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Sample records for highly tumorigenic lung

  1. The CD44(high tumorigenic subsets in lung cancer biospecimens are enriched for low miR-34a expression.

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    Saroj K Basak

    Full Text Available Cellular heterogeneity is an integral part of cancer development and progression. Progression can be associated with emergence of cells that exhibit high phenotypic plasticity (including "de-differentiation" to primitive developmental states, and aggressive behavioral properties (including high tumorigenic potentials. We observed that many biomarkers that are used to identify Cancer Stem Cells (CSC can label cell subsets in an advanced clinical stage of lung cancer (malignant pleural effusions, or MPE. Thus, CSC-biomarkers may be useful for live sorting functionally distinct cell subsets from individual tumors, which may enable investigators to hone in on the molecular basis for functional heterogeneity. We demonstrate that the CD44(hi (CD44-high cancer cell subsets display higher clonal, colony forming potential than CD44(lo cells (n=3 and are also tumorigenic (n=2/2 when transplanted in mouse xenograft model. The CD44(hi subsets express different levels of embryonal (de-differentiation markers or chromatin regulators. In archived lung cancer tissues, ALDH markers co-localize more with CD44 in squamous cell carcinoma (n=5/7 than Adeno Carcinoma (n=1/12. MPE cancer cells and a lung cancer cell line (NCI-H-2122 exhibit chromosomal abnormalities and 1p36 deletion (n=3/3. Since miR-34a maps to the 1p36 deletion site, low miR-34a expression levels were detected in these cells. The colony forming efficiency of CD44(hi cells, characteristic property of CSC, can be inhibited by mir-34a replacement in these samples. In addition the highly tumorigenic CD44(hi cells are enriched for cells in the G2 phase of cell cycle.

  2. Napsin A is possibly useful marker to predict the tumorigenic potential of lung bronchiolo-alveolar hyperplasia in F344 rats.

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    Yokohira, Masanao; Kishi, Sosuke; Yamakawa, Keiko; Nakano, Yuko; Ninomiya, Fumiko; Kinouch, Shigemi; Tanizawa, Junko; Saoo, Kousuke; Imaida, Katsumi

    2014-03-01

    There are 2 types of bronchiolo-alveolar hyperplasia found in rat lungs. One is 'inflammatory hyperplasia' with a potential to recover in future with removal of the stimulating insult and the other is 'latent tumorigenic hyperplasia' as an independent preneoplastic lesion for adenocarcinoma. In the present experiment, we focused on rat lung bronchiolo-alveolar hyperplasia induced by 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which decreases with time after induction and reverts to normal, or by N-bis(2-hydroxypropyl)nitrosamine (DHPN), with tumorigenic potential to progress to adenoma and adenocarcinoma. Though NNK is a typical carcinogen inducing lung adenocarcinoma in female A/J mice, the tumorigenic potential by NNK in rats is weak. Differences between hyperplasias induced by DHPN and by NNK were here examined immunohistochemically. Formalin fixed paraffin embedded lung samples with hyperplastic and inflammatory lesions were obtained from rats exposed to DHPN or NNK and from lung inflammation models induced with fine particles like CuO, NiO and quartz. The 19 markers were examined immunohistochemically. Napsin A, in the inflammatory lesions and hyperplasia induced by NNK, was positive for macrophages and secretions in the alveoli spaces but less so in the walls of the alveoli. In the proliferative lesions including hyperplasia induced by DHPN, strong positive staining for napsin A was observed in the walls of the alveoli. Thus high expression was suggested to be possibly useful for detecting tumorigenic potential of rat lung hyperplasia.

  3. 空气燃烧排放提取物小鼠致肺癌作用%Lung tumorigenicity of airborne complex mixtures emitted from combustion effluents

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    唐莉莉; 唐萌; 贺霞; William F BUSBY Jr; 王加生

    2004-01-01

    目的评价6种具有致突变作用的空气燃烧排放提取物的致肺癌作用.方法用CD-1小鼠肺瘤生物测试方法,在小鼠断奶前处理受试物3次,6个月后观察肿瘤的发生率和病理组织学改变.并以苯并芘作为阳性对照.结果 6种具有突变作用的空气燃烧排放提取物均具有致肺癌作用,并呈剂量-效应关系,另外发现其致肺癌作用与其中是否含二氯甲烷无关.%AIM To evaluate lung tumorigenicity of six mutagenic complex mixtures extracted from combustion effluents or tar in a preweanling CD-1 mouse bioassay. METHODS Newborn mice were injected ip with test complex mixture sample in a total volume of 35 μL DMSO vehicle three times over a two-week-period. Potent carcinogen, benzo[a]pyrene, used as the positive control. Mice were sacrificed at 26 weeks of age and surface lung tumors were counted in the separated lobes of the Formalin-fixed lungs. Sections of lung tumors were stained with hematoxylin-eosin for histopathologic evaluation. RESULTS Four mixture samples extracted from a natural gas flame doped with high or low amounts of toluene in the presence or absence of methylene chloride were found to be tumorigenic as compared to the vehicle-controls. The two high-toluene mixture samples induced more lung tumors(64%-76%) than tumors(43%-45%) induced by two low-toluene mixtures on a weight basis (700 μg/animal). The presence or absence of methylene chloride did not significantly alter lung tumor incidence. A mixture sample (WSR-30) extracted from an ethylene-fueled jet-stirred reactor induced a dose-dependent increase in lung tumor incidence over a total dose range of 140-700 μg/animal. An extract mixture of tar from pyrolyzed wood (sweet gum) was also found to be tumorigenic in the bioassay. CONCLUSION Six mutagenic complex mixtures extracted from combustion effluents or tar are lung tumorigenic in the preweanling CD-1 mouse bioassay.

  4. Tumor-mast cell interactions: induction of pro-tumorigenic genes and anti-tumorigenic 4-1BB in MCs in response to Lewis Lung Carcinoma.

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    Wensman, Helena; Kamgari, Nona; Johansson, Anna; Grujic, Mirjana; Calounova, Gabriela; Lundequist, Anders; Rönnberg, Elin; Pejler, Gunnar

    2012-04-01

    Mast cells (MCs) can have either detrimental or beneficial effects on malignant processes but the underlying mechanisms are poorly understood. Here we addressed this issue by examining the interaction between Lewis Lung Carcinoma (LLC) cells and MCs. In vivo, LLC tumors caused a profound accumulation of MCs, suggesting that LLC tumors have the capacity to attract MCs. Indeed, transwell migration assays showed that LLC-conditioned medium had chemotactic activity towards MCs, which was blocked by an antibody towards stem cell factor. In order to gain insight into the molecular mechanisms operative in tumor-MC interactions, the effect of LLC on the MC gene expression pattern was examined. As judged by gene array analysis, conditioned medium from LLC cells caused significant upregulation of numerous cell surface receptors and a pro-angiogenic Runx2/VEGF/Dusp5 axis in MCs, the latter in line with a role for MCs in promoting tumor angiogenesis. Among the genes showing the highest extent of upregulation was Tnfrsf9, encoding the anti-tumorigenic protein 4-1BB, suggesting that also anti-tumorigenic factors are induced. Quantitative RT-PCR analysis showed that 4-1BB was upregulated in a transient manner, and it was also shown that tumor cells induce 4-1BB in human MCs. Immunohistochemical analysis showed that LLC-conditioned medium induced 4-1BB also at the protein level. Together, this study provides novel insight into the molecular events associated with MC-tumor interactions and suggests that tumor cells induce both pro- and anti-tumorigenic responses in MCs. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. Molecular alterations in tumorigenic human bronchial and breast epithelial cells induced by high let radiation

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    Hei, T. K.; Zhao, Y. L.; Roy, D.; Piao, C. Q.; Calaf, G.; Hall, E. J.

    Carcinogenesis is a multi-stage process with sequence of genetic events governing the phenotypic expression of a series of transformation steps leading to the development of metastatic cancer. In the present study, immortalized human bronchial (BEP2D) and breast (MCF-10F) cells were irradiated with graded doses of either 150 keV/μm alpha particles or 1 GeV/nucleon 56Fe ions. Transformed cells developed through a series of successive steps before becoming tumorigenic in nude mice. Cell fusion studies indicated that radiation-induced tumorigenic phenotype in BEP2D cells could be completely suppressed by fusion with non-tumorigenic BEP2D cells. The differential expressions of known genes between tumorigenic bronchial and breast cells induced by alpha particles and their respective control cultures were compared using cDNA expression array. Among the 11 genes identified to be differentially expressed in BEP2D cells, three ( DCC, DNA-PK and p21 CIPI) were shown to be consistently down-regulated by 2 to 4 fold in all the 5 tumor cell lines examined. In contrast, their expressions in the fusion cell lines were comparable to control BEP2D cells. Similarly, expression levels of a series of genes were found to be altered in a step-wise manner among tumorigenic MCF-10F cells. The results are highly suggestive that functional alterations of these genes may be causally related to the carcinogenic process.

  6. Development and characterization of two human triple-negative breast cancer cell lines with highly tumorigenic and metastatic capabilities.

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    Su, Yanrong; Pogash, Thomas J; Nguyen, Theresa D; Russo, Jose

    2016-03-01

    Triple-negative breast cancer (TNBC) is a group of cancer with high diversity, limited therapies, and poor prognosis. TNBC cell lines and animal models provide effective tools for studies and drug discovery. Here, we report the development of two TNBC cell lines (XtMCF and LmMCF) based on our existing cell model that consists of normal breast epithelial cell line MCF10F, estradiol-transformed cells trMCF, and Boyden chamber-selected tumorigenic cells bsMCF. The XtMCF and LmMCF cell line were derived from xenograft and lung metastasis of bsMCF cells, respectively. The bsMCF, XtMCF, and LmMCF cells have undergone epithelial-mesenchymal transition (EMT), exhibiting a mesenchymal-like feature. In vivo studies showed XtMCF and LmMCF cells were highly tumorigenic and metastatic. The injection of 5 × 10(4) cells to CB17/SCID mice mammary fat pad produced xenografts in 9/9 mice and tumors reached 10 millimeters in diameter in 5 weeks. The injection of 1 × 10(6) XtMCF or 8 × 10(4) LmMCF cells into the mice tail vein was sufficient to form extensive lung metastases in 4 weeks. The two new cell lines exhibited CD44(+) /CD49f(+) and CD44(+) /EpCAM(+) cancer stem cell (CSC) characteristics, and the EGF-like domain of EpCAM was cleaved off. Together with the normal and early transformed counterparts, herein we provide a complete cancer model for the study of initiation, evolution, and identification of new therapeutics for TNBC. The finding that EGF-like domain of EpCAM was cleaved off in cells which have undergone EMT suggests this cleavage may be involved in the EMT process and the cancer stem cell properties of these cells.

  7. Lung cancer tumorigenicity and drug resistance are maintained through ALDH(hi)CD44(hi) tumor initiating cells.

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    Liu, Jing; Xiao, Zhijie; Wong, Sunny Kit-Man; Tin, Vicky Pui-Chi; Ho, Ka-Yan; Wang, Junwen; Sham, Mai-Har; Wong, Maria Pik

    2013-10-01

    Limited improvement in long term survival of lung cancer patients has been achieved by conventional chemotherapy or targeted therapy. To explore the potentials of tumor initiating cells (TIC)-directed therapy, it is essential to identify the cell targets and understand their maintenance mechanisms. We have analyzed the performance of ALDH/CD44 co-expression as TIC markers and treatment targets of lung cancer using well-validated in vitro and in vivo analyses in multiple established and patient-derived lung cancer cells. The ALDH(hi)CD44(hi) subset showed the highest enhancement of stem cell phenotypic properties compared to ALDH(hi)CD44(lo), ALDH(lo)CD44(hi), ALDH(lo)CD44(lo) cells and unsorted controls. They showed higher invasion capacities, pluripotency genes and epithelial-mesenchymal transition transcription factors expression, lower intercellular adhesion protein expression and higher G2/M phase cell cycle fraction. In immunosuppressed mice, the ALDH(hi)CD44(hi)xenografts showed the highest tumor induction frequency, serial transplantability, shortest latency, largest volume and highest growth rates. Inhibition of sonic Hedgehog and Notch developmental pathways reduced ALDH+CD44+ compartment. Chemotherapy and targeted therapy resulted in higher AALDH(hi)CD44(hi) subset viability and ALDH(lo)CD44(lo) subset apoptosis fraction. ALDH inhibition and CD44 knockdown led to reduced stemness gene expression and sensitization to drug treatment. In accordance, clinical lung cancers containing a higher abundance of ALDH and CD44-coexpressing cells was associated with lower recurrence-free survival. Together, results suggested theALDH(hi)CD44(hi)compartment was the cellular mediator of tumorigenicity and drug resistance. Further investigation of the regulatory mechanisms underlying ALDH(hi)CD44(hi)TIC maintenance would be beneficial for the development of long term lung cancer control.

  8. mTORC1 Maintains the Tumorigenicity of SSEA-4+ High-Grade Osteosarcoma

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    Zhang, Wu; Ding, Meng-Lei; Zhang, Jia-Nian; Qiu, Jian-Ru; Shen, Yu-Hui; Ding, Xiao-Yi; Deng, Lian-Fu; Zhang, Wei-Bin; Zhu, Jiang

    2015-01-01

    Inactivation of p53 and/or Rb pathways restrains osteoblasts from cell-cycle exit and terminal differentiation, which underpins osteosarcoma formation coupled with dedifferentiation. Recently, the level of p-S6K was shown to independently predict the prognosis for osteosarcomas, while the reason behind this is not understood. Here we show that in certain high-grade osteosarcomas, immature SSEA-4+ tumor cells represent a subset of tumor-initiating cells (TICs) whose pool size is maintained by mTORC1 activity. mTORC1 supports not only SSEA-4+ cell self-renewal through S6K but also the regeneration of SSEA-4+ TICs by SSEA-4− osteosarcoma cell dedifferentiation. Mechanistically, active mTORC1 is required to prevent a likely upregulation of the cell-cycle inhibitor p27 independently of p53 or Rb activation, which otherwise effectively drives the terminal differentiation of SSEA-4− osteosarcoma cells at the expense of dedifferentiation. Thus, mTORC1 is shown to critically regulate the retention of tumorigenicity versus differentiation in discrete differentiation phases in SSEA-4+ TICs and their progeny. PMID:25853231

  9. Integrin α11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells

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    Zhu, Chang-Qi; Popova, Svetlana N.; Brown, Ewan R. S.; Barsyte-Lovejoy, Dalia; Navab, Roya; Shih, Warren; Li, Ming; Lu, Ming; Jurisica, Igor; Penn, Linda Z.; Gullberg, Donald; Tsao, Ming-Sound

    2007-01-01

    Integrin α11 (ITGA11/α11) is localized to stromal fibroblasts and commonly overexpressed in non-small-cell lung carcinoma (NSCLC). We hypothesized that stromal α11 could be important for the tumorigenicity of NSCLC cells. SV40 immortalized mouse embryonic fibroblasts established from wild-type (WT) and Itga11-deficient [knockout (KO)] mice were tested for their tumorigenicity in immune-deficient mice when implanted alone or coimplanted with the A549 human lung adenocarcinoma cells. A549 coimplanted with the fibroblasts showed a markedly enhanced tumor growth rate compared with A549, WT, or KO, which alone formed only small tumors. Importantly, the growth was significantly greater for A549+WT compared with A549+KO tumors. Reexpression of human α11 cDNA in KO cells rescued a tumor growth rate to that comparable with the A549+WT tumors. These findings were validated in two other NSCLC cell lines, NCI-H460 and NCI-H520. Gene expression profiling indicated that IGF2 mRNA expression level was >200 times lower in A549+KO compared with A549+WT tumors. Stable short-hairpin RNA (shRNA) down-regulation of IGF2 in WT (WTshIGF2) fibroblasts resulted in a decreased growth rate of A549+WTshIGF2, compared with A549+WT tumors. The results indicate that α11 is an important stromal factor in NSCLC and propose a paradigm for carcinoma–stromal interaction indirectly through interaction between the matrix collagen and stromal fibroblasts to stimulate cancer cell growth. PMID:17600088

  10. Establishment of highly tumorigenic human colorectal cancer cell line (CR4 with properties of putative cancer stem cells.

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    Rebecca A Rowehl

    Full Text Available BACKGROUND: Colorectal cancer (CRC has the third highest mortality rates among the US population. According to the most recent concept of carcinogenesis, human tumors are organized hierarchically, and the top of it is occupied by malignant stem cells (cancer stem cells, CSCs, or cancer-initiating cells, CICs, which possess unlimited self-renewal and tumor-initiating capacities and high resistance to conventional therapies. To reflect the complexity and diversity of human tumors and to provide clinically and physiologically relevant cancer models, large banks of characterized patient-derived low-passage cell lines, and especially CIC-enriched cell lines, are urgently needed. PRINCIPAL FINDINGS: Here we report the establishment of a novel CIC-enriched, highly tumorigenic and clonogenic colon cancer cell line, CR4, derived from liver metastasis. This stable cell line was established by combining 3D culturing and 2D culturing in stem cell media, subcloning of cells with particular morphology, co-culture with carcinoma associated fibroblasts (CAFs and serial transplantation to NOD/SCID mice. Using RNA-Seq complete transcriptome profiling of the tumorigenic fraction of the CR4 cells in comparison to the bulk tumor cells, we have identified about 360 differentially expressed transcripts, many of which represent stemness, pluripotency and resistance to treatment. Majority of the established CR4 cells express common markers of stemness, including CD133, CD44, CD166, EpCAM, CD24 and Lgr5. Using immunocytochemical, FACS and western blot analyses, we have shown that a significant ratio of the CR4 cells express key markers of pluripotency markers, including Sox-2, Oct3/4 and c-Myc. Constitutive overactivation of ABC transporters and NF-kB and absence of tumor suppressors p53 and p21 may partially explain exceptional drug resistance of the CR4 cells. CONCLUSIONS: The highly tumorigenic and clonogenic CIC-enriched CR4 cell line may provide an important new

  11. High mobility group A1 enhances tumorigenicity of human cholangiocarcinoma and confers resistance to therapy

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    Quintavalle, Cristina; Burmeister, Katharina; Piscuoglio, Salvatore

    2017-01-01

    High mobility group A1 (HMGA1) protein has been described to play an important role in numerous types of human carcinoma. By the modulation of several target genes HMGA1 promotes proliferation and epithelial-mesenchymal transition of tumor cells. However, its role in cholangiocarcinoma (CCA) has ...

  12. High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells.

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    da Silva, Patrícia Benites Gonçalves; Teixeira Dos Santos, Márcia Cristina; Rodini, Carolina Oliveira; Kaid, Carolini; Pereira, Márcia Cristina Leite; Furukawa, Gabriela; da Cruz, Daniel Sanzio Gimenes; Goldfeder, Mauricio Barbugiani; Rocha, Clarissa Ribeiro Reily; Rosenberg, Carla; Okamoto, Oswaldo Keith

    2017-03-21

    Medulloblastoma is a highly aggressive pediatric brain tumor, in which sporadic expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However the contribution of specific OCT4 isoforms to tumor aggressiveness is still poorly understood. Here, we report that medulloblastoma cells stably overexpressing the OCT4A isoform displayed enhanced clonogenic, tumorsphere generation, and invasion capabilities. Moreover, in an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic OCT4A effects were expression-level dependent and accompanied by distinct chromosomal aberrations. OCT4A overexpression in medulloblastoma cells also induced a marked differential expression of non-coding RNAs, including poorly characterized long non-coding RNAs and small nucleolar RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer.

