg (IL-4/NAg fusion protein) or NAg lacked tolerogenic activity. In the presence of IL-2R(+) MHC class II(+) T cells, IL2NAg fusion proteins were at least 1,000 times more potent as an Ag than NAg alone. The tolerogenic activity of IL2NAg in vivo and the enhanced potency in vitro were both dependent upon covalent linkage of IL-2 and NAg. IL4NAg also exhibited enhanced antigenic potency. IL4NAg was approximately 100-fold more active than NAg alone in the presence of splenic APC. The enhanced potency of IL4NAg also required covalent linkage of cytokine and NAg and was blocked by soluble IL-4 or by a mAb specific for IL-4. Other control cytokine/NAg fusion proteins did not exhibit a similar enhancement of Ag potency compared with NAg alone. Thus, the IL2NAg and IL4NAg fusion proteins targeted NAg for enhanced presentation by particular subsets of APC. The activities of IL2NAg revealed a potential relationship between NAg targeting to activated T cells, T cell-mediated Ag presentation, and tolerance induction.

  13. Trypanosoma cruzi Adjuvants Potentiate T Cell-Mediated Immunity Induced by a NY-ESO-1 Based Antitumor Vaccine

    Science.gov (United States)

    Junqueira, Caroline; Guerrero, Ana Tereza; Galvão-Filho, Bruno; Andrade, Warrison A.; Salgado, Ana Paula C.; Cunha, Thiago M.; Ropert, Catherine; Campos, Marco Antônio; Penido, Marcus L. O.; Mendonça-Previato, Lúcia; Previato, José Oswaldo; Ritter, Gerd; Cunha, Fernando Q.; Gazzinelli, Ricardo T.

    2012-01-01

    Immunological adjuvants that induce T cell-mediate immunity (TCMI) with the least side effects are needed for the development of human vaccines. Glycoinositolphospholipids (GIPL) and CpGs oligodeoxynucleotides (CpG ODNs) derived from the protozoa parasite Trypanosoma cruzi induce potent pro-inflammatory reaction through activation of Toll-Like Receptor (TLR)4 and TLR9, respectively. Here, using mouse models, we tested the T. cruzi derived TLR agonists as immunological adjuvants in an antitumor vaccine. For comparison, we used well-established TLR agonists, such as the bacterial derived monophosphoryl lipid A (MPL), lipopeptide (Pam3Cys), and CpG ODN. All tested TLR agonists were comparable to induce antibody responses, whereas significant differences were noticed in their ability to elicit CD4+ T and CD8+ T cell responses. In particular, both GIPLs (GTH, and GY) and CpG ODNs (B344, B297 and B128) derived from T. cruzi elicited interferon-gamma (IFN-γ) production by CD4+ T cells. On the other hand, the parasite derived CpG ODNs, but not GIPLs, elicited a potent IFN-γ response by CD8+ T lymphocytes. The side effects were also evaluated by local pain (hypernociception). The intensity of hypernociception induced by vaccination was alleviated by administration of an analgesic drug without affecting protective immunity. Finally, the level of protective immunity against the NY-ESO-1 expressing melanoma was associated with the magnitude of both CD4+ T and CD8+ T cell responses elicited by a specific immunological adjuvant. PMID:22567144

  14. Influence of Ganoderma lucidum (Curt.: Fr.) P. Karst. on T-cell-mediated immunity in normal and immunosuppressed mice line CBA/Ca.

    Science.gov (United States)

    Nizhenkovska, Iryna V; Pidchenko, Vitalii T; Bychkova, Nina G; Bisko, Nina A; Rodnichenko, Angela Y; Kozyko, Natalya O

    2015-09-01

    The article presents the results of the investigation of the effect of biomass powder of the fungus Ganoderma lucidum on T-cell-mediated immunity in normal and immunosuppressed mice CBA/Ca. Delayed-type hypersensitivity assay was used. Experimental immunodeficiency was established with intraperitoneal injection of the immunosuppressant cyclophosphamide at a single dose of 150 mg/kg on the first day of the experiment. Results of the study show that the administration of biomass powder of Ganoderma lucidum in a dose of 0.5 mg/kg orally for 10 days increases the delayed-type hypersensitivity response in normal mice CBA/Ca. Administration of 0.5 mg/kg of biomass powder of the fungus Ganoderma lucidum for 10 days blocked the development of the T-cell-mediated immunosuppression, induced by administration of cyclophosphamide and restored the delayed-type hypersensitivity response in immunosuppressed mice. Key words: fungus Ganoderma lucidum cyclophosphamide immunodeficiency T-cell-mediated immunity delayed-type hypersensitivity.

  15. HPV-E7 Delivered by Engineered Exosomes Elicits a Protective CD8+ T Cell-Mediated Immune Response

    Science.gov (United States)

    Di Bonito, Paola; Ridolfi, Barbara; Columba-Cabezas, Sandra; Giovannelli, Andrea; Chiozzini, Chiara; Manfredi, Francesco; Anticoli, Simona; Arenaccio, Claudia; Federico, Maurizio

    2015-01-01

    We developed an innovative strategy to induce a cytotoxic T cell (CTL) immune response against protein antigens of choice. It relies on the production of exosomes, i.e., nanovesicles spontaneously released by all cell types. We engineered the upload of huge amounts of protein antigens upon fusion with an anchoring protein (i.e., HIV-1 Nefmut), which is an inactive protein incorporating in exosomes at high levels also when fused with foreign proteins. We compared the immunogenicity of engineered exosomes uploading human papillomavirus (HPV)-E7 with that of lentiviral virus-like particles (VLPs) incorporating equivalent amounts of the same antigen. These exosomes, whose limiting membrane was decorated with VSV-G, i.e., an envelope protein inducing pH-dependent endosomal fusion, proved to be as immunogenic as the cognate VLPs. It is noteworthy that the immunogenicity of the engineered exosomes remained unaltered in the absence of VSV-G. Most important, we provide evidence that the inoculation in mouse of exosomes uploading HPV-E7 induces production of anti-HPV E7 CTLs, blocks the growth of syngeneic tumor cells inoculated after immunization, and controls the development of tumor cells inoculated before the exosome challenge. These results represent the proof-of-concept about both feasibility and efficacy of the Nefmut-based exosome platform for the induction of CD8+ T cell immunity. PMID:25760140

  16. HPV-E7 Delivered by Engineered Exosomes Elicits a Protective CD8+ T Cell-Mediated Immune Response

    Directory of Open Access Journals (Sweden)

    Paola Di Bonito

    2015-03-01

    Full Text Available We developed an innovative strategy to induce a cytotoxic T cell (CTL immune response against protein antigens of choice. It relies on the production of exosomes, i.e., nanovesicles spontaneously released by all cell types. We engineered the upload of huge amounts of protein antigens upon fusion with an anchoring protein (i.e., HIV-1 Nefmut, which is an inactive protein incorporating in exosomes at high levels also when fused with foreign proteins. We compared the immunogenicity of engineered exosomes uploading human papillomavirus (HPV-E7 with that of lentiviral virus-like particles (VLPs incorporating equivalent amounts of the same antigen. These exosomes, whose limiting membrane was decorated with VSV-G, i.e., an envelope protein inducing pH-dependent endosomal fusion, proved to be as immunogenic as the cognate VLPs. It is noteworthy that the immunogenicity of the engineered exosomes remained unaltered in the absence of VSV-G. Most important, we provide evidence that the inoculation in mouse of exosomes uploading HPV-E7 induces production of anti-HPV E7 CTLs, blocks the growth of syngeneic tumor cells inoculated after immunization, and controls the development of tumor cells inoculated before the exosome challenge. These results represent the proof-of-concept about both feasibility and efficacy of the Nefmut-based exosome platform for the induction of CD8+ T cell immunity.

  17. HIV-Specific CD8+ T Cell-Mediated Viral Suppression Correlates With the Expression of CD57

    DEFF Research Database (Denmark)

    Jensen, Sanne S; Tingstedt, Jeanette Linnea; Larsen, Tine Kochendorf

    2016-01-01

    BACKGROUND: Virus-specific CD8(+) T-cell responses are believed to play an important role in the control of HIV-1 infection; however, what constitutes an effective HIV-1 CD8(+) T-cell response remains a topic of debate. The ex vivo viral suppressive capacity was measured of CD8(+) T cells from 44...... HIV-1-positive individuals. The phenotypic and cytokine profiles, and also the specificity of the CD8(+) T cells, were correlated with the suppression of HIV-1 replication. We also aimed to determine whether antiretroviral therapy (ART) had any positive effect on the HIV-1 suppressive CD8(+) T cells....... METHOD: Ex vivo suppression assay was used to evaluate the ability of CD8(+) T cells to suppress HIV-1 replication in autologous CD4(+) T cells. The CD107a, interferon-γ, interleukin-2, tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein-1β (MIP-1β) responses to HIV-1 were evaluated...

  18. IL-2 complex treatment amplifies CD8+T cell mediated immunity following herpes simplex virus-1 infection.

    Science.gov (United States)

    Rajasagi, Naveen K; Rouse, Barry T

    2016-12-01

    CD8 + T cells play an important role in controlling numerous virus infections and some tumors and therefore several strategies have been adopted to modulate CD8 + T cell responses. One such approach includes treatment with IL-2 bound to a monoclonal antibody against IL-2 (IL-2 complex) which was shown to enhance CD8 + T cell responses and provide protection against some cancers and pathogens. This report analyses the value of IL-2 complex therapy to protect against a cutaneous virus infection as occurs with herpes simplex virus-1 (HSV-1) infection. Treatment with IL-2 complex after infection reduced virus levels and lesion severity in a zosteriform model of HSV infection in mice. Furthermore, IL-2 complex treatment expanded HSV-1-gB epitope-specific CD8 + T cells, IFN-γ and TNF-α producing CD8 + T cells as well as cells that produced more than one cytokine. In addition, IL-2 complex therapy recipients showed enhanced cytolytic activity of CD8 + T cells as shown by increased granzyme B expression and lytic granule release. Taken, together, these studies demonstrate that IL-2 complex therapy can be useful to boost protection against a cutaneous virus infection. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  19. Effect of Green Tea Extract on T cell Mediated Hypersensitivity Reaction in BALB/c Mice Exposed to Gamma Irradiation

    International Nuclear Information System (INIS)

    Hashim, A.M.; Ismail Al-kadey, M.M.I.; Shabon, M.H.; Hussien, S.M.

    2010-01-01

    Gamma radiation is widely used in the treatment of malignant neoplasms. However, it deprives the host immune function which may retard tumor rejection by the immune response. The main purpose of the present study is to test the ability of green tea dry extract to restore the T cell hypersensitivity reaction in gamma irradiated BALB/c mice. It aims also to elucidate the possible mechanism of action of ionizing radiation and green tea dry extract in the immune function. Four groups of BALB/c mice, each of ten, have been used in each experiment. The first group served as a control, the second group received green tea dry extract and the third group was exposed to 2 Gy gamma irradiation, while the fourth group received green tea dry extract before and after gamma irradiation. The following parameters were determined, the contact sensitivity reaction by the mouse ear swelling response, local dendritic cell migration, local lymph node weight, lymphocyte proliferation, spleen and thymus weight with their lymphocyte count. The effect of gamma irradiation and green tea dry extract on the elicitation phase of contact sensitivity was also determined. Data from the present study showed that gamma irradiation caused a significant decrease of the mouse ear swelling response and retarded dendritic cell migration. They also showed a significant decline in the lymphocytes proliferation in lymph node draining the contact sensitizer application. Total body exposure to 2 Gy gamma irradiation induced marked decline of thymus weight and thymocyte count, while it reduced spleen weight and spleenocyte count to a lesser extent. Exposure to gamma irradiation enhanced the elicitation phase of contact sensitivity. Administration of green tea dry extract partially preserved the contact sensitivity response to oxazolone in gamma irradiated BALB/c mice. It markedly minimized the enhancement of the elicitation phase of ear swelling. In conclusion, the present study heralds a beneficial role of

  20. The interleukin-15 system suppresses T cell-mediated autoimmunity by regulating negative selection and nT(H)17 cell homeostasis in the thymus.

    Science.gov (United States)

    Hou, Mau-Sheng; Huang, Shih-Ting; Tsai, Ming-Han; Yen, Ching-Cheng; Lai, Yein-Gei; Liou, Yae-Huei; Lin, Chih-Kung; Liao, Nan-Shih

    2015-01-01

    The interleukin-15 (IL-15) system is important for regulating both innate and adaptive immune responses, however, its role in autoimmune disease remained unclear. Here we found that Il15(-/-) and Il15ra(-/-) mice spontaneously developed late-onset autoimmune phenotypes. CD4(+) T cells of the knockout mice showed elevated autoreactivity as demonstrated by the induction of lymphocyte infiltration in the lacrimal and salivary glands when transferred into nude mice. The antigen-presenting cells in the thymic medullary regions expressed IL-15 and IL-15Rα, whose deficiency resulted in insufficient negative selection and elevated number of natural IL-17A-producing CD4(+) thymocytes. These findings reveal previously unknown functions of the IL-15 system in thymocyte development, and thus a new layer of regulation in T cell-mediated autoimmunity. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Determinates of tumor response to radiation: Tumor cells, tumor stroma and permanent local control

    International Nuclear Information System (INIS)

    Li, Wende; Huang, Peigen; Chen, David J.; Gerweck, Leo E.

    2014-01-01

    Background and purpose: The causes of tumor response variation to radiation remain obscure, thus hampering the development of predictive assays and strategies to decrease resistance. The present study evaluates the impact of host tumor stromal elements and the in vivo environment on tumor cell kill, and relationship between tumor cell radiosensitivity and the tumor control dose. Material and methods: Five endpoints were evaluated and compared in a radiosensitive DNA double-strand break repair-defective (DNA-PKcs −/− ) tumor line, and its DNA-PKcs repair competent transfected counterpart. In vitro colony formation assays were performed on in vitro cultured cells, on cells obtained directly from tumors, and on cells irradiated in situ. Permanent local control was assessed by the TCD 50 assay. Vascular effects were evaluated by functional vascular density assays. Results: The fraction of repair competent and repair deficient tumor cells surviving radiation did not substantially differ whether irradiated in vitro, i.e., in the absence of host stromal elements and factors, from the fraction of cells killed following in vivo irradiation. Additionally, the altered tumor cell sensitivity resulted in a proportional change in the dose required to achieve permanent local control. The estimated number of tumor cells per tumor, their cloning efficiency and radiosensitivity, all assessed by in vitro assays, were used to predict successfully, the measured tumor control doses. Conclusion: The number of clonogens per tumor and their radiosensitivity govern the permanent local control dose

  2. Environmental immunogens and T-cell-mediated responses in fibromyalgia: evidence for immune dysregulation and determinants of granuloma formation.

    Science.gov (United States)

    Shanklin, D R; Stevens, M V; Hall, M F; Smalley, D L

    2000-10-01

    Thirty-nine patients with fibromyalgia syndrome (FMS) according to American College of Rheumatology criteria were studied for cell-mediated sensitivity to environmental chemicals. Lymphocytes were tested by standard [(3)H]thymidine incorporation in vitro for T cell memory to 11 chemical substances. Concanavalin A (Con A) was used to demonstrate T cell proliferation. Controls were 25 contemporaneous healthy adults and 252 other concurrent standard controls without any aspect of FMS. Significantly higher (P P > 0.02) SI were found for cadmium and silicon. FMS patients showed sporadic responses to the specific substances tested, with no high-frequency result (>50%) and no obvious pattern. Mitogenic responses to Con A indicated some suppression of T cell functionality in FMS. Possible links between mitogenicity and immunogenic T cell proliferation, certain electrochemical specifics of granuloma formation, maintenance of connective tissue, and the fundamental nature of FMS are considered. Copyright 2000 Academic Press.

  3. Critical roles for LIGHT and its receptors in generating T cell-mediated immunity during Leishmania donovani infection.

    Directory of Open Access Journals (Sweden)

    Amanda C Stanley

    2011-10-01

    Full Text Available LIGHT (TNFSF14 is a member of the TNF superfamily involved in inflammation and defence against infection. LIGHT signals via two cell-bound receptors; herpes virus entry mediator (HVEM and lymphotoxin-beta receptor (LTβR. We found that LIGHT is critical for control of hepatic parasite growth in mice with visceral leishmaniasis (VL caused by infection with the protozoan parasite Leishmania donovani. LIGHT-HVEM signalling is essential for early dendritic cell IL-12/IL-23p40 production, and the generation of IFNγ- and TNF-producing T cells that control hepatic infection. However, we also discovered that LIGHT-LTβR interactions suppress anti-parasitic immunity in the liver in the first 7 days of infection by mechanisms that restrict both CD4(+ T cell function and TNF-dependent microbicidal mechanisms. Thus, we have identified distinct roles for LIGHT in infection, and show that manipulation of interactions between LIGHT and its receptors may be used for therapeutic advantage.

  4. Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-kappaB activation.

    Directory of Open Access Journals (Sweden)

    Caitlin O'Mahony

    Full Text Available Host defence against infection requires a range of innate and adaptive immune responses that may lead to tissue damage. Such immune-mediated pathologies can be controlled with appropriate T regulatory (Treg activity. The aim of the present study was to determine the influence of gut microbiota composition on Treg cellular activity and NF-kappaB activation associated with infection. Mice consumed the commensal microbe Bifidobacterium infantis 35624 followed by infection with Salmonella typhimurium or injection with LPS. In vivo NF-kappaB activation was quantified using biophotonic imaging. CD4+CD25+Foxp3+ T cell phenotypes and cytokine levels were assessed using flow cytometry while CD4+ T cells were isolated using magnetic beads for adoptive transfer to naïve animals. In vivo imaging revealed profound inhibition of infection and LPS induced NF-kappaB activity that preceded a reduction in S. typhimurium numbers and murine sickness behaviour scores in B. infantis-fed mice. In addition, pro-inflammatory cytokine secretion, T cell proliferation, and dendritic cell co-stimulatory molecule expression were significantly reduced. In contrast, CD4+CD25+Foxp3+ T cell numbers were significantly increased in the mucosa and spleen of mice fed B. infantis. Adoptive transfer of CD4+CD25+ T cells transferred the NF-kappaB inhibitory activity. Consumption of a single commensal micro-organism drives the generation and function of Treg cells which control excessive NF-kappaB activation in vivo. These cellular interactions provide the basis for a more complete understanding of the commensal-host-pathogen trilogue that contribute to host homeostatic mechanisms underpinning protection against aberrant activation of the innate immune system in response to a translocating pathogen or systemic LPS.

  5. Granzyme A Is Required for Regulatory T-Cell Mediated Prevention of Gastrointestinal Graft-versus-Host Disease.

    Directory of Open Access Journals (Sweden)

    Sarvari Velaga

    Full Text Available In our previous work we could identify defects in human regulatory T cells (Tregs likely favoring the development of graft-versus-host disease (GvHD following allogeneic stem cell transplantation (SCT. Treg transcriptome analyses comparing GvHD and immune tolerant patients uncovered regulated gene transcripts highly relevant for Treg cell function. Moreover, granzyme A (GZMA also showed a significant lower expression at the protein level in Tregs of GvHD patients. GZMA induces cytolysis in a perforin-dependent, FAS-FASL independent manner and represents a cell-contact dependent mechanism for Tregs to control immune responses. We therefore analyzed the functional role of GZMA in a murine standard model for GvHD. For this purpose, adoptively transferred CD4+CD25+ Tregs from gzmA-/- mice were analyzed in comparison to their wild type counterparts for their capability to prevent murine GvHD. GzmA-/- Tregs home efficiently to secondary lymphoid organs and do not show phenotypic alterations with respect to activation and migration properties to inflammatory sites. Whereas gzmA-/- Tregs are highly suppressive in vitro, Tregs require GZMA to rescue hosts from murine GvHD, especially regarding gastrointestinal target organ damage. We herewith identify GZMA as critical effector molecule of human Treg function for gastrointestinal immune response in an experimental GvHD model.

  6. Phosphoproteomics Reveals Regulatory T Cell-Mediated DEF6 Dephosphorylation That Affects Cytokine Expression in Human Conventional T Cells

    KAUST Repository

    Joshi, Rubin N.

    2017-09-25

    Regulatory T cells (Tregs) control key events of immune tolerance, primarily by suppression of effector T cells. We previously revealed that Tregs rapidly suppress T cell receptor (TCR)-induced calcium store depletion in conventional CD4CD25 T cells (Tcons) independently of IP levels, consequently inhibiting NFAT signaling and effector cytokine expression. Here, we study Treg suppression mechanisms through unbiased phosphoproteomics of primary human Tcons upon TCR stimulation and Treg-mediated suppression, respectively. Tregs induced a state of overall decreased phosphorylation as opposed to TCR stimulation. We discovered novel phosphosites (T595_S597) in the DEF6 (SLAT) protein that were phosphorylated upon TCR stimulation and conversely dephosphorylated upon coculture with Tregs. Mutation of these DEF6 phosphosites abrogated interaction of DEF6 with the IP receptor and affected NFAT activation and cytokine transcription in primary Tcons. This novel mechanism and phosphoproteomics data resource may aid in modifying sensitivity of Tcons to Treg-mediated suppression in autoimmune disease or cancer.

  7. Peripherally Generated Foxp3+ Regulatory T Cells Mediate the Immunomodulatory Effects of IVIg in Allergic Airways Disease.

    Science.gov (United States)

    Massoud, Amir H; Kaufman, Gabriel N; Xue, Di; Béland, Marianne; Dembele, Marieme; Piccirillo, Ciriaco A; Mourad, Walid; Mazer, Bruce D

    2017-04-01

    IVIg is widely used as an immunomodulatory therapy. We have recently demonstrated that IVIg protects against airway hyperresponsiveness (AHR) and inflammation in mouse models of allergic airways disease (AAD), associated with induction of Foxp3 + regulatory T cells (Treg). Using mice carrying a DTR/EGFP transgene under the control of the Foxp3 promoter (DEREG mice), we demonstrate in this study that IVIg generates a de novo population of peripheral Treg (pTreg) in the absence of endogenous Treg. IVIg-generated pTreg were sufficient for inhibition of OVA-induced AHR in an Ag-driven murine model of AAD. In the absence of endogenous Treg, IVIg failed to confer protection against AHR and airway inflammation. Adoptive transfer of purified IVIg-generated pTreg prior to Ag challenge effectively prevented airway inflammation and AHR in an Ag-specific manner. Microarray gene expression profiling of IVIg-generated pTreg revealed upregulation of genes associated with cell cycle, chromatin, cytoskeleton/motility, immunity, and apoptosis. These data demonstrate the importance of Treg in regulating AAD and show that IVIg-generated pTreg are necessary and sufficient for inhibition of allergen-induced AAD. The ability of IVIg to generate pure populations of highly Ag-specific pTreg represents a new avenue to study pTreg, the cross-talk between humoral and cellular immunity, and regulation of the inflammatory response to Ags. Copyright © 2017 by The American Association of Immunologists, Inc.

  8. CD4+ T cells mediate abscess formation in intra-abdominal sepsis by an IL-17-dependent mechanism.

    Science.gov (United States)

    Chung, Doo Ryeon; Kasper, Dennis L; Panzo, Ronald J; Chitnis, Tanuja; Grusby, Michael J; Sayegh, Mohamed H; Tzianabos, Arthur O; Chtinis, Tanuja

    2003-02-15

    Abscess formation associated with intra-abdominal sepsis causes severe morbidity and can be fatal. Previous studies have implicated T cells in the pathogenesis of abscess formation, and we have recently shown that CD4(+) T cells activated in vitro by zwitterionic capsular polysaccharides from abscess-inducing bacteria such as Staphylococcus aureus and Bacteroides fragilis initiate this host response when transferred to naive rats. In this study, we show that mice deficient in alphabetaTCR-bearing T cells or CD4(+) T cells fail to develop abscesses following challenge with B. fragilis or abscess-inducing zwitterionic polysaccharides, compared with CD8(-/-) or wild-type animals. Transfer of CD4(+) T cells from wild-type mice to alphabetaTCR(-/-) animals reconstituted this ability. The induction of abscesses required T cell costimulation via the CD28-B7 pathway, and T cell transfer experiments with STAT4(-/-) and STAT6(-/-) mice demonstrated that this host response is dependent on STAT4 signaling. Significantly higher levels of IL-17, a proinflammatory cytokine produced almost exclusively by activated CD4(+) T cells, were associated with abscess formation in Th2-impaired (STAT6(-/-)) mice, while STAT4(-/-) mice had significantly lower levels of this cytokine than control animals. The formation of abscesses was preceded by an increase in the number of activated CD4(+) T cells in the peritoneal cavity 24 h following bacterial challenge. Confocal laser-scanning microscopy analysis revealed that CD4(+) T cells comprise the abscess wall in these animals and produce IL-17 at this site. Administration of a neutralizing Ab specific for IL-17 prevented abscess formation following bacterial challenge in mice. These data delineate the specific T cell response necessary for the development of intra-abdominal abscesses and underscore the role of IL-17 in this disease process.

  9. Impact of T-cell-mediated immune response on xenogeneic heart valve transplantation: short-term success and mid-term failure.

    Science.gov (United States)

    Biermann, Anna C; Marzi, Julia; Brauchle, Eva; Schneider, Maria; Kornberger, Angela; Abdelaziz, Sherif; Wichmann, Julian L; Arendt, Christophe T; Nagel, Eike; Brockbank, Kelvin G M; Seifert, Martina; Schenke-Layland, Katja; Stock, Ulrich A

    2018-04-01

    Allogeneic frozen cryopreserved heart valves (allografts or homografts) are commonly used in clinical practice. A major obstacle for their application is the limited availability in particular for paediatrics. Allogeneic large animal studies revealed that alternative ice-free cryopreservation (IFC) results in better matrix preservation and reduced immunogenicity. The objective of this study was to evaluate xenogeneic (porcine) compared with allogeneic (ovine) IFC heart valves in a large animal study. IFC xenografts and allografts were transplanted in 12 juvenile merino sheep for 1-12 weeks. Immunohistochemistry, ex vivo computed tomography scans and transforming growth factor-β release profiles were analysed to evaluate postimplantation immunopathology. In addition, near-infrared multiphoton imaging and Raman spectroscopy were employed to evaluate matrix integrity of the leaflets. Acellular leaflets were observed in both groups 1 week after implantation. Allogeneic leaflets remained acellular throughout the entire study. In contrast, xenogeneic valves were infiltrated with abundant T-cells and severely thickened over time. No collagen or elastin changes could be detected in either group using multiphoton imaging. Raman spectroscopy with principal component analysis focusing on matrix-specific peaks confirmed no significant differences for explanted allografts. However, xenografts demonstrated clear matrix changes, enabling detection of distinct inflammatory-driven changes but without variations in the level of transforming growth factor-β. Despite short-term success, mid-term failure of xenogeneic IFC grafts due to a T-cell-mediated extracellular matrix-triggered immune response was shown.

  10. Earlier low-dose TBI or DST overcomes CD8+ T-cell-mediated alloresistance to allogeneic marrow in recipients of anti-CD40L.

    Science.gov (United States)

    Takeuchi, Yasuo; Ito, Hiroshi; Kurtz, Josef; Wekerle, Thomas; Ho, Leon; Sykes, Megan

    2004-01-01

    Treatment with a single injection of anti-CD40L (CD154) monoclonal antibody (mAb) and fully mismatched allogeneic bone marrow transplant (BMT) allows rapid tolerization of CD4+ T cells to the donor. The addition of in vivo CD8 T-cell depletion leads to permanent mixed hematopoietic chimerism and tolerance. We now describe two approaches that obviate the requirement for CD8 T-cell depletion by rapidly tolerizing recipient CD8 T cells in addition to CD4 cells. Administration of donor-specific transfusion (DST) to mice receiving 3 Gy total body irradiation (TBI), BMT and anti-CD40L mAb on day 0 uniformly led to permanent mixed chimerism and tolerance, compared with only 40% of mice receiving similar treatment without DST. In the absence of DST, moving the timing of 3 Gy TBI to day -1 or day -2 instead of day 0 led to rapid (by 2 weeks) induction of CD8+ cell tolerance, and also permitted uniform achievement of permanent mixed chimerism and donor-specific tolerance in recipients of anti-CD40L and BMT on day 0. These nontoxic regimens overcome CD8+ and CD4+ T-cell-mediated alloresistance without requiring host T-cell depletion, permitting the induction of permanent mixed chimerism and tolerance.

  11. 5-Azacytidine treatment sensitizes tumor cells to T-cell mediated cytotoxicity and modulates NK cells in patients with myeloid malignancies

    DEFF Research Database (Denmark)

    Gang, A O; Frøsig, T M; Brimnes, M K

    2014-01-01

    Treatment with the demethylating agent 5-Azacytidine leads to prolonged survival for patients with myelodysplastic syndrome, and the demethylation induces upregulation of cancer-testis antigens. Cancer-testis antigens are well-known targets for immune recognition in cancer, and the immune system ...

  12. Antigen-Specificity of T Cell Infiltrates in Biopsies With T Cell-Mediated Rejection and BK Polyomavirus Viremia: Analysis by Next Generation Sequencing.

    Science.gov (United States)

    Zeng, G; Huang, Y; Huang, Y; Lyu, Z; Lesniak, D; Randhawa, P

    2016-11-01

    This study interrogates the antigen-specificity of inflammatory infiltrates in renal biopsies with BK polyomavirus (BKPyV) viremia (BKPyVM) with or without allograft nephropathy (BKPyVN). Peripheral blood mononuclear cells (PBMC) from five healthy HLA-A0101 subjects were stimulated by peptides derived from the BKPYV proteome or polymorphic regions of HLA. Next generation sequencing of the T cell-receptor complementary DNA was performed on peptide-stimulated PBMC and 23 biopsies with T cell-mediated rejection (TCMR) or BKPyVN. Biopsies from patients with BKPyVM or BKVPyVN contained 7.7732 times more alloreactive than virus-reactive clones. Biopsies with TCMR also contained BKPyV-specific clones, presumably a manifestation of heterologous immunity. The mean cumulative T cell clonal frequency was 0.1378 for alloreactive clones and 0.0375 for BKPyV-reactive clones. Samples with BKPyVN and TCMR clustered separately in dendrograms of V-family and J-gene utilization patterns. Dendrograms also revealed that V-gene, J-gene, and D-gene usage patterns were a function of HLA type. In conclusion, biopsies with BKPyVN contain abundant allospecific clones that exceed the number of virus-reactive clones. The T cell component of tissue injury in viral nephropathy appears to be mediated primarily by an "innocent bystander" mechanism in which the principal element is secondary T cell influx triggered by both antiviral and anti-HLA immunity. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

  13. A marked reduction in priming of cytotoxic CD8+ T cells mediated by stress-induced glucocorticoids involves multiple deficiencies in cross-presentation by dendritic cells.

    Science.gov (United States)

    Hunzeker, John T; Elftman, Michael D; Mellinger, Jennifer C; Princiotta, Michael F; Bonneau, Robert H; Truckenmiller, Mary E; Norbury, Christopher C

    2011-01-01

    Protracted psychological stress elevates circulating glucocorticoids, which can suppress CD8(+) T cell-mediated immunity, but the mechanisms are incompletely understood. Dendritic cells (DCs), required for initiating CTL responses, are vulnerable to stress/corticosterone, which can contribute to diminished CTL responses. Cross-priming of CD8(+) T cells by DCs is required for initiating CTL responses against many intracellular pathogens that do not infect DCs. We examined the effects of stress/corticosterone on MHC class I (MHC I) cross-presentation and priming and show that stress/corticosterone-exposed DCs have a reduced ability to cross-present OVA and activate MHC I-OVA(257-264)-specific T cells. Using a murine model of psychological stress and OVA-loaded β(2)-microglobulin knockout "donor" cells that cannot present Ag, DCs from stressed mice induced markedly less Ag-specific CTL proliferation in a glucocorticoid receptor-dependent manner, and endogenous in vivo T cell cytolytic activity generated by cross-presented Ag was greatly diminished. These deficits in cross-presentation/priming were not due to altered Ag donation, Ag uptake (phagocytosis, receptor-mediated endocytosis, or fluid-phase uptake), or costimulatory molecule expression by DCs. However, proteasome activity in corticosterone-treated DCs or splenic DCs from stressed mice was partially suppressed, which limits formation of antigenic peptide-MHC I complexes. In addition, the lymphoid tissue-resident CD11b(-)CD24(+)CD8α(+) DC subset, which carries out cross-presentation/priming, was preferentially depleted in stressed mice. At the same time, CD11b(-)CD24(+)CD8α(-) DC precursors were increased, suggesting a block in development of CD8α(+) DCs. Therefore, glucocorticoid-induced changes in both the cellular composition of the immune system and intracellular protein degradation contribute to impaired CTL priming in stressed mice.

  14. Mathematical Modeling of Tumor-Tumor Distant Interactions Supports a Systemic Control of Tumor Growth.

    Science.gov (United States)

    Benzekry, Sebastien; Lamont, Clare; Barbolosi, Dominique; Hlatky, Lynn; Hahnfeldt, Philip

    2017-09-15

    Interactions between different tumors within the same organism have major clinical implications, especially in the context of surgery and metastatic disease. Three main explanatory theories (competition, angiogenesis inhibition, and proliferation inhibition) have been proposed, but precise determinants of the phenomenon remain poorly understood. Here, we formalized these theories into mathematical models and performed biological experiments to test them with empirical data. In syngeneic mice bearing two simultaneously implanted tumors, growth of only one of the tumors was significantly suppressed (61% size reduction at day 15, P < 0.05). The competition model had to be rejected, whereas the angiogenesis inhibition and proliferation inhibition models were able to describe the data. Additional models including a theory based on distant cytotoxic log-kill effects were unable to fit the data. The proliferation inhibition model was identifiable and minimal (four parameters), and its descriptive power was validated against the data, including consistency in predictions of single tumor growth when no secondary tumor was present. This theory may also shed new light on single cancer growth insofar as it offers a biologically translatable picture of how local and global action may combine to control local tumor growth and, in particular, the role of tumor-tumor inhibition. This model offers a depiction of concomitant resistance that provides an improved theoretical basis for tumor growth control and may also find utility in therapeutic planning to avoid postsurgery metastatic acceleration. Cancer Res; 77(18); 5183-93. ©2017 AACR . ©2017 American Association for Cancer Research.

  15. HPV-E7 delivered by engineered exosomes elicits a protective CD8⁺ T cell-mediated immune response.

    Science.gov (United States)

    Di Bonito, Paola; Ridolfi, Barbara; Columba-Cabezas, Sandra; Giovannelli, Andrea; Chiozzini, Chiara; Manfredi, Francesco; Anticoli, Simona; Arenaccio, Claudia; Federico, Maurizio

    2015-03-09

    We developed an innovative strategy to induce a cytotoxic T cell (CTL) immune response against protein antigens of choice. It relies on the production of exosomes, i.e., nanovesicles spontaneously released by all cell types. We engineered the upload of huge amounts of protein antigens upon fusion with an anchoring protein (i.e., HIV-1 Nefmut), which is an inactive protein incorporating in exosomes at high levels also when fused with foreign proteins. We compared the immunogenicity of engineered exosomes uploading human papillomavirus (HPV)-E7 with that of lentiviral virus-like particles (VLPs) incorporating equivalent amounts of the same antigen. These exosomes, whose limiting membrane was decorated with VSV-G, i.e., an envelope protein inducing pH-dependent endosomal fusion, proved to be as immunogenic as the cognate VLPs. It is noteworthy that the immunogenicity of the engineered exosomes remained unaltered in the absence of VSV-G. Most important, we provide evidence that the inoculation in mouse of exosomes uploading HPV-E7 induces production of anti-HPV E7 CTLs, blocks the growth of syngeneic tumor cells inoculated after immunization, and controls the development of tumor cells inoculated before the exosome challenge. These results represent the proof-of-concept about both feasibility and efficacy of the Nefmut-based exosome platform for the induction of CD8+ T cell immunity.

  16. Datamining approaches for modeling tumor control probability.

    Science.gov (United States)

    Naqa, Issam El; Deasy, Joseph O; Mu, Yi; Huang, Ellen; Hope, Andrew J; Lindsay, Patricia E; Apte, Aditya; Alaly, James; Bradley, Jeffrey D

    2010-11-01

    Tumor control probability (TCP) to radiotherapy is determined by complex interactions between tumor biology, tumor microenvironment, radiation dosimetry, and patient-related variables. The complexity of these heterogeneous variable interactions constitutes a challenge for building predictive models for routine clinical practice. We describe a datamining framework that can unravel the higher order relationships among dosimetric dose-volume prognostic variables, interrogate various radiobiological processes, and generalize to unseen data before when applied prospectively. Several datamining approaches are discussed that include dose-volume metrics, equivalent uniform dose, mechanistic Poisson model, and model building methods using statistical regression and machine learning techniques. Institutional datasets of non-small cell lung cancer (NSCLC) patients are used to demonstrate these methods. The performance of the different methods was evaluated using bivariate Spearman rank correlations (rs). Over-fitting was controlled via resampling methods. Using a dataset of 56 patients with primary NCSLC tumors and 23 candidate variables, we estimated GTV volume and V75 to be the best model parameters for predicting TCP using statistical resampling and a logistic model. Using these variables, the support vector machine (SVM) kernel method provided superior performance for TCP prediction with an rs=0.68 on leave-one-out testing compared to logistic regression (rs=0.4), Poisson-based TCP (rs=0.33), and cell kill equivalent uniform dose model (rs=0.17). The prediction of treatment response can be improved by utilizing datamining approaches, which are able to unravel important non-linear complex interactions among model variables and have the capacity to predict on unseen data for prospective clinical applications.

  17. Co-delivery of PLGA encapsulated invariant NKT cell agonist with antigenic protein induce strong T cell-mediated antitumor immune responses

    NARCIS (Netherlands)

    Dolen, Y.; Kreutz, M.; Gileadi, U.; Tel, J.; Vasaturo, A.; Dinther, E.A.W. van; Hout-Kuijer, M.A. van; Cerundolo, V.; Figdor, C.G.

    2016-01-01

    Antitumor immunity can be enhanced by the coordinated release and delivery of antigens and immune-stimulating agents to antigen-presenting cells via biodegradable vaccine carriers. So far, encapsulation of TLR ligands and tumor-associated antigens augmented cytotoxic T cell (CTLs) responses. Here,

  18. Histone deacetylase inhibitor AR-42 enhances E7-specific CD8⁺ T cell-mediated antitumor immunity induced by therapeutic HPV DNA vaccination.

    Science.gov (United States)

    Lee, Sung Yong; Huang, Zhuomin; Kang, Tae Heung; Soong, Ruey-Shyang; Knoff, Jayne; Axenfeld, Ellen; Wang, Chenguang; Alvarez, Ronald D; Chen, Ching-Shih; Hung, Chien-Fu; Wu, T-C

    2013-10-01

    We have previously created a potent DNA vaccine encoding calreticulin linked to the human papillomavirus (HPV) oncogenic protein E7 (CRT/E7). While treatment with the CRT/E7 DNA vaccine generates significant tumor-specific immune responses in vaccinated mice, the potency with the DNA vaccine could potentially be improved by co-administration of a histone deacetylase inhibitor (HDACi) as HDACi has been shown to increase the expression of MHC class I and II molecules. Thus, we aimed to determine whether co-administration of a novel HDACi, AR-42, with therapeutic HPV DNA vaccines could improve the activation of HPV antigen-specific CD8(+) T cells, resulting in potent therapeutic antitumor effects. To do so, HPV-16 E7-expressing murine TC-1 tumor-bearing mice were treated orally with AR-42 and/or CRT/E7 DNA vaccine via gene gun. Mice were monitored for E7-specific CD8(+) T cell immune responses and antitumor effects. TC-1 tumor-bearing mice treated with AR-42 and CRT/E7 DNA vaccine experienced longer survival, decreased tumor growth, and enhanced E7-specific immune response compared to mice treated with AR-42 or CRT/E7 DNA vaccine alone. Additionally, treatment of TC-1 cells with AR-42 increased the surface expression of MHC class I molecules and increased the susceptibility of tumor cells to the cytotoxicity of E7-specific T cells. This study indicates the ability of AR-42 to significantly enhance the potency of the CRT/E7 DNA vaccine by improving tumor-specific immune responses and antitumor effects. Both AR-42 and CRT/E7 DNA vaccines have been used in independent clinical trials; the current study serves as foundation for future clinical trials combining both treatments in cervical cancer therapy. AR-42, a novel HDAC inhibitor, enhances potency of therapeutic HPV DNA vaccines AR-42 treatment leads to strong E7-specific CD8+ T cell immune responses AR-42 improves tumor-specific immunity and antitumor effects elicited by HPV DNA vaccine AR-42 is more potent than

  19. Histone Deacetylase Inhibitor AR-42 Enhances E7-Specific CD8+ T Cell-Mediated Antitumor Immunity Induced by Therapeutic HPV DNA Vaccination

    OpenAIRE

    Lee, Sung Yong; Huang, Zhuomin; Kang, Tae Heung; Soong, Ruey-Shyang; Knoff, Jayne; Axenfeld, Ellen; Wang, Chenguang; Alvarez, Ronald D.; Chen, Ching-Shih; Hung, Chien-Fu; Wu, T.-C.

    2013-01-01

    We have previously created a potent DNA vaccine encoding calreticulin linked to the HPV oncogenic protein E7 (CRT/E7). While treatment of the CRT/E7 DNA vaccine generates significant tumor-specific immune responses in vaccinated mice, the potency of the DNA vaccine could potentially be improved by co-administration of a histone deacetylase inhibitor (HDACi) as HDACi have been shown to increase the expression of MHC class I and II molecules. Thus, we aimed to determine whether co-administratio...

  20. Cancer immunotherapy in a neglected population: The current use and future of T-cell-mediated checkpoint inhibitors in organ transplant patients.

    Science.gov (United States)

    Chae, Young Kwang; Galvez, Carlos; Anker, Jonathan F; Iams, Wade T; Bhave, Manali

    2018-02-01

    Although the indications for immune checkpoint inhibitors continue to grow, organ transplant recipients with advanced malignancies have been largely excluded from clinical trials testing the safety and efficacy of these therapies given their need for chronic immunosuppression and the risk of allograft rejection. With the rapid growth of transplant medicine and the increased risk of malignancy associated with chronic immunosuppression, it is critical that we systematically analyze the available data describing immune checkpoint blockade in the organ transplant population. Herein we provide a current and comprehensive review of cases in which immune checkpoint blockade was used on organ transplant recipients. Furthermore, we discuss the differences in efficacy and risk of allograft rejection between CTLA-4 and PD-1 inhibitors and make recommendations based on the limited available clinical data. We also discuss the future of immune checkpoint blockade in this subpopulation and explore the emerging data of promising combination therapies with mTOR, BRAF/MEK, and BTK/ITK inhibitors. Further clinical experience and larger clinical trials involving immune checkpoint inhibitors, whether as monotherapies or combinatorial therapies, will help develop regimens that optimize anti-tumor response and minimize the risk of allograft rejection in organ transplant patients. Copyright © 2017. Published by Elsevier Ltd.

  1. Single and 30 fraction tumor control doses correlate in xenografted tumor models: implications for predictive assays

    International Nuclear Information System (INIS)

    Gerweck, Leo E.; Dubois, Willum; Baumann, Michael; Suit, Herman D.

    1995-01-01

    Purpose/Objective: In a previous publication we reported that laboratory assays of tumor clonogen number, in combination with intrinsic radiosensitivity measured in-vitro, accurately predicted the rank-order of single fraction 50% tumor control doses, in six rodent and xenografted human tumors. In these studies, tumor hypoxia influenced the absolute value of the tumor control doses across tumor types, but not their rank-order. In the present study we hypothesize that determinants of the single fraction tumor control dose, may also strongly influence the fractionaled tumor control doses, and that knowledge of tumor clonogen number and their sensitivity to fractionated irradiation, may be useful for predicting the relative sensitivity of tumors treated by conventional fractionated irradiation. Methods/Materials: Five tumors of human origin were used for these studies. Special care was taken to ensure that all tumor control dose assays were performed over the same time frame, i.e., in-vitro cells of a similar passage were used to initiate tumor sources which were expanded and used in the 3rd or 4th generation. Thirty fraction tumor control doses were performed in air breathing mice, under normal blood flow conditions (two fractions/day). The results of these studies have been previously published. For studies under uniformly (clamp) hypoxic conditions, tumors arising from the same transplantation were randomized into single or fractionated dose protocols. For estimation of the fractionated TCD50 under hypoxic conditions, tumors were exposed to six 5.4 Gy fractions (∼ 2 Gy equivalent under air), followed by graded 'top-up' dose irradiation for determination of the TCD50; the time interval between doses was 6-9 hours. The single dose equivalent of the six 5.4 Gy doses was used to calculate an extrapolated 30 fraction hypoxic TCD50. Results: Fractionation substantially increased the dose required for tumor control in 4 of the 5 tumors investigated. For these 4 tumors

  2. Mathematical models of tumor growth: translating absorbed dose to tumor control probability

    International Nuclear Information System (INIS)

    Sgouros, G.

    1996-01-01

    cell loss due to irradiation, the log-kill model, therefore, predicts that incomplete treatment of a kinetically heterogeneous tumor will yield a more proliferative tumor. The probability of tumor control in such a simulation may be obtained from the nadir in tumor cell number. If the nadir is not sufficiently low to yield a high probability of tumor control, then the tumor will re-grow. Since tumors in each sub-population are assumed lost at the same rate, cells comprising the sub-population with the shortest potential doubling time will re-grow the fastest, yielding a recurrent tumor that is more proliferative. A number of assumptions and simplifications are both implicitly and explicitly made in converting absorbed dose to tumor control probability. The modeling analyses described above must, therefore, be viewed in terms of understanding and evaluating different treatment approaches with the goal of treatment optimization rather than outcome prediction

  3. T-cell-mediated immune response to pneumococcal conjugate vaccine (PCV-13) and tetanus toxoid vaccine in patients with moderate-to-severe psoriasis during tofacitinib treatment.

    Science.gov (United States)

    Winthrop, Kevin L; Korman, Neil; Abramovits, William; Rottinghaus, Scott T; Tan, Huaming; Gardner, Annie; Mukwaya, Geoffrey; Kaur, Mandeep; Valdez, Hernan

    2018-03-01

    Psoriasis is often treated with immunomodulatory therapies that can affect the immune response to common antigens. Tofacitinib is an oral Janus kinase inhibitor. To characterize the effect of long-term exposure to tofacitinib 10 mg twice daily on T-cell function in psoriasis patients. Patients completing at least 3 months' continuous treatment with tofacitinib 10 mg twice daily were vaccinated with T-cell-dependent vaccines (monovalent tetanus toxoid and 13-valent pneumococcal conjugate [PCV-13]). Patients were assessed at baseline (before vaccination) and then again 4 weeks after vaccination. For PCV-13, we evaluated serotype-specific, opsonophagocytic antibody responses, and for tetanus toxoid, we evaluated humoral responses. Among 60 patients who completed the study, the geometric mean fold rise from baseline for the 13 PCV serotypes at 4 weeks postvaccination varied from 8.3 (serotype 3) to 101.9 (serotype 6A). Similar results were observed for patients with and without lymphopenia at baseline. For tetanus toxoid, 51 (88%) patients had ≥2-fold and 35 (60%) patients had ≥4-fold rise in antibody concentration. There was no placebo control. Most psoriasis patients who receive tofacitinib can mount satisfactory T-cell-dependent responses to PCV-13 and tetanus vaccines. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  4. CD4+ T cell-mediated cytotoxicity is associated with MHC class II expression on malignant CD19+ B cells in diffuse large B cell lymphoma.

    Science.gov (United States)

    Zhou, Yong; Zha, Jie; Lin, Zhijuan; Fang, Zhihong; Zeng, Hanyan; Zhao, Jintao; Luo, Yiming; Li, Zhifeng; Xu, Bing

    2018-01-15

    Diffuse large B cell lymphoma (DLBCL) is a common B cell malignancy with approximately 30% of patients present relapsed or refractory disease after first-line therapy. Research of further treatment options is needed. Cytotoxic CD4 + T cells express cytolytic molecules and have potential antitumor function. Here, we showed that the CD19 + cells from DLBCL patients presented significantly reduced expression of MHC II molecules than those from healthy controls. Three years after the first-line treatment, patients that presented relapsed disease had significantly lower MHC II expression on their CD19 + cells than patients who did not show recurrence. Examining cytotoxic CD4 + T cells show that DLBCL patients presented significantly elevated frequencies of granzyme A-, granzyme B-, and/or perforin-expressing cytotoxic CD4 + T cells. Also, frequency of cytotoxic CD4 + T cells in DLBCL patients was positively correlated with the MHC II expression level. Subsequently, the cytotoxic potential of CD4 + T cells against autologous CD19 + cells was investigated. We found that the cytotoxic potential of CD4 + T cells was highest in MHC II-high, intermediate in MHC II-mid, and lowest in MHC II-low patients. The percentage of MHC II-expressing viable CD19 + cells presented a significant reduction after longer incubation with cytotoxic CD4 + T cells, suggesting that cytotoxic CD4 + T cells preferentially eliminated MHC II-expressing CD19 + cells. Blocking MHC II on CD19 + cells significantly reduced the cytolytic capacity of CD4 + T cells. Despite these discoveries, the frequency of cytotoxic CD4 + T cells did not predict the clinical outcome of DLBCL patients. Together, these results demonstrated that cytotoxic CD4 + T cells presented an MHC II-dependent cytotoxic potential against autologous CD19 + cells and could potentially represent a future treatment option for DLBCL. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. In vivo targeting of human DC-SIGN drastically enhances CD8⁺ T-cell-mediated protective immunity.

    Science.gov (United States)

    Hesse, Christina; Ginter, Wiebke; Förg, Theresa; Mayer, Christian T; Baru, Abdul Mannan; Arnold-Schrauf, Catharina; Unger, Wendy W J; Kalay, Hakan; van Kooyk, Yvette; Berod, Luciana; Sparwasser, Tim

    2013-10-01

    Vaccination is one of the oldest yet still most effective methods to prevent infectious diseases. However, eradication of intracellular pathogens and treatment of certain diseases like cancer requiring efficient cytotoxic immune responses remain a medical challenge. In mice, a successful approach to induce strong cytotoxic CD8⁺ T-cell (CTL) reactions is to target antigens to DCs using specific antibodies against surface receptors in combination with adjuvants. A major drawback for translating this strategy into one for the clinic is the lack of analogous targets in human DCs. DC-SIGN (DC-specific-ICAM3-grabbing-nonintegrin/CD209) is a C-type lectin receptor with potent endocytic capacity and a highly restricted expression on human immature DCs. Therefore, DC-SIGN represents an ideal candidate for DC targeting. Using transgenic mice that express human DC-SIGN under the control of the murine CD11c promoter (hSIGN mice), we explored the efficacy of anti-DC-SIGN antibodies to target antigens to DCs and induce protective immune responses in vivo. We show that anti-DC-SIGN antibodies conjugated to OVA induced strong and persistent antigen-specific CD4⁺ and CD8⁺ T-cell responses, which efficiently protected from infection with OVA-expressing Listeria monocytogenes. Thus, we propose DC targeting via DC-SIGN as a promising strategy for novel vaccination protocols against intracellular pathogens. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. HIV-1 adenoviral vector vaccines expressing multi-trimeric BAFF and 4-1BBL enhance T cell mediated anti-viral immunity.

    Directory of Open Access Journals (Sweden)

    Saravana Kanagavelu

    Full Text Available Adenoviral vectored vaccines have shown considerable promise but could be improved by molecular adjuvants. Ligands in the TNF superfamily (TNFSF are potential adjuvants for adenoviral vector (Ad5 vaccines based on their central role in adaptive immunity. Many TNFSF ligands require aggregation beyond the trimeric state (multi-trimerization for optimal biological function. Here we describe Ad5 vaccines for HIV-1 Gag antigen (Ad5-Gag adjuvanted with the TNFSF ligands 4-1BBL, BAFF, GITRL and CD27L constructed as soluble multi-trimeric proteins via fusion to Surfactant Protein D (SP-D as a multimerization scaffold. Mice were vaccinated with Ad5-Gag combined with Ad5 expressing one of the SP-D-TNFSF constructs or single-chain IL-12p70 as adjuvant. To evaluate vaccine-induced protection, mice were challenged with vaccinia virus expressing Gag (vaccinia-Gag which is known to target the female genital tract, a major route of sexually acquired HIV-1 infection. In this system, SP-D-4-1BBL or SP-D-BAFF led to significantly reduced vaccinia-Gag replication when compared to Ad5-Gag alone. In contrast, IL-12p70, SP-D-CD27L and SP-D-GITRL were not protective. Histological examination following vaccinia-Gag challenge showed a dramatic lymphocytic infiltration into the uterus and ovaries of SP-D-4-1BBL and SP-D-BAFF-treated animals. By day 5 post challenge, proinflammatory cytokines in the tissue were reduced, consistent with the enhanced control over viral replication. Splenocytes had no specific immune markers that correlated with protection induced by SP-D-4-1BBL and SP-D-BAFF versus other groups. IL-12p70, despite lack of anti-viral efficacy, increased the total numbers of splenic dextramer positive CD8+ T cells, effector memory T cells, and effector Gag-specific CD8+ T cells, suggesting that these markers are poor predictors of anti-viral immunity in this model. In conclusion, soluble multi-trimeric 4-1BBL and BAFF adjuvants led to strong protection from

  7. Tumorer

    DEFF Research Database (Denmark)

    Prause, J.U.; Heegaard, S.

    2005-01-01

    oftalmologi, øjenlågstumorer, conjunctivale tumorer, malignt melanom, retinoblastom, orbitale tumorer......oftalmologi, øjenlågstumorer, conjunctivale tumorer, malignt melanom, retinoblastom, orbitale tumorer...

  8. Epigenetic control of the tumor microenvironment

    Science.gov (United States)

    Marks, David L; Olson, Rachel LO; Fernandez-Zapico, Martin E

    2016-01-01

    Stromal cells of the tumor microenvironment have been shown to play important roles in both supporting and limiting cancer growth. The altered phenotype of tumor-associated stromal cells (fibroblasts, immune cells, endothelial cells etc.) is proposed to be mainly due to epigenetic dysregulation of gene expression; however, only limited studies have probed the roles of epigenetic mechanisms in the regulation of stromal cell function. We review recent studies demonstrating how specific epigenetic mechanisms (DNA methylation and histone post-translational modification-based gene expression regulation, and miRNA-mediated translational regulation) drive aspects of stromal cell phenotype, and discuss the implications of these findings for treatment of malignancies. We also summarize the effects of epigenetic mechanism-targeted drugs on stromal cells and discuss the consideration of the microenvironment response in attempts to use these drugs for cancer treatment. PMID:27700179

  9. Resident Bacteria-Stimulated Interleukin-10-Secreting B Cells Ameliorate T-Cell-Mediated Colitis by Inducing T-Regulatory-1 Cells That Require Interleukin-27 SignalingSummary

    Directory of Open Access Journals (Sweden)

    Yoshiyuki Mishima

    2015-05-01

    Full Text Available Background & Aims: The regulatory roles of interleukin-10 (IL10-producing B cells in colitis are not fully understood, so we explored the molecular mechanisms by which these cells modulate mucosal homeostasis. Methods: CD4+ T cells from wild-type (WT, Il10−/−, or Il27ra−/− mice were cotransferred with B cells from specific pathogen-free (SPF or germ-free (GF WT or Il10−/− mice into Rag2−/−Il10−/−(double-knockout mice, and the severity of colitis and intestinal regulatory T-cell populations were characterized. In vitro, WT or Il10−/− B cells were cocultured with unfractionated, naïve or regulatory T cells plus Il10−/− antigen-presenting cells and stimulated with cecal bacterial lysate (CBL with or without IL27 or anti-IL10R blockade. Gene expressions, cytokines in the supernatant and cell populations were assessed. Results: WT but not Il10−/− B cells attenuated T helper cell TH1/TH17-mediated colitis in double-knockout mice that also received WT but not Il10−/− T cells. In vitro, CBL-stimulated WT B cells secrete abundant IL10 and suppress interferon-γ (IFNγ and IL17a-production by T cells without requiring cell contact. Although both WT and Il10−/− B cells induced Foxp3+CD4+ T-regulatory cells, only WT B cells induced IL10-producing (Foxp3-negative T regulatory-1 (Tr-1 cells both in vivo and in vitro. However, IL10-producing B cells did not attenuate colitis or induce Tr-1 cells in the absence of T cell IL27 signaling in vivo. WT B cell-dependent Tr-1 induction and concomitant decreased IFNγ-secretion were also mediated by T-cell IL27-signaling in vitro. Conclusions: IL10-secreting B cells activated by physiologically relevant bacteria ameliorate T-cell-mediated colitis and contribute to intestinal homeostasis by suppressing effector T cells and inducing Tr-1 cells via IL27-signaling on T cells. Keywords: Experimental

  10. Factors affecting the local control of stereotactic body radiotherapy for lung tumors including primary lung cancer and metastatic lung tumors

    International Nuclear Information System (INIS)

    Hamamoto, Yasushi; Kataoka, Masaaki; Yamashita, Motohiro

    2012-01-01

    The purpose of this study was to identify factors affecting local control of stereotactic body radiotherapy (SBRT) for lung tumors including primary lung cancer and metastatic lung tumors. Between June 2006 and June 2009, 159 lung tumors in 144 patients (primary lung cancer, 128; metastatic lung tumor, 31) were treated with SBRT with 48-60 Gy (mean 50.1 Gy) in 4-5 fractions. Higher doses were given to larger tumors and metastatic tumors in principle. Assessed factors were age, gender, tumor origin (primary vs. metastatic), histological subtype, tumor size, tumor appearance (solid vs. ground glass opacity), maximum standardized uptake value of positron emission tomography using 18 F-fluoro-2-deoxy-D-glucose, and SBRT doses. Follow-up time was 1-60 months (median 18 months). The 1-, 2-, and 3-year local failure-free rates of all lesions were 90, 80, and 77%, respectively. On univariate analysis, metastatic tumors (p<0.0001), solid tumors (p=0.0246), and higher SBRT doses (p=0.0334) were the statistically significant unfavorable factors for local control. On multivariate analysis, only tumor origin was statistically significant (p=0.0027). The 2-year local failure-free rates of primary lung cancer and metastatic lung tumors were 87 and 50%, respectively. A metastatic tumor was the only independently significant unfavorable factor for local control after SBRT. (author)

  11. Bacteriophages support anti-tumor response initiated by DC-based vaccine against murine transplantable colon carcinoma.

    Science.gov (United States)

    Pajtasz-Piasecka, Elzbieta; Rossowska, Joanna; Duś, Danuta; Weber-Dabrowska, Beata; Zabłocka, Agnieszka; Górski, Andrzej

    2008-02-15

    Bacteriophages in eukaryotic hosts may behave as particulate antigens able to activate the innate immune system and generate adaptive immunity. Dendritic cells (DCs) play a key role in the initiation of the immune response, mainly by priming T cell-mediated immunity. For this reason, they are increasingly applied as an adjuvant for effective anti-tumor therapies in animal models as well as in a few clinical trials. The presented study focused on the application of mouse DCs which were activated with T4 bacteriophages (T4 phages, T4) and further loaded with tumor antigens (TAg) in inducing an anti-tumor response. The activation of bone marrow-derived DCs with T4 phages and TAg resulted in augmentation of their differentiation marker expression accompanied by an enhanced ability to prime T cells for IFN-gamma production. These activated DCs (BM-DC/T4+TAg) were used in experimental immunotherapy of C57BL/6 mice bearing advanced MC38 colon carcinoma tumors. As a result of their triple application, a significant tumor growth delay, up to 19 days, was observed compared with the controls - treated with BM-DCs activated only with T4 phages, TAg, or lipopolysaccharide solution ["solvent"], where the tumor growth delay did not exceed 7 days. The percentage of tumor growth inhibition estimated 10 days after the third cell injection ranged from 32% (for animals treated with BM-DC/TAg cells) to 76% (for animals treated with BM-DC/T4+TAg cells) over the tumor-bearing untreated control mice. The obtained data indicate that in vitro interactions between T4 phages and BM-DCs followed by TAg activation caused augmentation of the anti-tumor effect when DCs were used as a vaccine for tumor-bearing mice treatment. Therefore, pretreatment of DCs with the phages may be considered as a beneficial element of a novel strategy in anti-tumor immunotherapy.

  12. p53-Mediated Molecular Control of Autophagy in Tumor Cells

    Directory of Open Access Journals (Sweden)

    Maria Mrakovcic

    2018-03-01

    Full Text Available Autophagy is an indispensable mechanism of the eukaryotic cell, facilitating the removal and renewal of cellular components and thereby balancing the cell’s energy consumption and homeostasis. Deregulation of autophagy is now regarded as one of the characteristic key features contributing to the development of tumors. In recent years, the suppression of autophagy in combination with chemotherapeutic treatment has been approached as a novel therapy in cancer treatment. However, depending on the type of cancer and context, interference with the autophagic machinery can either promote or disrupt tumorigenesis. Therefore, disclosure of the major signaling pathways that regulate autophagy and control tumorigenesis is crucial. To date, several tumor suppressor proteins and oncogenes have emerged as eminent regulators of autophagy whose depletion or mutation favor tumor formation. The mammalian cell “janitor” p53 belongs to one of these tumor suppressors that are most commonly mutated in human tumors. Experimental evidence over the last decade convincingly reports that p53 can act as either an activator or an inhibitor of autophagy depending on its subcellular localization and its mode of action. This finding gains particular significance as p53 deficiency or mutant variants of p53 that accumulate in the cytoplasm of tumor cells enable activation of autophagy. Accordingly, we recently identified p53 as a molecular hub that regulates autophagy and apoptosis in histone deacetylase inhibitor-treated uterine sarcoma cells. In light of this novel experimental evidence, in this review, we focus on p53 signaling as a mediator of the autophagic pathway in tumor cells.

  13. Ontak reduces the immunosuppressive tumor environment and enhances successful therapeutic vaccination in HER-2/neu-tolerant mice.

    Science.gov (United States)

    Gritzapis, Angelos D; Voutsas, Ioannis F; Baxevanis, Constantin N

    2012-03-01

    Disrupting tumor-mediated mechanisms suppressing host immunity represents a novel approach to tumor immunotherapy. Depletion of regulatory T cells (Tregs) increases endogenous anti-tumor immunity and the efficacy of active immunotherapy in experimental tumor models. HLA-A2.1/HLA-DR1 (A2.1/DR1) × BALB- neuT+ (neuT+) triple transgenic mice represent an improvement over neuT+ mice for evaluating vaccination regimens to overcome tolerance against HER-2/neu. We questioned whether depletion of Tregs with Denileukin diftitox (Ontak) enhances the efficacy of a therapeutic vaccine consisting of HER-2(85-94) (p85) CTL and HER-2(776-790) (p776) Th peptides against the growth of TUBO.A2 transplantable tumor in male A2.1/DR1 × neuT+ Tg mice. While the therapeutic vaccine primed the tumor-reactive CD8+ CTLs and CD4+ effector T lymphocytes (Teffs) compartment, inducing activation, tumor infiltration, and tumor rejection or delay in tumor growth, treatment with Ontak 1 day prior to vaccination resulted in enhanced CD4+ and CD8+ T-cell-mediated vaccine-specific immune responses in the periphery. This was closely associated with greater infiltration and a striking change in the intratumor balance of Tregs and vaccine-specific CTLs/Teffs that directly correlated with markedly enhanced antitumor activity. The data suggest that Tregs control both CD4+ and CD8+ T-cell activity within the tumor, emphasize the importance of the intratumor ratio of vaccine-specific lymphocytes to Tregs, and demonstrate significant inversion of this ratio and correlation with tumor rejection during Ontak/vaccine immunotherapy.

  14. Adoptively transferred human lung tumor specific cytotoxic T cells can control autologous tumor growth and shape tumor phenotype in a SCID mouse xenograft model

    Directory of Open Access Journals (Sweden)

    Ferrone Soldano

    2007-06-01

    Full Text Available Abstract Background The anti-tumor efficacy of human immune effector cells, such as cytolytic T lymphocytes (CTLs, has been difficult to study in lung cancer patients in the clinical setting. Improved experimental models for the study of lung tumor-immune cell interaction as well as for evaluating the efficacy of adoptive transfer of immune effector cells are needed. Methods To address questions related to the in vivo interaction of human lung tumor cells and immune effector cells, we obtained an HLA class I + lung tumor cell line from a fresh surgical specimen, and using the infiltrating immune cells, isolated and characterized tumor antigen-specific, CD8+ CTLs. We then established a SCID mouse-human tumor xenograft model with the tumor cell line and used it to study the function of the autologous CTLs provided via adoptive transfer. Results The tumor antigen specific CTLs isolated from the tumor were found to have an activated memory phenotype and able to kill tumor cells in an antigen specific manner in vitro. Additionally, the tumor antigen-specific CTLs were fully capable of homing to and killing autologous tumors in vivo, and expressing IFN-γ, each in an antigen-dependent manner. A single injection of these CTLs was able to provide significant but temporary control of the growth of autologous tumors in vivo without the need for IL-2. The timing of injection of CTLs played an essential role in the outcome of tumor growth control. Moreover, immunohistochemical analysis of surviving tumor cells following CTL treatment indicated that the surviving tumor cells expressed reduced MHC class I antigens on their surface. Conclusion These studies confirm and extend previous studies and provide additional information regarding the characteristics of CTLs which can be found within a patient's tumor. Moreover, the in vivo model described here provides a unique window for observing events that may also occur in patients undergoing adoptive cellular

  15. Baroreflex control of muscle sympathetic nerve activity after carotid body tumor resection

    NARCIS (Netherlands)

    Timmers, Henri J. L. M.; Karemaker, John M.; Wieling, Wouter; Marres, Henri A. M.; Lenders, Jacques W. M.

    2003-01-01

    Bilateral carotid body tumor resection causes a permanent attenuation of vagal baroreflex sensitivity. We retrospectively examined the effects of bilateral carotid body tumor resection on the baroreflex control of sympathetic nerve traffic. Muscle sympathetic nerve activity was recorded in 5

  16. Antitumor immunization of mothers delays tumor development in cancer-prone offspring.

    Science.gov (United States)

    Barutello, Giuseppina; Curcio, Claudia; Spadaro, Michela; Arigoni, Maddalena; Trovato, Rosalinda; Bolli, Elisabetta; Zheng, Yujuan; Ria, Francesco; Quaglino, Elena; Iezzi, Manuela; Riccardo, Federica; Holmgren, Lars; Forni, Guido; Cavallo, Federica

    2015-05-01

    Maternal immunization is successfully applied against some life-threatening infectious diseases as it can protect the mother and her offspring through the passive transfer of maternal antibodies. Here, we sought to evaluate whether the concept of maternal immunization could also be applied to cancer immune-prevention. We have previously shown that antibodies induced by DNA vaccination against rat Her2 (neu) protect heterozygous neu-transgenic female (BALB-neuT) mice from autochthonous mammary tumor development. We, herein, seek to evaluate whether a similar maternal immunization can confer antitumor protection to BALB-neuT offspring. Significantly extended tumor-free survival was observed in BALB-neuT offspring born and fed by mothers vaccinated against neu, as compared to controls. Maternally derived anti-neu immunoglobulin G (IgG) was successfully transferred from mothers to newborns and was responsible for the protective effect. Vaccinated mothers and offspring also developed active immunity against neu as revealed by the presence of T-cell-mediated cytotoxicity against the neu immunodominant peptide. This active response was due to the milk transfer of immune complexes that were formed between the neu extracellular domain, shed from vaccine-transfected muscle cells, and the anti-neu IgG induced by the vaccine. These findings show that maternal immunization has the potential to hamper mammary cancer in genetically predestinated offspring and to develop into applications against lethal neonatal cancer diseases for which therapeutic options are currently unavailable.

  17. Overcoming immunoescape mechanisms of BCL1 leukemia and induction of CD8+ T-cell-mediated BCK1-specific resistance in mice cured by targeted polymer-bound doxorubicin

    Czech Academy of Sciences Publication Activity Database

    Kovář, Marek; Tomala, Jakub; Chmelová, Helena; Kovář, Lubomír; Mrkvan, Tomáš; Josková, Radka; Zákostelská, Zuzana; Etrych, Tomáš; Strohalm, Jiří; Ulbrich, Karel; Šírová, Milada; Říhová, Blanka

    2008-01-01

    Roč. 68, č. 23 (2008), s. 9875-9883 ISSN 0008-5472 R&D Projects: GA MŠk 1M0505; GA ČR GP301/07/P192; GA ČR GD310/08/H077; GA AV ČR IAAX00500803 Institutional research plan: CEZ:AV0Z50200510; CEZ:AV0Z40500505 Keywords : tumor * bcl1 leukemia * doxorubicin Subject RIV: EC - Immunology Impact factor: 7.514, year: 2008

  18. Repopulation of interacting tumor cells during fractionated radiotherapy: stochastic modeling of the tumor control probability.

    Science.gov (United States)

    Fakir, Hatim; Hlatky, Lynn; Li, Huamin; Sachs, Rainer

    2013-12-01

    Optimal treatment planning for fractionated external beam radiation therapy requires inputs from radiobiology based on recent thinking about the "five Rs" (repopulation, radiosensitivity, reoxygenation, redistribution, and repair). The need is especially acute for the newer, often individualized, protocols made feasible by progress in image guided radiation therapy and dose conformity. Current stochastic tumor control probability (TCP) models incorporating tumor repopulation effects consider "stem-like cancer cells" (SLCC) to be independent, but the authors here propose that SLCC-SLCC interactions may be significant. The authors present a new stochastic TCP model for repopulating SLCC interacting within microenvironmental niches. Our approach is meant mainly for comparing similar protocols. It aims at practical generalizations of previous mathematical models. The authors consider protocols with complete sublethal damage repair between fractions. The authors use customized open-source software and recent mathematical approaches from stochastic process theory for calculating the time-dependent SLCC number and thereby estimating SLCC eradication probabilities. As specific numerical examples, the authors consider predicted TCP results for a 2 Gy per fraction, 60 Gy protocol compared to 64 Gy protocols involving early or late boosts in a limited volume to some fractions. In sample calculations with linear quadratic parameters α = 0.3 per Gy, α∕β = 10 Gy, boosting is predicted to raise TCP from a dismal 14.5% observed in some older protocols for advanced NSCLC to above 70%. This prediction is robust as regards: (a) the assumed values of parameters other than α and (b) the choice of models for intraniche SLCC-SLCC interactions. However, α = 0.03 per Gy leads to a prediction of almost no improvement when boosting. The predicted efficacy of moderate boosts depends sensitively on α. Presumably, the larger values of α are the ones appropriate for individualized

  19. Repopulation of interacting tumor cells during fractionated radiotherapy: Stochastic modeling of the tumor control probability

    International Nuclear Information System (INIS)

    Fakir, Hatim; Hlatky, Lynn; Li, Huamin; Sachs, Rainer

    2013-01-01

    Purpose: Optimal treatment planning for fractionated external beam radiation therapy requires inputs from radiobiology based on recent thinking about the “five Rs” (repopulation, radiosensitivity, reoxygenation, redistribution, and repair). The need is especially acute for the newer, often individualized, protocols made feasible by progress in image guided radiation therapy and dose conformity. Current stochastic tumor control probability (TCP) models incorporating tumor repopulation effects consider “stem-like cancer cells” (SLCC) to be independent, but the authors here propose that SLCC-SLCC interactions may be significant. The authors present a new stochastic TCP model for repopulating SLCC interacting within microenvironmental niches. Our approach is meant mainly for comparing similar protocols. It aims at practical generalizations of previous mathematical models. Methods: The authors consider protocols with complete sublethal damage repair between fractions. The authors use customized open-source software and recent mathematical approaches from stochastic process theory for calculating the time-dependent SLCC number and thereby estimating SLCC eradication probabilities. As specific numerical examples, the authors consider predicted TCP results for a 2 Gy per fraction, 60 Gy protocol compared to 64 Gy protocols involving early or late boosts in a limited volume to some fractions. Results: In sample calculations with linear quadratic parameters α = 0.3 per Gy, α/β = 10 Gy, boosting is predicted to raise TCP from a dismal 14.5% observed in some older protocols for advanced NSCLC to above 70%. This prediction is robust as regards: (a) the assumed values of parameters other than α and (b) the choice of models for intraniche SLCC-SLCC interactions. However, α = 0.03 per Gy leads to a prediction of almost no improvement when boosting. Conclusions: The predicted efficacy of moderate boosts depends sensitively on α. Presumably, the larger values of α are

  20. Radiotherapy alone in breast cancer. I. Analysis of tumor parameters, tumor dose and local control: the experience of the Gustave-Roussy Institute and the Princess Margaret Hospital

    International Nuclear Information System (INIS)

    Arriagada, R.; Mouriesse, H.; Sarrazin, D.; Clark, R.M.; Deboer, G.