  13. High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells

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    Gonçalves da Silva, Patrícia Benites; Teixeira dos Santos, Márcia Cristina; Rodini, Carolina Oliveira; Kaid, Carolini; Leite Pereira, Márcia Cristina; Furukawa, Gabriela; Gimenes da Cruz, Daniel Sanzio; Goldfeder, Mauricio Barbugiani; Reily Rocha, Clarissa Ribeiro; Rosenberg, Carla; Okamoto, Oswaldo Keith

    2017-01-01

    Medulloblastoma is a highly aggressive pediatric brain tumor, in which sporadic expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However the contribution of specific OCT4 isoforms to tumor aggressiveness is still poorly understood. Here, we report that medulloblastoma cells stably overexpressing the OCT4A isoform displayed enhanced clonogenic, tumorsphere generation, and invasion capabilities. Moreover, in an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic OCT4A effects were expression-level dependent and accompanied by distinct chromosomal aberrations. OCT4A overexpression in medulloblastoma cells also induced a marked differential expression of non-coding RNAs, including poorly characterized long non-coding RNAs and small nucleolar RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer. PMID:28186969

  14. Internal radiotherapy with copper-64-diacetyl-bis (N{sup 4}-methylthiosemicarbazone) reduces CD133{sup +} highly tumorigenic cells and metastatic ability of mouse colon carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Yoshii, Yukie [Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Furukawa, Takako [Molecular Imaging Center, National Institute of Radiological Sciences, Inage, Chiba 263-8555 (Japan); Kiyono, Yasushi [Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Watanabe, Ryo [Faculty of Engineering, University of Fukui, Fukui 910-8507 (Japan); Mori, Tetsuya [Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Yoshii, Hiroshi [Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Asai, Tatsuya [Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Faculty of Engineering, University of Fukui, Fukui 910-8507 (Japan); Okazawa, Hidehiko [Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Welch, Michael J. [Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Fujibayashi, Yasuhisa, E-mail: yfuji@nirs.go.j [Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Molecular Imaging Center, National Institute of Radiological Sciences, Inage, Chiba 263-8555 (Japan)

    2011-02-15

    Introduction: {sup 64}Cu-diacetyl-bis (N{sup 4}-methylthiosemicarbazone) ({sup 64}Cu-ATSM) is an imaging agent for positron emission tomography (PET) that targets hypoxic tumors. {sup 64}Cu-ATSM is also reported to be a potential agent for internal radiotherapy. In a mouse colon carcinoma (Colon-26) model, we have shown that {sup 64}Cu-ATSM preferentially localizes in intratumoral regions with a high density of CD133{sup +} cells, which show characteristics of cancer stem cells or cancer stem cell-like cells (collectively referred here as CSCs). In this study, we evaluated the therapeutic effect of {sup 64}Cu-ATSM in relation to CD133 expression using this model. Methods: Systemic administration of 37 MBq {sup 64}Cu-ATSM or saline was conducted twice within a 1-week interval to mice bearing 1-week-old Colon-26 tumors (days 0-7). At day 19, tumor size measurement, flow cytometry analysis and experimental lung metastatic assay were performed. The therapeutic effect of {sup 64}Cu-ATSM on sorted CD133{sup +} and CD133{sup -} Colon-26 cells was also examined in vitro. Results: In vivo studies showed that {sup 64}Cu-ATSM treatment inhibited tumor growth. The percentage of CD133{sup +} cells and metastatic ability in {sup 64}Cu-ATSM treated tumors was decreased compared with that in control animals. In vitro studies demonstrated that {sup 64}Cu-ATSM accumulated in cells under hypoxic conditions and incorporation of {sup 64}Cu-ATSM under hypoxia caused cell death in both CD133{sup +} and CD133{sup -} cells in a similar extent. Conclusions: {sup 64}Cu-ATSM administration reduced tumor volume as well as the percentage of CD133{sup +} cells and the metastatic ability of Colon-26 tumors. Together with our data, it is suggested that {sup 64}Cu-ATSM accumulates in regions high in CD133{sup +} highly tumorigenic cells and kills such regions by radiation, resulting in a decrease of the percentage of CD133{sup +} cells.

  15. Tumorigenic DNA viruses

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    Klein, G.

    1989-01-01

    The eighth volume of Advances in Viral Oncology focuses on the three major DNA virus groups with a postulated or proven tumorigenic potential: papillomaviruses, animal hepatitis viruses, and the Epstein-Bar virus. In the opening chapters, the contributors analyze the evidence that papillomaviruses and animal hepatitis viruses are involved in tumorigenesis and describe the mechanisms that trigger virus-host cell interactions. A detailed section on the Epstein-Barr virus (EBV) - comprising more than half the book - examines the transcription and mRNA processing patterns of the virus genome; the mechanisms by which EBV infects lymphoid and epithelial cells; the immunological aspects of the virus; the actions of EBV in hosts with Acquired Immune Deficiency Syndrome; and the involvement of EBV in the etiology of Burkitt's lymphoma.

  16. Spheroid formation induced by human lung adenocarcinoma cell line SPC-A1 and the tumorigenic ability of lung cancer stem cells%人肺腺癌细胞株SPC-A1诱导球体形成及肺癌干细胞致瘤能力评估

    Institute of Scientific and Technical Information of China (English)

    郝光军; 刘青; 王娟; 马彦娥; 丁延慧

    2015-01-01

    背景:目前关于肺癌干细胞是否可以形成球体及其致瘤能力尚缺乏明确的定论。目的:观察人肺腺癌细胞株SPC-A1诱导球体形成及肺癌干细胞的致瘤能力。方法:利用无血清-DF12培养液培养增殖期肺癌细胞株SPC-A1,加入重组人胰岛素样生长因子1和重组人表皮生长因子及重组人成纤维细胞生长因子10诱导球体形成,获得球体细胞沉淀物,进行免疫荧光检测和PCR 扩增,了解干细胞相关标志的表达情况。将肺球体细胞植入 NOD-SCID 免疫缺陷小鼠皮下,观察肿瘤生长情况,并利用活体荧光成像仪进行摄片。结果与结论:培养肺腺癌细胞SPC-A15-10 d获得肺球体。RT-PCR检测发现,肺球体细胞表达肺癌干细胞及细支气管肺泡干细胞标志物,CD24、CD221、CCSP和SP-C;另外,肺球体细胞与纯化的CD24+、CD221+肺癌干细胞同样表达肺干细胞的主干基因TTF-1、胚胎干细胞主干基因OCT4、Nanog和Bmi-1肺干细胞的主干基因TTF-1。荧光检测显示,80%以上的肺球体细胞中表达CCSP和OCT4;SPC-A1细胞具有肺泡Ⅱ型细胞特征,并表达SP-C蛋白,但仅约5%的细胞表达CCSP和OCT4。肺球体细胞皮下植入50 d,活体荧光成像可清晰显示小鼠体内肿瘤直径达1 cm。表明人肺腺癌细胞株SPC-A1可诱导球体形成,球体中富含肺癌干细胞并具有致瘤能力。%BACKGROUND:There is no clear conclusion on whether the lung cancer stem cels can induce to spheroid formation and have tumorigenicity. OBJECTIVE: To observe the spheroid formation induced by human lung adenocarcinoma cel line SPC-A1 and the tumorigenic ability of lung cancer stem cels. METHODS:SPC-A1 at proliferating phase was cultured in serum-free DF12 culture medium, and then recombinant human insulin-like growth factor-1, recombinant human epidermal growth factor, and recombinant human fibroblast growth factor-10 were added to induce spheroid cels

  17. Tumorigenicity, Motility and Liver Metastasis of Human Gastric Carcinoma Lines with High Metastatic Potential in the Liver of Nude Mice

    OpenAIRE

    1995-01-01

    To analyze the human gastric carcinoma metastasis to the liver, a human gastric carcinoma line, AZ521 was injected into the spleens of nude mice. Cells from the few liver metastatic foci of injected AZ521 were expanded in vitro and subsequently injected into the spleens of nude mice. By repeating these proce-dures five times, we were able to obtain a cell line, designated AZ-H5c, with high metastatic potential in nude mice. It was observed that animals had liver metastasis in 10 of 12 (83%) c...

  18. Spontaneous breathing during high-frequency oscillatory ventilation improves regional lung characteristics in experimental lung injury

    NARCIS (Netherlands)

    van Heerde, M.; Roubik, K.; Kopelent, V.; Kneyber, M. C. J.; Markhorst, D. G.

    2010-01-01

    Background Maintenance of spontaneous breathing is advocated in mechanical ventilation. This study evaluates the effect of spontaneous breathing on regional lung characteristics during high-frequency oscillatory (HFO) ventilation in an animal model of mild lung injury. Methods Lung injury was

  19. Spontaneous breathing during high-frequency oscillatory ventilation improves regional lung characteristics in experimental lung injury

    NARCIS (Netherlands)

    van Heerde, M.; Roubik, K.; Kopelent, V.; Kneyber, M. C. J.; Markhorst, D. G.

    2010-01-01

    Background Maintenance of spontaneous breathing is advocated in mechanical ventilation. This study evaluates the effect of spontaneous breathing on regional lung characteristics during high-frequency oscillatory (HFO) ventilation in an animal model of mild lung injury. Methods Lung injury was induce

  20. Lung cancer screening: identifying the high risk cohort

    OpenAIRE

    Marcus, Michael W.; Raji, Olaide Y; John K. Field

    2015-01-01

    Low dose computed tomography (LDCT) is a viable screening tool for early lung cancer detection and mortality reduction. In practice, the success of any lung cancer screening programme will depend on successful identification of individuals at high risk in order to maximise the benefit-harm ratio. Risk prediction models incorporating multiple risk factors have been recognised as a method of identifying individuals at high risk of developing lung cancer. Identification of individuals at high ri...

  1. Metabolic Activation of the Tumorigenic Pyrrolizidine Alkaloid, Retrorsine, Leading to DNA Adduct Formation In Vivo

    Directory of Open Access Journals (Sweden)

    Ming W. Chou

    2005-04-01

    Full Text Available Pyrrolizidine alkaloids are naturally occurring genotoxic chemicals produced by a large number of plants. The high toxicity of many pyrrolizidine alkaloids has caused considerable loss of free-ranging livestock due to liver and pulmonary lesions. Chronic exposure of toxic pyrrolizidine alkaloids to laboratory animals induces cancer. This investigation studies the metabolic activation of retrorsine, a representative naturally occurring tumorigenic pyrrolizidine alkaloid, and shows that a genotoxic mechanism is correlated to the tumorigenicity of retrorsine. Metabolism of retrorsine by liver microsomes of F344 female rats produced two metabolites, 6, 7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP, at a rate of 4.8 ± 0.1 nmol/mg/min, and retrorsine-N-oxide, at a rate of 17.6±0.5 nmol/mg/min. Metabolism was enhanced 1.7-fold by using liver microsomes prepared from dexamethasone-treated rats. DHP formation was inhibited 77% and retrorsine N-oxide formation was inhibited 29% by troleandomycin, a P450 3A enzyme inhibitor. Metabolism of retrorsine with lung, kidney, and spleen microsomes from dexamethasone-treated rats also generated DHP and the N-oxide derivative. When rat liver microsomal metabolism of retrorsine occurred in the presence of calf thymus DNA, a set of DHP-derived DNA adducts was formed; these adducts were detected and quantified by using a previously developed 32P-postlabeling/HPLC method. These same DNA adducts were also found in liver DNA of rats gavaged with retrorsine. Since DHP-derived DNA adducts are suggested to be potential biomarkers of riddelliine-induced tumorigenicity, our results indicate that (i similar to the metabolic activation of riddelliine, the mechanism of retrorsine-induced carcinogenicity in rats is also through a genotoxic mechanism involving DHP; and (ii the set of DHP-derived DNA adducts found in liver DNA of rats gavaged with retrorsine or riddelliine can serve as biomarkers for the

  2. Factors associated with dropout in a lung cancer high-risk cohort - the Liverpool lung project

    National Research Council Canada - National Science Library

    MARCUS, MICHAEL W; RAJI, OLAIDE Y; CHEN, YING; DUFFY, STEPHEN W; FIELD, JOHN K

    2014-01-01

    ... of participants who drop out and those still active in the study differ significantly. The study aimed to investigate factors associated with dropout in a 5-year follow-up of individuals at 'high-risk' of lung cancer...

  3. Components Necessary for High-Quality Lung Cancer Screening

    Science.gov (United States)

    Powell, Charles A.; Arenberg, Douglas; Detterbeck, Frank; Gould, Michael K.; Jaklitsch, Michael T.; Jett, James; Naidich, David; Vachani, Anil; Wiener, Renda Soylemez; Silvestri, Gerard

    2015-01-01

    Lung cancer screening with a low-dose chest CT scan can result in more benefit than harm when performed in settings committed to developing and maintaining high-quality programs. This project aimed to identify the components of screening that should be a part of all lung cancer screening programs. To do so, committees with expertise in lung cancer screening were assembled by the Thoracic Oncology Network of the American College of Chest Physicians (CHEST) and the Thoracic Oncology Assembly of the American Thoracic Society (ATS). Lung cancer program components were derived from evidence-based reviews of lung cancer screening and supplemented by expert opinion. This statement was developed and modified based on iterative feedback of the committees. Nine essential components of a lung cancer screening program were identified. Within these components 21 Policy Statements were developed and translated into criteria that could be used to assess the qualification of a program as a screening facility. Two additional Policy Statements related to the need for multisociety governance of lung cancer screening were developed. High-quality lung cancer screening programs can be developed within the presented framework of nine essential program components outlined by our committees. The statement was developed, reviewed, and formally approved by the leadership of CHEST and the ATS. It was subsequently endorsed by the American Association of Throacic Surgery, American Cancer Society, and the American Society of Preventive Oncology. PMID:25356819

  4. Establishment of a Novel Chinese Human Lung Adenocarcinoma Cell Line CPA-Yang1 which Produces Highly Bone Metastases in Immunodeficient Mice

    Directory of Open Access Journals (Sweden)

    Jianying LU

    2009-07-01

    Full Text Available Background and objective Lung cancer is a common malignancy and is the major determinant of overall cancer mortality worldwidely. Approximately 70% of lung cancer patients will die from metastatic diseases. The aim of this study is to establish a Chinese lung adenocarcinoma cell line with high metastasis potency for exploring the mechanism of occurrence and development in lung cancer. Methods The cell came from the pericardial effusion of a fifty-year old male patient with lung adenocarcinoma and the cells in primary culture were obtained successfully. Immunodeficient mice tumorigenicity was assayed. The cell growth curve was mappinged. Analysis of chromosome karyotype was tested. Tumor marker was detected by radioimmunoassay. The gene expression was measured by real-time quantitative PCR. Results The first passage cells were planted in immunodeficient mice subcutaneously and the tumorigenesis rate was 100% as well as later passages. Under the microscope, the cell showed larger and semi-suspension, semi-adherence. Approximately 0.8×106 cancerous cells were injected into left cardiac ventricle or tail vein of immunodeficient mice resulted start to appear lower limb paralysis and spine swelling deformation in the mice after inoculation two-three weeks. The bone metastasis rate was 90% in the tumor bearing mice by bone scintigraphy and pathology and only pulmonary metastasis 10% at the same time. The chromosome karyotype analysis of the cells was sub-triploid. The tumor marker CEA was detected in higher secretion by radioimmunoassay in the cell culture suspension. Quantitative real-time PCR was used to examined and compared SPC-A-1 lung adenocarcinoma, VEGF-C, IL-6, IL-8, genes were overexpressed. The novel cell line was named CPA-Yang1. Conclusion Tne novel strain CPA-Yang1 is an parental cell with characteristics of bone metastasis of Chinese lung adenocarcinoma. It has stable traits, highly metastatic ability and a good experimental model for

  5. Expiratory high-resolution CT in diffuse lung disease

    Energy Technology Data Exchange (ETDEWEB)

    Arakawa, Hiroaki [St. Marianna Univ. School of Medicine, Kawasaki, Kanagawa (Japan)

    2000-08-01

    Expiratory high-resolution computed tomography (HRCT) is a powerful adjunct to inspiratory HRCT in the diagnosis of diffuse lung disease (DLD), revealing air-trapping even when the inspiratory scan is normal. Expiratory scans are also useful in the differentiation of inhomogeneous lung opacity, which is not uncommon in various types of DLD. The history and technique of expiratory HRCT are described as well as the basic understanding of lung attenuation and the diagnostic value of expiratory scans DLD. The clinical significance of the presence of expiratory air-trapping in the absence of inspiratory scan abnormality is also presented. (author)

  6. High lung volume increases stress failure in pulmonary capillaries

    Science.gov (United States)

    Fu, Z.; Costello, M. L.; Tsukimoto, K.; Prediletto, R.; Elliott, A. R.; Mathieu-Costello, O.; West, J. B.

    1992-01-01

    We previously showed that when pulmonary capillaries in anesthetized rabbits are exposed to a transmural pressure (Ptm) of approximately 40 mmHg, stress failure of the walls occurs with disruption of the capillary endothelium, alveolar epithelium, or sometimes all layers. The present study was designed to test whether stress failure occurred more frequently at high than at low lung volumes for the same Ptm. Lungs of anesthetized rabbits were inflated to a transpulmonary pressure of 20 cmH2O, perfused with autologous blood at 32.5 or 2.5 cmH2O Ptm, and fixed by intravascular perfusion. Samples were examined by both transmission and scanning electron microscopy. The results were compared with those of a previous study in which the lung was inflated to a transpulmonary pressure of 5 cmH2O. There was a large increase in the frequency of stress failure of the capillary walls at the higher lung volume. For example, at 32.5 cmH2O Ptm, the number of endothelial breaks per millimeter cell lining was 7.1 +/- 2.2 at the high lung volume compared with 0.7 +/- 0.4 at the low lung volume. The corresponding values for epithelium were 8.5 +/- 1.6 and 0.9 +/- 0.6. Both differences were significant (P less than 0.05). At 52.5 cmH2O Ptm, the results for endothelium were 20.7 +/- 7.6 (high volume) and 7.1 +/- 2.1 (low volume), and the corresponding results for epithelium were 32.8 +/- 11.9 and 11.4 +/- 3.7. At 32.5 cmH2O Ptm, the thickness of the blood-gas barrier was greater at the higher lung volume, consistent with the development of more interstitial edema. Ballooning of the epithelium caused by accumulation of edema fluid between the epithelial cell and its basement membrane was seen at 32.5 and 52.5 cmH2O Ptm. At high lung volume, the breaks tended to be narrower and fewer were oriented perpendicular to the axis of the pulmonary capillaries than at low lung volumes. Transmission and scanning electron microscopy measurements agreed well. Our findings provide a physiological

  7. Isolation of tumorigenic circulating melanoma cells

    Science.gov (United States)

    Ma, Jie; Lin, Jennifer Y.; Alloo, Allireza; Wilson, Brian J.; Schatton, Tobias; Zhan, Qian; Murphy, George F.; Waaga-Gasser, Ana-Maria; Gasser, Martin; Hodi, F. Stephen; Frank, Natasha Y.; Frank, Markus H.

    2010-01-01

    Circulating tumor cells (CTC) have been identified in several human malignancies, including malignant melanoma. However, whether melanoma CTC are tumorigenic and cause metastatic progression is currently unknown. Here we isolate for the first time viable tumorigenic melanoma CTC and demonstrate that this cell population is capable of metastasis formation in human-to-mouse xenotransplantation experiments. The presence of CTC among peripheral blood mononuclear cells (PBMC) of murine recipients of subcutaneous (s.c.) human melanoma xenografts could be detected based on mRNA expression for human GAPDH and/or ATP-binding cassette subfamily B member 5 (ABCB5), a marker of malignant melanoma-initiating cells previously shown to be associated with metastatic disease progression in human patients. ABCB5 expression could also be detected in PBMC preparations from human stage IV melanoma patients but not healthy controls. The detection of melanoma CTC in human-to-mouse s.c. tumor xenotransplantation models correlated significantly with pulmonary metastasis formation. Moreover, prospectively isolated CTC from murine recipients of s.c. melanoma xenografts were capable of primary tumor initiation and caused metastasis formation upon xenotransplantation to secondary murine NOD-scid IL2Rγnull recipients. Our results provide initial evidence that melanoma CTC are tumorigenic and demonstrate that CTC are capable of causing metastatic tumor progression. These findings suggest a need for CTC eradication to inhibit metastatic progression and provide a rationale for assessment of therapeutic responses of this tumorigenic cell population to promising emerging melanoma treatment modalities. PMID:20977885

  8. ALDH/CD44 identifies uniquely tumorigenic cancer stem cells in salivary gland mucoepidermoid carcinomas.

    Science.gov (United States)

    Adams, April; Warner, Kristy; Pearson, Alexander T; Zhang, Zhaocheng; Kim, Hong Sun; Mochizuki, Daiki; Basura, Gregory; Helman, Joseph; Mantesso, Andrea; Castilho, Rogério M; Wicha, Max S; Nör, Jacques E

    2015-09-29

    A small sub-population of cells characterized by increased tumorigenic potential, ability to self-renew and to differentiate into cells that make up the tumor bulk, has been characterized in some (but not all) tumor types. These unique cells, namedcancer stem cells, are considered drivers of tumor progression in these tumors. The purpose of this work is to understand if cancer stem cells play a functional role in the tumorigenesis of salivary gland mucoepidermoid carcinomas. Here, we investigated the expression of putative cancer stem cell markers (ALDH, CD10, CD24, CD44) in primary human mucoepidermoid carcinomas by immunofluorescence, in vitro salisphere assays, and in vivo tumorigenicity assays in immunodeficient mice. Human mucoepidermoid carcinoma cells (UM-HMC-1, UM-HMC-3A, UM-HMC-3B) sorted for high levels of ALDH activity and CD44 expression (ALDHhighCD44high) consistently formed primary and secondary salispheres in vitro, and showed enhanced tumorigenic potential in vivo (defined as time to tumor palpability, tumor growth after palpability), when compared to ALDHlowCD44low cells. Cells sorted for CD10/CD24, and CD10/CD44 showed varying trends of salisphere formation, but consistently low in vivo tumorigenic potential. And finally, cells sorted for CD44/CD24 showed inconsistent results in salisphere formation and tumorigenic potential assays when different cell lines were evaluated. Collectively, these data demonstrate that salivary gland mucoepidermoid carcinomas contain a small population of cancer stem cells with enhanced tumorigenic potential and that are characterized by high ALDH activity and CD44 expression. These results suggest that patients with mucoepidermoid carcinoma might benefit from therapies that ablate these highly tumorigenic cells.