    1985-01-01

    This retrospective study involved 463 breast cancer patients treated by radiotherapy alone at the Princess Margaret Hospital and at the Institut Gustave-Roussy. These patients either had operable tumors, but were unfit for general anesthesia, or had inoperable tumors due to local contraindications to surgery. Results were analyzed according to tumor response, local recurrence rate, tumor size, tumor fixation, nodal fixation and tumor dose. Conventional statistical analysis of local control showed two significant factors: tumor dose and tumor size. Multivariate analysis permitted to define an ''individual risk'' (IR) of local recurrence according to three independent factors: tumor size, tumor fixation, and nodal fixation. It was shown that the IR was a good prognostic factor for local control. Increase in tumor dose gave a similar effect in the local recurrence relative risk for all the IR groups. According to the slope of the dose-effect curve, it was deduced that a dose increase of 15 Gy can decrease the relative risk of local recurrence 2-fold. In fact, it was shown that tumor dose was the most significant independent factor on local control, able to produce up to a 10-fold increase compared to 2-fold decrease for tumor size. If the IR of local recurrence is known, a theoretical predictive value on local control, taking into account the tumor dose, can be determined according to the present data

  1. Tumor-specific chromosome mis-segregation controls cancer plasticity by maintaining tumor heterogeneity.

    Directory of Open Access Journals (Sweden)

    Yuanjie Hu

    Full Text Available Aneuploidy with chromosome instability is a cancer hallmark. We studied chromosome 7 (Chr7 copy number variation (CNV in gliomas and in primary cultures derived from them. We found tumor heterogeneity with cells having Chr7-CNV commonly occurs in gliomas, with a higher percentage of cells in high-grade gliomas carrying more than 2 copies of Chr7, as compared to low-grade gliomas. Interestingly, all Chr7-aneuploid cell types in the parental culture of established glioma cell lines reappeared in single-cell-derived subcultures. We then characterized the biology of three syngeneic glioma cultures dominated by different Chr7-aneuploid cell types. We found phenotypic divergence for cells following Chr7 mis-segregation, which benefited overall tumor growth in vitro and in vivo. Mathematical modeling suggested the involvement of chromosome instability and interactions among cell subpopulations in restoring the optimal equilibrium of tumor cell types. Both our experimental data and mathematical modeling demonstrated that the complexity of tumor heterogeneity could be enhanced by the existence of chromosomes with structural abnormality, in addition to their mis-segregations. Overall, our findings show, for the first time, the involvement of chromosome instability in maintaining tumor heterogeneity, which underlies the enhanced growth, persistence and treatment resistance of cancers.

  2. Tumor Hypoxia is Independent of Hemoglobin and Prognostic for Loco-regional Tumor Control after Primary Radiotherapy in Advanced Head and Neck Cancer

    International Nuclear Information System (INIS)

    Nordsmark, Marianne; Overgaard, Jens

    2004-01-01

    There is evidence that tumor hypoxia adversely affects loco-regional tumor control and survival in head and neck cancer. The aim of the current study was to compare pretreatment tumor oxygenation measured by Eppendorf pO2 electrodes with known prognostic factors in advanced head and neck tumors after definitive radiotherapy, and to evaluate the prognostic significance of these parameters on loco-regional tumor control. Sixty-seven patients, median age 56 years (22-82), all with primary stage III-IV squamous cell carcinoma were available for survival analysis. Tumor oxygenation was described as the fraction of pO2 values=2.5 mmHg (HP2.5) and the median tumor pO2. By regression analysis HP2.5 was independent of known prognostic factors including stage, pretreatment hemoglobin (Hb) and the largest tumor diameter at the site of pO2 measurement. By Kaplan-Meier analysis loco-regional tumor control at 5 years was in favor of less hypoxic tumors using either HP2.5 or median tumor pO2 as descriptors and stratifying by the median values. Also, Hb was prognostic of loco-regional tumor control at 5 years using the median value as cut off. HP2.5 as continuous parameter was highly significant for loco-regional tumor control in a multivariate analysis. In conclusion both HP2.5 and total Hb were prognostic for loco-regional tumor control, but HP2.5 as continuous variable was independently the strongest prognostic indicator for loco-regional tumor control after definitive primary radiotherapy in advanced head and neck tumors

  3. Loci controlling lymphocyte production of interferon gamma after alloantigen stimulation in vitro and their co-localization with genes controlling lymphocyte infiltration of tumors and tumor susceptibility

    Czech Academy of Sciences Publication Activity Database

    Lipoldová, Marie; Havelková, Helena; Badalová, Jana; Vojtíšková, Jarmila; Quan, L.; Krulová, Magdalena; Sohrabi, Yahya; Stassen, A. P. M.; Demant, P.

    2010-01-01

    Roč. 59, č. 2 (2010), s. 203-213 ISSN 0340-7004 R&D Projects: GA MŠk(CZ) LC06009; GA AV ČR IAA500520606; GA ČR GD310/08/H077 Institutional research plan: CEZ:AV0Z50520514 Keywords : Tumor susceptibility * Genetic control of interferon gamma production * Lymphocyte infiltration of tumors Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.293, year: 2010

  4. Inflammatory cytokine-mediated evasion of virus-induced tumors from NK cell control.

    Science.gov (United States)

    Mishra, Rabinarayan; Polic, Bojan; Welsh, Raymond M; Szomolanyi-Tsuda, Eva

    2013-07-15

    Infections with DNA tumor viruses, including members of the polyomavirus family, often result in tumor formation in immune-deficient hosts. The complex control involved in antiviral and antitumor immune responses during these infections can be studied in murine polyomavirus (PyV)-infected mice as a model. We found that NK cells efficiently kill cells derived from PyV-induced salivary gland tumors in vitro in an NKG2D (effector cell)-RAE-1 (target cell)-dependent manner; but in T cell-deficient mice, NK cells only delay but do not prevent the development of PyV-induced tumors. In this article, we show that the PyV-induced tumors have infiltrating functional NK cells. The freshly removed tumors, however, lack surface RAE-1 expression, and the tumor tissues produce soluble factors that downregulate RAE-1. These factors include the proinflammatory cytokines IL-1α, IL-1β, IL-33, and TNF. Each of these cytokines downregulates RAE-1 expression and susceptibility to NK cell-mediated cytotoxicity. CD11b(+)F4/80(+) macrophages infiltrating the PyV-induced tumors produce high amounts of IL-1β and TNF. Thus, our data suggest a new mechanism whereby inflammatory cytokines generated in the tumor environment lead to evasion of NK cell-mediated control of virus-induced tumors.

  5. Hemoglobin as a factor in the control of tumor oxygenation

    International Nuclear Information System (INIS)

    Hirst, D.G.

    1987-01-01

    The concentration of hemoglobin in the blood has been shown to have a market effect on the radiosensitivity of human and animal tumors. Experimental studies in mice indicate that radiosensitivity is influenced by a change in the hemoglobin level rather than by the absolute concentration. This dependence may be exploited to therapeutic advantage. Recent studies of hemoglobin/oxygen affinity have shown that the concentration of 2,3 diphosphoglycerate (2,3 DPG) affects tumor sensitivity to X-rays. Increased 2,3 DPG levels increase radiosensitivity in several mouse tumors. The time dependence of this effect remains to be established. The effective application of these effects in man may depend on the development of drugs which produce changes in hemoglobin affinity without the need for blood transfusions. Several drugs are currently being investigated

  6. Therapeutic profile of single-fraction radiosurgery of vestibular schwannoma: unrelated malignancy predicts tumor control.

    Science.gov (United States)

    Wowra, Berndt; Muacevic, Alexander; Fürweger, Christoph; Schichor, Christian; Tonn, Jörg-Christian

    2012-07-01

    Radiosurgery has become an accepted treatment option for vestibular schwannomas. Nevertheless, predictors of tumor control and treatment toxicity in current radiosurgery of vestibular schwannomas are not well understood. To generate new information on predictors of tumor control and cranial nerve toxicity of single-fraction radiosurgery of vestibular schwannomas, we conducted a single-institution long-term observational study of radiosurgery for sporadic vestibular schwannomas. Minimum follow-up was 3 years. Investigated as potential predictors of tumor control and cranial nerve toxicity were treatment technology; tumor resection preceding radiosurgery; tumor size; gender; patient age; history of cancer, vascular disease, or metabolic disease; tumor volume; radiosurgical prescription dose; and isodose line. Three hundred eighty-six patients met inclusion criteria. Treatment failure was observed in 27 patients. History of unrelated cancer (strongest predictor) and prescription dose significantly predicted tumor control. The cumulative incidence of treatment failure was 30% after 6.5 years in patients with unrelated malignancy and 10% after ≥15 years in patients without such cancer (P < .02). Tumor volume was the only predictor of trigeminal neuropathy (observed in 6 patients). No predictor of facial nerve toxicity was found. On the House and Brackmann scale, 1 patient had a permanent one-level drop and 7 a transient drop of 1 to 3 levels. Serviceable hearing was preserved in 75.1%. Tumor hearing before radiosurgery, recurrence, and prescription isodose predicted ototoxicity. Unrelated malignancy is a strong predictor of tumor control. Tumor recurrence predominantly predicts ototoxicity. These findings potentially will aid future clinical decision making in ambiguous cases.

  7. Gamma knife radiosurgery for acoustic neurinomas. Pt. 1. The analysis of tumor control

    International Nuclear Information System (INIS)

    Fukuoka, Seiji; Seo, Yoshinobu; Nakagawara, Jyoji

    1997-01-01

    Forty-three patients with the unilateral type of acoustic neurinoma who were treated with gamma knife radiosurgery were analyzed from the viewpoint of tumor control. The follow-up period ranged from 22 to 55 months. The tumors were treated with marginal radiation doses of 9-15 Gy with multiple isocenters. The actuarial tumor reduction rates were 42% at one year, 75% at 2 years, and 92% at 3 years after gamma knife radiosurgery. Transient tumor expansion was seen in 33% of patients, which correlated with previous surgical cases. The present control rate was 91%. SPECT was performed on 15 selected patients before and 1 year and 2 years after gamma knife radiosurgery. 201 TlCl SPECT was used to determine tumor viability, and the early and delayed 99m Tc-DTPA-HSA-D SPECT images were used to assess tumor vascularity and permeability, respectively. The Tl index and HSA-D index of the delayed images were not significantly different from the respective preoperative values. However, there was a statistically significant decrease in the HSA-D index of the early images 1 year after treatment. A statistically significant reduction in tumor volume was seen 2 years after treatment in these 15 patients, meaning that a reduction in tumor vascularity was followed by a reduction in tumor size. One patient underwent surgical excision of the tumor 18 months after gamma knife radiosurgery because the tumor had expanded and resulted in cerebellar ataxia. Histopathologic investigation revealed the presence of some tumor cells with irregularly shaped nuclei and marked intimal thickening or obliteration of the tumor vessels. (K.H.)

  8. Hypoxia-Inducible Factor Pathway Inhibition Resolves Tumor Hypoxia and Improves Local Tumor Control After Single-Dose Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Helbig, Linda [OncoRay–National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Koi, Lydia [OncoRay–National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Deutsches Konsortium für Translationale Krebsforschung, Site Dresden, Dresden (Germany); Brüchner, Kerstin [Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Institute of Radiooncology Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany); Gurtner, Kristin [Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Hess-Stumpp, Holger; Unterschemmann, Kerstin [Global Drug Discovery, Bayer Pharma, Berlin (Germany); Pruschy, Martin [Radiation Oncology, University of Zurich, Zurich (Switzerland); and others

    2014-01-01

    Purpose: To study the effects of BAY-84-7296, a novel orally bioavailable inhibitor of mitochondrial complex I and hypoxia-inducible factor 1 (HIF-1) activity, on hypoxia, microenvironment, and radiation response of tumors. Methods and Materials: UT-SCC-5 and UT-SCC-14 human squamous cell carcinomas were transplanted subcutaneously in nude mice. When tumors reached 4 mm in diameter BAY-84-7296 (Bayer Pharma AG) or carrier was daily administered to the animals. At 7 mm tumors were either excised for Western blot and immunohistologic investigations or were irradiated with single doses. After irradiation animals were randomized to receive BAY-84-7296 maintenance or carrier. Local tumor control was evaluated 150 days after irradiation, and the dose to control 50% of tumors (TCD{sub 50}) was calculated. Results: BAY-84-7296 decreased nuclear HIF-1α expression. Daily administration of inhibitor for approximately 2 weeks resulted in a marked decrease of pimonidazole hypoxic fraction in UT-SCC-5 (0.5% vs 21%, P<.0001) and in UT-SCC-14 (0.3% vs 19%, P<.0001). This decrease was accompanied by a significant increase in fraction of perfused vessels in UT-SCC-14 but not in UT-SCC-5. Bromodeoxyuridine and Ki67 labeling indices were significantly reduced only in UT-SCC-5. No significant changes were observed in vascular area or necrosis. BAY-84-7296 before single-dose irradiation significantly decreased TCD{sub 50}, with an enhancement ratio of 1.37 (95% confidence interval [CI] 1.13-1.72) in UT-SCC-5 and of 1.55 (95% CI 1.26-1.94) in UT-SCC-14. BAY-84-7296 maintenance after irradiation did not further decrease TCD{sub 50}. Conclusions: BAY-84-7296 resulted in a marked decrease in tumor hypoxia and substantially reduced radioresistance of tumor cells with the capacity to cause a local recurrence after irradiation. The data suggest that reduction of cellular hypoxia tolerance by BAY-84-7296 may represent the primary biological mechanism underlying the observed enhancement of

  9. Evidence of abnormal dopaminergic control of prolactin in patients with hypothalamic and pituitary tumors.

    Science.gov (United States)

    Cabranes, J A; Almoguera, I; del Olmo, J; Prensa, A; Pablos, I; Charro, A L

    1986-01-01

    Prolactin secretion was investigated in an attempt to identify the patterns of responses in different types of tumors. Forty four patients were studied: thirty patients with prolactinomas (Group 2); nine patients with growth-hormone (GH)-adrenocorticotropic hormone (ACTH)-secreting pituitary tumors and hypothalamic tumors (Group 3); and five patients with non-secreting pituitary tumors (Group 4). A control group (Group 1) consisted of 60 healthy subjects (30 males and 30 females). All were submitted to testing by nomifensine (Nom), domperidone (Dom) and thyrotropin releasing hormone (TRH). The prolactin levels were measured by radioimmunoassay (RIA). In group 2 the suppression of PRL with Nom and the stimulation with Dom and TRH were significantly lower than in the control group (p less than 0.001). There was no statistically significant difference between groups 2 and 3 in the suppression with Nom. The increase with Dom in group 3 was significantly greater than that in group 2 (p less than 0.001) and less than that in the control group (p less than 0.005). The rise in PRL with TRH was also significantly higher in group 3 than in group 2 (p less than 0.001) and similar to that of the control group. Group 4 gave the same results as the control group to all 3 tests. Our results indicate a dopaminergic irregularity in the hypothalamic and GH-ACTH-secreting pituitary tumors, thus supporting a hypothalamic etiopathogenesis of these tumors. The normality of the GH-ACTH-secreting pituitary tumors and hypothalamic tumor responses to TRH is one more factor in differentiating these from prolactinomas. The normal response of the non-secreting tumors may involve a primary pituitary etiology of these tumors.

  10. A switching control law approach for cancer immunotherapy of an evolutionary tumor growth model.

    Science.gov (United States)

    Doban, Alina I; Lazar, Mircea

    2017-02-01

    We propose a new approach for tumor immunotherapy which is based on a switching control strategy defined on domains of attraction of equilibria of interest. For this, we consider a recently derived model which captures the effects of the tumor cells on the immune system and viceversa, through predator-prey competition terms. Additionally, it incorporates the immune system's mechanism for producing hunting immune cells, which makes the model suitable for immunotherapy strategies analysis and design. For computing domains of attraction for the tumor nonlinear dynamics, and thus, for deriving immunotherapeutic strategies we employ rational Lyapunov functions. Finally, we apply the switching control strategy to destabilize an invasive tumor equilibrium and steer the system trajectories to tumor dormancy. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Towards Future T Cell-Mediated Influenza Vaccines

    Directory of Open Access Journals (Sweden)

    Thi H. O. Nguyen

    2016-04-01

    Full Text Available Influenza A virus (IAVs infections impact significantly on global health, being particularly problematic in children, the elderly, pregnant women, indigenous populations and people with co-morbidities. Antibody-based vaccines require annual administration to combat rapidly acquired mutations modifying the surface haemagglutinin (HA and neuraminidase (NA glycoproteins. Conversely, influenza-specific CD8+ T cell responses directed at peptides derived from the more conserved internal virus proteins are known to be protective, suggesting that T cell-based vaccines may provide long-lasting cross-protection. This review outlines the importance of CD8+ T cell immunity to seasonal influenza and pandemic IAVs and summarises current vaccination strategies for inducing durable CD8+ T cell memory. Aspects of future IAV vaccine design and the use of live virus challenge in humans to establish proof of principle are also discussed.

  12. T-cell mediated immunity in Wegener's granulomatosis

    NARCIS (Netherlands)

    Abdulahad, Wayel Habib

    2008-01-01

    Although the pathogenetic mechanisms involved in Wegener’s granulomatosis (WG) are not completely understood, considerable evidence support the concepts that activated T-cells play an important role in disease expression. It is, however, not clear which subsets of T-cells are involved in the

  13. Spontaneous T cell mediated keratoconjunctivitis in Aire-deficient mice

    Science.gov (United States)

    Yeh, S; de Paiva, C S; Hwang, C S; Trinca, K; Lingappan, A; Rafati, J K; Farley, W J; Li, D-Q; Pflugfelder, S C

    2013-01-01

    Background/aims Patients with autoimmune polyendocrinopathy-candiasis-ectodermal dystrophy (APECED) develop severe keratoconjunctivitis, corneal scarring and visual loss, but the precise pathogenesis is unknown. This study evaluated the ocular surface immune cell environment, conjunctival goblet cell density and response to desiccating environmental stress of the autoimmune regulatory (Aire) gene knockout murine model of APECED. Methods Aire-deficient and wild type (WT) mice were subjected to desiccating stress from a drafty, low-humidity environment and pharmacological inhibition of tear secretion for 5 days. Immune cell populations (CD4+, CD8+, CD11b+, CD45+) and goblet cell density were measured in ocular surface tissues and meibomian glands, and compared with baseline values. Results Greater CD4+ T cell populations were observed in the conjunctival epithelium of Aire-deficient mice (pAPECED. PMID:19429577

  14. SU-E-T-471: Improvement of Gamma Knife Treatment Planning Through Tumor Control Probability for Metastatic Brain Tumors

    International Nuclear Information System (INIS)

    Huang, Z; Feng, Y; Lo, S; Grecula, J; Mayr, N; Yuh, W

    2015-01-01

    Purpose: The dose–volume histogram (DVH) has been normally accepted as a tool for treatment plan evaluation. However, spatial information is lacking in DVH. As a supplement to the DVH in three-dimensional treatment planning, the differential DVH (DDVH) provides the spatial variation, the size and magnitude of the different dose regions within a region of interest, which can be incorporated into tumor control probability model. This study was to provide a method in evaluating and improving Gamma Knife treatment planning. Methods: 10 patients with brain metastases from different primary tumors including melanoma (#1,#4,#5, #10), breast cancer (#2), prostate cancer (#3) and lung cancer (#6–9) were analyzed. By using Leksell GammaPlan software, two plans were prepared for each patient. Special attention was given to the DDVHs that were different for different plans and were used for a comparison between two plans. Dose distribution inside target and tumor control probability (TCP) based on DDVH were calculated, where cell density and radiobiological parameters were adopted from literature. The plans were compared based on DVH, DDVH and TCP. Results: Using DVH, the coverage and selectivity were the same between plans for 10 patients. DDVH were different between two plans for each patient. The paired t-test showed no significant difference in TCP between the two plans. For brain metastases from melanoma (#1, #4–5), breast cancer (#2) and lung cancer (#6–8), the difference in TCP was less than 5%. But the difference in TCP was about 6.5% for patient #3 with the metastasis from prostate cancer, 10.1% and 178.7% for two patients (#9–10) with metastasis from lung cancer. Conclusion: Although DVH provides average dose–volume information, DDVH provides differential dose– volume information with respect to different regions inside the tumor. TCP provides radiobiological information and adds additional information on improving treatment planning as well as adaptive

  15. SU-E-T-471: Improvement of Gamma Knife Treatment Planning Through Tumor Control Probability for Metastatic Brain Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Z [East Carolina University, Greenville, NC (United States); Feng, Y [East Carolina Univ, Rockville, MD (United States); Lo, S [Case Western Reserve University, Cleveland, OH (United States); Grecula, J [Ohio State University, Columbus, OH (United States); Mayr, N; Yuh, W [University of Washington, Seattle, WA (United States)

    2015-06-15

    Purpose: The dose–volume histogram (DVH) has been normally accepted as a tool for treatment plan evaluation. However, spatial information is lacking in DVH. As a supplement to the DVH in three-dimensional treatment planning, the differential DVH (DDVH) provides the spatial variation, the size and magnitude of the different dose regions within a region of interest, which can be incorporated into tumor control probability model. This study was to provide a method in evaluating and improving Gamma Knife treatment planning. Methods: 10 patients with brain metastases from different primary tumors including melanoma (#1,#4,#5, #10), breast cancer (#2), prostate cancer (#3) and lung cancer (#6–9) were analyzed. By using Leksell GammaPlan software, two plans were prepared for each patient. Special attention was given to the DDVHs that were different for different plans and were used for a comparison between two plans. Dose distribution inside target and tumor control probability (TCP) based on DDVH were calculated, where cell density and radiobiological parameters were adopted from literature. The plans were compared based on DVH, DDVH and TCP. Results: Using DVH, the coverage and selectivity were the same between plans for 10 patients. DDVH were different between two plans for each patient. The paired t-test showed no significant difference in TCP between the two plans. For brain metastases from melanoma (#1, #4–5), breast cancer (#2) and lung cancer (#6–8), the difference in TCP was less than 5%. But the difference in TCP was about 6.5% for patient #3 with the metastasis from prostate cancer, 10.1% and 178.7% for two patients (#9–10) with metastasis from lung cancer. Conclusion: Although DVH provides average dose–volume information, DDVH provides differential dose– volume information with respect to different regions inside the tumor. TCP provides radiobiological information and adds additional information on improving treatment planning as well as adaptive

  16. Monitoring the systemic human memory B cell compartment of melanoma patients for anti-tumor IgG antibodies.

    Directory of Open Access Journals (Sweden)

    Amy E Gilbert

    Full Text Available Melanoma, a potentially lethal skin cancer, is widely thought to be immunogenic in nature. While there has been much focus on T cell-mediated immune responses, limited knowledge exists on the role of mature B cells. We describe an approach, including a cell-based ELISA, to evaluate mature IgG antibody responses to melanoma from human peripheral blood B cells. We observed a significant increase in antibody responses from melanoma patients (n = 10 to primary and metastatic melanoma cells compared to healthy volunteers (n = 10 (P<0.0001. Interestingly, we detected a significant reduction in antibody responses to melanoma with advancing disease stage in our patient cohort (n = 21 (P<0.0001. Overall, 28% of melanoma patient-derived B cell cultures (n = 1,800 compared to 2% of cultures from healthy controls (n = 600 produced antibodies that recognized melanoma cells. Lastly, a patient-derived melanoma-specific monoclonal antibody was selected for further study. This antibody effectively killed melanoma cells in vitro via antibody-mediated cellular cytotoxicity. These data demonstrate the presence of a mature systemic B cell response in melanoma patients, which is reduced with disease progression, adding to previous reports of tumor-reactive antibodies in patient sera, and suggesting the merit of future work to elucidate the clinical relevance of activating humoral immune responses to cancer.

  17. Monitoring the systemic human memory B cell compartment of melanoma patients for anti-tumor IgG antibodies.

    Science.gov (United States)

    Gilbert, Amy E; Karagiannis, Panagiotis; Dodev, Tihomir; Koers, Alexander; Lacy, Katie; Josephs, Debra H; Takhar, Pooja; Geh, Jenny L C; Healy, Ciaran; Harries, Mark; Acland, Katharine M; Rudman, Sarah M; Beavil, Rebecca L; Blower, Philip J; Beavil, Andrew J; Gould, Hannah J; Spicer, James; Nestle, Frank O; Karagiannis, Sophia N

    2011-04-29

    Melanoma, a potentially lethal skin cancer, is widely thought to be immunogenic in nature. While there has been much focus on T cell-mediated immune responses, limited knowledge exists on the role of mature B cells. We describe an approach, including a cell-based ELISA, to evaluate mature IgG antibody responses to melanoma from human peripheral blood B cells. We observed a significant increase in antibody responses from melanoma patients (n = 10) to primary and metastatic melanoma cells compared to healthy volunteers (n = 10) (P<0.0001). Interestingly, we detected a significant reduction in antibody responses to melanoma with advancing disease stage in our patient cohort (n = 21) (P<0.0001). Overall, 28% of melanoma patient-derived B cell cultures (n = 1,800) compared to 2% of cultures from healthy controls (n = 600) produced antibodies that recognized melanoma cells. Lastly, a patient-derived melanoma-specific monoclonal antibody was selected for further study. This antibody effectively killed melanoma cells in vitro via antibody-mediated cellular cytotoxicity. These data demonstrate the presence of a mature systemic B cell response in melanoma patients, which is reduced with disease progression, adding to previous reports of tumor-reactive antibodies in patient sera, and suggesting the merit of future work to elucidate the clinical relevance of activating humoral immune responses to cancer.

  18. Visual outcome, endocrine function and tumor control after fractionated stereotactic radiation therapy of craniopharyngiomas in adults

    DEFF Research Database (Denmark)

    Astradsson, Arnar; Munck Af Rosenschöld, Per; Feldt-Rasmussen, Ulla

    2017-01-01

    BACKGROUND: The purpose of this study was to examine visual outcome, endocrine function and tumor control in a prospective cohort of craniopharyngioma patients, treated with fractionated stereotactic radiation therapy (FSRT). MATERIAL AND METHODS: Sixteen adult patients with craniopharyngiomas were.......7-13.1) for visual outcome, endocrine function, and tumor control, respectively. RESULTS: Visual acuity impairment was present in 10 patients (62.5%) and visual field defects were present in 12 patients (75%) before FSRT. One patient developed radiation-induced optic neuropathy at seven years after FSRT. Thirteen...... of 16 patients (81.3%) had pituitary deficiency before FSRT, and did not develop further pituitary deficiency after FSRT. Mean tumor volume pre-FSRT was 2.72 cm3(range 0.20-9.90) and post-FSRT 1.2 cm3(range 0.00-13.10). Tumor control rate was 81.3% at two, five, and 10 years after FSRT. CONCLUSIONS...

  19. Expression of Translationally Controlled Tumor Protein in Human Kidney and in Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Maria R. Ambrosio

    2015-01-01

    Full Text Available Translationally controlled tumor protein is a multifaceted protein involved in several physiological and biological functions. Its expression in normal kidney and in renal carcinomas, once corroborated by functional data, may add elements to elucidate renal physiology and carcinogenesis. In this study, translationally controlled tumor protein expression was evaluated by quantitative real time polymerase chain reaction and western blotting, and its localization was examined by immunohistochemistry on 84 nephrectomies for cancer. In normal kidney protein expression was found in the cytoplasm of proximal and distal tubular cells, in cells of the thick segment of the loop of Henle, and in urothelial cells of the pelvis. It was also detectable in cells of renal carcinoma with different pattern of localization (membranous and cytoplasmic depending on tumor histotype. Our data may suggest an involvement of translationally controlled tumor protein in normal physiology and carcinogenesis. However, functional in vitro and in vivo studies are needed to verify this hypothesis.

  20. Preoperative balance control compensation in patients with a vestibular schwannoma: does tumor size matter?

    Science.gov (United States)

    Ribeyre, Laurence; Frère, Julien; Gauchard, Gérome; Lion, Alexis; Perrin, Philippe; Spitz, Elisabeth; Parietti-Winkler, Cécile

    2015-04-01

    The influence of tumor size on postural control of patients with vestibular schwannoma (VS) remains to be determined. This study aimed to compare the postural performances of VS patients, according to the size of the tumor, with healthy subjects. The six conditions (C1-C6) of the sensory organization test (SOT) were carried out in 87 patients, split into four groups according to the Koos classification (stage I-IV), and in 72 aged-matched controls to evaluate postural control. The vestibular reflectivity and compensation were estimated with videonystagmography. Among patients, lower C5 and C6 scores were found in stage I and IV patients than in stage II and III patients, whereas vestibular compensation did not impact the tumor size influence on the postural control. The scores were significantly (pvestibular-related SOT conditions (C5-C6). Patients with an unilateral VS displayed altered postural performances compared to the control subjects and tumor size had a bell-like pattern effect on balance control. The tumor size could be seen as a determining factor in the implementation of adaptive mechanisms that lead to the postural compensation and might be dissociated from vestibular compensation. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  1. Tumor Acidity/NIR Controlled Interaction of Transformable Nanoparticle with Biological Systems for Cancer Therapy.

    Science.gov (United States)

    Li, Dongdong; Ma, Yinchu; Du, Jinzhi; Tao, Wei; Du, Xiaojiao; Yang, Xianzhu; Wang, Jun

    2017-05-10

    Precisely controlling the interaction of nanoparticles with biological systems (nanobio interactions) from the injection site to biological targets shows great potential for biomedical applications. Inspired by the ability of nanoparticles to alter their physicochemical properties according to different stimuli, we explored the tumor acidity and near-infrared (NIR) light activated transformable nanoparticle DA TAT-NP IR&DOX . This nanoparticle consists of a tumor acidity-activated TAT [the TAT lysine residues' amines was modified with 2,3-dimethylmaleic anhydride (DA)], a flexible chain polyphosphoester core coencapsulated a NIR dye IR-780, and DOX (doxorubicin). The physicochemical properties of the nanoparticle can be controlled in a stepwise fashion using tumor acidity and NIR light, resulting in adjustable nanobio interactions. The resulting transformable nanoparticle DA TAT-NP IR&DOX efficiently avoids the interaction with mononuclear phagocyte system (MPS) ("stealth" state) due to the masking of the TAT peptide during blood circulation. Once it has accumulated in the tumor tissues, DA TAT-NP IR&DOX is reactivated by tumor acidity and transformed into the "recognize" state in order to promote interaction with tumor cells and enhance cellular internalization. Then, this nanoparticle is transformed into "attack" state under NIR irradiation, achieving the supersensitive DOX release from the flexible chain polyphosphoester core in order to increase the DOX-DNA interaction. This concept provides new avenues for the creation of transformable drug delivery systems that have the ability to control nanobio interactions.

  2. Primary intracranial tumors among atomic bomb survivors and controls, Hiroshima and Nagasaki, 1961-75

    International Nuclear Information System (INIS)

    Seyama, Shinichi; Ishimaru, Toranosuke; Iijima, Soichi; Mori, Kazuo.

    1980-02-01

    An analysis was made of the relationship of radiation dose to the occurrence of primary intracranial tumors among atomic bomb survivors and nonexposed controls, Hiroshima and Nagasaki, in the fixed cohort of the Life Span Study (LSS) extended sample during the period 1961-75, or 16 to 30 years after the A-bombs. Based on various medical sources, 104 cases of primary intracranial tumors were identified among approximately 99,000 LSS extended sample members who were alive as of 1 January 1961. Of these 104 cases, 45 had manifested clinical signs of brain tumors, but, 59 cases were identified incidentally at postmortem examination. The distributions of morphologic type, age, and size of tumor were quite different for those primary intracranial tumors with and without a clinical sign of brain tumor. Glioma was the most frequent type of tumor with a clinical sign and meningioma was the most frequent type without. In relation to radiation dose the incidence rate of primary intracranial tumors with a clinical sign showed a significant excess risk for males in the high dose group who received 100 rad or more after adjustment for age at the time of the bomb (ATB). The standardized relative risk is around 5 in this group. The data also suggest that the crude relative risk of glioma is greater in the high dose group for younger ages ATB. However, there is no increased risk in females. Among the 5,012 autopsy subjects in the LSS extended sample during 1961-75, there is no relationship between radiation dose and the prevalence rate of primary intracranial tumors in those identified incidentally by autopsy. The relative risk of subclinical adenoma of the pituitary gland between high dose subjects and controls was also examined for a sample of 95 sex- and age-matched pairs using Hiroshima autopsy materials for 1961-74, but no relationship to dose was observed. (author)

  3. State-Dependent Impulsive Control Strategies for a Tumor-Immune Model

    Directory of Open Access Journals (Sweden)

    Kwang Su Kim

    2016-01-01

    Full Text Available Controlling the number of tumor cells leads us to expect more efficient strategies for treatment of tumor. Towards this goal, a tumor-immune model with state-dependent impulsive treatments is established. This model may give an efficient treatment schedule to control tumor’s abnormal growth. By using the Poincaré map and analogue of Poincaré criterion, some conditions for the existence and stability of a positive order-1 periodic solution of this model are obtained. Moreover, we carry out numerical simulations to illustrate the feasibility of our main results and compare fixed-time impulsive treatment effects with state-dependent impulsive treatment effects. The results of our simulations say that, in determining optimal treatment timing, the model with state-dependent impulsive control is more efficient than that with fixed-time impulsive control.

  4. Impact of primary tumor volume on local control after definitive radiotherapy for head and neck cancer

    NARCIS (Netherlands)

    Mendenhall, William M.; Mancuso, Anthony A.; Strojan, Primoz; Beitler, Jonathan J.; Suarez, Carlos; Lee, Tsair-Fwu; Langendijk, Johannes A.; Corry, June; Eisbruch, Avraham; Rinaldo, Alessandra; Ferlito, Alfio

    Background. The impact of primary tumor volume (pTV) on local control after definitive radiotherapy (RT) for head and neck squamous cell carcinoma (HNSCC) is unclear. Methods. Pertinent literature was reviewed to address the impact of pTV on local control after definitive RT for HNSCC. Results.

  5. Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature

    Science.gov (United States)

    Kokolus, Kathleen M.; Capitano, Maegan L.; Lee, Chen-Ting; Eng, Jason W.-L.; Waight, Jeremy D.; Hylander, Bonnie L.; Sexton, Sandra; Hong, Chi-Chen; Gordon, Christopher J.; Abrams, Scott I.; Repasky, Elizabeth A.

    2013-01-01

    We show here that fundamental aspects of antitumor immunity in mice are significantly influenced by ambient housing temperature. Standard housing temperature for laboratory mice in research facilities is mandated to be between 20–26 °C; however, these subthermoneutral temperatures cause mild chronic cold stress, activating thermogenesis to maintain normal body temperature. When stress is alleviated by housing at thermoneutral ambient temperature (30–31 °C), we observe a striking reduction in tumor formation, growth rate and metastasis. This improved control of tumor growth is dependent upon the adaptive immune system. We observe significantly increased numbers of antigen-specific CD8+ T lymphocytes and CD8+ T cells with an activated phenotype in the tumor microenvironment at thermoneutrality. At the same time there is a significant reduction in numbers of immunosuppressive MDSCs and regulatory T lymphocytes. Notably, in temperature preference studies, tumor-bearing mice select a higher ambient temperature than non-tumor-bearing mice, suggesting that tumor-bearing mice experience a greater degree of cold-stress. Overall, our data raise the hypothesis that suppression of antitumor immunity is an outcome of cold stress-induced thermogenesis. Therefore, the common approach of studying immunity against tumors in mice housed only at standard room temperature may be limiting our understanding of the full potential of the antitumor immune response. PMID:24248371

  6. Microprocessor-controlled Nd:YAG laser for hyperthermia induction in the RIF-1 tumor.

    Science.gov (United States)

    Waldow, S M; Russell, G E; Wallner, P E

    1992-01-01

    Near-infrared radiation from a Nd:YAG laser at 1,064 nm was used interstitially or superficially to induce hyperthermia in RIF-1 tumors in C3H male mice. A single 600-microns quartz fiber with a 0.5-cm cylindrical diffusor or a weakly diverging microlens at its distal end was used to deliver laser energy to tumors in the hind leg (mean volume = 100 mm3). Two thermocouples were inserted into each tumor. One thermocouple controlled a microprocessor-driven hyperthermia program (maximum output of 3.5 Watts) to maintain the desired temperature. Tumors were exposed to various temperature-time combinations (42-45 degrees C/30 min). Our initial results indicated that excellent temperature control to within 0.2 degrees C of the desired temperature at the feedback thermocouple was achievable during both superficial and interstitial heat treatments. Temperatures at the second thermocouple, however, were found to be lower by as much as 2.3 degrees C (using the cylindrical diffusor) or higher by up to 4.6 degrees C (using the microlens) when compared to the feedback thermocouple temperature. Several correlations were seen between total dose, tumor growth delay, percent skin necrosis, and temperature at the second thermocouple after several superficial and interstitial treatments. Statistically significant improvements in tumor growth delay (at 42 and 45 degrees C) and increased percent skin necrosis at all temperatures were observed after superficial versus interstitial treatment.

  7. Modeling tumor control probability for spatially inhomogeneous risk of failure based on clinical outcome data

    DEFF Research Database (Denmark)

    Lühr, Armin; Löck, Steffen; Jakobi, Annika

    2017-01-01

    PURPOSE: Objectives of this work are (1) to derive a general clinically relevant approach to model tumor control probability (TCP) for spatially variable risk of failure and (2) to demonstrate its applicability by estimating TCP for patients planned for photon and proton irradiation. METHODS...... AND MATERIALS: The approach divides the target volume into sub-volumes according to retrospectively observed spatial failure patterns. The product of all sub-volume TCPi values reproduces the observed TCP for the total tumor. The derived formalism provides for each target sub-volume i the tumor control dose (D...... clinical target volume (CTV), and elective CTV (CTVE). The risk of a local failure in each of these sub-volumes was taken from the literature. RESULTS: Convenient expressions for D50,i and γ50,i were provided for the Poisson and the logistic model. Comparable TCP estimates were obtained for photon...

  8. CXCR5+CD8+T cells could induce the death of tumor cells in HBV-related hepatocellular carcinoma.

    Science.gov (United States)

    Jin, Yun; Lang, Cuicui; Tang, Jianzhong; Geng, Jiawei; Song, Haihan K; Sun, Zhiwei; Wang, Jinfeng

    2017-12-01

    The follicular CXCR5 + CD8 + T cells have recently emerged as a critical cell type in mediating peripheral tolerance as well as antiviral immune responses during chronic infections. In this study, we investigated the function of CXCR5 + CD8 + T cells in HBV-related hepatocellular carcinoma patients. Compared to CXCR5 - CD8 + T cells, CXCR5 + CD8 + T cells presented elevated PD-1 expression but reduced Tim-3 and CTLA-4 expression. Upon anti-CD3/CD28 stimulation, CXCR5 + CD8 + T cells demonstrated higher proliferation potency than CXCR5 - CD8 + T cells, especially after PD-1 blockade. CXCR5 + CD8 + T cells also demonstrated significantly higher granzyme B synthesis and release, as well as higher level of degranulation. Tumor cells were more readily eliminated by CXCR5 + CD8 + T cells than by CXCR5 - CD8 + T cells. Interestingly, we found that B cells were more resistant to CXCR5 + CD8 + T cell-mediated killing than tumor cells, possibly through IL-10-mediated protection. In addition, the CXCR5 + CD8 + T cell-mediated cytotoxic effects on tumor cells could be significantly enhanced by PD-L1 blockade. Together, we presented that in patients with in HBV-related hepatocellular carcinoma, CXCR5 + CD8 + T cells could mediate tumor cell death more potently than the CXCR5 - CD8 + T cells in vitro while the autologous B cells were protected. Copyright © 2017. Published by Elsevier B.V.

  9. Spine Cryoablation: Pain Palliation and Local Tumor Control for Vertebral Metastases.

    Science.gov (United States)

    Tomasian, A; Wallace, A; Northrup, B; Hillen, T J; Jennings, J W

    2016-01-01

    Percutaneous cryoablation has emerged as a minimally invasive technique for the management of osseous metastases. The purpose of this study was to assess the safety and effectiveness of percutaneous imaging-guided spine cryoablation for pain palliation and local tumor control for vertebral metastases. Imaging-guided spine cryoablation was performed in 14 patients (31 tumors) with vertebral metastases refractory to conventional chemoradiation therapy or analgesics, to achieve pain palliation and local tumor control in this retrospective study. Spinal nerve and soft-tissue thermal protection techniques were implemented in all ablations. Patient response was evaluated by a pain numeric rating scale administered before the procedure and 1 week, 1 month, and 3 months after the procedure. Pre- and postprocedural analgesic requirements (expressed as morphine-equivalent dosages) were also analyzed at the same time points. Pre- and postprocedural cross-sectional imaging was evaluated in all patients to assess local control (no radiographic evidence of disease at the treated sites). Complications were monitored. Analysis of the primary end points was undertaken via paired-comparison procedures by using the Wilcoxon signed rank test. Thirty-one tumors were ablated in 14 patients (9 women and 5 men; 20-73 years of age; mean age, 53 years). The most common tumor location was in the lumbar spine (n = 14, 45%), followed by the thoracic spine (n = 8, 26%), sacrum (n = 6, 19%), coccyx (n = 2, 6%), and cervical spine (n = 1, 3%). There were statistically significant decreases in the median numeric rating scale score and analgesic usage at 1-week, 1-month, and 3-month time points (P pain palliation and local tumor control for vertebral metastases. © 2016 by American Journal of Neuroradiology.

  10. Singlet oxygen explicit dosimetry to predict local tumor control for HPPH-mediated photodynamic therapy

    Science.gov (United States)

    Penjweini, Rozhin; Kim, Michele M.; Ong, Yi Hong; Zhu, Timothy C.

    2017-02-01

    This preclinical study examines four dosimetric quantities (light fluence, photosensitizer photobleaching ratio, PDT dose, and reacted singlet oxygen ([1O2]rx)) to predict local control rate (LCR) for 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH)-mediated photodynamic therapy (PDT). Mice bearing radiation-induced fibrosarcoma (RIF) tumors were treated with different in-air fluences (135, 250 and 350 J/cm2) and in-air fluence rates (50, 75 and 150 mW/cm2) at 0.25 mg/kg HPPH and a drug-light interval of 24 hours using a 1 cm diameter collimated laser beam at 665 nm wavelength. A macroscopic model was used to calculate ([1O2]rx)) based on in vivo explicit dosimetry of the initial tissue oxygenation, photosensitizer concentration, and tissue optical properties. PDT dose was defined as a temporal integral of drug concentration and fluence rate (φ) at a 3 mm tumor depth. Light fluence rate was calculated throughout the treatment volume based on Monte-Carlo simulation and measured tissue optical properties. The tumor volume of each mouse was tracked for 30 days after PDT and Kaplan-Meier analyses for LCR were performed based on a tumor volume <=100 mm3, for four dose metrics: fluence, HPPH photobleaching rate, PDT dose, and ([1O2]rx)). The results of this study showed that ([1O2]rx)) is the best dosimetric quantity that can predict tumor response and correlate with LCR.

  11. Phosphorylation of carbonic anhydrase IX controls its ability to mediate extracellular acidification in hypoxic tumors.

    Science.gov (United States)

    Ditte, Peter; Dequiedt, Franck; Svastova, Eliska; Hulikova, Alzbeta; Ohradanova-Repic, Anna; Zatovicova, Miriam; Csaderova, Lucia; Kopacek, Juraj; Supuran, Claudiu T; Pastorekova, Silvia; Pastorek, Jaromir

    2011-12-15

    In the hypoxic regions of a tumor, carbonic anhydrase IX (CA IX) is an important transmembrane component of the pH regulatory machinery that participates in bicarbonate transport. Because tumor pH has implications for growth, invasion, and therapy, determining the basis for the contributions of CA IX to the hypoxic tumor microenvironment could lead to new fundamental and practical insights. Here, we report that Thr443 phosphorylation at the intracellular domain of CA IX by protein kinase A (PKA) is critical for its activation in hypoxic cells, with the fullest activity of CA IX also requiring dephosphorylation of Ser448. PKA is activated by cAMP, which is elevated by hypoxia, and we found that attenuating PKA in cells disrupted CA IX-mediated extracellular acidification. Moreover, following hypoxia induction, CA IX colocalized with the sodium-bicarbonate cotransporter and other PKA substrates in the leading edge membranes of migrating tumor cells, in support of the concept that bicarbonate metabolism is spatially regulated at cell surface sites with high local ion transport and pH control. Using chimeric CA IX proteins containing heterologous catalytic domains derived from related CA enzymes, we showed that CA IX activity was modulated chiefly by the intracellular domain where Thr443 is located. Our findings indicate that CA IX is a pivotal mediator of the hypoxia-cAMP-PKA axis, which regulates pH in the hypoxic tumor microenvironment.

  12. Mammographic density and risk of breast cancer by tumor characteristics: a case-control study.

    Science.gov (United States)

    Krishnan, Kavitha; Baglietto, Laura; Stone, Jennifer; McLean, Catriona; Southey, Melissa C; English, Dallas R; Giles, Graham G; Hopper, John L

    2017-12-16

    In a previous paper, we had assumed that the risk of screen-detected breast cancer mostly reflects inherent risk, and the risk of whether a breast cancer is interval versus screen-detected mostly reflects risk of masking. We found that inherent risk was predicted by body mass index (BMI) and dense area (DA) or percent dense area (PDA), but not by non-dense area (NDA). Masking, however, was best predicted by PDA but not BMI. In this study, we aimed to investigate if these associations vary by tumor characteristics and mode of detection. We conducted a case-control study nested within the Melbourne Collaborative Cohort Study of 244 screen-detected cases matched to 700 controls and 148 interval cases matched to 446 controls. DA, NDA and PDA were measured using the Cumulus software. Tumor characteristics included size, grade, lymph node involvement, and ER, PR, and HER2 status. Conditional and unconditional logistic regression were applied as appropriate to estimate the Odds per Adjusted Standard Deviation (OPERA) adjusted for age and BMI, allowing the association with BMI to be a function of age at diagnosis. For screen-detected cancer, both DA and PDA were associated to an increased risk of tumors of large size (OPERA ~ 1.6) and positive lymph node involvement (OPERA ~ 1.8); no association was observed for BMI and NDA. For risk of interval versus screen-detected breast cancer, the association with risk for any of the three mammographic measures did not vary by tumor characteristics; an association was observed for BMI for positive lymph nodes (OPERA ~ 0.6). No associations were observed for tumor grade and ER, PR and HER2 status of tumor. Both DA and PDA were predictors of inherent risk of larger breast tumors and positive nodal status, whereas for each of the three mammographic density measures the association with risk of masking did not vary by tumor characteristics. This might raise the hypothesis that the risk of breast tumours with poorer prognosis

  13. Intratumoral interleukin-21 increases antitumor immunity, tumor-infiltrating CD8+ T-cell density and activity, and enlarges draining lymph nodes

    DEFF Research Database (Denmark)

    Søndergaard, Henrik; Galsgaard, Elisabeth D; Bartholomaeussen, Monica

    2010-01-01

    Interleukin (IL)-21 is a novel cytokine in clinical development for the treatment of cancer. In this study, we have compared the efficacy of subcutaneous and intratumoral (IT) administration of IL-21 protein in two syngeneic mouse tumor models, RenCa renal cell carcinoma and B16 melanoma......, and investigated the mechanisms by which IL-21 enhances CD8 T-cell-mediated antitumor immunity. We found that in comparison to subcutaneous administration, IT administration of IL-21 more potently inhibited tumor growth and increased survival. This correlated with increased densities of tumor-infiltrating CD8...... and CD4CD25 T cells, but not CD4CD25FoxP3 T cells. Furthermore, IT administration of IL-21 increased degranulation, and expression of interferon-gamma and granzyme B in tumor-infiltrating CD8 T cells. Tumors injected with IL-21 grew slower than contralateral tumors, suggesting that the increased efficacy...

  14. Intratumoral Interleukin-21 Increases Antitumor Immunity, Tumor-infiltrating CD8(+) T-cell Density and Activity, and Enlarges Draining Lymph Nodes

    DEFF Research Database (Denmark)

    Sondergaard, H.; Galsgaard, E.D.; Bartholomaeussen, M.

    2010-01-01

    Interleukin (IL)-21 is a novel cytokine in clinical development for the treatment of cancer. In this study, we have compared the efficacy of subcutaneous and intratumoral (IT) administration of IL-21 protein in two syngeneic mouse tumor models, RenCa renal cell carcinoma and B16 melanoma......, and investigated the mechanisms by which IL-21 enhances CD8(+) T-cell-mediated antitumor immunity. We found that in comparison to subcutaneous administration, IT administration of IL-21 more potently inhibited tumor growth and increased survival. This correlated with increased densities of tumor-infiltrating CD8......(+) and CD4(+) CD25(-) T cells, but not CD4(+) CD25(+) FoxP3(+) T cells. Furthermore, IT administration of IL-21 increased degranulation, and expression of interferon-gamma and granzyme B in tumor-infiltrating CD8(+) T cells. Tumors injected with IL-21 grew slower than contralateral tumors, suggesting...

  15. Tumor necrosis factor induces tumor promoting and anti-tumoral effects on pancreatic cancer via TNFR1.

    Directory of Open Access Journals (Sweden)

    Martin Chopra

    Full Text Available Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5%, TNF deficient (12.5%, and TNFR2 deficient mice (22.2% were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4(+ T cells and CD4(+ forkhead box P3 (FoxP3(+ regulatory T cells (Treg but reduced numbers of CD8(+ T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8(+ T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome.

  16. Five-chlorodeoxycytidine, a tumor-selective enzyme-driven radiosensitizer, effectively controls five advanced human tumors in nude mice

    International Nuclear Information System (INIS)

    Greer, Sheldon; Alvarez, Marcy; Mas, Marisol; Wozniak, Chandra; Arnold, David; Knapinska, Anna; Norris, Christina; Burk, Ronald; Aller, Alex; Dauphinee, Michael

    2001-01-01

    Purpose: The study's goals were as follows: (1) to extend our past findings with rodent tumors to human tumors in nude mice, (2) to determine if the drug protocol could be simplified so that only CldC and one modulator, tetrahydrouridine (H 4 U), would be sufficient to obtain efficacy, (3) to determine the levels of deoxycytidine kinase and dCMP deaminase in human tumors, compared to adjacent normal tissue, and (4) to determine the effect of CldC on normal tissue radiation damage to the cervical spinal cord of nude mice. Methods and Materials: The five human tumors used were as follows: prostate tumors, PC-3 and H-1579; glioblastoma, SF-295; breast tumor, GI-101; and lung tumor, H-165. The duration of treatment was 3-5 weeks, with drugs administered on Days 1-4 and radiation on Days 3-5 of each week. The biomodulators of CldC were N-(Phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartyl transcarbamoylase, 5-fluorodeoxycytidine (FdC), resulting in tumor-directed inhibition of thymidylate synthetase, and H 4 U, an inhibitor of cytidine deaminase. The total dose of focused irradiation of the tumors was usually 45 Gy in 12 fractions. Results: Marked radiosensitization was obtained with CldC and the three modulators. The average days in tumor regrowth delay for X-ray compared to drugs plus X-ray, respectively, were: PC-3 prostate, 42-97; H-1579 prostate, 29-115; glioblastoma, 5-51; breast, 50-80; lung, 32-123. Comparative studies with PC-3 and H-1579 using CldC coadministered with H 4 U, showed that both PALA and FdC are dispensable, and the protocol can be simplified with equal and possibly heightened efficacy. For example, PC-3 with X-ray and (1) no drugs, (2) CldC plus the three modulators, (3) a high dose of CldC, and (4) escalating doses of CldC resulted in 0/10, 3/9, 5/10, and 6/9 cures, respectively. The tumor regrowth delay data followed a similar pattern. After treating mice only 1((1)/(2)) weeks with CldC + H 4 U, 92% of the PC-3 tumor cells were found

  17. Tumor Restrictive Suicide Gene Therapy for Glioma Controlled by the FOS Promoter.

    Directory of Open Access Journals (Sweden)

    Jianqing Pan

    Full Text Available Effective suicide gene delivery and expression are crucial to achieving successful effects in gene therapy. An ideal tumor-specific promoter expresses therapeutic genes in tumor cells with minimal normal tissue expression. We compared the activity of the FOS (FBJ murine osteosarcoma viral oncogene homolog promoter with five alternative tumor-specific promoters in glioma cells and non-malignant astrocytes. The FOS promoter caused significantly higher transcriptional activity in glioma cell lines than all alternative promoters with the exception of CMV. The FOS promoter showed 13.9%, 32.4%, and 70.8% of the transcriptional activity of CMV in three glioma cell lines (U87, U251, and U373. Importantly, however, the FOS promoter showed only 1.6% of the transcriptional activity of CMV in normal astrocytes. We also tested the biologic activity of recombinant adenovirus containing the suicide gene herpes simplex virus thymidine kinase (HSV-tk driven by the FOS promoter, including selective killing efficacy in vitro and tumor inhibition rate in vivo. Adenoviral-mediated delivery of the HSV-tk gene controlled by the FOS promoter conferred a cytotoxic effect on human glioma cells in vitro and in vivo. This study suggests that use of the FOS-tk adenovirus system is a promising strategy for glioma-specific gene therapy but still much left for improvement.

  18. Symptom resolution, tumor control, and side effects following postoperative radiotherapy for pituitary macroadenomas

    International Nuclear Information System (INIS)

    Rush, Stephen; Cooper, Paul R.

    1997-01-01

    This study reports the outcome of 70 patients who were treated by a consistent treatment plan of surgery and postoperative radiotherapy (RT) for pituitary macroadenomas in the modern era [computed tomographic scan or magnetic resonance imaging (MRI), dopamine agonist therapy (DA) added as indicated, and immunohistochemical staining]. Sixty-two patients underwent transsphenoidal surgery (vs. transcranial surgery) and 61 received 45-Gy/25 fractions postoperatively (vs. other dose fractionation schemes). Twenty-four patients received DA for prolactin-secreting tumors. With a median follow-up of 8 years (range 2-15), 68 patients have experienced continuous control of their tumors. Most symptoms related to mass effect abated, while physiologic symptoms such as amenorrhea from markedly elevated prolactin levels tended to persist. Treatment-induced hypopituitarism occurred in 42% of the patients at risk. No patients in this series have died as a result of their pituitary tumor. No gross neuropsychologic dysfunction after treatment has been noted. While it is possible at this time with serial MRI to withhold postoperative RT and observe some patients who have had a 'gross total' resection of a macroadenoma, the therapeutic ratio for surgery and adjuvant radiotherapy for patients with nonfunctional tumors as well as select patients with secretory macroadenomas is favorable

  19. Immunohistochemical localization of translationally controlled tumor protein in the mouse digestive system.

    Science.gov (United States)

    Sheverdin, Vadim; Jung, Jiwon; Lee, Kyunglim

    2013-09-01

    Translationally controlled tumor protein (TCTP) is a housekeeping protein, highly conserved among various species. It plays a major role in cell differentiation, growth, proliferation, apoptosis and carcinogenesis. Studies reported so far on TCTP expression in different digestive organs have not led to any understanding of the role of TCTP in digestion, so we localized TCTP in organs of the mouse digestive system employing immunohistochemical techniques. Translationally controlled tumor protein was found expressed in all organs studied: tongue, salivary glands, esophagus, stomach, small and large intestines, liver and pancreas. The expression of TCTP was found to be predominant in epithelia and neurons of myenteric nerve ganglia; high in serous glands (parotid, submandibular, gastric, intestinal crypts, pancreatic acini) and in neurons of myenteric nerve ganglia, and moderate to low in epithelia. In epithelia, expression of TCTP varied depending on its type and location. In enteric neurons, TCTP was predominantly expressed in the processes. Translationally controlled tumor protein expression in the liver followed porto-central gradient with higher expression in pericentral hepatocytes. In the pancreas, TCTP was expressed in both acini and islet cells. Our finding of nearly universal localization and expression of TCTP in mouse digestive organs points to the hitherto unrecognized functional importance of TCTP in the digestive system and suggests the need for further studies of the possible role of TCTP in the proliferation, secretion, absorption and neural regulation of the digestive process and its importance in the physiology and pathology of digestive process. © 2013 Anatomical Society.

  20. Simulations of adaptive temperature control with self-focused hyperthermia system for tumor treatment.

    Science.gov (United States)

    Hu, Jiwen; Ding, Yajun; Qian, Shengyou; Tang, Xiangde

    2013-01-01

    The control problem in ultrasound therapy is to destroy the tumor tissue while not harming the intervening healthy tissue with a desired temperature elevation. The objective of this research is to present a robust and feasible method to control the temperature distribution and the temperature elevation in treatment region within the prescribed time, which can improve the curative effect and decrease the treatment time for heating large tumor (≥2.0cm in diameter). An adaptive self-tuning-regulator (STR) controller has been introduced into this control method by adding a time factor with a recursive algorithm, and the speed of sound and absorption coefficient of the medium is considered as a function of temperature during heating. The presented control method is tested for a self-focused concave spherical transducer (0.5MHz, 9cm aperture, 8.0cm focal length) through numerical simulations with three control temperatures of 43°C, 50°C and 55°C. The results suggest that this control system has adaptive ability for variable parameters and has a rapid response to the temperature and acoustic power output in the prescribed time for the hyperthermia interest. There is no overshoot during temperature elevation and no oscillation after reaching the desired temperatures. It is found that the same results can be obtained for different frequencies and temperature elevations. This method can obtain an ellipsoid-shaped ablation region, which is meaningful for the treatment of large tumor. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. Rac2 controls tumor growth, metastasis and M1-M2 macrophage differentiation in vivo.

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    Shweta Joshi

    Full Text Available Although it is well-established that the macrophage M1 to M2 transition plays a role in tumor progression, the molecular basis for this process remains incompletely understood. Herein, we demonstrate that the small GTPase, Rac2 controls macrophage M1 to M2 differentiation and the metastatic phenotype in vivo. Using a genetic approach, combined with syngeneic and orthotopic tumor models we demonstrate that Rac2-/- mice display a marked defect in tumor growth, angiogenesis and metastasis. Microarray, RT-PCR and metabolomic analysis on bone marrow derived macrophages isolated from the Rac2-/- mice identify an important role for Rac2 in M2 macrophage differentiation. Furthermore, we define a novel molecular mechanism by which signals transmitted from the extracellular matrix via the α4β1 integrin and MCSF receptor lead to the activation of Rac2 and potentially regulate macrophage M2 differentiation. Collectively, our findings demonstrate a macrophage autonomous process by which the Rac2 GTPase is activated downstream of the α4β1 integrin and the MCSF receptor to control tumor growth, metastasis and macrophage differentiation into the M2 phenotype. Finally, using gene expression and metabolomic data from our Rac2-/- model, and information related to M1-M2 macrophage differentiation curated from the literature we executed a systems biologic analysis of hierarchical protein-protein interaction networks in an effort to develop an iterative interactome map which will predict additional mechanisms by which Rac2 may coordinately control macrophage M1 to M2 differentiation and metastasis.

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

    Directory of Open Access Journals (Sweden)

    Jochen Gohlke

    Full Text Available 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

  3. Tumor control and normal tissue complications in BNCT treatment of nodular melanoma: A search for predictive quantities

    Energy Technology Data Exchange (ETDEWEB)

    Gonzalez, S.J. [Comision Nacional de Energia Atomica, Av. del Libertador 8250, (1429) Cdad. de Buenos Aires (Argentina); CONICET, Avda. Rivadavia 1917, (1033) Cdad. de Buenos Aires (Argentina)], E-mail: srgonzal@cnea.gov.ar; Casal, M. [Instituto de Oncologia Angel H. Roffo, Av. San Martin 5481, (1417) Cdad. de Buenos Aires (Argentina); Pereira, M.D. [Instituto de Oncologia Angel H. Roffo, Av. San Martin 5481, (1417) Cdad. de Buenos Aires (Argentina); Agencia Nacional de Promocion Cientifica y Tecnologica, PAV 22393 (Argentina); Santa Cruz, G.A. [Comision Nacional de Energia Atomica, Av. del Libertador 8250, (1429) Cdad. de Buenos Aires (Argentina); Carando, D.G. [CONICET, Avda. Rivadavia 1917, (1033) Cdad. de Buenos Aires (Argentina); Dpto. de Matematica, Pab. I Ciudad Universitaria, UBA, (1428) Cdad. de Buenos Aires (Argentina); Blaumann, H. [Comision Nacional de Energia Atomica, Av. del Libertador 8250, (1429) Cdad. de Buenos Aires (Argentina); Bonomi, M. [CONICET, Avda. Rivadavia 1917, (1033) Cdad. de Buenos Aires (Argentina); Calzetta Larrieu, O.; Feld, D.; Fernandez, C. [Comision Nacional de Energia Atomica, Av. del Libertador 8250, (1429) Cdad. de Buenos Aires (Argentina); Gossio, S. [FCEyN, Pab. II Ciudad Universitaria, UBA, (1428) Cdad. de Buenos Aires (Argentina); Jimenez Rebagliatti, R.; Kessler, J.; Longhino, J. [Comision Nacional de Energia Atomica, Av. del Libertador 8250, (1429) Cdad. de Buenos Aires (Argentina); Menendez, P. [Instituto de Oncologia Angel H. Roffo, Av. San Martin 5481, (1417) Cdad. de Buenos Aires (Argentina); Nievas, S. [Comision Nacional de Energia Atomica, Av. del Libertador 8250, (1429) Cdad. de Buenos Aires (Argentina); Roth, B.M.C [Instituto de Oncologia Angel H. Roffo, Av. San Martin 5481, (1417) Cdad. de Buenos Aires (Argentina); Liberman, S.J. [Comision Nacional de Energia Atomica, Av. del Libertador 8250, (1429) Cdad. de Buenos Aires (Argentina)

    2009-07-15

    A previous work concerning tumor control and skin damage in cutaneous melanoma treatments with BNCT has been extended to include doses, volumes and responses of 104 subcutaneous lesions from all patients treated in Argentina. Acute skin reactions were also scored for these patients, and cumulative dose-area histograms and dose-based figures of merit for skin were calculated. Broadening the tumor response analysis with the latest data showed that the (minimum or mean) tumor dose is not a good predictor of the observed clinical outcome by itself. However, when the tumor volume was included in the model as second explicative variable, the dose increases its significance and becomes a critical variable jointly with the volume (p-values<0.05). A preliminary analysis to estimate control doses for two groups of tumor sizes revealed that for small tumor volumes (< 0.1 cm{sup 3}) doses greater than 20 Gy-Eq produce a high tumor control (> 80%). However, when tumor volumes are larger than 0.1 cm{sup 3}, control is moderate (< 40%) even for minimum doses up to 40 Gy-Eq. Some quantities based on skin doses, areas and complication probabilities were proposed as candidates for predicting the severity of the early skin reactions. With the current data, all the evaluated figures of merit derived similar results: ulceration is present among the cases for which these quantities take the highest values.

  4. IMRT for Sinonasal Tumors Minimizes Severe Late Ocular Toxicity and Preserves Disease Control and Survival

    Energy Technology Data Exchange (ETDEWEB)

    Duprez, Frederic, E-mail: frederic.duprez@ugent.be [Department of Radiotherapy, Ghent University Hospital, Ghent (Belgium); Madani, Indira; Morbee, Lieve [Department of Radiotherapy, Ghent University Hospital, Ghent (Belgium); Bonte, Katrien; Deron, Philippe; Domjan, Vilmos [Department of Head and Neck Surgery, Ghent University Hospital, Ghent (Belgium); Boterberg, Tom; De Gersem, Werner; De Neve, Wilfried [Department of Radiotherapy, Ghent University Hospital, Ghent (Belgium)

    2012-05-01

    Purpose: To report late ocular (primary endpoint) and other toxicity, disease control, and survival (secondary endpoints) after intensity-modulated radiotherapy (IMRT) for sinonasal tumors. Methods and Materials: Between 1998 and 2009, 130 patients with nonmetastatic sinonasal tumors were treated with IMRT at Ghent University Hospital. Prescription doses were 70 Gy (n = 117) and 60-66 Gy (n = 13) at 2 Gy per fraction over 6-7 weeks. Most patients had adenocarcinoma (n = 82) and squamous cell carcinoma (n = 23). One hundred and one (101) patients were treated postoperatively. Of 17 patients with recurrent tumors, 9 were reirradiated. T-stages were T1-2 (n = 39), T3 (n = 21), T4a (n = 38), and T4b (n = 22). Esthesioneuroblastoma was staged as Kadish A, B, and C in 1, 3, and 6 cases, respectively. Results: Median follow-up was 52, range 15-121 months. There was no radiation-induced blindness in 86 patients available for late toxicity assessment ({>=}6 month follow-up). We observed late Grade 3 tearing in 10 patients, which reduced to Grade 1-2 in 5 patients and Grade 3 visual impairment because of radiation-induced ipsilateral retinopathy and neovascular glaucoma in 1 patient. There was no severe dry eye syndrome. The worst grade of late ocular toxicity was Grade 3 (n = 11), Grade 2 (n = 31), Grade 1 (n = 33), and Grade 0 (n = 11). Brain necrosis and osteoradionecrosis occurred in 6 and 1 patients, respectively. Actuarial 5-year local control and overall survival were 59% and 52%, respectively. On multivariate analysis local control was negatively affected by cribriform plate and brain invasion (p = 0.044 and 0.029, respectively) and absence of surgery (p = 0.009); overall survival was negatively affected by cribriform plate and orbit invasion (p = 0.04 and <0.001, respectively) and absence of surgery (p = 0.001). Conclusions: IMRT for sinonasal tumors allowed delivering high doses to targets at minimized ocular toxicity, while maintaining disease control and survival

  5. Local control of extra-abdominal desmoid tumors: systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Michelle A. Ghert

    2013-02-01

    Full Text Available The local control of desmoid tumors constitutes a continuing treatment dilemma due to its high recurrence rates. The purpose of this systematic review was to critically examine the current treatment of these rare tumors and to specifically evaluate the local failure and response rates of surgery, radiation and systemic therapy. We comprehensively searched the literature for relevant studies across Cinahl, Embase, Medline and the Cochrane databases. Articles were categorized as surgery, radiation, surgery + radiation and systemic therapy (including cytotoxic and non cytotoxic. Methodological quality of included studies was assessed using the Newcastle-Ottawa Scale. Pooled odd ratios (OR for comparative studies and weighted proportions with 95% confidence intervals (CI are reported. Thirty-five articles were included in the final analysis. Weighted mean local failure rates were 22% [95% CI (16-28%], 35% [95% CI (26-44%] and 28% [95% CI (18-39%] for radiation alone, surgery alone and surgery + radiation respectively. In the analysis of comparative studies, surgery and radiation in combination had lower local failure rates than radiation alone [OR 0.7 (0.4, 1.2] and surgery alone [OR 0.7 (0.4, 1.0]. Weighted mean stable disease rates were 91% [95% CI (85-96%] and 52% [95% CI (38-65%] for non cytotoxic and cytotoxic chemotherapy respectively. The current evidence suggests that surgery alone has a consistently high rate of local recurrence in managing extra-abdominal desmoid tumors. Radiation therapy in combination with surgery improves local control rates. However, the limited data on systemic therapy for this rare tumor suggests the benefit of using both cytotoxic and non cytotoxic chemotherapy to achieve stable disease.

  6. Optimal distributed control of a diffuse interface model of tumor growth

    Science.gov (United States)

    Colli, Pierluigi; Gilardi, Gianni; Rocca, Elisabetta; Sprekels, Jürgen

    2017-06-01

    In this paper, a distributed optimal control problem is studied for a diffuse interface model of tumor growth which was proposed by Hawkins-Daruud et al in Hawkins-Daruud et al (2011 Int. J. Numer. Math. Biomed. Eng. 28 3-24). The model consists of a Cahn-Hilliard equation for the tumor cell fraction φ coupled to a reaction-diffusion equation for a function σ representing the nutrient-rich extracellular water volume fraction. The distributed control u monitors as a right-hand side of the equation for σ and can be interpreted as a nutrient supply or a medication, while the cost function, which is of standard tracking type, is meant to keep the tumor cell fraction under control during the evolution. We show that the control-to-state operator is Fréchet differentiable between appropriate Banach spaces and derive the first-order necessary optimality conditions in terms of a variational inequality involving the adjoint state variables. The financial support of the FP7-IDEAS-ERC-StG #256872 (EntroPhase) and of the project Fondazione Cariplo-Regione Lombardia MEGAsTAR ‘Matematica d’Eccellenza in biologia ed ingegneria come accelleratore di una nuona strateGia per l’ATtRattività dell’ateneo pavese’ is gratefully acknowledged. The paper also benefited from the support of the MIUR-PRIN Grant 2015PA5MP7 ‘Calculus of Variations’ for PC and GG, and the GNAMPA (Gruppo Nazionale per l’Analisi Matematica, la Probabilità e le loro Applicazioni) of INdAM (Istituto Nazionale di Alta Matematica) for PC, GG and ER.

  7. HORMONAL CONTROL OF OVARIAN FUNCTION FOLLOWING CHLOROTRIAZINE EXPOSURE: EFFECT ON REPRODUCTIVE FUNCTION AND MAMMARY GLAND TUMOR DEVELOPMENT

    Science.gov (United States)

    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. StokerAbstractThe studies review...

  8. miR-221/222 control luminal breast cancer tumor progression by regulating different targets.