  9. Copper-64-diacetyl-bis (N{sup 4}-methylthiosemicarbazone) accumulates in rich regions of CD133{sup +} highly tumorigenic cells in mouse colon carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Yoshii, Yukie [Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Furukawa, Takako [Molecular Imaging Center, National Institute of Radiological Sciences, Inage, Chiba 263-8555 (Japan); Kiyono, Yasushi [Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Watanabe, Ryo [Faculty of Engineering, University of Fukui, Eiheiji, Fukui 910-8507 (Japan); Waki, Atsuo [Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Mori, Tetsuya [Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110 (United States); Yoshii, Hiroshi; Oh, Myungmi [Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Asai, Tatsuya [Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Faculty of Engineering, University of Fukui, Eiheiji, Fukui 910-8507 (Japan); Okazawa, Hidehiko [Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Welch, Michael J. [Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110 (United States); Fujibayashi, Yasuhisa [Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Molecular Imaging Center, National Institute of Radiological Sciences, Inage, Chiba 263-8555 (Japan)], E-mail: yfuji@u-fukui.ac.jp

    2010-05-15

    Introduction: {sup 64}Cu-diacetyl-bis (N{sup 4}-methylthiosemicarbazone) ({sup 64}Cu-ATSM) is a potential imaging agent of hypoxic tumor for use with PET. Recent literature demonstrated that cancer cells expressing CD133, which is a frequently used marker for so-called cancer stem cells or cancer stem cell-like cells (collectively referred to here as CSCs), contribute to tumor's therapeutic resistance and metastasis ability. Culturing under hypoxia is also reported to enlarge the proportion of CD133{sup +} cells, which would indicate survival advantage of CD133{sup +} cells under hypoxia. Here, we investigated the relationships between {sup 64}Cu-ATSM accumulation and existence of CD133{sup +} cells using mouse colon carcinoma (colon-26) tumor. Methods: Intratumor distribution of {sup 64}Cu-ATSM and {sup 18}F-fluorodeoxyglucose ({sup 18}FDG) was compared with immunohistochemical staining for CD133 with a colon-26 model. In vitro characterization of CD133{sup +} colon-26 cells was also performed. Results: In colon-26 tumors, {sup 64}Cu-ATSM localized preferentially in regions with a high density of CD133{sup +} cells. The percentage of CD133{sup +} cells was 11-fold higher in {sup 64}Cu-ATSM high-uptake regions compared with {sup 18}FDG high- (but {sup 64}Cu-ATSM low-) uptake regions. CD133{sup +} colon-26 cells showed characteristics previously linked with CSCs in other cancer cell lines, such as high colony-forming ability, high tumor-initiating ability and enrichment under hypoxic cultivation. The proportion of CD133{sup +} cells was enlarged by culturing under glucose starvation as well as hypoxia, and {sup 64}Cu-ATSM uptake was increased under such conditions. Conclusions: Our findings showed that, in colon-26 tumors, {sup 64}Cu-ATSM accumulates in rich regions of CD133{sup +} cells with characteristics of CSCs. Therefore {sup 64}Cu-ATSM could be a potential imaging agent for rich regions of CD133{sup +} cells, associated with CSCs, within tumors.

  10. Skin tumorigenic potential of crude and refined coal liquids and analogous petroleum products.

    Science.gov (United States)

    Witschi, H P; Smith, L H; Frome, E L; Pequet-Goad, M E; Griest, W H; Ho, C H; Guerin, M R

    1987-08-01

    The skin tumorigenic potential of seven complex hydrocarbon mixtures was determined: a coal-derived raw blend composed of light and heavy oils, a low- and high-severity hydrotreated product of that blend, and naphthas and fuel oils from the raw blend or from natural petroleum. Male and female C3H/Bdf mice were exposed three times per week to each test mixture by dermal application of 50 microliters of neat, 50, or 25% (w/v) preparations. Room, vehicle, and benzo[alpha]pyrene control groups were run concurrently. The raw blend produced an almost 100% incidence of skin tumors at all three doses while tumorigenicity was considerably decreased by hydrotreating the blend both in terms of incidence and onset. The tumorigenicities of the naphthas and fuel oils derived from the raw blend or from petroleums were low relative to that of the parent mixture. Although tumorigens in the raw blend were much reduced by hydrotreatment, tumorigenicity of the other agents did not parallel the content of polycyclic aromatic hydrocarbons known to be good tumor initiators.

  11. Soft fibrin gels promote selection and growth of tumorigenic cells

    Science.gov (United States)

    Liu, Jing; Tan, Youhua; Zhang, Huafeng; Zhang, Yi; Xu, Pingwei; Chen, Junwei; Poh, Yeh-Chuin; Tang, Ke; Wang, Ning; Huang, Bo

    2012-08-01

    The identification of stem-cell-like cancer cells through conventional methods that depend on stem cell markers is often unreliable. We developed a mechanical method for selecting tumorigenic cells by culturing single cancer cells in fibrin matrices of ~100 Pa in stiffness. When cultured within these gels, primary human cancer cells or single cancer cells from mouse or human cancer cell lines grew within a few days into individual round colonies that resembled embryonic stem cell colonies. Subcutaneous or intravenous injection of 10 or 100 fibrin-cultured cells in syngeneic or severe combined immunodeficiency mice led to the formation of solid tumours at the site of injection or at the distant lung organ much more efficiently than control cancer cells selected using conventional surface marker methods or cultured on conventional rigid dishes or on soft gels. Remarkably, as few as ten such cells were able to survive and form tumours in the lungs of wild-type non-syngeneic mice.

  12. Tumorigenic Potential of Extracellular Matrix Metalloproteinase Inducer

    Science.gov (United States)

    Zucker, Stanley; Hymowitz, Michelle; Rollo, Ellen E.; Mann, Richard; Conner, Cathleen E.; Cao, Jian; Foda, Hussein D.; Tompkins, David C.; Toole, Bryan P.

    2001-01-01

    Extracellular matrix metalloproteinase inducer (EMMPRIN), a glycoprotein present on the cancer cell plasma membrane, enhances fibroblast synthesis of matrix metalloproteinases (MMPs). The demonstration that peritumoral fibroblasts synthesize most of the MMPs in human tumors rather than the cancer cells themselves has ignited interest in the role of EMMPRIN in tumor dissemination. In this report we have demonstrated a role for EMMPRIN in cancer progression. Human MDA-MB-436 breast cancer cells, which are tumorigenic but slow growing in vivo, were transfected with EMMPRIN cDNA and injected orthotopically into mammary tissue of female NCr nu/nu mice. Green fluorescent protein was used to visualize metastases. In three experiments, breast cancer cell clones transfected with EMMPRIN cDNA were considerably more tumorigenic and invasive than plasmid-transfected cancer cells. Increased gelatinase A and gelatinase B expression (demonstrated by in situ hybridization and gelatin substrate zymography) was demonstrated in EMMPRIN-enhanced tumors. In contrast to de novo breast cancers in humans, human tumors transplanted into mice elicited minimal stromal or inflammatory cell reactions. Based on these experimental studies and our previous demonstration that EMMPRIN is prominently displayed in human cancer tissue, we propose that EMMPRIN plays an important role in cancer progression by increasing synthesis of MMPs. PMID:11395366

  13. Identification of lung cancer with high sensitivity and specificity by blood testing

    Directory of Open Access Journals (Sweden)

    Stephan Bernhard

    2010-02-01

    Full Text Available Abstract Background Lung cancer is a very frequent and lethal tumor with an identifiable risk population. Cytological analysis and chest X-ray failed to reduce mortality, and CT screenings are still controversially discussed. Recent studies provided first evidence for the potential usefulness of autoantigens as markers for lung cancer. Methods We used extended panels of arrayed antigens and determined autoantibody signatures of sera from patients with different kinds of lung cancer, different common non-tumor lung pathologies, and controls without any lung disease by a newly developed computer aided image analysis procedure. The resulting signatures were classified using linear kernel Support Vector Machines and 10-fold cross-validation. Results The novel approach allowed for discriminating lung cancer patients from controls without any lung disease with a specificity of 97.0%, a sensitivity of 97.9%, and an accuracy of 97.6%. The classification of stage IA/IB tumors and controls yielded a specificity of 97.6%, a sensitivity of 75.9%, and an accuracy of 92.9%. The discrimination of lung cancer patients from patients with non-tumor lung pathologies reached an accuracy of 88.5%. Conclusion We were able to separate lung cancer patients from subjects without any lung disease with high accuracy. Furthermore, lung cancer patients could be seprated from patients with other non-tumor lung diseases. These results provide clear evidence that blood-based tests open new avenues for the early diagnosis of lung cancer.

  14. High-sensitive C-reactive protein is associated with reduced lung function in young adults

    DEFF Research Database (Denmark)

    Rasmussen, F; Mikkelsen, D; Hancox, R J;

    2009-01-01

    Systemic inflammation has been associated with reduced lung function. However, data on the interrelationships between lung function and inflammation are sparse, and it is not clear if low-grade inflammation leads to reduced lung function. Associations between high-sensitive C-reactive protein (CR...

  15. [Continuous positive airway pressure and high-frequency independent lung ventilation in patients with chronic obstructive lung diseases].

    Science.gov (United States)

    Fedorova, E A; Vyzhigina, M A; Gal'perin, Iu S; Zhukova, S G; Titov, V A; Godin, A V

    2004-01-01

    The original hypoxemia, hypercapnia, high pulmonary hypertension, high resistance of microcirculation vessels, right volumetric ventricular overload, persistent sub-edema of pulmonary intersticium as well as disparity of ventilation and perfusion between both lungs are the main problems in patients with chronic obstructive disease of the lungs (CODL). Such patients are, as a rule, intolerant to the independent lung collaboration or artificial single-stage ventilation (ASV). Patients with respiratory insufficiency, stages 2 and 3, and with a pronounced impaired type of ventilation have originally a deranged blood gas composition, like hypoxemia or hypercapnia. The application of volume-controllable bi-pulmonary ASV in such patients maintains an adequate gas exchange hemodynamics. However, ASV is accompanied by a significantly reduced gas-exchange function of the single ventilated lung and by essentially worsened intrapulmonary hemodynamics. Therefore, what is needed is to use alternative methods of independent lung ventilation in order to eliminate the gas-exchange impairments and to enable surgical interventions at thoracic organs in such patients (who are intolerant to ASV). A choice of a method and means of oxygen supply to the independent lung is of great importance. The possibility to avoid a high pressure in the airways, while maintaining, simultaneously, an adequate gas exchange, makes the method related with maintaining a constant positive pressure in the airways (CPPA) a priority one in case of CODL patients. The use of constant high-frequency ventilation in the independent lung in patients with obstructive pulmonary lesions does not improve the gas exchange or hemodynamics. Simultaneously, a growing total pulmonary resistance and an increasing pressure in the pulmonary artery are observed. Consequently, the discussed method must not be used for the ventilation support of the independent lung in patients with the obstructive type of the impaired external

  16. Interfacial geometry dictates cancer cell tumorigenicity

    Science.gov (United States)

    Lee, Junmin; Abdeen, Amr A.; Wycislo, Kathryn L.; Fan, Timothy M.; Kilian, Kristopher A.

    2016-08-01

    Within the heterogeneous architecture of tumour tissue there exists an elusive population of stem-like cells that are implicated in both recurrence and metastasis. Here, by using engineered extracellular matrices, we show that geometric features at the perimeter of tumour tissue will prime a population of cells with a stem-cell-like phenotype. These cells show characteristics of cancer stem cells in vitro, as well as enhanced tumorigenicity in murine models of primary tumour growth and pulmonary metastases. We also show that interfacial geometry modulates cell shape, adhesion through integrin α5β1, MAPK and STAT activity, and initiation of pluripotency signalling. Our results for several human cancer cell lines suggest that interfacial geometry triggers a general mechanism for the regulation of cancer-cell state. Similar to how a growing tumour can co-opt normal soluble signalling pathways, our findings demonstrate how cancer can also exploit geometry to orchestrate oncogenesis.

  17. Impact of High-Priority Allocation on Lung and Heart-Lung Transplantation for Pulmonary Hypertension.

    Science.gov (United States)

    Savale, Laurent; Le Pavec, Jérôme; Mercier, Olaf; Mussot, Sacha; Jaïs, Xavier; Fabre, Dominique; O'Connell, Caroline; Montani, David; Stephan, François; Sitbon, Olivier; Simonneau, Gérald; Dartevelle, Philippe; Humbert, Marc; Fadel, Elie

    2017-08-01

    Since 2006 and 2007, patients in France with severe pulmonary hypertension (PH) who are at imminent risk of death, despite optimal treatment in the intensive care unit, are placed on a high-priority list (HPL) for heart-lung transplantation (HLT) or double-lung transplantation (DLT). We assessed the effect of this approach on the waiting list and outcomes after transplantation. We conducted a single-center, retrospective, before-and-after study of consecutive patients with severe group 1, 1', or 4 PH listed for DLT or HLT between 2000 and 2013 (ie, 6 years before and 6 years after HPL implementation). We included 234 patients. HPL implementation resulted in a significant decrease of the cumulative incidence of death on the waiting list at 1 and 2 years (p < 0.0001). The cumulative incidence of transplantation increased significantly from 48% to 76% after 2 years (p < 0.0001). Overall survival after transplantation was not significantly different between the pre-HPL and post-HPL era. In the HPL period, patients on the regular list who received a transplant had a nonsignificant trend toward improved overall survival compared with those on the HPL who received a transplant (at 1, 2, 3, and 5 years: 85%, 77%, 72%, and 72% vs 67%, 61%, 58%, and 50%; p = 0.053). Finally, survival after listing improved significantly after HPL implementation (at 1, 2, 3, and 5 years: 69%, 62%, 58%, and 54% vs 54%, 45%, 34%, and 26% before the HPL; p < 0.001). HPL implementation was followed by higher survival of PH patients after registration on the DLT or HLT waiting list and by a higher cumulative incidence of transplantation among waiting-list patients. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  18. Establishment and characterization of a new human pancreatic adenocarcinoma cell line with high metastatic potential to the lung

    Directory of Open Access Journals (Sweden)

    Schwarzenbach Heidi

    2010-06-01

    Full Text Available Abstract Background Pancreatic cancer is still associated with devastating prognosis. Real progress in treatment options has still not been achieved. Therefore new models are urgently needed to investigate this deadly disease. As a part of this process we have established and characterized a new human pancreatic cancer cell line. Methods The newly established pancreatic cancer cell line PaCa 5061 was characterized for its morphology, growth rate, chromosomal analysis and mutational analysis of the K-ras, EGFR and p53 genes. Gene-amplification and RNA expression profiles were obtained using an Affymetrix microarray, and overexpression was validated by IHC analysis. Tumorigenicity and spontaneous metastasis formation of PaCa 5061 cells were analyzed in pfp-/-/rag2-/- mice. Sensitivity towards chemotherapy was analysed by MTT assay. Results PaCa 5061 cells grew as an adhering monolayer with a doubling time ranging from 30 to 48 hours. M-FISH analyses showed a hypertriploid complex karyotype with multiple numerical and unbalanced structural aberrations. Numerous genes were overexpressed, some of which have previously been implicated in pancreatic adenocarcinoma (GATA6, IGFBP3, IGFBP6, while others were detected for the first time (MEMO1, RIOK3. Specifically highly overexpressed genes (fold change > 10 were identified as EGFR, MUC4, CEACAM1, CEACAM5 and CEACAM6. Subcutaneous transplantation of PaCa 5061 into pfp-/-/rag2-/- mice resulted in formation of primary tumors and spontaneous lung metastasis. Conclusion The established PaCa 5061 cell line and its injection into pfp-/-/rag2-/- mice can be used as a new model for studying various aspects of the biology of human pancreatic cancer and potential treatment approaches for the disease.

  19. RELATED GENES IN LUNG CANCER TISSUES ASSOCIATED WITH RESIDENTIAL HIGH RADON EXPOSURE

    Institute of Scientific and Technical Information of China (English)

    夏英; 杨梅英; 张守志; 叶常青

    2002-01-01

    Objective: To investigate the related genes in lung cancer tissues associated with residential high radon exposure. Methods: Differentially expressed gene fragments in lung cancer and normal lung tissues were discovered by differential display and reverse Northern blot hybridization method. The fragments positive in lung cancer and negative in normal lung tissue were determined. Results: Seven differential displayed fragments were sequenced. One of them named NA7 is 95% homologous with AI208667 in EAT of Genbank. Another fragment named NG2 is up to 98% homologous with five fragments. The remained one CA1 may be a new gene fragment. Conclusion: 3 gene fragments were discovered from lung cancer and normal lung tissues of high radon exposure resident.

  20. Sequential change of high-resolution CT findings of interstitial lung disease in polymyositis and dermatomyositis

    Energy Technology Data Exchange (ETDEWEB)

    Tsukada, Hiroshi; Furuizumi, Naoya; Akita, Shinichi; Oda, Junichi; Sakai, Kunio; Suzuki, Eiichi; Emura, Iwao (Niigata Univ. (Japan). School of Medicine)

    1994-01-01

    Sequential changes of interstitial lung disease in fourteen patients of polymyositis/dermatomyositis (PM/DM) were followed up by high-resolution CT (HRCT). Most frequent CT findings were intense lung attenuation (ILA) with volume loss and slightly increased lung attenuation (SILA). Open lung biopsy was performed in a case with ILA shadow which revealed so-called usual interstitial pneumonia (UIP). Most intense ILA and SILA shadows resolved after steroid therapy. Some of ILA, however, reappeared and accompanied more prominent volume loss findings than before treatment. We think HRCT findings of interstitial lung disease in PM/DM may indicate prognosis of these diagnoses to some degree. (author).

  1. Genotoxic and tumorigenic pyrrolizidine alkaloids in Chinese herbal plants

    Institute of Scientific and Technical Information of China (English)

    P.P. Fu; Q. Xia; M.W. Chou; G. Lin

    2005-01-01

    Pyrrolizidine alkaloids are a class of hepatotoxic and tumorigenic compounds detected in Chinese herbal plants,contaminated foods, and dietary supplements. In this review, the sources, toxicity, genotoxicity, tumorigenicity, and the metabolic pathways,particular the activation pathways leading to hepatotoxicity and tumorigenicity, of pyrrolizidine alkaloids are briefly discussed, with a focus on the most recent important findings concerning the genotoxic mechanism by which riddelliine liver tumors. This mechanism involves the formation of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts and may be general to most carcinogenic pyrrolizidine alkaloids.

  2. Three-dimensional scaffolds of acellular human and porcine lungs for high throughput studies of lung disease and regeneration.

    Science.gov (United States)

    Wagner, Darcy E; Bonenfant, Nicholas R; Sokocevic, Dino; DeSarno, Michael J; Borg, Zachary D; Parsons, Charles S; Brooks, Elice M; Platz, Joseph J; Khalpey, Zain I; Hoganson, David M; Deng, Bin; Lam, Ying W; Oldinski, Rachael A; Ashikaga, Takamaru; Weiss, Daniel J

    2014-03-01

    Acellular scaffolds from complex whole organs such as lung are being increasingly studied for ex vivo organ generation and for in vitro studies of cell-extracellular matrix interactions. We have established effective methods for efficient de and recellularization of large animal and human lungs including techniques which allow multiple small segments (∼ 1-3 cm(3)) to be excised that retain 3-dimensional lung structure. Coupled with the use of a synthetic pleural coating, cells can be selectively physiologically inoculated via preserved vascular and airway conduits. Inoculated segments can be further sliced for high throughput studies. Further, we demonstrate thermography as a powerful noninvasive technique for monitoring perfusion decellularization and for evaluating preservation of vascular and airway networks following human and porcine lung decellularization. Collectively, these techniques are a significant step forward as they allow high throughput in vitro studies from a single lung or lobe in a more biologically relevant, three-dimensional acellular scaffold. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Tumorigenic heterogeneity in cancer stem cells evolved from long-term cultures of telomerase-immortalized human mesenchymal stem cells

    DEFF Research Database (Denmark)

    Burns, Jorge S; Abdallah, Basem M; Guldberg, Per

    2005-01-01

    Long-term cultures of telomerase-transduced adult human mesenchymal stem cells (hMSC) may evolve spontaneous genetic changes leading to tumorigenicity in immunodeficient mice (e.g., hMSC-TERT20). We wished to clarify whether this unusual phenotype reflected a rare but dominant subpopulation...... or if the stem cell origin allowed most cells to behave as cancer stem cells. Cultures of the hMSC-TERT20 strain at population doubling 440 were highly clonogenic (94%). From 110 single-cell clones expanded by 20 population doublings, 6 underwent detailed comparison. Like the parental population, each clone had...... tumorigenicity correlated with good viability plus capillary morphogenesis on serum starvation and high cyclin D1 expression. Thus, hMSC-TERT20 clones represent cancer stem cells with hierarchical tumorigenicity, providing new models to explore the stem cell hypothesis for cancer....

  4. Crucial role of carbonic anhydrase IX in tumorigenicity of xenotransplanted adult T-cell leukemia-derived cells.

    Science.gov (United States)

    Nasu, Kentaro; Yamaguchi, Kazunori; Takanashi, Tomoka; Tamai, Keiichi; Sato, Ikuro; Ine, Shoji; Sasaki, Osamu; Satoh, Kennichi; Tanaka, Nobuyuki; Tanaka, Yuetsu; Fukushima, Takuya; Harigae, Hideo; Sugamura, Kazuo

    2017-03-01

    Carbonic anhydrase IX (CA9) is a membrane-associated carbonic anhydrase that regulates cellular pH, is upregulated in various solid tumors, and is considered to be a therapeutic target. Here, we describe the essential role of CA9 in the tumorigenicity of cells derived from human adult T-cell leukemia/lymphoma (ATL). We previously established the highly tumorigenic ST1-N6 subline from the ATL-derived ST1 cell line by serial xenotransplantation in NOG mice. In the present study, we first show that CA9 expression is strongly enhanced in ST1-N6 cells. We then sorted ST1 cells by high or low CA9 expression and established ST1-CA9(high) and ST1-CA9(low) sublines. ST1-CA9(high) cells, like ST1-N6 cells, were more strongly tumorigenic than ST1-CA9(low) or parental ST1 cells when injected into NOG mice. Knockdown of CA9 with shRNAs suppressed the ability of ST1-CA9(high) cells to initiate tumors, and the tumorigenicity of ST1 cells was significantly enhanced by introducing wild-type CA9 or a CA9 mutant with deletion of an intracytoplasmic domain. However, a CA9 with point mutations in the catalytic site did not increase the tumorigenicity of ST1 cells. Furthermore, we detected a small population of CA9(+) CD25(+) cells in lymph nodes of ATL patients. These findings suggest that CA9, and particularly its carbonic anhydrase activity, promotes the tumorigenicity of ATL-derived cells and may be involved in malignant development of lymphoma-type ATL. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  5. Identification of Coordinately Regulated Functional Modules in Thyroid Tissues from Rats Exposed to a Tumorigenic and a Non-Tumorigenic Conazole Fungicide Using Oncomine®

    Science.gov (United States)

    Conazoles are triazole- or imidazole-containing fungicides used in agriculture and medicine. Using transcriptomic analysis of rat thyroid tissues exposed to either tumorigenic or non-tumorigenic structurally related conazoles, we identified new findings on thyroid gene expressio...