    Science.gov (United States)

    Dentelli, Patrizia; Traversa, Matteo; Rosso, Arturo; Togliatto, Gabriele; Olgasi, Cristina; Marchiò, Caterina; Provero, Paolo; Lembo, Antonio; Bon, Giulia; Annaratone, Laura; Sapino, Anna; Falcioni, Rita; Brizzi, Maria Felice

    2014-01-01

    α6β4 integrin is an adhesion molecule for laminin receptors involved in tumor progression. We present a link between β4 integrin expression and miR-221/222 in the most prevalent human mammary tumor: luminal invasive carcinomas (Lum-ICs). Using human primary tumors that display different β4 integrin expression and grade, we show that miR-221/222 expression inversely correlates with tumor proliferating index, Ki67. Interestingly, most high-grade tumors express β4 integrin and low miR-221/222 levels. We ectopically transfected miR-221/222 into a human-derived mammary tumor cell line that recapitulates the luminal subtype to investigate whether miR-221/222 regulates β4 expression. We demonstrate that miR-221/222 overexpression results in β4 expression downregulation, breast cancer cell proliferation, and invasion inhibition. The role of miR-221/222 in driving β4 integrin expression is also confirmed via mutating the miR-221/222 seed sequence for β4 integrin 3'UTR. Furthermore, we show that these 2 miRNAs are also key breast cancer cell proliferation and invasion regulators, via the post-transcriptional regulation of signal transducer and activator of transcription 5A (STAT5A) and of a disintegrin and metalloprotease-17 (ADAM-17). We further confirm these data by silencing ADAM-17, using a dominant-negative or an activated STAT5A form. miR-221/222-driven β4 integrin, STAT5A, and ADAM-17 did not occur in MCF-10A cells, denoted "normal" breast epithelial cells, indicating that the mechanism is cancer cell-specific.   These results provide the first evidence of a post-transcriptional mechanism that regulates β4 integrin, STAT5A, and ADAM-17 expression, thus controlling breast cancer cell proliferation and invasion. Pre-miR-221/222 use in the aggressive luminal subtype may be a powerful therapeutic anti-cancer strategy.

  9. Impact of adjuvant inhibition of vascular endothelial growth factor receptor tyrosine kinases on tumor growth delay and local tumor control after fractionated irradiation in human squamous cell carcinomas in nude mice

    International Nuclear Information System (INIS)

    Zips, Daniel; Hessel, Franziska; Krause, Mechthild; Schiefer, Yvonne; Hoinkis, Cordelia; Thames, Howard D.; Haberey, Martin; Baumann, Michael

    2005-01-01

    Purpose: Previous experiments have shown that adjuvant inhibition of the vascular endothelial growth factor receptor after fractionated irradiation prolonged tumor growth delay and may also improve local tumor control. To test the latter hypothesis, local tumor control experiments were performed. Methods and materials: Human FaDu and UT-SCC-14 squamous cell carcinomas were studied in nude mice. The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 (50 mg/kg body weight b.i.d.) was administered for 75 days after irradiation with 30 fractions within 6 weeks. Tumor growth time and tumor control dose 50% (TCD 50 ) were determined and compared to controls (carrier without PTK787/ZK222584). Results: Adjuvant administration of PTK787/ZK222584 significantly prolonged tumor growth time to reach 5 times the volume at start of drug treatment by an average of 11 days (95% confidence interval 0.06;22) in FaDu tumors and 29 days (0.6;58) in UT-SCC-14 tumors. In both tumor models, TCD 50 values were not statistically significantly different between the groups treated with PTK787/ZK222584 compared to controls. Conclusions: Long-term inhibition of angiogenesis after radiotherapy significantly reduced the growth rate of local recurrences but did not improve local tumor control. This indicates that recurrences after irradiation depend on vascular endothelial growth factor-driven angiogenesis, but surviving tumor cells retain their clonogenic potential during adjuvant antiangiogenic treatment with PTK787/ZK222584

  10. The prognostic role of controlling nutritional status scores in patients with solid tumors.

    Science.gov (United States)

    Liang, Ruo-Fei; Li, Jun-Hong; Li, Mao; Yang, Yuan; Liu, Yan-Hui

    2017-11-01

    We conducted a meta-analysis to investigate the association between preoperative controlling nutritional status (CONUT) scores in various solid tumors and clinical outcomes. Relevant studies published up to August 12, 2017 were identified using electronic databases, including PubMed, Embase, and Web of Science. The pooled hazard ratios (HR) and their corresponding 95% confidence intervals (CI) for overall survival (OS) and event-free survival (EFS) were calculated to explore the relationship between preoperative CONUT score and prognosis. In total, 674 patients with solid tumors from four published studies were included in this meta-analysis. The pooled HR for OS was 1.98 (95% CI, 1.34-2.91, p=0.001), indicating that patients with high CONUT scores had worse OS. The pooled HR for EFS was 1.98 (95% CI, 1.34-2.93, p=0.001), revealing that high CONUT scores were significantly associated with short EFS. Our data suggest that high preoperative CONUT scores indicate poor prognosis for patients with solid tumors. Further studies are needed to verify the significance of CONUT scores in clinical practice. Copyright © 2017. Published by Elsevier B.V.

  11. A comprehensive quality control workflow for paired tumor-normal NGS experiments.

    Science.gov (United States)

    Schroeder, Christopher M; Hilke, Franz J; Löffler, Markus W; Bitzer, Michael; Lenz, Florian; Sturm, Marc

    2017-06-01

    Quality control (QC) is an important part of all NGS data analysis stages. Many available tools calculate QC metrics from different analysis steps of single sample experiments (raw reads, mapped reads and variant lists). Multi-sample experiments, as sequencing of tumor-normal pairs, require additional QC metrics to ensure validity of results. These multi-sample QC metrics still lack standardization. We therefore suggest a new workflow for QC of DNA sequencing of tumor-normal pairs. With this workflow well-known single-sample QC metrics and additional metrics specific for tumor-normal pairs can be calculated. The segmentation into different tools offers a high flexibility and allows reuse for other purposes. All tools produce qcML, a generic XML format for QC of -omics experiments. qcML uses quality metrics defined in an ontology, which was adapted for NGS. All QC tools are implemented in C ++ and run both under Linux and Windows. Plotting requires python 2.7 and matplotlib. The software is available under the 'GNU General Public License version 2' as part of the ngs-bits project: https://github.com/imgag/ngs-bits. christopher.schroeder@med.uni-tuebingen.de. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

  12. Quantification and controllability study of minimally invasive exothermic chemo-ablation therapy for tumor ablation.

    Science.gov (United States)

    Liu, Ran; Huang, Yu; Liu, Jing

    2009-01-01

    The recently proposed exothermic chemical reaction based tumor hyperthermia method presented a new way of realizing truly minimally invasive treatment for tumor. This method utilizes heat generated from the reaction between acid and alkali solutions to allow for tumor ablation. Successful clinical implementation of this method requires a clearer understanding and quantification of the ablation area such that a more controllable operation can be made. A number of in-vitro and in-vivo experiments are designed to examine the features of thermal chemo-ablation therapy which include micro and macro characteristics of ablated tissue and temperature change during the ablation process. A Quantitative study on the relationship between velocity and ablation volume as well as a Graphical User Interface in Matlab for computerized ablation area analysis are also presented in this article. We present in here two instrument designs for thermal chemo-ablation and have completed the prototype design for the injection pump which has been tested and successfully applied in ex-vivo and vivo experiments.

  13. Control of Tumor Initiation by NKG2D Naturally Expressed on Ovarian Cancer Cells

    Directory of Open Access Journals (Sweden)

    Xin Cai

    2017-06-01

    Full Text Available Cancer cells may co-opt the NKG2D lymphocyte receptor to complement the presence of its ligands for autonomous stimulation of oncogenic signaling. Previous studies raise the possibility that cancer cell NKG2D may induce high malignancy traits, but its full oncogenic impact is unknown. Using epithelial ovarian cancer as model setting, we show here that ex vivo NKG2D+ cancer cells have stem-like capacities, and provide formal in vivo evidence linking NKG2D stimulation with the development and maintenance of these functional states. NKG2D+ ovarian cancer cell populations harbor substantially greater capacities for self-renewing in vitro sphere formation and in vivo tumor initiation in immunodeficient (NOD scid gamma mice than NKG2D− controls. Sphere formation and tumor initiation are impaired by NKG2D silencing or ligand blockade using antibodies or a newly designed pan ligand-masking NKG2D multimer. In further support of pathophysiological significance, a prospective study of 47 high-grade serous ovarian cancer cases revealed that the odds of disease recurrence were significantly greater and median progression-free survival rates higher among patients with above and below median NKG2D+ cancer cell frequencies, respectively. Collectively, our results define cancer cell NKG2D as an important regulator of tumor initiation in ovarian cancer and presumably other malignancies and thus challenge current efforts in immunotherapy aimed at enhancing NKG2D function.

  14. A moderate elevation of blood glucose level increases the effectiveness of thermoradiotherapy in a rat tumor model II. improved tumor control at clinically achievable temperatures

    International Nuclear Information System (INIS)

    Berg, Ad P. van den; Berg-Blok, Anneke E. van den; Kal, Henk B.; Reinhold, Huib S.

    2001-01-01

    Purpose: To assess the therapeutic gain (at the TCD 50 level) that can be obtained by boosting thermoradiotherapy with intravenous glucose infusion at different temperatures. This completes our series of studies to determine the optimal conditions and the effectiveness of glucose administration at clinically achievable glucose levels and treatment temperatures. Methods and Materials: Subcutaneous rat rhabdomyosarcoma BA1112 was irradiated with graded single doses of 300-kV X-rays (dose range 0-60 Gy). Fifteen minutes after irradiation, a 100-min intravenous infusion was started, consisting of either glucose (20% solution, 2.4-3 g/kg/h) or saline as a control. Then heat was applied to the tumors at 42 deg. C or 43 deg. C (water bath) during a subsequent 100-min period of infusion. Tumor control was scored as the absence of palpable growth at 100 days after treatment. Results: Glucose infusion enhanced tumor control independent of temperature in the range 42-43 deg. C. At 42 deg. C, the TCD 50 for X-irradiation decreased by 5.9 Gy (SEM 1.8 Gy), from 41.6 (1.6) to 35.7 (1.5) Gy, and at 43 deg. C from 33.3 (1.6) to 27.3 (1.5) Gy, representing a glucose enhancement ratio of approximately 1.2. At doses corresponding to the TCD 50 at either 42 or 43 deg. C, the addition of glucose increased tumor control from 50% to 70%. An enhancement ratio of 2.1 was found for the combination of irradiation, glucose infusion, and heating at 43 deg. C, with respect to irradiation alone (TCD 50 56.3 Gy, reanalyzed earlier data). The contribution of combined heat and glucose to tumor control represented an additive effect, probably on the hypoxic cell population. Conclusion: Moderate glucose administration (blood concentration 300 mg/100 mL) sizably improves experimental tumor control after combined X-irradiation and hyperthermia under clinically feasible conditions. Clinical treatment should benefit from this additional modality, in particular if unsatisfactory local control rates are due

  15. Stereotactic radiosurgery vs. fractionated radiotherapy for tumor control in vestibular schwannoma patients

    DEFF Research Database (Denmark)

    Persson, Oscar; Bartek, Jiri; Shalom, Netanel Ben

    2017-01-01

    included in the systematic review. Loss of tumor control necessitating a new VS-targeted intervention was found in an average of 5.0% of the patients treated with SRS and in 4.8% treated with FSRT. Mean deterioration ratio for patients with serviceable hearing before treatment was 49% for SRS and 45...... noninvasive treatment alternatives for patients with VS with low rates of treatment failure in need of rescue therapy. In this selection of patients, the progression-free survival rates were on the order of 92-100% for both treatment options. There is a lack of high-quality studies comparing radiation therapy...

  16. Pituitary tumor risk in relation to mobile phone use: A case-control study.

    Science.gov (United States)

    Shrestha, Mithila; Raitanen, Jani; Salminen, Tiina; Lahkola, Anna; Auvinen, Anssi

    2015-01-01

    The number of mobile phone users has grown rapidly, which has generated mounting public concern regarding possible health hazards. This study aims to assess pituitary tumor risk, as it has rarely been investigated. A case-control study was conducted with 80 eligible cases identified from all five university hospitals in Finland and frequency-matched 240 controls from the national population register. Controls were matched to cases by age, sex, region of residence and date of interview. A detailed history of mobile phone use was obtained using a structured interview. Several indicators of mobile phone use were assessed using conditional logistic regression. A reduced odds ratio was seen among regular mobile phone users [OR 0.39, 95% confidence interval (CI) 0.21, 0.72] relative to never/non-regular users, possibly reflecting methodological limitations. Pituitary tumor risk was not increased after 10 or more years since first use (OR 0.69, 95% CI 0.25, 1.89). The risk was not increased in relation to duration, cumulative hours of use, or cumulative number of calls. The results were similar for analog and digital phones. We found no excess risk associated with self-reported short- or medium-term use of mobile phones. This is consistent with most of the published studies. However, uncertainties remained for longer duration of use, as a very small proportion of study participants reported use beyond 10 years.

  17. Tumor necrosis factor α inhibits expression of the iron regulating hormone hepcidin in murine models of innate colitis.

    Directory of Open Access Journals (Sweden)

    Nanda Kumar N Shanmugam

    Full Text Available Abnormal expression of the liver peptide hormone hepcidin, a key regulator of iron homeostasis, contributes to the pathogenesis of anemia in conditions such as inflammatory bowel disease (IBD. Since little is known about the mechanisms that control hepcidin expression during states of intestinal inflammation, we sought to shed light on this issue using mouse models.Hepcidin expression was evaluated in two types of intestinal inflammation caused by innate immune activation-dextran sulfate sodium (DSS-induced colitis in wild-type mice and the spontaneous colitis occurring in T-bet/Rag2-deficient (TRUC mice. The role of tumor necrosis factor (TNF α was investigated by in vivo neutralization, and by treatment of a hepatocyte cell line, as well as mice, with the recombinant cytokine. Expression and activation of Smad1, a positive regulator of hepcidin transcription, were assessed during colitis and following administration or neutralization of TNFα. Hepcidin expression progressively decreased with time during DSS colitis, correlating with changes in systemic iron distribution. TNFα inhibited hepcidin expression in cultured hepatocytes and non-colitic mice, while TNFα neutralization during DSS colitis increased it. Similar results were obtained in TRUC mice. These effects involved a TNFα-dependent decrease in Smad1 protein but not mRNA.TNFα inhibits hepcidin expression in two distinct types of innate colitis, with down-regulation of Smad1 protein playing an important role in this process. This inhibitory effect of TNFα may be superseded by other factors in the context of T cell-mediated colitis given that in the latter form of intestinal inflammation hepcidin is usually up-regulated.

  18. Trace metals and over-expression of metallothioneins in bladder tumoral lesions: a case-control study

    Directory of Open Access Journals (Sweden)

    Cymbron Teresa

    2009-07-01

    Full Text Available Abstract Background Previous studies have provided some evidence of a possible association between cancer and metallothioneins. Whether this relates to an exposure to carcinogenic metals remains unclear. Methods In order to examine the association between the expression of metallothioneins and bladder tumors, and to compare the levels of arsenic, cadmium, chromium, lead and nickel in animals with bladder tumors and animals without bladder tumors, 37 cases of bovine bladder tumors and 17 controls were collected. The detection and quantification of metallothioneins in bladder tissue of both cases and controls was performed by immunohistochemistry. And the quantification of metals in tissue and hair was assessed by inductively coupled plasma – mass spectrometry. Results Increased expression of metallothioneins was associated with bladder tumors when compared with non-tumoral bladder tissue (OR = 9.3, 95% CI: 1.0 – 480. The concentrations of cadmium, chromium, lead and nickel in hair of cases were significantly higher than those of controls. However, as for the concentration of metals in bladder tissue, the differences were not significant. Conclusion Though the sample size was small, the present study shows an association between bladder tumors and metallothioneins. Moreover, it shows that concentrations of metals such as cadmium, chromium, lead and nickel in hair may be used as a biomarker of exposure.

  19. Hypofractionated radiotherapy for lung tumors with online cone beam CT guidance and active breathing control

    Science.gov (United States)

    2010-01-01

    Background To study the set-up errors, PTV margin and toxicity of cone beam CT (CBCT) guided hypofractionated radiotherapy with active breathing control (ABC) for patients with non-small cell lung cancer (NSCLC) or metastatic tumors in lung. Methods 32 tumors in 20 patients were treated. Based on the location of tumor, dose per fraction given to tumor was divided into three groups: 12 Gy, 8 Gy and 6 Gy. ABC is applied for every patient. During each treatment, patients receive CBCT scan for online set-up correction. The pre- and post-correction setup errors between fractions, the interfractional and intrafractional, set-up errors, PTV margin as well as toxicity are analyzed. Results The pre-correction systematic and random errors in the left-right (LR), superior-inferior (SI), anterior-posterior (AP) directions were 3.7 mm and 5.3 mm, 3.1 mm and 2.1 mm, 3.7 mm and 2.8 mm, respectively, while the post-correction residual errors were 0.6 mm and 0.8 mm, 0.8 mm and 0.8 mm, 1.2 mm and 1.3 mm, respectively. There was an obvious intrafractional shift of tumor position. The pre-correction PTV margin was 9.5 mm in LR, 14.1 mm in SI and 8.2 mm in AP direction. After CBCT guided online correction, the PTV margin was markedly reduced in all three directions. The post-correction margins ranged 1.5 to 2.1 mm. The treatment was well tolerated by patients, of whom there were 4 (20%) grade1-2 acute pneumonitis, 3 (15%) grade1 acute esophagitis, 2 (10%) grade1 late pneumonitis and 1 (5%) grade 1 late esophagitis. Conclusion The positioning errors for lung SBRT using ABC were significant. Online correction with CBCT image guidance should be applied to reduce setup errors and PTV margin, which may reduce radiotherapy toxicity of tissues when ABC was used. PMID:20187962

  20. Hypofractionated radiotherapy for lung tumors with online cone beam CT guidance and active breathing control

    International Nuclear Information System (INIS)

    Shen, Yali; Zhang, Hong; Wang, Jin; Zhong, Renming; Jiang, Xiaoqing; Xu, Qinfeng; Wang, Xin; Bai, Sen; Xu, Feng

    2010-01-01

    To study the set-up errors, PTV margin and toxicity of cone beam CT (CBCT) guided hypofractionated radiotherapy with active breathing control (ABC) for patients with non-small cell lung cancer (NSCLC) or metastatic tumors in lung. 32 tumors in 20 patients were treated. Based on the location of tumor, dose per fraction given to tumor was divided into three groups: 12 Gy, 8 Gy and 6 Gy. ABC is applied for every patient. During each treatment, patients receive CBCT scan for online set-up correction. The pre- and post-correction setup errors between fractions, the interfractional and intrafractional, set-up errors, PTV margin as well as toxicity are analyzed. The pre-correction systematic and random errors in the left-right (LR), superior-inferior (SI), anterior-posterior (AP) directions were 3.7 mm and 5.3 mm, 3.1 mm and 2.1 mm, 3.7 mm and 2.8 mm, respectively, while the post-correction residual errors were 0.6 mm and 0.8 mm, 0.8 mm and 0.8 mm, 1.2 mm and 1.3 mm, respectively. There was an obvious intrafractional shift of tumor position. The pre-correction PTV margin was 9.5 mm in LR, 14.1 mm in SI and 8.2 mm in AP direction. After CBCT guided online correction, the PTV margin was markedly reduced in all three directions. The post-correction margins ranged 1.5 to 2.1 mm. The treatment was well tolerated by patients, of whom there were 4 (20%) grade1-2 acute pneumonitis, 3 (15%) grade1 acute esophagitis, 2 (10%) grade1 late pneumonitis and 1 (5%) grade 1 late esophagitis. The positioning errors for lung SBRT using ABC were significant. Online correction with CBCT image guidance should be applied to reduce setup errors and PTV margin, which may reduce radiotherapy toxicity of tissues when ABC was used

  1. Hypofractionated radiotherapy for lung tumors with online cone beam CT guidance and active breathing control

    Directory of Open Access Journals (Sweden)

    Wang Xin

    2010-02-01

    Full Text Available Abstract Background To study the set-up errors, PTV margin and toxicity of cone beam CT (CBCT guided hypofractionated radiotherapy with active breathing control (ABC for patients with non-small cell lung cancer (NSCLC or metastatic tumors in lung. Methods 32 tumors in 20 patients were treated. Based on the location of tumor, dose per fraction given to tumor was divided into three groups: 12 Gy, 8 Gy and 6 Gy. ABC is applied for every patient. During each treatment, patients receive CBCT scan for online set-up correction. The pre- and post-correction setup errors between fractions, the interfractional and intrafractional, set-up errors, PTV margin as well as toxicity are analyzed. Results The pre-correction systematic and random errors in the left-right (LR, superior-inferior (SI, anterior-posterior (AP directions were 3.7 mm and 5.3 mm, 3.1 mm and 2.1 mm, 3.7 mm and 2.8 mm, respectively, while the post-correction residual errors were 0.6 mm and 0.8 mm, 0.8 mm and 0.8 mm, 1.2 mm and 1.3 mm, respectively. There was an obvious intrafractional shift of tumor position. The pre-correction PTV margin was 9.5 mm in LR, 14.1 mm in SI and 8.2 mm in AP direction. After CBCT guided online correction, the PTV margin was markedly reduced in all three directions. The post-correction margins ranged 1.5 to 2.1 mm. The treatment was well tolerated by patients, of whom there were 4 (20% grade1-2 acute pneumonitis, 3 (15% grade1 acute esophagitis, 2 (10% grade1 late pneumonitis and 1 (5% grade 1 late esophagitis. Conclusion The positioning errors for lung SBRT using ABC were significant. Online correction with CBCT image guidance should be applied to reduce setup errors and PTV margin, which may reduce radiotherapy toxicity of tissues when ABC was used.

  2. FXR Controls the Tumor Suppressor NDRG2 and FXR Agonists Reduce Liver Tumor Growth and Metastasis in an Orthotopic Mouse Xenograft Model

    Science.gov (United States)

    Deuschle, Ulrich; Schüler, Julia; Schulz, Andreas; Schlüter, Thomas; Kinzel, Olaf; Abel, Ulrich; Kremoser, Claus

    2012-01-01

    The farnesoid X receptor (FXR) is expressed predominantly in tissues exposed to high levels of bile acids and controls bile acid and lipid homeostasis. FXR−/− mice develop hepatocellular carcinoma (HCC) and show an increased prevalence for intestinal malignancies, suggesting a role of FXR as a tumor suppressor in enterohepatic tissues. The N-myc downstream-regulated gene 2 (NDRG2) has been recognized as a tumor suppressor gene, which is downregulated in human hepatocellular carcinoma, colorectal carcinoma and many other malignancies. We show reduced NDRG2 mRNA in livers of FXR−/− mice compared to wild type mice and both, FXR and NDRG2 mRNAs, are reduced in human HCC compared to normal liver. Gene reporter assays and Chromatin Immunoprecipitation data support that FXR directly controls NDRG2 transcription via IR1-type element(s) identified in the first introns of the human, mouse and rat NDRG2 genes. NDRG2 mRNA was induced by non-steroidal FXR agonists in livers of mice and the magnitude of induction of NDRG2 mRNA in three different human hepatoma cell lines was increased when ectopically expressing human FXR. Growth and metastasis of SK-Hep-1 cells was strongly reduced by non-steroidal FXR agonists in an orthotopic liver xenograft tumor model. Ectopic expression of FXR in SK-Hep1 cells reduced tumor growth and metastasis potential of corresponding cells and increased the anti-tumor efficacy of FXR agonists, which may be partly mediated via increased NDRG2 expression. FXR agonists may show a potential in the prevention and/or treatment of human hepatocellular carcinoma, a devastating malignancy with increasing prevalence and limited therapeutic options. PMID:23056173

  3. FXR controls the tumor suppressor NDRG2 and FXR agonists reduce liver tumor growth and metastasis in an orthotopic mouse xenograft model.

    Directory of Open Access Journals (Sweden)

    Ulrich Deuschle

    Full Text Available The farnesoid X receptor (FXR is expressed predominantly in tissues exposed to high levels of bile acids and controls bile acid and lipid homeostasis. FXR(-/- mice develop hepatocellular carcinoma (HCC and show an increased prevalence for intestinal malignancies, suggesting a role of FXR as a tumor suppressor in enterohepatic tissues. The N-myc downstream-regulated gene 2 (NDRG2 has been recognized as a tumor suppressor gene, which is downregulated in human hepatocellular carcinoma, colorectal carcinoma and many other malignancies.We show reduced NDRG2 mRNA in livers of FXR(-/- mice compared to wild type mice and both, FXR and NDRG2 mRNAs, are reduced in human HCC compared to normal liver. Gene reporter assays and Chromatin Immunoprecipitation data support that FXR directly controls NDRG2 transcription via IR1-type element(s identified in the first introns of the human, mouse and rat NDRG2 genes. NDRG2 mRNA was induced by non-steroidal FXR agonists in livers of mice and the magnitude of induction of NDRG2 mRNA in three different human hepatoma cell lines was increased when ectopically expressing human FXR. Growth and metastasis of SK-Hep-1 cells was strongly reduced by non-steroidal FXR agonists in an orthotopic liver xenograft tumor model. Ectopic expression of FXR in SK-Hep1 cells reduced tumor growth and metastasis potential of corresponding cells and increased the anti-tumor efficacy of FXR agonists, which may be partly mediated via increased NDRG2 expression. FXR agonists may show a potential in the prevention and/or treatment of human hepatocellular carcinoma, a devastating malignancy with increasing prevalence and limited therapeutic options.

  4. Ipsilateral irradiation for well lateralized carcinomas of the oral cavity and oropharynx: results on tumor control and xerostomia

    OpenAIRE

    Marín Alicia; López Mario; Martín Margarita; Cerezo Laura; Gómez Alberto

    2009-01-01

    Abstract Background In head and neck cancer, bilateral neck irradiation is the standard approach for many tumor locations and stages. Increasing knowledge on the pattern of nodal invasion leads to more precise targeting and normal tissue sparing. The aim of the present study was to evaluate the morbidity and tumor control for patients with well lateralized squamous cell carcinomas of the oral cavity and oropharynx treated with ipsilateral radiotherapy. Methods Twenty consecutive patients with...

  5. Tumor control and normal tissue complications in BNCT treatment of nodular melanoma: A search for predictive quantities

    International Nuclear Information System (INIS)

    Gonzalez, S.J.; Casal, M.; Pereira, M.D.; Santa Cruz, G.A.; Carando, D.G.; Blaumann, H.; Bonomi, M.; Calzetta Larrieu, O.; Feld, D.; Fernandez, C.; Gossio, S.; Jimenez Rebagliatti, R.; Kessler, J.; Longhino, J.; Menendez, P.; Nievas, S.; Roth, B.M.C; Liberman, S.J.

    2009-01-01

    A previous work concerning tumor control and skin damage in cutaneous melanoma treatments with BNCT has been extended to include doses, volumes and responses of 104 subcutaneous lesions from all patients treated in Argentina. Acute skin reactions were also scored for these patients, and cumulative dose-area histograms and dose-based figures of merit for skin were calculated. Broadening the tumor response analysis with the latest data showed that the (minimum or mean) tumor dose is not a good predictor of the observed clinical outcome by itself. However, when the tumor volume was included in the model as second explicative variable, the dose increases its significance and becomes a critical variable jointly with the volume (p-values 3 ) doses greater than 20 Gy-Eq produce a high tumor control (> 80%). However, when tumor volumes are larger than 0.1 cm 3 , control is moderate (< 40%) even for minimum doses up to 40 Gy-Eq. Some quantities based on skin doses, areas and complication probabilities were proposed as candidates for predicting the severity of the early skin reactions. With the current data, all the evaluated figures of merit derived similar results: ulceration is present among the cases for which these quantities take the highest values.

  6. Tumor control, eye preservation, and visual outcomes of ruthenium plaque brachytherapy for choroidal melanoma.

    Science.gov (United States)

    Marconi, Daniel Grossi; de Castro, Douglas Guedes; Rebouças, Lievin Matos; Bernardes Gil, Gabriel Oliveira; Fogaroli, Ricardo Cesar; Conte Maia, Maria Aparecida; Gobo Silva, Maria Leticia; Assis Pellizzon, Antonio Cassio; Motono Chojniak, Maria Marta

    2013-01-01

    To evaluate outcomes in patients with posterior choroidal melanoma treated with ruthenium ((106)Ru) brachytherapy. A retrospective single institutional analysis of 83 of 94 consecutive patients who underwent (106)Ru brachytherapy was performed. Disease was mainly staged as small- and medium-sized nonmetastatic melanoma. The main parameters evaluated were tumor control (local control [LC] and progression-free survival [PFS]) and ocular preservation (enucleation-free survival [EFS]). Besides, functional evaluation was performed and complications were described. The median follow-up was 39 (6-83) months. The median values of height and maximal basal diameter were 4.3 and 9.3mm, respectively. Median apical and basal doses were 100 and 307Gy, respectively. The actuarial 2-year LC, PFS, and EFS were 96.2%, 96.2%, and 95.5%, respectively. Actuarial 5-year LC, PFS, and EFS were 93.6%, 93.6%, and 84.1%, respectively. Preinsertion visual acuity (VA) maintenance was 34% (equal or better than before treatment). Approximately 56% of patients stayed with a minimum functional VA of 0.1 or more, from whom more than half stayed with 0.5 or more. Cataract was seen in 16% of treated eyes, and glaucoma was the rarest complication, with an incidence of 3%. Small- and medium-sized choroidal melanomas can be adequately treated with (106)Ru brachytherapy, with high rates of tumor control and ocular preservation. Moreover, acceptable incidence of complications such as glaucoma and cataract are seen, and a reasonable part of patients stay with a minimum functional VA. Copyright © 2013 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

  7. Radiation therapy for primary carcinoma of the eyelid. Tumor control and visual function

    International Nuclear Information System (INIS)

    Hata, M.; Koike, I.; Odagiri, K.; Kasuya, T.; Minagawa, Y.; Kaizu, H.; Mukai, Y.; Inoue, T.; Maegawa, J.; Kaneko, A.

    2012-01-01

    Background and purpose: Surgical excision remains the standard and most reliable curative treatment for eyelid carcinoma, but frequently causes functional and cosmetic impairment of the eyelid. We therefore investigated the efficacy and safety of radiation therapy in eyelid carcinoma. Patients and methods: Twenty-three patients with primary carcinoma of the eyelid underwent radiation therapy. Sebaceous carcinoma was histologically confirmed in 16 patients, squamous cell carcinoma in 6, and basal cell carcinoma in 1. A total dose of 50-66.6 Gy (median, 60 Gy) was delivered to tumor sites in 18-37 fractions (median, 30 fractions). Results: All but 3 of the 23 patients had survived at a median follow-up period of 49 months. The overall survival and local progression-free rates were 87% and 93% at 2 years, and 80% and 93% at 5 years, respectively. Although radiation-induced cataracts developed in 3 patients, visual acuity in the other patients was relatively well preserved. There were no other therapy-related toxicities of grade 3 or greater. Conclusion: Radiation therapy is safe and effective for patients with primary carcinoma of the eyelid. It appears to contribute to prolonged survival as a result of good tumor control, and it also facilitates functional and cosmetic preservation of the eyelid. (orig.)

  8. Radiation therapy for primary carcinoma of the eyelid. Tumor control and visual function

    Energy Technology Data Exchange (ETDEWEB)

    Hata, M.; Koike, I.; Odagiri, K.; Kasuya, T.; Minagawa, Y.; Kaizu, H.; Mukai, Y.; Inoue, T. [Yokohama City Univ. Graduate School of Medicine, Kanagawa (Japan). Dept. of Radiology; Maegawa, J. [Yokohama City Univ. Graduate School of Medicine, Kanagawa (Japan). Dept. of Plastic and Reconstructive Surgery; Kaneko, A. [Yokohama City Univ. Graduate School of Medicine, Kanagawa (Japan). Dept. of Ophthalmology

    2012-12-15

    Background and purpose: Surgical excision remains the standard and most reliable curative treatment for eyelid carcinoma, but frequently causes functional and cosmetic impairment of the eyelid. We therefore investigated the efficacy and safety of radiation therapy in eyelid carcinoma. Patients and methods: Twenty-three patients with primary carcinoma of the eyelid underwent radiation therapy. Sebaceous carcinoma was histologically confirmed in 16 patients, squamous cell carcinoma in 6, and basal cell carcinoma in 1. A total dose of 50-66.6 Gy (median, 60 Gy) was delivered to tumor sites in 18-37 fractions (median, 30 fractions). Results: All but 3 of the 23 patients had survived at a median follow-up period of 49 months. The overall survival and local progression-free rates were 87% and 93% at 2 years, and 80% and 93% at 5 years, respectively. Although radiation-induced cataracts developed in 3 patients, visual acuity in the other patients was relatively well preserved. There were no other therapy-related toxicities of grade 3 or greater. Conclusion: Radiation therapy is safe and effective for patients with primary carcinoma of the eyelid. It appears to contribute to prolonged survival as a result of good tumor control, and it also facilitates functional and cosmetic preservation of the eyelid. (orig.)

  9. Radiotherapy in desmoid tumors. Treatment response, local control, and analysis of local failures

    Energy Technology Data Exchange (ETDEWEB)

    Santti, Kirsi; Beule, Annette; Tuomikoski, Laura; Jaeaeskelaeinen, Anna-Stina; Saarilahti, Kauko; Tarkkanen, Maija; Blomqvist, Carl [Helsinki University Hospital and University of Helsinki, Comprehensive Cancer Center, Helsinki (Finland); Roenty, Mikko [HUSLAB and University of Helsinki, Department of Pathology, Helsinki (Finland); Ihalainen, Hanna [Helsinki University Hospital and University of Helsinki, Department of Plastic Surgery, Helsinki (Finland)

    2017-04-15

    Desmoid tumors (aggressive fibromatosis) are rare soft tissue tumors which frequently recur after surgery. Desmoid tumors arise from musculoaponeurotic tissue in the extremities, head and neck, abdominal wall, or intra-abdominally. Our aim was to examine the outcome of radiotherapy of desmoid tumors in a single institution series. We evaluated 41 patients with desmoid tumors treated with 49 radiotherapies between 1987 and 2012. Radiologic images for response evaluation were reassessed and responses to treatment registered according to RECIST criteria 1.1. For patients with local failures radiation dose distribution was determined in each local failure volume using image co-registration. Recurrences were classified as in-target, marginal, or out-of-target. Prognostic factors for radiotherapy treatment failure were evaluated. Radiotherapy doses varied from 20-63 Gy (median 50 Gy) with a median fraction size of 2 Gy. The objective response rate to definitive radiotherapy was 55% (12/22 patients). Median time to response was 14 months. A statistically significant dose-response relation for definitive and postoperative radiotherapy was observed both in univariate (p-value 0.002) and in multivariate analysis (p-value 0.02) adjusted for potential confounding factors. Surgery before radiotherapy or surgical margin had no significant effect on time to progression. Nine of 11 (82%) local failures were classified as marginal and two of 11 (18%) in-target. None of the recurrences occurred totally out-of-target. Radiotherapy is a valuable option for treating desmoid tumors. Radiotherapy dose appears to be significantly associated to local control. (orig.) [German] Desmoide (aggressive Fibromatosen) sind seltene Weichteiltumore der muskulaeren Membranen von Kopf, Hals, Extremitaeten und Bauchwand. Ziel war es, die Wirksamkeit der Strahlentherapie bei aggressiver Fibromatose an einer einzelnen Klinik zu untersuchen. Ausgewertet wurden 41 Patienten mit aggressiver Fibromatose, die

  10. Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma.

    Science.gov (United States)

    Sekar, Divya; Govene, Luisa; Del Río, María-Luisa; Sirait-Fischer, Evelyn; Fink, Annika F; Brüne, Bernhard; Rodriguez-Barbosa, José I; Weigert, Andreas

    2018-03-07

    Natural Killer T cells (NKT cells) are emerging as critical regulators of pro- and anti-tumor immunity, both at baseline and in therapeutic settings. While type I NKT cells can promote anti-tumor immunity, their activity in the tumor microenvironment may be limited by negative regulators such as inhibitory immune checkpoints. We observed dominant expression of B- and T-lymphocyte attenuator (BTLA) on type I NKT cells in polyoma middle T oncogene-driven (PyMT) murine autochthonous mammary tumors. Other immune checkpoint receptors, such as programmed cell death 1 (PD-1) were equally distributed among T cell populations. Interference with BTLA using neutralizing antibodies limited tumor growth and pulmonary metastasis in the PyMT model in a therapeutic setting, correlating with an increase in type I NKT cells and expression of cytotoxic marker genes. While therapeutic application of an anti-PD-1 antibody increased the number of CD8+ cytotoxic T cells and elevated IL-12 expression, tumor control was not established. Expression of ZBTB16, the lineage-determining transcription factor of type I NKT cells, was correlated with a favorable patient prognosis in the METABRIC dataset, and BTLA levels were instrumental to further distinguish prognosis in patents with high ZBTB16 expression. Taken together, these data support a role of BTLA on type I NKT cells in limiting anti-tumor immunity.

  11. Plasma metabolomic profiles in breast cancer patients and healthy controls: by race and tumor receptor subtypes.

    Science.gov (United States)

    Shen, Jie; Yan, Li; Liu, Song; Ambrosone, Christine B; Zhao, Hua

    2013-12-01

    A few studies in the last several years have shown that metabolomics, the study of metabolites and small intermediate molecules, may help better understand the breast carcinogenesis. However, breast cancer is a heterogeneous disease with different subtypes. Additionally, there is a significant racial difference in terms of breast cancer incidence and mortality. Few, if any, metabolomics studies in breast cancer have considered race and tumor subtypes in the study design. We performed a global metabolomic profiling using mass spectrometry and samples from 60 breast cancer cases and 60 matched controls. A total of 375 named metabolites were observed, with 117 metabolites whose levels were significantly different between African American and Caucasian American women (P racial difference.

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

    Science.gov (United States)

    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

  13. Cervix cancer: clinical aspects of tumoral control and radiotherapy treatment time

    International Nuclear Information System (INIS)

    Petitto, J.V.

    1994-01-01

    The author analyzed 35 patients with recurrence or residual tumor at the end of the radiotherapy program. These patients were selected out of a group of 338 patients cervix cancer who had also undergone on the same radiotherapy program. Those patients were compared with control group of 30 patients without clinical evidence of the disease, from the same group of 338 patients. It has studied the clinical results considering the total radiotherapy time to developed the radiation program and factors that could modify the time for a longer program, and also modify the final survival results. No significant difference was shown in this study, but it should be taken in consideration the total radiotherapy time, because this is a factor that could change the final results if the time would be longer than what was shown in this work. (author). 26 refs, 10 tabs

  14. Risk factors for central nervous system tumors in children: New findings from a case-control study.

    Directory of Open Access Journals (Sweden)

    Rebeca Ramis

    Full Text Available Central nervous system tumors (CNS are the most frequent solid tumor in children. Causes of CNS tumors are mainly unknown and only 5% of the cases can be explained by genetic predisposition. We studied the effects of environmental exposure on the incidence of CNS tumors in children by subtype, according to exposure to industrial and/or urban environment, exposure to crops and according to socio-economic status of the child.We carried out a population-based case-control study of CNS tumors in Spain, covering 714 incident cases collected from the Spanish Registry of Childhood Tumors (period 1996-2011 and 4284 controls, individually matched by year of birth, sex, and autonomous region of residence. We built a covariate to approximate the exposure to industrial and/or urban environment and a covariate for the exposure to crops (GCI using the coordinates of the home addresses of the children. We used the 2001 Census to obtain information about socio-economic status (SES. We fitted logistic regression models to estimate odds ratios (ORs and 95% confidence intervals (95%CIs.The results for all CNS tumors showed an excess risk (OR = 1.37; 95%CI = 1.09-1.73 for SES, i.e., children living in the least deprived areas had 37% more risk of CNS tumor than children living in the most deprived areas. For GCI, an increase of 10% in crop surface in the 1-km buffer around the residence implied an increase of 22% in the OR (OR = 1.22; 95%CI = 1.15-1.29. Children living in the intersection of industrial and urban areas could have a greater risk of CNS tumors than children who live outside these areas (OR = 1.20; 95%CI = 0.82-1.77. Living in urban areas (OR = 0.90; 95%CI = 0.65-1.24 or industrial areas (OR = 0.96; 95%CI = 0.81-1.77 did not seem to increase the risk for all CNS tumors together. By subtype, Astrocytomas, Intracranial and intraspinal embryonal tumors, and other gliomas showed similar results.Our results suggest that higher socioeconomic status and

  15. Differential control of the cholesterol biosynthetic pathway in tumor versus liver: evidence for decontrolled tumor cholesterogenesis in a cell-free system

    International Nuclear Information System (INIS)

    Azrolan, N.

    1987-01-01

    Cholesterol biosynthesis was characterized in cell-free post-mitochondrial supernatant (PMS) systems prepared from both normal rat liver and Morris hepatoma 3924A. Per cell, the rate of cholesterol synthesis from either 14 C-citrate of 14 -acetate in the hepatoma system was 9-fold greater than that observed in the liver system. Furthermore, the ratio of sterol-to-fatty acid synthesis rates from 14 C-citrate was more than 3-fold greater in the tumor than in the normal liver system. Incubations using radiolabeled acetate and mevalonate have demonstrated the loss of a normally rate-limiting control site within the early portion of the cholesterol biosynthetic pathway in the tumor system. Upon analysis of the steady-state levels of early lipogenic intermediates, the specific site of decontrol in the tumor was identified as the 3-hydroxy-3-methylglutaryl-CoA → mevalonate site of this pathway. In contrast, this reaction appeared to retain its rate-limiting properties in the cell-free system from normal liver

  16. Therapeutic T cells induce tumor-directed chemotaxis of innate immune cells through tumor-specific secretion of chemokines and stimulation of B16BL6 melanoma to secrete chemokines

    Directory of Open Access Journals (Sweden)

    Fox Bernard A

    2007-11-01

    Full Text Available Abstract Background The mechanisms by which tumor-specific T cells induce regression of established metastases are not fully characterized. In using the poorly immunogenic B16BL6-D5 (D5 melanoma model we reported that T cell-mediated tumor regression can occur independently of perforin, IFN-γ or the combination of both. Characterization of regressing pulmonary metastases identified macrophages as a major component of the cells infiltrating the tumor after adoptive transfer of effector T cells. This led us to hypothesize that macrophages played a central role in tumor regression following T-cell transfer. Here, we sought to determine the factors responsible for the infiltration of macrophages at the tumor site. Methods These studies used the poorly immunogenic D5 melanoma model. Tumor-specific effector T cells, generated from tumor vaccine-draining lymph nodes (TVDLN, were used for adoptive immunotherapy and in vitro analysis of chemokine expression. Cellular infiltrates into pulmonary metastases were determined by immunohistochemistry. Chemokine expression by the D5 melanoma following co-culture with T cells, IFN-γ or TNF-α was determined by RT-PCR and ELISA. Functional activity of chemokines was confirmed using a macrophage migration assay. T cell activation of macrophages to release nitric oxide (NO was determined using GRIES reagent. Results We observed that tumor-specific T cells with a type 1 cytokine profile also expressed message for and secreted RANTES, MIP-1α and MIP-1β following stimulation with specific tumor. Unexpectedly, D5 melanoma cells cultured with IFN-γ or TNF-α, two type 1 cytokines expressed by therapeutic T cells, secreted Keratinocyte Chemoattractant (KC, MCP-1, IP-10 and RANTES and expressed mRNA for MIG. The chemokines released by T cells and cytokine-stimulated tumor cells were functional and induced migration of the DJ2PM macrophage cell line. Additionally, tumor-specific stimulation of wt or perforin

  17. Cloning, expression and characterization of translationally controlled tumor protein (TCTP) gene from flatfish turbot ( Scophthalmus maximus)

    Science.gov (United States)

    Wang, Jian; Guo, Huarong; Zhang, Shicui; Yin, Licheng; Guo, Bin; Wang, Shaojie

    2008-05-01

    A full-length cDNA encoding translationally controlled tumor protein of marine flatfish turbot ( Scophthalmus maximus), SmTCTP, was isolated with rapid amplification of cDNA Ends (RACE). SmTCTP consisted of a 5' untranslated region (UTR) of 84 bp, a 3' UTR of 451 bp and an open reading frame (ORF) of 513 bp, encoding a protein of 170 amino acid residues, which contained two signature sequences of TCTP family. The 5'UTR of SmTCTP started with a 5'-terminal oligopyrimidine tract (5'-TOP), a typical feature for translationally controlled mRNAs. The deduced amino acid sequence of SmTCTP was similar to the other known vertebrate TCTPs in a range of 58.8% to 64.1%. The length of fish TCTPs was diverse among species, e.g., TCP of turbot and sea perch ( Lateolabrax japonicus) is 170 aa in length, while that of zebrafish ( Danio rerio) and rohu ( Labeo rohita) is 171 aa in length. Northern blot analysis revealed that SmTCTP has only one type of mRNA. Its expression level in albino skin was slightly higher than that in normal skin. We constructed the pET30a- SmTCTP expression plasmid. The recombinant protein of His-tag SmTCTP was over-expressed in E. coli, purified and identified with peptide mass fingerprinting. These results may pave the way of further investigation of the biological function of TCTP in fish.

  18. IL4-induced gene 1 promotes tumor growth by shaping the immune microenvironment in melanoma.

    Science.gov (United States)

    Bod, Lloyd; Lengagne, Renée; Wrobel, Ludovic; Ramspott, Jan Philipp; Kato, Masashi; Avril, Marie-Françoise; Castellano, Flavia; Molinier-Frenkel, Valérie; Prévost-Blondel, Armelle

    2017-01-01

    Amino acid catabolizing enzymes emerged as a crucial mechanism used by tumors to dampen immune responses. The L-phenylalanine oxidase IL-4 induced gene 1 (IL4I1) is expressed by tumor-associated myeloid cells of most solid tumors, including melanoma. We previously provided the only evidence that IL4I1 accelerates tumor growth by limiting the CD8 + T cell mediated immune response, in a mouse model of melanoma cell transplantation. Here, we explored the role of IL4I1 in Ret mice, a spontaneous model of melanoma. We found that IL4I1 was expressed by CD11b + myeloid cells and that its activity correlated with disease aggressiveness. IL4I1 did not enhance tumor cell proliferation or angiogenesis, but orchestrated the remodeling of the immune compartment within the primary tumor. Indeed, the inactivation of IL4I1 limited the recruitment of polymorphonuclear myeloid-derived suppressor cells and enhanced the infiltration by Th1 and cytotoxic T cells, thus delaying tumor development and metastatic dissemination. Accordingly, human primary melanomas that were poorly infiltrated by IL4I1 + cells exhibited a higher density of CD8 + T cells. Collectively, our findings strengthen the rationale for therapeutic targeting of IL4I1 as one of the key immune regulators.

  19. Significance of hypoxia for tumor response to radiation: Mathematical modeling and analysis of local control and clonogenic assay data

    International Nuclear Information System (INIS)

    Buffa, Francesca Meteora

    2002-01-01

    Various hypotheses for radiation local tumor control probability (ltcp) were modeled, and assessed against local tumor control (LTC) and clonogenic assay (CA) data. For head-and-neck tumors receiving low-LET external-beam irradiation, the best model was a Poisson ltcp accounting for cell repopulation, hypoxia, and tumor volume dependence of radiosensitivity (α). This confirmed that hypoxia is limiting LTC of these tumors, with the magnitude depending upon tumor volume. However, LTC of cervical carcinoma receiving external-beam irradiation and brachytherapy was well described by a model not accounting for hypoxia. Furthermore, when the survival fraction at 2 Gy (SF 2 ) and colony forming efficiency (CFE) measured for individual patients were incorporated into this model, very good correlation with LTC was seen (p=0.0004). After multivariate analysis, this model was the best independent prognostic factor for LTC and patient survival. Furthermore, no difference in prediction was seen when a model based on birth-and-death stochastic theory was used. Two forms of hypoxia are known to be present in tumors: diffusion-limited, chronic hypoxia (CH), and acute, transient hypoxia (TH). A modeling study on WiDr multicellular spheroids showed that the CH effect on LTC is significantly lower than expected from CA. This could arise from energy charge depletion accompanying CH, reducing the number of proliferating clonogenic cells that can repair radiation damage, and thus mitigating the radioresistance of CH cells. This suggests that TH, rather than CH, may be the limiting factor for in vivo LTC. Finally, by computing ltcp using Monte Carlo calculated dose distributions, it was shown that Monte Carlo statistical noise can cause an underestimation of ltcp, with the magnitude depending upon the model hypotheses

  20. Au Nanoclusters and Photosensitizer Dual Loaded Spatiotemporal Controllable Liposomal Nanocomposites Enhance Tumor Photodynamic Therapy Effect by Inhibiting Thioredoxin Reductase.

    Science.gov (United States)

    Gao, Fuping; Zheng, Weiping; Gao, Liang; Cai, Pengju; Liu, Ru; Wang, Yaling; Yuan, Qing; Zhao, Yuliang; Gao, Xueyun

    2017-04-01

    Photodynamic therapy (PDT) is a minimally invasive therapeutic procedure of tumors with high selectivity and low side effect. However, it is usually not efficient in long-lasting tumor control. One of the main reasons is tumor cells develop some protective mechanisms that help them to deal with oxidative stress in the environment. The thioredoxin system in cancer is an important antioxidant defense system. Au nanoclusters could effectively inhibit thioredoxin reductase (TrxR) in tumor cell cytoplasm. Herein, Au nanoclusters and photosensitizer Chlorine 6 (Ce6) are co-loaded in spatiotemporal controllable liposomal nanocomposites. pH responsive molecule inserted in lipid bilayer greatly contributes to the instability of the lipid membrane in lysosomal at low pH environment. Then the payloads can rapidly release into cytoplasm. Au nanoclusters effectively inhibit TrxR in cytoplasm and enhance the photodynamic-induced intracellular reactive oxygen-free radical concentration, improving the effect of PDT. Breast cancer is chosen as a tumor model and the Au nanoclusters and photosensitizer co-loaded liposomal nanocomposites are studied to improve the effect of PDT both in vitro and in vivo, and its corresponding mechanism is investigated. This study develops a new application of gold nanoclusters and provides a new train of thoughts for enhancing the effect of PDT. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Quality of life in young patients after bone tumor surgery around the knee joint and comparison with healthy controls.

    NARCIS (Netherlands)

    Bekkering, W.P.; Vliet Vlieland, T.P.M.; Koopman, H.M.; Schaap, G.R.; Schreuder, H.W.B.; Beishuizen, A.; Tissing, W.J.; Hoogerbrugge, P.M.; Anninga, J.K.; Taminiau, A.H.M.

    2010-01-01

    BACKGROUND: This study aimed to compare the health related quality of life (HRQoL) of children and adolescents after malignant bone tumor surgery of the leg with healthy controls. PROCEDURE: Patients between 8 and 25 years old were cross-sectional recruited. Patients under 16 years of age received

  2. Quality of Life in Young Patients After Bone Tumor Surgery Around the Knee Joint and Comparison With Healthy Controls

    NARCIS (Netherlands)

    Bekkering, W. Peter; Vlieland, Theodora P. M. Vliet; Koopman, Hendrik M.; Schaap, Gerard R.; Schreuder, H. W. Bart; Beishuizen, Auke; Tissing, Wim J. E.; Hoogerbrugge, Peter M.; Anninga, Jacob K.; Taminiau, Antonie H. M.

    Background. This study aimed to compare the health related quality of life (HRQoL) of children and adolescents after malignant bone tumor surgery of the leg with healthy controls. Procedure. Patients between 8 and 25 years old were cross-sectional recruited. Patients under 16 years of age received

  3. Quality of life in young patients after bone tumor surgery around the knee joint and comparison with healthy controls

    NARCIS (Netherlands)

    Bekkering, W. Peter; Vliet Vlieland, Theodora P. M.; Koopman, Hendrik M.; Schaap, Gerard R.; Schreuder, H. W. Bart; Beishuizen, Auke; Tissing, Wim J. E.; Hoogerbrugge, Peter M.; Anninga, Jacob K.; Taminiau, Antonie H. M.

    2010-01-01

    This study aimed to compare the health related quality of life (HRQoL) of children and adolescents after malignant bone tumor surgery of the leg with healthy controls. Patients between 8 and 25 years old were cross-sectional recruited. Patients under 16 years of age received the TNO (Netherlands

  4. Modeling freedom from progression for standard-risk medulloblastoma: a mathematical tumor control model with multiple modes of failure

    DEFF Research Database (Denmark)

    Brodin, Nils Patrik; Vogelius, Ivan R.; Bjørk-Eriksson, Thomas

    2013-01-01

    As pediatric medulloblastoma (MB) is a relatively rare disease, it is important to extract the maximum information from trials and cohort studies. Here, a framework was developed for modeling tumor control with multiple modes of failure and time-to-progression for standard-risk MB, using published...

  5. Local tumor control and morbidity after one to three fractions of stereotactic external beam irradiation for uveal melanoma.

    Science.gov (United States)

    Zehetmayer, M; Kitz, K; Menapace, R; Ertl, A; Heinzl, H; Ruhswurm, I; Georgopoulos, M; Dieckmann, K; Pötter, R

    2000-05-01

    To evaluate prospectively local tumor control and morbidity after 1-3 fractions of stereotactic external beam irradiation (SEBI) in patients with uveal melanoma, unsuitable for ruthenium-106 brachytherapy or local resection. This phase I/II study includes 62 selected patients with uveal melanoma. The mean initial tumor height was 7.8+/-2.8 mm. With the Leskell gamma knife SEBI, 41 patients (66%) were irradiated with two equal fractions of 35, 30 or 25 Gy/fraction, 14 patients (22%) were treated with three fractions of 15 Gy each, and seven patients (11%) with small tumor volumes below 400 mm(3) were treated with one fraction of 45 Gy. The mean total dose was 54+/-8 Gy. The minimal follow-up period was 12 months, and the median follow-up was 28.3 months. Data on radiation-induced side-effects were analyzed with the Cox proportional hazards model for possible risk factors. Local tumor control was achieved in 98% and tumor height reduction in 97%. The mean relative tumor volume reductions were 44, 60 and 72% after 12, 24 and 36 months, respectively. Seven patients developed metastases (11%). Secondary enucleation was performed in eight eyes (13%). Morbidity was significant in tumors exceeding 8 mm in initial height; it was comparable and acceptable in those smaller. In the stepwise multiple Cox model, tumor localization, height and volume, planning target volume (PTV), total dose and patient age were identified as the strongest risk factors for radiation-induced lens opacities, secondary glaucoma, uveitis, eyelash loss and exudative retinal detachment. In this model, the high-dose volume irradiated with more than 10 Gy/fraction was the strongest risk factor for radiation-induced uveitis. Stereotactic external photon beam irradiation and a total dose of 45-70 Gy delivered in one to three fractions are highly effective at achieving local tumor control in uveal melanoma. Further clinical studies using smaller fraction doses, and consequent smaller high-dose volumes, are

  6. External beam irradiation of craniopharyngiomas: long-term analysis of tumor control and morbidity

    International Nuclear Information System (INIS)

    Varlotto, John M.; Flickinger, John C.; Kondziolka, Douglas; Lunsford, L.D.; Deutsch, Melvin

    2002-01-01

    Purpose: To delineate the long-term control and morbidity with external beam radiotherapy (EBRT) of craniopharyngiomas. Methods and Materials: Between 1971 and 1992, 24 craniopharyngioma patients underwent EBRT at the University of Pittsburgh. Most (19 of 24) were treated within 1-3 months after subtotal resection. The other prior surgical procedures were biopsy (n = 2) and gross total resection (n = 1); 2 patients did not undergo any surgical procedure. The median follow-up was 12.1 years. The median patient age was 29 years (range 5-69). The total radiation doses varied from 36 to 70 Gy (median 59.75). The normalized total dose (NTD, biologically equivalent dose given in 2 Gy/fraction [α/β ratio = 2]) varied from 28 to 83 Gy (median 55.35). Results: The actuarial survival rate at 10 and 20 years was 100% and 92.3%, respectively. The actuarial local control rate at 10 and 20 years was 89.1% and 54.0%, respectively. No local failures occurred with doses ≥60 Gy (n=12) or NTDs ≥55 Gy. The complication-free survival rate at 10 and 20 years was 80.1% and 72.1%, respectively. No complications were noted with an NTD of ≤55 Gy. The actuarial survival free from any adverse outcome (recurrence or complication) was 70.1% and 31.8% at 10 and 20 years, respectively. The adverse outcome-free survival appeared optimized (at 73%) with an NTD of 55-63 Gy. Multivariate analysis found that tumor control correlated significantly with the total dose (p=0.02), treatment complications with NTD (p=0.008), and adverse outcome with hypopituitarism on presentation (p=0.03). Conclusion: We recommend treating craniopharyngioma with 1.6-1.7-Gy dose fractions to 60 Gy to optimize outcome from EBRT

  7. Surgical Control of a Primary Hepatic Carcinoid Tumor: A Case Report

    Directory of Open Access Journals (Sweden)

    Norio Yokoigawa

    2009-04-01

    Full Text Available We report a primary hepatic carcinoid tumor occurring in a 47-year-old man. The patient consulted our hospital complaining of epigastralgia. Abdominal ultrasonography, computed tomography scanning, and magnetic resonance imaging showed a large mass in the right lobe of the liver. FDG-PET revealed 18F-FDG uptake by the right hepatic lobe. The tumor was a solid mass with cystic components, approximately 15 cm in diameter. We conducted an extended right lobectomy of the liver. The resected specimen was a solid tumor with cystic components and hemorrhagic lesion. Microscopic findings showed that the tumor cells had round nuclei and formed trabecular patterns. Immunohistologically, tumor cells were stained positive for chromogranin A, neuron specific enolase, CD56, and S-100. Careful examinations before and after the operation revealed no other possible origin of the tumor. Based on these findings, the tumor was diagnosed as a primary hepatic carcinoid. This is a report of a rare case of a primary hepatic carcinoid tumor with a discussion of several other relevant reports.

  8. Animal tumors

    International Nuclear Information System (INIS)

    Gillette, E.L.

    1983-01-01

    There are few trained veterinary radiation oncologists and the expense of facilities has limited the extent to which this modality is used. In recent years, a few cobalt teletherapy units and megavoltage x-ray units have been employed in larger veterinary institutions. In addition, some radiation oncologists of human medical institutions are interested and willing to cooperate with veterinarians in the treatment of animal tumors. Carefully designed studies of the response of animal tumors to new modalities serve two valuable purposes. First, these studies may lead to improved tumor control in companion animals. Second, these studies may have important implications to the improvement of therapy of human tumors. Much remains to be learned of animal tumor biology so that appropriate model systems can be described for such studies. Many of the latter studies can be sponsored by agencies interested in the improvement of cancer management

  9. Development of one control and one tumor-specific induced pluripotent stem cell line from laryngeal carcinoma patient

    Directory of Open Access Journals (Sweden)

    Yamin Zhang

    2017-12-01

    Full Text Available Skin fibroblasts and tumor fibroblasts were extracted from a 64-year old male patient clinically diagnosed with laryngeal carcinoma. Control and tumor specific induced pluripotent stem cells were reprogrammed with 5 reprogramming factors, Klf-4, c-Myc, Oct-4, Sox-2, and Lin-28, using the messenger RNA reprogramming system. The transgene-free iPSC lines showed pluripotency, confirmed by immunofluorescence staining. The iPSC lines also showed normal karyotype, and could form embryoid bodies in vitro and differentiate into the 3 germ layers in vivo. This in vitro cellular model can be used to study the oncogenesis and pathogenesis of laryngeal carcinoma.

  10. Characterization of the pumpkin Translationally-Controlled Tumor Protein CmTCTP.

    Science.gov (United States)

    Hinojosa-Moya, J Jesús; Xoconostle-Cázares, Beatriz; Toscano-Morales, Roberto; Ramírez-Ortega, Francisco; Cabrera-Ponce, José Luis; Ruiz-Medrano, Roberto

    2013-01-01

    In higher plants, the phloem plays a central role in the delivery of nutrients and signals from source to sink tissues. These signals likely coordinate different aspects of plant development, as well as its response to environmental cues. Although some phloem-transported proteins and RNAs may function as signaling molecules in plants, their mode of action remains poorly understood. Previous analysis of transcripts from CMV-infected pumpkin (Cucurbita maxima cv Big Max) identified a Translationally-Controlled Tumor Protein (TCTP) mRNA homolog, designated CmTCTP. In the present work this transcript was analyzed in terms of its expression pattern. This RNA accumulates, both in healthy and CMV-infected plants, in developing and mature phloem in petiole and roots, as well as in apices at high levels. The protein was present at lower levels in most cell types, and almost no signal was detected in apices, suggesting translational regulation of this RNA. Additionally, CmTCTP harbored by Agrobacterium rhizogenes is capable of inducing whole plant regeneration. These data suggest a role for CmTCTP in growth regulation, possibly through long-distance signaling.

  11. Insulin Induces Phosphorylation of Serine Residues of Translationally Controlled Tumor Protein in 293T Cells

    Directory of Open Access Journals (Sweden)

    Jeehye Maeng

    2015-04-01

    Full Text Available Insulin induces the activation of Na,K-ATPase while translationally controlled tumor protein (TCTP inhibits this enzyme and the associated pump activity. Because binding of insulin with its membrane receptor is known to mediate the phosphorylation of multiple intracellular proteins, phosphorylation of TCTP by insulin might be related to the sodium pump regulation. We therefore examined whether insulin induces TCTP phosphorylation in embryonic kidney 293T cells. Using immunoprecipitation and Western blotting, we found that insulin phosphorylates serine (Ser residues of TCTP. Following fractionation of the insulin-treated cells into cytosol and membrane fractions, phosphorylated TCTP at its Ser residue (p-Ser-TCTP was detected exclusively in the cytosolic part and not in the membrane fraction. Phosphorylation of TCTP reached maximum in about 10 min after insulin treatment in 293T cells. In studies of cell-type specificity of insulin-mediated phosphorylation of TCTP, insulin did not phosphorylate TCTP in HeLa cells. Computational prediction and immunoprecipitation using several constructs having Ser to Ala mutation at potential p-Ser sites of TCTP revealed that insulin phosphorylated the serine-9 and -15 residues of TCTP. Elucidations of how insulin-mediated TCTP phosphorylation promotes Na,K-ATPase activation, may offer potential therapeutic approaches to diseases associated with vascular activity and sodium pump dysregulation.

  12. Characterization of the pumpkin Translationally-Controlled Tumor Protein CmTCTP

    Science.gov (United States)

    Hinojosa-Moya, J Jesús; Xoconostle-Cázares, Beatriz; Toscano-Morales, Roberto; Ramírez-Ortega, Francisco; Luis Cabrera-Ponce, José; Ruiz-Medrano, Roberto

    2013-01-01

    In higher plants, the phloem plays a central role in the delivery of nutrients and signals from source to sink tissues. These signals likely coordinate different aspects of plant development, as well as its response to environmental cues. Although some phloem-transported proteins and RNAs may function as signaling molecules in plants, their mode of action remains poorly understood. Previous analysis of transcripts from CMV-infected pumpkin (Cucurbita maxima cv Big Max) identified a Translationally-Controlled Tumor Protein (TCTP) mRNA homolog, designated CmTCTP. In the present work this transcript was analyzed in terms of its expression pattern. This RNA accumulates, both in healthy and CMV-infected plants, in developing and mature phloem in petiole and roots, as well as in apices at high levels. The protein was present at lower levels in most cell types, and almost no signal was detected in apices, suggesting translational regulation of this RNA. Additionally, CmTCTP harbored by Agrobacterium rhizogenes is capable of inducing whole plant regeneration. These data suggest a role for CmTCTP in growth regulation, possibly through long-distance signaling. PMID:24065051

  13. Limited Margin Radiation Therapy for Children and Young Adults With Ewing Sarcoma Achieves High Rates of Local Tumor Control

    Energy Technology Data Exchange (ETDEWEB)

    Talleur, Aimee C.; Navid, Fariba [Department of Oncology, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Spunt, Sheri L. [Department of Pediatrics, Stanford University School of Medicine, Stanford, California (United States); McCarville, M. Beth [Department of Diagnostic Imaging, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Wu, John; Mao, Shenghua [Department of Biostatistics, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Davidoff, Andrew M. [Department of Surgery, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee (United States); Neel, Michael D. [Department of Surgery, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Krasin, Matthew J., E-mail: matthew.krasin@stjude.org [Department of Radiation Oncology, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States)

    2016-09-01

    Purpose: To determine the rate of local failure using focal conformal, limited margin radiation therapy (RT) and dose escalation for tumors ≥8 cm (greatest dimension at diagnosis) in children and young adults with Ewing sarcoma (EWS). Methods and Materials: Eligible patients with EWS were treated on a phase 2 institutional trial of focal conformal, limited margin RT using conformal or intensity modulated techniques. The treatment volume incorporated a 1-cm constrained margin around the gross tumor. Unresected tumors, <8 cm at diagnosis, received a standard dose of 55.8 Gy and tumors ≥8 cm, an escalated dose to 64.8 Gy. Patients with microscopic residual disease after resection received adjuvant RT to 50.4 Gy. Adjuvant brachytherapy was permitted in selected patients. Results: Forty-five patients were enrolled: 26 with localized and 19 with metastatic disease. Median (range) age, tumor size, and follow-up were 13.0 years (2.9-24.7 years), 9.0 cm (2.4-17.0 cm), and 54.5 months (1.9-122.2 months), respectively. All patients received systemic chemotherapy. The median (range) RT dose for all patients was 56.1 Gy (45-65.5 Gy). Seventeen patients received adjuvant, 16 standard-dose, and 12 escalated-dose RT. Failures included 1 local, 10 distant, and 1 local/distant. The estimated 10-year cumulative incidence of local failure was 4.4% ± 3.1%, with no statistical difference seen between RT treatment groups and no local failures in the escalated-dose RT treatment group. Conclusions: Treatment with focal conformal, limited margin RT, including dose escalation for larger tumors, provides favorable local tumor control in EWS.

  14. Stability of lyophilized pooled sera as quality control materials for tumor marker assays in external quality assessment.

    Science.gov (United States)

    Ahn, Sunyoung; Park, Jungyong; Kim, Young Ran; Kim, Jeong-Ho; Kim, Hyon-Suk

    2017-08-01

    External quality assessment (EQA) requires stable quality control (QC) materials. We evaluated the stability of QC materials made of lyophilized and liquid pooled sera for the tumor markers α-fetoprotein, carcinoembryonic antigen, carbohydrate antigen 125, and carbohydrate antigen 19-9. Specimens of the 4 tumor markers were collected from the sera of patients and stored at -20°C. After sera collection and pooling, liquid or lyophilized samples were stored at -20°C, 5°C, or room temperature. Tumor markers were quantified on days 0, 1, 4, 7, 14, 30, and 90 of storage. Internal QC results were analyzed, and the effects of heat inactivation and sucrose addition were assessed. Heat inactivation lowered tumor marker levels in lyophilized pooled sera, whereas sucrose addition had no effect. The coefficients of variation of the internal QC results were stable, whereas those of lyophilized samples were higher than those of liquid samples. Tumor marker levels were significantly lower in lyophilized samples (ptumor markers. Lyophilized QC materials are insufficiently stable for use in EQA among clinical laboratories. Copyright © 2017. Published by Elsevier B.V.

  15. Radiolabeled anti-EGFR-antibody improves local tumor control after external beam radiotherapy and offers theragnostic potential

    International Nuclear Information System (INIS)

    Koi, Lydia; Bergmann, Ralf; Brüchner, Kerstin; Pietzsch, Jens; Pietzsch, Hans-Jürgen; Krause, Mechthild

    2014-01-01

    Purpose: The effect of radioimmunotherapy (RIT) using the therapeutic radionuclide Y-90 bound to the anti-EGFR antibody cetuximab combined with external beam irradiation (EBRT) (EBRIT) on permanent local tumor control in vivo was examined. Methods: Growth delay was evaluated in three human squamous cell carcinoma models after RIT with [ 90 Y]Y-(CHX-A′′-DTPA) 4 -cetuximab (Y-90-cetuximab). The EBRT dose required to cure 50% of the tumors (TCD 50 ) for EBRT alone or EBRIT was evaluated in one RIT-responder (FaDu) and one RIT-non-responder (UT-SCC-5). EGFR expression and microenvironmental parameters were evaluated in untreated tumors, bioavailability was visualized by PET using ([ 86 Y]Y-(CHX-A′′-DTPA) 4 -cetuximab (Y-86-cetuximab) and biodistribution using Y-90-cetuximab. Results: In UT-SCC-8 and FaDu but not in UT-SCC-5 radiolabeled cetuximab led to significant tumor growth delay. TCD 50 after EBRT was significantly decreased by EGFR-targeted RIT in FaDu but not in UT-SCC-5. In contrast to EGFR expression, parameters of the tumor micromilieu and in particular the Y-90-cetuximab biodistribution or Y-86-cetuximab visualization in PET correlated with the responsiveness to RIT or EBRIT. Conclusion: EGFR-targeted EBRIT can improve permanent local tumor control compared to EBRT alone. PET imaging of bioavailability of labeled cetuximab appears to be a suitable predictor for response to EBRIT. This theragnostic approach should be further explored for clinical translation

  16. Expanding roles for CD4 T cells and their subpopulations in tumor immunity and therapy

    Directory of Open Access Journals (Sweden)

    Mark J Dobrzanski

    2013-03-01

    Full Text Available The importance of CD4 T cells in orchestrating the immune system and their role in inducing effective T cell-mediated therapies for the treatment of patients with select established malignancies are undisputable. Through a complex and balanced array of direct and indirect mechanisms of cellular activation and regulation, this functionally diverse family of lymphocytes can potentially promote tumor eradication, long-term tumor immunity and aid in establishing and/or rebalancing immune cell homeostasis through interaction with other immune cell populations within the highly dynamic tumor environment. However, recent studies have uncovered additional functions and roles for CD4 T cells, some of which are independent of other lymphocytes, that can not only influence and contribute to tumor immunity but paradoxically promote tumor growth and progression. Here, we review the recent advances in our understanding of the various CD4 T cell lineages and their signature cytokines in disease progression and/or regression. We discuss their direct and indirect mechanistic interplay among themselves and with other responding cells of the antitumor response, their potential roles and abilities for "plasticity" and memory cell generation within the hostile tumor environment and their potentials in cancer treatment and adoptive immunotherapies.

  17. Local control and intermediate-term cosmetic outcome following IMRT for nasal tumors. An update

    Energy Technology Data Exchange (ETDEWEB)

    Mukai, Yuki [University Hospital Zurich, Department of Radiation Oncology, Head Neck Cancer Center, Zurich (Switzerland); Yokohama City University Graduate School of Medicine, Department of Radiology, Yokohama (Japan); Janssen, Stefan [University Hospital Zurich, Department of Radiation Oncology, Head Neck Cancer Center, Zurich (Switzerland); Glanzmann, Christoph; Studer, Gabriela [University Hospital Zurich, Department of Radiation Oncology, Head Neck Cancer Center, Zurich (Switzerland); Cantonal Hospital Lucerne, Institute for Radiation Oncology, Lucerne (Switzerland); Holzmann, David [University Hospital Zurich, Department of Otorhinolaryngology, Head and Neck Surgery, Head Neck Cancer Center, Zurich (Switzerland)

    2017-04-15

    This study aims to evaluate local control and intermediate-term cosmetic outcome in patients with cancer of the nose treated with intensity-modulated radiotherapy (IMRT). From June 2008 to September 2015, 36 consecutive patients presenting with nasal cavity, ala of the nose, or nasal vestibule tumors were treated at the Department of Radiation Oncology, University Hospital Zurich either postoperatively (n = 14; 3/14 with nasal ablation) or with definitive IMRT (n = 22). Of these 36 patients, 8 presented with recurrent disease after surgery only and 1/36 with N1 disease. Concurrent systemic therapy was administered in 18/36 patients (50%). Nasal follow-up (FU) imaging documentation of 13 patients with preserved organ and >6 months FU offers a pre/post IMRT FU comparison. In addition, these patients' subjective evaluation of cosmesis was assessed. Mean/median FU was 41/33 months (range 5-92 months). Salvage ablation with curative intent was undergone by 3 patients with local relapse after definitive (n = 2) and postoperative (n = 1) IMRT. The 3-year local control, ultimate local control, and overall survival rates were 90, 97, and 90 %, respectively. Subjective and objective cosmetic outcome after IMRT is very satisfying so far. IMRT for nasal tumors was found to be effective and well tolerated. Intermediate-term cosmetic results are good. Radical surgical procedures may be saved for curative salvage treatment. (orig.) [German] Evaluation der Lokalkontrolle und des mittelfristigen kosmetischen Resultats nach intensitaetsmodulierter Radiotherapie (IMRT) von Patienten mit Nasentumoren. Von Juni 2008 bis September 2015 wurden an der Klinik fuer RadioOnkologie am UniversitaetsSpital Zuerich 36 konsekutive Patienten mit Tumoren der Nasenhoehle, der Nasenfluegel oder des Vestibulum nasi postoperativ (n = 14; 3/14 nach Nasenablation) oder definitiv IMRT-bestrahlt (n = 22). Von diesen 36 Patienten zeigten 8 ein Lokalrezidiv nach alleiniger vorangegangener Chirurgie und

  18. Stochastic modelling of slow-progressing tumors: Analysis and applications to the cell interplay and control of low grade gliomas

    Science.gov (United States)

    Rodríguez, Clara Rojas; Fernández Calvo, Gabriel; Ramis-Conde, Ignacio; Belmonte-Beitia, Juan

    2017-08-01

    Tumor-normal cell interplay defines the course of a neoplastic malignancy. The outcome of this dual relation is the ultimate prevailing of one of the cells and the death or retreat of the other. In this paper we study the mathematical principles that underlay one important scenario: that of slow-progressing cancers. For this, we develop, within a stochastic framework, a mathematical model to account for tumor-normal cell interaction in such a clinically relevant situation and derive a number of deterministic approximations from the stochastic model. We consider in detail the existence and uniqueness of the solutions of the deterministic model and study the stability analysis. We then focus our model to the specific case of low grade gliomas, where we introduce an optimal control problem for different objective functionals under the administration of chemotherapy. We derive the conditions for which singular and bang-bang control exist and calculate the optimal control and states.

  19. Magnesium intake and colorectal tumor risk: a case-control study and meta-analysis.

    NARCIS (Netherlands)

    Wark, P.A.; Lau, R.; Norat, T.; Kampman, E.

    2012-01-01

    BACKGROUND: Dietary magnesium might be related to colorectal tumor risk through the pivotal roles of magnesium in cellular metabolism, insulin resistance, and systemic inflammation. OBJECTIVE: We evaluated the hypothesis of whether higher dietary magnesium intake is associated with reduced

  20. Magnesium intake and colorectal tumor risk : a case-control study and meta-analysis

    NARCIS (Netherlands)

    Wark, P.A.; Lau, R.; Norat, T.; Kampman, E.

    2012-01-01

    Background: Dietary magnesium might be related to colorectal tumor risk through the pivotal roles of magnesium in cellular metabolism, insulin resistance, and systemic inflammation. Objective: We evaluated the hypothesis of whether higher dietary magnesium intake is associated with reduced

  1. Estimating the risk of brain tumors from cellphone use: Published case-control studies.

    Science.gov (United States)

    Morgan, L Lloyd

    2009-08-01

    This paper reviews the results of early cellphone studies, where exposure duration was too short to expect tumorigenesis, as well as two sets of more recent studies with longer exposure duration: the Interphone studies and the Swedish studies led by Dr. Lennart Hardell. The recent studies reach very different conclusions. With four exceptions the industry-funded Interphone studies found no increased risk of brain tumors from cellphone use, while the Swedish studies, independent of industry funding, reported numerous findings of significant increased brain tumor risk from cellphone and cordless phone use. An analysis of the data from the Interphone studies suggests that either the use of a cellphone protects the user from a brain tumor, or the studies had serious design flaws. Eleven flaws are identified: (1) selection bias, (2) insufficient latency time, (3) definition of 'regular' cellphone user, (4) exclusion of young adults and children, (5) brain tumor risk from cellphones radiating higher power levels in rural areas were not investigated, (6) exposure to other transmitting sources are excluded, (7) exclusion of brain tumor types, (8) tumors outside the cellphone radiation plume are treated as exposed, (9) exclusion of brain tumor cases because of death or illness, (10) recall accuracy of cellphone use, and (11) funding bias. The Interphone studies have all 11 flaws, and the Swedish studies have 3 flaws (8, 9 and 10). The data from the Swedish studies are consistent with what would be expected if cellphone use were a risk for brain tumors, while the Interphone studies data are incredulous. If a risk does exist, the public health cost will be large. These are the circumstances where application of the Precautionary Principle is indicated, especially if low-cost options could reduce the absorbed cellphone radiation by several orders of magnitude.

  2. IDO, PTEN-expressing Tregs and control of antigen-presentation in the murine tumor microenvironment.

    Science.gov (United States)

    Munn, David H; Sharma, Madhav D; Johnson, Theodore S; Rodriguez, Paulo

    2017-08-01

    The tumor microenvironment is profoundly immunosuppressive. This creates a major barrier for attempts to combine immunotherapy with conventional chemotherapy or radiation, because the tumor antigens released by these cytotoxic agents are not cross-presented in an immunogenic fashion. In this Focused Research Review, we focus on mouse preclinical studies exploring the role of immunosuppressive Tregs expressing the PTEN lipid phosphatase, and the links between PTEN+ Tregs and the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). IDO has received attention because it can be expressed by a variety of human tumor types in vivo, but IDO can also be induced in host immune cells of both humans and mice in response to inflammation, infection or dying (apoptotic) cells. Mechanistically, IDO and PTEN+ Tregs are closely connected, with IDO causing activation of the PTEN pathway in Tregs. Genetic ablation or pharmacologic inhibition of PTEN in mouse Tregs destabilizes their suppressive phenotype, and this prevents transplantable and autochthonous tumors from creating their normal immunosuppressive microenvironment. Genetic ablation of either IDO or PTEN+ Tregs in mice results in a fundamental defect in the ability to maintain tolerance to antigens associated with apoptotic cells, including dying tumor cells. Consistent with this, pharmacologic inhibitors of either pathway show synergy when combined with cytotoxic agents such as chemotherapy or radiation. Thus, we propose that IDO and PTEN+ Tregs represent closely linked checkpoints that can influence the choice between immune activation versus tolerance to dying tumor cells.

  3. Dimerization of translationally controlled tumor protein is essential for its cytokine-like activity.

    Directory of Open Access Journals (Sweden)

    Miyoung Kim

    Full Text Available BACKGROUND: Translationally Controlled Tumor Protein (TCTP found in nasal lavage fluids of allergic patients was named IgE-dependent histamine-releasing factor (HRF. Human recombinant HRF (HrHRF has been recently reported to be much less effective than HRF produced from activated mononuclear cells (HRFmn. METHODS AND FINDINGS: We found that only NH(2-terminal truncated, but not C-terminal truncated, TCTP shows cytokine releasing activity compared to full-length TCTP. Interestingly, only NH(2-terminal truncated TCTP, unlike full-length TCTP, forms dimers through intermolecular disulfide bonds. We tested the activity of dimerized full-length TCTP generated by fusing it to rabbit Fc region. The untruncated-full length protein (Fc-HrTCTP was more active than HrTCTP in BEAS-2B cells, suggesting that dimerization of TCTP, rather than truncation, is essential for the activation of TCTP in allergic responses. We used confocal microscopy to evaluate the affinity of TCTPs to its putative receptor. We detected stronger fluorescence in the plasma membrane of BEAS-2B cells incubated with Del-N11TCTP than those incubated with rat recombinant TCTP (RrTCTP. Allergenic activity of Del-N11TCTP prompted us to see whether the NH(2-terminal truncated TCTP can induce allergic airway inflammation in vivo. While RrTCTP had no influence on airway inflammation, Del-N11TCTP increased goblet cell hyperplasia in both lung and rhinal cavity. The dimerized protein was found in sera from allergic patients, and bronchoalveolar lavage fluids from airway inflamed mice. CONCLUSIONS: Dimerization of TCTP seems to be essential for its cytokine-like activity. Our study has potential to enhance the understanding of pathogenesis of allergic disease and provide a target for allergic drug development.

  4. Nuclear DNA but not mtDNA controls tumor phenotypes in mouse cells

    International Nuclear Information System (INIS)

    Akimoto, Miho; Niikura, Mamoru; Ichikawa, Masami; Yonekawa, Hiromichi; Nakada, Kazuto; Honma, Yoshio; Hayashi, Jun-Ichi

    2005-01-01

    Recent studies showed high frequencies of homoplasmic mtDNA mutations in various human tumor types, suggesting that the mutated mtDNA haplotypes somehow contribute to expression of tumor phenotypes. We directly addressed this issue by isolating mouse mtDNA-less (ρ 0 ) cells for complete mtDNA replacement between normal cells and their carcinogen-induced transformants, and examined the effect of the mtDNA replacement on expression of tumorigenicity, a phenotype forming tumors in nude mice. The results showed that genome chimera cells carrying nuclear DNA from tumor cells and mtDNA from normal cells expressed tumorigenicity, whereas those carrying nuclear DNA from normal cells and mtDNA from tumor cells did not. These observations provided direct evidence that nuclear DNA, but not mtDNA, is responsible for carcinogen-induced malignant transformation, although it remains possible that mtDNA mutations and resultant respiration defects may influence the degree of malignancy, such as invasive or metastatic properties

  5. Long-term results of radiotherapy for pituitary adenomas. Evaluation of tumor control and hypopituitarism after radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Tsuchida, Emiko; Sakai, Kunio; Matsumoto, Yasuo; Sugita, Tadashi; Sasamoto, Ryuta [Niigata Univ. (Japan). School of Medicine

    1999-09-01

    To evaluate the results of conventional radiotherapy for pituitary adenomas assessed with computed tomography (CT) or magnetic resonance imaging (MRI). Endpoints include tumor control, normalization of hormone levels in functioning adenomas, and hypopituitarism after radiotherapy as an adverse effect. Forty-two patients were treated with radiotherapy from 1982 to 1995 at Niigata University Hospital. Forty patients were irradiated after surgery because of residual adenomas in 33 patients and tumor regrowth in 7 patients. One patient was treated with radiotherapy alone, and the remaining 1 patient was treated with preoperative radiotherapy. Tumor size and extension were evaluated using CT or MRI, and all tumors were macroadenomas. They consisted of 18 non-functioning and 24 functioning adenomas (growth hormone (GH)-secreting: 11, prolactinomas: 7, concomitant GH and prolactin (PRL)-secreting: 5, gonadotropin-secreting: 1). Treatment was given in 200 cGy daily fraction size and a total dose of 50 Gy was given to most patients. Sixteen patients with GH- and/or PRL-secreting adenomas received bromocriptine. Tumor progression was determined by increase in tumor size as shown by CT or MRI. Hypopituitarism after radiotherapy was evaluated using the functions of corticotropin (ACTH), thyrotropin (TSH), and gonadotropin. Median follow-up time from the end of radiotherapy was 103 months. Tumor progression occurred in 2 out of 42 patients and 10-year progression-free rate for all patients was 93.7%. Normalization of GH levels was obtained in 12 of 16 GH-secreting adenomas with a mean time of 27 months after radiotherapy, and 9 of 12 PRL-secreting adenomas achieved normalization of PRL levels with a mean time of 34 months. One gonadotropin-secreting adenoma achieved normalization of gonadotropin level at 21 months after radiotherapy. The incidence of hypopituitarism after radiotherapy increased with time, and cumulative risk of deficiencies of ACTH, TSH, and gonadotropin at 10

  6. Long-term results of radiotherapy for pituitary adenomas. Evaluation of tumor control and hypopituitarism after radiotherapy

    International Nuclear Information System (INIS)

    Tsuchida, Emiko; Sakai, Kunio; Matsumoto, Yasuo; Sugita, Tadashi; Sasamoto, Ryuta

    1999-01-01

    To evaluate the results of conventional radiotherapy for pituitary adenomas assessed with computed tomography (CT) or magnetic resonance imaging (MRI). Endpoints include tumor control, normalization of hormone levels in functioning adenomas, and hypopituitarism after radiotherapy as an adverse effect. Forty-two patients were treated with radiotherapy from 1982 to 1995 at Niigata University Hospital. Forty patients were irradiated after surgery because of residual adenomas in 33 patients and tumor regrowth in 7 patients. One patient was treated with radiotherapy alone, and the remaining 1 patient was treated with preoperative radiotherapy. Tumor size and extension were evaluated using CT or MRI, and all tumors were macroadenomas. They consisted of 18 non-functioning and 24 functioning adenomas (growth hormone (GH)-secreting: 11, prolactinomas: 7, concomitant GH and prolactin (PRL)-secreting: 5, gonadotropin-secreting: 1). Treatment was given in 200 cGy daily fraction size and a total dose of 50 Gy was given to most patients. Sixteen patients with GH- and/or PRL-secreting adenomas received bromocriptine. Tumor progression was determined by increase in tumor size as shown by CT or MRI. Hypopituitarism after radiotherapy was evaluated using the functions of corticotropin (ACTH), thyrotropin (TSH), and gonadotropin. Median follow-up time from the end of radiotherapy was 103 months. Tumor progression occurred in 2 out of 42 patients and 10-year progression-free rate for all patients was 93.7%. Normalization of GH levels was obtained in 12 of 16 GH-secreting adenomas with a mean time of 27 months after radiotherapy, and 9 of 12 PRL-secreting adenomas achieved normalization of PRL levels with a mean time of 34 months. One gonadotropin-secreting adenoma achieved normalization of gonadotropin level at 21 months after radiotherapy. The incidence of hypopituitarism after radiotherapy increased with time, and cumulative risk of deficiencies of ACTH, TSH, and gonadotropin at 10

  7. Identification of translationally controlled tumor protein in promotion of DNA homologous recombination repair in cancer cells by affinity proteomics

    OpenAIRE

    Li, Y; Sun, H; Zhang, C; Liu, J; Zhang, H; Fan, F; Everley, R A; Ning, X; Sun, Y; Hu, J; Zhang, J; Ye, W; Qiu, X; Dai, S; Liu, B

    2017-01-01

    Translationally controlled tumor protein(TCTP) has been implicated in the regulation of apoptosis, DNA repair and drug resistance. However, the underlying molecular mechanisms are poorly defined. To better understand the molecular mechanisms underlying TCTP involved in cellular processes, we performed an affinity purification-based proteomic profiling to identify proteins interacting with TCTP in human cervical cancer HeLa cells. We found that a group of proteins involved in DNA repair are en...

  8. Edema‐induced changes in tumor cell surviving fraction and tumor control probability in  131Cs permanent prostate brachytherapy implant patients

    Science.gov (United States)

    Jones, Heather A.; Huq, M. Saiful; Smith, Ryan P.

    2013-01-01

    The study is designed to investigate the effect of edema on the delivered dose, tumor cell surviving fraction (SF), and tumor control probability (TCP) in the patients of prostate cancer who underwent  131Cs permanent seed implantation. The dose reduction, the SF, and the TCP for edematous prostate implants were calculated for 31 patients who underwent real‐time  131Cs permanent seed implantation for edema half‐lives (EHL), ranging from 4 days to 34 days and for edema magnitudes (M0) varying from 5% to 60% of the actual prostate volume. A dose reduction in  131Cs implants varied from 1.1% (for EHL=4 days and M0=5%) to 32.3% (for EHL=34 days and M0=60%). These are higher than the dose reduction in  125I implants, which vary from 0.3% (for EHL=4 days and M0=5%) to 17.5% (for EHL=34 days and M0=60%). As EHL increased from 4 days to 34 days and edema magnitude increased from 5% to 60%, the natural logarithmic value of SF increased by 4.57 and the TCP decreased by 0.80. Edema induced increase in the SF and decrease in the TCP in  131Cs seed implants, is significantly more pronounced in a combination of higher edema magnitude and larger edema half‐lives than for less edema magnitude and lower edema half‐lives, as compared for M0=60% and EHL=34, and M0=5% and EHL=4 days. PACS number: 87.53.Jw PMID:23318378

  9. Analysis of the relationship between tumor dose inhomogeneity and local control in patients with skull base chordoma

    International Nuclear Information System (INIS)

    Terahara, Atsuro; Niemierko, Andrzej; Goitein, Michael; Finkelstein, Dianne; Hug, Eugen; Liebsch, Norbert; O'Farrell, Desmond; Lyons, Sue; Munzenrider, John

    1999-01-01

    Purpose: When irradiating a tumor that abuts or displaces any normal structures, the dose constraints to those structures (if lower than the prescribed dose) may cause dose inhomogeneity in the tumor volume at the tumor-critical structure interface. The low-dose region in the tumor volume may be one of the reasons for local failure. The aim of this study is to quantitate the effect of tumor dose inhomogeneity on local control and recurrence-free survival in patients with skull base chordoma. Methods and Materials: 132 patients with skull base chordoma were treated with combined photon and proton irradiation between 1978 and 1993. This study reviews 115 patients whose dose-volume data and follow-up data are available. The prescribed doses ranged from 66.6 Cobalt-Gray-Equivalent (CGE) to 79.2 CGE (median of 68.9 CGE). The dose to the optic structures (optic nerves and chiasma), the brain stem surface, and the brain stem center was limited to 60, 64, and 53 CGE, respectively. We used the dose-volume histogram data derived with the three-dimensional treatment planning system to evaluate several dose-volume parameters including the Equivalent Uniform Dose (EUD). We also analyzed several other patient and treatment factors in relation to local control and recurrence-free survival. Results: Local failure developed in 42 of 115 patients, with the actuarial local control rates at 5 and 10 years being 59% and 44%. Gender was a significant predictor for local control with the prognosis in males being significantly better than that in females (P 0.004, hazard ratio = 2.3). In a Cox univariate analysis, with stratification by gender, the significant predictors for local control (at the probability level of 0.05) were EUD, the target volume, the minimum dose, and the D 5cc dose. The prescribed dose, histology, age, the maximum dose, the mean dose, the median dose, the D 90% dose, and the overall treatment time were not significant factors. In a Cox multivariate analysis, the

  10. Control of Disease Recurrence by Tumor-Infiltrating T Cells in Ovarian Cancer

    Science.gov (United States)

    2010-03-01

    of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med 2005 Mar;11 (3):312–9. [14] Qian F, Villella J, Wallace PK, Mhawech...PLoS Med 5: e232. 55. Gilks CB, Ionescu DN, Kalloger SE, Kobel M, Irving J, et al. (2008) Tumor cell type can be reproducibly diagnosed and is of

  11. Normalization of gene expression measurements in tumor tissues: comparison of 13 endogenous control genes.

    NARCIS (Netherlands)

    Kok, J.B. de; Roelofs, R.W.; Giesendorf, B.A.J.; Pennings, J.L.; Waas, E.T.; Feuth, A.B.; Swinkels, D.W.; Span, P.N.

    2005-01-01

    For interpretation of quantitative gene expression measurements in clinical tumor samples, a normalizer is necessary to correct expression data for differences in cellular input, RNA quality, and RT efficiency between samples. In many studies, a single housekeeping gene is used for normalization.

  12. Singlet oxygen explicit dosimetry to predict long-term local tumor control for Photofrin-mediated photodynamic therapy

    Science.gov (United States)

    Penjweini, Rozhin; Kim, Michele M.; Ong, Yi Hong; Zhu, Timothy C.

    2017-02-01

    Although photodynamic therapy (PDT) is an established modality for the treatment of cancer, current dosimetric quantities do not account for the variations in PDT oxygen consumption for different fluence rates (φ). In this study we examine the efficacy of reacted singlet oxygen concentration ([1O2]rx) to predict long-term local control rate (LCR) for Photofrin-mediated PDT. Radiation-induced fibrosarcoma (RIF) tumors in the right shoulders of female C3H mice are treated with different in-air fluences of 225-540 J/cm2 and in-air fluence rate (φair) of 50 and 75 mW/cm2 at 5 mg/kg Photofrin and a drug-light interval of 24 hours using a 1 cm diameter collimated laser beam at 630 nm wavelength. [1O2]rx is calculated by using a macroscopic model based on explicit dosimetry of Photofrin concentration, tissue optical properties, tissue oxygenation and blood flow changes during PDT. The tumor volume of each mouse is tracked for 90 days after PDT and Kaplan-Meier analyses for LCR are performed based on a tumor volume <=100 mm3, for the four dose metrics light fluence, photosensitizer photobleaching rate, PDT dose and [1O2]rx. PDT dose is defined as a temporal integral of photosensitizer concentration and Φ at a 3 mm tumor depth. φ is calculated throughout the treatment volume based on Monte-Carlo simulation and measured tissue optical properties. Our preliminary studies show that [1O2]rx is the best dosimetric quantity that can predict tumor response and correlate with LCR. Moreover, [1O2]rx calculated using the blood flow changes was in agreement with [1O2]rx calculated based on the actual tissue oxygenation.

  13. Short-term and long-term reproducibility of lung tumor position using active breathing control (ABC)

    International Nuclear Information System (INIS)

    Koshani, Rojano; Balter, James M.; Hayman, James A.; Henning, George T.; Herk, Marcel van

    2006-01-01

    Purpose: To evaluate the short-term and long-term reproducibility of lung tumor position for scans acquired using an active breathing control (ABC) device. Methods and Materials: Ten patients with lung cancer were scanned over three sessions during the course of treatment. For each session, two scans were acquired at deep inhale, and one scan each at half of deep inhale and at exhale. Long-term reproducibility was evaluated by comparing the same breathing state scans from two sessions, with setup variation removed by skeletal alignment. Tumor alignment was based on intensity matching of a small volume around the tumor. For short-term reproducibility, the two inhale volumes from the same session were compared. Results: For the short-term reproducibility, the mean and the standard deviation (SD) of the displacement of the center of tumor were 0.0 (1.5) mm in anteroposterior (AP), 0.3 (1.4) mm in superior/inferior (SI), and 0.2 (0.7) mm in right/left (RL) directions. For long-term reproducibility, the mean (SD) were -1.3 (3.1) mm AP, -0.5 (3.8) mm SI, and 0.3 (1.6) mm RL for inhale and -0.2 (2.8) mm AP, 0.2 (2.1) mm SI, and -0.7 (1.1) mm RL for exhale. Conclusion: The ABC device demonstrates very good short-term and long-term reproducibility. Increased long-term variability in position, primarily in the SI and AP directions, indicates the role of tumor-directed localization in combination with breath-held immobilization

  14. Effect of virtual reality-based rehabilitation on upper-extremity function in patients with brain tumor: controlled trial.

    Science.gov (United States)

    Yoon, Jisun; Chun, Min Ho; Lee, Sook Joung; Kim, Bo Ryun

    2015-06-01

    The aim of this study was to evaluate the benefit of virtual reality-based rehabilitation on upper-extremity function in patients with brain tumor. Patients with upper-extremity dysfunction were divided into age-matched and tumor type-matched two groups. The intervention group performed the virtual reality program 30 mins per session for 9 sessions and conventional occupational therapy 30 mins per session for 6 sessions for 3 wks, whereas the control group received conventional occupational therapy alone 30 mins per session for 15 sessions for 3 wks. The Box and Block test, the Manual Function test, and the Fugl-Meyer scale were used to evaluate upper-extremity function. The Korean version of the Modified Barthel Index was used to assess activities of daily living. Forty patients completed the study (20 for each group). Each group exhibited significant posttreatment improvements in the Box and Block test, Manual Function test, Fugl-Meyer scale, and Korean version of the Modified Barthel Index scores. The Box and Block test, the Fugl-Meyer scale, and the Manual Function test showed greater improvements in shoulder/elbow/forearm function in the intervention group and hand function in the control group. Virtual reality-based rehabilitation combined with conventional occupational therapy may be more effective than conventional occupational therapy, especially for proximal upper-extremity function in patients with brain tumor. Further studies considering hand function, such as use of virtual reality programs that targeting hand use, are required.

  15. Protection against HPV-16-Associated Tumors Requires the Activation of CD8+ Effector Memory T Cells and the Control of Myeloid-Derived Suppressor Cells.

    Science.gov (United States)

    Diniz, Mariana O; Sales, Natiely S; Silva, Jamile R; Ferreira, Luís Carlos S

    2016-08-01

    Active anticancer immunotherapeutic approaches have been shown to induce cellular or humoral immune responses in patients, but, thus far, the observed outcomes did not ensure their recommendation for clinical use. The induction of tumor-specific CD8(+) T cells, although required for the clearance of most solid tumors, was shown to be insufficient for the development of a successful immunotherapeutic approach. The suppressive immune environment triggered by tumors, including the expansion of myeloid-derived suppressor cells (MDSC), is detrimental to the development of antitumor immune responses and precludes the generation of more promising clinical outcomes. In this work, we characterized the CD8(+) T-cell population specifically involved in the control of tumor growth and the role of MDSCs after administration of an antitumor therapeutic DNA vaccine targeting human papillomavirus type 16 (HPV-16)-associated tumors. Activation of cytotoxic high-avidity CD8(+) T cells with an effector memory phenotype was found in mice grafted with tumor cells expressing the HPV-16 oncoproteins. In addition, MDSC antibody depletion further enhanced the immunotherapeutic effects of the vaccine, resulting in the complete eradication of tumor cells. Collectively, the current results indicate that the simultaneous control of MDSCs and activation of high-avidity tumor-specific effector memory CD8(+) T cells are key features for tumor protection by immunotherapeutic approaches and deserve further testing under clinical conditions. Mol Cancer Ther; 15(8); 1920-30. ©2016 AACR. ©2016 American Association for Cancer Research.

  16. Bone tumor

    Science.gov (United States)

    Tumor - bone; Bone cancer; Primary bone tumor; Secondary bone tumor; Bone tumor - benign ... The cause of bone tumors is unknown. They often occur in areas of the bone that grow rapidly. Possible causes include: Genetic defects ...

  17. Changed adipocytokine concentrations in colorectal tumor patients and morbidly obese patients compared to healthy controls

    International Nuclear Information System (INIS)

    Hillenbrand, Andreas; Fassler, Juliane; Huber, Nadine; Xu, Pengfei; Henne-Bruns, Doris; Templin, Markus; Schrezenmeier, Hubert; Wolf, Anna Maria; Knippschild, Uwe

    2012-01-01

    Obesity has been associated with increased incidence of colorectal cancer. Adipose tissue dysfunction accompanied with alterations in the release of adipocytokines has been proposed to contribute to cancer pathogenesis and progression. The aim of this study was to analyze plasma concentrations of several adipose tissue expressed hormones in colorectal cancer patients (CRC) and morbidly obese (MO) patients and to compare these concentrations to clinicopathological parameters. Plasma concentrations of adiponectin, resistin, leptin, active plasminogen activator inhibitor (PAI)-1, monocyte chemotactic protein (MCP)-1, interleukin (IL)-1 alpha, and tumor necrosis factor (TNF)-alpha were determined in 67 patients operated on for CRC (31 rectal cancers, 36 colon cancers), 37 patients operated on for morbid obesity and 60 healthy blood donors (BD). Compared to BD, leptin concentrations were lowered in CRC patients whereas those of MO patients were elevated. Adiponectin concentrations were only lowered in MO patients. Concentrations of MCP-1, PAI-1, and IL-1 alpha were elevated in both CRC and MO patients, while resistin and TNF-alpha were similarly expressed in MO and CRC patients compared to BD. Resistin concentrations positively correlated with tumor staging (p<0.002) and grading (p=0.015) of rectal tumor patients. The results suggest that both MO and CRC have low-grade inflammation as part of their etiology

  18. Epigenetic control of MHC class II expression in tumor-associated macrophages by decoy receptor 3.

    Science.gov (United States)

    Chang, Yung-Chi; Chen, Tse-Ching; Lee, Chun-Ting; Yang, Chih-Ya; Wang, Hsei-Wei; Wang, Chao-Ching; Hsieh, Shie-Liang

    2008-05-15

    Decoy receptor 3 (DcR3) is a member of the TNF receptor superfamily and is up-regulated in tumors originating from a diversity of lineages. DcR3 is capable of promoting angiogenesis, inducing dendritic cell apoptosis, and modulating macrophage differentiation. Since tumor-associated macrophages (TAMs) are the major infiltrating leukocytes in most malignant tumors, we used microarray technology to investigate whether DcR3 contributes to the development of TAMs. Among the DcR3-modulated genes expressed by TAMs, those that encode proteins involved in MHC class II (MHC-II)-dependent antigen presentation were down-regulated substantially, together with the master regulator of MHC-II expression (the class II transactivator, CIITA). The ERK- and JNK-induced deacetylation of histones associated with the CIITA promoters was responsible for DcR3-mediated down-regulation of MHC-II expression. Furthermore, the expression level of DcR3 in cancer cells correlated inversely with HLA-DR levels on TAMs and with the overall survival time of pancreatic cancer patients. The role of DcR3 in the development of TAMs was further confirmed using transgenic mice overexpressing DcR3. This elucidates the molecular mechanism of impaired MHC-II-mediated antigen presentation by TAMs, and raises the possibility that subversion of TAM-induced immunosuppression via inhibition of DcR3 expression might represent a target for the design of new therapeutics.

  19. How do CD4+ T cells detect and eliminate tumor cells that either lack or express MHC class II molecules?

    Directory of Open Access Journals (Sweden)

    Ole Audun Werner Haabeth

    2014-04-01

    Full Text Available CD4+ T cells contribute to tumor eradication, even in the absence of CD8+ T cells. Cytotoxic CD4+ T cells can directly kill MHC class II positive tumor cells. More surprisingly, CD4+ T cells can indirectly eliminate tumor cells that lack MHC class II expression. Here, we review the mechanisms of direct and indirect CD4+ T cell-mediated elimination of tumor cells. An emphasis is put on T cell receptor (TCR transgenic models, where anti-tumor responses of naïve CD4+ T cells of defined specificity can be tracked. Some generalizations can tentatively be made. For both MHCIIPOS and MHCIINEG tumors, presentation of tumor specific antigen by host antigen presenting cells (APCs appears to be required for CD4+ T cell priming. This has been extensively studied in a myeloma model (MOPC315, where host APCs in tumor-draining lymph nodes are primed with secreted tumor antigen. Upon antigen recognition, naïve CD4+ T cells differentiate into Th1 cells and migrate to the tumor. At the tumor site, the mechanisms for elimination of MHCIIPOS and MHCIINEG tumor cells differ. In a TCR transgenic B16 melanoma model, MHCIIPOS melanoma cells are directly killed by cytotoxic CD4+ T cells in a perforin/granzyme B-dependent manner. By contrast, MHCIINEG myeloma cells are killed by IFN-g stimulated M1-like macrophages. In summary, while the priming phase of CD4+ T cells appears similar for MHCIIPOS and MHCIINEG tumors, the killing mechanisms are different. Unresolved issues and directions for future research are addressed.

  20. Suppressive versus augmenting effect of the same pretreatment regimen in two murine tumor systems with distinct effector mechanisms

    International Nuclear Information System (INIS)

    Fujiwara, Hiromi; Hamaoka, Toshiyuki; Kitagawa, Masayasu

    1978-01-01

    The effect of presensitization with x-irradiated tumor cells on the development of host's immune resistance against the tumor-associated transplantation antigens (TATA) was investigated in two syngeneic tumor systems with distinct effector mechanisms. When X5563 plasmacytoma, to which immune resistance was mediated exclusively by killer T lymphocytes, was intravenously inoculated into syngeneic C3H/He mice with lower number after 7000 R x-irradiation, the mice failed to exhibit any protective immunity against the subsequent challenge with viable tumor cells. Moreover, these mice lost their capability to develop any immune resistance even after an appropriate immunization procedure. The immunodepression induced by such a pretreatment regimen was specific for X5563 tumor. While no suppressor cell activity was detected in the above pretreated mice, serum factor(s) from these mice was virtually responsible for this suppression. When the serum factor mediating this tumor-specific suppression was fractionated on the Sephadex G-200 column, the suppressive activity was found in albumin-corresponding fraction, free of any immunoglobulin component. In contrast, in MM102 mammary tumor system, in which immune resistance is solely mediated by tumor-specific antibody, the pretreatment with x-irradiated MM102 cells augmented the induction of anti-tumor immunity. These results indicate that while tumor antigens given in the form of x-irradiated tumor cells suppress the induction of killer T cell-mediated immunity in one system, the same presensitization regimen of tumor antigens augments the antibody-mediated immunity in another system, thus giving a divergent effect on the distinct effector mechanisms of syngeneic tumor immunity. (author)

  1. Lack of MHC class II molecules favors CD8+T-cell infiltration into tumors associated with an increased control of tumor growth.

    Science.gov (United States)

    Chaoul, Nada; Tang, Alexandre; Desrues, Belinda; Oberkampf, Marine; Fayolle, Catherine; Ladant, Daniel; Sainz-Perez, Alexander; Leclerc, Claude

    2018-01-01

    Regulatory T-cells (Tregs) are crucial for the maintenance of immune tolerance and homeostasis as well as for preventing autoimmune diseases, but their impact on the survival of cancer patients remains controversial. In the TC-1 mouse model of human papillomavirus (HPV)-related carcinoma, we have previously demonstrated that the therapeutic efficacy of the CyaA-E7-vaccine, targeting the HPV-E7 antigen, progressively declines with tumor growth, in correlation with increased intratumoral recruitment of Tregs. In the present study, we demonstrated that these TC-1 tumor-infiltrating Tregs were highly activated, with increased expression of immunosuppressive molecules. Both intratumoral effector CD4 + T-cells (Teffs) and Tregs expressed high levels of PD-1, but anti-PD-1 antibody treatment did not impact the growth of the TC-1 tumor nor restore the therapeutic effect of the CyaA-E7 vaccine. To analyze the mechanisms by which Tregs are recruited to the tumor site, we used MHC-II KO mice with drastically reduced numbers of CD4 + effector T-cells. We demonstrated that these mice still had significant numbers of Tregs in their lymphoid organs which were recruited to the tumor. In MHC-II KO mice, the growth of the TC-1 tumor was delayed in correlation with a strong increase in the intratumoral recruitment of CD8 + T-cells. In addition, in mice that spontaneously rejected their tumors, the infiltration of E7-specific CD8 + T-cells was significantly higher than in MHC-II KO mice with a growing tumor. These results demonstrate that tumor-specific CD8 + T-cells can be efficiently activated and recruited in the absence of MHC class II molecules and of CD4 + T-cell help.

  2. Singlet oxygen explicit dosimetry to predict long-term local tumor control for BPD-mediated photodynamic therapy

    Science.gov (United States)

    Kim, Michele M.; Penjweini, Rozhin; Ong, Yi Hong; Zhu, Timothy C.

    2017-02-01

    Photodynamic therapy (PDT) is a well-established treatment modality for cancer and other malignant diseases; however, quantities such as light fluence, photosensitizer photobleaching rate, and PDT dose do not fully account for all of the dynamic interactions between the key components involved. In particular, fluence rate (Φ) effects are not accounted for, which has a large effect on the oxygen consumption rate. In this preclinical study, reacted singlet oxygen [1O2]rx was investigated as a dosimetric quantity for PDT outcome. The ability of [1O2]rx to predict the long-term local tumor control rate (LCR) for BPD-mediated PDT was examined. Mice bearing radioactivelyinduced fibrosarcoma (RIF) tumors were treated with different in-air fluences (250, 300, and 350 J/cm2) and in-air ϕ (75, 100, and150 mW/cm2) with a BPD dose of 1 mg/kg and a drug-light interval of 3 hours. Treatment was delivered with a collimated laser beam of 1 cm diameter at 690 nm. Explicit dosimetry of initial tissue oxygen concentration, tissue optical properties, and BPD concentration was used to calculate [1O2]rx. Φ was calculated for the treatment volume based on Monte-Carlo simulations and measured tissue optical properties. Kaplan-Meier analyses for LCR were done for an endpoint of tumor volume <= 100 mm3 using four dose metrics: light fluence, photosensitizer photobleaching rate, PDT dose, and [1O2]rx. PDT dose was defined as the product of the timeintegral of photosensitizer concentration and Φ at a 3 mm tumor depth. Preliminary studies show that [1O2]rx better correlates with LCR and is an effective dosimetric quantity that can predict treatment outcome.

  3. Modeling Freedom From Progression for Standard-Risk Medulloblastoma: A Mathematical Tumor Control Model With Multiple Modes of Failure

    International Nuclear Information System (INIS)

    Brodin, N. Patrik; Vogelius, Ivan R.; Björk-Eriksson, Thomas; Munck af Rosenschöld, Per; Bentzen, Søren M.

    2013-01-01

    Purpose: As pediatric medulloblastoma (MB) is a relatively rare disease, it is important to extract the maximum information from trials and cohort studies. Here, a framework was developed for modeling tumor control with multiple modes of failure and time-to-progression for standard-risk MB, using published pattern of failure data. Methods and Materials: Outcome data for standard-risk MB published after 1990 with pattern of relapse information were used to fit a tumor control dose-response model addressing failures in both the high-dose boost volume and the elective craniospinal volume. Estimates of 5-year event-free survival from 2 large randomized MB trials were used to model the time-to-progression distribution. Uncertainty in freedom from progression (FFP) was estimated by Monte Carlo sampling over the statistical uncertainty in input data. Results: The estimated 5-year FFP (95% confidence intervals [CI]) for craniospinal doses of 15, 18, 24, and 36 Gy while maintaining 54 Gy to the posterior fossa was 77% (95% CI, 70%-81%), 78% (95% CI, 73%-81%), 79% (95% CI, 76%-82%), and 80% (95% CI, 77%-84%) respectively. The uncertainty in FFP was considerably larger for craniospinal doses below 18 Gy, reflecting the lack of data in the lower dose range. Conclusions: Estimates of tumor control and time-to-progression for standard-risk MB provides a data-driven setting for hypothesis generation or power calculations for prospective trials, taking the uncertainties into account. The presented methods can also be applied to incorporate further risk-stratification for example based on molecular biomarkers, when the necessary data become available

  4. Magnetic resonance guided focused ultrasound surgery (MRgFUS) of bone metastases: From primary pain palliation to local tumor control

    Science.gov (United States)

    Napoli, A.; Leonardi, A.; Andrani, F.; Boni, F.; Anzidei, M.; Catalano, C.

    2017-03-01

    Purpose: To evaluate the clinical performance of MRgFUS in primary pain palliation of painful bone metastases and in local tumor control. Materials and Methods: We enrolled 26 consecutive patients (female/male 12/14; age: 64.7±7.5yrs) with painful bone metastases. Before and 3 months after MRgFUS treatment pain severity and pain interference scores were assessed according to Brief Pain Inventory-Quality of Life (BPI-QoL) criteria and patients underwent both CT and MRI. Local tumor control was evaluated according to lesion size, density and perfusion at CT, dynamic contrast enhancement at MRI (Discovery 750HD, GE; Gd-Bopta, Bracco) and metabolic activity at PET or scintigraphy. Patients were classified as responders or non-responders. Results: No treatment-related adverse events were recorded during the study. As statistically significant difference between baseline and follow-up values for both pain severity and pain interference scores was observed (pbone density was observed in 9/26 (34.6%) patients. Non-Perfused Volume values ranged between 20% and 92%. There was no difference in NPV values between responders and non-responders (46.7±24.2% [25 - 90 %] vs. 45±24.9% [20 - 93 %]; p=0.7). In 6 patients (5 prostate and 1 breast primary cancer) there was nearly absence of metabolic activity after treatment (mean SUV=1.2). Conclusion: MRgFUS can be safely and effectively used as the primary treatment for pain palliation in patients with painful bone metastases; moreover our experience demonstrated also a potential role for the MRgFUS in local tumor control.

  5. Population-based multicase-control study in common tumors in Spain (MCC-Spain): rationale and study design.

    Science.gov (United States)

    Castaño-Vinyals, Gemma; Aragonés, Nuria; Pérez-Gómez, Beatriz; Martín, Vicente; Llorca, Javier; Moreno, Victor; Altzibar, Jone M; Ardanaz, Eva; de Sanjosé, Sílvia; Jiménez-Moleón, José Juan; Tardón, Adonina; Alguacil, Juan; Peiró, Rosana; Marcos-Gragera, Rafael; Navarro, Carmen; Pollán, Marina; Kogevinas, Manolis

    2015-01-01

    We present the protocol of a large population-based case-control study of 5 common tumors in Spain (MCC-Spain) that evaluates environmental exposures and genetic factors. Between 2008-2013, 10,183 persons aged 20-85 years were enrolled in 23 hospitals and primary care centres in 12 Spanish provinces including 1,115 cases of a new diagnosis of prostate cancer, 1,750 of breast cancer, 2,171 of colorectal cancer, 492 of gastro-oesophageal cancer, 554 cases of chronic lymphocytic leukaemia (CLL) and 4,101 population-based controls matched by frequency to cases by age, sex and region of residence. Participation rates ranged from 57% (stomach cancer) to 87% (CLL cases) and from 30% to 77% in controls. Participants completed a face-to-face computerized interview on sociodemographic factors, environmental exposures, occupation, medication, lifestyle, and personal and family medical history. In addition, participants completed a self-administered food-frequency questionnaire and telephone interviews. Blood samples were collected from 76% of participants while saliva samples were collected in CLL cases and participants refusing blood extractions. Clinical information was recorded for cases and paraffin blocks and/or fresh tumor samples are available in most collaborating hospitals. Genotyping was done through an exome array enriched with genetic markers in specific pathways. Multiple analyses are planned to assess the association of environmental, personal and genetic risk factors for each tumor and to identify pleiotropic effects. This study, conducted within the Spanish Consortium for Biomedical Research in Epidemiology & Public Health (CIBERESP), is a unique initiative to evaluate etiological factors for common cancers and will promote cancer research and prevention in Spain. Copyright © 2014 SESPAS. Published by Elsevier Espana. All rights reserved.

  6. Bypassing the EPR effect with a nanomedicine harboring a sustained-release function allows better tumor control.

    Science.gov (United States)

    Shen, Yao An; Shyu, Ing Luen; Lu, Maggie; He, Chun Lin; Hsu, Yen Mei; Liang, Hsiang Fa; Liu, Chih Peng; Liu, Ren Shyan; Shen, Biing Jiun; Wei, Yau Huei; Chuang, Chi Mu

    2015-01-01

    The current enhanced permeability and retention (EPR)-based approved nanomedicines have had little impact in terms of prolongation of overall survival in patients with cancer. For example, the two Phase III trials comparing Doxil(®), the first nanomedicine approved by the US Food and Drug Administration, with free doxorubicin did not find an actual translation of the EPR effect into a statistically significant increase in overall survival but did show less cardiotoxicity. In the current work, we used a two-factor factorial experimental design with intraperitoneal versus intravenous delivery and nanomedicine versus free drug as factors to test our hypothesis that regional (intraperitoneal) delivery of nanomedicine may better increase survival when compared with systemic delivery. In this study, we demonstrate that bypassing, rather than exploiting, the EPR effect via intraperitoneal delivery of nanomedicine harboring a sustained-release function demonstrates dual pharmacokinetic advantages, producing more efficient tumor control and suppressing the expression of stemness markers, epithelial-mesenchymal transition, angiogenesis signals, and multidrug resistance in the tumor microenvironment. Metastases to vital organs (eg, lung, liver, and lymphatic system) are also better controlled by intraperitoneal delivery of nanomedicine than by standard systemic delivery of the corresponding free drug. Moreover, the intraperitoneal delivery of nanomedicine has the potential to replace hyperthermic intraperitoneal chemotherapy because it shows equal efficacy and lower toxicity. In terms of efficacy, exploiting the EPR effect may not be the best approach for developing a nanomedicine. Because intraperitoneal chemotherapy is a type of regional chemotherapy, the pharmaceutical industry might consider the regional delivery of nanomedicine as a valid alternative pathway to develop their nanomedicine(s) with the goal of better tumor control in the future.

  7. (1)H, (15)N and (13)C resonance assignments of translationally-controlled tumor protein from photosynthetic microalga Nannochloropsis oceanica.

    Science.gov (United States)

    Yao, Xingzhe; Xiao, Yan; Cui, Qiu; Feng, Yingang

    2015-10-01

    Translationally-controlled tumor protein (TCTP) is a eukaryote-conserved protein with crucial roles in cellular growth. It has also been proposed that plant TCTP has functions specific to plant, while no structure of TCTP from photosynthetic organism has been reported. Nannochloropsis is a photosynthetic microalga with high yield of lipid and high-value polyunsaturated fatty acid, which is promising for biodiesel production. Study of growth-related proteins may provide new clue for improving the yield of lipid. TCTP from Nannochloropsis oceanica shares low sequence identity with structure-known TCTPs. Here we reported the NMR resonance assignments of TCTP from N. oceanica for further structural and functional studies.

  8. Mediastinal tumor

    Science.gov (United States)

    Thymoma - mediastinal; Lymphoma - mediastinal ... mediastinal tumors in adults occur in the anterior mediastinum. They are usually cancerous (malignant) lymphomas, germ cell tumors, or thymomas. These tumors are ...

  9. Combination of Id2 Knockdown Whole Tumor Cells and Checkpoint Blockade: A Potent Vaccine Strategy in a Mouse Neuroblastoma Model.

    Directory of Open Access Journals (Sweden)

    Lina Chakrabarti

    Full Text Available Tumor vaccines have held much promise, but to date have demonstrated little clinical success. This lack of success is conceivably due to poor tumor antigen presentation combined with immuno-suppressive mechanisms exploited by the tumor itself. Knock down of Inhibitor of differentiation protein 2 (Id2-kd in mouse neuroblastoma whole tumor cells rendered these cells immunogenic. Id2-kd neuroblastoma (Neuro2a cells (Id2-kd N2a failed to grow in most immune competent mice and these mice subsequently developed immunity against further wild-type Neuro2a tumor cell challenge. Id2-kd N2a cells grew aggressively in immune-compromised hosts, thereby establishing the immunogenicity of these cells. Therapeutic vaccination with Id2-kd N2a cells alone suppressed tumor growth even in established neuroblastoma tumors and when used in combination with immune checkpoint blockade eradicated large established tumors. Mechanistically, immune cell depletion studies demonstrated that while CD8+ T cells are critical for antitumor immunity, CD4+ T cells are also required to induce a sustained long-lasting helper effect. An increase in number of CD8+ T-cells and enhanced production of interferon gamma (IFNγ was observed in tumor antigen stimulated splenocytes of vaccinated mice. More importantly, a massive influx of cytotoxic CD8+ T-cells infiltrated the shrinking tumor following combined immunotherapy. These findings show that down regulation of Id2 induced tumor cell immunity and in combination with checkpoint blockade produced a novel, potent, T-cell mediated tumor vaccine strategy.

  10. The management of tumor motions in the stereotactic irradiation to lung cancer under the use of Abches to control active breathing

    Energy Technology Data Exchange (ETDEWEB)

    Tarohda, Tohru I.; Ishiguro, Mitsuru; Hasegawa, Kouhei; Kohda, Yukihiko; Onishi, Hiroaki; Aoki, Tetsuya; Takanaka, Tsuyoshi [Department of Radiology, Asanogawa General Hospital, 83 Kosaka-naka, Kanazawa 920-8621 (Japan); Department of Neurosurgery, Asanogawa General Hospital, 83 Kosaka-naka, Kanazawa 920-8621 (Japan); Naruwa Clinic, 1-16-6 Naruwa, Kanazawa 920-0818 (Japan); Department of Radiation Therapy, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-8641 (Japan)

    2011-07-15

    Purpose: Breathing control is crucial to ensuring the accuracy of stereotactic irradiation for lung cancer. This study monitored respiration in patients with inoperable nonsmall-cell lung cancer using a respiration-monitoring apparatus, Abches, and investigated the reproducibility of tumor position in these patients. Methods: Subjects comprised 32 patients with nonsmall-cell lung cancer who were administered stereotactic radiotherapy under breath-holding conditions monitored by Abches. Computed tomography (CT) was performed under breath-holding conditions using Abches (Abches scan) for treatment planning. A free-breathing scan was performed to determine the range of tumor motions in a given position. After the free-breathing scan, Abches scan was repeated and the tumor position thus defined was taken as the intrafraction tumor position. Abches scan was also performed just before treatment, and the tumor position thus defined was taken as the interfraction tumor position. To calculate the errors, tumor positions were compared based on Abches scan for the initial treatment plan. The error in tumor position was measured using the BrainSCAN treatment-planning device, then compared for each lung lobe. Results: Displacements in tumor position were calculated in three dimensions (i.e., superior-inferior (S-I), left-right (L-R), and anterior-posterior (A-P) dimensions) and recorded as absolute values. For the whole lung, average intrafraction tumor displacement was 1.1 mm (L-R), 1.9 mm (A-P), and 2.0 mm (S-I); the average interfraction tumor displacement was 1.1 mm (L-R), 2.1 mm (A-P), and 2.0 mm (S-I); and the average free-breathing tumor displacement was 2.3 mm (L-R), 3.5 mm (A-P), and 7.9 mm (S-I). The difference between using Abches and free breathing could be reduced from approximately 20 mm at the maximum to approximately 3 mm in the S-I direction for both intrafraction and interfraction positions in the lower lobe. In addition, maximum intrafraction tumor

  11. The management of tumor motions in the stereotactic irradiation to lung cancer under the use of Abches to control active breathing

    International Nuclear Information System (INIS)

    Tarohda, Tohru I.; Ishiguro, Mitsuru; Hasegawa, Kouhei; Kohda, Yukihiko; Onishi, Hiroaki; Aoki, Tetsuya; Takanaka, Tsuyoshi

    2011-01-01

    Purpose: Breathing control is crucial to ensuring the accuracy of stereotactic irradiation for lung cancer. This study monitored respiration in patients with inoperable nonsmall-cell lung cancer using a respiration-monitoring apparatus, Abches, and investigated the reproducibility of tumor position in these patients. Methods: Subjects comprised 32 patients with nonsmall-cell lung cancer who were administered stereotactic radiotherapy under breath-holding conditions monitored by Abches. Computed tomography (CT) was performed under breath-holding conditions using Abches (Abches scan) for treatment planning. A free-breathing scan was performed to determine the range of tumor motions in a given position. After the free-breathing scan, Abches scan was repeated and the tumor position thus defined was taken as the intrafraction tumor position. Abches scan was also performed just before treatment, and the tumor position thus defined was taken as the interfraction tumor position. To calculate the errors, tumor positions were compared based on Abches scan for the initial treatment plan. The error in tumor position was measured using the BrainSCAN treatment-planning device, then compared for each lung lobe. Results: Displacements in tumor position were calculated in three dimensions (i.e., superior-inferior (S-I), left-right (L-R), and anterior-posterior (A-P) dimensions) and recorded as absolute values. For the whole lung, average intrafraction tumor displacement was 1.1 mm (L-R), 1.9 mm (A-P), and 2.0 mm (S-I); the average interfraction tumor displacement was 1.1 mm (L-R), 2.1 mm (A-P), and 2.0 mm (S-I); and the average free-breathing tumor displacement was 2.3 mm (L-R), 3.5 mm (A-P), and 7.9 mm (S-I). The difference between using Abches and free breathing could be reduced from approximately 20 mm at the maximum to approximately 3 mm in the S-I direction for both intrafraction and interfraction positions in the lower lobe. In addition, maximum intrafraction tumor

  12. Perfusion MRI derived indices of microvascular shunting and flow control correlate with tumor grade and outcome in patients with cerebral glioma

    DEFF Research Database (Denmark)

    Tietze, Anna; Mouridsen, Kim; Lassen-Ramshad, Yasmin

    2015-01-01

    Objectives: Deficient microvascular blood flow control is thought to cause tumor hypoxia and increase resistance to therapy. In glioma patients, we tested whether perfusion-weighted MRI (PWI) based indices of microvascular flow control provide more information on tumor grade and patient outcome...... than does the established PWI angiogenesis marker, cerebral blood volume (CBV). Material and Methods: Seventy-two glioma patients (sixty high-grade, twelve low-grade gliomas) were included. Capillary transit time heterogeneity (CTH) and COV, its ratio to blood mean transit time, provide indices...... of microvascular flow control and the extent to which oxygen can be extracted by tumor tissue. The ability of these parameters and CBV to differentiate tumor grade were assessed by receiver operating characteristic curves and logistic regression. Their ability to predict time to progression and overall survival...

  13. Changed adipocytokine concentrations in colorectal tumor patients and morbidly obese patients compared to healthy controls

    Directory of Open Access Journals (Sweden)

    Hillenbrand Andreas

    2012-11-01

    Full Text Available Abstract Background Obesity has been associated with increased incidence of colorectal cancer. Adipose tissue dysfunction accompanied with alterations in the release of adipocytokines has been proposed to contribute to cancer pathogenesis and progression. The aim of this study was to analyze plasma concentrations of several adipose tissue expressed hormones in colorectal cancer patients (CRC and morbidly obese (MO patients and to compare these concentrations to clinicopathological parameters. Methods Plasma concentrations of adiponectin, resistin, leptin, active plasminogen activator inhibitor (PAI-1, monocyte chemotactic protein (MCP-1, interleukin (IL-1 alpha, and tumor necrosis factor (TNF-alpha were determined in 67 patients operated on for CRC (31 rectal cancers, 36 colon cancers, 37 patients operated on for morbid obesity and 60 healthy blood donors (BD. Results Compared to BD, leptin concentrations were lowered in CRC patients whereas those of MO patients were elevated. Adiponectin concentrations were only lowered in MO patients. Concentrations of MCP-1, PAI-1, and IL-1 alpha were elevated in both CRC and MO patients, while resistin and TNF-alpha were similarly expressed in MO and CRC patients compared to BD. Resistin concentrations positively correlated with tumor staging (p Conclusions The results suggest that both MO and CRC have low-grade inflammation as part of their etiology.

  14. MMP19 is essential for T cell development and T cell-mediated cutaneous immune responses

    Czech Academy of Sciences Publication Activity Database

    Beck, Inken; Ruckert, R.; Brandt, K.; Mueller, M.S.; Sadowski, T.; Brauer, R.; Schirmacher, P.; Mentlein, R.; Sedláček, Radislav

    2008-01-01

    Roč. 3, č. 6 (2008), e2343-e2343 E-ISSN 1932-6203 Institutional research plan: CEZ:AV0Z50520514; CEZ:AV0Z50520701 Keywords : matrix metalloproteinase * T cell * immune response Subject RIV: EB - Genetics ; Molecular Biology

  15. Nutritional imbalances and infections affect the thymus: consequences on T-cell-mediated immune responses.

    Science.gov (United States)

    Savino, Wilson; Dardenne, Mireille

    2010-11-01

    The thymus gland, where T lymphocyte development occurs, is targeted in malnutrition secondary to protein energy deficiency. There is a severe thymic atrophy, resulting from massive thymocyte apoptosis (particularly affecting the immature CD4+CD8+ cell subset) and decrease in cell proliferation. The thymic microenvironment (the non-lymphoid compartment that drives intrathymic T-cell development) is also affected in malnutrition: morphological changes in thymic epithelial cells were found, together with a decrease of thymic hormone production, as well as an increase of intrathymic contents of extracellular proteins. Profound changes in the thymus can also be seen in deficiencies of vitamins and trace elements. Taking Zn deficiency as an example, there is a substantial thymic atrophy. Importantly, marginal Zn deficiency in AIDS subjects, children with diarrhoea and elderly persons, significantly impairs the host's immunity, resulting in an increased risk of opportunistic infections and mortality; effects that are reversed by Zn supplementation. Thymic changes also occur in acute infectious diseases, including a severe thymic atrophy, mainly due to the depletion of CD4+CD8+ thymocytes, decrease in thymocyte proliferation, in parallel to densification of the epithelial network and increase in the extracellular matrix contents, with consequent disturbances in thymocyte migration and export. In conclusion, the thymus is targeted in several conditions of malnutrition as well as in acute infections. These changes are related to the impaired peripheral immune response seen in malnourished and infected individuals. Thus, strategies inducing thymus replenishment should be considered as adjuvant therapeutics to improve immunity in malnutrition and/or acute infectious diseases.

  16. Immunomodulatory effects of dietary non-digestible oligosaccharides in T cell-mediated autoimmune arthritis

    NARCIS (Netherlands)

    Rogier, R.; Ederveen, T.; Hartog, A.; Walgreen, B.; Van Den Bersselaar, L.; Helsen, M.; Vos, P.; Garssen, J.; Willemsen, L.; Van Den Berg, W.; Koenders, M.; Abdollahi-Roodsaz, S.

    2015-01-01

    Background: Accumulating evidence indicates the relevance of intestinal microbiota in shaping the immune response and supports its contribution to the development of autoimmune diseases. Prebiotic non-digestible oligosaccharides are known to selectively support growth of commensal Bifidobacteria and

  17. Mixed Signals: Co-Stimulation in Invariant Natural Killer T Cell-Mediated Cancer Immunotherapy

    Directory of Open Access Journals (Sweden)

    Susannah C. Shissler

    2017-11-01

    Full Text Available Invariant natural killer T (iNKT cells are an integral component of the immune system and play an important role in antitumor immunity. Upon activation, iNKT cells can directly kill malignant cells as well as rapidly produce cytokines that stimulate other immune cells, making them a front line defense against tumorigenesis. Unfortunately, iNKT cell number and activity are reduced in multiple cancer types. This anergy is often associated with upregulation of co-inhibitory markers such as programmed death-1. Similar to conventional T cells, iNKT cells are influenced by the conditions of their activation. Conventional T cells receive signals through the following three types of receptors: (1 T cell receptor (TCR, (2 co-stimulation molecules, and (3 cytokine receptors. Unlike conventional T cells, which recognize peptide antigen presented by MHC class I or II, the TCRs of iNKT cells recognize lipid antigen in the context of the antigen presentation molecule CD1d (Signal 1. Co-stimulatory molecules can positively and negatively influence iNKT cell activation and function and skew the immune response (Signal 2. This study will review the background of iNKT cells and their co-stimulatory requirements for general function and in antitumor immunity. We will explore the impact of monoclonal antibody administration for both blocking inhibitory pathways and engaging stimulatory pathways on iNKT cell-mediated antitumor immunity. This review will highlight the incorporation of co-stimulatory molecules in antitumor dendritic cell vaccine strategies. The use of co-stimulatory intracellular signaling domains in chimeric antigen receptor-iNKT therapy will be assessed. Finally, we will explore the influence of innate-like receptors and modification of immunosuppressive cytokines (Signal 3 on cancer immunotherapy.

  18. Micronutrient supplementation and T-cell mediated immune responses in patients with tuberculosis in Tanzania

    Science.gov (United States)

    Limited studies exist regarding whether incorporating micronutrient supplements during tuberculosis (TB) treatment may improve cell-mediated immune response. We examine the effect of micronutrient supplementation on lymphocyte proliferation response to mycobacteria or T cell mitogens in a randomize...

  19. Long Terminal Repeat CRISPR-CAR-Coupled "Universal" T Cells Mediate Potent Anti-leukemic Effects.

    Science.gov (United States)

    Georgiadis, Christos; Preece, Roland; Nickolay, Lauren; Etuk, Aniekan; Petrova, Anastasia; Ladon, Dariusz; Danyi, Alexandra; Humphryes-Kirilov, Neil; Ajetunmobi, Ayokunmi; Kim, Daesik; Kim, Jin-Soo; Qasim, Waseem

    2018-03-06

    Gene editing can be used to overcome allo-recognition, which otherwise limits allogeneic T cell therapies. Initial proof-of-concept applications have included generation of such "universal" T cells expressing chimeric antigen receptors (CARs) against CD19 target antigens combined with transient expression of DNA-targeting nucleases to disrupt the T cell receptor alpha constant chain (TRAC). Although relatively efficient, transgene expression and editing effects were unlinked, yields variable, and resulting T cell populations heterogeneous, complicating dosing strategies. We describe a self-inactivating lentiviral "terminal" vector platform coupling CAR expression with CRISPR/Cas9 effects through incorporation of an sgRNA element into the ΔU3 3' long terminal repeat (LTR). Following reverse transcription and duplication of the hybrid ΔU3-sgRNA, delivery of Cas9 mRNA resulted in targeted TRAC locus cleavage and allowed the enrichment of highly homogeneous (>96%) CAR + (>99%) TCR - populations by automated magnetic separation. Molecular analyses, including NGS, WGS, and Digenome-seq, verified on-target specificity with no evidence of predicted off-target events. Robust anti-leukemic effects were demonstrated in humanized immunodeficient mice and were sustained longer than by conventional CAR + TCR + T cells. Terminal-TRAC (TT) CAR T cells offer the possibility of a pre-manufactured, non-HLA-matched CAR cell therapy and will be evaluated in phase 1 trials against B cell malignancies shortly. Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  20. L-selectin is not required for T cell-mediated autoimmune diabetes.

    Science.gov (United States)

    Friedline, Randall H; Wong, Carmen P; Steeber, Douglas A; Tedder, Thomas F; Tisch, Roland

    2002-03-15

    Administration of anti-L-selectin (CD62L) mAb to neonatal nonobese diabetic (NOD) mice mediates long term protection against the development of insulitis and overt diabetes. These results suggested that CD62L has a key role in the general function of beta cell-specific T cells. To further examine the role of CD62L in the development of type 1 diabetes, NOD mice lacking CD62L were established. The onset and frequency of overt diabetes were equivalent among CD62L(+/+), CD62L(+/-), and CD62L(-/-) NOD littermates. Furthermore, patterns of T cell activation, migration, and beta cell-specific reactivity were similar in NOD mice of all three genotypes. Adoptive transfer experiments with CD62L(-/-) CD4(+) T cells prepared from BDC2.5 TCR transgenic mice revealed no apparent defects in migration to pancreatic lymph nodes, proliferation in response to beta cell Ag, or induction of diabetes in NOD.scid recipients. In conclusion, CD62L expression is not essential for the development of type 1 diabetes in NOD mice.

  1. Tryptophan biosynthesis protects mycobacteria from CD4 T cell-mediated killing

    Science.gov (United States)

    Zhang, Yanjia J.; Reddy, Manchi C.; Ioerger, Thomas R.; Rothchild, Alissa C.; Dartois, Veronique; Schuster, Brian M.; Trauner, Andrej; Wallis, Deeann; Galaviz, Stacy; Huttenhower, Curtis; Sacchettini, James C.; Behar, Samuel M.; Rubin, Eric J.

    2014-01-01

    Summary Bacteria that cause disease rely on their ability to counteract and overcome host defenses. Here we present a genome-scale study of Mycobacterium tuberculosis (Mtb) that uncovers the bacterial determinants of surviving host immunity, sets of genes we term “counteractomes.” Through this, we find that CD4 T cells attempt to starve Mtb of tryptophan through a mechanism that limits Chlamydia and Leishmania infections. In those cases, tryptophan starvation works well, since those pathogens are natural tryptophan auxotrophs. Mtb, however, can synthesize tryptophan, and thus starvation fails as an Mtb-killing mechanism. We then describe a small molecule inhibitor of Mtb tryptophan synthesis, which turns Mtb into a tryptophan auxotroph and restores the efficacy of a failed host defense. Together, our findings demonstrate that the Mtb determinants for surviving host immunity—Mtb’s immune counteractomes—serve as probes of host immunity, uncovering immune-mediated stresses that can be leveraged for therapeutic discovery. PMID:24315099

  2. Mechanisms of Invariant Natural Killer T Cell-Mediated Immunoregulation in Cancer

    Science.gov (United States)

    2012-05-01

    regulatory iNKT cells may act at the level of antigen presentation since NKT -/- mice were found to have significantly more dendritic cells of a highly...the generation and maintenance of regulatory T- cells . BODY We have previously shown that NKT cells can have an inhibitory effect on anti... NKT -/- mice. 4-1BB is a co-stimulatory molecule that is stably upregulated on activated T- cells and provides survival signal that promotes expansion

  3. Green tea EGCG, T-cell function, and T-cell-mediated autoimmune encephalomyelitis

    Science.gov (United States)

    Autoimmune diseases are common, disabling immune disorders affecting millions of people. Recent studies indicate that dysregulated balance of different CD4+ T-cell subpopulations plays a key role in immune pathogenesis of several major autoimmune diseases. Green tea and its active ingredient, epigal...

  4. MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration

    OpenAIRE

    Cebrián, Carolina; Zucca, Fabio A.; Mauri, Pierluigi; Steinbeck, Julius A.; Studer, Lorenz; Scherzer, Clemens R.; Kanter, Ellen; Budhu, Sadna; Mandelbaum, Jonathan; Vonsattel, Jean P.; Zecca, Luigi; Loike, John D.; Sulzer, David

    2014-01-01

    Subsets of rodent neurons are reported to express major histocompatibilty complex class I (MHC-I), but such expression has not been reported in normal adult human neurons. Here we provide evidence from immunolabel, RNA expression, and mass spectrometry analysis of postmortem samples that human catecholaminergic substantia nigra and locus coeruleus neurons express MHC-I, and that this molecule is inducible in human stem cell derived dopamine (DA) neurons. Catecholamine murine cultured neurons ...

  5. Follicular helper T cells mediate IgE antibody response to airborne allergens.

    Science.gov (United States)

    Kobayashi, Takao; Iijima, Koji; Dent, Alexander L; Kita, Hirohito

    2017-01-01

    T H 2 cells have long been believed to play a pivotal role in allergic immune responses, including IgE antibody production and type 2 cytokine-mediated inflammation and pathology. A new T-cell subset, follicular helper T (T FH ) cells, is specialized in supporting B-cell maturation and antibody production. We sought to investigate the roles of T FH cells in allergic immune responses. Naive mice were exposed to cytokines or natural allergens through the airways. Development of allergic immune responses was analyzed by collecting draining lymph nodes and sera and by challenging the animals. Cytokine reporter mice and gene-deficient mice were used to dissect the immunologic mechanisms. We observed the development of IL-4-producing T FH cells and T H 2 cells in draining lymph nodes after airway exposure to IL-1 family cytokines or natural allergens. T FH and T H 2 cells demonstrated unique phenotypes, tissue localization, and cytokine responses. T FH cells supported the sustained production of IgE antibody in vivo in the absence of other T-cell subsets or even when T H 2 cell functions were severely compromised. Conversely, conditional deficiency of the master regulator Bcl6 in CD4 + T cells resulted in a marked reduction in T FH cell numbers and IgE antibody levels, but type 2 cytokine responses and eosinophilic inflammation in the airways remained unaffected. T FH cells play critical roles in the regulation of IgE antibody production. Allergic immune responses to airborne allergens likely involve 2 distinct subsets of IL-4-producing CD4 + T cells, namely T FH and Th2 cells. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  6. Histamine suppresses regulatory T cells mediated by TGF-β in murine chronic allergic contact dermatitis.

    Science.gov (United States)

    Tamaka, Kyoko; Seike, Masahiro; Hagiwara, Tamio; Sato, Atsushi; Ohtsu, Hiroshi

    2015-04-01

    Regulatory T cells (Tregs) suppress effector T cells and ameliorate contact hypersensitivity (CH); however, the role of Tregs in chronic allergic contact dermatitis (CACD) has not been assessed. Repeated elicitation of CH has been used to produce CACD models in mice. We previously showed that the presence of histamine facilitates the creation of eczematous lesions in this model using histidine decarboxylase (HDC) (-/-) mice. Therefore, the effects of histamine on Tregs in the CACD model were investigated in this study. CACD was developed by repeated epicutaneous application of 2, 4, 6-trinitro-1-chlorobenzene (TNCB) on HDC (+/+) and HDC (-/-) murine skin to assess the effects of histamine in CACD. Histamine aggravated CACD in the murine model and suppressed the number of Tregs in the skin. Histamine also suppressed the level of TGF-β1 in this model. Recombinant TGF-β1 or anti-TGF-β1 antibody was injected into the dorsal dermis of HDC (+/+) mice daily just before TNCB challenge to determine the effects of histamine-regulated TGF-β on the Treg population in CACD. Recombinant TGF-β1 injection promoted the infiltration of Tregs in the skin and the production of IL-10; however, anti-TGF-β1 antibody injection suppressed the number of Tregs in the skin and the production of IL-10. Histamine suppresses the number of Tregs in CACD, and this effect is mediated by TGF-β. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Green tea EGCG, T cells, and T cell-mediated autoimmune diseases

    Science.gov (United States)

    One of the proposed health benefits of consuming green tea is its protective effect on autoimmune diseases. Research on the immunopathogenesis of autoimmune diseases has made significant progression in the past few years and several key concepts have been revised. T cells, particularly CD4+ T helper...

  8. Revisiting the phenotypic and genetic profiling of anergic T cells mediating long-term transplant tolerance.

    Science.gov (United States)

    You, Sylvaine; Chatenoud, Lucienne

    2018-02-01

    Herein our focus will be to revisit peripheral tolerance mechanisms and in particular 'active' or 'dominant' tolerance as originally defined and mediated by regulatory CD4FoxP3 T lymphocytes (Treg) and also T-cell anergy that appears as a major mainstay to support long-term allograft survival. It is at the same time interesting and rewarding that the tool that recently guided our efforts along this path is the in-vivo use of CD3 antibody, the first monoclonal introduced in the clinic (Orthoclone OKT3) about 35 years ago to treat and prevent rejection of renal allografts. Beyond their immunosuppressive activity, whenever administered judiciously, CD3 antibodies promote robust allograft tolerance through selective purging of alloreactive effectors, resetting Treg-mediated active tolerance and promoting a unique subset of anergic CD8 T cells. The new findings discussed open up new perspectives from both a fundamental and a clinical point of view. In basic research, concrete molecular signaling paths are now spotted to finely dissect the conditions that lead to the establishment and maintenance of robust T-lymphocyte anergy mediating allograft tolerance. In the clinic, this may rapidly translate into novel biomarkers to be used in parallel to the ones already available, to better adapt posttransplant immunotherapy and monitor for long-term allograft acceptance.

  9. CD8+ T cells mediate recovery and immunopathology in West Nile virus encephalitis.

    Science.gov (United States)

    Wang, Yang; Lobigs, Mario; Lee, Eva; Müllbacher, Arno

    2003-12-01

    C57BL/6J mice infected intravenously with the Sarafend strain of West Nile virus (WNV) develop a characteristic central nervous system (CNS) disease, including an acute inflammatory reaction. Dose response studies indicate two distinct kinetics of mortality. At high doses of infection (10(8) PFU), direct infection of the brain occurred within 24 h, resulting in 100% mortality with a 6-day mean survival time (MST), and there was minimal destruction of neural tissue. A low dose (10(3) PFU) of infection resulted in 27% mortality (MST, 11 days), and virus could be detected in the CNS 7 days postinfection (p.i.). Virus was present in the hypogastric lymph nodes and spleens at days 4 to 7 p.i. Histology of the brains revealed neuronal degeneration and inflammation within leptomeninges and brain parenchyma. Inflammatory cell infiltration was detectable in brains from day 4 p.i. onward in the high-dose group and from day 7 p.i. in the low-dose group, with the severity of infiltration increasing over time. The cellular infiltrates in brain consisted predominantly of CD8(+), but not CD4(+), T cells. CD8(+) T cells in the brain and the spleen expressed the activation markers CD69 early and expressed CD25 at later time points. CD8(+) T-cell-deficient mice infected with 10(3) PFU of WNV showed increased mortalities but prolonged MST and early infection of the CNS compared to wild-type mice. Using high doses of virus in CD8-deficient mice leads to increased survival. These results provide evidence that CD8(+) T cells are involved in both recovery and immunopathology in WNV infection.