  6. Highly Sensitive Marker Panel for Guidance in Lung Cancer Rapid Diagnostic Units

    Science.gov (United States)

    Blanco-Prieto, Sonia; De Chiara, Loretta; Rodríguez-Girondo, Mar; Vázquez-Iglesias, Lorena; Rodríguez-Berrocal, Francisco Javier; Fernández-Villar, Alberto; Botana-Rial, María Isabel; de la Cadena, María Páez

    2017-01-01

    While evidence for lung cancer screening implementation in Europe is awaited, Rapid Diagnostic Units have been established in many hospitals to accelerate the early diagnosis of lung cancer. We seek to develop an algorithm to detect lung cancer in a symptomatic population attending such unit, based on a sensitive serum marker panel. Serum concentrations of Epidermal Growth Factor, sCD26, Calprotectin, Matrix Metalloproteinases −1, −7, −9, CEA and CYFRA 21.1 were determined in 140 patients with respiratory symptoms (lung cancer and controls with/without benign pathology). Logistic Lasso regression was performed to derive a lung cancer prediction model, and the resulting algorithm was tested in a validation set. A classification rule based on EGF, sCD26, Calprotectin and CEA was established, able to reasonably discriminate lung cancer with 97% sensitivity and 43% specificity in the training set, and 91.7% sensitivity and 45.4% specificity in the validation set. Overall, the panel identified with high sensitivity stage I non-small cell lung cancer (94.7%) and 100% small-cell lung cancers. Our study provides a sensitive 4-marker classification algorithm for lung cancer detection to aid in the management of suspicious lung cancer patients in the context of Rapid Diagnostic Units. PMID:28117344

  7. Results of the Randomized Danish Lung Cancer Screening Trial with Focus on High-Risk Profiling

    DEFF Research Database (Denmark)

    M. W. Wille, Mathilde; Dirksen, Asger; Ashraf, Haseem;

    2016-01-01

    RATIONALE: As of April 2015, participants in the Danish Lung Cancer Screening Trial had been followed for at least 5 years since their last screening. OBJECTIVES: Mortality, causes of death, and lung cancer findings are reported to explore the effect of computed tomography (CT) screening. METHODS...... fewer deaths in the screening group. CONCLUSIONS: No statistically significant effects of CT screening on lung cancer mortality were found, but the results of post hoc high-risk subgroup analyses showed nonsignificant trends that seem to be in good agreement with the results of the National Lung...

  8. Attitudes towards Lung Cancer Screening in an Australian High-Risk Population

    Directory of Open Access Journals (Sweden)

    Alexandra E. Flynn

    2013-01-01

    Full Text Available Objectives. To determine whether persons at high risk of lung cancer would participate in lung cancer screening test if available in Australia and to elicit general attitudes towards cancer screening and factors that might affect participation in a screening program. Methods. We developed a 20-item written questionnaire, based on two published telephone interview scripts, addressing attitudes towards cancer screening, perceived risk of lung cancer, and willingness to be screened for lung cancer and to undertake surgery if lung cancer were detected. The questionnaire was given to 102 current and former smokers attending the respiratory clinic and pulmonary rehabilitation programmes. Results. We gained 90 eligible responses (M:F, 69:21. Mean [SD] age was 63 [11] and smoking history was 32 [21] pack years. 95% of subjects would participate in a lung cancer screening test, and 91% of these would consider surgery if lung cancer was detected. 44% of subjects considered that they were at risk of lung cancer. This was lower in ex-smokers than in current smokers. Conclusions. There is high willingness for lung cancer screening and surgical treatment. There is underrecognition of risk among ex-smokers. This misperception could be a barrier to a successful screening or case-finding programme in Australia.

  9. Lung findings on high resolution CT in early ankylosing spondylitis

    Energy Technology Data Exchange (ETDEWEB)

    Kiris, Adem E-mail: ademkiris@hotmail.com; Ozgocmen, Salih; Kocakoc, Ercan; Ardicoglu, Ozge; Ogur, Erkin

    2003-07-01

    Objective: Ankylosing spondylitis (AS) is a chronic inflammatory disease mainly affecting the axial skeleton and pulmonary involvement is a well known feature of the disease. The aim of this study was to investigate the pulmonary high resolution computed tomography (HRCT) findings of patients with early AS. The relationship between pulmonary function tests (PFT) and HRCT findings was also determined. Subjects and methods: Twenty-eight patients with AS (mean age 30.8{+-}7.4 and disease duration 7.0{+-}2.6) were included in the study. Patients with a disease duration of >10 years or had other pulmonary diseases were excluded. All patients underwent plain chest radiography (posteroanterior and lateral views), thoracic HRCT and PFT. Results: All chest radiographs were normal and HRCT revealed abnormalities in 18 patients. The most common abnormalities seen on HRCT were mosaic pattern (ten of 28), subpleural nodule (seven of 28) and parenchymal bands (five of 28). Seven of ten patients with mosaic pattern revealed air trapping areas on end expiratory scans. Twelve patients had abnormal PFT and all had restrictive type of involvement. Ten of these 12 patients had abnormal HRCT and the remaining two patients had normal HRCT. On the other hand, eight patients with normal PFT had abnormalities on HRCT. Conclusion: Patients with early AS frequently have abnormalities on HRCT, even though they have normal PFT and chest X-ray. Small airway involvement was found as frequent as interstitial lung disease in early AS.

  10. MIF Maintains the Tumorigenic Capacity of Brain Tumor-Initiating Cells by Directly Inhibiting p53.

    Science.gov (United States)

    Fukaya, Raita; Ohta, Shigeki; Yaguchi, Tomonori; Matsuzaki, Yumi; Sugihara, Eiji; Okano, Hideyuki; Saya, Hideyuki; Kawakami, Yutaka; Kawase, Takeshi; Yoshida, Kazunari; Toda, Masahiro

    2016-05-01

    Tumor-initiating cells thought to drive brain cancer are embedded in a complex heterogeneous histology. In this study, we isolated primary cells from 21 human brain tumor specimens to establish cell lines with high tumorigenic potential and to identify the molecules enabling this capability. The morphology, sphere-forming ability upon expansion, and differentiation potential of all cell lines were indistinguishable in vitro However, testing for tumorigenicity revealed two distinct cell types, brain tumor-initiating cells (BTIC) and non-BTIC. We found that macrophage migration inhibitory factor (MIF) was highly expressed in BTIC compared with non-BTIC. MIF bound directly to both wild-type and mutant p53 but regulated p53-dependent cell growth by different mechanisms, depending on glioma cell line and p53 status. MIF physically interacted with wild-type p53 in the nucleus and inhibited its transcription-dependent functions. In contrast, MIF bound to mutant p53 in the cytoplasm and abrogated transcription-independent induction of apoptosis. Furthermore, MIF knockdown inhibited BTIC-induced tumor formation in a mouse xenograft model, leading to increased overall survival. Collectively, our findings suggest that MIF regulates BTIC function through direct, intracellular inhibition of p53, shedding light on the molecular mechanisms underlying the tumorigenicity of certain malignant brain cells. Cancer Res; 76(9); 2813-23. ©2016 AACR. ©2016 American Association for Cancer Research.

  11. Foraging behavior of humpback whales: kinematic and respiratory patterns suggest a high cost for a lunge.

    Science.gov (United States)

    Goldbogen, Jeremy A; Calambokidis, John; Croll, Donald A; Harvey, James T; Newton, Kelly M; Oleson, Erin M; Schorr, Greg; Shadwick, Robert E

    2008-12-01

    Lunge feeding in rorqual whales is a drag-based feeding mechanism that is thought to entail a high energetic cost and consequently limit the maximum dive time of these extraordinarily large predators. Although the kinematics of lunge feeding in fin whales supports this hypothesis, it is unclear whether respiratory compensation occurs as a consequence of lunge-feeding activity. We used high-resolution digital tags on foraging humpback whales (Megaptera novaengliae) to determine the number of lunges executed per dive as well as respiratory frequency between dives. Data from two whales are reported, which together performed 58 foraging dives and 451 lunges. During one study, we tracked one tagged whale for approximately 2 h and examined the spatial distribution of prey using a digital echosounder. These data were integrated with the dive profile to reveal that lunges are directed toward the upper boundary of dense krill aggregations. Foraging dives were characterized by a gliding descent, up to 15 lunges at depth, and an ascent powered by steady swimming. Longer dives were required to perform more lunges at depth and these extended apneas were followed by an increase in the number of breaths taken after a dive. Maximum dive durations during foraging were approximately half of those previously reported for singing (i.e. non-feeding) humpback whales. At the highest lunge frequencies (10 to 15 lunges per dive), respiratory rate was at least threefold higher than that of singing humpback whales that underwent a similar degree of apnea. These data suggest that the high energetic cost associated with lunge feeding in blue and fin whales also occurs in intermediate sized rorquals.

  12. Iron supplementation at high altitudes induces inflammation and oxidative injury to lung tissues in rats

    Energy Technology Data Exchange (ETDEWEB)

    Salama, Samir A., E-mail: salama.3@buckeyemail.osu.edu [High Altitude Research Center, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia); Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11751 (Egypt); Department of Pharmacology and GTMR Unit, College of Clinical Pharmacy, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia); Omar, Hany A. [Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514 (Egypt); Maghrabi, Ibrahim A. [Department of Clinical Pharmacy, College of Clinical Pharmacy, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia); AlSaeed, Mohammed S. [Department of Surgery, College of Medicine, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia); EL-Tarras, Adel E. [High Altitude Research Center, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia)

    2014-01-01

    Exposure to high altitudes is associated with hypoxia and increased vulnerability to oxidative stress. Polycythemia (increased number of circulating erythrocytes) develops to compensate the high altitude associated hypoxia. Iron supplementation is, thus, recommended to meet the demand for the physiological polycythemia. Iron is a major player in redox reactions and may exacerbate the high altitudes-associated oxidative stress. The aim of this study was to explore the potential iron-induced oxidative lung tissue injury in rats at high altitudes (6000 ft above the sea level). Iron supplementation (2 mg elemental iron/kg, once daily for 15 days) induced histopathological changes to lung tissues that include severe congestion, dilatation of the blood vessels, emphysema in the air alveoli, and peribronchial inflammatory cell infiltration. The levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), lipid peroxidation product and protein carbonyl content in lung tissues were significantly elevated. Moreover, the levels of reduced glutathione and total antioxidant capacity were significantly reduced. Co-administration of trolox, a water soluble vitamin E analog (25 mg/kg, once daily for the last 7 days of iron supplementation), alleviated the lung histological impairments, significantly decreased the pro-inflammatory cytokines, and restored the oxidative stress markers. Together, our findings indicate that iron supplementation at high altitudes induces lung tissue injury in rats. This injury could be mediated through excessive production of reactive oxygen species and induction of inflammatory responses. The study highlights the tissue injury induced by iron supplementation at high altitudes and suggests the co-administration of antioxidants such as trolox as protective measures. - Highlights: • Iron supplementation at high altitudes induced lung histological changes in rats. • Iron induced oxidative stress in lung tissues of rats at high altitudes. • Iron

  13. Soluble Suppression of Tumorigenicity 2 and Echocardiography in Sepsis.

    Science.gov (United States)

    Yang, Hyun Suk; Hur, Mina; Kim, Hanah; Magrini, Laura; Marino, Rossella; Di Somma, Salvatore

    2016-11-01

    Soluble suppression of tumorigenicity 2 (sST2) has emerged as a biomarker of cardiac stretch or remodeling, and has demonstrated a role in acutely decompensated heart failure. However, its role in sepsis-induced cardiac dysfunction is still unknown. We explored whether sST2 serum concentration reflects either systolic or diastolic dysfunction as measured by Doppler echocardiography. In a total of 127 patients with sepsis, correlations between sST2 and blood pressure, left ventricular (LV) ejection fraction, LV diastolic filling (ratio of early transmitral flow velocity to early diastolic mitral annulus velocity), and resting pulmonary arterial pressure were evaluated. Correlations between sST2 and other sepsis biomarkers (high-sensitivity C-reactive protein [hs-CRP] and procalcitonin) were also examined. sST2 showed a moderate correlation with mean arterial pressure (r=-0.3499) but no correlation with LV ejection fraction, diastolic filling, or resting pulmonary hypertension. It showed moderate correlations with hs-CRP and procalcitonin (r=0.2608 and r=0.3829, respectively). sST2 might have a role as a biomarker of shock or inflammation, but it cannot reflect echocardiographic findings of LV ejection fraction or diastolic filling in sepsis.

  14. Suppression of tumorigenicity and metastatic potential of melanoma cells by transduction of interferon gene

    Directory of Open Access Journals (Sweden)

    Lykhova A. A.

    2014-01-01

    Full Text Available The aim of this study was to investigate an inhibitory effect of baculovirus-mediated transduction of the murine interferon-beta gene on mouse melanoma in vitro and in vivo. Methods. Studies were performed on B16 mouse melanoma (MM-4 cell line. Transduction, immunocytochemical and tumor cell biology approaches have been used in this study. Results. Transduction of MM-4 cells by the recombinant baculovirus with IFN-beta gene is accompanied by morphological changes of tumor cells, suppression of cell proliferation, significant inhibition of platting efficiency of cells and their colonies formation in semisolid agar. Moreover, transduction of melanoma MM-4 cells by the baculovirus IFN-transgene leads to inhibition of tumorigenicity and metastatic ability of the cells in vivo. The intravenous administration of recombinant baculovirus vector with IFN gene inhibits growth of metastases induced in the lungs of mice by intravenously injected tumor cells. Conclusions. Transduction of mouse melanoma cells by the recombinant baculovirus with murine IFN-beta gene inhibits their proliferative potential, tumorigenicity and metastatic activity.

  15. REST controls self-renewal and tumorigenic competence of human glioblastoma cells.

    Science.gov (United States)

    Conti, Luciano; Crisafulli, Laura; Caldera, Valentina; Tortoreto, Monica; Brilli, Elisa; Conforti, Paola; Zunino, Franco; Magrassi, Lorenzo; Schiffer, Davide; Cattaneo, Elena

    2012-01-01

    The Repressor Element 1 Silencing Transcription factor (REST/NRSF) is a master repressor of neuronal programs in non-neuronal lineages shown to function as a central regulator of developmental programs and stem cell physiology. Aberrant REST function has been associated with a number of pathological conditions. In cancer biology, REST has been shown to play a tumor suppressor activity in epithelial cancers but an oncogenic role in brain childhood malignancies such as neuroblastoma and medulloblastoma. Here we examined REST expression in human glioblastoma multiforme (GBM) specimens and its role in GBM cells carrying self-renewal and tumorigenic competence. We found REST to be expressed in GBM specimens, its presence being particularly enriched in tumor cells in the perivascular compartment. Significantly, REST is highly expressed in self-renewing tumorigenic-competent GBM cells and its knock down strongly reduces their self-renewal in vitro and tumor-initiating capacity in vivo and affects levels of miR-124 and its downstream targets. These results indicate that REST contributes to GBM maintenance by affecting its self-renewing and tumorigenic cellular component and that, hence, a better understanding of these circuitries in these cells might lead to new exploitable therapeutic targets.

  16. Senescence-Induced Alterations of Laminin Chain Expression Modulate Tumorigenicity of Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Cynthia C.T. Sprenger

    2008-12-01

    Full Text Available Prostate cancer is an age-associated epithelial cancer, and as such, it contributes significantly to the mortality of the elderly. Senescence is one possible mechanism by which the body defends itself against various epithelial cancers. Senescent cells alter the microenvironment, in part, through changes to the extracellular matrix. Laminins (LMs are extracellular proteins important to both the structure and function of the microenvironment. Overexpression of the senescence-associated gene mac25 in human prostate cancer cells resulted in increased mRNA levels of the LM α4 and β2 chains compared to empty vector control cells. The purpose of this study was to examine the effects of these senescence-induced LM chains on tumorigenicity of prostate cancer cells. We created stable M12 human prostate cancer lines overexpressing either the LM α4 or β2 chain or both chains. Increased expression of either the LM α4 or β2 chain resulted in increased in vitro migration and in vivo tumorigenicity of those cells, whereas high expression of both chains led to decreased in vitro proliferation and in vivo tumorigenicity compared to M12 control cells. This study demonstrates that senescent prostate epithelial cells can alter the microenvironment and that these changes modulate progression of prostate cancer.

  17. pattern of interstitial lung disease as seen by high resolution ...

    African Journals Online (AJOL)

    2012-09-01

    Sep 1, 2012 ... by dyspnoea (53.5%, n=53) and chest pain [24.8% (n = 25)]. ... Conclusion: The study demonstrated marked lung parenchymal ... lesions and their distribution compared to plain chest radiography. ... dates back to the foundation laid by Itoh et al(2) who ..... plain film radiographs had a pattern identified on.

  18. Lung sounds auscultation technology based on ANC-ICA algorithm in high battlefield noise environment

    Institute of Scientific and Technical Information of China (English)

    牛海军; 冯安吉; 万明习; 白培瑞

    2003-01-01

    AIM:To explore the more accurate lung sounds auscultation technology in high battlefield noise environment.METHODS: In this study, we restrain high background noise using a new method-adaptive noise canceling based on independent component analysis (ANC-ICA), the method, by incorporating both second-order and higher-order statistics can remove noise components of the primary input signal based on statistical independence.RESULTS:The algorithm retained the local feature of lung sounds while eliminating high background noise, and performed more effectively than the conventional LMS algorithm.CONCLUSION:This method can cancel high battlefield noise of lung sounds effectively thus can help diagnose lung disease more accurately.

  19. Lung density on high resolution computer tomography (HRCT) reflects degree of inflammation in smokers

    Science.gov (United States)

    2014-01-01

    Background Smokers have increased cell concentration in the lower respiratory tract indicating a chronic inflammatory state, which in some individuals may lead to development of chronic obstructive pulmonary disease (COPD). Computer tomography (CT) imaging provides means of quantifying pulmonary structure and early signs of disease. We investigated whether lung density on high resolution CT differs between smokers and never-smokers and if this were associated to intensity of inflammation. Methods Forty smoking volunteers with normal pulmonary function, 40 healthy never-smokers and 40 patients with COPD of GOLD stage I-II, were included. Mean lung attenuation and percentage of pixels in the lung with attenuation between −750 and −900 HU (percentage higher density spectrum (%HDS)) were calculated on inspiratory CT-scans. Markers of systemic inflammation in blood and cell counts in bronchoalveolar lavage (BAL) fluid were recorded. Results Lung density expressed as %HDS was increased in smokers (44.0 ± 5.8%) compared to both never-smokers (38.3 ± 5.8%) and patients with COPD (39.1 ± 5.8%), (p lungs than males, which was dependent on body height. Cell concentration in BAL were correlated to lung density in smokers (r = 0.50, p Lung density on CT is associated with cell concentration in BAL in smokers and may mirror an inflammatory response in the lung. Gender difference in lung density is dependent on height. In COPD with emphysema, loss of lung tissue may counterbalance the expected increase in density due to inflammation. The findings may help to interpret high resolution CT in the context of smoking and gender and highlight the heterogeneity of structural changes in COPD. PMID:24564813

  20. High bias gas flows increase lung injury in the ventilated preterm lamb.

    Directory of Open Access Journals (Sweden)

    Katinka P Bach

    Full Text Available BACKGROUND: Mechanical ventilation of preterm babies increases survival but can also cause ventilator-induced lung injury (VILI, leading to the development of bronchopulmonary dysplasia (BPD. It is not known whether shear stress injury from gases flowing into the preterm lung during ventilation contributes to VILI. METHODS: Preterm lambs of 131 days' gestation (term = 147 d were ventilated for 2 hours with a bias gas flow of 8 L/min (n = 13, 18 L/min (n = 12 or 28 L/min (n = 14. Physiological parameters were measured continuously and lung injury was assessed by measuring mRNA expression of early injury response genes and by histological analysis. Control lung tissue was collected from unventilated age-matched fetuses. Data were analysed by ANOVA with a Tukey post-hoc test when appropriate. RESULTS: High bias gas flows resulted in higher ventilator pressures, shorter inflation times and decreased ventilator efficiency. The rate of rise of inspiratory gas flow was greatest, and pulmonary mRNA levels of the injury markers, EGR1 and CTGF, were highest in lambs ventilated with bias gas flows of 18 L/min. High bias gas flows resulted in increased cellular proliferation and abnormal deposition of elastin, collagen and myofibroblasts in the lung. CONCLUSIONS: High ventilator bias gas flows resulted in increased lung injury, with up-regulation of acute early response genes and increased histological lung injury. Bias gas flows may, therefore, contribute to VILI and BPD.