  10. Perforin-deficient CD8+ T cells mediate fatal lymphocytic choriomeningitis despite impaired cytokine production

    DEFF Research Database (Denmark)

    Storm, Pernille; Bartholdy, Christina; Sørensen, Maria Rathmann

    2006-01-01

    Intracerebral (i.c.) infection with lymphocytic choriomeningitis virus (LCMV) is one of the most studied models for virus-induced immunopathology, and based on results from perforin-deficient mice, it is currently assumed that fatal disease directly reflects perforin-mediated cell lysis. However...... the outcome of i.c. infection with LCMV. We confirmed that the expansion of virus-specific CD8(+) T cells is unimpaired in perforin-deficient mice. However, despite the fact that the virus-specific CD8(+) effector T cells in perforin-deficient mice are broadly impaired in their effector function, these mice...... invariably succumb to i.c. infection with LCMV strain Armstrong, although a few days later than matched wild-type mice. Upon further investigation, we found that this delay correlates with the delayed recruitment of inflammatory cells to the central nervous system (CNS). However, CD8(+) effector T cells were...

  11. Cytomegalovirus-Infected Cells Resist T Cell Mediated Killing in an HLA-Recognition Independent Manner.

    Science.gov (United States)

    Proff, Julia; Walterskirchen, Christian; Brey, Charlotte; Geyeregger, Rene; Full, Florian; Ensser, Armin; Lehner, Manfred; Holter, Wolfgang

    2016-01-01

    In order to explore the potential of HLA-independent T cell therapy for human cytomegalovirus (HCMV) infections, we developed a chimeric antigen receptor (CAR) directed against the HCMV encoded glycoprotein B (gB), which is expressed at high levels on the surface of infected cells. T cells engineered with this anti-gB CAR recognized HCMV-infected cells and released cytokines and cytotoxic granules. Unexpectedly, and in contrast to analogous approaches for HIV, Hepatitis B or Hepatitis C virus, we found that HCMV-infected cells were resistant to killing by the CAR-modified T cells. In order to elucidate whether this phenomenon was restricted to the use of CARs, we extended our experiments to T cell receptor (TCR)-mediated recognition of infected cells. To this end we infected fibroblasts with HCMV-strains deficient in viral inhibitors of antigenic peptide presentation and targeted these HLA-class I expressing peptide-loaded infected cells with peptide-specific cytotoxic T cells (CTLs). Despite strong degranulation and cytokine production by the T cells, we again found significant inhibition of lysis of HCMV-infected cells. Impairment of cell lysis became detectable 1 day after HCMV infection and gradually increased during the following 3 days. We thus postulate that viral anti-apoptotic factors, known to inhibit suicide of infected host cells, have evolved additional functions to directly abrogate T cell cytotoxicity. In line with this hypothesis, CAR-T cell cytotoxicity was strongly inhibited in non-infected fibroblasts by expression of the HCMV-protein UL37x1, and even more so by additional expression of UL36. Our data extend the current knowledge on Betaherpesviral evasion from T cell immunity and show for the first time that, beyond impaired antigen presentation, infected cells are efficiently protected by direct blockade of cytotoxic effector functions through viral proteins.

  12. Genome-wide Gene Expression Profiling of SCID Mice with T-cell-mediated Colitis

    DEFF Research Database (Denmark)

    Brudzewsky, D.; Pedersen, A. E.; Claesson, M. H.

    2009-01-01

    disease. Here, we have investigated severe combined immunodeficient (SCID) mice, which upon adoptive transfer with concanavalin A-activated CD4(+) T cells develop inflammation of the colon with predominance in rectum. Mice with increasing level of inflammation was studied. RNA from rectum of transplanted...

  13. TCR down-regulation boosts T-cell-mediated cytotoxicity and protection against poxvirus infections

    DEFF Research Database (Denmark)

    Hansen, Ann Kathrine; Regner, Matthias; Bonefeld, Charlotte Menne

    2011-01-01

    Cytotoxic T (Tc) cells play a key role in the defense against virus infections. Tc cells recognize infected cells via the T-cell receptor (TCR) and subsequently kill the target cells by one or more cytotoxic mechanisms. Induction of the cytotoxic mechanisms is finely tuned by the activation signals...... from the TCR. To determine whether TCR down-regulation affects the cytotoxicity of Tc cells, we studied TCR down-regulation-deficient CD3¿LLAA mice. We found that Tc cells from CD3¿LLAA mice have reduced cytotoxicity due to a specific deficiency in exocytosis of lytic granules. To determine whether......-regulation critically increases Tc cell cytotoxicity and protection against poxvirus infection....

  14. Poxvirus-encoded serpins do not prevent cytolytic T cell-mediated recovery from primary infections.

    Science.gov (United States)

    Müllbacher, A; Wallich, R; Moyer, R W; Simon, M M

    1999-06-15

    Previous observations that the highly conserved poxvirus-encoded serpins inhibit cytotoxic activities of alloreactive CTL via granule and/or Fas-mediated pathways was taken to indicate their involvement in immune evasion by poxviruses. We now show that interference with 51Cr release from target cells by ectromelia and cowpoxvirus is limited to alloreactive but not MHC-restricted CTL. The data are in support of the paramount importance of CTL and its effector molecule perforin in the recovery from primary ectromelia virus infection and question the role of serpins in the evasion of poxviruses from killing by CTL. Further analysis of poxvirus interference with target cell lysis by alloreactive CTL revealed that suppression primarily affects the Fas-mediated, and to a lesser extent, the granule exocytosis pathway. Serpin-2 is the main contributor to suppression for both killing pathways. In addition, inhibition of lysis was shown to be both target cell type- and MHC allotype-dependent. We hypothesize that differences in TCR affinities and/or state of activation between alloreactive and MHC-restricted CTL as well as the quality (origin) of target cells are responsible for the observed phenomenon.

  15. Vitamin D, PTH, and calcium and tumor aggressiveness in prostate cancer: a prospective nested case-control study.

    Science.gov (United States)

    Brändstedt, Johan; Almquist, Martin; Ulmert, David; Manjer, Jonas; Malm, Johan

    2016-01-01

    Epidemiological studies suggest that low levels of vitamin D (25OHD) constitute a risk factor for more aggressive prostate cancer. We examined the relationship between pre-diagnostic serum levels of vitamin D, parathyroid hormone (PTH), and calcium and risk of prostate cancer according to tumor aggressiveness. We performed a nested case-control study within the Malmö Diet and Cancer Study on 943 incident prostate cancer cases. Tumor aggressiveness was defined by Gleason score, TNM stage, and serum levels of total prostate-specific antigen. Odds ratios (OR) were calculated for different quartiles of serum levels of 25OHD, PTH, and calcium, and for interactions between them. We found no significant association when comparing aggressive to non-aggressive disease regarding vitamin D, PTH, or calcium. There was a trend toward an increased risk in low-grade tumors, i.e., Gleason score ≤6, and a significant association regarding Gleason score 7 tumors with OR 1.70 (1.09-2.65) in the highest quartile of vitamin D. Stratifying the analysis yielded several significant findings demonstrating a nonspecific interaction between the metabolites. In men with PTH above median, the risk of aggressive prostate cancer was double in the highest vitamin D quartile, OR 2.01 (1.24-3.25), and for non-aggressive cancer 1.82 (1.25-2.66). There was an inverse effect on risk of prostate cancer in men with PTH above median and vitamin D ≤50 nmol/L, OR 0.25 (0.09-0.71) and calcium ≤2.37 mmol/L, OR 0.53 (0.34-0.82) for aggressive cancer. This study showed no significant association when comparing aggressive to non-aggressive disease. There was a possible relationship between vitamin D and low-risk tumors. There were both positive and negative interactions between PTH, calcium, and vitamin D and risk of prostate cancer. These results were similar for low-risk and aggressive cases.

  16. A HLA-A2-restricted CTL epitope induces anti-tumor effects against human lung cancer in mouse xenograft model.

    Science.gov (United States)

    Sher, Yuh-Pyng; Lin, Su-I; Chen, I-Hua; Liu, Hsin-Yu; Lin, Chen-Yuan; Chiang, I-Ping; Roffler, Steve; Chen, Hsin-Wei; Liu, Shih-Jen

    2016-01-05

    Cancer immunotherapy is attractive for antigen-specific T cell-mediated anti-tumor therapy, especially in induction of cytotoxic T lymphocytes. In this report, we evaluated human CTL epitope-induced anti-tumor effects in human lung cancer xenograft models. The tumor associated antigen L6 (TAL6) is highly expressed in human lung cancer cell lines and tumor specimens as compared to normal lung tissues. TAL6 derived peptides strongly inhibited tumor growth, cancer metastasis and prolonged survival time in HLA-A2 transgenic mice immunized with a formulation of T-helper (Th) peptide, synthetic CpG ODN, and adjuvant Montanide ISA-51 (ISA-51). Adoptive transfer of peptide-induced CTL cells from HLA-A2 transgenic mice into human tumor xenograft SCID mice significantly inhibited tumor growth. Furthermore, combination of CTL-peptide immunotherapy and gemcitabine additively improved the therapeutic effects. This pre-clinical evaluation model provides a useful platform to develop efficient immunotherapeutic drugs to treat lung cancer and demonstrates a promising strategy with benefit of antitumor immune responses worthy of further development in clinical trials.

  17. Characterization of the Translationally Controlled Tumor Protein (TCTP) Interactome Reveals Novel Binding Partners in Human Cancer Cells.

    Science.gov (United States)

    Li, Siting; Chen, Minghai; Xiong, Qian; Zhang, Jia; Cui, Zongqiang; Ge, Feng

    2016-10-07

    Translationally controlled tumor protein (TCTP) is a highly conserved housekeeping protein present in eukaryotic organisms. It is involved in regulating many fundamental processes and plays a critical role in tumor reversion and tumorigenesis. Increasing evidence suggests that TCTP plays a role in the regulation of cell fate determination and is a promising therapeutic target for cancer. To decipher the exact mechanisms by which TCTP functions and how all these functions are integrated, we analyzed the interactome of TCTP in HeLa cells by coimmunoprecipitation (IP) and mass spectrometry (MS). A total of 98 proteins were identified. We confirmed the in vitro and in vivo association of TCTP with six of the identified binding proteins using reciprocal IP and bimolecular fluorescence complementation (BiFC) analysis, respectively. Moreover, TCTP interacted with Y-box-binding protein 1 (YBX1), and their interaction was localized to the N-terminal region of TCTP and the 1-129 amino acid (aa) residues of YBX1. The YBX1 protein plays an important role in cell proliferation, RNA splicing, DNA repair, drug resistance, and stress response to extracellular signals. These data suggest that the interaction of TCTP with YBX1 might cooperate or coordinate their functions in the control of diverse regulatory pathways in cancer cells. Taken together, our results not only reveal a large number of TCTP-associated proteins that possess pleiotropic functions, but also provide novel insights into the molecular mechanisms of TCTP in tumorigenesis.

  18. Programming controlled adhesion of E. coli to target surfaces, cells, and tumors with synthetic adhesins.

    Science.gov (United States)

    Piñero-Lambea, Carlos; Bodelón, Gustavo; Fernández-Periáñez, Rodrigo; Cuesta, Angel M; Álvarez-Vallina, Luis; Fernández, Luis Ángel

    2015-04-17

    In this work we report synthetic adhesins (SAs) enabling the rational design of the adhesion properties of E. coli. SAs have a modular structure comprising a stable β-domain for outer membrane anchoring and surface-exposed immunoglobulin domains with high affinity and specificity that can be selected from large repertoires. SAs are constitutively and stably expressed in an E. coli strain lacking a conserved set of natural adhesins, directing a robust, fast, and specific adhesion of bacteria to target antigenic surfaces and cells. We demonstrate the functionality of SAs in vivo, showing that, compared to wild type E. coli, lower doses of engineered E. coli are sufficient to colonize solid tumors expressing an antigen recognized by the SA. In addition, lower levels of engineered bacteria were found in non-target tissues. Therefore, SAs provide stable and specific adhesion capabilities to E. coli against target surfaces of interest for diverse applications using live bacteria.

  19. Metabolic switching and fuel choice during T-cell differentiation and memory development

    NARCIS (Netherlands)

    van der Windt, Gerritje J. W.; Pearce, Erika L.

    2012-01-01

    Clearance or control of pathogens or tumors usually requires T-cell-mediated immunity. As such, understanding the mechanisms that govern the function, maintenance, and persistence of T cells will likely lead to new treatments for controlling disease. During an immune response, T-cell development is

  20. Donepezil for Irradiated Brain Tumor Survivors: A Phase III Randomized Placebo-Controlled Clinical Trial.

    Science.gov (United States)

    Rapp, Stephen R; Case, L Doug; Peiffer, Ann; Naughton, Michelle M; Chan, Michael D; Stieber, Volker W; Moore, Dennis F; Falchuk, Steven C; Piephoff, James V; Edenfield, William J; Giguere, Jeffrey K; Loghin, Monica E; Shaw, Edward G

    2015-05-20

    Neurotoxic effects of brain irradiation include cognitive impairment in 50% to 90% of patients. Prior studies have suggested that donepezil, a neurotransmitter modulator, may improve cognitive function. A total of 198 adult brain tumor survivors ≥ 6 months after partial- or whole-brain irradiation were randomly assigned to receive a single daily dose (5 mg for 6 weeks, 10 mg for 18 weeks) of donepezil or placebo. A cognitive test battery assessing memory, attention, language, visuomotor, verbal fluency, and executive functions was administered before random assignment and at 12 and 24 weeks. A cognitive composite score (primary outcome) and individual cognitive domains were evaluated. Of this mostly middle-age, married, non-Hispanic white sample, 66% had primary brain tumors, 27% had brain metastases, and 8% underwent prophylactic cranial irradiation. After 24 weeks of treatment, the composite scores did not differ significantly between groups (P = .48); however, significant differences favoring donepezil were observed for memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016). Significant interactions between pretreatment cognitive function and treatment were found for cognitive composite (P = .01), immediate recall (P = .05), delayed recall (P = .004), attention (P = .01), visuomotor skills (P = .02), and motor speed and dexterity (P < .001), with the benefits of donepezil greater for those who were more cognitively impaired before study treatment. Treatment with donepezil did not significantly improve the overall composite score, but it did result in modest improvements in several cognitive functions, especially among patients with greater pretreatment impairments. © 2015 by American Society of Clinical Oncology.

  1. Defining the role of the tumor vasculature in antitumor immunity and immunotherapy.

    Science.gov (United States)

    Schaaf, Marco B; Garg, Abhishek D; Agostinis, Patrizia

    2018-01-25

    It is now well established that cancer cells co-exist within a complex environment with stromal cells and depend for their growth and dissemination on tight and plastic interactions with components of the tumor microenvironment (TME). Cancer cells incite the formation of new blood and lymphatic vessels from preexisting vessels to cope with their high nutrient/oxygen demand and favor tumor outgrowth. Research over the past decades has highlighted the crucial role played by tumor-associated blood and lymphatic vasculature in supporting immunoevasion and in subverting T-cell-mediated immunosurveillance, which are the main hallmarks of cancers. The structurally and functionally aberrant tumor vasculature contributes to the protumorigenic and immunosuppressive TME by maintaining a cancer cell's permissive environment characterized by hypoxia, acidosis, and high interstitial pressure, while simultaneously generating a physical barrier to T cells' infiltration. Recent research moreover has shown that blood endothelial cells forming the tumor vessels can actively suppress the recruitment, adhesion, and activity of T cells. Likewise, during tumorigenesis the lymphatic vasculature undergoes dramatic remodeling that facilitates metastatic spreading of cancer cells and immunosuppression. Beyond carcinogenesis, the erratic tumor vasculature has been recently implicated in mechanisms of therapy resistance, including those limiting the efficacy of clinically approved immunotherapies, such as immune checkpoint blockers and adoptive T-cell transfer. In this review, we discuss emerging evidence highlighting the major role played by tumor-associated blood and lymphatic vasculature in thwarting immunosurveillance mechanisms and antitumor immunity. Moreover, we also discuss novel therapeutic approaches targeting the tumor vasculature and their potential to help overcoming immunotherapy resistance.

  2. An implantable smart magnetic nanofiber device for endoscopic hyperthermia treatment and tumor-triggered controlled drug release.

    Science.gov (United States)

    Sasikala, Arathyram Ramachandra Kurup; Unnithan, Afeesh Rajan; Yun, Yeo-Heung; Park, Chan Hee; Kim, Cheol Sang

    2016-02-01

    The study describes the design and synthesis of an implantable smart magnetic nanofiber device for endoscopic hyperthermia treatment and tumor-triggered controlled drug release. This device is achieved using a two-component smart nanofiber matrix from monodisperse iron oxide nanoparticles (IONPs) as well as bortezomib (BTZ), a chemotherapeutic drug. The IONP-incorporated nanofiber matrix was developed by electrospinning a biocompatible and bioresorbable polymer, poly (d,l-lactide-co-glycolide) (PLGA), and tumor-triggered anticancer drug delivery is realized by exploiting mussel-inspired surface functionalization using 2-(3,4-dihydroxyphenyl)ethylamine (dopamine) to conjugate the borate-containing BTZ anticancer drug through a catechol metal binding in a pH-sensitive manner. Thus, an implantable smart magnetic nanofiber device can be exploited to both apply hyperthermia with an alternating magnetic field (AMF) and to achieve cancer cell-specific drug release to enable synergistic cancer therapy. These results confirm that the BTZ-loaded mussel-inspired magnetic nanofiber matrix (BTZ-MMNF) is highly beneficial not only due to the higher therapeutic efficacy and low toxicity towards normal cells but also, as a result of the availability of magnetic nanoparticles for repeated hyperthermia application and tumor-triggered controlled drug release. The current work report on the design and development of a smart nanoplatform responsive to a magnetic field to administer both hyperthermia and pH-dependent anticancer drug release for the synergistic anticancer treatment. The iron oxide nanoparticles (IONPs) incorporated nanofiber matrix was developed by electrospinning a biocompatible polymer, poly (d,l-lactide-co-glycolide) (PLGA), and tumor-triggered anticancer drug delivery is realized by surface functionalization using 2-(3,4-dihydroxyphenyl)ethylamine (dopamine) to conjugate the boratecontaining anticancer drug bortezomib through a catechol metal binding in a p

  3. Effects of nursing intervention models on social adaption capability development in preschool children with malignant tumors: a randomized control trial.

    Science.gov (United States)

    Yu, Lu; Mo, Lin; Tang, Yan; Huang, Xiaoyan; Tan, Juan

    2014-06-01

    The objectives of this study are to compare the effects of two nursing intervention models on the ability of preschool children with malignant tumors to socialize and to determine if these interventions improved their social adaption capability (SAC) and quality of life. Inpatient preschool children with malignant tumors admitted to the hospital between December 2009 and March 2012 were recruited and randomized into either the experimental or control groups. The control group received routine nursing care, and the experimental group received family-centered nursing care, including physical, psychological, and social interventions. The Infants-Junior Middle School Student's Social-Life Abilities Scale was used to evaluate SAC development of participants. Participants (n = 240) were recruited and randomized into two groups. After the intervention, the excellent and normal SAC rates were 27.5% and 55% in the experimental group, respectively, compared with 2.5% and 32.5% in the control group (p intervention, SAC in experimental group was improved compared with before intervention (54.68 ± 10.85 vs 79.9 ± 22.3, p intervention in the control group (54.70 ± 11.47 vs. 52 ± 15.8, p = 0.38). The family-centered nursing care model that included physical, psychological, and social interventions improved the SAC of children with malignancies compared with children receiving routine nursing care. Establishing a standardized family-school-community-hospital hierarchical multi-management intervention model for children is important to the efficacy of long-term interventions and to the improvement of SAC of children with malignancies. Copyright © 2014 John Wiley & Sons, Ltd.

  4. Long term results after fractionated stereotactic radiotherapy (FSRT) in patients with craniopharyngioma: maximal tumor control with minimal side effects

    International Nuclear Information System (INIS)

    Harrabi, Semi B; Adeberg, Sebastian; Welzel, Thomas; Rieken, Stefan; Habermehl, Daniel; Debus, Jürgen; Combs, Stephanie E

    2014-01-01

    There are already numerous reports about high local control rates in patients with craniopharyngioma but there are only few studies with follow up times of more than 10 years. This study is an analysis of long term control, tumor response and side effects after fractionated stereotactic radiotherapy (FSRT) for patients with craniopharyngioma. 55 patients who were treated with FSRT for craniopharyngioma were analyzed. Median age was 37 years (range 6–70 years), among them eight children < 18 years. Radiotherapy (RT) was indicated for progressive disease after neurosurgical resection or postoperatively after repeated resection or partial resection. A median dose of 52.2 Gy (50 – 57.6 Gy) was applied with typical dose per fraction of 1.8 Gy five times per week. The regular follow up examinations comprised in addition to contrast enhanced MRI scans thorough physical examinations and clinical evaluation. During median follow up of 128 months (2 – 276 months) local control rate was 95.3% after 5 years, 92.1% after 10 years and 88.1% after 20 years. Overall survival after 10 years was 83.3% and after 20 years 67.8% whereby none of the deaths were directly attributed to craniopharyngioma. Overall treatment was tolerated well with almost no severe acute or chronic side effects. One patient developed complete anosmia, another one’s initially impaired vision deteriorated further. In 83.6% of the cases with radiological follow up a regression of irradiated tumor residues was monitored, in 7 cases complete response was achieved. 44 patients presented themselves initially with endocrinologic dysfunction none of them showed signs of further deterioration during follow up. No secondary malignancies were observed. Long term results for patients with craniopharyngioma after stereotactic radiotherapy are with respect to low treatment related side effects as well as to local control and overall survival excellent

  5. Quality of life in young patients after bone tumor surgery around the knee joint and comparison with healthy controls.

    Science.gov (United States)

    Bekkering, W Peter; Vliet Vlieland, Theodora P M; Koopman, Hendrik M; Schaap, Gerard R; Schreuder, H W Bart; Beishuizen, Auke; Tissing, Wim J E; Hoogerbrugge, Peter M; Anninga, Jacob K; Taminiau, Antonie H M

    2010-05-01

    This study aimed to compare the health related quality of life (HRQoL) of children and adolescents after malignant bone tumor surgery of the leg with healthy controls. Patients between 8 and 25 years old were cross-sectional recruited. Patients under 16 years of age received the TNO (Netherlands Organization for Applied Scientific Research) and AZL (Leiden University Medical Center) Children's Quality of Life Questionnaire (TACQOL), patients aged 16 years and older received the TNO-AZL Questionnaire for Adult's Quality of Life (TAAQOL) and the Short Form-36 (SF-36). Three age- and sex-matched normative random samples, drawn from large, nationwide studies, were used for the comparison with healthy controls. Patients were interviewed regarding their most important problems related to the disease and its treatment. Eighty-one patients with a mean age of 16.9 years (SD 4.2) were included (41 female). Limb sparing surgery was executed in 38 patients, ablative surgery in 43 patients. In comparison with healthy controls, patients had significantly poorer HRQoL within the domains autonomy and motor function of the TACQOL, gross motor function, cognitive functioning, daily functioning and sexuality of the TAAQOL, and physical functioning, role physical, general health, and the physical and mental component summary scales of the SF-36. Patients reported limitations in physical activities, participation in sports, and cosmetic aspects as the most detrimental consequences of their disease and its treatment. In children and adolescents who underwent surgery for a malignant tumor of the leg physical, functioning was significantly impaired as compared to healthy controls.

  6. Dexmedetomidine versus labetalol infusions for controlling emergence hypertension in cranial surgeries for supratentorial tumors

    Directory of Open Access Journals (Sweden)

    Tarek Ahmed Mostafa Radwan

    2016-10-01

    Conclusion: Both dexmedetomidine and labetalol had favorable effects on hemodynamics at time of emergence from anesthesia in comparison with control group without prolongation of the time of extubation.

  7. Ipsilateral irradiation for well lateralized carcinomas of the oral cavity and oropharynx: results on tumor control and xerostomia.

    Science.gov (United States)

    Cerezo, Laura; Martín, Margarita; López, Mario; Marín, Alicia; Gómez, Alberto

    2009-09-01

    In head and neck cancer, bilateral neck irradiation is the standard approach for many tumor locations and stages. Increasing knowledge on the pattern of nodal invasion leads to more precise targeting and normal tissue sparing. The aim of the present study was to evaluate the morbidity and tumor control for patients with well lateralized squamous cell carcinomas of the oral cavity and oropharynx treated with ipsilateral radiotherapy. Twenty consecutive patients with lateralized carcinomas of the oral cavity and oropharynx were treated with a prospective management approach using ipsilateral irradiation between 2000 and 2007. This included 8 radical oropharyngeal and 12 postoperative oral cavity carcinomas, with Stage T1-T2, N0-N2b disease. The actuarial freedom from contralateral nodal recurrence was determined. Late xerostomia was evaluated using the European Organization for Research and Treatment of Cancer QLQ-H&N35 questionnaire and the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3. At a median follow-up of 58 months, five-year overall survival and loco-regional control rates were 82.5% and 100%, respectively. No local or contralateral nodal recurrences were observed. Mean dose to the contralateral parotid gland was 4.72 Gy and to the contralateral submandibular gland was 15.30 Gy. Mean score for dry mouth was 28.1 on the 0-100 QLQ-H&N35 scale. According to CTCAE v3 scale, 87.5% of patients had grade 0-1 and 12.5% grade 2 subjective xerostomia. The unstimulated salivary flow was > 0.2 ml/min in 81.2% of patients and 0.1-0.2 ml/min in 19%. None of the patients showed grade 3 xerostomia. In selected patients with early and moderate stages, well lateralized oral and oropharyngeal carcinomas, ipsilateral irradiation treatment of the primary site and ipsilateral neck spares salivary gland function without compromising loco-regional control.

  8. Ipsilateral irradiation for well lateralized carcinomas of the oral cavity and oropharynx: results on tumor control and xerostomia

    International Nuclear Information System (INIS)

    Cerezo, Laura; Martín, Margarita; López, Mario; Marín, Alicia; Gómez, Alberto

    2009-01-01

    In head and neck cancer, bilateral neck irradiation is the standard approach for many tumor locations and stages. Increasing knowledge on the pattern of nodal invasion leads to more precise targeting and normal tissue sparing. The aim of the present study was to evaluate the morbidity and tumor control for patients with well lateralized squamous cell carcinomas of the oral cavity and oropharynx treated with ipsilateral radiotherapy. Twenty consecutive patients with lateralized carcinomas of the oral cavity and oropharynx were treated with a prospective management approach using ipsilateral irradiation between 2000 and 2007. This included 8 radical oropharyngeal and 12 postoperative oral cavity carcinomas, with Stage T1-T2, N0-N2b disease. The actuarial freedom from contralateral nodal recurrence was determined. Late xerostomia was evaluated using the European Organization for Research and Treatment of Cancer QLQ-H&N35 questionnaire and the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3. At a median follow-up of 58 months, five-year overall survival and loco-regional control rates were 82.5% and 100%, respectively. No local or contralateral nodal recurrences were observed. Mean dose to the contralateral parotid gland was 4.72 Gy and to the contralateral submandibular gland was 15.30 Gy. Mean score for dry mouth was 28.1 on the 0-100 QLQ-H&N35 scale. According to CTCAE v3 scale, 87.5% of patients had grade 0-1 and 12.5% grade 2 subjective xerostomia. The unstimulated salivary flow was > 0.2 ml/min in 81.2% of patients and 0.1-0.2 ml/min in 19%. None of the patients showed grade 3 xerostomia. In selected patients with early and moderate stages, well lateralized oral and oropharyngeal carcinomas, ipsilateral irradiation treatment of the primary site and ipsilateral neck spares salivary gland function without compromising loco-regional control

  9. MicroRNA-140 mediates RB tumor suppressor function to control stem cell-like activity through interleukin-6.

    Science.gov (United States)

    Yoshida, Akiyo; Kitajima, Shunsuke; Li, Fengkai; Cheng, Chaoyang; Takegami, Yujiro; Kohno, Susumu; Wan, Yuan Song; Hayashi, Naoyuki; Muranaka, Hayato; Nishimoto, Yuuki; Nagatani, Naoko; Nishiuchi, Takumi; Thai, Tran C; Suzuki, Sawako; Nakao, Shinji; Tanaka, Tomoaki; Hirose, Osamu; Barbie, David A; Takahashi, Chiaki

    2017-02-21

    We established an in vitro cell culture system to determine novel activities of the retinoblastoma (Rb) protein during tumor progression. Rb depletion in p53-null mouse-derived soft tissue sarcoma cells induced a spherogenic phenotype. Cells retrieved from Rb-depleted spheres exhibited slower proliferation and less efficient BrdU incorporation, however, much higher spherogenic activity and aggressive behavior. We discovered six miRNAs, including mmu-miR-18a, -25, -29b, -140, -337, and -1839, whose expression levels correlated tightly with the Rb status and spherogenic activity. Among these, mmu-miR-140 appeared to be positively controlled by Rb and to antagonize the effect of Rb depletion on spherogenesis and tumorigenesis. Furthermore, among genes potentially targeted by mmu-miR-140, Il-6 was upregulated by Rb depletion and downregulated by mmu-mir-140 overexpression. Altogether, we demonstrate the possibility that mmu-mir-140 mediates the Rb function to downregulate Il-6 by targeting its 3'-untranslated region. Finally, we detected the same relationship among RB, hsa-miR-140 and IL-6 in a human breast cancer cell line MCF-7. Because IL-6 is a critical modulator of malignant features of cancer cells and the RB pathway is impaired in the majority of cancers, hsa-miR-140 might be a promising therapeutic tool that disrupts linkage between tumor suppressor inactivation and pro-inflammatory cytokine response.

  10. Controlling micro- and nano-environment of tumor and stem cells for novel research and therapy of brain cancer

    Science.gov (United States)

    Smith, Christopher Lloyd

    The use of modern technologies in cancer research has engendered a great deal of excitement. Many of these advanced approaches involve in-depth mathematical analyses of the inner working of cells, via genomic and proteomic analyses. However these techniques may not be ideal for the study of complex cell phenotypes and behaviors. This dissertation explores cancer and potential therapies through phenotypic analysis of cell behaviors, an alternative approach. We employ this experimental framework to study brain cancer (glioma), a particularly formidable example of this diverse ailment. Through the application of micro- and nanotechnology, we carefully control the surrounding environments of cells to understand their responses to various cues and to manipulate their behaviors. Subsequently we obtain clinically relevant information that allows better understanding of glioma, and enhancement of potential therapies. We first aim to address brain tumor dispersal, through analysis of cell migration. Utilizing nanometer-scale topographic models of the extracellular matrix, we study the migratory response of glioma cells to various stimuli in vitro. Second, we implement knowledge gained from these investigations to define characteristics of tumor progression in patients, and to develop treatments inhibiting cell migration. Next we use microfluidic and nanotopographic models to study the behaviors of stem cells in vitro. Here we attempt to improve their abilities to deliver therapeutic proteins to cancer, an innovative treatment approach. We analyze the multi-step process by which adipose-derived stem cells naturally home to tumor sites, and identify numerous environmental perturbations to enhance this behavior. Finally, we attempt to demonstrate that these cell culture-based manipulations can enhance the localization of adipose stem cells to glioma in vivo using animal models. Throughout this work we utilize environmental cues to analyze and induce particular behaviors in

  11. Bypassing the EPR effect with a nanomedicine harboring a sustained-release function allows better tumor control

    Directory of Open Access Journals (Sweden)

    Shen YA

    2015-03-01

    Full Text Available Yao An Shen,1,* Ing Luen Shyu,2,* Maggie Lu,3 Chun Lin He,4 Yen Mei Hsu,2 Hsiang Fa Liang,3 Chih Peng Liu,3 Ren Shyan Liu,5,6 Biing Jiun Shen,7 Yau Huei Wei,1 Chi Mu Chuang2,4 1Institute of Biochemistry and Molecular Biology, School of Life Sciences, 2Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, 3Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, 4Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, 5Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, 6National PET/Cyclotron Center, Taipei Veterans General Hospital, Taipei, Taiwan; 7Division of Psychology, Nanyang Technological University, Singapore *These authors contributed equally to the work Abstract: The current enhanced permeability and retention (EPR-based approved nanomedicines have had little impact in terms of prolongation of overall survival in patients with cancer. For example, the two Phase III trials comparing Doxil®, the first nanomedicine approved by the US Food and Drug Administration, with free doxorubicin did not find an actual translation of the EPR effect into a statistically significant increase in overall survival but did show less cardiotoxicity. In the current work, we used a two-factor factorial experimental design with intraperitoneal versus intravenous delivery and nanomedicine versus free drug as factors to test our hypothesis that regional (intraperitoneal delivery of nanomedicine may better increase survival when compared with systemic delivery. In this study, we demonstrate that bypassing, rather than exploiting, the EPR effect via intraperitoneal delivery of nanomedicine harboring a sustained-release function demonstrates dual pharmacokinetic advantages, producing more efficient tumor control and suppressing the expression of stemness markers, epithelial

  12. WE-AB-202-10: Modelling Individual Tumor-Specific Control Probability for Hypoxia in Rectal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Warren, S; Warren, DR; Wilson, JM; Muirhead, R; Hawkins, MA; Maughan, T; Partridge, M [University of Oxford, Oxford, Oxfordshire (United Kingdom)

    2016-06-15

    Purpose: To investigate hypoxia-guided dose-boosting for increased tumour control and improved normal tissue sparing using FMISO-PET images Methods: Individual tumor-specific control probability (iTSCP) was calculated using a modified linear-quadratic model with rectal-specific radiosensitivity parameters for three limiting-case assumptions of the hypoxia / FMISO uptake relationship. {sup 18}FMISO-PET images from 2 patients (T3N0M0) from the RHYTHM trial (Investigating Hypoxia in Rectal Tumours NCT02157246) were chosen to delineate a hypoxic region (GTV-MISO defined as tumor-to-muscle ratio > 1.3) within the anatomical GTV. Three VMAT treatment plans were created in Eclipse (Varian): STANDARD (45Gy / 25 fractions to PTV4500); BOOST-GTV (simultaneous integrated boost of 60Gy / 25fr to GTV +0.5cm) and BOOST-MISO (60Gy / 25fr to GTV-MISO+0.5cm). GTV mean dose (in EQD2), iTSCP and normal tissue dose-volume metrics (small bowel, bladder, anus, and femoral heads) were recorded. Results: Patient A showed small hypoxic volume (15.8% of GTV) and Patient B moderate hypoxic volume (40.2% of GTV). Dose escalation to 60Gy was achievable, and doses to femoral heads and small bowel in BOOST plans were comparable to STANDARD plans. For patient A, a reduced maximum bladder dose was observed in BOOST-MISO compared to BOOST-GTV (D0.1cc 49.2Gy vs 54.0Gy). For patient B, a smaller high dose volume was observed for the anus region in BOOST-MISO compared to BOOST-GTV (V55Gy 19.9% vs 100%), which could potentially reduce symptoms of fecal incontinence. For BOOST-MISO, the largest iTSCPs (A: 95.5% / B: 90.0%) assumed local correlation between FMISO uptake and hypoxia, and approached iTSCP values seen for BOOST-GTV (A: 96.1% / B: 90.5%). Conclusion: Hypoxia-guided dose-boosting is predicted to improve local control in rectal tumors when FMISO is spatially correlated to hypoxia, and to reduce dose to organs-at-risk compared to boosting the whole GTV. This could lead to organ

  13. Enhanced tumor control of human Glioblastoma Multiforme xenografts with the concomitant use of radiotherapy and an attenuated herpes simplex-1 virus (ASTRO research fellowship)

    International Nuclear Information System (INIS)

    Song, Paul Y.; Sibley, Gregory S.; Advani, Sunil; Hallahan, Dennis; Hyland, John; Kufe, Donald W.; Chou, Joany; Roizman, Bernard; Weichselbaum, Ralph R.

    1996-01-01

    Purpose: Glioblastoma Multiforme remains one of the most incurable of human tumors. The current treatment outcomes are dismal. There are several recent reports which suggest that some human glioblastoma xenografts implanted in the brains of athymic mice may be potentially cured with the use of an attenuated herpes simplex-1 virus alone. We have chosen a replication competent, non-neurovirulent HSV-1 mutant, designated R3616 to determine whether there is an interactive cell killing and enhanced tumor control with radiotherapy in the treatment of a human glioblastoma xenograft. Materials and Methods: In vivo, 1 mm 3 pieces of U-87 human glioblastoma cell line xenografts were implanted into the right hind limb of athymic mice and grown to > 200 mm 3 . A total of 112 mice were then equally distributed within four treatment arms (see chart below) based upon tumor volume. Xenografts selected to receive virus as part of the therapy were inoculated with three injections of 2 x 10 7 plaque forming units (PFU) of R3616 virus given on day 1, 2, and 3 for a total dose of 6 x 10 7 PFU. R3616 is a non-neurovirulent HSV-1 mutant created by the deletion of the γ 34.5 gene. Local field irradiation was delivered on day 2 (20 Gy) and day 3 (25 Gy). The mice were then followed for 60 days during which time the xenografts were measured twice weekly. A clinically non-palpable tumor (< 10% original volume) was scored as a cure. In addition percent-fractional tumor volume (FTV) and mean tumor volume (MTV) were calculated for each group. Results: Conclusion: While our tumor control with R3616 alone is similar to that reported in the literature, we have seen significantly enhanced tumor control and cell killing with the addition of RT suggesting a synergistic interaction between an oncolytic virus and radiation in the treatment of human glioblastoma multiforme xenografts

  14. Absence of PD-L1 on tumor cells is associated with reduced MHC I expression and PD-L1 expression increases in recurrent serous ovarian cancer.

    Science.gov (United States)

    Aust, Stefanie; Felix, Sophie; Auer, Katharina; Bachmayr-Heyda, Anna; Kenner, Lukas; Dekan, Sabine; Meier, Samuel M; Gerner, Christopher; Grimm, Christoph; Pils, Dietmar

    2017-03-07

    Immune-evasion and immune checkpoints are promising new therapeutic targets for several cancer entities. In ovarian cancer, the clinical role of programmed cell death receptor ligand 1 (PD-L1) expression as mechanism to escape immune recognition has not been clarified yet. We analyzed PD-L1 expression of primary ovarian and peritoneal tumor tissues together with several other parameters (whole transcriptomes of isolated tumor cells, local and systemic immune cells, systemic cytokines and metabolites) and compared PD-L1 expression between primary tumor and tumor recurrences. All expressed major histocompatibility complex (MHC) I genes were negatively correlated to PD-L1 abundances on tumor tissues, indicating two mutually exclusive immune-evasion mechanisms in ovarian cancer: either down-regulation of T-cell mediated immunity by PD-L1 expression or silencing of self-antigen presentation by down-regulation of the MHC I complex. In our cohort and in most of published evidences in ovarian cancer, low PD-L1 expression is associated with unfavorable outcome. Differences in immune cell populations, cytokines, and metabolites strengthen this picture and suggest the existence of concurrent pathways for progression of this disease. Furthermore, recurrences showed significantly increased PD-L1 expression compared to the primary tumors, supporting trials of checkpoint inhibition in the recurrent setting.

  15. Long-term tumor control after brachytherapy for base-of-prostate cancer

    Directory of Open Access Journals (Sweden)

    Seungtaek Choi

    2011-12-01

    Full Text Available Purpose: To evaluate the outcomes of patients presenting with cancer at the base of the prostate after brachytherapyas monotherapy. Material and methods: We retrospectively reviewed the medical records of all patients who had undergone transpe -ri neal ultrasound-guided implantation with 125I or 103Pd seeds as monotherapy between March 1998 and December2006, at our institution. A minimum follow-up interval of 2 years was required for inclusion in our analysis. Dosimetrywas assessed using computed tomography 30 days after the implant. Treatment failure was defined as the appearanceof biopsy-proved tumor after seed implantation, radiographic evidence of metastases, receipt of salvage therapy,or elevation of the prostate-specific antigen level beyond the nadir value plus 2 ng/mL. Results: With a median follow-up interval of 89 months (range 25-128 months, all 52 of the identified patients hadno evidence of disease progression or biochemical failure. The mean number of cores sampled at the prostate base was2.84 (median 2; Gleason scores assigned at central review were 6-8 in all patients. Of the 30 patients (58% for whomdosimetric data were available at day 30, the median V100 values of the right and left base were 92.0% and 93.5%, respectively,and the median D90 values of the right and left base were 148 Gy and 151 Gy, respectively. Conclusion: Permanent prostate brachytherapy as monotherapy results in a high probability of disease-free survivalfor men with cancer at the base of the prostate.

  16. Up-regulation of GITRL on dendritic cells by WGP improves anti-tumor immunity in murine Lewis lung carcinoma.

    Directory of Open Access Journals (Sweden)

    Jie Tian

    Full Text Available BACKGROUND: β-Glucans have been shown to function as a potent immunomodulator to stimulate innate and adaptive immune responses, which contributes to their anti-tumor property. However, their mechanisms of action are still elusive. Glucocorticoid-induced TNF receptor ligand (GITRL, a member of the TNF superfamily, binds to its receptor, GITR, on both effector and regulatory T cells, generates a positive co-stimulatory signal implicated in a wide range of T cell functions, which is important for the development of immune responses. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we found that whole β-glucan particles (WGPs could activate dendritic cells (DCs via dectin-1 receptor, and increase the expression of GITRL on DCs in vitro and in vivo. Furthermore, we demonstrated that the increased GITRL on DCs could impair the regulartory T cell (Treg-mediated suppression and enhance effector T cell proliferation in a GITR/GITRL dependent way. In tumor models, DCs with high levels of GITRL were of great potential to prime cytotoxic T lymphocyte (CTL responses and down-regulate the suppressive activity of Treg cells, thereby leading to the delayed tumor progression. CONCLUSIONS/SIGNIFICANCE: These findings suggest that particulate β-glucans can be used as an immunomodulator to stimulate potent T cell-mediated adaptive immunity while down-regulate suppressive immune activity via GITR/GITRL interaction, leading to a more efficient defense mechanism against tumor development.

  17. Suitability of quality control materials for prostate-specific antigen (PSA) measurement: inter-method variability of common tumor marker control materials.

    Science.gov (United States)

    Vucetic, Zivjena; Dnistrian, Ann; Nilsson, Olle; Lilja, Hans G; Plebani, Mario

    2013-04-01

    Quality control materials with minimal inter-assay differences and clinically relevant proportions of different molecular forms of the analyte are needed to optimize intra- and inter-laboratory accuracy and precision. We assessed if clinically relevant total prostate-specific antigen (tPSA) levels were present in seven commercially available Multi Constituent Tumor Marker Controls (MC-TMC). Further, we determined the concentration of free PSA (fPSA) and calculated the percentage of free PSA (%fPSA) in all materials. Finally, we determined variability of TMC materials across several commonly used PSA platforms. All MC-TMC materials contained at least one concentration of tPSA in normal and pathologic range. Control materials varied in the amount of fPSA and %fPSA, with most controls consisting of fPSA only and only one MC-TMC containing medically relevant levels of around 35% fPSA. Only a minority of MC-TMC materials showed minimal variability across four PSA methods while the majority of PSA controls showed wide inter-method differences. Use of many commercially available controls for PSA could lead to biased PSA measurements because they contain medically irrelevant proportions of fPSA and show significant variation among different PSA assay platforms.

  18. The Plasmodium falciparum translationally controlled tumor protein (TCTP is incorporated more efficiently into B cells than its human homologue.

    Directory of Open Access Journals (Sweden)

    Berenice Calderón-Pérez

    Full Text Available Plasmodium falciparum secretes a homologue of the translationally controlled tumor protein (TCTP into serum of infected individuals, although its role in pathogenesis or virulence is unknown. To determine the effect of P. falciparum TCTP on B cells as compared to human TCTP, fluorescently labeled proteins were incubated on primary cultures of mouse splenic B cells and analyzed by flow cytometry and confocal microscopy. Our results indicate that both recombinant proteins are incorporated into B cells, but differ significantly in their rate and percentage of incorporation, being significantly higher for P. falciparum TCTP. Furthermore, P. falciparum TCTP showed a lower B cell proliferative effect than human TCTP, suggesting a mechanism through which the former could interfere in the host's immune response.

  19. A test of the claim that plan rankings are determined by relative complication and tumor-control probabilities.

    Science.gov (United States)

    Langer, M; Morrill, S S; Lane, R

    1998-05-01

    This study tests an accepted claim regarding tumor control (TCP) and normal tissue complication (NTCP) probability functions. The claim is that treatment plans can be ranked using relative probabilities, even when the absolute probabilities are unknown. The assumption supports the use of probability models for plan optimization and the comparison of treatment techniques. The claim was tested using a hypothetical model consisting of two tissues, and illustrated with clinical data. Plans were scored using the probability of uncomplicated tumor control. The scores of different plans were compared by fixing their relative risks for an individual tissue complication, but adjusting the absolute probability levels up or down. The tested claim is that the plan rankings should not change. In the two-tissue model, the rankings of competing plans were reversed by doubling all the probabilities. The preference ordering of lung cancer plans changed after the risk of pulmonary complication was reduced by 3-fold. In another site, the ranking of plans by overall complication-free probability was disturbed by errors that preserved the ordering of plans with respect to any individual complication. An adjustment of +/- 2.5% in the initial NTCP values for two tissues changed the direction in which a plan score moved in response to a fixed tradeoff in complication risk in an optimization search. Contrary to claims, plan rankings are not determined by the relative probabilities of adverse events. The effect on plan scores of trading one complication for another depends on the absolute levels of risk. Absolute errors in NTCP and TCP functions result in the wrong ranking of plans, even when relative probabilities are correct. An optimization routine based on TCP and NTCP calculations may be forced in the wrong direction by small errors in the probability estimates.

  20. Anti-tumor effect of adenovirus-mediated suicide gene therapy under control of tumor-specific and radio-inducible chimeric promoter in combination with γ-ray irradiation in vivo

    International Nuclear Information System (INIS)

    Sun Wenjie; Yu Haijun; Xiongjie; Xu Yu; Liao Zhengkai; Zhou Fuxiang; Xie Conghua; Zhou Yunfeng

    2011-01-01

    Objective: To detect the selective inhibitory effects of irradiation plus adenovirus-mediated horseradish peroxidase (HRP)/indole-3-acetic acid (IAA) suicide gene system using tumor-specific and radio-inducible chimeric promoter on human hepatocellular carcinoma subcutaneously xenografted in nude mouse. Methods: Recombinant replicated-deficient adenovirus vector containing HRP gene and chimeric human telomerase reverse transcriptase (hTERT) promoter carrying 6 radio-inducible CArG elements was constructed. A human subcutaneous transplanting hepatocellular carcinoma (MHCC97 cell line) model was treated with γ-ray irradiation plus intra-tumor injections of adenoviral vector and intra-peritoneal injections of prodrug IAA. The change of tumor volume and tumor growth inhibiting rate, the survival time of nude mice, as well as histopathology of xenograft tumor and normal tissues were evaluated. Results: Thirty one days after the treatment, the relative tumor volumes in the negative, adenovirus therapy, irradiation, and combination groups were 49.23±4.55, 27.71±7.74, 28.53±10.48 and 11.58±3.23, respectively.There was a significantly statistical difference among them (F=16.288, P<0.01).The inhibition effect in the combination group was strongest as compared with that in other groups, and its inhibition ratio was 76.5%. The survival period extended to 43 d in the combination group, which showed a significantly difference with that in the control group (χ 2 =18.307, P<0.01). The area of tumors necrosis in the combination group was larger than that in the other groups, and the normal tissues showed no treatment-related toxic effect in all groups. However, multiple hepatocellular carcinoma metastases were observed in the liver in the control group, there were a few metastases in the monotherapy groups and no metastasis in the combination group. Conclusions: Adenovirus-mediated suicide gene therapy plus radiotherapy dramatically could inhibit tumor growth and prolong

  1. Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy.

    Science.gov (United States)

    Takara, Kazuhiro; Hatakeyama, Hiroto; Kibria, Golam; Ohga, Noritaka; Hida, Kyoko; Harashima, Hideyoshi

    2012-08-20

    Anti-angiogenic therapy is a potential chemotherapeutic strategy for the treatment of drug resistant cancers. However, a method for delivering such drugs to tumor endothelial cells remains to be a major impediment to the success of anti-angiogenesis therapy. We designed liposomes (LPs) with controlled diameter of around 300 nm, and modified them with a specific ligand and a cell penetrating peptide (CPP) (a dual-ligand LP) for targeting CD13-expressing neovasculature in a renal cell carcinoma (RCC). We modified the LPs with an NGR motif peptide on the top of poly(ethylene glycol) and tetra-arginine (R4) on the surface of the liposome membrane as a specific and CPP ligand, respectively. The large size prevented extravasation of the dual-ligand LP, which allowed it to associate with target vasculature. While a single modification with either the specific or CPP ligand showed no increase in targetability, the dual-ligand enhanced the amount of delivered liposomes after systemic administration to OS-RC-2 xenograft mice. The anti-tumor activity of a dual-ligand LP encapsulating doxorubicin was evaluated and the results were compared with Doxil, which is clinically used to target tumor cells. Even though Doxil showed no anti-tumor activity, the dual-ligand LP suppressed tumor growth because the disruption of tumor vessels was efficiently induced. The comparison showed that tumor endothelial cells (TECs) were more sensitive to doxorubicin by 2 orders than RCC tumor cells, and the disruption of tumor vessels was efficiently induced. Collectively, the dual-ligand LP is promising carrier for the treatment of drug resistant RCC via the disruption of TECs. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. ETS transcription factors control transcription of EZH2 and epigenetic silencing of the tumor suppressor gene Nkx3.1 in prostate cancer.

    Directory of Open Access Journals (Sweden)

    Paolo Kunderfranco

    2010-05-01

    Full Text Available ETS transcription factors regulate important signaling pathways involved in cell differentiation and development in many tissues and have emerged as important players in prostate cancer. However, the biological impact of ETS factors in prostate tumorigenesis is still debated.We performed an analysis of the ETS gene family using microarray data and real-time PCR in normal and tumor tissues along with functional studies in normal and cancer cell lines to understand the impact in prostate tumorigenesis and identify key targets of these transcription factors. We found frequent dysregulation of ETS genes with oncogenic (i.e., ERG and ESE1 and tumor suppressor (i.e., ESE3 properties in prostate tumors compared to normal prostate. Tumor subgroups (i.e., ERG(high, ESE1(high, ESE3(low and NoETS tumors were identified on the basis of their ETS expression status and showed distinct transcriptional and biological features. ERG(high and ESE3(low tumors had the most robust gene signatures with both distinct and overlapping features. Integrating genomic data with functional studies in multiple cell lines, we demonstrated that ERG and ESE3 controlled in opposite direction transcription of the Polycomb Group protein EZH2, a key gene in development, differentiation, stem cell biology and tumorigenesis. We further demonstrated that the prostate-specific tumor suppressor gene Nkx3.1 was controlled by ERG and ESE3 both directly and through induction of EZH2.These findings provide new insights into the role of the ETS transcriptional network in prostate tumorigenesis and uncover previously unrecognized links between aberrant expression of ETS factors, deregulation of epigenetic effectors and silencing of tumor suppressor genes. The link between aberrant ETS activity and epigenetic gene silencing may be relevant for the clinical management of prostate cancer and design of new therapeutic strategies.

  3. Intracavitary brachytherapy significantly enhances local control of early T-stage nasopharyngeal carcinoma: the existence of a dose-tumor-control relationship above conventional tumoricidal dose

    International Nuclear Information System (INIS)

    Teo, Peter Man Lung; Leung, Sing Fai; Lee, Wai Yee; Zee, Benny

    2000-01-01

    the chronic radiation complications, with the exception of chronic radiation nasopharyngeal ulceration/necrosis which occurred in 10 patients in Group A and 1 patient in Group B. Headache (n = 4) and foul smell (n = 8) consequential to ulceration/necrosis were mild and manageable by conservative means. A significant dose-tumor-control relationship existed when local failure was studied as a function of the total physical dose or the total biological equivalent dose (linear quadratic equation, α/β = 10) uncorrected for tumor repopulation during the time course of the radiotherapy. Conclusions: Supplementing ERT which delivered tumoricidal dose (uncorrected BED-10 ≥75 Gy), ICT significantly enhanced ultimate local control and avoided the necessity for morbid salvage treatments in early T-stage (T1/T2 nasal infiltration) NPC. The slight increase in chronic radiation ulceration/necrosis after ICT was acceptable with mild and manageable symptoms. Other late complications were not increased. A significant dose-tumor-control relationship exists above the conventional tumoricidal dose level

  4. HPMA copolymer-drug conjugates with controlled tumor-specific drug release

    Czech Academy of Sciences Publication Activity Database

    Chytil, Petr; Koziolová, Eva; Etrych, Tomáš; Ulbrich, Karel

    2018-01-01

    Roč. 18, č. 1 (2018), s. 1-15, č. článku 1700209. ISSN 1616-5187 R&D Projects: GA ČR(CZ) GA15-02986S; GA ČR(CZ) GA17-13283S; GA ČR(CZ) GA17-08084S; GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 Keywords : biodegradable spacer * controlled drug release * drug delivery systems Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 3.238, year: 2016

  5. Long-Term Disease Control of a Pancreatic Neuroendocrine Tumor with Lanreotide Autogel®: A Case Report

    Directory of Open Access Journals (Sweden)

    Willem Lybaert

    2014-09-01

    Full Text Available The CLARINET study (ClinicalTrials.gov: NCT00353496 showed that somatostatin analogs are able to stabilize tumor growth in patients with intestinal and pancreatic neuroendocrine tumors (NETs. Here, we present a case of NET originating from the pancreatic tail that was treated with lanreotide Autogel®. A 60-year-old patient underwent resection of a pancreatic NET with splenectomy and distal pancreatectomy. Four months after surgery, there was an increase in chromogranin A levels, along with a hypercaptating lesion of approximately 3.5 cm at the residual part of the pancreatic corpus. Treatment with 30 mg monthly-administered octreotide long-acting release (LAR was initiated. After 3 months of treatment, a control CT scan revealed diffuse metastases in the liver, although the patient presented no symptoms and liver tests were normal. Due to difficulties with the administration of octreotide LAR, treatment was switched to lanreotide Autogel® 120 mg, administered as monthly deep-subcutaneous injections. Progression-free survival, as shown by 3-monthly CT scans, was obtained for 2 years without the need to increase the lanreotide Autogel® dose, and the patient reported no side effects. After these 2 years, deterioration of the patient's clinical status and weight loss were observed, along with increased size of the liver lesions and appearance of peritoneal metastases. Chemotherapy treatment with cisplatinum-etoposide was initiated, while the lanreotide Autogel® injections were continued. After three chemotherapy cycles, a rapid decline in the patient's quality of life was noted, and she requested discontinuation of the chemotherapy and lanreotide injections. One month later, the patient died due to clinical progressive disease.

  6. Translationally Controlled Tumor Protein Stimulates Dopamine Release from PC12 Cells via Ca2+-Independent Phospholipase A2 Pathways

    Directory of Open Access Journals (Sweden)

    Jihui Seo

    2016-10-01

    Full Text Available The translationally controlled tumor protein (TCTP, initially identified as a tumor- and growth-related protein, is also known as a histamine-releasing factor (HRF. TCTP is widely distributed in the neuronal systems, but its function is largely uncharacterized. Here, we report a novel function of TCTP in the neurotransmitter release from a neurosecretory, pheochromocytoma (PC12 cells. Treatment with recombinant TCTP (rTCTP enhanced both basal and depolarization (50 mM KCl-evoked [3H]dopamine release in concentration- and time-dependent manners. Interestingly, even though rTCTP induced the increase in intracellular calcium levels ([Ca2+]i, the rTCTP-driven effect on dopamine release was mediated by a Ca2+-independent pathway, as evidenced by the fact that Ca2+-modulating agents such as Ca2+ chelators and a voltage-gated L-type Ca2+-channel blocker did not produce any changes in rTCTP-evoked dopamine release. In a study to investigate the involvement of phospholipase A2 (PLA2 in rTCTP-induced dopamine release, the inhibitor for Ca2+-independent PLA2 (iPLA2 produced a significant inhibitory effect on rTCTP-induced dopamine release, whereas this release was not significantly inhibited by Ca2+-dependent cytosolic PLA2 (cPLA2 and secretory PLA2 (sPLA2 inhibitors. We found that rTCTP-induced dopamine release from neuronal PC12 cells was modulated by a Ca2+-independent mechanism that involved PLA2 in the process, suggesting the regulatory role of TCTP in the neuronal functions.

  7. Upregulation of HLA Class I Expression on Tumor Cells by the Anti-EGFR Antibody Nimotuzumab

    Directory of Open Access Journals (Sweden)

    Greta Garrido

    2017-10-01

    Full Text Available Defining how epidermal growth factor receptor (EGFR-targeting therapies influence the immune response is essential to increase their clinical efficacy. A growing emphasis is being placed on immune regulator genes that govern tumor – T cell interactions. Previous studies showed an increase in HLA class I cell surface expression in tumor cell lines treated with anti-EGFR agents. In particular, earlier studies of the anti-EGFR blocking antibody cetuximab, have suggested that increased tumor expression of HLA class I is associated with positive clinical response. We investigated the effect of another commercially available anti-EGFR antibody nimotuzumab on HLA class I expression in tumor cell lines. We observed, for the first time, that nimotuzumab increases HLA class I expression and its effect is associated with a coordinated increase in mRNA levels of the principal antigen processing and presentation components. Moreover, using 7A7 (a specific surrogate antibody against murine EGFR, we obtained results suggesting the importance of the increased MHC-I expression induced by EGFR-targeted therapies display higher in antitumor immune response. 7A7 therapy induced upregulation of tumor MHC-I expression in vivo and tumors treated with this antibody display higher susceptibility to CD8+ T cells-mediated lysis. Our results represent the first evidence suggesting the importance of the adaptive immunity in nimotuzumab-mediated antitumor activity. More experiments should be conducted in order to elucidate the relevance of this mechanism in cancer patients. This novel immune-related antitumor mechanism mediated by nimotuzumab opens new perspectives for its combination with various immunotherapeutic agents and cancer vaccines.

  8. Multitype Network-Guided Target Controllability in Phenotypically Characterized Osteosarcoma: Role of Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Ankush Sharma

    2017-07-01

    Full Text Available This study highlights the relevance of network-guided controllability analysis as a precision oncology tool. Target controllability through networks is potentially relevant to cancer research for the identification of therapeutic targets. With reference to a recent study on multiple phenotypes from 22 osteosarcoma (OS cell lines characterized both in vitro and in vivo, we found that a variety of critical proteins in OS regulation circuits were in part phenotype specific and in part shared. To generalize our inference approach and match cancer phenotypic heterogeneity, we employed multitype networks and identified targets in correspondence with protein sub-complexes. Therefore, we established the relevance for diagnostic and therapeutic purposes of inspecting interactive targets, namely those enriched by significant connectivity patterns in protein sub-complexes. Emerging targets appeared with reference to the OS microenvironment, and relatively to small leucine-rich proteoglycan members and D-type cyclins, among other collagen, laminin, and keratin proteins. These described were evidences shared across all phenotypes; instead, specific evidences were provided by critical proteins including IGFBP7 and PDGFRA in the invasive phenotype, and FGFR3 and THBS1 in the colony forming phenotype.

  9. Ipsilateral irradiation for well lateralized carcinomas of the oral cavity and oropharynx: results on tumor control and xerostomia

    Directory of Open Access Journals (Sweden)

    Marín Alicia

    2009-09-01

    Full Text Available Abstract Background In head and neck cancer, bilateral neck irradiation is the standard approach for many tumor locations and stages. Increasing knowledge on the pattern of nodal invasion leads to more precise targeting and normal tissue sparing. The aim of the present study was to evaluate the morbidity and tumor control for patients with well lateralized squamous cell carcinomas of the oral cavity and oropharynx treated with ipsilateral radiotherapy. Methods Twenty consecutive patients with lateralized carcinomas of the oral cavity and oropharynx were treated with a prospective management approach using ipsilateral irradiation between 2000 and 2007. This included 8 radical oropharyngeal and 12 postoperative oral cavity carcinomas, with Stage T1-T2, N0-N2b disease. The actuarial freedom from contralateral nodal recurrence was determined. Late xerostomia was evaluated using the European Organization for Research and Treatment of Cancer QLQ-H&N35 questionnaire and the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 3. Results At a median follow-up of 58 months, five-year overall survival and loco-regional control rates were 82.5% and 100%, respectively. No local or contralateral nodal recurrences were observed. Mean dose to the contralateral parotid gland was 4.72 Gy and to the contralateral submandibular gland was 15.30 Gy. Mean score for dry mouth was 28.1 on the 0-100 QLQ-H&N35 scale. According to CTCAE v3 scale, 87.5% of patients had grade 0-1 and 12.5% grade 2 subjective xerostomia. The unstimulated salivary flow was > 0.2 ml/min in 81.2% of patients and 0.1-0.2 ml/min in 19%. None of the patients showed grade 3 xerostomia. Conclusion In selected patients with early and moderate stages, well lateralized oral and oropharyngeal carcinomas, ipsilateral irradiation treatment of the primary site and ipsilateral neck spares salivary gland function without compromising loco-regional control.

  10. Ipsilateral irradiation for well lateralized carcinomas of the oral cavity and oropharynx: results on tumor control and xerostomia

    Science.gov (United States)

    Cerezo, Laura; Martín, Margarita; López, Mario; Marín, Alicia; Gómez, Alberto

    2009-01-01

    Background In head and neck cancer, bilateral neck irradiation is the standard approach for many tumor locations and stages. Increasing knowledge on the pattern of nodal invasion leads to more precise targeting and normal tissue sparing. The aim of the present study was to evaluate the morbidity and tumor control for patients with well lateralized squamous cell carcinomas of the oral cavity and oropharynx treated with ipsilateral radiotherapy. Methods Twenty consecutive patients with lateralized carcinomas of the oral cavity and oropharynx were treated with a prospective management approach using ipsilateral irradiation between 2000 and 2007. This included 8 radical oropharyngeal and 12 postoperative oral cavity carcinomas, with Stage T1-T2, N0-N2b disease. The actuarial freedom from contralateral nodal recurrence was determined. Late xerostomia was evaluated using the European Organization for Research and Treatment of Cancer QLQ-H&N35 questionnaire and the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3. Results At a median follow-up of 58 months, five-year overall survival and loco-regional control rates were 82.5% and 100%, respectively. No local or contralateral nodal recurrences were observed. Mean dose to the contralateral parotid gland was 4.72 Gy and to the contralateral submandibular gland was 15.30 Gy. Mean score for dry mouth was 28.1 on the 0-100 QLQ-H&N35 scale. According to CTCAE v3 scale, 87.5% of patients had grade 0-1 and 12.5% grade 2 subjective xerostomia. The unstimulated salivary flow was > 0.2 ml/min in 81.2% of patients and 0.1-0.2 ml/min in 19%. None of the patients showed grade 3 xerostomia. Conclusion In selected patients with early and moderate stages, well lateralized oral and oropharyngeal carcinomas, ipsilateral irradiation treatment of the primary site and ipsilateral neck spares salivary gland function without compromising loco-regional control. PMID:19723329

  11. GTL001 and bivalent CyaA-based therapeutic vaccine strategies against human papillomavirus and other tumor-associated antigens induce effector and memory T-cell responses that inhibit tumor growth.

    Science.gov (United States)

    Esquerré, Michaël; Momot, Marie; Goubier, Anne; Gonindard, Christophe; Leung-Theung-Long, Stéphane; Misseri, Yolande; Bissery, Marie-Christine

    2017-03-13

    GTL001 is a bivalent therapeutic vaccine containing human papillomavirus (HPV) 16 and HPV18 E7 proteins inserted in the Bordetella pertussis adenylate cyclase (CyaA) vector intended to prevent cervical cancer in HPV-infected women with normal cervical cytology or mild abnormalities. To be effective, therapeutic cervical cancer vaccines should induce both a T cell-mediated effector response against HPV-infected cells and a robust CD8 + T-cell memory response to prevent potential later infection. We examined the ability of GTL001 and related bivalent CyaA-based vaccines to induce, in parallel, effector and memory CD8 + T-cell responses to both vaccine antigens. Intradermal vaccination of C57BL/6 mice with GTL001 adjuvanted with a TLR3 agonist (polyinosinic-polycytidylic acid) or a TLR7 agonist (topical 5% imiquimod cream) induced strong HPV16 E7-specific T-cell responses capable of eradicating HPV16 E7-expressing tumors. Tumor-free mice also had antigen-specific memory T-cell responses that protected them against a subsequent challenge with HPV18 E7-expressing tumor cells. In addition, vaccination with bivalent vaccines containing CyaA-HPV16 E7 and CyaA fused to a tumor-associated antigen (melanoma-specific antigen A3, MAGEA3) or to a non-viral, non-tumor antigen (ovalbumin) eradicated HPV16 E7-expressing tumors and protected against a later challenge with MAGEA3- and ovalbumin-expressing tumor cells, respectively. These results show that CyaA-based bivalent vaccines such as GTL001 can induce both therapeutic and prophylactic anti-tumor T-cell responses. The CyaA platform can be adapted to different antigens and adjuvants, and therefore may be useful for developing other therapeutic vaccines. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  12. Distribution of copper-64 in control mice and in mice bearing ascitic Krebs tumor cells

    International Nuclear Information System (INIS)

    Apelgot, S.; Coppey, J.; Grisvard, J.; Guille, E.; Sissoeeff, I.

    1981-01-01

    Three to 20 hr after an i.p. injection of 64 Cu (half-life, 12.8 hr) into mice bearing Krebs ascites cells, a high amount of the radioisotope was recovered in the ascites cells themselves. In the control group, the radioisotope was mainly present in the liver. Similar amounts of 64 Cu were recovered in regenerating as well as in normal liver, whereas in the liver of mice bearing ascites cells, this amount was lower by 40 to 50% regardless of the ascitic volume. Thus, the copper metabolism seems to be disturbed at the hepatic level in mice bearing ascites cells. The distribution of 64 Cu was 'analyzed in DNA, RNA, and proteins from cellular lysates fractionated by CsCl gradient. There was a uniform pattern of distribution in the macromolecules from ascites cells, while 64 Cu' was preferentially associated with the protein fraction from liver. Further experiments indicated that, in vivo, 64 Cu was bound to the DNA of ascites cells

  13. [Immune system and tumors].

    Science.gov (United States)

    Terme, Magali; Tanchot, Corinne

    2017-02-01

    Despite having been much debated, it is now well established that the immune system plays an essential role in the fight against cancer. In this article, we will highlight the implication of the immune system in the control of tumor growth and describe the major components of the immune system involved in the antitumoral immune response. The immune system, while exerting pressure on tumor cells, also will play a pro-tumoral role by sculpting the immunogenicity of tumors cells as they develop. Finally, we will illustrate the numerous mechanisms of immune suppression that take place within the tumoral microenvironment which allow tumor cells to escape control from the immune system. The increasingly precise knowledge of the brakes to an effective antitumor immune response allows the development of immunotherapy strategies more and more innovating and promising of hope. Copyright © 2016. Published by Elsevier Masson SAS.

  14. A randomized control intervention trial to improve social skills and quality of life in pediatric brain tumor survivors.

    Science.gov (United States)

    Barrera, Maru; Atenafu, Eshetu G; Sung, Lillian; Bartels, Ute; Schulte, Fiona; Chung, Joanna; Cataudella, Danielle; Hancock, Kelly; Janzen, Laura; Saleh, Amani; Strother, Douglas; Downie, Andrea; Zelcer, Shayna; Hukin, Juliette; McConnell, Dina

    2018-01-01

    To determine if a group social skills intervention program improves social competence and quality of life (QOL) in pediatric brain tumor survivors (PBTS). We conducted a randomized control trial in which PBTS (8-16 years old, off therapy for over 3 months) were allocated to receive social skills training (eg, cooperation, assertion, using social cognitive problem solving strategies, role playing, games, and arts and crafts) in 8 weekly 2-hour sessions, or an attention placebo control (games and arts and crafts only). Outcomes were self-reported, proxy-reported (caregiver), and teacher-reported using the Social Skills Rating System (SSRS), to measure social competence, and the Pediatric Quality of Life (PedsQL4.0, generic) to measure QOL at baseline, after intervention, and at 6 months follow-up. At baseline, SSRS were stratified into low and high scores and included as a covariate in the analysis. Compared to controls (n = 48), PBTS in the intervention group (n = 43) reported significantly better total and empathy SSRS scores, with improvements persisting at follow-up. The PBTS in the intervention group who had low scores at baseline reported the greatest improvements. Proxy and teacher reports showed no intervention effect. Participating in group social skills intervention can improve self-reported social competence that persisted to follow up. The PBTS should be given the opportunity to participate in social skills groups to improve social competence. Copyright © 2017 John Wiley & Sons, Ltd.

  15. Extended Tumor Control After Dendritic Cell Vaccination With Low Dose Cyclophosphamide as Adjuvant Treatment in Patients With Malignant Pleural Mesothelioma

    NARCIS (Netherlands)

    R. Cornelissen (Robin); J.P.J.J. Hegmans (Joost); A.W.P.M. Maat (Alex); M.E.H. Lambers (Margaretha); K. Bezemer (Koen); R.W. Hendriks (Rudi); H.C. Hoogsteden (Henk); J.G.J.V. Aerts (Joachim)

    2015-01-01

    markdownabstract__Rationale:__ We demonstrated before that autologous tumor lysate-pulsed dendritic cell-based immunotherapy in patients with malignant pleural mesothelioma is feasible, well-tolerated, and capable of inducing immunological responses against tumors. In our murine model we found that

  16. Urokinase-Type Plasminogen Activator Receptor Transcriptionally Controlled Adenoviruses Eradicate Pancreatic Tumors and Liver Metastasis in Mouse Models12

    Science.gov (United States)

    Huch, Meritxell; Gros, Alena; José, Anabel; González, Juan Ramon; Alemany, Ramon; Fillat, Cristina

    2009-01-01

    Treatment options for pancreatic cancer have shown limited success mainly owing to poor selectivity for pancreatic tumor tissue and to a lack of activity in the tumor. In this study, we describe the ability of the urokinase-type plasminogen activator receptor (uPAR) promoter to efficiently and selectively target pancreatic tumors and metastases, which enables the successful management of pancreatic cancer. We have generated a replication-defective reporter adenovirus, AduPARLuc, and a conditionally replicating adenovirus, AduPARE1A, and we have studied the selectivity and antitumoral efficacy in pancreatic tumors and metastases. Toxicity was studied on intravascular delivery. We demonstrate that the uPAR promoter is highly active in pancreatic tumors but very weak in normal tissues. Tumor specificity is evidenced by a 100-fold increase in the tumor-to-liver ratio and by selective targeting of liver metastases (P < .001). Importantly, the AduPARE1A maintains the oncolytic activity of the wild-type virus, with reduced toxicity, and exhibits significant antitumoral activity (25% tumor eradication) and prolonged survival in pancreatic xenograft models (P < .0001). Furthermore, upon intravascular delivery, we demonstrate complete eradication of liver metastasis in 33% of mice, improving median survival (P = 5.43 x 10-5). The antitumoral selective activity of AduPARE1A shows the potential of uPAR promoter-based therapies in pancreatic cancer treatment. PMID:19484141

  17. The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells

    International Nuclear Information System (INIS)

    Kerl, Kornelius; Eveslage, Maria; Jung, Manfred; Meisterernst, Michael; Frühwald, Michael; Ries, David; Unland, Rebecca; Borchert, Christiane; Moreno, Natalia; Hasselblatt, Martin; Jürgens, Heribert; Kool, Marcel; Görlich, Dennis

    2013-01-01

    Rhabdoid tumors are highly aggressive malignancies affecting infants and very young children. In many instances these tumors are resistant to conventional type chemotherapy necessitating alternative approaches. Proliferation assays (MTT), apoptosis (propidium iodide/annexin V) and cell cycle analysis (DAPI), RNA expression microarrays and western blots were used to identify synergism of the HDAC (histone deacetylase) inhibitor SAHA with fenretinide, tamoxifen and doxorubicin in rhabdoidtumor cell lines. HDAC1 and HDAC2 are overexpressed in primary rhabdoid tumors and rhabdoid tumor cell lines. Targeting HDACs in rhabdoid tumors induces cell cycle arrest and apoptosis. On the other hand HDAC inhibition induces deregulated gene programs (MYCC-, RB program and the stem cell program) in rhabdoid tumors. These programs are in general associated with cell cycle progression. Targeting these activated pro-proliferative genes by combined approaches of HDAC-inhibitors plus fenretinide, which inhibits cyclinD1, exhibit strong synergistic effects on induction of apoptosis. Furthermore, HDAC inhibition sensitizes rhabdoid tumor cell lines to cell death induced by chemotherapy. Our data demonstrate that HDAC inhibitor treatment in combination with fenretinide or conventional chemotherapy is a promising tool for the treatment of chemoresistant rhabdoid tumors

  18. Tumor control induced by Boron Neutron Capture Therapy (BNCT) as a function of dose in an experimental model of liver metastases at 5 weeks follow-up

    International Nuclear Information System (INIS)

    Pozzi, E C C; Trivillin, V A; Colombo, L L; Monti Hughes, A; Thorp, S; Cardoso, J E; Garabalino, M A; Molinari, A J; Heber, E M; Curotto, Paula; Miller, M; Itoiz, M E; Aromando, R F; Nigg, D W; Schwint, A E

    2012-01-01

    BNCT has been proposed for the treatment of multifocal, non-resectable, bilobar colorectal liver metastases that do not respond to chemotherapy. We recently reported that BNCT mediated by boronophenylalanine (BPA) induced significant remission of experimental colorectal tumor nodules in rat liver at 3 weeks follow-up with no contributory liver toxicity (Pozzi et al.,2012). The aim of the present study was to evaluate tumor control and potential liver toxicity of BPA-BNCT at 5 weeks follow-up. Prescribed dose was retrospectively evaluated based on blood boron values, allowing for assessment of response over a range of delivered dose values (author)

  19. A fine balance: epigenetic control of cellular quiescence by the tumor suppressor PRDM2/RIZ at a bivalent domain in the cyclin a gene

    OpenAIRE

    Cheedipudi, Sirisha; Puri, Deepika; Saleh, Amena; Gala, Hardik P.; Rumman, Mohammed; Pillai, Malini S.; Sreenivas, Prethish; Arora, Reety; Sellathurai, Jeeva; Schr?der, Henrik Daa; Mishra, Rakesh K.; Dhawan, Jyotsna

    2015-01-01

    Adult stem cell quiescence is critical to ensure regeneration while minimizing tumorigenesis. Epigenetic regulation contributes to cell cycle control and differentiation, but few regulators of the chromatin state in quiescent cells are known. Here we report that the tumor suppressor PRDM2/RIZ, an H3K9 methyltransferase, is enriched in quiescent muscle stem cells in vivo and controls reversible quiescence in cultured myoblasts. We find that PRDM2 associates with >4400 promoters in G0 myobla...

  20. Card9 controls Dectin‐1‐induced T‐cell cytotoxicity and tumor growth in mice

    Science.gov (United States)

    Haas, Tobias; Heidegger, Simon; Wintges, Alexander; Bscheider, Michael; Bek, Sarah; Fischer, Julius C.; Eisenkolb, Gabriel; Schmickl, Martina; Spoerl, Silvia; Peschel, Christian; Poeck, Hendrik

    2017-01-01

    Activation of the C‐type lectin receptor Dectin‐1 by β‐glucans triggers multiple signals within DCs that result in activation of innate immunity. While these mechanisms can potently prime CD8+ cytotoxic T‐cell (CTL) responses without additional adjuvants, the Dectin‐1 effector pathways that control CTL induction remain unclear. Here we demonstrate that Dectin‐1‐induced CTL cross‐priming in mice does not require inflammasome activation but strictly depends on the adapter protein Card9 in vitro. In vivo, Dectin‐1‐mediated Card9 activation after vaccination drives both expansion and activation of Ag‐specific CTLs, resulting in long‐lasting CTL responses that are sufficient to protect mice from tumor challenge. This Dectin‐1‐induced antitumor immune response was independent of NK cell function and completely abrogated in Card9‐deficient mice. Thus, our results demonstrate that Dectin‐1‐triggered Card9 signaling but not inflammasome activation can potently cross‐prime Ag‐specific CTLs, suggesting that this pathway would be a candidate for immunotherapy and vaccine development. PMID:28295265

  1. The effect of modafinil on fatigue, cognitive functioning, and mood in primary brain tumor patients: a multicenter randomized controlled trial

    Science.gov (United States)

    Boele, Florien W.; Douw, Linda; de Groot, Marjolein; van Thuijl, Hinke F.; Cleijne, Wilmy; Heimans, Jan J.; Taphoorn, Martin J.B.; Reijneveld, Jaap C.; Klein, Martin

    2013-01-01

    Background Fatigue, cognitive deficits, and depression are frequently reported but often undertreated symptoms that can profoundly affect daily life in patients with primary brain tumors (PBTs). To evaluate the effects of the psychostimulant modafinil on fatigue, depression, health-related quality of life (HRQOL), and cognitive functioning in PBT patients, we performed a multicenter, double-blind placebo-controlled crossover trial. Methods Patients randomly received either 6 weeks of treatment with modafinil (up to 400 mg/day) or 6 weeks with placebo. After a 1-week washout period, the opposite treatment was provided. Assessments took place at baseline and immediately after the first and second condition. Patients completed self-report questionnaires on fatigue (Checklist Individual Strength [CIS]), depression (Center for Epidemiologic Studies Depression Scale [CES-D]), HRQOL (Short-Form Health Survey [SF-36]), and self-perceived cognitive functioning (Medical Outcomes Study [MOS]). They also underwent comprehensive neurocognitive testing. Results In total, 37 patients participated. Relative to baseline, patients reported lower fatigue severity (CIS) and better motivation (CIS) in both the modafinil (P = .010 and P = .021, respectively) and the placebo condition (P Modafinil did not exceed the effects of placebo with respect to symptom management. Patient accrual was slow, and relatively many patients dropped out during the trial, due mostly to side effects. Other, preferably nonpharmacologic intervention studies should be considered to improve symptom management of PBT patients. PMID:23925452

  2. The effect of modafinil on fatigue, cognitive functioning, and mood in primary brain tumor patients: a multicenter randomized controlled trial.

    Science.gov (United States)

    Boele, Florien W; Douw, Linda; de Groot, Marjolein; van Thuijl, Hinke F; Cleijne, Wilmy; Heimans, Jan J; Taphoorn, Martin J B; Reijneveld, Jaap C; Klein, Martin

    2013-10-01

    Fatigue, cognitive deficits, and depression are frequently reported but often undertreated symptoms that can profoundly affect daily life in patients with primary brain tumors (PBTs). To evaluate the effects of the psychostimulant modafinil on fatigue, depression, health-related quality of life (HRQOL), and cognitive functioning in PBT patients, we performed a multicenter, double-blind placebo-controlled crossover trial. Patients randomly received either 6 weeks of treatment with modafinil (up to 400 mg/day) or 6 weeks with placebo. After a 1-week washout period, the opposite treatment was provided. Assessments took place at baseline and immediately after the first and second condition. Patients completed self-report questionnaires on fatigue (Checklist Individual Strength [CIS]), depression (Center for Epidemiologic Studies Depression Scale [CES-D]), HRQOL (Short-Form Health Survey [SF-36]), and self-perceived cognitive functioning (Medical Outcomes Study [MOS]). They also underwent comprehensive neurocognitive testing. In total, 37 patients participated. Relative to baseline, patients reported lower fatigue severity (CIS) and better motivation (CIS) in both the modafinil (P = .010 and P = .021, respectively) and the placebo condition (P Modafinil did not exceed the effects of placebo with respect to symptom management. Patient accrual was slow, and relatively many patients dropped out during the trial, due mostly to side effects. Other, preferably nonpharmacologic intervention studies should be considered to improve symptom management of PBT patients.

  3. AtTCTP2, an Arabidopsis thaliana homolog of Translationally Controlled Tumor Protein, enhances in vitro plant regeneration

    Directory of Open Access Journals (Sweden)

    Roberto eToscano-Morales

    2015-07-01

    Full Text Available The Translationally Controlled Tumor Protein (TCTP is a central regulator of cell proliferation and differentiation in animals, and probably also in plants. Arabidopsis harbors two TCTP genes, AtTCTP1 (At3g16640, which is an important mitotic regulator, and AtTCTP2 (At3g05540, which is considered a pseudogene. Nevertheless, we have obtained evidence suggesting that this gene is functional. Indeed, a T-DNA insertion mutant, SALK_045146, displays a lethal phenotype during early rosette stage. Also, both the AtTCTP2 promoter and structural gene are functional, and heterozygous plants show delayed development. AtTCTP1 cannot compensate for the loss of AtTCTP2, since the accumulation levels of the AtTCTP1 transcript are even higher in heterozygous plants than in wild-type plants. Leaf explants transformed with Agrobacterium rhizogenes harboring AtTCTP2, but not AtTCTP1, led to whole plant regeneration with a high frequency. Insertion of a sequence present in AtTCTP1 but absent in AtTCP2 demonstrates that this suppresses the capacity for plant regeneration; also, this phenomenon requires the presence of TCTP (AtTCTP1 or 2 in the nuclei of root cells. This confirms that AtTCTP2 is not a pseudogene and suggests the involvement of certain TCTP isoforms in vegetative reproduction in some plant species.

  4. Identification of translationally controlled tumor protein in promotion of DNA homologous recombination repair in cancer cells by affinity proteomics.

    Science.gov (United States)

    Li, Y; Sun, H; Zhang, C; Liu, J; Zhang, H; Fan, F; Everley, R A; Ning, X; Sun, Y; Hu, J; Liu, J; Zhang, J; Ye, W; Qiu, X; Dai, S; Liu, B; Xu, H; Fu, S; Gygi, S P; Zhou, C

    2017-12-14

    Translationally controlled tumor protein(TCTP) has been implicated in the regulation of apoptosis, DNA repair and drug resistance. However, the underlying molecular mechanisms are poorly defined. To better understand the molecular mechanisms underlying TCTP involved in cellular processes, we performed an affinity purification-based proteomic profiling to identify proteins interacting with TCTP in human cervical cancer HeLa cells. We found that a group of proteins involved in DNA repair are enriched in the potential TCTP interactome. Silencing TCTP by short hairpin RNA in breast carcinoma MCF-7 cells leads to the declined repair efficiency for DNA double-strand breaks on the GFP-Pem1 reporter gene by homologous recombination, the persistent activation and the prolonged retention of γH2AX and Rad51 foci following ionizing radiation. Reciprocal immunoprecipitations indicated that TCTP forms complexes with Rad51 in vivo, and the stability maintenance of Rad51 requires TCTP in MCF-7 cells under normal cell culture conditions. Moreover, inactivation of TCTP by sertraline treatment enhances UVC irradiation-induced apoptosis in MCF-7 cells, and causes sensitization to DNA-damaging drug etoposide and DNA repair inhibitor olaparib. Thus, we have identified an important role of TCTP in promoting DNA double-stand break repair via facilitating DNA homologous recombination processes and highlighted the great potential of TCTP as a drug target to enhance conventional chemotherapy for cancer patients with high levels of TCTP expression.

  5. The in vivo study on the radiobiologic effect of prolonged delivery time to tumor control in C57BL mice implanted with Lewis lung cancer

    Directory of Open Access Journals (Sweden)

    Zhu Guo-Pei

    2011-01-01

    Full Text Available Abstract Background High-precision radiation therapy techniques such as IMRT or sterotactic radiosurgery, delivers more complex treatment fields than conventional techniques. The increased complexity causes longer dose delivery times for each fraction. The purpose of this work is to explore the radiobiologic effect of prolonged fraction delivery time on tumor response and survival in vivo. Methods 1-cm-diameter Lewis lung cancer tumors growing in the legs of C57BL mice were used. To evaluate effect of dose delivery prolongation, 18 Gy was divided into different subfractions. 48 mice were randomized into 6 groups: the normal control group, the single fraction with 18 Gy group, the two subfractions with 30 min interval group, the seven subfractions with 5 min interval group, the two subfractions with 60 min interval group and the seven subfractions with 10 min interval group. The tumor growth tendency, the tumor growth delay and the mice survival time were analyzed. Results The tumor growth delay of groups with prolonged delivery time was shorter than the group with single fraction of 18 Gy (P 0.05. Compared to the group with single fraction of 18 Gy, the groups with prolonged delivery time shorten the mice survival time while there was no significant difference between the groups with prolonged delivery time 30 min and the groups with prolonged delivery time 60 min. Conclusions The prolonged delivery time with same radiation dose shorten the tumor growth delay and survival time in the mice implanted with Lewis lung cancer. The anti-tumor effect decreased with elongation of the total interfractional time.

  6. Tumor Control Probability Modeling for Stereotactic Body Radiation Therapy of Early-Stage Lung Cancer Using Multiple Bio-physical Models

    Science.gov (United States)

    Liu, Feng; Tai, An; Lee, Percy; Biswas, Tithi; Ding, George X.; El Naqa, Isaam; Grimm, Jimm; Jackson, Andrew; Kong, Feng-Ming (Spring); LaCouture, Tamara; Loo, Billy; Miften, Moyed; Solberg, Timothy; Li, X Allen

    2017-01-01

    Purpose To analyze pooled clinical data using different radiobiological models and to understand the relationship between biologically effective dose (BED) and tumor control probability (TCP) for stereotactic body radiotherapy (SBRT) of early-stage non-small cell lung cancer (NSCLC). Method and Materials The clinical data of 1-, 2-, 3-, and 5-year actuarial or Kaplan-Meier TCP from 46 selected studies were collected for SBRT of NSCLC in the literature. The TCP data were separated for Stage T1 and T2 tumors if possible, otherwise collected for combined stages. BED was calculated at isocenters using six radiobiological models. For each model, the independent model parameters were determined from a fit to the TCP data using the least chi-square (χ2) method with either one set of parameters regardless of tumor stages or two sets for T1 and T2 tumors separately. Results The fits to the clinic data yield consistent results of large α/β ratios of about 20 Gy for all models investigated. The regrowth model that accounts for the tumor repopulation and heterogeneity leads to a better fit to the data, compared to other 5 models where the fits were indistinguishable between the models. The models based on the fitting parameters predict that the T2 tumors require about additional 1 Gy physical dose at isocenters per fraction (≤5 fractions) to achieve the optimal TCP when compared to the T1 tumors. Conclusion This systematic analysis of a large set of published clinical data using different radiobiological models shows that local TCP for SBRT of early-stage NSCLC has strong dependence on BED with large α/β ratios of about 20 Gy. The six models predict that a BED (calculated with α/β of 20) of 90 Gy is sufficient to achieve TCP ≥ 95%. Among the models considered, the regrowth model leads to a better fit to the clinical data. PMID:27871671

  7. Neurofeedback to improve neurocognitive functioning of children treated for a brain tumor: design of a randomized controlled double-blind trial

    International Nuclear Information System (INIS)

    Ruiter, Marieke A de; Meeteren, Antoinette YN Schouten-Van; Mourik, Rosa van; Janssen, Tieme WP; Greidanus, Juliette EM; Oosterlaan, Jaap; Grootenhuis, Martha A

    2012-01-01

    Neurotoxicity caused by treatment for a brain tumor is a major cause of neurocognitive decline in survivors. Studies have shown that neurofeedback may enhance neurocognitive functioning. This paper describes the protocol of the PRISMA study, a randomized controlled trial to investigate the efficacy of neurofeedback to improve neurocognitive functioning in children treated for a brain tumor. Efficacy of neurofeedback will be compared to placebo training in a randomized controlled double-blind trial. A total of 70 brain tumor survivors in the age range of 8 to 18 years will be recruited. Inclusion also requires caregiver-reported neurocognitive problems and being off treatment for more than two years. A group of 35 healthy siblings will be included as the control group. On the basis of a qEEG patients will be assigned to one of three treatment protocols. Thereafter patients will be randomized to receive either neurofeedback training (n=35) or placebo training (n=35). Neurocognitive tests, and questionnaires administered to the patient, caregivers, and teacher, will be used to evaluate pre- and post-intervention functioning, as well as at 6-month follow-up. Siblings will be administered the same tests and questionnaires once. If neurofeedback proves to be effective for pediatric brain tumor survivors, this can be a valuable addition to the scarce interventions available to improve neurocognitive and psychosocial functioning. ClinicalTrials.gov NCT00961922

  8. Neurofeedback to improve neurocognitive functioning of children treated for a brain tumor: design of a randomized controlled double-blind trial

    Directory of Open Access Journals (Sweden)

    de Ruiter Marieke A

    2012-12-01

    Full Text Available Abstract Background Neurotoxicity caused by treatment for a brain tumor is a major cause of neurocognitive decline in survivors. Studies have shown that neurofeedback may enhance neurocognitive functioning. This paper describes the protocol of the PRISMA study, a randomized controlled trial to investigate the efficacy of neurofeedback to improve neurocognitive functioning in children treated for a brain tumor. Methods/Design Efficacy of neurofeedback will be compared to placebo training in a randomized controlled double-blind trial. A total of 70 brain tumor survivors in the age range of 8 to 18 years will be recruited. Inclusion also requires caregiver-reported neurocognitive problems and being off treatment for more than two years. A group of 35 healthy siblings will be included as the control group. On the basis of a qEEG patients will be assigned to one of three treatment protocols. Thereafter patients will be randomized to receive either neurofeedback training (n=35 or placebo training (n=35. Neurocognitive tests, and questionnaires administered to the patient, caregivers, and teacher, will be used to evaluate pre- and post-intervention functioning, as well as at 6-month follow-up. Siblings will be administered the same tests and questionnaires once. Discussion If neurofeedback proves to be effective for pediatric brain tumor survivors, this can be a valuable addition to the scarce interventions available to improve neurocognitive and psychosocial functioning. Trial registration ClinicalTrials.gov NCT00961922.

  9. Local tumor control and toxicity in HIV-associated anal carcinoma treated with radiotherapy in the era of antiretroviral therapy

    International Nuclear Information System (INIS)

    Oehler-Jänne, Christoph; Seifert, Burkhardt; Lütolf, Urs M; Ciernik, I Frank

    2006-01-01

    To investigate the outcome of HIV-seropositive patients under highly active antiretroviral treatment (HAART) with anal cancer treated with radiotherapy (RT) alone or in combination with standard chemotherapy (CT). Clinical outcome of 81 HIV-seronegative patients (1988 – 2003) and 10 consecutive HIV-seropositive patients under HAART (1997 – 2003) that were treated with 3-D conformal RT of 59.4 Gy and standard 5-fluorouracil and mitomycin-C were retrospectively analysed. 10 TNM-stage and age matched HIV-seronegative patients (1992 – 2003) were compared with the 10 HIV-seropositive patients. Pattern of care, local disease control (LC), overall survival (OS), cancer-specific survival (CSS), and toxicity were assessed. RT with or without CT resulted in complete response in 100 % of HIV-seropositive patients. LC was impaired compared to matched HIV-seronegative patients after a median follow-up of 44 months (p = 0.03). OS at 5 years was 70 % in HIV-seropositive patients receiving HAART and 69 % in the matched controls. Colostomy-free survival was 70 % (HIV+) and 100 % (matched HIV-) and 78 % (all HIV-). No HIV-seropositive patient received an interstitial brachytherapy boost compared to 42 % of all HIV-seronegative patients and adherence to chemotherapy seemed to be difficult in HIV-seropositive patients. Acute hematological toxicity reaching 50 % was high in HIV-seropositive patients receiving MMC compared with 0 % in matched HIV-seronegative patients (p = 0.05) or 12 % in all HIV-seronegative patients. The rate of long-term side effects was low in HIV-seropositive patients. Despite high response rates to organ preserving treatment with RT with or without CT, local tumor failure seems to be high in HIV-positive patients receiving HAART. HIV-seropositive patients are subject to treatment bias, being less likely treated with interstitial brachytherapy boost probably due to HIV-infection, and they are at risk to receive less chemotherapy

  10. Pelvic Inflammatory Disease and the Risk of Ovarian Cancer and Borderline Ovarian Tumors: A Pooled Analysis of 13 Case-Control Studies.

    Science.gov (United States)

    Rasmussen, Christina B; Kjaer, Susanne K; Albieri, Vanna; Bandera, Elisa V; Doherty, Jennifer A; Høgdall, Estrid; Webb, Penelope M; Jordan, Susan J; Rossing, Mary Anne; Wicklund, Kristine G; Goodman, Marc T; Modugno, Francesmary; Moysich, Kirsten B; Ness, Roberta B; Edwards, Robert P; Schildkraut, Joellen M; Berchuck, Andrew; Olson, Sara H; Kiemeney, Lambertus A; Massuger, Leon F A G; Narod, Steven A; Phelan, Catherine M; Anton-Culver, Hoda; Ziogas, Argyrios; Wu, Anna H; Pearce, Celeste L; Risch, Harvey A; Jensen, Allan

    2017-01-01

    Inflammation has been implicated in ovarian carcinogenesis. However, studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent. We investigated the association between PID and the risk of epithelial ovarian cancer according to tumor behavior and histotype. We pooled data from 13 case-control studies, conducted between 1989 and 2009, from the Ovarian Cancer Association Consortium (OCAC), including 9,162 women with ovarian cancers, 2,354 women with borderline tumors, and 14,736 control participants. Study-specific odds ratios were estimated and subsequently combined into a pooled odds ratio using a random-effects model. A history of PID was associated with an increased risk of borderline tumors (pooled odds ratio (pOR) = 1.32, 95% confidence interval (CI): 1.10, 1.58). Women with at least 2 episodes of PID had a 2-fold increased risk of borderline tumors (pOR = 2.14, 95% CI: 1.08, 4.24). No association was observed between PID and ovarian cancer risk overall (pOR = 0.99, 95% CI: 0.83, 1.19); however, a statistically nonsignificantly increased risk of low-grade serous tumors (pOR = 1.48, 95% CI: 0.92, 2.38) was noted. In conclusion, PID was associated with an increased risk of borderline ovarian tumors, particularly among women who had had multiple episodes of PID. Although our results indicated a histotype-specific association with PID, the association of PID with ovarian cancer risk is still somewhat uncertain and requires further investigation. © The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  11. Tumor vaccines

    International Nuclear Information System (INIS)

    Frank, M.; Ihan, A.

    2006-01-01

    Tumor vaccines have several potential advantages over standard anticancer regiments. They represent highly specific anticancer therapy. Inducing tumor-specific memory T-lymphocytes, they have potential for long-lived antitumor effects. However, clinical trials, in which cancer patients were vaccinated with tumor vaccines, have been so far mainly disappointing. There are many reasons for the inefficiency of tumor vaccines. Most cancer antigens are normal self-molecules to which immune tolerance exists. That is why the population of tumor-specific lymphocytes is represented by a small number of low-affinity T-lymphocytes that induce weak antitumor immune response. Simultaneously, tumors evolve many mechanisms to actively evade immune system, what makes them poorly immunogenic or even tolerogenic. Novel immunotherapeutic strategies are directed toward breaking immune tolerance to tumor antigens, enhancing immunogenicity of tumor vaccines and overcoming mechanisms of tumor escape. There are several approaches, unfortunately, all of them still far away from an ideal tumor vaccine that would reject a tumor. Difficulties in the activation of antitumor immune response by tumor vaccines have led to the development of alternative immunotherapeutic strategies that directly focus on effector mechanisms of immune system (adoptive tumor- specific T-lymphocyte transfer and tumor specific monoclonal antibodies). (author)

  12. Mir-513a-3p contributes to the controlling of cellular migration processes in the A549 lung tumor cells by modulating integrin β-8 expression.

    Science.gov (United States)

    da Silveira, Marina Bonfogo; Lima, Kelvin Furtado; da Silva, Andrea Renata; Dos Santos, Robson Augusto Souza; Moraes, Karen C M

    2017-12-04

    Lung tumors are a frequent type of cancer in humans and a leading cause of death, and the late diagnostic contributes to high mortality rates. New therapeutic strategies are needed, and the heptapeptide angiotensin-(1-7) [ang-(1-7)] demonstrated the ability to control cancer growth rates and migration in vitro and in vivo. However, the possible use of the heptapeptide in clinical trials demands deeper analyses to elucidate molecular mechanisms of its effect in the target cells. In this study, we investigated relevant elements that control pro-inflammatory environment and cellular migration, focusing in the post-transcription mechanism using lung tumor cell line. In our cellular model, the microRNA-513a-3p was identified as a novel element targeting ITG-β8, thereby controlling the protein level and its molecular function in the controlling of migration and pro-inflammatory environment. These findings provide useful information for future studies, using miR-513a-3p as an innovative molecular tool to control lung tumor cell migration, which will support more effective clinical treatment of the patients with the widely used chemotherapeutic agents, increasing survival rates.

  13. Mechanisms of Altered Control of Proliferation by Cyclic Amp/Protein Kinase A During Mammary Tumor Progression

    National Research Council Canada - National Science Library

    Imagawa, Walter

    1999-01-01

    We hypothesize that alterations in the regulation of growth by growth factors and cAMP during mammary tumor progression are related to MAP kinase signaling pathways known to be affected by cAMP and pertussis toxin (PT...

  14. IL-12 Expressing oncolytic herpes simplex virus promotes anti-tumor activity and immunologic control of metastatic ovarian cancer in mice.

    Science.gov (United States)

    Thomas, Eric D; Meza-Perez, Selene; Bevis, Kerri S; Randall, Troy D; Gillespie, G Yancey; Langford, Catherine; Alvarez, Ronald D

    2016-10-27

    Despite advances in surgical aggressiveness and conventional chemotherapy, ovarian cancer remains the most lethal cause of gynecologic cancer mortality; consequently there is a need for new therapeutic agents and innovative treatment paradigms for the treatment of ovarian cancer. Several studies have demonstrated that ovarian cancer is an immunogenic disease and immunotherapy represents a promising and novel approach that has not been completely evaluated in ovarian cancer. Our objective was to evaluate the anti-tumor activity of an oncolytic herpes simplex virus "armed" with murine interleukin-12 and its ability to elicit tumor-specific immune responses. We evaluated the ability of interleukin-12-expressing and control oncolytic herpes simplex virus to kill murine and human ovarian cancer cell lines in vitro. We also administered interleukin-12-expressing oncolytic herpes simplex virus to the peritoneal cavity of mice that had developed spontaneous, metastatic ovarian cancer and determined overall survival and tumor burden at 95 days. We used flow cytometry to quantify the tumor antigen-specific CD8 + T cell response in the omentum and peritoneal cavity. All ovarian cancer cell lines demonstrated susceptibility to oncolytic herpes simplex virus in vitro. Compared to controls, mice treated with interleukin-12-expressing oncolytic herpes simplex virus demonstrated a more robust tumor antigen-specific CD8 + T-cell immune response in the omentum (471.6 cells vs 33.1 cells; p = 0.02) and peritoneal cavity (962.3 cells vs 179.5 cells; p = 0.05). Compared to controls, mice treated with interleukin-12-expressing oncolytic herpes simplex virus were more likely to control ovarian cancer metastases (81.2 % vs 18.2 %; p = 0.008) and had a significantly longer overall survival (p = 0.02). Finally, five of 6 mice treated with interleukin-12-expressing oHSV had no evidence of metastatic tumor when euthanized at 6 months, compared to two of 4 mice treated with

  15. STAT3β controls inflammatory responses and early tumor onset in skin and colon experimental cancer models

    Science.gov (United States)

    Marino, Francesca; Orecchia, Valeria; Regis, Gabriella; Musteanu, Monica; Tassone, Beatrice; Jon, Cristina; Forni, Marco; Calautti, Enzo; Chiarle, Roberto; Eferl, Robert; Poli, Valeria

    2014-01-01

    Chronic inflammation is a well-recognized pathogenic factor in tumor initiation and progression. Mice lacking the pro-oncogenic transcription factor STAT3 were shown to be protected from both colitis-associated and epidermal cancers induced by the AOM/DSS and DMBA/TPA protocols, respectively. However, these murine models did not distinguish between the two STAT3 isoforms, the full-length STAT3α, believed to exert most pro-oncogenic functions attributed to STAT3, and the shorter STAT3β, often referred to as a dominant-negative, but possessing specific transcriptional activities. Here we assessed the contribution of STAT3β to inflammation-driven tumorigenesis making use of mice lacking this isoform, but still expressing STAT3α (STAT3Δβ/Δβ). We show that the lack of STAT3β leads to exacerbated acute responses to both TPA and DSS, thus confirming its anti-inflammatory role. Enhanced inflammation correlates with earlier tumor onset in both the epidermis and the intestine in STAT3Δβ/Δβ mice. In contrast, overall tumor development and final tumor burden were unaffected. These results suggest that STAT3β, by limiting inflammation during the initial phases of tumorigenesis, contributes to tissue homeostasis and counteracts malignant transformation and initial tumor growth. Accordingly, the balance between the two STAT3 isoforms, likely determined by the complex signaling networks shaping the tumor microenvironment and driving tumor transformation and progression, is apparently crucial to determine the initial tumor transformation rates in inflammation-associated cancers. PMID:25232490

  16. Control of cellular proliferation by modulation of oxidative phosphorylation in human and rodent fast-growing tumor cells

    International Nuclear Information System (INIS)

    Rodriguez-Enriquez, Sara; Vital-Gonzalez, Paola A.; Flores-Rodriguez, Fanny L.; Marin-Hernandez, Alvaro; Ruiz-Azuara, Lena; Moreno-Sanchez, Rafael

    2006-01-01

    The relationship between cell proliferation and the rates of glycolysis and oxidative phosphorylation in HeLa (human) and AS-30D (rodent) tumor cells was evaluated. In glutamine plus glucose medium, both tumor lines grew optimally. Mitochondria were the predominant source of ATP in both cell types (66-75%), despite an active glycolysis. In glucose-free medium with glutamine, proliferation of both lines diminished by 30% but oxidative phosphorylation and the cytosolic ATP level increased by 50%. In glutamine-free medium with glucose, proliferation, oxidative phosphorylation and ATP concentration diminished drastically, although the cells were viable. Oligomycin, in medium with glutamine plus glucose, abolished growth of both tumor lines, indicating an essential role of mitochondrial ATP for tumor progression. The presumed mitochondrial inhibitors rhodamines 123 and 6G, and casiopeina II-gly, inhibited tumor cell proliferation and oxidative phosphorylation, but also glycolysis. In contrast, gossypol, iodoacetate and arsenite strongly blocked glycolysis; however, they did not affect tumor proliferation or mitochondrial metabolism. Growth of both tumor lines was highly sensitive to rhodamines and casiopeina II-gly, with IC 5 values for HeLa cells lower than 0.5 μM, whereas viability and proliferation of human lymphocytes were not affected by these drugs (IC 5 > 30 μM). Moreover, rhodamine 6G and casiopeina II-gly, at micromolar doses, prolonged the survival of animals bearing i.p. implanted AS-30D hepatoma. It is concluded that fast-growing tumor cells have a predominantly oxidative type of metabolism, which might be a potential therapeutic target

  17. Interaction of platelet-derived autotaxin with tumor integrin αVβ3 controls metastasis of breast cancer cells to bone

    Science.gov (United States)

    Leblanc, Raphael; Lee, Sue-Chin; David, Marion; Bordet, Jean-Claude; Norman, Derek D.; Patil, Renukadevi; Miller, Duane; Sahay, Debashish; Ribeiro, Johnny; Clézardin, Philippe; Tigyi, Gabor J.

    2014-01-01

    Autotaxin (ATX), through its lysophospholipase D activity controls physiological levels of lysophosphatidic acid (LPA) in blood. ATX is overexpressed in multiple types of cancers, and together with LPA generated during platelet activation promotes skeletal metastasis of breast cancer. However, the pathophysiological sequelae of regulated interactions between circulating LPA, ATX, and platelets remain undefined in cancer. In this study, we show that ATX is stored in α-granules of resting human platelets and released upon tumor cell-induced platelet aggregation, leading to the production of LPA. Our in vitro and in vivo experiments using human breast cancer cells that do not express ATX (MDA-MB-231 and MDA-B02) demonstrate that nontumoral ATX controls the early stage of bone colonization by tumor cells. Moreover, expression of a dominant negative integrin αvβ3-Δ744 or treatment with the anti-human αvβ3 monoclonal antibody LM609, completely abolished binding of ATX to tumor cells, demonstrating the requirement of a fully active integrin αvβ3 in this process. The present results establish a new mechanism for platelet contribution to LPA-dependent metastasis of breast cancer cells, and demonstrate the therapeutic potential of disrupting the binding of nontumor-derived ATX with the tumor cells for the prevention of metastasis. PMID:25277122

  18. The Never ripe Mutant Provides Evidence That Tumor-Induced Ethylene Controls the Morphogenesis of Agrobacterium tumefaciens-Induced Crown Galls on Tomato Stems12

    Science.gov (United States)

    Aloni, Roni; Wolf, Asnat; Feigenbaum, Pua; Avni, Adi; Klee, Harry J.

    1998-01-01

    We confirm the hypothesis that Agrobacterium tumefaciens-induced galls produce ethylene that controls vessel differentiation in the host stem of tomato (Lycopersicon esculentum Mill.). Using an ethylene-insensitive mutant, Never ripe (Nr), and its isogenic wild-type parent we show that infection by A. tumefaciens results in high rates of ethylene evolution from the developing crown galls. Ethylene evolution from isolated internodes carrying galls was up to 50-fold greater than from isolated internodes of control plants when measured 21 and 28 d after infection. Tumor-induced ethylene substantially decreased vessel diameter in the host tissues beside the tumor in wild-type stems but had a very limited effect in the Nr stems. Ethylene promoted the typical unorganized callus shape of the gall, which maximized the tumor surface in wild-type stems, whereas the galls on the Nr stems had a smooth surface. The combination of decreased vessel diameter in the host and increased tumor surface ensured water-supply priority to the growing gall over the host shoot. These results indicate that in addition to the well-defined roles of auxin and cytokinin, there is a critical role for ethylene in determining crown-gall morphogenesis. PMID:9662526

  19. Dynamic contrast-enhanced case-control analysis in 3T MRI of prostate cancer can help to characterize tumor aggressiveness

    Energy Technology Data Exchange (ETDEWEB)

    Sanz-Requena, Roberto, E-mail: roberto.sanz@quironsalud.es [Biomedical Engineering, Hospital Quirónsalud Valencia, Valencia (Spain); Radiology Department, Hospital Quirónsalud Valencia, Valencia (Spain); GIBI230, Instituto de Investigación Sanitaria y Hospital Universitari i Politècnic La Fe, Valencia (Spain); Martí-Bonmatí, Luis [Radiology Department, Hospital Quirónsalud Valencia, Valencia (Spain); GIBI230, Instituto de Investigación Sanitaria y Hospital Universitari i Politècnic La Fe, Valencia (Spain); Pérez-Martínez, Rosario [Radiology Department, Hospital Quirónsalud Valencia, Valencia (Spain); García-Martí, Gracián [Biomedical Engineering, Hospital Quirónsalud Valencia, Valencia (Spain); Radiology Department, Hospital Quirónsalud Valencia, Valencia (Spain); GIBI230, Instituto de Investigación Sanitaria y Hospital Universitari i Politècnic La Fe, Valencia (Spain); CIBER-SAM, Instituto de Salud Carlos III, Madrid (Spain)

    2016-11-15

    Highlights: • Curve types showed no statistical association with healthy/tumor peripheral areas. • K{sup trans}, v{sub e}, upslope and AUC showed significant differences in controls vs. tumors. • The global diagnostic performance of standard MRI perfusion parameters is poor. • Normalized K{sup trans}, upslope and AUC had good diagnostic accuracy for tumor grading. - Abstract: Purpose: The aim of this work is to establish normality and tumor tissue ranges for perfusion parameters from dynamic contrast-enhanced (DCE) MR of the peripheral prostate at 3T and to compare the diagnostic performance of quantitative and semi-quantitative parameters. Materials and methods: Thirty-six patients with prostate carcinomas (18 Gleason-6, 15 Gleason-7, and 3 Gleason-8) and 33 healthy subjects were included. Image analysis workflow comprised four steps: manual segmentation of whole prostate and lesions, series registration, voxelwise T1 mapping and calculation of pharmacokinetic and semi-quantitative parameters. Results: K{sup trans}, v{sub e}, upslope and AUC60 showed statistically significant differences between healthy peripheral areas and tumors. Curve type showed no association with healthy/tumor peripheral areas (chi-square = 0.702). Areas under the ROC curves were 0.64 (95% CI: 0.54–0.75), 0.70 (0.60–0.80), 0.62 (0.51–0.72) and 0.63 (0.52–0.74) for K{sup trans}, v{sub e}, upslope and AUC60, respectively. The optimal cutoff values were: K{sup trans} = 0.21 min{sup −1} (sensitivity = 0.61, specificity = 0.64), v{sub e} = 0.36 (0.63, 0.71), upslope = 0.59 (0.59, 0.59) and AUC60 = 2.4 (0.63, 0.64). Significant differences were found between Gleason scores 6 and 7 for normalized K{sup trans}, upslope and AUC60, with good diagnostic accuracy (area under ROC curve 0.80, 95% CI: 0.60–1.00). Conclusion: Quantitative (K{sup trans} and v{sub e}) and semi-quantitative (upslope and AUC60) perfusion parameters showed significant differences between tumors and control

  20. High-Dose-Rate Brachytherapy Boost Effect on Local Tumor Control in Young Women With Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Guinot, Jose-Luis, E-mail: jguinot@fivo.org [Department of Radiation Oncology, Fundacion Instituto Valenciano de Oncologia, Valencia (Spain); Baixauli-Perez, Cristobal [Health Services Research Unit, Center for Public Health Research, Valencia (Spain); Soler, Pablo; Tortajada, Maria Isabel; Moreno, Araceli; Santos, Miguel Angel; Mut, Alejandro [Department of Radiation Oncology, Fundacion Instituto Valenciano de Oncologia, Valencia (Spain); Gozalbo, Francisco [Department of Pathology, Fundacion Instituto Valenciano de Oncologia, Valencia (Spain); Arribas, Leoncio [Department of Radiation Oncology, Fundacion Instituto Valenciano de Oncologia, Valencia (Spain)

    2015-01-01

    Purpose: To evaluate the local control rate and complications of a single fraction of high-dose-rate brachytherapy (HDR BT) boost in women aged 45 yeas and younger after breast-conserving therapy. Methods and Materials: Between 1999 and 2007, 167 patients between the ages of 26 and 45 years old (72 were 40 years old or younger), with stages T1 to T2 invasive breast cancer with disease-free margin status of at least 5 mm after breast-conserving surgery received 46 to 50 Gy whole-breast irradiation plus a 7-Gy HDR-BT boost (“fast boost”). An axillary dissection was performed in 72.5% of the patients and sentinel lymph node biopsy in 27.5%. A supraclavicular area was irradiated in 19% of the patients. Chemotherapy was used in 86% of the patients and hormone treatment in 77%. Clinical nodes were present in 18% and pathological nodes in 29%. The pathological stage was pT0: 5%, pTis: 3%, pT1: 69% and pT2: 23%. Intraductal component was present in 40% and 28% were G3. Results: At a median follow-up of 92 months, 9 patients relapsed on the margin of the implant, and 1 patient in another quadrant, resulting in a 10-year local relapse rate of 4.3% and a breast relapse rate of 4.9%, with breast preservation in 93.4%; no case of mastectomy due to poor cosmesis arose. Actuarial 5- and 10-year disease-free, cause-specific, and overall survival rates were 87.9% and 85.8%, and 92.1% and 88.4%, and 92.1% and 87.3%, respectively. In a univariate analysis, triple-negative cases and negative hormone receptors did worse, but in a multivariate analysis, only the last factor was significant for local and breast control. Asymptomatic fibrosis G2 was recorded in 3 cases, and there were no other late complications. Cosmetic results were good to excellent in 97% of cases. Conclusions: A single dose of 7 Gy using the fast-boost technique is well tolerated, with a low rate of late complications and improved local tumor control in women aged 45 and younger, compared to published data

  1. Tumors markers

    International Nuclear Information System (INIS)

    Yamaguchi-Mizumoto, N.H.

    1989-01-01

    In order to study blood and cell components alterations (named tumor markers) that may indicate the presence of a tumor, several methods are presented. Aspects as diagnostic, prognostic, therapeutic value and clinical evaluation are discussed. (M.A.C.)

  2. Mammary tumors

    International Nuclear Information System (INIS)

    Weller, R.E.

    1988-10-01

    Mammary neoplasia is one of the more common malignancies affecting domestic species. Despite their importance, they are often over- diagnosed, undertreated and subject to several misconceptions propagated by veterinarians and pet owners alike. Mammary neoplasia is the most frequent tumor type encountered in the female accounting for almost half of all malignancies reported. The canine has the highest incidence of mammary tumors of all domestic species. In the dog, about 65 percent of mammary tumors are benign mixed tumors, and 25 percent are carcinomas. The rest are adenomas, myoepitheliomas, and malignant mixed tumors. The age distribution of mammary tumors closely follows the age distribution of most tumors in the dog. Mammary tumors are rare in dogs 2 years old, but incidence begins to increase sharply at approximately 6 years of age. Median age at diagnosis is about 10 years. No breed predilection has been consistently reported

  3. Long-term local control with radiofrequency ablation or radiotherapy for second, third, and fourth lung tumors after lobectomy for primary lung cancer

    International Nuclear Information System (INIS)

    Yokouchi, Hideoki; Murata, Kohei; Miyazaki, Masaki; Miyamoto, Takeaki; Minami, Takafumi; Tsuji, Fumio; Mikami, Koji

    2016-01-01

    A 78-year-old woman developed second, third, and fourth lung tumors at intervals of 1-3 years after left upper lobectomy for primary lung cancer. The tumors were controlled with radiofrequency ablation (RFA) or conventional conformal radiotherapy for 9 years postoperatively. For the treatment of second primary lung cancer or lung metastasis after surgical resection of the primary lung cancer, reoperation is not recommended because of the impaired respiratory reserve. Thus, local therapy such as radiotherapy or RFA is applied in some cases. Among these, stereotactic body radiotherapy (SBRT) is a feasible option because of its good local control and safety, which is comparable with surgery. On the other hand, for cases of multiple lesions that are not suitable for radiotherapy or combination therapy, RFA could be an option because of its short-term local control, easiness, safety, and repeatability. After surgery for primary lung cancer, a second lung tumor could be controlled with highly effective and minimally invasive local therapy if it is recognized as a local disease but is medically inoperable. Therefore, long-term postoperative follow-up for primary lung cancer is beneficial. (author)

  4. Spinal tumors

    International Nuclear Information System (INIS)

    Goethem, J.W.M. van; Hauwe, L. van den; Oezsarlak, Oe.; Schepper, A.M.A. de; Parizel, P.M.

    2004-01-01

    Spinal tumors are uncommon lesions but may cause significant morbidity in terms of limb dysfunction. In establishing the differential diagnosis for a spinal lesion, location is the most important feature, but the clinical presentation and the patient's age and gender are also important. Magnetic resonance (MR) imaging plays a central role in the imaging of spinal tumors, easily allowing tumors to be classified as extradural, intradural-extramedullary or intramedullary, which is very useful in tumor characterization. In the evaluation of lesions of the osseous spine both computed tomography (CT) and MR are important. We describe the most common spinal tumors in detail. In general, extradural lesions are the most common with metastasis being the most frequent. Intradural tumors are rare, and the majority is extramedullary, with meningiomas and nerve sheath tumors being the most frequent. Intramedullary tumors are uncommon spinal tumors. Astrocytomas and ependymomas comprise the majority of the intramedullary tumors. The most important tumors are documented with appropriate high quality CT or MR images and the characteristics of these tumors are also summarized in a comprehensive table. Finally we illustrate the use of the new World Health Organization (WHO) classification of neoplasms affecting the central nervous system

  5. Urogenital tumors

    Energy Technology Data Exchange (ETDEWEB)

    Weller, R.E.

    1994-03-01

    An overview is provided for veterinary care of urogenital tumors in companion animals, especially the dog. Neoplasms discussed include tumors of the kidney, urinary bladder, prostate, testis, ovary, vagina, vulva and the canine transmissible venereal tumor. Topics addressed include description, diagnosis and treatment.

  6. Brain Tumors

    Science.gov (United States)

    A brain tumor is a growth of abnormal cells in the tissues of the brain. Brain tumors can be benign, with no cancer cells, ... cancer cells that grow quickly. Some are primary brain tumors, which start in the brain. Others are ...

  7. Incorporating biologic measurements (SF2, CFE) into a tumor control probability model increases their prognostic significance: a study in cervical carcinoma treated with radiation therapy

    International Nuclear Information System (INIS)

    Buffa, Francesca Meteora; Davidson, Susan E.; Hunter, Robert D.; Nahum, Alan E.; West, Catharine M.L.

    2001-01-01

    Purpose: To assess whether incorporation of measurements of surviving fraction at 2 Gy (SF 2 ) and colony-forming efficiency (CFE) into a tumor control probability (tcp) model increases their prognostic significance. Methods and Materials: Measurements of SF 2 and CFE were available from a study on carcinoma of the cervix treated with radiation alone. These measurements, as well as tumor volume, dose, and treatment time, were incorporated into a Poisson tcp model (tcp α,ρ ). Regression analysis was performed to assess the prognostic power of tcp α,ρ vs. the use of either tcp models with biologic parameters fixed to best-fit estimates (but incorporating individual dose, volume, and treatment time) or the use of SF 2 and CFE measurements alone. Results: In a univariate regression analysis of 44 patients, tcp α,ρ was a better prognostic factor for both local control and survival (p 2 alone (p=0.009 for local control, p=0.29 for survival) or CFE alone (p=0.015 for local control, p=0.38 for survival). In multivariate analysis, tcp α,ρ emerged as the most important prognostic factor for local control (p α,ρ , CFE was still a significant independent prognostic factor for local control, whereas SF 2 was not. The sensitivities of tcp α,ρ and SF 2 as predictive tests for local control were 87% and 65%, respectively. Specificities were 70% and 77%, respectively. Conclusions: A Poisson tcp model incorporating individual SF 2 , CFE, dose, tumor volume, and treatment time was found to be the best independent prognostic factor for local control and survival in cervical carcinoma patients

  8. Evaluation of quantitative contrast harmonic imaging to assess malignancy of liver tumors: A prospective controlled two-center study

    Science.gov (United States)

    Jung, EM; Clevert, DA; Schreyer, AG; Schmitt, S; Rennert, J; Kubale, R; Feuerbach, S; Jung, F

    2007-01-01

    AIM: To establish the extent to which contrast enhancement with SonoVue in combination with quantitative evaluation of contrast-medium dynamics facilitates the detection of hepatic tumors. METHODS: One hundred patients with histologically confirmed malignant or benign hepatic tumor (maximum size 5 cm) were analyzed. Contrast-enhanced ultrasound (bolus injection 2.5 mL SonoVue) was carried out with intermittent breath-holding technique using a multifrequency transducer (2.5-4 MHz). Native vascularization was analyzed with power Doppler. The contrast-enhanced dynamic ultrasound investigation was carried out with contrast harmonic imaging in true detection mode during the arterial, portal venous and late phases. Mechanical index was set at 0.15. Perfusion analysis was performed by post-processing of the raw data [time intensity curve (TIC) analysis]. The cut-off of the gray value differences between tumor and normal liver tissue was established using Receiver Operating Characteristic (ROC) analysis 64-line multi-slice computed tomography served as reference method in all cases. Magnetic resonance tomography was used additionally in 19 cases. RESULTS: One hundred patients with 59 malignant (43 colon, 5 breast, 2 endocrine metastases, 7 hepatocellular carcinomas and 2 kidney cancers) and 41 benign (15 hemangiomas, 7 focal nodular hyperplasias, 5 complicated cysts, 2 abscesses and 12 circumscribed fatty changes) tumors were included. The late venous phase proved to be the most sensitive for classification of the tumor type. Fifty-eight of the 59 malignant tumors were classified as true positive, and one as false negative. This resulted in a sensitivity of 98.3%. Of the 41 benign tumors, 37 were classified as true negative and 4 as false negative, which corresponds to a specificity of 90.2%. Altogether, 95.0% of the diagnoses were classified as correct on the basis of the histological classification. No investigator-dependency (P = 0.23) was noted. CONCLUSION: The results

  9. Inferring the Impact of Regulatory Mechanisms that Underpin CD8+ T Cell Control of B16 Tumor GrowthIn vivoUsing Mechanistic Models and Simulation.

    Science.gov (United States)

    Klinke, David J; Wang, Qing

    2016-01-01

    A major barrier for broadening the efficacy of immunotherapies for cancer is identifying key mechanisms that limit the efficacy of tumor infiltrating lymphocytes. Yet, identifying these mechanisms using human samples and mouse models for cancer remains a challenge. While interactions between cancer and the immune system are dynamic and non-linear, identifying the relative roles that biological components play in regulating anti-tumor immunity commonly relies on human intuition alone, which can be limited by cognitive biases. To assist natural intuition, modeling and simulation play an emerging role in identifying therapeutic mechanisms. To illustrate the approach, we developed a multi-scale mechanistic model to describe the control of tumor growth by a primary response of CD8+ T cells against defined tumor antigens using the B16 C57Bl/6 mouse model for malignant melanoma. The mechanistic model was calibrated to data obtained following adenovirus-based immunization and validated to data obtained following adoptive transfer of transgenic CD8+ T cells. More importantly, we use simulation to test whether the postulated network topology, that is the modeled biological components and their associated interactions, is sufficient to capture the observed anti-tumor immune response. Given the available data, the simulation results also provided a statistical basis for quantifying the relative importance of different mechanisms that underpin CD8+ T cell control of B16F10 growth. By identifying conditions where the postulated network topology is incomplete, we illustrate how this approach can be used as part of an iterative design-build-test cycle to expand the predictive power of the model.

  10. Micro-environmental mechanical stress controls tumor spheroid size and morphology by suppressing proliferation and inducing apoptosis in cancer cells.

    Directory of Open Access Journals (Sweden)

    Gang Cheng

    Full Text Available Compressive mechanical stress produced during growth in a confining matrix limits the size of tumor spheroids, but little is known about the dynamics of stress accumulation, how the stress affects cancer cell phenotype, or the molecular pathways involved.We co-embedded single cancer cells with fluorescent micro-beads in agarose gels and, using confocal microscopy, recorded the 3D distribution of micro-beads surrounding growing spheroids. The change in micro-bead density was then converted to strain in the gel, from which we estimated the spatial distribution of compressive stress around the spheroids. We found a strong correlation between the peri-spheroid solid stress distribution and spheroid shape, a result of the suppression of cell proliferation and induction of apoptotic cell death in regions of high mechanical stress. By compressing spheroids consisting of cancer cells overexpressing anti-apoptotic genes, we demonstrate that mechanical stress-induced apoptosis occurs via the mitochondrial pathway.Our results provide detailed, quantitative insight into the role of micro-environmental mechanical stress in tumor spheroid growth dynamics, and suggest how tumors grow in confined locations where the level of solid stress becomes high. An important implication is that apoptosis via the mitochondrial pathway, induced by compressive stress, may be involved in tumor dormancy, in which tumor growth is held in check by a balance of apoptosis and proliferation.

  11. SU-E-T-630: Predictive Modeling of Mortality, Tumor Control, and Normal Tissue Complications After Stereotactic Body Radiotherapy for Stage I Non-Small Cell Lung Cancer

    International Nuclear Information System (INIS)

    Lindsay, WD; Berlind, CG; Gee, JC; Simone, CB

    2015-01-01

    Purpose: While rates of local control have been well characterized after stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC), less data are available characterizing survival and normal tissue toxicities, and no validated models exist assessing these parameters after SBRT. We evaluate the reliability of various machine learning techniques when applied to radiation oncology datasets to create predictive models of mortality, tumor control, and normal tissue complications. Methods: A dataset of 204 consecutive patients with stage I non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT) at the University of Pennsylvania between 2009 and 2013 was used to create predictive models of tumor control, normal tissue complications, and mortality in this IRB-approved study. Nearly 200 data fields of detailed patient- and tumor-specific information, radiotherapy dosimetric measurements, and clinical outcomes data were collected. Predictive models were created for local tumor control, 1- and 3-year overall survival, and nodal failure using 60% of the data (leaving the remainder as a test set). After applying feature selection and dimensionality reduction, nonlinear support vector classification was applied to the resulting features. Models were evaluated for accuracy and area under ROC curve on the 81-patient test set. Results: Models for common events in the dataset (such as mortality at one year) had the highest predictive power (AUC = .67, p < 0.05). For rare occurrences such as radiation pneumonitis and local failure (each occurring in less than 10% of patients), too few events were present to create reliable models. Conclusion: Although this study demonstrates the validity of predictive analytics using information extracted from patient medical records and can most reliably predict for survival after SBRT, larger sample sizes are needed to develop predictive models for normal tissue toxicities and more advanced

  12. Tumor immunology

    International Nuclear Information System (INIS)

    Otter, W. den

    1987-01-01

    Tumor immunology, the use of immunological techniques for tumor diagnosis and approaches to immunotherapy of cancer are topics covered in this multi-author volume. Part A, 'Tumor Immunology', deals with present views on tumor-associated antigens, the initiation of immune reactions of tumor cells, effector cell killing, tumor cells and suppression of antitumor immunity, and one chapter dealing with the application of mathematical models in tumor immunology. Part B, 'Tumor Diagnosis and Imaging', concerns the use of markers to locate the tumor in vivo, for the histological diagnosis, and for the monitoring of tumor growth. In Part C, 'Immunotherapy', various experimental approaches to immunotherapy are described, such as the use of monoclonal antibodies to target drugs, the use of interleukin-2 and the use of drugs inhibiting suppression. In the final section, the evaluation, a pathologist and a clinician evaluate the possibilities and limitations of tumor immunology and the extent to which it is useful for diagnosis and therapy. refs.; figs.; tabs

  13. Bmi1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma.

    Science.gov (United States)

    Bruggeman, Sophia W M; Hulsman, Danielle; Tanger, Ellen; Buckle, Tessa; Blom, Marleen; Zevenhoven, John; van Tellingen, Olaf; van Lohuizen, Maarten

    2007-10-01

    The Polycomb group and oncogene Bmi1 is required for the proliferation of various differentiated cells and for the self-renewal of stem cells and leukemic cancer stem cells. Repression of the Ink4a/Arf locus is a well described mechanism through which Bmi1 can exert its proliferative effects. However, we now demonstrate in an orthotopic transplantation model for glioma, a type of cancer harboring cancer stem cells, that Bmi1 is also required for tumor development in an Ink4a/Arf-independent manner. Tumors derived from Bmi1;Ink4a/Arf doubly deficient astrocytes or neural stem cells have a later time of onset and different histological grading. Moreover, in the absence of Ink4a/Arf, Bmi1-deficient cells and tumors display changes in differentiation capacity.

  14. Evaluation on Usefulness of Abdomen and Chest Motion Control Device (ABCHES) for the Tumor with a Large Respiratory Motion in Radiotherapy

    International Nuclear Information System (INIS)

    Cho, Yoon Jin; Jeon, Mi Jin; Shin, Dong Bong; Kim, Jong Dae; Kim, Sel Joon; Ha, Jin Sook; Im, Jung Ho; Lee, Ik Jae

    2012-01-01

    It is essential to minimize the respiratory-induced motion of involved organs in the Tomotherapy for tumor located in the chest and abdominal region. However, the application of breathing control system to Tomotherapy is limited. This study was aimed to investigate the possible application of the ABCHES system and its efficacy as a means of breathing control in the tomotherapy treatment. Five subjects who were treated with a Hi-Art Tomotherapy system for lung, liver, gallbladder and pancreatic tumors. All patients undertook trained on two breathing method using an ABCHES, free breathing method and shallow breathing method. When the patients could carry out the breathing control, 4D-CT scan was a total of 10 4D tomographic images were acquired. A radiologist resident manually drew the tumor region, including surrounding normal organs, on each of CT images at the inhalation phase, the exhalation phase and the 40% phase (mid-inhalation) and average CT image. Those CT images were then exported to the Tomotherapy planning station. Data exported from the Tomotherapy planning station was analyzed to quantify characteristics of dose-volume histograms and motion of tumors. Organ motions under free breathing and shallow breathing were examined six directions, respectively. Radiation exposure to the surrounding organs were also measured and compared. Organ motion is in the six directions with more than a 5 mm displacement. A total of 12 Organ motions occurred during free breathing while organ motions decreased to 2 times during shallow breathing under the use of Abches. Based on the quantitative analysis of the dose-volume histograms shallow breathing showed lower resulting values, compared to free breathing, in every measure. That is, treatment volume, the dose of radiation to the tumor and two surrounding normal organs (mean doses), the volume of healthy tissue exposed to radiation were lower at the shallow breathing state. This study proposes that the use of ABCHES is

  15. High-Throughput Flow Cytometric Method for the Simultaneous Measurement of CAR-T Cell Characterization and Cytotoxicity against Solid Tumor Cell Lines.

    Science.gov (United States)

    Martinez, Emily M; Klebanoff, Samuel D; Secrest, Stephanie; Romain, Gabrielle; Haile, Samuel T; Emtage, Peter C R; Gilbert, Amy E

    2018-04-01

    High-throughput flow cytometry is an attractive platform for the analysis of adoptive cellular therapies such as chimeric antigen receptor T cell therapy (CAR-T) because it allows for the concurrent measurement of T cell-dependent cellular cytotoxicity (TDCC) and the functional characterization of engineered T cells with respect to percentage of CAR transduction, T cell phenotype, and measurement of T cell function such as activation in a single assay. The use of adherent tumor cell lines can be challenging in these flow-based assays. Here, we present the development of a high-throughput flow-based assay to measure TDCC for a CAR-T construct co-cultured with multiple adherent tumor cell lines. We describe optimal assay conditions (such as adherent cell dissociation techniques to minimize impact on cell viability) that result in robust cytotoxicity assays. In addition, we report on the concurrent use of T cell transduction and activation antibody panels (CD25) that provide further dissection of engineered T cell function. In conclusion, we present the development of a high-throughput flow cytometry method allowing for in vitro interrogation of solid tumor, targeting CAR-T cell-mediated cytotoxicity, CAR transduction, and engineered T cell characterization in a single assay.

  16. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma

    NARCIS (Netherlands)

    Wenzel, Sally E.; Barnes, Peter J.; Bleecker, Eugene R.; Bousquet, Jean; Busse, William; Dahlén, Sven-Erik; Holgate, Stephen T.; Meyers, Deborah A.; Rabe, Klaus F.; Antczak, Adam; Baker, James; Horvath, Ildiko; Mark, Zsuzsanna; Bernstein, David; Kerwin, Edward; Schlenker-Herceg, Rozsa; Lo, Kim Hung; Watt, Rosemary; Barnathan, Elliot S.; Chanez, Pascal; Chanez, P.; Tunon-de-Lara, M.; Antczak, A.; Pierzchala, W.; Bukowczan, Z.; Trawinska, E.; Baker, J.; Wenzel, S. E.; Katial, R.; Bernstein, D.; Kerwin, E.; Bensch, G.; Castro, M.; Noonan, M.; Nayak, A.; Chupp, G.; Kline, J.; Busse, W.; Kavuru, M. S.; Lang, D.; Wolfe, R.; Baughman, R.; Korenblat, P.; Mansfield, L.; Bleecker, E.; Lisberg, E.; Liu, M.; Panettieri, R.; Spangenthal, S.; Bel, E. H.

    2009-01-01

    RATIONALE: The treatment effect of golimumab, a human monoclonal antibody against tumor necrosis factor (TNF)-alpha, in severe persistent asthma is unknown. OBJECTIVES: To assess the safety and efficacy of golimumab in a large population of patients with uncontrolled, severe persistent asthma.

  17. Extended Tumor Control after Dendritic Cell Vaccination with Low-Dose Cyclophosphamide as Adjuvant Treatment in Patients with Malignant Pleural Mesothelioma.

    Science.gov (United States)

    Cornelissen, Robin; Hegmans, Joost P J J; Maat, Alexander P W M; Kaijen-Lambers, Margaretha E H; Bezemer, Koen; Hendriks, Rudi W; Hoogsteden, Henk C; Aerts, Joachim G J V

    2016-05-01

    We demonstrated previously that autologous tumor lysate-pulsed dendritic cell-based immunotherapy in patients with malignant pleural mesothelioma is feasible, well-tolerated, and capable of inducing immunologic responses against tumor cells. In our murine model, we found that reduction of regulatory T cells with metronomic cyclophosphamide increased the efficacy of immunotherapy. To assess the decrease in number of peripheral blood regulatory T cells during combination therapy of low-dose cyclophosphamide and dendritic cell immunotherapy and determine the induction of immunologic responses with this treatment in patients with mesothelioma. Ten patients with malignant pleural mesothelioma received metronomic cyclophosphamide and dendritic cell-based immunotherapy. During the treatment, peripheral blood mononuclear cells were analyzed for regulatory T cells and immunologic responses. Administration of dendritic cells pulsed with autologous tumor lysate combined with cyclophosphamide in patients with mesothelioma was safe, the only side effect being moderate fever. Dendritic cell vaccination combined with cyclophosphamide resulted in radiographic disease control in 8 of the 10 patients. Overall survival was promising, with 7 out of 10 patients having a survival of greater than or equal to 24 months and two patients still alive after 50 and 66 months. Low-dose cyclophosphamide reduced the percentage of regulatory T cells of total CD4 cells in peripheral blood from 9.43 (range, 4.34-26.10) to 4.51 (range, 0.27-10.30) after 7 days of cyclophosphamide treatment (P = 0.02). Consolidation therapy with autologous tumor lysate-pulsed dendritic cell-based therapy and simultaneously reducing the tumor-induced immune suppression is well-tolerated and shows signs of clinical activity in patients with mesothelioma. Clinical trial registered with www.clinicaltrials.gov (NCT 01241682).

  18. Effect of Ovariohysterectomy at the Time of Tumor Removal in Dogs with Mammary Carcinomas: A Randomized Controlled Trial.

    Science.gov (United States)

    Kristiansen, V M; Peña, L; Díez Córdova, L; Illera, J C; Skjerve, E; Breen, A M; Cofone, M A; Langeland, M; Teige, J; Goldschmidt, M; Sørenmo, K U

    2016-01-01

    Ovarian hormones play crucial roles in mammary carcinogenesis. However, whether ovarian ablation by ovariohysterectomy (OHE) improves the prognosis in dogs with mammary carcinomas is unclear. Determine if OHE at the time of mastectomy improves the prognosis in dogs with mammary carcinomas and evaluate if hormonal factors influence the effect of OHE. Sixty intact dogs with mammary carcinomas. Dogs were randomly assigned in a 1:1 ratio to undergo OHE (n = 31) or not (n = 29) at the time of tumor removal. Peri-surgical serum estradiol (E2) and progesterone concentrations were measured, tumor diagnosis was confirmed histologically, and tumor estrogen and progesterone receptor status was immunohistochemically determined. The dogs were monitored for recurrence and metastases every 3-4 months for at least 2 years. Uni- and multivariable survival analyses were performed with relapse and all-cause death as endpoints in addition to univariable subgroup analyses. Overall, OHE did not significantly decrease hazard of relapse (hazard ratio [HR], 0.64; P = .18) or all-cause death (HR, 0.87; P = .64) in univariable analyses. In multivariable analysis OHE did not significantly influence the hazard of relapse (HR, 0.54; P = .12), but an interaction effect was identified between ER status and E2 (P = .037). Subgroup analysis identified decreased hazard of relapse in the OHE group compared to the non-OHE group in the subsets of dogs with increased E2 (HR, 0.22; P = .012) or grade 2 tumors (HR, 0.26; P = .02). Dogs with grade 2, ER-positive tumors, or with increased peri-surgical serum E2 concentration represent a subset of dogs with mammary carcinomas likely to benefit from OHE. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  19. Percutaneous treatment of liver tumors with an adapted probe for cooled-tip, impedance-controlled radio-frequency ablation under open-magnet MR guidance: initial results

    Energy Technology Data Exchange (ETDEWEB)

    Kelekis, Alexis D.; Terraz, Sylvain; Roggan, Andre; Terrier, Francois; Majno, Pietro; Mentha, Gilles; Roth, Arnaud; Becker, Christoph D. [Department of Diagnostic and Interventional Radiology, University Hospital, 24 rue Micheli-du-Crest, 1211, Geneva (Switzerland)

    2003-05-01

    Percutaneous radio-frequency (RF) ablation of liver tumors is usually performed under guidance of real-time US, but some tumor nodules in some patients cannot be adequately visualized with this technique. We report our preliminary results with an MR-compatible, internally perfused 17-G RF probe adapted to a standard RF generator for impedance-controlled RF ablation under MR guidance. Following initial testing of the probe for MR compatibility, artifacts and macroscopic effects on an ex vivo pig liver, four patients with eight neoplastic liver nodules (five metastatic and three primary), which could not be properly targeted by US, were treated with the cooled-tip technique under MRI guidance in an open 0.23-T magnet. Metallic artifacts produced by the probe were useful for accurate placement and did not interfere with MRI monitoring at the end of the procedure. Based on imaging findings, the immediate result of RF was considered adequate in all instances. Local recurrence occurred in one instance after 6 months, requiring repeat treatment. No adverse effects were noted. Initial experience suggests that the probe we used allows to perform impedance-controlled cooled-tip RF ablation of liver tumors under open-magnet MR guidance. (orig.)

  20. Attenuation of G2 cell cycle checkpoint control in human tumor cells is associated with increased frequencies of unrejoined chromosome breaks but not increased cytotoxicity following radiation exposure

    International Nuclear Information System (INIS)

    Schwartz, J.L.; Cowan, J.; Grdina, D.J.

    1997-01-01

    The contribution of G 2 cell cycle checkpoint control to ionizing radiation responses was examined in ten human tumor cell lines. Most of the delay in cell cycle progression seen in the first cell cycle following radiation exposure was due to blocks in G 2 and there were large cell line-to-cell line variations in the length of the G 2 block. Longer delays were seen in cell lines that had mutations in p53. There was a highly significant inverse correlation between the length of G 2 delay and the frequency of unrejoined chromosome breaks seen as chromosome terminal deletions in mitosis, and observation that supports the hypothesis that the signal for G 2 delay in mammalian cells is an unrejoined chromosome break. There were also an inverse correlation between the length of G 2 delay and the level of chromosome aneuploidy in each cell line, suggesting that the G 2 and mitotic spindel checkpoints may be linked to each other. Attenuation in G 2 checkpoint control was not associated with alterations in either the frequency of induced chromosome rearrangements or cell survival following radiation exposure suggesting that chromosome rearrangements, the major radiation-induced lethal lesion in tumor cells, form before cells enters G 2 . Thus, agents that act solely to override G 2 arrest should produce little radiosensitization in human tumor cells

  1. Tumor vaccines:

    OpenAIRE

    Frank, Mojca; Ihan, Alojz

    2006-01-01

    Tumor vaccines have several potential advantages over standard anticancer regirrcents. They represent highly specific anticancer therapy. Inducing tumor-specific memory T-lymphocytes, they have potential for long-lived antitumor effects. However, clinical trials, in which cancer patients were vaccinated with tccmor aaccines, have been so far mainly disappointing. There are many reasons for the inefficiency of tumor vaccines. Most cancer antigens are normal self-molecules to which imrrtune tol...

  2. Effect of tumor dose, volume and overall treatment time on local control after radiochemotherapy including MRI guided brachytherapy of locally advanced cervical cancer

    DEFF Research Database (Denmark)

    Tanderup, Kari; Fokdal, Lars Ulrik; Sturdza, Alina

    2016-01-01

    (CTVHR) (p = 0.022, HR = 0.967 per Gy) was significant for local control, whereas increasing CTVHR volume (p = 0.004, HR = 1.017 per cm3), and longer OTT (p = 0.004, HR = 1.023 per day) were associated with worse local control. Histology (p = 0.084), chemotherapy (p = 0.49) and dose rate (p = 1.00) did...... Hazards model was applied to analyze the effect on local control of dose-volume metrics as well as overall treatment time (OTT), dose rate, chemotherapy, and tumor histology. Results With a median follow up of 46 months, 43 local failures were observed. Dose (D90) to the High Risk Clinical Target Volume...... not have significant impact on local control. Separate analyses according to stage of disease showed that dose to CTVHR, residual gross tumor volume (GTVres), and Intermediate Risk CTV (CTVIR) has significant impact on local control. Conclusion CTVHR dose of ⩾85 Gy (D90) delivered in 7 weeks provides 3...

  3. Central nervous system tumors

    International Nuclear Information System (INIS)

    Gavin, P.R.; Fike, J.R.; Hoopes, P.J.

    1995-01-01

    Central nervous system (CNS) tumors are relatively common in veterinary medicine, with most diagnoses occurring in the canine and feline species. Numerous tumor types from various cells or origins have been identified with the most common tumors being meningiomas and glial cell tumors. Radiation therapy is often used as an aid to control the clinical signs associated with these neoplasms. In general, these tumors have a very low metastatic potential, such that local control offers substantial benefit. Experience in veterinary radiation oncology would indicate that many patients benefit from radiation treatment. Current practice indicates the need for computed tomography or magnetic resonance imaging studies. These highly beneficial studies are used for diagnosis, treatment planning, and to monitor treatment response. Improvements in treatment planning and radiation delivered to the tumor, while sparing the normal tissues, should improve local control and decrease potential radiation related problems to the CNS. When possible, multiple fractions of 3 Gy or less should be used. The tolerance dose to the normal tissue with this fractionation schedule is 50 to 55 Gy. The most common and serious complications of radiation for CNS tumors is delayed radiation myelopathy and necrosis. Medical management of the patient during radiation therapy requires careful attention to anesthetic protocols, and medications to reduce intracranial pressure that is often elevated in these patients. Canine brain tumors have served as an experimental model to test numerous new treatments. Increased availability of advanced imaging modalities has spawned increased detection of these neoplasms. Early detection of these tumors with appropriate aggressive therapy should prove beneficial to many patients

  4. CT diagnosis of brain tumor types with the aid of a new, CT-controlled stereotactical device

    International Nuclear Information System (INIS)

    Huk, W.