  1. High Bias Gas Flows Increase Lung Injury in the Ventilated Preterm Lamb

    Science.gov (United States)

    Bach, Katinka P.; Kuschel, Carl A.; Hooper, Stuart B.; Bertram, Jean; McKnight, Sue; Peachey, Shirley E.; Zahra, Valerie A.; Flecknoe, Sharon J.; Oliver, Mark H.; Wallace, Megan J.; Bloomfield, Frank H.

    2012-01-01

    Background Mechanical ventilation of preterm babies increases survival but can also cause ventilator-induced lung injury (VILI), leading to the development of bronchopulmonary dysplasia (BPD). It is not known whether shear stress injury from gases flowing into the preterm lung during ventilation contributes to VILI. Methods Preterm lambs of 131 days’ gestation (term = 147 d) were ventilated for 2 hours with a bias gas flow of 8 L/min (n = 13), 18 L/min (n = 12) or 28 L/min (n = 14). Physiological parameters were measured continuously and lung injury was assessed by measuring mRNA expression of early injury response genes and by histological analysis. Control lung tissue was collected from unventilated age-matched fetuses. Data were analysed by ANOVA with a Tukey post-hoc test when appropriate. Results High bias gas flows resulted in higher ventilator pressures, shorter inflation times and decreased ventilator efficiency. The rate of rise of inspiratory gas flow was greatest, and pulmonary mRNA levels of the injury markers, EGR1 and CTGF, were highest in lambs ventilated with bias gas flows of 18 L/min. High bias gas flows resulted in increased cellular proliferation and abnormal deposition of elastin, collagen and myofibroblasts in the lung. Conclusions High ventilator bias gas flows resulted in increased lung injury, with up-regulation of acute early response genes and increased histological lung injury. Bias gas flows may, therefore, contribute to VILI and BPD. PMID:23056572

  2. High blood pressure, antihypertensive medication and lung function in a general adult population

    Directory of Open Access Journals (Sweden)

    Meisinger Christa

    2011-04-01

    Full Text Available Abstract Background Several studies showed that blood pressure and lung function are associated. Additionally, a potential effect of antihypertensive medication, especially beta-blockers, on lung function has been discussed. However, side effects of beta-blockers have been investigated mainly in patients with already reduced lung function. Thus, aim of this analysis is to determine whether hypertension and antihypertensive medication have an adverse effect on lung function in a general adult population. Methods Within the population-based KORA F4 study 1319 adults aged 40-65 years performed lung function tests and blood pressure measurements. Additionally, information on anthropometric measurements, medical history and use of antihypertensive medication was available. Multivariable regression models were applied to study the association between blood pressure, antihypertensive medication and lung function. Results High blood pressure as well as antihypertensive medication were associated with lower forced expiratory volume in one second (p = 0.02 respectively p = 0.05; R2: 0.65 and forced vital capacity values (p = 0.01 respectively p = 0.05, R2: 0.73. Furthermore, a detailed analysis of antihypertensive medication pointed out that only the use of beta-blockers was associated with reduced lung function, whereas other antihypertensive medication had no effect on lung function. The adverse effect of beta-blockers was significant for forced vital capacity (p = 0.04; R2: 0.65, while the association with forced expiratory volume in one second showed a trend toward significance (p = 0.07; R2: 0.73. In the same model high blood pressure was associated with reduced forced vital capacity (p = 0.01 and forced expiratory volume in one second (p = 0.03 values, too. Conclusion Our analysis indicates that both high blood pressure and the use of beta-blockers, but not the use of other antihypertensive medication, are associated with reduced lung function in a

  3. Increasing inspiratory time exacerbates ventilator-induced lung injury during high-pressure/high-volume mechanical ventilation.

    Science.gov (United States)

    Casetti, Alfredo V; Bartlett, Robert H; Hirschl, Ronald B

    2002-10-01

    Ventilator-induced lung injury may be caused by overdistension of alveoli during high-pressure ventilation. In this study, we examined the effects of increasing inspiratory time on ventilator-induced lung injury. Sprague-Dawley rats were divided into four different groups with ten animals per group. Each group was then ventilated for 30 mins with one of four ventilator strategies. All groups were ventilated with an Fio2 of 1.0 and a positive end-expiratory pressure of 0 cm H2O. Group LoP was the negative control group and was ventilated with low pressures (peak inspiratory pressure = 12 cm H2O, rate = 30, and inspiratory time = 0.5 secs). Groups iT = 0.5, iT = 1.0, and iT = 1.5 were the experimental groups and were ventilated with high pressures (peak inspiratory pressure = 45 cm H2O, rate = 10, and inspiratory times = 0.5 secs, iT = 1.0 sec, and iT = 1.5 secs, respectively). Outcome measures included lung compliance, Pao /Fio ratio, wet/dry lung weight, and dry lung/body weight. Final static lung compliance (p =.0002) and Pao2/Fio2 (p =.001) decreased as inspiratory time increased. Wet/dry lung weights (p <.0001) and dry lung/body weights (p <.0001) increased as inspiratory time increased. Light microscopy revealed evidence of intra-alveolar edema and hemorrhage in the iT = 1.0 and iT = 1.5 animals but not the LoP and iT = 0.5 animals. Increasing inspiratory time during high-pressure/high-volume mechanical ventilation is associated with an increase in variables of lung injury.

  4. Collateral Expression of Proangiogenic and Tumorigenic Properties in Intestinal Epithelial Cell Variants Selected for Resistance to Anoikis

    Directory of Open Access Journals (Sweden)

    Janusz Rak

    1999-04-01

    Full Text Available Although in vitro anchorage-independent growth is widely used as a marker of cell transformation, the biological implications of this trait are poorly understood. We previously demonstrated that enforced anchorage-independent growth of a nontumorigenic, immortalized epithelial cell line (IEC-18 in multicellular spheroid culture results in massive apoptotic cell death. This death process, termed anoikis, is prevented by expression of transforming oncogenes, which also confer tumorigenic competence. This study examines whether acquisition of an anoikis-resistant phenotype is causally related to the tumorigenic capacity of transformed epithelial cells. Parental IEC-18 cells were subjected to 10 cycles of selection for survival in speroid culture. Unlike parental cells, the resulting anoikis-resistant variants (AR1.10 and AR2.10 formed relatively large tumors in nude mice. Both anoikis-resistant sublines displayed upregulated expression of vascular endothelial growth factor (VEGF, a potent angiogenesis stimulator. VEGF121 overexpression alone did not induce tumorigenic conversion of parental IEC-18 cells, which remained highly susceptible to anoikis. We postulate that both anoikis-resistance and angiogenic-competence contribute to tumor formation. Development of anoikis-resistance can be then viewed as a precondition for expression of the tumorigenic phenotype. Our results suggest that even when angiogenesis is not a rate limiting factor (e.g. in vitro the selective pressures of solid tumor-like, 3—dimensional growth conditions favoring anoikis resistance result in collateral induction of a proangiogenic phenotype.

  5. Familial aggregation of lung cancer in a high incidence area in China

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Y.T.; Xu, Y.C.; Yang, R.D.; Huang, C.F.; Xu, C.W.; He, X.Z. [Anhui Medical University, Anhui (China). School of Public Health

    2005-04-11

    To investigate whether lung cancer clusters in families in a high incidence county of China, an analysis was conducted using data on domestic fuel history and tobacco use for family members of 740 deceased lung cancer probands and 740 controls (probands' spouses). Lung cancer prevalence was compared among first-degree relatives of probands and of controls, taking into account various factors using logistic regression and generalised estimating equations. First-degree relatives of probands, compared with those of controls, showed an excess risk of lung cancer (odds ratio (OR) = 2.05, 95% confidence interval (CI): 1.68 - 2.53). Overall, female relatives of probands had a greater risk than did their male counterparts, and the risk was 2.90- fold for parents of probands as compared with parents of spouses. Female relatives of probands had 2.67-fold greater risk than female controls. Lung cancer risk was particularly marked among mothers (OR = 3.78, 95% CI: 2.03 - 7.12). Having two or more affected relatives was associated with a 2.69 - 5.40-fold risk increase. The risk elevation was also found for other cancers overall. Results confirm previous findings of a genetic predisposition to lung cancer, and also imply that lung cancer may share a genetic background with other cancers.

  6. Results of the Randomized Danish Lung Cancer Screening Trial with Focus on High-Risk Profiling.

    Science.gov (United States)

    Wille, Mathilde M W; Dirksen, Asger; Ashraf, Haseem; Saghir, Zaigham; Bach, Karen S; Brodersen, John; Clementsen, Paul F; Hansen, Hanne; Larsen, Klaus R; Mortensen, Jann; Rasmussen, Jakob F; Seersholm, Niels; Skov, Birgit G; Thomsen, Laura H; Tønnesen, Philip; Pedersen, Jesper H

    2016-03-01

    As of April 2015, participants in the Danish Lung Cancer Screening Trial had been followed for at least 5 years since their last screening. Mortality, causes of death, and lung cancer findings are reported to explore the effect of computed tomography (CT) screening. A total of 4,104 participants aged 50-70 years at the time of inclusion and with a minimum 20 pack-years of smoking were randomized to have five annual low-dose CT scans (study group) or no screening (control group). Follow-up information regarding date and cause of death, lung cancer diagnosis, cancer stage, and histology was obtained from national registries. No differences between the two groups in lung cancer mortality (hazard ratio, 1.03; 95% confidence interval, 0.66-1.6; P = 0.888) or all-cause mortality (hazard ratio, 1.02; 95% confidence interval, 0.82-1.27; P = 0.867) were observed. More cancers were found in the screening group than in the no-screening group (100 vs. 53, respectively; P risk of death due to lung cancer, with nonsignificantly fewer deaths in the screening group. No statistically significant effects of CT screening on lung cancer mortality were found, but the results of post hoc high-risk subgroup analyses showed nonsignificant trends that seem to be in good agreement with the results of the National Lung Screening Trial. Clinical trial registered with www.clinicaltrials.gov (NCT00496977).

  7. Oral kanglaite injection (KLTI) attenuates the lung cancer-promoting effect of high-fat diet (HFD)-induced obesity

    OpenAIRE

    Cao, Ning; Ma, Xiaofang; Guo, Zhenzhen; Zheng, Yaqiu; Geng, Shengnan; Meng, Mingjing; Du, Zhenhua; Lin, Haihong; Duan, Yongjian; Du, Gangjun

    2016-01-01

    Obesity is a risk factor for cancer and cancer-related mortality, however, its role in lung cancer progression remains controversial. This study aimed to assess whether high-fat diet (HFD)-induced obesity promotes lung cancer progression and whether the promotion can be decreased by Kanglaite injection (KLTI). In vivo, HFD-induced overweight or obesity increases the lung carcinoma incidence and multiplicity in a urethane-induced lung carcinogenic model and cancer-related mortality in a LLC al...

  8. Antibody desensitization therapy in highly sensitized lung transplant candidates.

    Science.gov (United States)

    Snyder, L D; Gray, A L; Reynolds, J M; Arepally, G M; Bedoya, A; Hartwig, M G; Davis, R D; Lopes, K E; Wegner, W E; Chen, D F; Palmer, S M

    2014-04-01

    As HLAs antibody detection technology has evolved, there is now detailed HLA antibody information available on prospective transplant recipients. Determining single antigen antibody specificity allows for a calculated panel reactive antibodies (cPRA) value, providing an estimate of the effective donor pool. For broadly sensitized lung transplant candidates (cPRA ≥ 80%), our center adopted a pretransplant multi-modal desensitization protocol in an effort to decrease the cPRA and expand the donor pool. This desensitization protocol included plasmapheresis, solumedrol, bortezomib and rituximab given in combination over 19 days followed by intravenous immunoglobulin. Eight of 18 candidates completed therapy with the primary reasons for early discontinuation being transplant (by avoiding unacceptable antigens) or thrombocytopenia. In a mixed-model analysis, there were no significant changes in PRA or cPRA changes over time with the protocol. A sub-analysis of the median fluorescence intensity (MFI) change indicated a small decline that was significant in antibodies with MFI 5000-10,000. Nine of 18 candidates subsequently had a transplant. Posttransplant survival in these nine recipients was comparable to other pretransplant-sensitized recipients who did not receive therapy. In summary, an aggressive multi-modal desensitization protocol does not significantly reduce pretransplant HLA antibodies in a broadly sensitized lung transplant candidate cohort. © Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.

  9. Multiple breast cancer cell-lines derived from a single tumor differ in their molecular characteristics and tumorigenic potential.

    Directory of Open Access Journals (Sweden)

    Goar Mosoyan

    Full Text Available BACKGROUND: Breast cancer cell lines are widely used tools to investigate breast cancer biology and to develop new therapies. Breast cancer tissue contains molecularly heterogeneous cell populations. Thus, it is important to understand which cell lines best represent the primary tumor and have similarly diverse phenotype. Here, we describe the development of five breast cancer cell lines from a single patient's breast cancer tissue. We characterize the molecular profiles, tumorigenicity and metastatic ability in vivo of all five cell lines and compare their responsiveness to 4-hydroxytamoxifen (4-OHT treatment. METHODS: Five breast cancer cell lines were derived from a single patient's primary breast cancer tissue. Expression of different antigens including HER2, estrogen receptor (ER, CK8/18, CD44 and CD24 was determined by flow cytometry, western blotting and immunohistochemistry (IHC. In addition, a Fluorescent In Situ Hybridization (FISH assay for HER2 gene amplification and p53 genotyping was performed on all cell lines. A xenograft model in nude mice was utilized to assess the tumorigenic and metastatic abilities of the breast cancer cells. RESULTS: We have isolated, cloned and established five new breast cancer cell lines with different tumorigenicity and metastatic abilities from a single primary breast cancer. Although all the cell lines expressed low levels of ER, their growth was estrogen-independent and all had high-levels of expression of mutated non-functional p53. The HER2 gene was rearranged in all cell lines. Low doses of 4-OHT induced proliferation of these breast cancer cell lines. CONCLUSIONS: All five breast cancer cell lines have different antigenic expression profiles, tumorigenicity and organ specific metastatic abilities although they derive from a single tumor. None of the studied markers correlated with tumorigenic potential. These new cell lines could serve as a model for detailed genomic and proteomic analyses to

  10. High-resolution CT study of interstitial lung disease in polymyositis and dermatomyositis

    Energy Technology Data Exchange (ETDEWEB)

    Tomii, Keisuke; Iwata, Takekuni; Oida, Kazukiyo (Tenri Hospital, Nara (Japan)) (and others)

    1992-01-01

    High-resolution CT scans of lung parenchyma were obtained in 8 patients with pure polymyositis or dermatomyositis (PM-DM) with interstitial lung involvement. The most frequent findings were subpleural curved band-like shadows (A 2), which were demonstrated in 7 patients (88%). Open lung biopsy was performed in a case of A 2 shadow, which revealed non-specific interstitial pneumonia (chronic interstitial pneumonia, not otherwise specified). Most of the A 2 shadows gradually shrinked with steroids or immunosuppressants, and then disappeared completely or changed into subpleural curvilinear shadows (A 1). Peri-bronchovascular shadows (B) were detected in 4 patients (50%). Acute exacerbation had occurred in the two of them, but after all every B shadow reduced or disappeared with therapy. We think A 2 and B shadows are characteristic HRCT findings of interstitial lung disease in PM-DM and their prognosis is fairly good. (author).

  11. Pleuritis in slaughter pigs: relations between lung lesions and bacteriology in 10 herds with high pleuritis.

    Science.gov (United States)

    Jirawattanapong, Pichai; Stockhofe-Zurwieden, Norbert; van Leengoed, Leo; Wisselink, Henk; Raymakers, Rudolf; Cruijsen, Toine; van der Peet-Schwering, Carola; Nielen, Mirjam; van Nes, Arie

    2010-02-01

    Pleuritis in slaughter pigs has increased in recent years in the Netherlands. The aim of the present study was to determine what respiratory pathogens were involved in pleuritis. In total, lungs of 968 slaughter pigs from 10 herds with high prevalence of pleuritis were morphologically examined for size, location, and type of lesions. Moreover, histology and bacteriology were performed. Examination of gross lung lesions showed 45% pleuritis, 14% pleuropneumonia and 38% catarrhal pneumonia. Peribronchiolar cuffing was found in 61 of 142 samples. Actinobacillus pleuropneumoniae was cultured from 22 lung samples from four herds. Pasteurella multocida was cultured from 55 lung samples in eight herds. No specific pattern with respect to the causal pathogens was found. In conclusion, no single infectious cause of pleuritis was found. A variety of infectious agents combined with environmental factors should be considered as a cause of pleuritis.

  12. Experimental Researches on Carcinogenesis or Tumorigenicity of MDCK Canine Kidney Cell(CKC) Lines and Analysis of Their Chromosome Karyotypes

    Institute of Scientific and Technical Information of China (English)

    ZHANG De-li; FANG Fu-de; LI Liu-jin; XIA Geng-tian; HE Xu-yu; GAO Bu-xian; BAI Xiao-hong; HUANG Gao-sheng; LIU Shang-gao; YAN Long-fei

    2002-01-01

    The chromosomal number variations & structural aberrations of the MDCK cell line, primary feline or canine kidney cell(FKC or CKC) and Hela cell line were investigated and their karyotypes of conventional chromosome bands were analyzed. The carcinogenesis or tumorigenicity testing of these cell lines in about 232 nude mice and for colony formation in soft agarose and for haemagglutination under different concentration of plant lectins of these cells were carried out. Under the prerequisite that the incidence of cancer or tumor in negative-control nude mice inoculated subcutaneously with primary feline or canine kidney cell cultures purified in vitro at passage 3 was 0 (0/22) and 0 (0/10), respectively. The incidence of the progressively-growing malignant tumor(MT) in positive-control nude mice inoculated subcutaneously with Hela cell cultures of KB, X, or NM20/X strain was 10/10, 25/25 and 5/51, respectively. The results showed that the incidence of tumor in nude mice with tetrapioid YA strain of MDCK cell during 20 - 45 passages, with hypodiploid JB strain of MDCK cell on passage 25, with di-and hypoploid JC strain of MDCK cell during 2 - 15passages or with hypoploid M strain of MDCK cell during 9 - 27 passages was 28/58, 1/5, 4/18 and 0/31,respectively. The chromosomal analysis results showed that the ratio of difference in the rate of modal chromosome number between high (mcs + n) and lowest (mcs)passages was not more than 5 % - 15 % and the structure aberrations was generally 0 - 3%. These results proved that the genetic characteristics of chromosomal number of cell lines determines their tumorigenicity, but it is species-specific. MDCK line has tumorigenicity no matter what its chromosome karyotype is, at least it has very low tumorigenicity even when its modal chromosome number is hypoploid. The repeatedly frozen, thawed and split controls of tumorigenicity-positive cell lines(X strain of Hela, M strain of BHK-21, JA strain of Vero, YA strain of MDCK) have

  13. Smoking Related Interstitial Lung Disease - High Resolution Computed Tomography (HRCT findings in 40 smokers

    Directory of Open Access Journals (Sweden)

    Youssriah Yahia Sabri

    2014-06-01

    In the appropriate clinical context high-resolution CT plays an integral role in the evaluation of SR-ILD, the presence of typical changes at high-resolution CT renders the diagnosis almost certain and may obviate further testing. Lung biopsy may be needed when the findings at high-resolution CT are relatively nonspecific or when a confident definitive diagnosis is needed.

  14. Calibration of the Accuscan II IN Vivo System for High Energy Lung Counting

    Energy Technology Data Exchange (ETDEWEB)

    Ovard R. Perry; David L. Georgeson

    2011-07-01

    This report describes the April 2011 calibration of the Accuscan II HpGe In Vivo system for high energy lung counting. The source used for the calibration was a NIST traceable lung set manufactured at the University of Cincinnati UCLL43AMEU & UCSL43AMEU containing Am-241 and Eu-152 with energies from 26 keV to 1408 keV. The lung set was used in conjunction with a Realistic Torso phantom. The phantom was placed on the RMC II counting table (with pins removed) between the v-ridges on the backwall of the Accuscan II counter. The top of the detector housing was positioned perpendicular to the junction of the phantom clavicle with the sternum. This position places the approximate center line of the detector housing with the center of the lungs. The energy and efficiency calibrations were performed using a Realistic Torso phantom (Appendix I) and the University of Cincinnati lung set. This report includes an overview introduction and records for the energy/FWHM and efficiency calibration including performance verification and validation counting. The Accuscan II system was successfully calibrated for high energy lung counting and verified in accordance with ANSI/HPS N13.30-1996 criteria.

  15. Mouse lung contains endothelial progenitors with high capacity to form blood and lymphatic vessels

    Directory of Open Access Journals (Sweden)

    Barleon Bernhard

    2010-07-01

    Full Text Available Abstract Background Postnatal endothelial progenitor cells (EPCs have been successfully isolated from whole bone marrow, blood and the walls of conduit vessels. They can, therefore, be classified into circulating and resident progenitor cells. The differentiation capacity of resident lung endothelial progenitor cells from mouse has not been evaluated. Results In an attempt to isolate differentiated mature endothelial cells from mouse lung we found that the lung contains EPCs with a high vasculogenic capacity and capability of de novo vasculogenesis for blood and lymph vessels. Mouse lung microvascular endothelial cells (MLMVECs were isolated by selection of CD31+ cells. Whereas the majority of the CD31+ cells did not divide, some scattered cells started to proliferate giving rise to large colonies (> 3000 cells/colony. These highly dividing cells possess the capacity to integrate into various types of vessels including blood and lymph vessels unveiling the existence of local microvascular endothelial progenitor cells (LMEPCs in adult mouse lung. EPCs could be amplified > passage 30 and still expressed panendothelial markers as well as the progenitor cell antigens, but not antigens for immune cells and hematopoietic stem cells. A high percentage of these cells are also positive for Lyve1, Prox1, podoplanin and VEGFR-3 indicating that a considerabe fraction of the cells are committed to develop lymphatic endothelium. Clonogenic highly proliferating cells from limiting dilution assays were also bipotent. Combined in vitro and in vivo spheroid and matrigel assays revealed that these EPCs exhibit vasculogenic capacity by forming functional blood and lymph vessels. Conclusion The lung contains large numbers of EPCs that display commitment for both types of vessels, suggesting that lung blood and lymphatic endothelial cells are derived from a single progenitor cell.

  16. ATM kinase sustains HER2 tumorigenicity in breast cancer.

    Science.gov (United States)

    Stagni, Venturina; Manni, Isabella; Oropallo, Veronica; Mottolese, Marcella; Di Benedetto, Anna; Piaggio, Giulia; Falcioni, Rita; Giaccari, Danilo; Di Carlo, Selene; Sperati, Francesca; Cencioni, Maria Teresa; Barilà, Daniela

    2015-04-16

    ATM kinase preserves genomic stability by acting as a tumour suppressor. However, its identification as a component of several signalling networks suggests a dualism for ATM in cancer. Here we report that ATM expression and activity promotes HER2-dependent tumorigenicity in vitro and in vivo. We reveal a correlation between ATM activation and the reduced time to recurrence in patients diagnosed with invasive HER2-positive breast cancer. Furthermore, we identify ATM as a novel modulator of HER2 protein stability that acts by promoting a complex of HER2 with the chaperone HSP90, therefore preventing HER2 ubiquitination and degradation. As a consequence, ATM sustains AKT activation downstream of HER2 and may modulate the response to therapeutic approaches, suggesting that the status of ATM activity may be informative for the treatment and prognosis of HER2-positive tumours. Our findings provide evidence for ATM's tumorigenic potential revising the canonical role of ATM as a pure tumour suppressor.

  17. Spectrum of high-resolution computed tomography imaging in occupational lung disease

    Directory of Open Access Journals (Sweden)

    Bhawna Satija

    2013-01-01

    Full Text Available Damage to the lungs caused by dusts or fumes or noxious substances inhaled by workers in certain specific occupation is known as occupational lung disease. Recognition of occupational lung disease is especially important not only for the primary worker, but also because of the implications with regard to primary and secondary disease prevention in the exposed co-workers. Although many of the disorders can be detected on chest radiography, high-resolution computed tomography (HRCT is superior in delineating the lung architecture and depicting pathology. The characteristic radiological features suggest the correct diagnosis in some, whereas a combination of clinical features, occupational history, and radiological findings is essential in establishing the diagnosis in others. In the presence of a history of exposure and consistent clinical features, the diagnosis of even an uncommon occupational lung disease can be suggested by the characteristic described HRCT findings. In this article, we briefly review the HRCT appearance of a wide spectrum of occupational lung diseases.

  18. High mobility group box 1 protein as a late-acting mediator of acute lung inflammation.

    Science.gov (United States)

    Lutz, Waldemar; Stetkiewicz, Jan

    2004-01-01

    Acute inflammatory lung injury is often a delayed complication of critical illness and is associated with increased mortality. High mobility group box 1 (HMGB1) protein, in addition to its role as a transcriptional regulator factor, has been identified as a late mediator of endotoxin lethality and might be also involved in the development and progression of acute lung injury. HMGB1 protein itself can cause an acute inflammatory response manifested by increased production of proinflammatory cytokines and neutrophil accumulation. The delayed kinetics of HMGB1 protein release indicate that this protein is a distal mediator of acute inflamatory lung injury. Anti-HMGB1 protein antibodies attenuated endotoxin-induced lung injury, but not the early release of TNF-alpha and IL-1beta, indicating that HMGB1 protein is a late mediator of endotoxin-induced acute lung injury. HMGB1 protein is not released by apoptotic cells but is passively released by necrotic or damaged somatic and immune cells and it functions as a major stimulus of necrosis-induced inflammation. HMGB1 protein is also released by activated monocytes/macrophages and induces delayed and biphasic release of proinflammatory mediators from these cells. HMGB1 protein failed to stimulate cytokines release in lymphocytes, indicating that cellular stimulation is specific. We would like to suggest that HMGB1 protein may be also a primary mediator of the inflammatory responses to lung cells injury caused by toxic environmental chemicals.

  19. NFAT Signaling and the Tumorigenic Microenvironment of the Prostate

    Science.gov (United States)

    2016-10-01

    two main areas ( divided into 3 specific aims). First, the detailed study of the tumorigenic microenvironment and the correlation between NFATc1 and...antigen deprivation in mice with NFAT activation in the prostate. We have completed the study if termination of NFATc1 activation halts prostate...of the prostate gland and for the survival and proliferation of the epithelial cells,2 androgen deprivation has been a key therapeutic strategy in

  20. First Report of Tumorigenic Agrobacterium radiobacter on Raspberry in Serbia

    Directory of Open Access Journals (Sweden)

    Svetlana Milijašević

    2007-01-01

    Full Text Available During the spring of 2003, gall symptoms on the roots and crowns of young raspberry plants cv. Vilamette were observed near Valjevo. Phytopathogenic bacteria were isolated from diseased plant samples. Based on the pathogenic, morphological, differential biochemicaland physiological characteristics, the isolated strains were identified as tumorigenic Agrobacterium radiobacter (biovar 1 Agrobacterium. In order to confirm the identity of isolated strains by polymerase chain reaction (PCR primers complementary to tms2 genelocated on the Ti plasmid were used. In the first PCR protocol using a tms2F1 + tms2R2 primer pair, 617 bp products specific for tumorigenic Agrobacterium strains were amplified. The second PCR protocol, using a tms2F1 + tms2B primer pair, amplified the expected 458 bp products. On the basis of multiplex PCR with primers complementary to chromosomal gene coding for 23S rRNA, the isolated strains were classified as biovar 1 Agrobacterium (A. radiobacter. This is the first report of tumorigenic A. radiobacter on raspberry in Serbia.

  1. Raised mortality from lung cancer and high sex ratios of births associated with industrial pollution.

    Science.gov (United States)

    Lloyd, O L; Smith, G; Lloyd, M M; Holland, Y; Gailey, F

    1985-07-01

    Geographical and temporal associations were shown between high mortality from lung cancer and a high sex ratio of births both in the town of Bathgate (Scotland) and in the area of that town which was most exposed to polluted air from a local steel foundry. These findings constituted a replication of a similar association in an adjacent town.

  2. Lung mechanics and high-resolution computed tomography of the chest in very low birth weight premature infants

    Directory of Open Access Journals (Sweden)

    Rosane Reis de Mello

    Full Text Available CONTEXT: Premature infant lung development may be affected by lung injuries during the first few weeks of life. Lung injuries have been associated with changes in lung mechanics. OBJECTIVE: To evaluate an association between lung mechanics and lung structural alterations in very low birth weight infants (birth weight less than 1500 g. DESIGN: A cross-sectional evaluation of pulmonary mechanics (lung compliance and lung resistance and high resolution computed tomography of the chest at the time of discharge, in 86 very low birth weight infants born at Instituto Fernandes Figueira, a tertiary public healthcare institution in Rio de Janeiro, Brazil. Lung compliance and resistance were measured during quiet sleep. High resolution computed tomography was performed using Pro Speed-S equipment. MAIN MEASUREMENTS: Statistical analysis was performed by means of variance analysis (ANOVA/ Kruskal Wallis. The significance level was set at 0.05. RESULTS: Abnormal values for both lung compliance and lung resistance were found in 34 babies (43%, whereas 20 (23.3% had normal values for both lung compliance and lung resistance. The mean lung compliance and lung resistance for the group were respectively 1.30 ml/cm H2O/kg and 63.7 cm H2O/l/s. Lung alterations were found via high-resolution computed tomography in 62 (72% infants. Most infants showed more than one abnormality, and these were described as ground glass opacity, parenchymal bands, atelectasis and bubble/cyst. The mean compliance values for infants with normal (1.49 ml/cm H2O/kg high resolution computed tomography, 1 or 2 abnormalities (1.31 ml/cm H2O/kg and 3 or more abnormalities (1.16 ml/cm H2O/kg were significantly different (p = 0.015. Our data were insufficient to find any association between lung resistance and the number of alterations via high-resolution computed tomography. CONCLUSION: The results show high prevalence of lung functional and tomographic abnormalities in asymptomatic very low

  3. Lung mechanics and high-resolution computed tomography of the chest in very low birth weight premature infants

    Energy Technology Data Exchange (ETDEWEB)

    Mello, Rosane Reis de; Dutra, Maria Virginia Peixoto; Ramos, Jose Roberto; Daltro, Pedro; Boechat, Marcia; Andrade Lopes, Jose Maria de [Fundacao Inst. Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, RJ (Brazil). Instituto Fernandes Figueira

    2003-07-01

    Premature infant lung development may be affected by lung injuries during the first few weeks of life. Lung injuries have been associated with changes in lung mechanics. The objective is to evaluate an association between lung mechanics and lung structural alterations in very low birth weight infants (birth weight less than 1500 g). The design presents a cross-sectional evaluation of pulmonary mechanics (lung compliance and lung resistance) and high resolution computed tomography of the chest at the time of discharge, in 86 very low birth weight infants born at Instituto Fernandes Figueira, a tertiary public health care institution in Rio de Janeiro, Brazil. Lung compliance and resistance were measured during quiet sleep. High resolution computed tomography was performed using Pro Speed-S equipment. Statistical analysis was performed by means of variance analysis (ANOVA/ Kruskal Wallis). The significance level was set at 0.05. The results showed abnormal values for both lung compliance and lung resistance were found in 34 babies (43%), whereas 20 (23.3%) had normal values for both lung compliance and lung resistance. The mean lung compliance and lung resistance for the group were respectively 1.30 ml/cm H{sub 2} O/kg and 63.7 cm H{sub 2} O/l/s. Lung alterations were found via high-resolution computed tomography in 62 (72%) infants. Most infants showed more than one abnormality, and these were described as ground glass opacity, parenchymal bands, atelectasis and bubble/cyst. The mean compliance values for infants with normal (1.49 ml/cm H{sub 2} O/kg) high resolution computed tomography, 1 or 2 abnormalities (1.31 ml/cm H{sub 2} O/kg) and 3 or more abnormalities (1.16 ml/cm H{sub 2} O/kg) were significantly different (p = 0.015). Our data were insufficient to find any association between lung resistance and the number of alterations via high-resolution computed tomography. The conclusion was that the results show high prevalence of lung functional and tomographic

  4. Establishment of a human lung cancer cell line with high metastatic potential to multiple organs: gene expression associated with metastatic potential in human lung cancer.

    Science.gov (United States)

    Nakano, Tetsuhiro; Shimizu, Kimihiro; Kawashima, Osamu; Kamiyoshihara, Mitsuhiro; Kakegawa, Seiichi; Sugano, Masayuki; Ibe, Takashi; Nagashima, Toshiteru; Kaira, Kyoichi; Sunaga, Noriaki; Ohtaki, Youichi; Atsumi, Jun; Takeyoshi, Izumi

    2012-11-01

    Convenient and reliable multiple organ metastasis model systems might contribute to understanding the mechanism(s) of metastasis of lung cancer, which may lead to overcoming metastasis and improvement in the treatment outcome of lung cancer. We isolated a highly metastatic subline, PC14HM, from the human pulmonary adenocarcinoma cell line, PC14, using an in vivo selection method. The expression of 34,580 genes was compared between PC14HM and parental PC14 by cDNA microarray analysis. Among the differentially expressed genes, expression of four genes in human lung cancer tissues and adjacent normal lung tissues were compared using real-time reverse transcription polymerase chain reaction. Although BALB/c nude mice inoculated with parental PC14 cells had few metastases, almost all mice inoculated with PC14HM cells developed metastases in multiple organs, including the lung, bone and adrenal gland, the same progression seen in human lung cancer. cDNA microarray analysis revealed that 981 genes were differentially (more than 3-fold) expressed between the two cell lines. Functional classification revealed that many of those genes were associated with cell growth, cell communication, development and transcription. Expression of three upregulated genes (HRB-2, HS3ST3A1 and RAB7) was higher in human cancer tissue compared to normal lung tissue, while expression of EDG1, which was downregulated, was lower in the cancer tissue compared to the normal lung. These results suggest that the newly established PC14HM cell line may provide a mouse model of widespread metastasis of lung cancer. This model system may provide insights into the key genetic determinants of widespread metastasis of lung cancer.

  5. High-grade primary myxoid lung sarcoma presenting as recurrent hemorrhagic pleural effusions in a young woman.

    Science.gov (United States)

    Tahir, Hassan; Coleman, Cinthia; Sagi, Jahnavi; Wani, Adil; Daruwalla, Vistasp

    2015-01-01

    Primary lung sarcomas are rare but aggressive tumors accounting for less than 0.5% of all lung tumors. The diagnosis of primary lung sarcoma should only be considered after exclusion of other sites. A 32-year-old female presented with recurrent hemorrhagic pleural effusions, shortness of breath and persistent cough. Pleural effusion was drained twice, and each time its analysis was normal. Patient developed atelectasis of left lung with hemothorax for which she underwent video-assisted thoracoscopic surgery. A large mass was found compressing the entire lower lobe of left lung with extension into mediastinum, the biopsy of which showed myxoid sarcoma. The tumor was inoperable and options of chemotherapy or radiotherapy were discussed with the patient. Primary lung sarcoma can rarely present with recurrent hemorrhagic pleural effusion. A high degree of suspicion is required for early diagnosis as large hemothorax on computed tomography or chest X-ray may obscure lung mass and make its diagnosis difficult.

  6. Fetal lung volume measurement by MRI with high-speed imaging systems

    Energy Technology Data Exchange (ETDEWEB)

    Osada, Hisao; Kaku, Kenshi [Chiba Univ. (Japan). Hospital

    2002-08-01

    Although ultrasonography is widely used for fetal morphologic observation, magnetic resonance imaging (MRI) has gained popularity as a new prenatal diagnostic method with recent introduction of high-speed imaging systems. Infants with lung hypoplasia affecting respiratory function require intensive management starting immediately after birth. Therefore, accurate prenatal differential diagnosis and severity evaluation are extremely important for these fetuses. The aim of this study is to measure fetal lung volume using a computer-based, three-dimensional MRI imaging system and to evaluate the possibility of clinical applications of this procedure. A total of 96 fetuses were evaluated, all were morphologically abnormal, and MRI was done for advanced assessment from 24 to 39 weeks gestation. Three-directional views of fetal chest were imaged by Signa Horizon, 1.5 Tesla, version 5.6 (General Electronics) with the following conditions; coil: TORSO coil, sequence: SSFSE (single shot fast spin echo), slice thickness: 5 mm, and imaging speed: 2 seconds/slice. To calculate the lung volume and create three-dimensional image, the lung area in each slice was traced out, then multiplied using computer image processing. Simultaneously, the volumes of all slices were summed to give the volume of each lung. Linear regression analysis and analysis of covariance (ANCOVA) were used for statistical analyses. In all cases, clear images were obtained, and were adequate for three-dimensional evaluation of the fetal lung. Thirty-five fetuses had poor outcomes, such as intrauterine fetal death, neonatal death, and intensive respiratory care. Regression lines of lung volume versus gestational week were calculated for these fetuses with poor outcome and 61 other fetuses with good outcome. ANCOVA, with gestational week as a covariant, revealed a significant intergroup difference in the lung volume (p<0.001). Similarly, regression lines of lung volume versus fetal body weight estimated by

  7. [High-frequency ventilation. I. Distribution of alveolar pressure amplitudes during high frequency oscillation in the lung model].

    Science.gov (United States)

    Theissen, J; Lunkenheimer, P P; Niederer, P; Bush, E; Frieling, G; Lawin, P

    1987-09-01

    The pattern of intrapulmonary pressure distribution was studied during high-frequency ventilation in order to explain the inconsistent results reported in the literature. Methods. Pressure and flow velocity (hot-wire anemometry) were measured in different lung compartments: 1. In transalveolar chambers sealed to the perforated pleural surfaces of dried pig lungs; 2. In emphysema-simulating airbags sealed to the isolated bronchial trees of dried pig lungs; and 3. In transalveolar chambers sealed to the perforated pleural surfaces of freshly excised pig lungs. Results. 1. The pressure amplitudes change from one area to another and depending on the exciting frequency. 2. High-frequency oscillation is associated with an increase in pressure amplitude when the exciting frequency rises, whereas with conventional high-frequency jet ventilation the pressure amplitude is more likely to decrease with frequency. 3. During high-frequency jet ventilation the local pressure amplitude changes with the position of the tube in the trachea rather than with the exciting frequency. 4. When the volume of the measuring chamber is doubled the resulting pressure amplitude falls to half the control value. 5. The pressure amplitude and mean pressure measured in the transalveolar chamber vary more or less independently from the peak flow velocity. High-frequency ventilation is thus seen to be a frequency-dependant, inhomogeneous mode of ventilation that can essentially be homogenized by systematically changing the exciting frequency. The frequency-dependant response to different lung areas to excitation is likely to result from an intrabronchially-localized aerodynamic effect rather than the mechanical properties of the lung parenchyma.

  8. CNE article: pain after lung transplant: high-frequency chest wall oscillation vs chest physiotherapy.

    Science.gov (United States)

    Esguerra-Gonzalez, Angeli; Ilagan-Honorio, Monina; Fraschilla, Stephanie; Kehoe, Priscilla; Lee, Ai Jin; Marcarian, Taline; Mayol-Ngo, Kristina; Miller, Pamela S; Onga, Jay; Rodman, Betty; Ross, David; Sommer, Susan; Takayanagi, Sumiko; Toyama, Joy; Villamor, Filma; Weigt, S Samuel; Gawlinski, Anna

    2013-03-01

    Background Chest physiotherapy and high-frequency chest wall oscillation (HFCWO) are routinely used after lung transplant to facilitate removal of secretions. To date, no studies have been done to investigate which therapy is more comfortable and preferred by lung transplant recipients. Patients who have less pain may mobilize secretions, heal, and recover faster. Objectives To compare effects of HFCWO versus chest physiotherapy on pain and preference in lung transplant recipients. Methods In a 2-group experimental, repeated-measures design, 45 lung transplant recipients (27 single lung, 18 bilateral) were randomized to chest physiotherapy (10 AM, 2 PM) followed by HFCWO (6 PM, 10 PM; group 1, n=22) or vice versa (group 2, n=23) on postoperative day 3. A verbal numeric rating scale was used to measure pain before and after treatment. At the end of the treatment sequence, a 4-item patient survey was administered to assess treatment preference, pain, and effectiveness. Data were analyzed with χ(2) and t tests and repeated-measures analysis of variance. Results A significant interaction was found between mean difference in pain scores from before to after treatment and treatment method; pain scores decreased more when HFCWO was done at 10 AM and 6 PM (P =.04). Bilateral transplant recipients showed a significant preference for HFCWO over chest physiotherapy (11 [85%] vs 2 [15%], P=.01). However, single lung recipients showed no significant difference in preference between the 2 treatments (11 [42%] vs 14 [54%]). Conclusions HFCWO seems to provide greater decreases in pain scores than does chest physiotherapy. Bilateral lung transplant recipients preferred HFCWO to chest physiotherapy. HFCWO may be an effective, feasible alternative to chest physiotherapy. (American Journal of Critical Care. 2013;22:115-125).

  9. Pleuritis in slaughter pigs: Relations between lung lesions and bacteriology in 10 herds with high pleuritis

    NARCIS (Netherlands)

    Jirawattanapong, P.; Stockhofe, N.; Leengoed, van L.A.M.G.; Wisselink, H.J.; Raymakers, R.; Cruijsen, T.; Peet-Schwering, van der C.M.C.; Nielen, M.; Nes, van A.

    2010-01-01

    Pleuritis in slaughter pigs has increased in recent years in the Netherlands. The aim of the present study was to determine what respiratory pathogens were involved in pleuritis. In total, lungs of 968 slaughter pigs from 10 herds with high prevalence of pleuritis were morphologically examined for s

  10. Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling.

    Science.gov (United States)

    Sullivan, James P; Spinola, Monica; Dodge, Michael; Raso, Maria G; Behrens, Carmen; Gao, Boning; Schuster, Katja; Shao, Chunli; Larsen, Jill E; Sullivan, Laura A; Honorio, Sofia; Xie, Yang; Scaglioni, Pier P; DiMaio, J Michael; Gazdar, Adi F; Shay, Jerry W; Wistuba, Ignacio I; Minna, John D

    2010-12-01

    Aldehyde dehydrogenase (ALDH) is a candidate marker for lung cancer cells with stem cell-like properties. Immunohistochemical staining of a large panel of primary non-small cell lung cancer (NSCLC) samples for ALDH1A1, ALDH3A1, and CD133 revealed a significant correlation between ALDH1A1 (but not ALDH3A1 or CD133) expression and poor prognosis in patients including those with stage I and N0 disease. Flow cytometric analysis of a panel of lung cancer cell lines and patient tumors revealed that most NSCLCs contain a subpopulation of cells with elevated ALDH activity, and that this activity is associated with ALDH1A1 expression. Isolated ALDH(+) lung cancer cells were observed to be highly tumorigenic and clonogenic as well as capable of self-renewal compared with their ALDH(-) counterparts. Expression analysis of sorted cells revealed elevated Notch pathway transcript expression in ALDH(+) cells. Suppression of the Notch pathway by treatment with either a γ-secretase inhibitor or stable expression of shRNA against NOTCH3 resulted in a significant decrease in ALDH(+) lung cancer cells, commensurate with a reduction in tumor cell proliferation and clonogenicity. Taken together, these findings indicate that ALDH selects for a subpopulation of self-renewing NSCLC stem-like cells with increased tumorigenic potential, that NSCLCs harboring tumor cells with ALDH1A1 expression have inferior prognosis, and that ALDH1A1 and CD133 identify different tumor subpopulations. Therapeutic targeting of the Notch pathway reduces this ALDH(+) component, implicating Notch signaling in lung cancer stem cell maintenance.