    1980-01-01

    The hitherto unparalleled information quality of computerized tomography elicited hopes that it might also be possible to differentiate cerebral tumors according to their histologic character and degree of malignity. The present work proposes to investigate whether CT information can be useful in the diagnosis of types of brain tumors. A first part contains a critical analysis of CT findings as to their specific information value and a comparison with the possibilities previously offered by neuroradiology. In a second part, and as a consequence of the investigations in Part I, a newly developed stereotactical procedure is described combining the capacity of CT for precise location with the accuracy of aim of a stereotactical device so that cerebral proliferations evading other diagnostical attempts can be histologically cleared up. (orig./MG) [de

  5. Analysis of biopsy outcome after three-dimensional conformal radiation therapy of prostate cancer using dose-distribution variables and tumor control probability models

    International Nuclear Information System (INIS)

    Levegruen, Sabine; Jackson, Andrew; Zelefsky, Michael J.; Venkatraman, Ennapadam S.; Skwarchuk, Mark W.; Schlegel, Wolfgang; Fuks, Zvi; Leibel, Steven A.; Ling, C. Clifton

    2000-01-01

    Purpose: To investigate tumor control following three-dimensional conformal radiation therapy (3D-CRT) of prostate cancer and to identify dose-distribution variables that correlate with local control assessed through posttreatment prostate biopsies. Methods and Material: Data from 132 patients, treated at Memorial Sloan-Kettering Cancer Center (MSKCC), who had a prostate biopsy 2.5 years or more after 3D-CRT for T1c-T3 prostate cancer with prescription doses of 64.8-81 Gy were analyzed. Variables derived from the dose distribution in the PTV included: minimum dose (Dmin), maximum dose (Dmax), mean dose (Dmean), dose to n% of the PTV (Dn), where n = 1%, ..., 99%. The concept of the equivalent uniform dose (EUD) was evaluated for different values of the surviving fraction at 2 Gy (SF 2 ). Four tumor control probability (TCP) models (one phenomenologic model using a logistic function and three Poisson cell kill models) were investigated using two sets of input parameters, one for low and one for high T-stage tumors. Application of both sets to all patients was also investigated. In addition, several tumor-related prognostic variables were examined (including T-stage, Gleason score). Univariate and multivariate logistic regression analyses were performed. The ability of the logistic regression models (univariate and multivariate) to predict the biopsy result correctly was tested by performing cross-validation analyses and evaluating the results in terms of receiver operating characteristic (ROC) curves. Results: In univariate analysis, prescription dose (Dprescr), Dmax, Dmean, dose to n% of the PTV with n of 70% or less correlate with outcome (p 2 : EUD correlates significantly with outcome for SF 2 of 0.4 or more, but not for lower SF 2 values. Using either of the two input parameters sets, all TCP models correlate with outcome (p 2 , is limited because the low dose region may not coincide with the tumor location. Instead, for MSKCC prostate cancer patients with their

  6. C-Myc negatively controls the tumor suppressor PTEN by upregulating miR-26a in glioblastoma multiforme cells

    International Nuclear Information System (INIS)

    Guo, Pin; Nie, Quanmin; Lan, Jin; Ge, Jianwei; Qiu, Yongming; Mao, Qing

    2013-01-01

    Highlights: •The c-Myc oncogene directly upregulates miR-26a expression in GBM cells. •ChIP assays demonstrate that c-Myc interacts with the miR-26a promoter. •Luciferase reporter assays show that PTEN is a specific target of miR-26a. •C-Myc–miR-26a suppression of PTEN may regulate the PTEN/AKT pathway. •Overexpression of c-Myc enhances the proliferative capacity of GBM cells. -- Abstract: The c-Myc oncogene is amplified in many tumor types. It is an important regulator of cell proliferation and has been linked to altered miRNA expression, suggesting that c-Myc-regulated miRNAs might contribute to tumor progression. Although miR-26a has been reported to be upregulated in glioblastoma multiforme (GBM), the mechanism has not been established. We have shown that ectopic expression of miR-26a influenced cell proliferation by targeting PTEN, a tumor suppressor gene that is inactivated in many common malignancies, including GBM. Our findings suggest that c-Myc modulates genes associated with oncogenesis in GBM through deregulation of miRNAs via the c-Myc–miR-26a–PTEN signaling pathway. This may be of clinical relevance

  7. C-Myc negatively controls the tumor suppressor PTEN by upregulating miR-26a in glioblastoma multiforme cells

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Pin; Nie, Quanmin; Lan, Jin; Ge, Jianwei [Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 (China); Qiu, Yongming, E-mail: qiuzhoub@hotmail.com [Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 (China); Shanghai Institute of Head Trauma, Shanghai 200127 (China); Mao, Qing, E-mail: maoq@netease.com [Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 (China); Shanghai Institute of Head Trauma, Shanghai 200127 (China)

    2013-11-08

    Highlights: •The c-Myc oncogene directly upregulates miR-26a expression in GBM cells. •ChIP assays demonstrate that c-Myc interacts with the miR-26a promoter. •Luciferase reporter assays show that PTEN is a specific target of miR-26a. •C-Myc–miR-26a suppression of PTEN may regulate the PTEN/AKT pathway. •Overexpression of c-Myc enhances the proliferative capacity of GBM cells. -- Abstract: The c-Myc oncogene is amplified in many tumor types. It is an important regulator of cell proliferation and has been linked to altered miRNA expression, suggesting that c-Myc-regulated miRNAs might contribute to tumor progression. Although miR-26a has been reported to be upregulated in glioblastoma multiforme (GBM), the mechanism has not been established. We have shown that ectopic expression of miR-26a influenced cell proliferation by targeting PTEN, a tumor suppressor gene that is inactivated in many common malignancies, including GBM. Our findings suggest that c-Myc modulates genes associated with oncogenesis in GBM through deregulation of miRNAs via the c-Myc–miR-26a–PTEN signaling pathway. This may be of clinical relevance.

  8. Lack of correlation between natural killer activity and tumor growth control in nude mice with different immune defects.

    Science.gov (United States)

    Fodstad, O; Hansen, C T; Cannon, G B; Statham, C N; Lichtenstein, G R; Boyd, M R

    1984-10-01

    To elucidate the in vivo role of natural killer (NK) cells, the growth of several murine and human tumors was studied in four variants of athymic, nude mice with different levels of NK activity. Beige-nude mice, homozygous for both the beige and the nude genes, had very low levels of NK activity, and their response to the B-cell mitogen, bacterial lipopolysaccharide, was lower than that of high-NK, adult NIH nude mice. Young and adult NIH nudes had different NK levels and showed different response in assays for K-cell, T-cell, and B-cell activity. The B-cell-defective NIH-II mice had slightly lower NK levels than adult NIH animals, but much lower response in the antibody-dependent cell-mediated cytotoxicity assay. No correlation was found between host NK activity and the s.c. growth of various human (LOX, CEM, K562) and murine (YAC-1) tumor cells. Low NK activity was not associated with increased lung colony formation in a metastasis model using i.v.-injected human (LOX) and murine (B16F10) melanoma cells. No relationship was found between host NK activity and the rate of elimination of i.v.-injected 5-iodo-2'-deoxyuridine-labeled LOX, B16F10, and YAC-1 cells from lungs, liver, or spleen. The results fail to support the view that NK cells exert significant direct effects on tumor cells in vivo.

  9. Intensity-modulated radiotherapy for laryngeal and hypopharyngeal cancer. Minimization of late dysphagia without jeopardizing tumor control

    Energy Technology Data Exchange (ETDEWEB)

    Modesto, Anouchka; Laprie, Anne; Graff, Pierre; Rives, Michel [Institut Universitaire du Cancer, Department of Radiation Oncology, Institut Claudius Regaud, Toulouse (France); Vieillevigne, Laure [Institut Universitaire du Cancer, Department of Medical Physics, Toulouse (France); Sarini, Jerome; Vergez, Sebastien; Farenc, Jean-Claude [Institut Universitaire du Cancer, Department of Head and Neck Surgery, Toulouse (France); Delord, Jean-Pierre [Institut Universitaire du Cancer, Department of Medical Oncology, Toulouse (France); Vigarios, Emmanuelle [Centre Hospitalo Universitaire de Rangueil, Dental Surgery Department, Toulouse (France); Filleron, Thomas [Institut Universitaire du Cancer, Department of Biostatistics, Toulouse (France)

    2014-11-01

    The purpose of this work was to retrospectively determine the value of intensity-modulated radiotherapy (IMRT) in patients with laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC), on outcome and treatment-related toxicity compared to 3-dimensional conformal radiotherapy (3D-CRT). A total of 175 consecutive patients were treated between 2007 and 2012 at our institution with curative intent RT and were included in this study: 90 were treated with 3D-CRT and 85 with IMRT. Oncologic outcomes were estimated using Kaplan-Meier statistics; acute and late toxicities were scored according to the Common Toxicity Criteria for Adverse Events scale v 3.0. Median follow-up was 35 months (range 32-42 months; 95% confidence interval 95 %). Two-year disease-free survival did not vary, regardless of the technique used (69 % for 3D-CRT vs. 72 %; for IMRT, p = 0.16). Variables evaluated as severe late toxicities were all statistically lower with IMRT compared with 3D-CRT: xerostomia (0 vs. 12 %; p < 0.0001), dysphagia (4 vs. 26 %; p < 0.0001), and feeding-tube dependency (1 vs 13 %; p = 0.0044). The rates of overall grade ≥ 3 late toxicities for the IMRT and 3D-CRT groups were 4.1 vs. 41.4 %, respectively (p < 0.0001). IMRT for laryngeal and hypopharyngeal cancer minimizes late dysphagia without jeopardizing tumor control and outcome. (orig.) [German] Das Ziel dieser Studie war es, retrospektiv den Nutzen der intensitaetsmodulierten Strahlentherapie (IMRT) in der Behandlung von Patienten mit Plattenepithelkarzinom von Kehlkopf und Hypopharynx (LHSCC) zu bewerten und mit dem Outcome und den Spaetfolgen der 3-D-konformalen Strahlentherapie (3D-CRT) zu vergleichen. Insgesamt wurden zwischen Januar 2007 und Dezember 2012175 LHSCC-Patienten mit einer RT behandelt und in die Studie aufgenommen: 85 Patienten wurden mit 3D-CRT und 90 Patienten mit IMRT behandelt.Das onkologische Outcome wurde mittels Kaplan-Meier-Statistik ermittelt und Akut- und Spaettoxizitaeten anhand der CTCAE

  10. Tumoral tracers

    International Nuclear Information System (INIS)

    Camargo, E.E.

    1979-01-01

    Direct tumor tracers are subdivided in the following categories:metabolite tracers, antitumoral tracers, radioactive proteins and cations. Use of 67 Ga-citrate as a clinically important tumoral tracer is emphasized and gallium-67 whole-body scintigraphy is discussed in detail. (M.A.) [pt

  11. Carcinoid Tumors

    Science.gov (United States)

    ... spread to other parts of the body. Doctors don't know what causes the mutations that can lead to carcinoid tumors. But they know that carcinoid tumors develop in neuroendocrine cells. Neuroendocrine cells are found in various organs throughout the body. They perform some nerve cell ...

  12. Effect of the pringle maneuver on tumor recurrence of hepatocellular carcinoma after curative resection (EPTRH): a randomized, prospective, controlled multicenter trial

    International Nuclear Information System (INIS)

    Xiaobin, Feng; Shuguang, Wang; Ping, Bie; Jiahong, Dong; Shuguo, Zheng; Jian, Zhou; Yudong, Qiu; Lijian, Liang; Kuansheng, Ma; Xiaowu, Li; Feng, Xia; Dong, Yi

    2012-01-01

    Hepatic resection is currently still the best choice of therapeutic strategies for liver cancer, but the long-term survival rate after surgery is unsatisfactory. Most patients develop intra- and/or extrahepatic recurrence. The reasons for this high recurrence rate are not entirely clear. Recent studies have indicated that ischemia-reperfusion injury to the liver may be a significant factor promoting tumor recurrence and metastasis in animal models. If this is also true in humans, the effects of the Pringle maneuver, which has been widely used in hepatectomy for the past century, should be examined. To date, there are no reported data or randomized controlled studies examining the relationship between use of the Pringle maneuver and local tumor recurrence. We hypothesize that the long-term prognosis of patients with liver cancer could be worsened by use of the Pringle maneuver due to an increase in the rate of tumor recurrence in the liver remnant. We designed a multicenter, prospective, randomized surgical trial to test this hypothesis. At least 498 eligible patients from five participating centers will be enrolled and randomized into either the Pringle group or the non-Pringle group in a ratio of 1:1 using a permuted-blocks randomization protocol. After the completion of surgical intervention, patients will be included in a 3-year follow-up program. This multicenter surgical trial will examine whether the Pringle maneuver has a negative effect on the long-term outcome of hepatocellular carcinoma patients. The trial will also provide information about prognostic differences, safety, advantages and disadvantages between Pringle and non-Pringle surgical procedures. Ultimately, the results will increase the available information about the effects of ischemia-reperfusion injury on tumor recurrence, which will be of immense benefit to general surgery.

  13. Tumor control probability and the utility of 4D vs 3D dose calculations for stereotactic body radiotherapy for lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Valdes, Gilmer, E-mail: gilmer.valdes@uphs.upenn.edu [Department of Radiation Oncology, Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia, PA (United States); Robinson, Clifford [Department of Radiation Oncology, Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO (United States); Lee, Percy [Department of Radiation Oncology, David Geffen School of Medicine, UCLA, Los Angeles, CA (United States); Morel, Delphine [Department of Biomedical Engineering, AIX Marseille 2 University, Marseille (France); Department of Medical Physics, Joseph Fourier University, Grenoble (France); Low, Daniel; Iwamoto, Keisuke S.; Lamb, James M. [Department of Radiation Oncology, David Geffen School of Medicine, UCLA, Los Angeles, CA (United States)

    2015-04-01

    Four-dimensional (4D) dose calculations for lung cancer radiotherapy have been technically feasible for a number of years but have not become standard clinical practice. The purpose of this study was to determine if clinically significant differences in tumor control probability (TCP) exist between 3D and 4D dose calculations so as to inform the decision whether 4D dose calculations should be used routinely for treatment planning. Radiotherapy plans for Stage I-II lung cancer were created for 8 patients. Clinically acceptable treatment plans were created with dose calculated on the end-exhale 4D computed tomography (CT) phase using a Monte Carlo algorithm. Dose was then projected onto the remaining 9 phases of 4D-CT using the Monte Carlo algorithm and accumulated onto the end-exhale phase using commercially available deformable registration software. The resulting dose-volume histograms (DVH) of the gross tumor volume (GTV), planning tumor volume (PTV), and PTV{sub setup} were compared according to target coverage and dose. The PTV{sub setup} was defined as a volume including the GTV and a margin for setup uncertainties but not for respiratory motion. TCPs resulting from these DVHs were estimated using a wide range of alphas, betas, and tumor cell densities. Differences of up to 5 Gy were observed between 3D and 4D calculations for a PTV with highly irregular shape. When the TCP was calculated using the resulting DVHs for fractionation schedules typically used in stereotactic body radiation therapy (SBRT), the TCP differed at most by 5% between 4D and 3D cases, and in most cases, it was by less than 1%. We conclude that 4D dose calculations are not necessary for most cases treated with SBRT, but they might be valuable for irregularly shaped target volumes. If 4D calculations are used, 4D DVHs should be evaluated on volumes that include margin for setup uncertainty but not respiratory motion.

  14. Immune-Modulation by Epidermal Growth Factor Receptor Inhibitors: Implication on Anti-Tumor Immunity in Lung Cancer

    Science.gov (United States)

    Herrmann, Amanda C.; Bernatchez, Chantale; Haymaker, Cara; Molldrem, Jeffrey J.; Hong, Waun Ki; Perez-Soler, Roman

    2016-01-01

    Skin toxicity is the most common toxicity caused by Epidermal Growth Factor Receptor (EGFR) inhibitors, and has been associated with clinical efficacy. As EGFR inhibitors enhance the expression of antigen presenting molecules in affected skin keratinocytes, they may concurrently facilitate neo-antigen presentation in lung cancer tumor cells contributing to anti-tumor immunity. Here, we investigated the modulatory effect of the EGFR inhibitor, erlotinib on antigen presenting molecules and PD-L1, prominent immune checkpoint protein, of skin keratinocytes and lung cancer cell lines to delineate the link between EGFR signaling pathway inhibition and potential anti-tumor immunity. Erlotinib up-regulated MHC-I and MHC-II proteins on IFNγ treated keratinocytes but abrogated IFNγ-induced expression of PD-L1, suggesting the potential role of infiltrating autoreactive T cells in the damage of keratinocytes in affected skin. Interestingly, the surface expression of MHC-I, MHC-II, and PD-L1 was up-regulated in response to IFNγ more often in lung cancer cell lines sensitive to erlotinib, but only expression of PD-L1 was inhibited by erlotinib. Further, erlotinib significantly increased T cell mediated cytotoxicity on lung cancer cells. Lastly, the analysis of gene expression dataset of 186 lung cancer cell lines from Cancer Cell Line Encyclopedia demonstrated that overexpression of PD-L1 was associated with sensitivity to erlotinib and higher expression of genes related to antigen presenting pathways and IFNγ signaling pathway. Our findings suggest that the EGFR inhibitors can facilitate anti-tumor adaptive immune responses by breaking tolerance especially in EGFR driven lung cancer that are associated with overexpression of PD-L1 and genes related to antigen presentation and inflammation. PMID:27467256

  15. Immune-Modulation by Epidermal Growth Factor Receptor Inhibitors: Implication on Anti-Tumor Immunity in Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Jin S Im

    Full Text Available Skin toxicity is the most common toxicity caused by Epidermal Growth Factor Receptor (EGFR inhibitors, and has been associated with clinical efficacy. As EGFR inhibitors enhance the expression of antigen presenting molecules in affected skin keratinocytes, they may concurrently facilitate neo-antigen presentation in lung cancer tumor cells contributing to anti-tumor immunity. Here, we investigated the modulatory effect of the EGFR inhibitor, erlotinib on antigen presenting molecules and PD-L1, prominent immune checkpoint protein, of skin keratinocytes and lung cancer cell lines to delineate the link between EGFR signaling pathway inhibition and potential anti-tumor immunity. Erlotinib up-regulated MHC-I and MHC-II proteins on IFNγ treated keratinocytes but abrogated IFNγ-induced expression of PD-L1, suggesting the potential role of infiltrating autoreactive T cells in the damage of keratinocytes in affected skin. Interestingly, the surface expression of MHC-I, MHC-II, and PD-L1 was up-regulated in response to IFNγ more often in lung cancer cell lines sensitive to erlotinib, but only expression of PD-L1 was inhibited by erlotinib. Further, erlotinib significantly increased T cell mediated cytotoxicity on lung cancer cells. Lastly, the analysis of gene expression dataset of 186 lung cancer cell lines from Cancer Cell Line Encyclopedia demonstrated that overexpression of PD-L1 was associated with sensitivity to erlotinib and higher expression of genes related to antigen presenting pathways and IFNγ signaling pathway. Our findings suggest that the EGFR inhibitors can facilitate anti-tumor adaptive immune responses by breaking tolerance especially in EGFR driven lung cancer that are associated with overexpression of PD-L1 and genes related to antigen presentation and inflammation.

  16. The combination of IL-21 and IFN-alpha boosts STAT3 activation, cytotoxicity and experimental tumor therapy

    DEFF Research Database (Denmark)

    Eriksen, Karsten W; Søndergaard, Henrik; Woetmann, Anders

    2008-01-01

    such as IFN-alpha and IL-2 have multiple and severe side effects. Accordingly, they are generally used at sub-optimal doses, which limit their clinical efficacy. Here we hypothesized that a combination of IFN-alpha and IL-21, a novel cytokine of the IL-2 family with anti-cancer effects, will increase the anti......-cancer efficacy at sub-optimal cytokine doses. We show that the combined stimulation of target-cells with IFN-alpha and IL-21 triggers an increased STAT3 activation whereas the activation of other STATs including STAT1/2 is unaffected. In parallel, the combined stimulation with IFN-alpha and IL-21 triggers...... a selective increase in MHC class I expression and NK- and CD8(+) T-cell-mediated cytotoxicity. In an experimental in vivo model of renal carcinoma, the combined treatment of IFN-alpha and IL-21 also produces a significant anti-cancer effect as judged by an inhibition of tumor growth and an increased survival...

  17. Lidocaine Did Not Reduce Neuropsychological-Cognitive Decline in Patients 6 Months After Supratentorial Tumor Surgery: A Randomized, Controlled Trial.

    Science.gov (United States)

    Peng, Yuming; Zhang, Wei; Zhou, Xiaoli; Ji, Yong; Kass, Ira S; Han, Ruquan

    2016-01-01

    : There is equivocal evidence examining cognitive improvement in response to lidocaine during cardiac surgery; however, no study has examined its effect on postoperative neuropsychological-cognitive decline after supratentorial tumor surgery. Ninety-four patients scheduled for supratentorial craniotomy were enrolled. Patients received either a dose of lidocaine (2%) via an intravenous bolus (1.5 mg/kg) after induction followed by an infusion at a rate of 2 mg/kg/h until the end of surgery (Lidocaine group) or the same volume of normal saline. The neuropsychological-cognitive decline was evaluated using the following tests: the Mini-Mental State Examination, the Information-Memory-Concentration test, the Hamilton Rating Scale for Depression, and the Hamilton Rating Scale for Anxiety. The cerebral oxygen extraction ratio and the difference in lactic acid levels between the bulb of the jugular vein and a peripheral artery were measured. Eighty patients completed the neuropsychological tests, with 40 patients in each group. The incidence of postoperative decline at up to 6 months in the Lidocaine group was not significantly different than that in the Normal saline group. When the 2 cognitive tests were examined independent of the other tests, there was no difference between groups at 6 months. The cerebral oxygen extraction ratio was significantly lower in the Lidocaine group after surgery (Pcognitive decline in patients 6 months after supratentorial tumor surgery.

  18. Tumor Markers

    Science.gov (United States)

    ... only a small number of people will test positive for the disease who do not have it—in other words, it will result in very few false-positive results. Although tumor markers are extremely useful in ...

  19. Tumor Grade

    Science.gov (United States)

    ... Peer Review and Funding Outcomes Step 4: Award Negotiation & Issuance Manage Your Award Grants Management Contacts Monitoring ... may require immediate or more aggressive treatment. The importance of tumor grade in planning treatment and determining ...

  20. Fractionated Conformal Radiotherapy for Management of Optic Nerve Sheath Meningiomas: Long-Term Outcomes of Tumor Control and Visual Function at a Single Institution

    International Nuclear Information System (INIS)

    Metellus, Philippe; Kapoor, Sumit; Kharkar, Siddharth; Batra, Sachin; Jackson, Juan F.; Kleinberg, Lawrence; Miller, Neil R.; Rigamonti, Daniele

    2011-01-01

    Purpose: To provide the long-term outcomes of patients treated with fractionated conformal radiotherapy (FCRT) for presumed optic nerve sheath meningiomas (ONSMs). Patients and Methods: Between 1995 and 2002, 9 patients with a presumed ONSM were treated with FCRT at our institution. The indications for FCRT were significant visual dysfunction at presentation, progression of visual dysfunction during a period of observation, tumor growth documented by sequential imaging, or a combination of these findings. In 2 patients, FCRT was performed as adjuvant therapy, and in 7, it was the initial and primary treatment. Results: Of the 9 patients, 6 were women and 3 were men, with a mean age of 47 years. All 9 patients had evidence of optic nerve dysfunction in the affected eye, characterized by reduced visual acuity, a visual field defect, and a relative afferent pupillary defect. In addition, 2 patients had proptosis and 1 had diplopia. The mean follow-up period was 98 ± 31.7 months (median, 90; range, 61-151). After FCRT, the visual function improved in the 7 patients who had undergone FCRT as the primary treatment. However, 2 patients who were blind in their affected eye at FCRT remained blind. In 4 of the 7 patients with improvement, the improvement was documented within 1-3 months after FCRT. The tumor control rate was 100%. Proptosis and diplopia also regressed in 100% of patients. At 2 years after FCRT, 1 patient had developed radiation retinopathy. Conclusion: The results of our study have shown that FCRT is a safe and effective treatment of ONSMs, affording satisfactory long-term tumor control, good functional outcome, and low treatment morbidity. FCRT should be considered the treatment of choice for patients with presumed ONSMs for whom the treatment has been deemed appropriate.

  1. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network.

    Directory of Open Access Journals (Sweden)

    Caroline J Voskens

    Full Text Available Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4 blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.Patient files (n = 752 were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS, granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.

  2. Involvement of EZH2, SUV39H1, G9a and associated molecules in pathogenesis of urethane induced mouse lung tumors: Potential targets for cancer control

    Energy Technology Data Exchange (ETDEWEB)

    Pandey, Manuraj; Sahay, Satya; Tiwari, Prakash [Carcinogenesis Laboratory, CSIR-Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow –226001 (India); Upadhyay, Daya S. [Laboratory Animals Services, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow (India); Sultana, Sarwat [Dept. Medical Elementology and Toxicology, Jamia Hamdard, Hamdard Nagar, New Delhi (India); Gupta, Krishna P., E-mail: krishnag522@yahoo.co.in [Carcinogenesis Laboratory, CSIR-Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow –226001 (India)

    2014-10-15

    In the present study, we showed the correlation of EZH2, SUV39H1 or G9a expression and histone modifications with the urethane induced mouse lung tumorigenesis in the presence or absence of antitumor agent, inositol hexaphosphate (IP6). Tumorigenesis and the molecular events involved therein were studied at 1, 4, 12 or 36 weeks after the exposure. There were no tumors at 1 or 4 weeks but tumors started appearing at 12 weeks and grew further till 36 weeks after urethane exposure. Among the molecular events, upregulation of EZH2 and SUV39H1 expressions appeared to be time dependent, but G9a expression was altered significantly only at later stages of 12 or 36 weeks. Alteration in miR-138 expression supports the upregulation of its target, EZH2. H3K9me2, H3K27me3 or H4K20me3 was found to be altered at 12 or 36 weeks. However, ChIP analysis of p16 and MLH1 promoters showed their binding with H3K9me2 and H3K27me3 which was maximum at 36 weeks. Thus, histone modification and their interactions with gene promoter resulted in the reduced expression of p16 and MLH1. IP6 prevented the incidence and the size of urethane induced lung tumors. IP6 also prevented the urethane induced alterations in EZH2, SUV39H1, G9a expressions and histone modifications. Our results suggest that the alterations in the histone modification pathways involving EZH2 and SUV39H1 expressions are among the early events in urethane induced mouse lung tumorigenesis and could be exploited for cancer control. - Highlights: • Urethane induces mouse lung tumor in a time dependent manner. • EZH2, SUV39H1, G9a induced by urethane and progress with time • Downregulation of miRNA-138 supports the EZH2 upregulation. • Methylation of histones showed a consequence of upregulated EZH2, SUV39H1 and G9a. • IP6 inhibits urethane induced changes and prevents tumor development.

  3. Ultraviolet-Mediated Activation of Photo toxins from Peganum Harmala L. Seedlings to Control both Human-and Phyto-Pathogenic Microorganisms and Tumor Cells

    International Nuclear Information System (INIS)

    Kord, M.; Khafagi, I.; Dewedar, A.

    2003-01-01

    The medicinal plant Peganum harmala L. (zygophyllaceae) contains a number of Beta-carboline alkaloids, which are photosensitizers to bacteria, yeasts and eukaryotic cells in the presence of sunlight and artificial sources of long-wave UV radiation (365 nm). Ultraviolet irradiation of ten-day old aseptically germinated Peganum harmala inoculated on bacterial and yeast bioassay plates elicits strong phototoxic antimicrobials. Callus as well as crude methanol extracts of in vitro cultures were also investigated for the accumulation of photosensitizers. High performance liquid chromatographic analyses of irradiated and control tissues followed by fluorescent detection at 302 nm revealed the formation of serotonin (5-hydroxytryptamine) in irradiated tissues only. Eluted compounds detected at 330 nm revealed more than ten-fold accumulation of harmine, isoharmine and harmol in irradiated tissues. Moreover, several simple beta-carboline alkaloids were produced through irradiation with UV such as harmalanine and harmalacidine. UV-induced phototoxicity was proven against phyto pathogenic bacteria and human-pathogenic bacteria and yeasts. Photo-induced cytotoxicity was observed from two different toxicity bioassays, which are Artemia saline and potato discs tumor assay. The selective UV-dependent biological activities may imply a pharmacological potential of Peganum harmala in the control of infectious diseases and tumor tissues

  4. Radiosynthesis and modified quality control of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) for brain tumor imaging.

    Science.gov (United States)

    Siddiq, Ibrahim Saber; Atwa, Shoukar Tawfik; Shama, Sayed Ahmed; Eltaoudy, Magdy Hafez; Omar, Walid Mohamed

    2018-03-01

    O-(2-[ 18 F]fluoroethyl)-L-tyrosine ([ 18 F]FET) is the most promising radio-labeled amino acid tracer for brain tumor imaging due to the limitation of 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) and L-methyl-[ 11 C]methionine ( 11 C-MET). However, it has some limitations in radiosynthesis and related quality control that make it less frequently used in many PET centers, in this study, we report a new modification of [ 18 F]FET production using a commercially available fully automated GRP SCINTOMICS module overcoming some of the existing limitations along with a suggestion of a simplified quality control procedure with special focus placed on enantiomeric and radiochemical purity. ([ 18 F]FET) was produced in high radiochemical and enantiomeric purity more than 99% and non-decay corrected yield 25±5% in about 55min. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Tumor Types: Understanding Brain Tumors

    Science.gov (United States)

    Search Menu Facebook Twitter YouTube Flickr Instagram LinkedIn Brain Tumor Information | News & Blog Our Mission Our History Mission Leadership & Staff Financials Careers News & Blog Contact Us Donate Now Our Impact Our Impact Recent News News & ...

  6. PB1 as a potential target for increasing the breadth of T-cell mediated immunity to Influenza A

    DEFF Research Database (Denmark)

    Uddbäck, Ida E M; Steffensen, Maria A; Pedersen, Sara R

    2016-01-01

    Recently, we showed that combined intranasal and subcutaneous immunization with a non-replicating adenoviral vector expressing NP of influenza A, strain PR8, induced long-standing protection against a range of influenza A viruses. However, H-2(b) mice challenged with an influenza A strain mutated...... in the dominant NP366 epitope were not efficiently protected. To address this problem, we envision the use of a cocktail of adenovectors targeting different internal proteins of influenza A virus. Consequently, we investigated the possibility of using PB1 as a target for an adenovector-based vaccine against...... influenza A. Our results showed that PB1 is not as immunogenic as the NP protein. However, by tethering PB1 to the murine invariant chain we were able to circumvent this problem and raise quite high numbers of PB1-specific CD8(+) T cells in the circulation. Nevertheless, mice immunized against PB1 were...

  7. Flow cytometric assessment of chicken T cell-mediated immune responses after Newcastle disease virus vaccination and challenge

    DEFF Research Database (Denmark)

    Dalgaard, T. S.; Norup, L. R.; Pedersen, A.R.

    2010-01-01

    . Despite a delayed NDV-specific antibody response to vaccination, L133 appeared to be better protected than L130 in the subsequent infection challenge as determined by the presence of viral genomes. Peripheral blood was analyzed by flow cytometry and responses in vaccinated/challenged birds were studied...... by 5-color immunophenotyping as well as by measuring the proliferative capacity of NDV-specific T cells after recall stimulation. Immunophenotyping identified L133 as having a significantly lower CD4/CD8 ratio and a lower frequency of γδ T cells than L130 in the peripheral T cell compartment...

  8. Syndecan-1 displays a protective role in aortic aneurysm formation by modulating T cell-mediated responses.

    Science.gov (United States)

    Xiao, Jiantao; Angsana, Julianty; Wen, Jing; Smith, Sumona V; Park, Pyong Woo; Ford, Mandy L; Haller, Carolyn A; Chaikof, Elliot L

    2012-02-01

    Chronic inflammation drives progressive and pathological remodeling inherent to formation of abdominal aortic aneurysm (AAA). Syndecan-1 (Sdc-1) is a cell surface heparan sulfate proteoglycan that displays the capacity to modulate inflammatory processes within the vascular wall. In the current investigation, the role of Sdc-1 in AAA formation was examined using 2 models of experimental aneurysm induction, angiotensin II infusion and elastase perfusion. Sdc-1 deficiency exacerbated AAA formation in both experimental models and was associated with increased degradation of elastin, greater protease activity, and enhanced inflammatory cell recruitment into the aortic wall. Bone marrow transplantation studies indicated that deficiency of Sdc-1 in marrow-derived cells significantly contributed to AAA severity. Immunostaining revealed augmented Sdc-1 expression in a subset of AAA localized macrophages. We specifically characterized a higher percentage of CD4(+) T cells in Sdc-1-deficient AAA, and antibody depletion studies established the active role of T cells in aneurysmal dilatation. Finally, we confirmed the ability of Sdc-1 macrophage to modulate the inflammatory chemokine environment. These investigations identify cross-talk between Sdc-1-expressing macrophages and AAA-localized CD4(+) T cells, with Sdc-1 providing an important counterbalance to T-cell-driven inflammation in the vascular wall.

  9. CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice.

    Science.gov (United States)

    Bernard-Valnet, Raphaël; Yshii, Lidia; Quériault, Clémence; Nguyen, Xuan-Hung; Arthaud, Sébastien; Rodrigues, Magda; Canivet, Astrid; Morel, Anne-Laure; Matthys, Arthur; Bauer, Jan; Pignolet, Béatrice; Dauvilliers, Yves; Peyron, Christelle; Liblau, Roland S

    2016-09-27

    Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin(+) neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a "neo-self-antigen" specifically in hypothalamic orexin(+) neurons (called Orex-HA), which were transferred with effector neo-self-antigen-specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin(+) neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin(+) neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin(+) neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy.

  10. Maternal IL-6 can cause T-cell-mediated juvenile alopecia by non-scarring follicular dystrophy in mice.

    Science.gov (United States)

    Smith, Stephen E P; Maus, Rachel L G; Davis, Tessa R; Sundberg, John P; Gil, Diana; Schrum, Adam G

    2016-03-01

    Aiming to decipher immunological mechanisms of the autoimmune disorder alopecia areata (AA), we hypothesized that interleukin-6 (IL-6) might be associated with juvenile-onset AA, for which there is currently no experimental model. Upon intramuscular transgenesis to overexpress IL-6 in pregnant female C57BL/6 (B6) mice, we found that the offspring displayed an initial normal and complete juvenile hair growth cycle, but developed alopecia around postnatal day 18. This alopecia was patchy and reversible (non-scarring) and was associated with upregulation of Ulbp1 expression, the only mouse homolog of the human AA-associated ULBP3 gene. Alopecia was also associated with inflammatory infiltration of hair follicles by lymphocytes, including alpha-beta T cells, which contributed to surface hair loss. Despite these apparently shared traits with AA, lesions were dominated by follicular dystrophy that was atypical of human AA disease, sharing some traits consistent with B6 alopecia and dermatitis. Additionally, juvenile-onset alopecia was followed by complete, spontaneous recovery of surface hair, without recurrence of hair loss. Prolonging exposure to IL-6 prolonged the time to recovery, but once recovered, repeating high-dose IL-6 exposure de novo did not re-induce alopecia. These data suggest that although substantial molecular and cellular pathways may be shared, functionally similar alopecia disorders can occur via distinct pathological mechanisms. © 2015 The Authors. Experimental Dermatology Published by John Wiley & Sons Ltd.

  11. IFN-Gamma-Dependent and Independent Mechanisms of CD4+ Memory T Cell-Mediated Protection from Listeria Infection

    Science.gov (United States)

    Meek, Stephanie M.; Williams, Matthew A.

    2018-01-01

    While CD8+ memory T cells can promote long-lived protection from secondary exposure to intracellular pathogens, less is known regarding the direct protective mechanisms of CD4+ T cells. We utilized a prime/boost model in which mice are initially exposed to an acutely infecting strain of lymphocytic choriomeningitis virus (LCMV), followed by a heterologous rechallenge with Listeria monocytogenes recombinantly expressing the MHC Class II-restricted LCMV epitope, GP61–80 (Lm-gp61). We found that heterologous Lm-gp61 rechallenge resulted in robust activation of CD4+ memory T cells and that they were required for rapid bacterial clearance. We further assessed the relative roles of TNF and IFNγ in the direct anti-bacterial function of CD4+ memory T cells. We found that disruption of TNF resulted in a complete loss of protection mediated by CD4+ memory T cells, whereas disruption of IFNγ signaling to macrophages results in only a partial loss of protection. The protective effect mediated by CD4+ T cells corresponded to the rapid accumulation of pro-inflammatory macrophages in the spleen and an altered inflammatory environment in vivo. Overall, we conclude that protection mediated by CD4+ memory T cells from heterologous Listeria challenge is most directly dependent on TNF, whereas IFNγ only plays a minor role. PMID:29438281

  12. GILT: Shaping the MHC Class II-Restricted Peptidome and CD4(+) T Cell-Mediated Immunity.

    Science.gov (United States)

    Hastings, Karen Taraszka

    2013-12-04

    The MHC class II-restricted antigen processing pathway generates peptide:MHC complexes in the endocytic pathway for the activation of CD4(+) T cells. Gamma-interferon-inducible lysosomal thiol reductase (GILT) reduces protein disulfide bonds in the endocytic compartment, thereby exposing buried epitopes for MHC class II binding and presentation. T cell hybridoma responses and elution of MHC class II bound peptides have identified GILT-dependent epitopes, GILT-independent epitopes, and epitopes that are more efficiently presented in the absence of GILT termed GILT-prevented epitopes. GILT-mediated alteration in the MHC class II-restricted peptidome modulates T cell development in the thymus and peripheral tolerance and influences the pathogenesis of autoimmunity. Recent studies suggest an emerging role for GILT in the response to pathogens and cancer survival.

  13. Secondary B cell receptor diversification is necessary for T cell mediated neuro-inflammation during experimental autoimmune encephalomyelitis.

    Directory of Open Access Journals (Sweden)

    Georgina Galicia

    Full Text Available Clinical studies of B cell depletion in Multiple Sclerosis (MS have revealed that B Lymphocytes are involved in the neuro-inflammatory process, yet it remains unclear how B cells can exert pro- and anti-inflammatory functions during MS. Experimental Autoimmune Encephalomyelitis (EAE is an animal model of MS whereby myelin-specific T cells become activated and subsequently migrate to the Central Nervous System (CNS where they perform pro-inflammatory functions such as cytokine secretion. Typically EAE is induced by immunization of mice of a susceptible genetic background with peptide antigen emulsified in Complete Freund's Adjuvant. However, novel roles for B-lymphocytes in EAE may also be explored by immunization with full-length myelin oligodendrocyte glycoprotein (MOG that contains the B cell conformational epitope. Here we show that full length MOG immunization promotes a chronic disease in mice that depends on antigen-driven secondary diversification of the B cell receptor.Activation-Induced Deaminase (AID is an enzyme that is essential for antigen-driven secondary diversification of the B cell receptor. We immunized AID(-/- mice with the extracellular domain (amino acids 1-120 of recombinant human MOG protein (rhMOG and examined the incidence and severity of disease in AID(-/- versus wild type mice. Corresponding with these clinical measurements, we also evaluated parameters of T cell activation in the periphery and the CNS as well as the generation of anti-MOG antibodies (Ab.AID(-/- mice exhibit reduced severity and incidence of EAE. This suggests that the secondary diversification of the B cell receptor is required for B cells to exert their full encephalogenic potential during rhMOG-induced EAE, and possibly also during MS.

  14. T Cell-Mediated Beta Cell Destruction: Autoimmunity and Alloimmunity in the Context of Type 1 Diabetes

    Directory of Open Access Journals (Sweden)

    Adam L. Burrack

    2017-12-01

    Full Text Available Type 1 diabetes (T1D results from destruction of pancreatic beta cells by T cells of the immune system. Despite improvements in insulin analogs and continuous blood glucose level monitoring, there is no cure for T1D, and some individuals develop life-threatening complications. Pancreas and islet transplantation have been attractive therapeutic approaches; however, transplants containing insulin-producing cells are vulnerable to both recurrent autoimmunity and conventional allograft rejection. Current immune suppression treatments subdue the immune system, but not without complications. Ideally a successful approach would target only the destructive immune cells and leave the remaining immune system intact to fight foreign pathogens. This review discusses the autoimmune diabetes disease process, diabetic complications that warrant a transplant, and alloimmunity. First, we describe the current understanding of autoimmune destruction of beta cells including the roles of CD4 and CD8 T cells and several possibilities for antigen-specific tolerance induction. Second, we outline diabetic complications necessitating beta cell replacement. Third, we discuss transplant recognition, potential sources for beta cell replacement, and tolerance-promoting therapies under development. We hypothesize that a better understanding of autoreactive T cell targets during disease pathogenesis and alloimmunity following transplant destruction could enhance attempts to re-establish tolerance to beta cells.

  15. Differentiation between Acute Skin Rejection in Allotransplantation and T-Cell Mediated Skin Inflammation Based on Gene Expression Analysis

    Directory of Open Access Journals (Sweden)

    Dolores Wolfram

    2015-01-01

    Full Text Available Advances in microsurgical techniques and immunosuppressive medication have rendered transplantation of vascularized composite allografts possible, when autologous tissue is neither available nor sufficient for reconstruction. However, skin rejection and side effects of long-term immunosuppression still remain a major hurdle for wide adoption of this excellent reconstructive technique. Histopathologic changes during acute skin rejection in vascular composite allotransplantation often mimic inflammatory skin disorders and are hard to distinguish. Hence, the identification of diagnostic and therapeutic markers specific for skin rejection is of particular clinical need. Here we present novel markers allowing for early differentiation between rejection in hind limb allotransplantation and contact hypersensitivity. Assessment of Ccl7, Il18, and Il1b expression is most indicative of distinguishing skin rejection from skin inflammatory disorders. Gene expression levels varied significantly across skin types and regions, indicating localization specific mechanism of leukocyte migration and infiltration. Expression of Il12b, Il17a, and Il1b gene expression levels differed significantly between rejection and inflammation, independent of the skin type. In synopsis of the RNA expression profile and previously assessed protein expression, the Il1 family appears as a promising option for accurate skin rejection diagnosis and, as a following step, for development of novel rejection treatments.

  16. T Cell-Mediated Chronic Inflammatory Diseases Are Candidates for Therapeutic Tolerance Induction with Heat Shock Proteins

    Directory of Open Access Journals (Sweden)

    Ariana Barbera Betancourt

    2017-10-01

    Full Text Available Failing immunological tolerance for critical self-antigens is the problem underlying most chronic inflammatory diseases of humans. Despite the success of novel immunosuppressive biological drugs, the so-called biologics, in the treatment of diseases such rheumatoid arthritis (RA and type 1 diabetes, none of these approaches does lead to a permanent state of medicine free disease remission. Therefore, there is a need for therapies that restore physiological mechanisms of self-tolerance. Heat shock proteins (HSPs have shown disease suppressive activities in many models of experimental autoimmune diseases through the induction of regulatory T cells (Tregs. Also in first clinical trials with HSP-based peptides in RA and diabetes, the induction of Tregs was noted. Due to their exceptionally high degree of evolutionary conservation, HSP protein sequences (peptides are shared between the microbiota-associated bacterial species and the self-HSP in the tissues. Therefore, Treg mechanisms, such as those induced and maintained by gut mucosal tolerance for the microbiota, can play a role by targeting the more conserved HSP peptide sequences in the inflamed tissues. In addition, the stress upregulated presence of HSP in these tissues may well assist the targeting of the HSP induced Treg specifically to the sites of inflammation.

  17. A Two-Step Model of Acute CD4 T-Cell Mediated Cardiac Allograft Rejection1

    OpenAIRE

    Grazia, Todd J.; Pietra, Biagio A.; Johnson, Zachary A.; Kelly, Brian P.; Plenter, Robert J.; Gill, Ronald G.

    2004-01-01

    CD4 T cells are both necessary and sufficient to mediate acute cardiac allograft rejection in mice. This process requires “direct” engagement of donor MHC class II molecules. That is, acute rejection by CD4+ T cells requires target MHC class II expression by the donor and not by the host. However, it is unclear whether CD4+ T cell rejection requires MHC class II expression on donor hemopoietic cells, nonhemopoietic cells, or both. To address this issue, bone marrow transplantation in mice was...

  18. CD8+ T cells mediate the regenerative PTH effect in hPDL cells via Wnt10b signaling.

    Science.gov (United States)

    Wolf, Michael; Lossdörfer, Stefan; Marciniak, Jana; Römer, Piero; Kirschneck, Christian; Craveiro, Rogerio; Deschner, James; Jäger, Andreas

    2016-11-01

    It was the aim of the present investigation to examine whether the stimulating effect of parathyroid hormone (PTH) on human periodontal ligament (hPDL) cell proliferation and differentiation would be enhanced by hPDL/T-cell interaction involving Wnt10b signaling as a mediating pathway. hPDL cells were cultured from healthy premolar tissues of three adolescent orthodontic patients and exposed to PTH(1-34) in monocultures or co-cultures with CD8 + T cells. At harvest, proliferation, alkaline phosphatase-specific activity (ALP), and osteocalcin production were determined by immunofluorescence cytochemistry, real-time PCR, biochemical assay, and ELISA. Wnt10b signaling was analyzed by the use of a specific WNT10b neutralizing antibody. PTH(1-34) stimulation of T cells significantly increased Wnt10b expression and production. Wnt10b exposure of hPDL cells enhanced proliferation and differentiation. PDL cells co-cultured with T cells showed a Wnt10b-dependent regulation of proliferation and differentiation parameters. The addition of a Wnt10b-neutralizing Ab to the co-culture medium resulted in a significant inhibition of the PTH(1-34) effect on proliferation, ALP-specific activity, and osteocalcin protein expression. Our findings provide novel insight into the mechanism of action of PTH on hPDL cells and establish the interplay of T cells and hPDL cells via the Wnt10b pathway as a modulating factor for the anabolic properties of the hormone in periodontal regeneration.

  19. CD8+ T cells mediate the regenerative PTH effect in hPDL cells via Wnt10b signaling

    OpenAIRE

    Römer, Piero; Kirschneck, Christian

    2016-01-01

    It was the aim of the present investigation to examine whether the stimulating effect of parathyroid hormone (PTH) on human periodontal ligament (hPDL) cell proliferation and differentiation would be enhanced by hPDL/T-cell interaction involving Wnt10b signaling as a mediating pathway. hPDL cells were cultured from healthy premolar tissues of three adolescent orthodontic patients and exposed to PTH(1-34) in monocultures or co-cultures with CD8+ T cells. At harvest, proliferation, alkaline pho...

  20. CD20-Specific Immunoligands Engaging NKG2D Enhance γδ T Cell-Mediated Lysis of Lymphoma Cells

    DEFF Research Database (Denmark)

    Peipp, M.; Wesch, D.; Oberg, H. H.

    2017-01-01

    Human γδ T cells are innate-like T cells which are able to kill a broad range of tumour cells and thus may have potential for cancer immunotherapy. The activating receptor natural killer group 2 member D (NKG2D) plays a key role in regulating immune responses driven by γδ T cells. Here, we explor...

  1. Only a subset of phosphoantigen-responsive gamma9delta2 T cells mediate protective tuberculosis immunity.

    Science.gov (United States)

    Spencer, Charles T; Abate, Getahun; Blazevic, Azra; Hoft, Daniel F

    2008-10-01

    Mycobacterium tuberculosis and Mycobacterium bovis bacillus Calmette-Guérin (BCG) induce potent expansions of human memory Vgamma(9)(+)Vdelta(2)(+) T cells capable of IFN-gamma production, cytolytic activity, and mycobacterial growth inhibition. Certain phosphoantigens expressed by mycobacteria can stimulate gamma(9)delta(2) T cell expansions, suggesting that purified or synthetic forms of these phosphoantigens may be useful alone or as components of new vaccines or immunotherapeutics. However, we show that while mycobacteria-activated gamma(9)delta(2) T cells potently inhibit intracellular mycobacterial growth, phosphoantigen-activated gamma(9)delta(2) T cells fail to inhibit mycobacteria, although both develop similar effector cytokine and cytolytic functional capacities. gamma(9)delta(2) T cells receiving TLR-mediated costimulation during phosphoantigen activation also failed to inhibit mycobacterial growth. We hypothesized that mycobacteria express Ags, other than the previously identified phosphoantigens, that induce protective subsets of gamma(9)delta(2) T cells. Testing this hypothesis, we compared the TCR sequence diversity of gamma(9)delta(2) T cells expanded with BCG-infected vs phosphoantigen-treated dendritic cells. BCG-stimulated gamma(9)delta(2) T cells displayed a more restricted TCR diversity than phosphoantigen-activated gamma(9)delta(2) T cells. In addition, only a subset of phosphoantigen-activated gamma(9)delta(2) T cells functionally responded to mycobacteria-infected dendritic cells. Furthermore, differential inhibitory functions of BCG- and phosphoantigen-activated gamma(9)delta(2) T cells were confirmed at the clonal level and were not due to differences in TCR avidity. Our results demonstrate that BCG infection can activate and expand protective subsets of phosphoantigen-responsive gamma(9)delta(2) T cells, and provide the first indication that gamma(9)delta(2) T cells can develop pathogen specificity similar to alphabeta T cells. Specific targeting of protective gamma(9)delta(2) T cell subsets will be important for future tuberculosis vaccines.

  2. IFN-Gamma-Dependent and Independent Mechanisms of CD4+ Memory T Cell-Mediated Protection from Listeria Infection

    Directory of Open Access Journals (Sweden)

    Stephanie M. Meek

    2018-02-01

    Full Text Available While CD8+ memory T cells can promote long-lived protection from secondary exposure to intracellular pathogens, less is known regarding the direct protective mechanisms of CD4+ T cells. We utilized a prime/boost model in which mice are initially exposed to an acutely infecting strain of lymphocytic choriomeningitis virus (LCMV, followed by a heterologous rechallenge with Listeria monocytogenes recombinantly expressing the MHC Class II-restricted LCMV epitope, GP61–80 (Lm-gp61. We found that heterologous Lm-gp61 rechallenge resulted in robust activation of CD4+ memory T cells and that they were required for rapid bacterial clearance. We further assessed the relative roles of TNF and IFNγ in the direct anti-bacterial function of CD4+ memory T cells. We found that disruption of TNF resulted in a complete loss of protection mediated by CD4+ memory T cells, whereas disruption of IFNγ signaling to macrophages results in only a partial loss of protection. The protective effect mediated by CD4+ T cells corresponded to the rapid accumulation of pro-inflammatory macrophages in the spleen and an altered inflammatory environment in vivo. Overall, we conclude that protection mediated by CD4+ memory T cells from heterologous Listeria challenge is most directly dependent on TNF, whereas IFNγ only plays a minor role.

  3. Combined local and systemic immunization is essential for durable T-cell mediated heterosubtypic immunity against influenza A virus

    DEFF Research Database (Denmark)

    Uddbäck, Ida Elin Maria; Pedersen, Line M I; Pedersen, Sara R

    2016-01-01

    nucleoprotein have previously been found to induce short-term protection in mice. In this study we confirm that systemic (subcutaneous (s.c.) immunization rapidly induced heterosubtypic protection predominantly mediated by CD8 T cells, but within three months clinical protection completely disappeared. Local...... (intranasal (i.n.)) immunization elicited delayed, but more lasting protection despite relatively inefficient immunization. However, by far, the most robust protection was induced by simultaneous, combined (i.n. + s.c.) vaccination, and, notably, in this case clinical protection lasted at least 8 months...... positioned in the lungs prior to challenge, but at the same time underscores an important back-up role for circulating antigen-specific cells with the capacity to expand and infiltrate the infected lungs....

  4. MHC ligand generation in T cell-mediated immunity and MHC multimer technologies for T cell detection

    NARCIS (Netherlands)

    Bakker, Arnold Hendrik

    2009-01-01

    This thesis focuses on the generation of MHC ligands and their use in analyzing T cell immunity, both in mouse and men. It is roughly split into two sections: the first part deals specifically with the rules governing the generation of MHC ligands, while the second part describes technological

  5. T cell-mediated cytotoxicity against p53-protein derived peptides in bulk and limiting dilution cultures of healthy donors

    DEFF Research Database (Denmark)

    Röpke, M; Regner, M; Claesson, M H

    1995-01-01

    -I restricted epitopes for T cell recognition and p53-derived peptides have been suggested as targets for tumour-specific cytotoxic T lymphocytes (CTL). Our primary aim was to estimate the frequencies of p53-peptide reactive CTL precursors (CTLp) in peripheral blood from healthy young individuals. We selected...

  6. Smarter vaccine design will circumvent regulatory T cell-mediated evasion in chronic HIV and HCV infection

    Directory of Open Access Journals (Sweden)

    Anne Searls De Groot

    2014-10-01

    Full Text Available Despite years of research, vaccines against HIV and HCV are not yet available, due largely to effective viral immunoevasive mechanisms. A novel escape mechanism observed in viruses that cause chronic infection is suppression of viral-specific effector CD4+ and CD8+ T cells by stimulating regulatory T cells (Tregs educated on host sequences during tolerance induction. Viral class II MHC epitopes that share a TCR-face with host epitopes may activate Tregs capable of suppressing protective responses. We designed an immunoinformatic algorithm, JanusMatrix, to identify such epitopes and discovered that among human-host viruses, chronic viruses appear more human-like than viruses that cause acute infection. Furthermore, an HCV epitope that activates Tregs in chronically infected patients, but not clearers, shares a TCR-face with numerous human sequences. To boost weak CD4+ T cell responses associated with persistent infection, vaccines for HIV and HCV must circumvent potential Treg activation that can handicap efficacy. Epitope-driven approaches to vaccine design that involve careful consideration of the T cell subsets primed during immunization will advance HIV and HCV vaccine development.

  7. Mediastinal tumors

    International Nuclear Information System (INIS)

    Canizares, Claudio; Araujo, Ivan; Rodriguez, Amparo; Robles, Wilson; Simba, Catalina

    2005-01-01

    In our practice the mediastinal tumors are infrequent. The mediastinum is the portion of the thoracic cavity that contains numerous organs and structures which makes a crossroad for the diagnostic process. Within which congenital cysts, inflammatory and benign tumors, malignant neoplasms may develop. In the superior compartment are found: thymoma and thymic cysts, germ cell tumors, thyroid lesions, parathyroid adenomas, malignant lymphomas, paragangliomas, hemangiomas, lipomas, and inflammatory lesions such as fibrosing mediastinitis. In the middle portion: pericardial cysts, bronchial cysts, malignant lymphomas. In the posterior region: neurogenic tumors such as Shawnomas, neurofibromas, ganglioneuroblastomas, neuroblastomas, paragangliomas, and gastro enteric cysts. We describe two cases. One of a female patient with a prominent tumor in the anterior compartment of the mediastinum, detected by the x-ray films. Initially a cardiac lesion was excluded by echographic, angiographic studies. The biopsy exhibited a prominent fibrosis that suggested fibrosing mediastinitis (sclerosing). Whoever the immunohistochemical phenotype was positive for lambda chains, determining the diagnosis of lymphoma. The other case is of a young male with a thymoma associated to a pure red cell aplasia, which was the initial clinical symptom. Computerized tomography and thyroid scintigraphy was used. (The author)

  8. Imaging of brain tumors

    International Nuclear Information System (INIS)

    Gaensler, E.H.L.

    1995-01-01

    The contents are diagnostic approaches, general features of tumors -hydrocephalus, edema, attenuation and/or intensity value, hemorrhage, fat, contrast enhancement, intra-axial supratentorial tumors - tumors of glial origin, oligodendrogliomas, ependymomas, subependymomas, subependymal giant cell astrocytomas, choroid plexus papilloma; midline tumors - colloid cysts, craniopharyngiomas; pineal region tumors and miscellaneous tumors i.e. primary intracerebral lymphoma, primitive neuroectodermal tumors, hemangioblastomas; extraaxial tumors - meningiomas; nerve sheath tumors -schwannomas, epidermoids, dermoids, lipomas, arachnoid cysts; metastatic tumors (8 refs.)

  9. Radiation response and cure rate of human colon adenocarcinoma spheroids of different size: the significance of hypoxia on tumor control modelling.

    Science.gov (United States)

    Buffa, F M; West, C; Byrne, K; Moore, J V; Nahum, A E

    2001-03-15

    To evaluate the adequacy of a Poisson tumor control probability (tcp) model and the impact of hypoxia on tumor cure. A human colon adenocarcinoma cell line, WiDr, was grown as multicellular spheroids of different diameters. Measurements were made of cell survival and spheroid cure following 300-kV X-ray external beam irradiation in air and nitrogen. Cell survival data were fitted using a two-compartment and an oxygen diffusion model. Spheroid cure data were fitted using the tcp model. Hypoxia was seen only for spheroids greater than 500 microm in diameter. For small spheroids tcp estimates of radiosensitivity and clonogenic number showed excellent agreement with experimentally derived values. For large spheroids, although tcp estimates of radiosensitivity were comparable with measurements, estimates of the clonogenic number were considerably lower than the experimental count. Reoxygenation of large spheroids before irradiation resulted in the tcp estimates of the number of clonogenic cells agreeing with measured values. When hypoxia was absent, the tcp model accurately predicted cure from measured radiosensitivity and clonogen number. When hypoxia was present, the number of cells capable of regrowth in situ was considerably lower than the number of clonogenic cells that initially survived irradiation. As this counteracted the decreased radiosensitivity, hypoxia was less important for cure than predicted from cell survival assays. This finding suggests that chronic hypoxia may not limit directly the success of radiation therapy.

  10. The role of primary tumor resection in colorectal cancer patients with asymptomatic, synchronous unresectable metastasis: Study protocol for a randomized controlled trial.

    Science.gov (United States)

    Kim, Chang Woo; Baek, Jeong-Heum; Choi, Gyu-Seog; Yu, Chang Sik; Kang, Sung Bum; Park, Won Cheol; Lee, Bong Hwa; Kim, Hyeong Rok; Oh, Jae Hwan; Kim, Jae-Hwang; Jeong, Seung-Yong; Ahn, Jung Bae; Baik, Seung Hyuk

    2016-01-19

    Approximately 20 % of all patients with colorectal cancer are diagnosed as having Stage IV cancer; 80 % of these present with unresectable metastatic lesions. It is controversial whether chemotherapy with or without primary tumor resection (PTR) is effective for the treatment of patients with colorectal cancer with unresectable metastasis. Primary tumor resection could prevent tumor-related complications such as intestinal obstruction, perforation, bleeding, or fistula. Moreover, it may be associated with an increase in overall survival. However, surgery delays the use of systemic chemotherapy and affects the systemic spread of malignancy. Patients with colon and upper rectal cancer patients with asymptomatic, synchronous, unresectable metastasis will be included after screening. They will be randomized and assigned to receive chemotherapy with or without PTR. The primary endpoint measure is 2-year overall survival rate and the secondary endpoint measures are primary tumor-related complications, quality of life, surgery-related morbidity and mortality, interventions with curative intent, chemotherapy-related toxicity, and total cost until death or study closing day. The authors hypothesize that the group receiving PTR following chemotherapy would show a 10 % improvement in 2-year overall survival, compared with the group receiving chemotherapy alone. The accrual period is 3 years and the follow-up period is 2 years. Based on the inequality design, a two-sided log-rank test with α-error of 0.05 and a power of 80 % was conducted. Allowing for a drop-out rate of 10 %, 480 patients (240 per group) will need to be recruited. Patients will be followed up at every 3 months for 3 years and then every 6 months for 2 years after the last patient has been randomized. This randomized controlled trial aims to investigate whether PTR with chemotherapy shows better overall survival than chemotherapy alone for patients with asymptomatic, synchronous unresectable

  11. 4π Noncoplanar Stereotactic Body Radiation Therapy for Head-and-Neck Cancer: Potential to Improve Tumor Control and Late Toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Rwigema, Jean-Claude M.; Nguyen, Dan [Department of Radiation Oncology, University of California Los Angeles, Los Angeles, California (United States); Heron, Dwight E. [Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (United States); Chen, Allen M.; Lee, Percy; Wang, Pin-Chieh [Department of Radiation Oncology, University of California Los Angeles, Los Angeles, California (United States); Vargo, John A. [Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (United States); Low, Daniel A. [Department of Radiation Oncology, University of California Los Angeles, Los Angeles, California (United States); Huq, M. Saiful [Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (United States); Tenn, Stephen; Steinberg, Michael L.; Kupelian, Patrick [Department of Radiation Oncology, University of California Los Angeles, Los Angeles, California (United States); Sheng, Ke, E-mail: ksheng@mednet.ucla.edu [Department of Radiation Oncology, University of California Los Angeles, Los Angeles, California (United States)

    2015-02-01

    Purpose: To evaluate the potential benefit of 4π radiation therapy in recurrent, locally advanced, or metastatic head-and-neck cancer treated with stereotactic body radiation therapy (SBRT). Methods and Materials: Twenty-seven patients with 29 tumors who were treated using SBRT were included. In recurrent disease (n=26), SBRT was delivered with a median 44 Gy (range, 35-44 Gy) in 5 fractions. Three patients with sinonasal mucosal melanoma, metastatic breast cancer, and primary undifferentiated carcinoma received 35 Gy, 22.5 Gy, and 40 Gy in 5 fractions, respectively. Novel 4π treatment plans were created for each patient to meet the objective that 95% of the planning target volume was covered by 100% of the prescription dose. Doses to organs at risk (OARs) and 50% dose spillage volumes were compared against the delivered clinical SBRT plans. Local control (LC), late toxicity, tumor control probability (TCP), and normal tissue complication probability were determined. Results: Using 4π plans, mean/maximum doses to all OARs were reduced by 22% to 89%/10% to 86%. With 4π plans, the 50% dose spillage volume was decreased by 33%. Planning target volume prescription dose escalation by 10 Gy and 20 Gy were achieved while keeping doses to OARs significantly improved or unchanged from clinical plans, except for the carotid artery maximum dose at 20-Gy escalation. At a median follow-up of 10 months (range, 1-41 months), crude LC was 52%. The 2-year LC of 39.2% approximated the predicted mean TCP of 42.2%, which increased to 45.9% with 4π plans. For 10-Gy and 20-Gy dose escalation, 4π plans increased TCP from 80.1% and 88.1% to 85.5% and 91.4%, respectively. The 7.4% rate of grade ≥3 late toxicity was comparable to the predicted 5.6% mean normal tissue complication probability for OARs, which was significantly reduced by 4π planning at the prescribed and escalated doses. Conclusions: 4π plans may allow dose escalation with significant and consistent

  12. Does Wrist Arthrodesis With Structural Iliac Crest Bone Graft After Wide Resection of Distal Radius Giant Cell Tumor Result in Satisfactory Function and Local Control?

    Science.gov (United States)

    Wang, Tao; Chan, Chung Ming; Yu, Feng; Li, Yuan; Niu, Xiaohui

    2017-03-01

    Many techniques have been described for reconstruction after distal radius resection for giant cell tumor with none being clearly superior. The favored technique at our institution is total wrist fusion with autogenous nonvascularized structural iliac crest bone graft because it is structurally robust, avoids the complications associated with obtaining autologous fibula graft, and is useful in areas where bone banks are not available. However, the success of arthrodesis and the functional outcomes with this approach, to our knowledge, have only been limitedly reported. (1) What is the success of union of these grafts and how long does it take? (2) How effective is the technique in achieving tumor control? (3) What complications occur with this type of arthrodesis? (4) What are the functional results of wrist arthrodesis by this technique for treating giant cell tumor of the distal radius? Between 2005 and 2013, 48 patients were treated for biopsy-confirmed Campanacci Grade III giant cell tumor of the distal radius. Of those, 39 (81% [39 of 48]) were treated with wrist arthrodesis using autogenous nonvascularized iliac crest bone graft. Of those, 27 (69% [27 of 39]) were available for followup at a minimum of 24 months (mean, 45 months; range, 24-103 months). During that period, the general indications for this approach were Campanacci Grade III and estimated resection length of 8 cm or less. Followup included clinical and radiographic assessment and functional assessment using the Disabilities of the Arm, Shoulder and Hand (DASH) score, the Musculoskeletal Tumor Society (MSTS) score, grip strength, and range of motion at every followup by the treating surgeon and his team. All functional results were from the latest followup of each patient. Union of the distal junction occurred at a mean of 4 months (± 2 months) and union of the proximal junction occurred at a mean of 9 months (± 5 months). Accounting for competing events, at 12 months, the rate of proximal

  13. Tumor markers: applications and recommendations. New IZOTOPE products

    International Nuclear Information System (INIS)

    Gyenes, Ana Rosa

    2016-01-01

    At work aspects are discussed: Tumor markers; New products IZOTOP; Measuring principle of IRMA kits for tumor markers; Guidelines and Recommendations for the use of tumor markers. pre-analytical, post-analytical and Quality control recommendations are given

  14. Captopril improves tumor nanomedicine delivery by increasing tumor blood perfusion and enlarging endothelial gaps in tumor blood vessels.

    Science.gov (United States)

    Zhang, Bo; Jiang, Ting; Tuo, Yanyan; Jin, Kai; Luo, Zimiao; Shi, Wei; Mei, Heng; Hu, Yu; Pang, Zhiqing; Jiang, Xinguo

    2017-12-01

    Poor tumor perfusion and unfavorable vessel permeability compromise nanomedicine drug delivery to tumors. Captopril dilates blood vessels, reducing blood pressure clinically and bradykinin, as the downstream signaling moiety of captopril, is capable of dilating blood vessels and effectively increasing vessel permeability. The hypothesis behind this study was that captopril can dilate tumor blood vessels, improving tumor perfusion and simultaneously enlarge the endothelial gaps of tumor vessels, therefore enhancing nanomedicine drug delivery for tumor therapy. Using the U87 tumor xenograft with abundant blood vessels as the tumor model, tumor perfusion experiments were carried out using laser Doppler imaging and lectin-labeling experiments. A single treatment of captopril at a dose of 100 mg/kg significantly increased the percentage of functional vessels in tumor tissues and improved tumor blood perfusion. Scanning electron microscopy of tumor vessels also indicated that the endothelial gaps of tumor vessels were enlarged after captopril treatment. Immunofluorescence-staining of tumor slices demonstrated that captopril significantly increased bradykinin expression, possibly explaining tumor perfusion improvements and endothelial gap enlargement. Additionally, imaging in vivo, imaging ex vivo and nanoparticle distribution in tumor slices indicated that after a single treatment with captopril, the accumulation of 115-nm nanoparticles in tumors had increased 2.81-fold with a more homogeneous distribution pattern in comparison to non-captopril treated controls. Finally, pharmacodynamics experiments demonstrated that captopril combined with paclitaxel-loaded nanoparticles resulted in the greatest tumor shrinkage and the most extensive necrosis in tumor tissues among all treatment groups. Taken together, the data from the present study suggest a novel strategy for improving tumor perfusion and enlarging blood vessel permeability simultaneously in order to improve

  15. N-Acetylcysteine Supplementation Controls Total Antioxidant Capacity, Creatine Kinase, Lactate, and Tumor Necrotic Factor-Alpha against Oxidative Stress Induced by Graded Exercise in Sedentary Men

    Directory of Open Access Journals (Sweden)

    Donrawee Leelarungrayub

    2011-01-01

    Full Text Available Aim of this study was to evaluate the effects of short-term (7 days N-acetylcysteine (NAC at 1,200 mg daily supplementation on muscle fatigue, maximal oxygen uptake (VO2max, total antioxidant capacity (TAC, lactate, creatine kinase (CK, and tumor necrotic factor-alpha (TNF-α. Twenty-nine sedentary men (13 controls; 16 in the supplement group from a randomized control were included. At before and after supplementation, fatigue index (FI was evaluated in the quadriceps muscle, and performed a graded exercise treadmill test to induce oxidative stress, and as a measure of VO2max. Blood samples were taken before exercise and 20 minutes after it at before and after supplementation, to determine TAC, CK, lactate, and TNF-α levels. Results showed that FI and VO2max increased significantly in the supplement group. After exercise decreased the levels of TAC and increased lactate, CK, and TNF-α of both groups at before supplementation. After supplementation, lactate, CK, and TNF-α levels significantly increased and TAC decreased after exercise in the control group. Whereas the TAC and lactate levels did not change significantly, but CK and TNF-α increased significantly in the supplement group. Therefore, this results showed that NAC improved the muscle fatigue, VO2max, maintained TAC, controlled lactate production, but had no influence on CK and TNF-α.

  16. Pituitary Tumors

    Science.gov (United States)

    ... nursing, or cause a man to lose his sex drive or lower his sperm count. Pituitary tumors often go undiagnosed because their symptoms resemble those of so many other more common diseases. × Definition The pituitary is a small, bean-sized gland ...

  17. Nephrogenic tumors

    International Nuclear Information System (INIS)

    Wiesbauer, P.

    2008-01-01

    Nephroblastomas are the most common malignant renal tumors in childhood. According to the guidelines of the SIOP (Societe Internationale d'Oncologie Pediatrique) and GPOH (Gesellschaft fuer Paediatrische Onkologie und Haematologie) pre-operative chemotherapy can be started without histological confirmation and thus initial imaging studies, in particular ultrasound, play an outstanding role for diagnostic purposes

  18. Long-Term Results of Conformal Radiotherapy for Prostate Cancer: Impact of Dose Escalation on Biochemical Tumor Control and Distant Metastases-Free Survival Outcomes

    International Nuclear Information System (INIS)

    Zelefsky, Michael J.; Yamada, Yoshiya; Fuks, Zvi; Zhang Zhigang; Hunt, Margie; Cahlon, Oren; Park, Jessica; Shippy, Alison

    2008-01-01

    Purpose: To report prostate-specific antigen (PSA) relapse-free survival and distant metastases-free survival (DMFS) outcomes for patients with clinically localized prostate cancer treated with high-dose conformal radiotherapy. Methods and Materials: Between 1988 and 2004, a total of 2,047 patients with clinically localized prostate cancer were treated with three-dimensional conformal radiotherapy or intensity-modulated radiotherapy. Prescribed dose levels ranged from 66-86.4 Gy. Median follow-up was 6.6 years (range, 3-18 years). Results: Although no differences were noted among low-risk patients for the various dose groups, significant improvements were observed with higher doses for patients with intermediate- and high-risk features. In patients with intermediate-risk features, multivariate analysis showed that radiation dose was an important predictor for improved PSA relapse-free survival (p < 0.0001) and improved DMFS (p = 0.04). In patients with high-risk features, multivariate analysis showed that the following variables predict for improved PSA relapse-free survival: dose (p < 0.0001); age (p = 0.0005), and neoadjuvant-concurrent androgen deprivation therapy (ADT; p = 0.01). In this risk group, only higher radiation dose was an important predictor for improved DMFS (p = 0.04). Conclusions: High radiation dose levels were associated with improved biochemical tumor control and decreased risk of distant metastases. For high-risk patients, despite the delivery of high radiation dose levels, the use of ADT conferred an additional benefit for improved tumor control outcomes. We observed a benefit for ADT in high-risk patients who received higher doses

  19. Long-term follow-up of patients with pituitary macroadenomas after postoperative radiation therapy. Analysis of tumor control and functional outcome

    International Nuclear Information System (INIS)

    Langsenlehner, T.; Jakse, G.; Kapp, K.S.; Mayer, R.; Stiegler, C.; Quehenberger, F.; Feigl, G.C.; Mokry, M.; Langsenlehner, U.