  11. No relationship between lung function and high-sensitive C-reactive protein in adolescence.

    Science.gov (United States)

    Nybo, Mads; Hansen, Henrik Steen; Siersted, Hans Christian; Rasmussen, Finn

    2010-10-01

      Several studies on adults have indicated that lower spirometric lung function may be associated with increased systemic inflammation, but no studies have investigated if this association is already present in adolescence.   We explored the temporal relationship between changes in lung function and concentrations of plasma C-reactive protein (CRP) in a population-based cohort study at ages 14 and 20 years using a high-sensitivity CRP assay.   CRP measurements were performed in a total of 420 subjects at mean age of 13.9 years. Of these, 262 subjects (62%) participated in the follow-up investigation at mean age of 20.1 years.   Levels of log-CRP at age 14 were not significantly associated with forced expiratory volume (FEV(1) ) or FEV(1) / forced vital capacity (FVC) ratio at age 20, nor with the change in FEV(1) , FVC or FEV(1) /FVC ratio between 14 and 20 years after controlling for body mass index (BMI), airway hyperresponsiveness (AHR), eosinophil cationic protein (ECP), asthma, smoking, sex, and height at 14 years, and change in height between 14 and 20 years. Sex, BMI, AHR, ECP and change in height between 14 and 20 years were identified as independent factors associated with the change in FEV(1) , FVC and FEV(1) /FVC ratio in adolescence.   We did not find an association between CRP levels at age 14 and change in lung function by age 20; whereas, sex, change in height, BMI, AHR and ECP were associated with lung function change in adolescence. Our findings indicate that systemic inflammation is of less importance for change in lung function in adolescence. Please cite this paper as: Nybo M, Hansen HS, Siersted HC and Rasmussen F. No relationship between lung function and high-sensitive C-reactive protein in adolescence. © 2009 Blackwell Publishing Ltd.

  12. Concise Review: LIN28/let-7 Signaling, a Critical Double-Negative Feedback Loop During Pluripotency, Reprogramming, and Tumorigenicity.

    Science.gov (United States)

    Farzaneh, Maryam; Attari, Farnoosh; Khoshnam, Seyed Esmaeil

    2017-08-28

    MicroRNAs (miRNAs) with 20-30 nucleotides have recently emerged as the multidimensional regulators of cell fate decisions. Recent improvement in high-throughput sequencing has highlighted the potential role of LIN28/let-7 regulatory network in several developmental events. It was proposed that this pathway might represent a functional signature in cell proliferation, transition between commitment and pluripotency, and regulation of cancer and tumorigenicity. LIN28/let-7 regulatory pathway is one of the excellent examples of the relationship between an miRNA and mRNAs. This review article highlights the potentials of LIN28/let-7 signaling in gene regulatory pathways during pluripotency, reprogramming, and tumorigenicity.

  13. Lung cancer stem cells%肺癌干细胞

    Institute of Scientific and Technical Information of China (English)

    江妹; 岳文涛

    2011-01-01

    Recently,studies have demonstrated that several signaling pathways including Wnt,Notch,and Hedgehog which are involved in the regulation of the stem cells are abnormally activated in lung cancer.They are closely associated with some properties of the lung cancer stem cells,such as high tumorigenic,high metastasis,drug resistance and so on.In addition,several studies have shown that the population of the lung cancer stem cells,which are resistant to radiotherapy and chemotherapy significantly,highly express drug resistance proteins.Therefore,how to target lung cancer stem cells and ultimately cure the disease is becoming a hotspot in the cancer targeted therapy.%现有研究表明,在肺癌中与干细胞功能相关的Wnt、Notch和Hedgehog信号通路被异常激活,它们与肺癌干细胞的高致瘤性、高转移性、耐药性等特性密切相关.多项研究显示肺癌干细胞群高度表达肿瘤耐药蛋白并且对放化疗明显耐受.因此,如何靶向治疗肺癌干细胞,最终根治肺癌,正逐渐成为肿瘤靶向治疗研究中的热点.

  14. Oral kanglaite injection (KLTI) attenuates the lung cancer-promoting effect of high-fat diet (HFD)-induced obesity.

    Science.gov (United States)

    Cao, Ning; Ma, Xiaofang; Guo, Zhenzhen; Zheng, Yaqiu; Geng, Shengnan; Meng, Mingjing; Du, Zhenhua; Lin, Haihong; Duan, Yongjian; Du, Gangjun

    2016-09-20

    Obesity is a risk factor for cancer and cancer-related mortality, however, its role in lung cancer progression remains controversial. This study aimed to assess whether high-fat diet (HFD)-induced obesity promotes lung cancer progression and whether the promotion can be decreased by Kanglaite injection (KLTI). In vivo, HFD-induced overweight or obesity increases the lung carcinoma incidence and multiplicity in a urethane-induced lung carcinogenic model and cancer-related mortality in a LLC allograft model by increasing oxidative stress and cellular signaling molecules including JAK, STAT3, Akt, mTOR, NF-κB and cyclin D1. These changes resulted in increases in vascular disruption and the lung water content, thereby promoting lung epithelial proliferation and the epithelial-mesenchymal transition (EMT) during carcinogenesis. Chronic KLTI treatment substantially prevented the weight gain resulting from HFD consumption, thereby reversing the metabolic dysfunction-related physiological changes and reducing susceptibility to lung carcinogenesis. In vitro, KLTI significantly suppressed the proliferation and induced apoptosis and differentiation in 3T3-L1 preadipocyte cells and attenuated endothelial cell permeability in HUVECs. Our study indicates that there is a potential relationship between obesity and lung cancer. This is the first study to show that obesity can directly accelerate carcinogen-induced lung cancer progression and that KLTI can decrease the lung cancer-promoting effect of HFD-induced obesity.

  15. Detected troponin elevation is associated with high early mortality after lung resection for cancer

    Directory of Open Access Journals (Sweden)

    Van Tornout Fillip

    2006-10-01

    Full Text Available Abstract Background Myocardial infarction can be difficult to diagnose after lung surgery. As recent diagnostic criteria emphasize serum cardiac markers (in particular serum troponin we set out to evaluate its clinical utility and to establish the long term prognostic impact of detected abnormal postoperative troponin levels after lung resection. Methods We studied a historic cohort of patients with primary lung cancer who underwent intended surgical resection. Patients were grouped according to known postoperative troponin status and survival calculated by Kaplan Meier method and compared using log rank. Parametric survival analysis was used to ascertain independent predictors of mortality. Results From 2001 to 2004, a total of 207 patients underwent lung resection for primary lung cancer of which 14 (7% were identified with elevated serum troponin levels within 30 days of surgery, with 9 (64% having classical features of myocardial infarction. The median time to follow up (interquartile range was 22 (1 to 52 months, and the one and five year survival probabilities (95% CI for patients without and with postoperative troponin elevation were 92% (85 to 96 versus 60% (31 to 80 and 61% (51 to 71 versus 18% (3 to 43 respectively (p T stage and postoperative troponin elevation remained independent predictors of mortality in the final multivariable model. The acceleration factor for death of elevated serum troponin after adjusting for tumour stage was 9.19 (95% CI 3.75 to 22.54. Conclusion Patients with detected serum troponin elevation are at high risk of early mortality with or without symptoms of myocardial infarction after lung resection.

  16. A Highly Efficient Gene Expression Programming (GEP Model for Auxiliary Diagnosis of Small Cell Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Zhuang Yu

    Full Text Available Lung cancer is an important and common cancer that constitutes a major public health problem, but early detection of small cell lung cancer can significantly improve the survival rate of cancer patients. A number of serum biomarkers have been used in the diagnosis of lung cancers; however, they exhibit low sensitivity and specificity.We used biochemical methods to measure blood levels of lactate dehydrogenase (LDH, C-reactive protein (CRP, Na+, Cl-, carcino-embryonic antigen (CEA, and neuron specific enolase (NSE in 145 small cell lung cancer (SCLC patients and 155 non-small cell lung cancer and 155 normal controls. A gene expression programming (GEP model and Receiver Operating Characteristic (ROC curves incorporating these biomarkers was developed for the auxiliary diagnosis of SCLC.After appropriate modification of the parameters, the GEP model was initially set up based on a training set of 115 SCLC patients and 125 normal controls for GEP model generation. Then the GEP was applied to the remaining 60 subjects (the test set for model validation. GEP successfully discriminated 281 out of 300 cases, showing a correct classification rate for lung cancer patients of 93.75% (225/240 and 93.33% (56/60 for the training and test sets, respectively. Another GEP model incorporating four biomarkers, including CEA, NSE, LDH, and CRP, exhibited slightly lower detection sensitivity than the GEP model, including six biomarkers. We repeat the models on artificial neural network (ANN, and our results showed that the accuracy of GEP models were higher than that in ANN. GEP model incorporating six serum biomarkers performed by NSCLC patients and normal controls showed low accuracy than SCLC patients and was enough to prove that the GEP model is suitable for the SCLC patients.We have developed a GEP model with high sensitivity and specificity for the auxiliary diagnosis of SCLC. This GEP model has the potential for the wide use for detection of SCLC in less

  17. Construction and application of a lung cancer stem cell model: antitumor drug screening and molecular mechanism of the inhibitory effects of sanguinarine.

    Science.gov (United States)

    Yang, Jia; Fang, Zhihong; Wu, Jianchun; Yin, Xiaoling; Fang, Yuan; Zhao, Fanchen; Zhu, Shiguo; Li, Yan

    2016-10-01

    Lung cancer is a neoplasm with a 5-year survival rate of less than 15 % and a leading cause of death worldwide, despite recent progress in treatment and diagnostic methods. Lung cancer stem-like cells (CSCs) are pivotal in lung cancer metastasis and drug resistance. This study aimed to develop lung CSCs that stably express stem cell properties through transfection to further screen traditional Chinese herbal compounds. Lung adenocarcinoma stem cells, which include various phenotypic subgroups, are normally characterized by high expression levels of pluripotent stem cell genes, particularly Nanog and OCT4. Plasmids containing Nanog and OCT4 were constructed and transfected into cells, and lung CSCs were identified not only in vitro using RT-PCR, Western blotting, plate cloning, sphere formation, drug resistance, and transwell migration but also in vivo using a nude mouse tumorigenicity assay. Subsequently, sanguinarine, which is derived from the whole leaves of the traditional Chinese medicine celandine, was identified through the high-throughput screening of a small-molecule compound library. Investigation of the molecular mechanisms of the effects of sanguinarine revealed that it significantly inhibited lung CSC proliferation, invasion, and apoptosis, possibly via downregulation of the Wnt/β-catenin signaling pathway. Our results indicate that lung CSCs established by gene transfection may provide a stable and effective method of constructing CSCs to effectively screen potential antitumor drugs. Furthermore, these results suggest that sanguinarine may be a natural antitumor compound that targets lung CSCs, laying a foundation for further clinical study.

  18. Lung transplantation for high-risk patients with idiopathic pulmonary fibrosis.

    Science.gov (United States)

    De Oliveira, Nilto C; Julliard, Walker; Osaki, Satoru; Maloney, James D; Cornwell, Richard D; Sonetti, David A; Meyer, Keith C

    2016-10-07

    Survival for patients with idiopathic pulmonary fibrosis (IPF) and high lung allocation score (LAS) values may be significantly reduced in comparison to those with lower LAS values. To evaluate outcomes for high-risk IPF patients as defined by LAS values ≥46 (N=42) versus recipients with LAS values lung transplants at our institution between 1999 and 2013. The mean LAS was significantly higher (59.5, interquartile range 43.9-75.9 vs. 39.3, interquartile range 37.7-44.3; plung transplantation in patients with IPF and high LAS values is associated with increased risk of early post-transplant complications, long-term post-transplant survival for our high-LAS cohort was equivalent to that for the lower LAS recipients.

  19. Down-regulation of cytoplasmic PLZF correlates with high tumor grade and tumor aggression in non-small cell lung carcinoma.

    Science.gov (United States)

    Xiao, Guang-Qian; Li, Faqian; Findeis-Hosey, Jennifer; Hyrien, Ollivier; Unger, Pamela D; Xiao, Lu; Dunne, Richard; Kim, Eric S; Yang, Qi; McMahon, Loralee; Burstein, David E

    2015-11-01

    There are currently no effective prognostic biomarkers for lung cancer. Promyelocytic leukemia zinc finger (PLZF), a transcriptional repressor, has a role in cell cycle progression and tumorigenicity in various cancers. The expression and value of PLZF in lung carcinoma, particularly in the subclass of non-small cell lung carcinoma (NSCLC), has not been studied. Our aim was to study the immunohistochemical expression of PLZF in lung adenocarcinoma and squamous cell carcinoma and correlate the alteration of PLZF expression with tumor differentiation, lymph node metastasis, tumor stage, and overall survival. A total of 296 NSCLCs being mounted on tissue microarray (181 adenocarcinomas and 91 squamous cell carcinomas) were investigated. Moderate to strong expression of PLZF was found in the cytoplasm of all the nonneoplastic respiratory epithelium and most (89.9%) well-differentiated adenocarcinoma. The proportions of moderately differentiated, poorly differentiated adenocarcinoma, and paired lymph node adenocarcinoma metastases that demonstrated negative or only weak PLZF reactivity were 75.6%, 97.2%, and 89.9%, respectively. The expression of PLZF in squamous cell carcinoma was mostly weak or absent and significantly lower than that in adenocarcinoma of the same grade (P carcinoma and adenocarcinoma (P < .0001). Down-regulation of PLZF also correlated with higher tumor stage and shorter overall survival (P < .05). These results support a prognostic value for loss of cytoplasmic PLZF expression in the stratification of NSCLC and a possible role of cytoplasmic shift and down-regulation of PLZF in the pathogenesis of NSCLC.

  20. High Mallampati score, obesity and obstructive sleep apnea: triple insult to lung function?

    Directory of Open Access Journals (Sweden)

    Nazia Uzma

    2014-07-01

    Full Text Available The paper assesses the combined effect of high Mallampati score, obesity and obstructive sleep apnea (OSA on lung function as measured by spirometry. Our results showed that the combination of sleep apnea, obesity and high Mallampati score resulted in a degree of restriction that was significantly greater than that produced by each factor alone. These observations underscore the importance of factoring in the Mallampati score in the assessment of respiratory disease.

  1. High-resolution computed tomography of the lungs in pediatric patients; Hochaufloesende Computertomographie der Lunge im Kindesalter

    Energy Technology Data Exchange (ETDEWEB)

    Reuter, M.; Oppermann, H.C.; Biederer, J.; Heller, M. [Klinik fuer Diagnostische Radiologie, Universitaetsklinikum Kiel (Germany); Ankermann, T. [Klinik fuer Allgemeine Paediatrie, Universitaetsklinikum Kiel (Germany)

    2002-06-01

    Since the introduction of the high-resolution technique more than ten years ago, HRCT has become an established modality for diagnosing diseases of the respiratory system. This is especially true for the diagnosis of lung diseases in adults. Experience in HRCT of the lungs is limited in pediatric patients. This review gives an overview of frequent and less frequent HRCT findings in pulmonary diseases in childhood. A purely reticular pattern is rarely observed in infants. Pulmonary diseases associated with overinflation are relatively frequent. Paired inspiratory-expiratory scans combine morphological analysis with functional information and have improved the diagnosis of air trapping, e.g. in post-infectious bronchiolitis obliterans or bronchopulmonary dysplasia. Especially in children the high radiation exposure is a problem. Even when applying a low-dose protocol the radiation dose of HRCT will still exceed the dose of a chest X-ray by 100 times. The indication for pediatric pulmonary HRCT is limited to selected cases and it should be decided in agreement with the pediatric radiologists and the pediatric pulmonologists. (orig.) [German] Seit Einfuehrung der hochaufloesenden Computertomographie (HRCT) vor gut 10 Jahren hat sich diese Untersuchungstechnik fuer die Diagnostik von Erkrankungen der Atemwege und des Lungenparenchyms etabliert. Dies gilt vor allem fuer Lungenerkrankungen im Erwachsenenalter. Demgegenueber bestehen vergleichsweise wenig Erfahrungen mit der HRCT in der paediatrischen Lungendiagnostik. In der vorliegenden Uebersichtsarbeit werden HRCT-Befunde bei haeufigen und seltener vorkommenden Lungenerkrankungen bei Kindern beschrieben. Ein rein retikulaeres Muster ist im Kindesalter selten. Demgegenueber werden mit einer pulmonalen Obstruktion (Air trapping) einhergehende Erkrankungen gehaeuft beobachtet. Paarige Inspirations-Exspirationsaufnahmen ergaenzen die rein strukturelle Analyse um eine funktionelle Komponente und haben sich bei obstruktiven

  2. Matrix metalloproteinase-10 is required for lung cancer stem cell maintenance, tumor initiation and metastatic potential.

    Directory of Open Access Journals (Sweden)

    Verline Justilien

    Full Text Available Matrix metalloproteinases (Mmps stimulate tumor invasion and metastasis by degrading the extracellular matrix. Here we reveal an unexpected role for Mmp10 (stromelysin 2 in the maintenance and tumorigenicity of mouse lung cancer stem-like cells (CSC. Mmp10 is highly expressed in oncosphere cultures enriched in CSCs and RNAi-mediated knockdown of Mmp10 leads to a loss of stem cell marker gene expression and inhibition of oncosphere growth, clonal expansion, and transformed growth in vitro. Interestingly, clonal expansion of Mmp10 deficient oncospheres can be restored by addition of exogenous Mmp10 protein to the culture medium, demonstrating a direct role for Mmp10 in the proliferation of these cells. Oncospheres exhibit enhanced tumor-initiating and metastatic activity when injected orthotopically into syngeneic mice, whereas Mmp10-deficient cultures show a severe defect in tumor initiation. Conversely, oncospheres implanted into syngeneic non-transgenic or Mmp10(-/- mice show no significant difference in tumor initiation, growth or metastasis, demonstrating the importance of Mmp10 produced by cancer cells rather than the tumor microenvironment in lung tumor initiation and maintenance. Analysis of gene expression data from human cancers reveals a strong positive correlation between tumor Mmp10 expression and metastatic behavior in many human tumor types. Thus, Mmp10 is required for maintenance of a highly tumorigenic, cancer-initiating, metastatic stem-like cell population in lung cancer. Our data demonstrate for the first time that Mmp10 is a critical lung cancer stem cell gene and novel therapeutic target for lung cancer stem cells.

  3. Pouterin, a novel potential cytotoxic lectin-like protein with apoptosis-inducing activity in tumorigenic mammalian cells.

    Science.gov (United States)

    Boleti, Ana Paula de A; Ventura, Cláudio A; Justo, Giselle Z; Silva, Rodrigo A; de Sousa, Ana Carolina T; Ferreira, Carmen V; Yano, Tomomasa; Macedo, Maria Lígia R

    2008-06-15

    In this study, the cytotoxicity of pouterin in tumorigenic and non-tumorigenic mammalian cell lines was investigated. We found that HeLa, Hep-2 and HT-29 tumor cells were highly sensitive to pouterin cytotoxicity in a dose-dependent manner, whereas non-tumorigenic Vero cells and human lymphocytes were relatively resistant to the protein. Among the tumor cell lines, HeLa cells showed the highest susceptibility to pouterin cytotoxicity, exhibiting a time-dependent increase in LDH leakage and an IC(50) value of 5mug/mL. Morphological alterations such as rounding, cell shrinkage and chromatin condensation, consistent with apoptotic cell death were observed. Apoptosis induction was demonstrated by DNA fragmentation as detected by terminal dUTP nick-end labeling (TUNEL). Furthermore, HeLa cells incubated with pouterin showed disruption of the actin cytoskeleton. Western blot analysis revealed that pouterin caused increased expression of p21, thus indicating cell cycle arrest. Subsequent studies provided evidence that apoptosis may be partially explained in the activation of the tumor necrosis factor receptor 1 (TNFR1) signaling. Interestingly, a time-dependent decrease of the expression of p65 nuclear factor kappa B (NFkappaB) subunit, concomitant with a downregulation of the inhibitor of apoptosis protein 1 (IAP1) was observed, suggesting that TNFR-mediated apoptosis is the predominant pathway induced by pouterin in HeLa cells.