    2007-01-01

    Purpose: Evaluation of long-term tumor control, normalization of hormonal hypersecretion, including incidence and time course of pituitary dysfunction following postoperative radiotherapy of pituitary macroadenomas. Patients and Methods: In a retrospective study, the data of 87 patients with pituitary macroadenomas (61 non-secreting adenomas, 26 secreting adenomas) treated between 1984 and 1994 were analyzed. All patients underwent surgery and received postoperative external-beam radiotherapy with a mean dose of 50.4 Gy (range 46-54 Gy). Results: After a follow-up of 15 years the local tumor control rate achieved was 93.0% for non-secreting adenomas and 100% for secreting adenomas, respectively. Normalization of endocrine hypersecretion was noted in 24 of 26 patients (92%). Detailed endocrinological follow-up data were analyzed by an experienced endocrinologist in 77 patients. After a median follow-up of 10.54 years (mean 10.22; range 1.39-20.75 years), in 75 of 77 patients (97%) a hypopituitarism was observed (partial hypopituitarism, n = 28 [36%], panhypopituitarism, n = 47 [61%]), and 68 out of 77 patients (88%) showed evidence of radiotherapy-induced pituitary disorders. The somatotropic function was most commonly affected, followed by gonadal, thyroid and adrenal function. The gonadal axis showed to be the first to be disturbed. 67 patients (87%) required a hormone replacement therapy. Conclusion: Radiotherapy after pituitary surgery is highly effective in reducing hormonal hypersecretion and preventing recurrences of pituitary adenomas. However, pituitary insufficiencies are commonly observed after radiotherapy requiring a close follow-up to ensure timely diagnosis of pituitary dysfunction and an early inception of hormone replacement therapy. (orig.)

  20. Long-term follow-up of patients with pituitary macroadenomas after postoperative radiation therapy. Analysis of tumor control and functional outcome

    Energy Technology Data Exchange (ETDEWEB)

    Langsenlehner, T.; Jakse, G.; Kapp, K.S.; Mayer, R. [Medical Univ. of Graz (Austria). Dept. of Therapeutic Radiology and Oncology; Stiegler, C. [Medical Univ. of Graz (Austria). Div. of Endocrinology and Nuclear Medicine; Quehenberger, F. [Medical Univ. of Graz (Austria). Inst. for Medical Informatics, Statistics and Documentation; Feigl, G.C. [Regensburg Univ. (Germany). Dept. of Neurosurgery; Mokry, M. [Medical Univ. of Graz (Austria). Dept. of Neurosurgery; Langsenlehner, U. [Medical Univ. of Graz (Austria). Div. of Oncology

    2007-05-15

    Purpose: Evaluation of long-term tumor control, normalization of hormonal hypersecretion, including incidence and time course of pituitary dysfunction following postoperative radiotherapy of pituitary macroadenomas. Patients and Methods: In a retrospective study, the data of 87 patients with pituitary macroadenomas (61 non-secreting adenomas, 26 secreting adenomas) treated between 1984 and 1994 were analyzed. All patients underwent surgery and received postoperative external-beam radiotherapy with a mean dose of 50.4 Gy (range 46-54 Gy). Results: After a follow-up of 15 years the local tumor control rate achieved was 93.0% for non-secreting adenomas and 100% for secreting adenomas, respectively. Normalization of endocrine hypersecretion was noted in 24 of 26 patients (92%). Detailed endocrinological follow-up data were analyzed by an experienced endocrinologist in 77 patients. After a median follow-up of 10.54 years (mean 10.22; range 1.39-20.75 years), in 75 of 77 patients (97%) a hypopituitarism was observed (partial hypopituitarism, n = 28 [36%], panhypopituitarism, n = 47 [61%]), and 68 out of 77 patients (88%) showed evidence of radiotherapy-induced pituitary disorders. The somatotropic function was most commonly affected, followed by gonadal, thyroid and adrenal function. The gonadal axis showed to be the first to be disturbed. 67 patients (87%) required a hormone replacement therapy. Conclusion: Radiotherapy after pituitary surgery is highly effective in reducing hormonal hypersecretion and preventing recurrences of pituitary adenomas. However, pituitary insufficiencies are commonly observed after radiotherapy requiring a close follow-up to ensure timely diagnosis of pituitary dysfunction and an early inception of hormone replacement therapy. (orig.)

  1. The allelic distribution of -308 Tumor Necrosis Factor-alpha gene polymorphism in South African women with cervical cancer and control women

    Directory of Open Access Journals (Sweden)

    Williamson Anna-Lise

    2006-01-01

    Full Text Available Abstract Background Cervical cancer is due to infection with specific high-risk types of human papillomavirus (HPV. Although the incidence of genital HPV infection in various population groups is high, most of these regress without intervention. Investigating genetic host factors and cellular immune responses, particularly cytokines, could help to understand the association between genital HPV infection and carcinogenesis. The tumor necrosis factor alpha (TNF-α cytokine plays an important role in all stages of cervical cancer and has the ability to induce the regression of human tumors. Therefore the aim of the study was to investigate the allelic distribution of -308 TNF-α gene polymorphism in South African women with cervical cancer compared to control women. Methods Included in our study were women with histologically proven cancer of the cervix (n = 244 and hospital-based controls (n = 228. All patients and controls were from mixed race and black population groups in South Africa. The detection of a bi-allelic -308 (A/G polymorphism in the promoter region of TNF-α was investigated using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR technique. The distributions of the allelic frequencies were stratified in both patients and controls into two South African ethnic population groups. Results In this study we observed no association between the distribution of -308 TNF-α polymorphism and the risk of developing cervical cancer even after combining the data from the two ethnic populations (X2 = 2.26. In addition, using the chi-squared test we found no significant association between the known risk factors for cervical cancer and the allele distribution of -308 TNF-α. However, the frequency of the rare high-producing allele -308A of TNF-α was significantly lower in the South African population when compared to Caucasians and Chinese population groups. Conclusion We demonstrated no association between -308 TNF

  2. The allelic distribution of -308 Tumor Necrosis Factor-alpha gene polymorphism in South African women with cervical cancer and control women

    International Nuclear Information System (INIS)

    Govan, Vandana A; Constant, Debbie; Hoffman, Margaret; Williamson, Anna-Lise

    2006-01-01

    Cervical cancer is due to infection with specific high-risk types of human papillomavirus (HPV). Although the incidence of genital HPV infection in various population groups is high, most of these regress without intervention. Investigating genetic host factors and cellular immune responses, particularly cytokines, could help to understand the association between genital HPV infection and carcinogenesis. The tumor necrosis factor alpha (TNF-α) cytokine plays an important role in all stages of cervical cancer and has the ability to induce the regression of human tumors. Therefore the aim of the study was to investigate the allelic distribution of -308 TNF-α gene polymorphism in South African women with cervical cancer compared to control women. Included in our study were women with histologically proven cancer of the cervix (n = 244) and hospital-based controls (n = 228). All patients and controls were from mixed race and black population groups in South Africa. The detection of a bi-allelic -308 (A/G) polymorphism in the promoter region of TNF-α was investigated using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique. The distributions of the allelic frequencies were stratified in both patients and controls into two South African ethnic population groups. In this study we observed no association between the distribution of -308 TNF-α polymorphism and the risk of developing cervical cancer even after combining the data from the two ethnic populations (X 2 = 2.26). In addition, using the chi-squared test we found no significant association between the known risk factors for cervical cancer and the allele distribution of -308 TNF-α. However, the frequency of the rare high-producing allele -308A of TNF-α was significantly lower in the South African population when compared to Caucasians and Chinese population groups. We demonstrated no association between -308 TNF-α polymorphism and the risk of cervical cancer among two

  3. Multiparametric classification links tumor microenvironments with tumor cell phenotype.

    Directory of Open Access Journals (Sweden)

    Bojana Gligorijevic

    2014-11-01

    Full Text Available While it has been established that a number of microenvironment components can affect the likelihood of metastasis, the link between microenvironment and tumor cell phenotypes is poorly understood. Here we have examined microenvironment control over two different tumor cell motility phenotypes required for metastasis. By high-resolution multiphoton microscopy of mammary carcinoma in mice, we detected two phenotypes of motile tumor cells, different in locomotion speed. Only slower tumor cells exhibited protrusions with molecular, morphological, and functional characteristics associated with invadopodia. Each region in the primary tumor exhibited either fast- or slow-locomotion. To understand how the tumor microenvironment controls invadopodium formation and tumor cell locomotion, we systematically analyzed components of the microenvironment previously associated with cell invasion and migration. No single microenvironmental property was able to predict the locations of tumor cell phenotypes in the tumor if used in isolation or combined linearly. To solve this, we utilized the support vector machine (SVM algorithm to classify phenotypes in a nonlinear fashion. This approach identified conditions that promoted either motility phenotype. We then demonstrated that varying one of the conditions may change tumor cell behavior only in a context-dependent manner. In addition, to establish the link between phenotypes and cell fates, we photoconverted and monitored the fate of tumor cells in different microenvironments, finding that only tumor cells in the invadopodium-rich microenvironments degraded extracellular matrix (ECM and disseminated. The number of invadopodia positively correlated with degradation, while the inhibiting metalloproteases eliminated degradation and lung metastasis, consistent with a direct link among invadopodia, ECM degradation, and metastasis. We have detected and characterized two phenotypes of motile tumor cells in vivo, which

  4. Cryoablation for pulmonary tumor

    International Nuclear Information System (INIS)

    Kawamura, Masafumi; Izumi, Yotaro; Tsukada, Norimasa; Asakura, Keisuke; Nakatsuka, Seishi; Yashiro, Hideki; Inoue, Masanori; Kuribayashi, Sachio; Kobayashi, Koichi

    2008-01-01

    We have experienced more than 200 sessions for mainly metastatic lung tumor and small number of primary lung cancer since 2002. Cryo-probe is inserted percutaneously with local anesthesia under CT scan guide. Co-axial technique is adopted to prevent from hemorrhage and massive air leakage. The average of hospital stay after treatment is 2.6 days. Although pneumothorax was associated with more than half patients, 5% of them experienced chest tube insertion. Local recurrence 1 year after treatment was found 10% of tumors of 10 mm or less diameter, 30% of 11-20 mm diameter, and 40% of 20-30 mm diameter and 100% of 31 mm or more diameter. In case of large vessels (3 mm or more diameter) running within 4 mm from tumor, recurrence rate was higher compared with the same sized tumors without large vessels running nearby. We are eager for the development of 3D-simulation system considering the distribution of caloric value is strongly requested to improve the local control power of cryoablation for lung tumor. (author)

  5. Experimental pain ratings and reactivity of cortisol and soluble tumor necrosis factor-α receptor II following a trial of hypnosis: Results of a randomized controlled pilot study

    Science.gov (United States)

    Goodin, Burel R.; Quinn, Noel B.; Kronfli, Tarek; King, Christopher D.; Page, Gayle G.; Haythornthwaite, Jennifer A.; Edwards, Robert R.; Stapleton, Laura M.; McGuire, Lynanne

    2011-01-01

    Objective Current evidence supports the efficacy of hypnosis for reducing the pain associated with experimental stimulation and various acute and chronic conditions; however, the mechanisms explaining how hypnosis exerts its effects remain less clear. The hypothalamic-pituitary-adrenal (HPA) axis and pro-inflammatory cytokines represent potential targets for investigation given their purported roles in the perpetuation of painful conditions; yet, no clinical trials have thus far examined the influence of hypnosis on these mechanisms. Design Healthy participants, highly susceptible to the effects of hypnosis, were randomized to either a hypnosis intervention or a no-intervention control. Using a cold pressor task, assessments of pain intensity and pain unpleasantness were collected prior to the intervention (Pre) and following the intervention (Post) along with pain-provoked changes in salivary cortisol and the soluble receptor of tumor necrosis factor-α (sTNFαRII). Results Compared to the no-intervention control, data analyses revealed that hypnosis significantly reduced pain intensity and pain unpleasantness. Hypnosis was not significantly associated with suppression of cortisol or sTNFαRII reactivity to acute pain from Pre to Post; however, the effect sizes for these associations were medium-sized. Conclusions Overall, the findings from this randomized controlled pilot study support the importance of a future large-scale study on the effects of hypnosis for modulating pain-related changes of the HPA axis and pro-inflammatory cytokines. PMID:22233394

  6. Significance of tumor size and radiation dose to local control in stage I-III diffuse large cell lymphoma treated with CHOP-Bleo and radiation

    International Nuclear Information System (INIS)

    Fuller, Lillian M.; Krasin, Matthew J.; Velasquez, William S.; Allen, Pamela K.; McLaughlin, Peter; Rodriguez, M. Alma; Hagemeister, Fredrick B.; Swan, Forrest; Cabanillas, Fernando; Palmer, Judy L.; Cox, James D.

    1995-01-01

    Purpose: The purpose of this study was to evaluate the possible effect of adjunctive involved field (IF) radiotherapy on long-term local control for patients with Ann Arbor Stage I-III diffuse large cell lymphoma (DLCL) who achieved a complete remission on a combined modality program which included cyclophosphamide, doxorubicin, vincristine, prednisone, and Bleomycin (CHOP-Bleo). Methods and Materials: One hundred and ninety patients with Ann Arbor Stage I-III DLCL were treated with CHOP-Bleo and radiotherapy. Analyses were undertaken to determine (a) response to treatment according to stage, extent of maximum local disease, and irradiation dose either < 40 Gy or ≥ 40 Gy and (b) relapse patterns. Results: A complete remission (CR) was achieved in 162 patients. Among patients who achieved a CR, local control was better for those who received tumor doses of ≥ 40 Gy (97%) than for those who received < 40 Gy (83%) (p = 0.002.) Among those with extensive local disease, the corresponding control rates were 88% and 71%, respectively. A study of distant relapse patterns following a CR showed that the first relapse usually involved an extranodal site. Conclusion: Radiotherapy was an effective adjunctive treatment to CHOP-Bleo for patients with stage I-III DLCL who achieved a CR. Patterns of relapse suggested that total nodal irradiation (TNI) possibly could have benefited a small subset of patients

  7. CXCR5+CD8+T cells present elevated capacity in mediating cytotoxicity toward autologous tumor cells through interleukin 10 in diffuse large B-cell lymphoma.

    Science.gov (United States)

    Tang, Jiahong; Zha, Jie; Guo, Xutao; Shi, Pengcheng; Xu, Bing

    2017-09-01

    Diffuse large B-cell lymphoma (DLBCL) is a common and aggressive subtype of non-Hodgkin's lymphomas, with limited treatment options in refractory and relapsed patients. Growing evidence supports the notion that CD8 + T cell immunity could be utilized to eliminate B cell lymphomas. CXCR5 + CD8 + T cell is a novel cell subtype and share CXCR5 expression with CD19 + tumor cells. In this study, we investigated the frequency and function of existing CXCR5 + CD8 + T cells in DLBCL patients. We found that DLBCL patients as a group demonstrated significantly higher level of CXCR5 + CD8 + T cells than healthy individuals, with huge variability in each patient. Using anti-CD3/CD28-stimulated CD8 + T cells as effector (E) cells and autologous CD19 + tumor cells as target (T) cells, at high E:T ratio, no difference between the intensities of CXCR5 + CD8 + T cell- and CXCR5 - CD8 + T cell-mediated cytotoxicity were observed. However, at intermediate and low E:T ratios, the CXCR5 + CD8 + T cells presented stronger cytotoxicity than CXCR5 - CD8 + T cells. The expressions of granzyme A, granzyme B, and perforin were significantly higher in CXCR5 + CD8 + T cells than in CXCR5 - CD8 + T cells, with no significant difference in the level of degranulation. Tumor cells in DLBCL were known to secrete high level of interleukin 10 (IL-10). We therefore blocked the IL-10/IL-10R pathway, and found that the expressions of granzyme A, granzyme B, and perforin by CXCR5 + CD8 + T cells were significantly elevated. Together, these results suggest that CXCR5 + CD8 + T cells are potential candidates of CD8 + T cell-based immunotherapies, could mediate elimination of autologous tumor cells in DLBCL patients, but are also susceptible to IL-10-mediated suppression. Copyright © 2017. Published by Elsevier B.V.

  8. Study Design for a Case Control Investigation of Cellular Telephones and Other Risk Factors for Brain Tumors in Adults

    International Nuclear Information System (INIS)

    Inskip, P.D.; Hatch, E.E.; Stewart, P.A.; Heineman, E.F.; Ziegler, R.G.; Dosemeci, M.; Parry, D.; Rothman, N.; Boice, J.D. Jr.; Wilcosky, T.C.; Watson, D.J.; Shapiro, W.R.; Selker, R.G.; Fine, H.A.; Black, P. McL.; Loeffler, J.S.; Linet, M.S.

    1999-01-01

    The aetiology of brain tumours is poorly understood. Due, in part, to public concern about a postulated relationship between the use of cellular telephones or other increasingly prevalent environmental exposures and the incidence of brain cancer in adults, the National Cancer Institute is collaborating with three US hospitals in a comprehensive case control study of malignant and benign brain tumours. Factors under consideration include use of cellular phones and other wireless communication devices, workplace exposures to chemical agents and electromagnetic fields, dietary factors, family history of tumours, genetic determinants of susceptibility, home appliance use, reproductive history and hormonal exposures, viruses, medical and dental exposure to ionising radiation, and other aspects of medical history. Approximately 800 newly diagnosed brain tumour cases and 800 controls were enrolled at hospitals in Boston, Phoenix and Pittsburgh from 1994 to 1998. Cases include all adults (age ≥ 18 y) newly diagnosed with a histologically confirmed intracranial glioma, histologically confirmed intracranial meningioma or acoustic neuroma. Controls are patients admitted to the same hospitals as the cases, and treated for any of a variety of non-malignant conditions. Key features of the study include its large size, the emphasis on rapid ascertainment of incident cases and interview of study subjects rather than surrogate respondents, the use of detailed, job-specific questions developed by industrial hygienists to ascertain occupational exposures, and the storage of blood samples for future evaluation of inherited susceptibility, biomarkers of exposure and gene environment interactions. (author)

  9. Synergies of Targeting Tumor Angiogenesis and Immune Checkpoints in Non-Small Cell Lung Cancer and Renal Cell Cancer: From Basic Concepts to Clinical Reality.

    Science.gov (United States)

    Pircher, Andreas; Wolf, Dominik; Heidenreich, Axel; Hilbe, Wolfgang; Pichler, Renate; Heidegger, Isabel

    2017-10-31

    In recent years, considerable advances concerning therapeutic strategies in patients with metastatic cancer have been achieved. Particularly in renal cell cancer (RCC) and advanced stage non-small cell lung cancer (NSCLC), immune-activating and antiangiogenic (AA) drugs (i.e., checkpoint antibodies and vascular endothelial growth factor (VEGF)/VEGF receptors (VEGFR) targeting compounds, respectively) have been successfully developed. As immune-effector cells have to enter the tumor, it is tempting to speculate that the combination of immunotherapy with AA treatment may induce synergistic effects. In this short review, we explore the theoretical background and the therapeutic potential of this novel treatment option for patients with advanced RCC or NSCLC. We discuss the growing body of evidence that pro-angiogenic factors negatively modulate the T-cell-mediated immune response and examine the preclinical evidence for testing combined immune-activating and AA therapy concepts in clinical practice. Particular attention will also be paid to potential novel treatment-related adverse events induced by combination treatment.

  10. Randomized controlled trial of a structured training program in breast cancer patients with tumor-related chronic fatigue.

    Science.gov (United States)

    Heim, Manfred E; v d Malsburg, Marie-Luise Elsner; Niklas, Andree

    2007-09-01

    Cancer-related fatigue is the most disabling symptom experienced by breast cancer patients following the cancer treatment. The positive effects of physical activity in the rehabilitation of breast cancer patients are documented in several studies. In a randomized controlled study the effects of a structured physical training program on fatigue and health-related quality of life were evaluated. 63 breast cancer patients with cancer-related chronic fatigue were randomized at the beginning of the inpatient rehabilitation. The control group received the standard complex rehabilitation program, the intervention group a structured physical training program and additional muscle strength and aerobic exercises. The effects of the treatment were evaluated by questionnaires at the start of rehabilitation (t1), end of rehabilitation (t2), and 3 months after t2 (t3). Isometric muscle strength and aerobic capacity were evaluated at t1 and t2. There was an improvement of muscle strength at the end of rehabilitation for both groups. The increase from t1 to t2 was significantly higher for the training group. The scores for global quality of life, physical well-being, and functionality increased from t1 to t2, but further improvement in the follow-up (t3) was only observed in the training group. The cancer-related fatigue was significantly reduced in the training group from t1 to t3, however, not in the control group. Structured physical training programs initiated during inpatient rehabilitation and continuously practiced in the time thereafter can improve symptoms of chronic fatigue and quality of life in breast cancer patients.

  11. Interaction of translationally controlled tumor protein with Apaf-1 is involved in the development of chemoresistance in HeLa cells

    International Nuclear Information System (INIS)

    Jung, Jaehoon; Kim, Hyo Young; Maeng, Jeehye; Kim, Moonhee; Shin, Dong Hae; Lee, Kyunglim

    2014-01-01

    Translationally controlled tumor protein (TCTP), alternatively called fortilin, is believed to be involved in the development of the chemoresistance of tumor cells against anticancer drugs such as etoposide, taxol, and oxaliplatin, the underlying mechanisms of which still remain elusive. Cell death analysis of TCTP-overexpressing HeLa cells was performed following etoposide treatment to assess the mitochondria-dependent apoptosis. Apoptotic pathway was analyzed through measuring the cleavage of epidermal growth factor receptor (EGFR) and phospholipase C-γ (PLC-γ), caspase activation, mitochondrial membrane perturbation, and cytochrome c release by flow cytometry and western blotting. To clarify the role of TCTP in the inhibition of apoptosome, in vitro apoptosome reconstitution and immunoprecipitation was used. Pull-down assay and silver staining using the variants of Apaf-1 protein was applied to identify the domain that is responsible for its interaction with TCTP. In the present study, we confirmed that adenoviral overexpression of TCTP protects HeLa cells from cell death induced by cytotoxic drugs such as taxol and etoposide. TCTP antagonized the mitochondria-dependent apoptotic pathway following etoposide treatment, including mitochondrial membrane damage and resultant cytochrome c release, activation of caspase-9, and -3, and eventually, the cleavage of EGFR and PLC-γ. More importantly, TCTP interacts with the caspase recruitment domain (CARD) of Apaf-1 and is incorporated into the heptameric Apaf-1 complex, and that C-terminal cleaved TCTP specifically associates with Apaf-1 of apoptosome in apoptosome-forming condition thereby inhibiting the amplification of caspase cascade. TCTP protects the cancer cells from etoposide-induced cell death by inhibiting the mitochondria-mediated apoptotic pathway. Interaction of TCTP with Apaf-1 in apoptosome is involved in the molecular mechanism of TCTP-induced chemoresistance. These findings suggest that TCTP may serve

  12. Development of phosphonate-terminated magnetic mesoporous silica nanoparticles for pH-controlled release of doxorubicin and improved tumor accumulation

    Directory of Open Access Journals (Sweden)

    Erxi Che

    2014-12-01

    Full Text Available In this study, phosphonate-terminated magnetic mesoporous nanoparticles (pMMSNs was designed by incorporation of MNPs in the center of mesoporous silica nanoparticles (MSNs and followed by grafting phosphonate group on to the surface of MMSNs. The carrier exhibited a typical superparamagnetic feature and the saturation magnetization was 4.89 emu/g measured by vibrating sample magnetometer (VSM. pMMSNs had a spherical morphology and a pore size of 2.2 nm. From N2 adsorption-desorption analysis, pMMSNs had a surface area of 613.4 m2/g and a pore volume of 0.78 cm3/g. Phosphonate modification improved the colloidal stability of MMSNs, and the hydrodynamic diameter of pMMSNs was around 175 nm. The hydrophilic phosphonate group significantly enhanced the negative surface charge of MMSNs from −19.3 mV to −28.8 mV pMMSNs with more negative surface charge had a 2.3-fold higher drug loading capacity than that of MMSNs. In addition, the rate and amount of release of doxorubicin (DOX from DOX/pMMSNs was pH-dependent and increased with the decrease of pH. At pH 7.4, the release amount was quite low and only approximately 17 wt% of DOX was released in 48 h. At pH 5.0 and 3.0, the release rate increased significantly and the release amount achieved 31 wt% and 60 wt% in 48 h, respectively. To evaluate the magnetic targeting performance of pMMSNs, FITC labeled pMMSNs was injected into mice bearing S180 solid tumor. FITC labeled pMMSNs controlled by an external magnetic field showed higher tumor accumulation and lower normal tissue distribution.

  13. Pretreatment Endorectal Coil Magnetic Resonance Imaging Findings Predict Biochemical Tumor Control in Prostate Cancer Patients Treated With Combination Brachytherapy and External-Beam Radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Riaz, Nadeem [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Afaq, Asim; Akin, Oguz [Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Pei Xin; Kollmeier, Marisa A.; Cox, Brett [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Hricak, Hedvig [Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Zelefsky, Michael J., E-mail: zelefskm@mskcc.org [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

    2012-11-01

    Purpose: To investigate the utility of endorectal coil magenetic resonance imaging (eMRI) in predicting biochemical relapse in prostate cancer patients treated with combination brachytherapy and external-beam radiotherapy. Methods and Materials: Between 2000 and 2008, 279 men with intermediate- or high-risk prostate cancer underwent eMRI of their prostate before receiving brachytherapy and supplemental intensity-modulated radiotherapy. Endorectal coil MRI was performed before treatment and retrospectively reviewed by two radiologists experienced in genitourinary MRI. Image-based variables, including tumor diameter, location, number of sextants involved, and the presence of extracapsular extension (ECE), were incorporated with other established clinical variables to predict biochemical control outcomes. The median follow-up was 49 months (range, 1-13 years). Results: The 5-year biochemical relapse-free survival for the cohort was 92%. Clinical findings predicting recurrence on univariate analysis included Gleason score (hazard ratio [HR] 3.6, p = 0.001), PSA (HR 1.04, p = 0.005), and National Comprehensive Cancer Network risk group (HR 4.1, p = 0.002). Clinical T stage and the use of androgen deprivation therapy were not correlated with biochemical failure. Imaging findings on univariate analysis associated with relapse included ECE on MRI (HR 3.79, p = 0.003), tumor size (HR 2.58, p = 0.04), and T stage (HR 1.71, p = 0.004). On multivariate analysis incorporating both clinical and imaging findings, only ECE on MRI and Gleason score were independent predictors of recurrence. Conclusions: Pretreatment eMRI findings predict for biochemical recurrence in intermediate- and high-risk prostate cancer patients treated with combination brachytherapy and external-beam radiotherapy. Gleason score and the presence of ECE on MRI were the only significant predictors of biochemical relapse in this group of patients.

  14. High symptom improvement and local tumor control using stereotactic radiotherapy when given early after diagnosis of meningioma. A multicentre study

    Energy Technology Data Exchange (ETDEWEB)

    Compter, I.; Houben, R.M.A.; Bosmans, G.; Baumert, B.G. [Maastricht Univ. Medical Centre (Netherlands). Dept. of Radiation-Oncology (MAASTRO); Zaugg, K.; Buescher, C. [University Hospital Zurich (Switzerland). Clinic and Policlinic of Radiation-Oncology; Dings, J.T.A. [Maastricht Univ. Medical Centre (Netherlands). Dept. of Neurosurgery; Anten, M.M.H.M.E. [Maastricht Univ. Medical Centre (Netherlands). Dept. of Neurology

    2012-10-15

    Purpose: The goal of the present study was to analyze long-term results of fractionated stereotactic radiotherapy (SRT) in patients with a meningioma. Methods and materials: A total of 72 patients treated between 1996 and 2008 in MAASTRO clinic (n = 45) and University Hospital Zurich (n = 27) were included. SRT was given as primary treatment (n = 46), postoperatively (n = 19) or at recurrence (n = 7); 49 tumours (68%) were located in the skull base. Median total dose was 54 Gy. Results: Median follow-up was 4.13 years (range 0.66-11 years). The 3- and 5-year overall survival were 92 and 79% for grade 0 and I meningioma. Progression-free survival for grade 0 and I was 95% at 3 and 5 years, and 40% for grade II and III at 3 years. In 98.4% of patients, clinical symptoms were stable or improved. The majority of symptoms improved within 24 months after SRT. Local control is significantly better if patients are irradiated immediately after diagnosis compared to a watchful waiting policy (p = 0.017). Grade IV toxicity was low (4.2%, n = 3) Conclusion: SRT is an effective treatment with high local and clinical control. Early SRT resulted in better outcome than late treatment at progression. (orig.)

  15. A 25-Year Experience of Gastroenteropancreatic Neuroendocrine Tumors and Somatostatin (Congeners) Analogs: From Symptom Control to Antineoplastic Therapy.

    Science.gov (United States)

    O'Dorisio, Thomas M; Anthony, Lowell B

    2015-01-01

    Radioimmunoassay technology was utilized in the discovery of somatostatin and was quickly brought into therapeutics; however, it took the development of somatostatin congeners to solve its limitations of a short half-life. Therapeutic medical control of hyperhormonal states such as acromegaly, carcinoid syndrome and VIPoma significantly advanced from a nonspecific approach to one that specifically and effectively targeted the underlying pathophysiology. Clinical care was transformed from nonspecific symptom control to one of a significant improvement in not only quality of life, but also quantity of life. These data submitted to US and European regulatory authorities for approval included many investigative sites with no uniform protocol and multiple investigational new drugs, and have not been previously published. This review includes the original data demonstrating the transformational impact this class of agents had on specific disease subsets resulting in regulatory approval 25 years ago. Autoradiography techniques using somatostatin resulted in identifying, localizing and characterizing its receptor subtypes. Translating in vitro data to in vivo resulted in scintigraphic whole body and SPECT scans with (111)In-pentetreotide and was incorporated into standard clinical care 20 years ago. (68)Ga-octreotide congeners using PET scanning offers a major imaging advance. Peptide receptor radiotherapy has evolved over the last 2 decades and utilizes several therapeutic isotopes, including (90)Y and (177)Lu. © 2015 S. Karger AG, Basel.

  16. Adrenal Gland Tumors: Statistics

    Science.gov (United States)

    ... Gland Tumor: Statistics Request Permissions Adrenal Gland Tumor: Statistics Approved by the Cancer.Net Editorial Board , 03/ ... primary adrenal gland tumor is very uncommon. Exact statistics are not available for this type of tumor ...

  17. Brain Tumor Symptoms

    Science.gov (United States)

    ... Brain Anatomy Brain Tumor Symptoms Headaches Seizures Memory Depression Mood Swings & Cognitive Changes Fatigue Other Symptoms Diagnosis Types of Tumors Risk Factors Brain Tumor Statistics Brain Tumor Dictionary Webinars Anytime Learning About Us ...

  18. Understanding Brain Tumors

    Science.gov (United States)

    ... to Know About Brain Tumors . What is a Brain Tumor? A brain tumor is an abnormal growth
 ... Tumors” from Frankly Speaking Frankly Speaking About Cancer: Brain Tumors Download the full book Questions to ask ...

  19. Dual turn-on fluorescence signal-based controlled release system for real-time monitoring of drug release dynamics in living cells and tumor tissues.

    Science.gov (United States)

    Kong, Xiuqi; Dong, Baoli; Song, Xuezhen; Wang, Chao; Zhang, Nan; Lin, Weiying

    2018-01-01

    Controlled release systems with capabilities for direct and real-time monitoring of the release and dynamics of drugs in living systems are of great value for cancer chemotherapy. Herein, we describe a novel dual turn-on fluorescence signal-based controlled release system ( CDox ), in which the chemotherapy drug doxorubicin ( Dox ) and the fluorescent dye ( CH ) are conjugated by a hydrazone moiety, a pH-responsive cleavable linker. CDox itself shows nearly no fluorescence as the fluorescence of CH and Dox is essentially quenched by the C=N isomerization and N-N free rotation. However, when activated under acidic conditions, CDox could be hydrolyzed to afford Dox and CH , resulting in dual turn-on signals with emission peaks at 595 nm and 488 nm, respectively. Notably, CDox exhibits a desirable controlled release feature as the hydrolysis rate is limited by the steric hindrance effect from both the Dox and CH moieties. Cytotoxicity assays indicate that CDox shows much lower cytotoxicity relative to Dox , and displays higher cell inhibition rate to cancer than normal cells. With the aid of the dual turn-on fluorescence at different wavelengths, the drug release dynamics of CDox in living HepG2 and 4T-1 cells was monitored in double channels in a real-time fashion. Importantly, two-photon fluorescence imaging of CDox in living tumor tissues was also successfully performed by high-definition 3D imaging. We expect that the unique controlled release system illustrated herein could provide a powerful means to investigate modes of action of drugs, which is critical for development of much more robust and effective chemotherapy drugs.

  20. Stereotactic Radiosurgery of the Postoperative Resection Cavity for Brain Metastases: Prospective Evaluation of Target Margin on Tumor Control

    International Nuclear Information System (INIS)

    Choi, Clara Y.H.; Chang, Steven D.; Gibbs, Iris C.; Adler, John R.; Harsh, Griffith R.; Lieberson, Robert E.; Soltys, Scott G.

    2012-01-01

    Purpose: Given the neurocognitive toxicity associated with whole-brain irradiation (WBRT), approaches to defer or avoid WBRT after surgical resection of brain metastases are desirable. Our initial experience with stereotactic radiosurgery (SRS) targeting the resection cavity showed promising results. We examined the outcomes of postoperative resection cavity SRS to determine the effect of adding a 2-mm margin around the resection cavity on local failure (LF) and toxicity. Patients and Methods: We retrospectively evaluated 120 cavities in 112 patients treated from 1998-2009. Factors associated with LF and distant brain failure (DF) were analyzed using competing risks analysis, with death as a competing risk. The overall survival (OS) rate was calculated by the Kaplan-Meier product-limit method; variables associated with OS were evaluated using the Cox proportional hazards and log rank tests. Results: The 12-month cumulative incidence rates of LF and DF, with death as a competing risk, were 9.5% and 54%, respectively. On univariate analysis, expansion of the cavity with a 2-mm margin was associated with decreased LF; the 12-month cumulative incidence rates of LF with and without margin were 3% and 16%, respectively (P=.042). The 12-month toxicity rates with and without margin were 3% and 8%, respectively (P=.27). On multivariate analysis, melanoma histology (P=.038) and number of brain metastases (P=.0097) were associated with higher DF. The median OS time was 17 months (range, 2-114 months), with a 12-month OS rate of 62%. Overall, WBRT was avoided in 72% of the patients. Conclusion: Adjuvant SRS targeting the resection cavity of brain metastases results in excellent local control and allows WBRT to be avoided in a majority of patients. A 2-mm margin around the resection cavity improved local control without increasing toxicity compared with our prior technique with no margin.

  1. Use of the Concept of Equivalent Biologically Effective Dose (BED) to Quantify the Contribution of Hyperthermia to Local Tumor Control in Radiohyperthermia Cervical Cancer Trials, and Comparison With Radiochemotherapy Results

    International Nuclear Information System (INIS)

    Plataniotis, George A.; Dale, Roger G.

    2009-01-01

    Purpose: To express the magnitude of contribution of hyperthermia to local tumor control in radiohyperthermia (RT/HT) cervical cancer trials, in terms of the radiation-equivalent biologically effective dose (BED) and to explore the potential of the combined modalities in the treatment of this neoplasm. Materials and Methods: Local control rates of both arms of each study (RT vs. RT+HT) reported from randomized controlled trials (RCT) on concurrent RT/HT for cervical cancer were reviewed. By comparing the two tumor control probabilities (TCPs) from each study, we calculated the HT-related log cell-kill and then expressed it in terms of the number of 2 Gy fraction equivalents, for a range of tumor volumes and radiosensitivities. We have compared the contribution of each modality and made some exploratory calculations on the TCPs that might be expected from a combined trimodality treatment (RT+CT+HT). Results: The HT-equivalent number of 2-Gy fractions ranges from 0.6 to 4.8 depending on radiosensitivity. Opportunities for clinically detectable improvement by the addition of HT are only available in tumors with an alpha value in the approximate range of 0.22-0.28 Gy -1 . A combined treatment (RT+CT+HT) is not expected to improve prognosis in radioresistant tumors. Conclusion: The most significant improvements in TCP, which may result from the combination of RT/CT/HT for locally advanced cervical carcinomas, are likely to be limited only to those patients with tumors of relatively low-intermediate radiosensitivity.

  2. The synthetic inhibitor of Fibroblast Growth Factor Receptor PD166866 controls negatively the growth of tumor cells in culture

    Directory of Open Access Journals (Sweden)

    Castelli Mauro

    2009-12-01

    Full Text Available Abstract Background Many experimental data evidence that over-expression of various growth factors cause disorders in cell proliferation. The role of the Fibroblast Growth Factors (FGF in growth control is indisputable: in particular, FGF1 and its tyrosine kinase receptor (FGFR1 act through a very complex network of mechanisms and pathways. In this work we have evaluated the antiproliferative activity effect of PD166866, a synthetic molecule inhibiting the tyrosin kinase action of FGFR1. Methods Cells were routinely grown in Dulbecco Modified Eagle's medium supplemented with newborn serum and a penicillin-streptomycin mixture. Cell viability was evaluated by Mosmann assay and by trypan blue staining. DNA damage was assessed by in situ fluorescent staining with Terminal Deoxynucleotidyl Transferase dUTP nick end labeling (TUNEL assay. Assessment of oxidative stress at membrane level was measured by quantitative analysis of the intra-cellular formation of malonyl-dialdheyde (MDA deriving from the decomposition of poly-unsaturated fatty acids. The expression of Poly-ADP-Ribose-Polymerase (PARP, consequent to DNA fragmentation, was evidenced by immuno-histochemistry utilizing an antibody directed against an N-terminal fragment of the enzyme. Results The bioactivity of the drug was investigated on Hela cells. Cytoxicity was assessed by the Mosmann assay and by vital staining with trypan blue. The target of the molecule is most likely the cell membrane as shown by the significant increase of the intracellular concentration of malonyl-dihaldheyde. The increase of this compound, as a consequence of the treatment with PD166866, is suggestive of membrane lipoperoxidation. The TUNEL assay gave a qualitative, though clear, indication of DNA damage. Furthermore we demonstrate intracellular accumulation of poly-ADP-ribose polymerase I. This enzyme is a sensor of nicks on the DNA strands and this supports the idea that treatment with the drug induces cell

  3. Relationship of time--dose factors to tumor control and complications in the treatment of Cushing's disease by irradiation

    International Nuclear Information System (INIS)

    Aristizabal, S.; Caldwell, W.L.; Avila, J.; Mayer, E.G.

    1977-01-01

    The records of the Radiotherapy Division of the Radiology Department of Vanderbilt University Hospital were reviewed for the period 1952 to 1970. During those 19 years 45 patients with a well-documented diagnosis of Cushing's disease were treated initially by external irradiation of the pituitary. All of the patients were treated with megavoltage equipment using photons. When the results of irradiation are compared against total doses of radiation, it is evident that the control rate is unsatisfactory at doses less than 4000 rad and the maximum benefits of irradiation are evident in the 4500 to 5000 rad dose range. It is also clear that the complication rate increases as the dose exceeds 4800 rad. If the various treatment regimens of irradiation are converted to ''equivalent'' doses by the Nominal Standard Dose (NSD) or Time-Dose-Fractionation (TDF) methods, the relationship between ''dose'' and efficacy of therapy and complications is demonstrated. In order to reduce the possibility of treatment-related morbidity, the use of three or more small (4 x 4 cm) treatment portals or rotational techniques is recommended to a pituitary dose of 4600 to 5000 rad treating 5 days a week for 5 to 6 weeks

  4. Golimumab in patients with active rheumatoid arthritis after treatment with tumor necrosis factor a inhibitors: findings with up to five years of treatment in the multicenter, randomized, double-blind, placebo-controlled, phase 3 GO-AFTER study

    NARCIS (Netherlands)

    Smolen, Josef S.; Kay, Jonathan; Doyle, Mittie; Landewé, Robert; Matteson, Eric L.; Gaylis, Norman; Wollenhaupt, Jürgen; Murphy, Frederick T.; Xu, Stephen; Zhou, Yiying; Hsia, Elizabeth C.

    2015-01-01

    Introduction: The aim of this study was to assess long-term golimumab therapy in rheumatoid arthritis (RA) patients who discontinued previous tumor necrosis factor-alpha (TNF)-inhibitor(s). Methods: Patients enrolled into this multicenter, randomized, double-blind, placebo-controlled study of active

  5. Childhood folate, B6, B12, and food group intake and the risk of childhood brain tumors: results from an Australian case-control study.

    Science.gov (United States)

    Greenop, Kathryn R; Miller, Margaret; Bailey, Helen D; de Klerk, Nicholas H; Attia, John; Kellie, Stewart J; Bower, Carol; Armstrong, Bruce K; Milne, Elizabeth

    2015-06-01

    The etiology of childhood brain tumors (CBT) is poorly understood, but dietary factors could be involved. In this case-control study of CBT, the possible associations of childhood intake of dietary and supplemental folate, vitamin B6, and vitamin B12 with the risk of CBT were investigated, along with various food groups. Cases diagnosed between 2005 and 2010 were identified from 10 pediatric oncology centers in Australia and controls by nationwide random-digit dialling. For study children of ages 3-14 years, diet in the year before diagnosis (or recruitment) was assessed using food frequency questionnaires. Folate intake was adjusted for bioavailability, and dietary micronutrient intake was energy-adjusted. Micronutrients and food groups were analyzed using logistic regression adjusting for relevant confounders. Principal components analysis was conducted to assess food group intake patterns for analysis. Food and micronutrient data were available for 216 cases and 523 controls. Folate intake was associated with a reduced risk of CBT overall (odds ratio for highest tertile vs. lowest: 0.63, 95% confidence interval 0.41, 0.97) and particularly low-grade gliomas (odds ratio for highest tertile vs. lowest: 0.52, 95% confidence interval 0.29, 0.92). Vitamin B6 and B12 intake was not associated with CBT risk, nor was processed meat. High folate intake during childhood may reduce the risk of CBT. This potentially important finding needs to be corroborated in other studies. If replicated, these results could have important implications for public health recommendations regarding diet during childhood.

  6. Effect of dipeptidyl peptidase-4 inhibitors on circulating tumor necrosis factor-α concentrations: A systematic review and meta-analysis of controlled trials.

    Science.gov (United States)

    Atkin, Stephen L; Katsiki, Niki; Banach, Maciej; Mikhailidis, Dimitri P; Pirro, Matteo; Sahebkar, Amirhossein

    2017-09-01

    Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes mellitus. There are also reports of an effect of these drugs in reducing inflammation through inhibition of tumor necrosis factor-α (TNF-α) that is an important mediator for several inflammatory processes. The present systematic review and meta-analysis were performed to evaluate the effect of DPP-4 inhibitors on circulating TNF-α levels in T2DM patients. A systematic review and a meta-analysis were undertaken on all controlled trials of DPP-4 inhibitors that included measurement of TNF-α. The search included PubMed-Medline, Scopus, ISI Web of Knowledge and Google Scholar databases. Quantitative data synthesis was performed using a random-effects model, with standardized mean difference (SMD) and 95% confidence interval (CI) as summary statistics. Meta-regression and leave-one-out sensitivity analysis were performed to assess the modifiers of treatment response. Eight eligible articles (6 with sitagliptin and 2 with vildagliptin) comprising 9 treatment arms were selected for this meta-analysis. Meta-analysis suggested a significant reduction of circulating TNF-α concentrations following treatment with DPP-4 inhibitors (SMD: -1.84, 95% CI: -2.88, -0.80, p=0.001). The effect size was robust in the sensitivity analysis and not mainly driven by a single study. A subgroup analysis did not suggest any significant difference between the TNF-α-lowering activity of sitagliptin (SMD: -1.49, 95% CI: -2.89, -0.10) and vildagliptin (SMD: -2.80, 95% CI: -4.98, -0.61) (p=0.326). This meta-analysis of the 8 available controlled trials showed that DPP-4 inhibition in patients with type 2 diabetes mellitus was associated with significant reductions in plasma TNF-α levels with no apparent difference between sitagliptin and vildagliptin. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Locoregional control of non-small cell lung cancer in relation to automated early assessment of tumor regression on cone beam computed tomography

    DEFF Research Database (Denmark)

    Brink, Carsten; Bernchou, Uffe; Bertelsen, Anders

    2014-01-01

    PURPOSE: Large interindividual variations in volume regression of non-small cell lung cancer (NSCLC) are observable on standard cone beam computed tomography (CBCT) during fractionated radiation therapy. Here, a method for automated assessment of tumor volume regression is presented and its...... therapy provides biological information on the specific tumor. This could potentially form the basis for personalized response adaptive therapy....

  8. SU-C-BRE-02: BED Vs. Local Control: Radiobiological Effect of Tumor Volume in Monte Carlo (MC) Lung SBRT Planning

    Energy Technology Data Exchange (ETDEWEB)

    Pokhrel, D; Badkul, R; Jiang, H; Estes, C; Park, J; Kumar, P; Wang, F [UniversityKansas Medical Center, Kansas City, KS (United States)

    2014-06-15

    Purpose: SBRT with hypofractionated dose schemata has emerged a compelling treatment modality for medically inoperable early stage lung cancer patients. It requires more accurate dose calculation and treatment delivery technique. This report presents the relationship between tumor control probability(TCP) and size-adjusted biological effective dose(sBED) of tumor volume for MC lung SBRT patients. Methods: Fifteen patients who were treated with MC-based lung SBRT to 50Gy in 5 fractions to PTVV100%=95% were studied. ITVs were delineated on MIP images of 4DCT-scans. PTVs diameter(ITV+5mm margins) ranged from 2.7–4.9cm (mean 3.7cm). Plans were generated using non-coplanar conformal arcs/beams using iPlan XVMC algorithm (BrainLABiPlan ver.4.1.2) for Novalis-TX with HD-MLCs and 6MVSRS(1000MU/min) mode, following RTOG-0813 dosimetric guidelines. To understand the known uncertainties of conventional heterogeneities-corrected/uncorrected pencil beam (PBhete/ PB-homo) algorithms, dose distributions were re-calculated with PBhete/ PB-homo using same beam configurations, MLCs and monitor units. Biologically effective dose(BED10) was computed using LQ-model with α/β=10Gy for meanPTV and meanITV. BED10-c*L, gave size-adjusted BED(sBED), where c=10Gy/cm and L=PTV diameter in centimeter. The TCP model was adopted from Ohri et al.(IJROBP, 2012): TCP = exp[sBEDTCD50]/ k /(1.0 + exp[sBED-TCD50]/k), where k=31Gy corresponding to TCD50=0Gy; and more realistic MC-based TCP was computed for PTV(V99%). Results: Mean PTV PB-hete TCP value was 6% higher, but, mean PTV PB-homo TCP value was 4% lower compared to mean PTV MC TCP. Mean ITV PB-hete/PB-homo TCP values were comparable (within ±3.0%) to mean ITV MC TCP. The mean PTV(V99%)had BED10=90.9±3.7%(median=92.2%),sBED=54.1±8.2%(median=53.5%) corresponding to mean MC TCP value of 84.8±3.3%(median=84.9%) at 2- year local control. Conclusion: The TCP model which incorporates BED10 and tumor diameter indicates that radiobiological

  9. Chemokines in tumor proximal fluids.

    Science.gov (United States)

    Kotyza, Jaromir

    2017-03-01

    Chemokines are chemotactic cytokines produced by leukocytes and other types of cells including tumor cells. Their action is determined by the expression of cognate receptors and subsequent signaling in target cells, followed by the modulation of cytoskeletal proteins and the induction of other responses. In tumors, chemokines produced by neoplastic/stroma cells control the leukocyte infiltrate influencing tumor growth and progression. Tumor cells also express functional chemokine receptors responding to chemokine signals, promoting cell survival, proliferation and metastasis formation. Chemokines may be detected in serum of cancer patients, but due to the paracrine nature of these molecules, more significant concentrations are found in the tumor adjacent, non-vascular fluids, collectively called tumor proximal fluids. This review summarizes the expression of CC and CXC chemokines in these fluids, namely in interstitial fluid, pleural, ascitic, and cyst fluids, but also in urine, saliva, cerebrospinal fluid, cervical secretions and bronchoalveolar lavage fluid. Most comparative clinical studies reveal increased chemokine levels in high-grade tumor proximal fluids rather than in low-grade tumors and benign conditions, indicating shorter survival periods. The data confirm peritumoral fluid chemokines as sensitive diagnostic and prognostic markers, as well as offer support for chemokines and their receptors as potential targets for antitumor therapy.

  10. The Significance of Tumor Necrosis Factor Receptor Type II in CD8+Regulatory T Cells and CD8+Effector T Cells.

    Science.gov (United States)

    Ye, Lin-Lin; Wei, Xiao-Shan; Zhang, Min; Niu, Yi-Ran; Zhou, Qiong

    2018-01-01

    Tumor necrosis factor (TNF) is a pleiotropic cytokine that has both pro-inflammatory and anti-inflammatory functions. The biological functions of TNF are mediated by two receptors, TNF receptor type I (TNFR1) and TNF receptor type II (TNFR2). TNFR1 is expressed universally on almost all cell types and has been extensively studied, whereas TNFR2 is mainly restricted to immune cells and some tumor cells and its role is far from clarified. Studies have shown that TNFR2 mediates the stimulatory activity of TNF on CD4 + Foxp3 + regulatory T cells (Tregs) and CD8 + Foxp3 + Tregs, and is involved in the phenotypic stability, proliferation, activation, and suppressive activity of Tregs. TNFR2 can also be expressed on CD8 + effector T cells (Teffs), which delivers an activation signal and cytotoxic ability to CD8 + Teffs during the early immune response, as well as an apoptosis signal to terminate the immune response. TNFR2-induced abolition of TNF receptor-associated factor 2 (TRAF2) degradation may play an important role in these processes. Consequently, due to the distribution of TNFR2 and its pleiotropic effects, TNFR2 appears to be critical to keeping the balance between Tregs and Teffs, and may be an efficient therapeutic target for tumor and autoimmune diseases. In this review, we summarize the biological functions of TNFR2 expressed on CD8 + Foxp3 + Tregs and CD8 + Teffs, and highlight how TNF uses TNFR2 to coordinate the complex events that ultimately lead to efficient CD8 + T cell-mediated immune responses.

  11. The bantam microRNA acts through Numb to exert cell growth control and feedback regulation of Notch in tumor-forming stem cells in the Drosophila brain.

    Science.gov (United States)

    Wu, Yen-Chi; Lee, Kyu-Sun; Song, Yan; Gehrke, Stephan; Lu, Bingwei

    2017-05-01

    Notch (N) signaling is central to the self-renewal of neural stem cells (NSCs) and other tissue stem cells. Its deregulation compromises tissue homeostasis and contributes to tumorigenesis and other diseases. How N regulates stem cell behavior in health and disease is not well understood. Here we show that N regulates bantam (ban) microRNA to impact cell growth, a process key to NSC maintenance and particularly relied upon by tumor-forming cancer stem cells. Notch signaling directly regulates ban expression at the transcriptional level, and ban in turn feedback regulates N activity through negative regulation of the Notch inhibitor Numb. This feedback regulatory mechanism helps maintain the robustness of N signaling activity and NSC fate. Moreover, we show that a Numb-Myc axis mediates the effects of ban on nucleolar and cellular growth independently or downstream of N. Our results highlight intricate transcriptional as well as translational control mechanisms and feedback regulation in the N signaling network, with important implications for NSC biology and cancer biology.

  12. Hypofraction radiotherapy of liver tumor using cone beam computed tomography guidance combined with active breath control by long breath-holding.

    Science.gov (United States)

    Zhong, Renming; Wang, Jin; Jiang, Xiaoqin; He, Yinbo; Zhang, Hong; Chen, Nianyong; Bai, Sen; Xu, Feng

    2012-09-01

    To evaluate the feasibility and validity of cone beam computed tomography (CBCT) and active breath control (ABC) by long breath-holding in hypofraction radiotherapy of liver tumor. Twenty-four patients received hypofraction radiotherapy of liver tumor with long breath-holding at end-inhale; four prescriptions were used: 6 Gy×7 (n=8), 10 Gy×4 (n=7), 5 Gy×9 (n=6), 4 Gy×10 (n=3). For each fraction, all patients received pre-correction CBCT scans with ABC, some patients received post-correction and post-treatment CBCT. The interfraction and intrafraction liver positioning errors on medial-lateral (ML), cranial-caudal (CC) and anterior-posterior (AP) directions were obtained. The theoretic margin from clinical target volume (CTV) to planning target volume (PTV) was calculated based on post-treatment error. The dosimetric parameters of PTV and normal tissue were compared between ABC and free breathing (FB). The interfraction error in liver positioning showed system errors (Σ) of 3.18 mm (ML), 6.80 mm (CC) and 3.05 mm (AP); random error (σ) of 3.03 mm (ML), 6.78 mm (CC) and 3.62 mm (AP). These errors were significantly reduced with CBCT guided online correction. The intrafraction systematic error was 0.72 mm (ML), 2.21 mm (CC), 1.49 mm (AP), and random error was 2.30 mm (ML), 3.58 mm (CC), 2.49 mm (AP). Dosimetric parameters such as PTV, the liver's volume included by 23, 30 Gy isodose curve (V23, V30), mean dose to normal liver (MDTNL) and mean dose to cord were significantly larger for FB (Pbreath-holding at end-inhale is an effective method to reduce liver motion, PTV and dose to normal tissue. Interfraction and intrafraction liver positioning errors were substantial. CBCT guided online correction of positioning error is recommended for liver radiotherapy with end-inhale ABC. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  13. Adaptive Radiotherapy for Locally Advanced Non–Small-Cell Lung Cancer Does Not Underdose the Microscopic Disease and has the Potential to Increase Tumor Control

    International Nuclear Information System (INIS)

    Guckenberger, Matthias; Richter, Anne; Wilbert, Juergen; Flentje, Michael; Partridge, Mike

    2011-01-01

    Purpose: To evaluate doses to the microscopic disease (MD) in adaptive radiotherapy (ART) for locally advanced non–small-cell lung cancer (NSCLC) and to model tumor control probability (TCP). Methods and Materials: In a retrospective planning study, three-dimensional conformal treatment plans for 13 patients with locally advanced NSCLC were adapted to shape and volume changes of the gross tumor volume (GTV) once or twice during conventionally fractionated radiotherapy with total doses of 66 Gy; doses in the ART plans were escalated using an iso-mean lung dose (MLD) approach compared to non-adapted treatment. Dose distributions to the volumes of suspect MD were simulated for a scenario with synchronous shrinkage of the MD and GTV and for a scenario of a stationary MD despite GTV shrinkage; simulations were performed using deformable image registration. TCP calculations considering doses to the GTV and MD were performed using three different models. Results: Coverage of the MD at 50 Gy was not compromised by ART. Coverage at 60 Gy in the scenario of a stationary MD was significantly reduced from 92% ± 10% to 73% ± 19% using ART; however, the coverage was restored by iso-MLD dose escalation. Dose distributions in the MD were sufficient to achieve a TCP >80% on average in all simulation experiments, with the clonogenic cell density the major factor influencing TCP. The combined TCP for the GTV and MD was 19.9% averaged over all patients and TCP models in non-adaptive treatment with 66 Gy. Iso-MLD dose escalation achieved by ART increased the overall TCP by absolute 6% (adapting plan once) and by 8.7% (adapting plan twice) on average. Absolute TCP values were significantly different between the TCP models; however, all TCP models suggested very similar TCP increase by using ART. Conclusions: Adaptation of radiotherapy to the shrinking GTV did not compromise dose coverage of volumes of suspect microscopic disease and has the potential to increase TCP by >40% compared

  14. Cirurgia da hipófise por via trans-esfenoidal sob controle radiofluoroscópico e microdissecção novo tratamento da retinopatia diabética, tumores selares e neoplasias endocrinodependentes The surgery of the pituitary gland using a transphenoidal approach under radiofluoroscopic control and microdisection: a new treatment for diabetic retinopathy, pituitary tumors and endocrinodependent growths

    Directory of Open Access Journals (Sweden)

    Jules Hardy

    1968-03-01

    Full Text Available É apresentada nova técnica para a ablação total ou seletiva da hipófise utilizando via de acesso trans-esfenoidal, controle radiofluoroscópico e microdissecção, com traumatismo desprezível às estruturas circunvizinhas. Os autores comentam as aplicações do método à prática neurocirúrgica, relatando parte de uma série de mais 140 casos já operados. São discutidos os resultados obtidos no tratamento de 17 casos de retinopatia diabética, em 11 dos quais apenas o lobo anterior da hipófise foi removido, assim como aqueles obtidos na exérese de 20 casos de tumores selares. As indicações da hipofisectomia por via trans-esfenoidal no controle da sintomatologia das neoplasias endòcrinodependentes é estudada à luz dos resultados obtidos em 17 casos, sendo os resultados comparados com casos nos quais foi feita a implantação selar de ítrio90. As complicações operatorias em relação às três entidades nosológicas acima estudadas são também analisadas. Os autores salientam que a técnica descrita constitui, no presente estado das técnicas neurocirúrgicas utilizadas para a produção de uma insuficiência hipofisária duradoura, a intervenção de escolha.A new neurosurgical technique for the partial or total exéresis of the pituitary gland, using a transphenoidal approach under radiofluoroscopic control and microdisection is described. Part of a series of more than 140 cases operated upon by this method is reported. Results obtained in the treatment of diabetic retinopathy in 17 cases, 11 of which had only the pars anterior removed, are discussed. The applications of the transphenoidal route in 20 cases of pituitary fossa tumors are analysed. The indications of this type of operation in the management of endocrinodependent cancer is studied in 17 cases and compared with the results of 36 cases submitted to implant of Yttrium90 in the sella turcica. The operative complications following transphenoidal exéresis of the

  15. A fine balance: epigenetic control of cellular quiescence by the tumor suppressor PRDM2/RIZ at a bivalent domain in the cyclin a gene.

    Science.gov (United States)

    Cheedipudi, Sirisha; Puri, Deepika; Saleh, Amena; Gala, Hardik P; Rumman, Mohammed; Pillai, Malini S; Sreenivas, Prethish; Arora, Reety; Sellathurai, Jeeva; Schrøder, Henrik Daa; Mishra, Rakesh K; Dhawan, Jyotsna

    2015-07-27

    Adult stem cell quiescence is critical to ensure regeneration while minimizing tumorigenesis. Epigenetic regulation contributes to cell cycle control and differentiation, but few regulators of the chromatin state in quiescent cells are known. Here we report that the tumor suppressor PRDM2/RIZ, an H3K9 methyltransferase, is enriched in quiescent muscle stem cells in vivo and controls reversible quiescence in cultured myoblasts. We find that PRDM2 associates with >4400 promoters in G0 myoblasts, 55% of which are also marked with H3K9me2 and enriched for myogenic, cell cycle and developmental regulators. Knockdown of PRDM2 alters histone methylation at key promoters such as Myogenin and CyclinA2 (CCNA2), and subverts the quiescence program via global de-repression of myogenesis, and hyper-repression of the cell cycle. Further, PRDM2 acts upstream of the repressive PRC2 complex in G0. We identify a novel G0-specific bivalent chromatin domain in the CCNA2 locus. PRDM2 protein interacts with the PRC2 protein EZH2 and regulates its association with the bivalent domain in the CCNA2 gene. Our results suggest that induction of PRDM2 in G0 ensures that two antagonistic programs-myogenesis and the cell cycle-while stalled, are poised for reactivation. Together, these results indicate that epigenetic regulation by PRDM2 preserves key functions of the quiescent state, with implications for stem cell self-renewal. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  16. Factors relating to pregnancy and birth and the risk of childhood brain tumors: results from an Australian case-control study.

    Science.gov (United States)

    Greenop, Kathryn R; Blair, Eve M; Bower, Carol; Armstrong, Bruce K; Milne, Elizabeth

    2014-03-01

    Childhood brain tumors (CBT) are the leading cause of cancer death in children, yet their causes are largely known. This study investigated the association between maternal and birth characteristics and risk of CBT. Cases families were recruited from all 10 Australian pediatric oncology centers between 2005 and 2010. Control families were recruited via random-digit dialing, frequency matched to cases on the basis of child's age, sex, and State of residence. Maternal and birth characteristics of children were ascertained by questionnaires. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using unconditional logistic regression, adjusting for relevant confounders. For this analysis, data on 319 case children and 1,079 control children were available. No association was found between risk of CBT and birth weight, fetal growth, birth order, gestational age, or maternal body mass index. The ORs for inadequate and excessive maternal gestational weight gain (GWG) (Institute of Medicine 2009 guidelines) were 1.8 (95% CI 1.2-2.6) and 1.4 (95% CI 1.0-2.1), respectively; similar findings for GWG were seen across categories of child's age, fetal growth, maternal body mass index and height, maternal smoking, and parental education. Risk of low grade glioma appeared increased with preterm birth (OR 1.6 (95% CI 0.8-3.1) and admission to neonatal intensive care (NICU) for >2 days (OR 1.7, 95% CI 0.9-3.6). We found little evidence of associations between risk of CBT and most birth characteristics. The associations we observed with GWG, prematurity and NICU admission require corroboration in other studies. © 2013 Wiley Periodicals, Inc.

  17. Magnitude of shift of tumor position as a function of moderated deep inspiration breath-hold: An analysis of pooled data of lung patients with active breath control in image-guided radiotherapy

    Directory of Open Access Journals (Sweden)

    Muralidhar K

    2008-01-01

    Full Text Available The purpose of this study was to evaluate the reproducibility and magnitude of shift of tumor position by using active breathing control and iView-GT for patients with lung cancer with moderate deep-inspiration breath-hold (mDIBH technique. Eight patients with 10 lung tumors were studied. CT scans were performed in the breath-holding phase. Moderate deep-inspiration breath-hold under spirometer-based monitoring system was used. Few important bony anatomic details were delineated by the radiation oncologist. To evaluate the interbreath-hold reproducibility of the tumor position, we compared the digital reconstruction radiographs (DRRs from planning system with the DRRs from the iView-GT in the machine room. We measured the shift in x, y, and z directions. The reproducibility was defined as the difference between the bony landmarks from the DRR of the planning system and those from the DRR of the iView-GT. The maximum shift of the tumor position was 3.2 mm, 3.0 mm, and 2.9 mm in the longitudinal, lateral, and vertical directions. In conclusion, the moderated deep-inspiration breath-hold method using a spirometer is feasible, with relatively good reproducibility of the tumor position for image-guided radiotherapy in lung cancers.

  18. Dose-escalated intensity-modulated radiotherapy and irradiation of subventricular zones in relation to tumor control outcomes of patients with glioblastoma multiforme

    Directory of Open Access Journals (Sweden)

    Kusumawidjaja G

    2016-03-01

    Full Text Available Grace Kusumawidjaja,1 Patricia Zhun Hong Gan,1 Whee Sze Ong,2 Achiraya Teyateeti,3 Pittaya Dankulchai,3 Daniel Yat Harn Tan,1 Eu Tiong Chua,1 Kevin Lee Min Chua,1 Chee Kian Tham,4 Fuh Yong Wong,1 Melvin Lee Kiang Chua1,5 1Division of Radiation Oncology, National Cancer Centre, Singapore; 2Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, Singapore; 3Department of Radiology, Division of Radiation Oncology, Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand; 4Division of Medical Oncology, National Cancer Centre, Singapore; 5Duke-NUS Graduate Medical School, Singapore Background: Glioblastoma multiforme (GBM is the most aggressive primary brain tumor with high relapse rate. In this study, we aimed to determine if dose-escalated (DE radiotherapy improved tumor control and survival in GBM patients. Methods: We conducted a retrospective analysis of 49 and 23 newly-diagnosed histology-proven GBM patients, treated with DE radiotherapy delivered in 70 Gy (2.33 Gy per fraction and conventional doses (60 Gy, respectively, between 2007 and 2013. Clinical target volumes for 70 and 60 Gy were defined by 0.5 and 2.0 cm expansion of magnetic resonance imaging T1-gadolinium-enhanced tumor/surgical cavity, respectively. Bilateral subventricular zones (SVZ were contoured on a co-registered pre-treatment magnetic resonance imaging and planning computed tomography dataset as a 5 mm wide structure along the lateral margins of the lateral ventricles. Survival outcomes of both cohorts were compared using log-rank test. Radiation dose to SVZ in the DE cohort was evaluated. Results: Median follow-up was 13.6 and 15.1 months for the DE- and conventionally-treated cohorts, respectively. Median overall survival (OS of patients who received DE radiotherapy was 15.2 months (95% confidence interval [CI] =11.0–18.6, while median OS of the latter cohort was 18.4 months (95% CI =12.5–31.4, P=0.253. Univariate analyses of

  19. Control of tumor size and disease activity during cotreatment with octreotide and the growth hormone receptor antagonist pegvisomant in an acromegalic patient

    NARCIS (Netherlands)

    A.F. Muller (Alex); R.J. Davis (Robert); K.A. Zib; J.A. Scarlett; S.W.J. Lamberts (Steven); J.A.M.J.L. Janssen (Joseph); A-J. van der Lely (Aart-Jan)

    2001-01-01

    textabstractWe describe the case of an acromegalic subject, who was the first patient ever treated with the GH receptor antagonist pegvisomant. Furthermore, in this particular patient, progression in tumor size was encountered during treatment with pegvisomant. The

  20. Contrast representation by computed tomography for the demonstration and therapy control of angiomatous tumors of the eye - the ocular manifestation of the Sturge-Weber disease

    Energy Technology Data Exchange (ETDEWEB)

    John, V.; Greber, H.; Alberti, W.

    1983-03-01

    Thin-layer computed tomography of the orbit together with contrast representation by computed tomography in form of circulation studies is the only non-invasive method to represent intraocular hemangiomatous tumors hidden under an exsudative detachment of the retina. This method allows to establish exact tumor parameters which are necessary for an efficient therapy. In this case, radiotherapy with Cs/sup 137/ is applied.

  1. Contrast representation by computed tomography for the demonstration and therapy control of angiomatous tumors of the eye - the ocular manifestation of the Sturge-Weber disease

    International Nuclear Information System (INIS)

    John, V.; Greber, H.; Alberti, W.

    1983-01-01

    Thin-layer computed tomography of the orbit together with contrast representation by computed tomography in form of circulation studies is the only non-invasive method to represent intraocular hemangiomatous tumors hidden under an exsudative detachment of the retina. This method allows to establish exact tumor parameters which are necessary for an efficient therapy. In this case, radiotherapy with Cs 137 is applied. (orig.) [de

  2. Decreased plasma DEK Oncogene Levels Correlate with p16-Negative Disease and Advanced Tumor Stage in a Case–Control Study of Patients with Head and Neck Squamous Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Trisha Wise-Draper

    2018-02-01

    Full Text Available Head and neck cancer (HNC remains the sixth most common malignancy worldwide and survival upon recurrence and/or metastasis remains poor. HNSCC has traditionally been associated with alcohol and nicotine use, but more recently the Human Papilloma Virus (HPV has emerged as a favorable prognostic risk factor for oropharyngeal HNSCC. However, further stratification with additional biomarkers to predict patient outcome continues to be essential. One candidate biomarker is the DEK oncogenic protein, which was previously detected in the urine of patients with bladder cancer and is known to be secreted by immune cells such as macrophages. Here, we investigated if DEK could be detected in human plasma and if DEK levels correlated with clinical and pathological variables of HNSCC. Plasma was separated from the peripheral blood of newly diagnosed, untreated HNSCC patients or age-matched normal healthy controls and analyzed for DEK protein using ELISA. Plasma concentrations of DEK protein were lower in p16-negative tumors compared to both normal controls and patients with p16-positive tumors. Patients with lower plasma concentrations of DEK were also more likely to have late stage tumors and a lower white blood cell count. Contrary to previously published work demonstrating a poor prognosis with high intratumoral DEK levels, we show for the first time that decreased concentrations of DEK in patient plasma correlates with poor prognostic factors, including HPV-negative status as determined by negative p16 expression and advanced tumor stage.

  3. Neuroendocrine Tumor: Statistics

    Science.gov (United States)

    ... Tumor > Neuroendocrine Tumor: Statistics Request Permissions Neuroendocrine Tumor: Statistics Approved by the Cancer.Net Editorial Board , 11/ ... the body. It is important to remember that statistics on the survival rates for people with a ...

  4. Tumors and Pregnancy

    Science.gov (United States)

    Tumors during pregnancy are rare, but they can happen. Tumors can be either benign or malignant. Benign tumors aren't cancer. Malignant ones are. The most common cancers in pregnancy are breast cancer, cervical cancer, lymphoma, and melanoma. ...

  5. DCB - Tumor Metastasis Research

    Science.gov (United States)

    Tumor metastasis research examines the mechanisms that allow cancer cells to leave the primary tumor and spread to another part of the body. Learn about recent tumor metastasis research studies supported by the Division of Cancer Biology.

  6. Childhood Brain Tumors

    Science.gov (United States)

    Brain tumors are abnormal growths inside the skull. They are among the most common types of childhood ... still be serious. Malignant tumors are cancerous. Childhood brain and spinal cord tumors can cause headaches and ...

  7. Pediatric Brain Tumor Foundation

    Science.gov (United States)

    ... navigate their brain tumor diagnosis. WATCH AND SHARE Brain tumors and their treatment can be deadly so ... Pediatric Central Nervous System Cancers Read more >> Pediatric Brain Tumor Foundation 302 Ridgefield Court, Asheville, NC 28806 ...

  8. Design of planning target volume margin using an active breathing control and Varian image-guided radiotherapy (IGRT) system in unresectable liver tumor

    International Nuclear Information System (INIS)

    Yue Jinbo; Yu Jinming; Liu Jing; Liu Tonghai; Yin Yong; Shi Xuetao; Song Jinlong

    2007-01-01

    Objective: To define the planning target volume(PTV) margin with an active breathing control (ABC) and the Varian image-guided radiotherapy (IGRT) system. Methods: Thirteen patients with liver cancer were treated with radiotherapy from May 2006 to September 2006. Prior to radiotherapy, all patients had undergone transarterial chemoembolization (TACE) by infusing a mixture of iodized oil contrast medium and chemotherapeutic agents, kV fluoroscopy was used to measure the potential motion of lipiodol spot positions during ABC breath-holds. ABC was used for planning CT scan and radiation delivery, with the breath held at the same phase of the respiratory cycle (near end-exhalation). Cone beam CT (CBCT) was taken using Varian IGRT system, which was then compared online with planning CT using a 3 D-3 D matching tool. Analysis relied on lipiodol spots on planning CT and CBCT manually. The treatment table was moved to produce acceptable setup before treatment delivery. Repeated CBCT image and another analysis were obtained after irradiation. Results: No motion of the intrahepatic tumor was observed on fluoroscopy during ABC breath-holds. The estimated required PTV margins, calculated according to the Stroom formula, were 4.4 mm, 5.3 mm and 7.8 mm in the x, y and z axis directions before radiotherapy. The corresponding parameters were 2.5m, 2.6 mm and 3.9 mm after radiotherapy. Conclusions: We have adopted a PTV margin of 5 mm, 6 mm and 8 mm in the x, y and z axis directions with ABC, and 3,3 and 4 mm with ABC and on-line kilovoltage CBCT. (authors)

  9. Ultrastructural Changes, Nuclear Factor-κB Activation, and Tumor Necrosis Factor-α Expression if Brain AfterAcute Normovolemic Hemodilution and Controlled Hypotension in Rats

    Science.gov (United States)

    Lv, Ran; Zhou, Wei; Duan, Manlin; Ge, Yali; Zhong, Taidi

    2008-01-01

    Aim To examine brain damage following different degrees of acute normovolemic hemodilution combined with controlled hypotension (ANH-CH) by neuronal