  4. Immune-associated proteins with potential in vivo anti-tumor activities are upregulated in lung cancer cells treated with umbelliprenin: A proteomic approach

    Science.gov (United States)

    Khaghanzadeh, Narges; Nakamura, Kazuyuki; Kuramitsu, Yasuhiro; Ghaderi, Abbas; Mojtahedi, Zahra

    2016-01-01

    Umbelliprenin (Umb), a natural coumarin, has demonstrated anti-tumor activities, both in vitro and particularly in vivo, in several types of cancer, including lung cancer. The present study aimed to identify molecular targets of Umb using a high-throughput approach. Lung cancer cell lines, QU-DB (large-cell lung carcinoma) and A549 (adenocarcinoma), were treated with Umb. Differentially-expressed proteins were identified using two-dimensional electrophoresis coupled to mass spectrometry. In the QU-DB cells, differential expression of proteins, including downregulation of the tumorigenic protein heat shock protein 90 kDa and upregulation of the potential anti-tumor proteins Nipsnap1 and glycine-tRNA ligase (GRS), suggested that Umb is a strong anti-tumor compound. In the A549 cells, differential expression of proteins indicated possible contradictory effects of Umbregarding tumorigenesis, which included downregulation of the tumorigenic protein cyclophilin and the tumor suppressor MST, and upregulation of stathmin (tumorigenic) and calreticulin. Calreticulun, in addition to GRS in QU-DB cells, stimulates anti-tumor immune responses in vivo. To the best of our knowledge, the present study is the first to use a high-throughput approach to identify targets of Umb in cancer. These molecular targets suggested that Umb may exhibit stronger in vitro anti-tumor activity against the large-cell carcinoma model than the adenocarcinoma model. Furthermore, it has been reported that Umb exhibits higher cytotoxicity against QU-DB cells than A549 cells in vitro, and significant Umb anti-tumor activity against lung cancer in vivo, which is consistent with previously published literature. In each cell type, immune-associated molecules were upregulated, indicating that this naturally occurring compound exhibits marked anti-tumor activity in vivo. However, further studies that investigate the effect of Umb in different in vitro models of cancer are required. PMID:28105238

  5. PCDH10 is required for the tumorigenicity of glioblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Echizen, Kanae [Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032 (Japan); Nakada, Mitsutoshi, E-mail: mnakada@med.kanazawa-u.ac.jp [Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, 13-1, Takara-machi, Kanazawa 920-8641 (Japan); Hayashi, Tomoatsu [Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032 (Japan); Sabit, Hemragul; Furuta, Takuya [Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, 13-1, Takara-machi, Kanazawa 920-8641 (Japan); Nakai, Miyuki; Koyama-Nasu, Ryo; Nishimura, Yukiko; Taniue, Kenzui [Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032 (Japan); Morishita, Yasuyuki [Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Hirano, Shinji [Department of Neurobiology and Anatomy, Kochi Medical School, Kochi University, Okoh-cho, Nangoku-City, Kochi 783-8505 (Japan); Terai, Kenta [Laboratory of Function and Morphology, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032 (Japan); Todo, Tomoki; Ino, Yasushi; Mukasa, Akitake; Takayanagi, Shunsaku; Ohtani, Ryohei; Saito, Nobuhito [Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655 (Japan); Akiyama, Tetsu, E-mail: akiyama@iam.u-tokyo.ac.jp [Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032 (Japan)

    2014-01-31

    Highlights: • PCDH10 is required for the proliferation, survival and self-renewal of glioblastoma cells. • PCDH10 is required for glioblastoma cell migration and invasion. • PCDH10 is required for the tumorigenicity of glioblastoma cells. • PCDH10 may be a promising target for the therapy of glioblastoma. - Abstract: Protocadherin10 (PCDH10)/OL-protocadherin is a cadherin-related transmembrane protein that has multiple roles in the brain, including facilitating specific cell–cell connections, cell migration and axon guidance. It has recently been reported that PCDH10 functions as a tumor suppressor and that its overexpression inhibits proliferation or invasion of multiple tumor cells. However, the function of PCDH10 in glioblastoma cells has not been elucidated. In contrast to previous reports on other tumors, we show here that suppression of the expression of PCDH10 by RNA interference (RNAi) induces the growth arrest and apoptosis of glioblastoma cells in vitro. Furthermore, we demonstrate that knockdown of PCDH10 inhibits the growth of glioblastoma cells xenografted into immunocompromised mice. These results suggest that PCDH10 is required for the proliferation and tumorigenicity of glioblastoma cells. We speculate that PCDH10 may be a promising target for the therapy of glioblastoma.

  6. High prevalence of lung cancer in a surgical cohort of lung cancer patients a decade after smoking cessation

    Directory of Open Access Journals (Sweden)

    Mosenifar Zab

    2011-02-01

    Full Text Available Abstract Background This study was designed to assess the prevalence of smoking at time of lung cancer diagnosis in a surgical patient cohort referred for cardiothoracic surgery. Methods Retrospective study of lung cancer patients (n = 626 referred to three cardiothoracic surgeons at a tertiary care medical center in Southern California from January 2006 to December 2008. Relationships among years of smoking cessation, smoking status, and tumor histology were analyzed with Chi-square tests. Results Seventy-seven percent (482 had a smoking history while 11.3% (71 were current smokers. The length of smoking cessation to cancer diagnosis was Conclusions In a surgical lung cancer cohort, the majority of patients were smoking abstinent greater than one decade before the diagnosis of lung cancer.

  7. ASBEL, an ANA/BTG3 antisense transcript required for tumorigenicity of ovarian carcinoma.

    Science.gov (United States)

    Yanagida, Satoshi; Taniue, Kenzui; Sugimasa, Hironobu; Nasu, Emiko; Takeda, Yasuko; Kobayashi, Mana; Yamamoto, Tadashi; Okamoto, Aikou; Akiyama, Tetsu

    2013-01-01

    Mammalian genomes encode numerous antisense non-coding RNAs, which are assumed to be involved in the regulation of the sense gene expression. However, the mechanisms of their action and involvement in the development of diseases have not been well elucidated. The ANA/BTG3 protein is an antiproliferative protein whose expression is downregulated in prostate and lung cancers. Here we show that an antisense transcript of the ANA/BTG3 gene, termed ASBEL, negatively regulates the levels of ANA/BTG3 protein, but not of ANA/BTG3 mRNA and is required for proliferation and tumorigenicity of ovarian clear cell carcinoma. We further show that knockdown of ANA/BTG3 rescues growth inhibition caused by ASBEL knockdown. Moreover, we demonstrate that ASBEL forms duplexes with ANA/BTG3 mRNA in the nucleus and suppresses its cytoplasmic transportation. Our findings illustrate a novel function for an antisense transcript that critically promotes tumorigenesis by suppressing translation of the sense gene by inhibiting its cytoplasmic transportation.

  8. Rheumatoid arthritis-associated interstitial lung disease: lung inflammation evaluated with high resolution computed tomography scan is correlated to rheumatoid arthritis disease activity.

    Science.gov (United States)

    Pérez-Dórame, Renzo; Mejía, Mayra; Mateos-Toledo, Heidegger; Rojas-Serrano, Jorge

    2015-01-01

    To describe the association between rheumatoid arthritis disease activity (RA) and interstitial lung damage (inflammation and fibrosis), in a group of patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). A retrospective study of RA patients with interstitial lung disease (restrictive pattern in lung function tests and evidence of interstitial lung disease in high resolution computed tomography (HRCT)). Patients were evaluated to exclude other causes of pulmonary disease. RA disease activity was measured with the CDAI index. Interstitial lung inflammation and fibrosis were determined by Kazerooni scale. We compared Kazerooni ground-glass score with the nearest CDAI score to HRCT date scan of the first medical evaluation at our institution. In nine patients, we compared the first ground-glass score with a second one after treatment with DMARDs and corticosteroids. Spearman's rank correlation coefficient was used to evaluate association between RA disease activity and the Kazerooni ground-glass and fibrosis scores. Thirty-four patients were included. A positive correlation between CDAI and ground-glass scores was found (rs=0.3767, PFibrosis and CDAI scores were not associated (rs=-0.0747, P<0.6745). After treatment, a downward tendency in the ground-glass score was observed (median [IQR]): (2.33 [2,3] vs. 2 [1.33-2.16]), P<0.056, along with a lesser CDAI score (27 [8-43] vs. 9 [5-12]), P<0.063. There is a correlation between RA disease activity and ground-glass appearance in the HRCT of RA-ILD patients. These results suggest a positive association between RA disease activity and lung inflammation in RA-ILD. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

  9. Propagation-based phase-contrast tomography for high-resolution lung imaging with laboratory sources

    Energy Technology Data Exchange (ETDEWEB)

    Krenkel, Martin, E-mail: mkrenke@gwdg.de; Töpperwien, Mareike; Salditt, Tim, E-mail: tsaldit@gwdg.de [Institute for X-Ray Physics, University of Göttingen, 37077 Göttingen (Germany); Dullin, Christian [Institute of Diagnostic and Interventional Radiology, University Medical Center Göttingen, 37075 Göttingen (Germany); Alves, Frauke [Institute of Diagnostic and Interventional Radiology, University Medical Center Göttingen, 37075 Göttingen (Germany); Department of Haematology and Medical Oncology, Medical Center Göttingen, 37075 Göttingen (Germany); Department of Molecular Biology of Neuronal Signals, Max-Planck-Institute of Experimental Medicine, 37075 Göttingen (Germany)

    2016-03-15

    We have performed high-resolution phase-contrast tomography on whole mice with a laboratory setup. Enabled by a high-brilliance liquid-metal-jet source, we show the feasibility of propagation-based phase contrast in local tomography even in the presence of strongly absorbing surrounding tissue as it is the case in small animal imaging of the lung. We demonstrate the technique by reconstructions of the mouse lung for two different fields of view, covering the whole organ, and a zoom to the local finer structure of terminal airways and alveoli. With a resolution of a few micrometers and the wide availability of the technique, studies of larger biological samples at the cellular level become possible.

  10. A high-throughput and sensitive method to measure Global DNA Methylation: Application in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Mamaev Sergey

    2008-08-01

    Full Text Available Abstract Background Genome-wide changes in DNA methylation are an epigenetic phenomenon that can lead to the development of disease. The study of global DNA methylation utilizes technology that requires both expensive equipment and highly specialized skill sets. Methods We have designed and developed an assay, CpGlobal, which is easy-to-use, does not utilize PCR, radioactivity and expensive equipment. CpGlobal utilizes methyl-sensitive restriction enzymes, HRP Neutravidin to detect the biotinylated nucleotides incorporated in an end-fill reaction and a luminometer to measure the chemiluminescence. The assay shows high accuracy and reproducibility in measuring global DNA methylation. Furthermore, CpGlobal correlates significantly with High Performance Capillary Electrophoresis (HPCE, a gold standard technology. We have applied the technology to understand the role of global DNA methylation in the natural history of lung cancer. World-wide, it is the leading cause of death attributed to any cancer. The survival rate is 15% over 5 years due to the lack of any clinical symptoms until the disease has progressed to a stage where cure is limited. Results Through the use of cell lines and paired normal/tumor samples from patients with non-small cell lung cancer (NSCLC we show that global DNA hypomethylation is highly associated with the progression of the tumor. In addition, the results provide the first indication that the normal part of the lung from a cancer patient has already experienced a loss of methylation compared to a normal individual. Conclusion By detecting these changes in global DNA methylation, CpGlobal may have a role as a barometer for the onset and development of lung cancer.

  11. Macrophages facilitate coal tar pitch extract-induced tumorigenic transformation of human bronchial epithelial cells mediated by NF-κB.

    Directory of Open Access Journals (Sweden)

    Feifei Feng

    Full Text Available OBJECTIVE: Chronic respiratory inflammation has been associated with lung cancer. Tumor-associated macrophages (TAMs play a critical role in the formation of inflammation microenvironment. We sought to characterize the role of TAMs in coal tar pitch extract (CTPE-induced tumorigenic transformation of human bronchial epithelial cells and the underlying mechanisms. METHODS: The expression of TAMs-specific CD68 in lung cancer tissues and paired adjacent tissues from cancer patients was determined using immunostaining. Co-culture of human bronchial epithelial cells (BEAS-2B and macrophage-like THP-1 cells were conducted to evaluate the promotive effect of macrophages on CTPE-induced tumorigenic transformation of BEAS-2B cells. BEAS-2B cells were first treated with 2.4 µg/mL CTPE for 72 hours. After removal of CTPE, the cells were continuously cultured either with or without THP-1 cells and passaged using trypsin-EDTA. Alterations of cell cycle, karyotype, colony formation in soft agar and tumor xenograft growth in nude mice of BEAS-2B cells at passages 10, 20 and 30, indicative of tumorigenecity, were determined, respectively. In addition, mRNA and protein levels of NF-κB in BEAS-2B cells were measured with RT-PCR and western blot, respectively. B(aP was used as the positive control. RESULTS: The over-expression of TAMs-specific CD68 around lung tumor tissues was detected and associated with lung cancer progression. The tumorigenic alterations of BEAS-2B cells including increase in cell growth rate, number of cells with aneuploidy, clonogenicity in soft agar, and tumor size in nude mice in vivo occurred at passage 10, becoming significant at passages 20 and 30 of the co-culture following CTPE removal in compared to BEAS-2B cells alone. In addition, the expression levels of NF-κB in BEAS-2B cells were positively correlated to the malignancy of BEAS-2B cells under different conditions of treatment. CONCLUSION: The presence of macrophages

  12. High Frequency/Small Tidal Volume Differential Lung Ventilation”: A Technique of Ventilating the Nondependent Lung of One Lung Ventilation for Robotically Assisted Thoracic Surgery

    Directory of Open Access Journals (Sweden)

    Bassam M. Shoman

    2015-01-01

    Full Text Available With the introduction of new techniques and advances in the thoracic surgery fields, challenges to the anesthesia techniques had became increasingly exponential. One of the great improvements that took place in the thoracic surgical field was the use of the robotically assisted thoracic surgical procedure and minimally invasive endoscopic thoracic surgery. One lung ventilation technique represents the core anesthetic management for the success of those surgical procedures. Even with the use of effective one lung ventilation, the patient hemodynamics and respiratory parameters could be deranged and could not be tolerating the procedure that could compromise the end result of surgery. We are presenting our experience in managing one patient who suffered persistent hypoxia and hemodynamic instability with one lung ventilation for robotically assisted thymectomy procedure and how it was managed till the completion of the surgery successfully.

  13. High-grade neuroendocrine carcinomas of the lung highly express enhancer of zeste homolog 2, but carcinoids do not.

    Science.gov (United States)

    Findeis-Hosey, Jennifer J; Huang, Jiaoti; Li, Faqian; Yang, Qi; McMahon, Loralee A; Xu, Haodong

    2011-06-01

    Enhancer of zeste homolog 2, the catalytic subunit of polycomb repressive complex 2, is a histone methyltransferase and plays an important role in cell proliferation and cell cycle regulation. It has been shown to be overexpressed in a number of malignant neoplasms. This study aimed to determine the expression pattern of enhancer of zeste homolog 2 in neuroendocrine tumors of the lung and the potential of enhancer of zeste homolog 2 to serve as a biomarker to segregate carcinoids from high-grade neuroendocrine carcinomas. Fifty-four cases, including 25 typical carcinoids, 7 atypical carcinoids, 9 large-cell neuroendocrine carcinomas, and 13 small-cell lung carcinomas, were immunohistochemically studied using a monoclonal antibody against enhancer of zeste homolog 2. All 13 small-cell lung carcinomas demonstrated moderate to strong nuclear staining with 12 exhibiting more than 90% of tumor cells staining. All 9 large-cell neuroendocrine carcinomas were moderately to strongly positive for enhancer of zeste homolog 2, with 6 cases having staining in more than 80% of tumor cells. In contrast, all 25 typical carcinoids and 6 atypical carcinoids showed only rare scattered enhancer of zeste homolog 2-positive tumor cells, with 1 case of atypical carcinoid exhibiting moderate staining in 40% of tumor cells. A subsequent validation study of the 14 specimens of lung or mediastinal lymph node biopsy and fine-needle aspiration, including 6 small-cell lung carcinomas, 2 large-cell neuroendocrine carcinomas, 5 typical carcinoids, and 1 atypical carcinoid, was performed. Enhancer of zeste homolog 2 was diffusely and strongly positive in all small-cell lung carcinomas and large-cell neuroendocrine carcinomas, even with severe crush artifact, whereas it was only positive in rare tumor cells in carcinoids. These findings support the formulation that enhancer of zeste homolog 2 may play an important role in the regulation of biologic behavior of high-grade neuroendocrine carcinomas

  14. Investigating the expression, effect and tumorigenic pathway of PADI2 in tumors

    Science.gov (United States)

    Guo, Wei; Zheng, Yabing; Xu, Bing; Ma, Fang; Li, Chang; Zhang, Xiaoqian; Wang, Yao; Chang, Xiaotian

    2017-01-01

    Background Peptidylarginine deiminase (PAD) catalyzes the conversion of arginine residues to citrulline residues, termed citrullination. Recent studies have suggested that PAD isoform 2 (PADI2) plays an important role in tumors, although its tumorigenic effect and mechanism are largely unknown. Materials and methods Immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) were used to investigate the expression level of PADI2 in various tumor tissues and patient blood samples, respectively. MNK-45 and Bel-7402 tumor cell lines originating from gastric and liver tumors, respectively, were treated with anti-PADI2 siRNA, and the subsequent cell proliferation, apoptosis and migration were observed. Polymerase chain reaction (PCR) arrays, including Cancer PathwayFinder, Oncogenes and Tumor Suppressor Genes, p53 Signaling Pathway, Signal Transduction Pathway and Tumor Metastasis PCR arrays, were used to investigate the tumorigenic pathway of PADI2 in the siRNA-treated tumor cells. This analysis was verified by real-time PCR. Results Immunohistochemistry detected significantly increased expression of PADI2 in invasive breast ductal carcinoma, cervical squamous cell carcinoma, colon adenocarcinoma, liver hepatocellular carcinoma, lung cancer, ovarian serous papillary adenocarcinoma and papillary thyroid carcinoma samples. ELISA detected a twofold increase in PADI2 expression in the blood of 48.3% of patients with liver cancer, 38% of patients with cervical carcinoma and 32% of patients with gastric carcinoma. Increased apoptosis and decreased cell proliferation and migration were observed in the anti-PADI2 siRNA-treated MNK-45 cells, and increased cell proliferation and migration and decreased apoptosis were observed in the treated Bel-7402 cells with suppressed PADI2 expression. PCR arrays and real-time PCR detected significantly decreased CXCR2 and EPO expression in the MNK-45 cells and Bel-7402 cells, respectively, with the anti-PADI2 siRNA treatments

  15. Fusing visual and clinical information for lung tissue classification in high-resolution computed tomography.

    Science.gov (United States)

    Depeursinge, Adrien; Racoceanu, Daniel; Iavindrasana, Jimison; Cohen, Gilles; Platon, Alexandra; Poletti, Pierre-Alexandre; Müller, Henning

    2010-09-01

    We investigate the influence of the clinical context of high-resolution computed tomography (HRCT) images of the chest on tissue classification. 2D regions of interest in HRCT axial slices from patients affected with an interstitial lung disease are automatically classified into five classes of lung tissue. Relevance of the clinical parameters is studied before fusing them with visual attributes. Two multimedia fusion techniques are compared: early versus late fusion. Early fusion concatenates features in one single vector, yielding a true multimedia feature space. Late fusion consisting of the combination of the probability outputs of two support vector machines. The late fusion scheme allowed a maximum of 84% correct predictions of testing instances among the five classes of lung tissue. This represents a significant improvement of 10% compared to a pure visual-based classification. Moreover, the late fusion scheme showed high robustness to the number of clinical parameters used, which suggests that it is appropriate for mining clinical attributes with missing values in clinical routine. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  16. Prenatal determinants of neonatal lung function in high-risk newborns

    DEFF Research Database (Denmark)

    Bisgaard, Hans; Loland, Lotte; Holst, Klaus Kähler

    2009-01-01

    complications including mother's asthma status; and mode of delivery. RESULTS: Lung function was determined in 404 neonates, age 6 weeks. Neonates with body mass index in the upper quartile had 14% lower baseline forced expiratory volume at 0.5 second, and neonates of mothers smoking during the third trimester......, but the statistical significance may have been driven by outliers. Bronchial responsiveness exhibited a parabola development with tripling of bronchial responsiveness reaching the nadir at 3 months of age, but this needs replication in a study with repetitive measurements within individuals. CONCLUSION: High body...... mass index in newborns and mothers smoking is associated with reduced neonatal lung function. This suggests that the association between body proportion and wheezing disorders may be a result of shared genes or prenatal nutrition....

  17. Effect of high tidal volume ventilation and lipopolysaccharide on mitogen-activated protein kinase in rat lung tissue

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    @@ Mechanical ventilation, a crucial therapy to acute respiratory distress syndrome (ARDS), could exacerbate lung injury, and even result in ventilator-induced lung injury (VILI) if misused in some condition1. Over-activating inflammatory cells and expanding inflammatory responses, which are induced by infection, are fundamental reasons for ARDS. Among them, mitogen-activated protein kinase (MAPK) intracellular signal transduction pathways are key processes. This study aimed to investigate the time course of MAPK activation in rat lung tissue after high tidal volume (VT) ventilation and the role of lipopolysaccharide (LPS) in high-sensitivity, and to elucidate the effect of the pathway on VILI.

  18. Cardiopulmonary exercise testing in the evaluation of high risk patients with lung cancer

    Institute of Scientific and Technical Information of China (English)

    MAO You-sheng; WANG Yong-gang; HUANG Jin-feng; HE Jie; YAN Shao-ping; Dong Jing-si; CHENG Gui-yu; SUN Ke-lin; LIU Xiang-yang; FANG De-kang; LI Jian

    2010-01-01

    Background It is still unclear whether pulmonary function tests (PFTs) are sufficient for predicting perioperative risk,and whether all patients or only a subset of them need a cardiopulmonary exercise test (CPET) for further assessment.Thus, this study was designed to evaluate the CPET and compare the results of CPET and conventional PFTs to identify which parameters are more reliable and valuable in predicting perioperative risks for high risk patients with lung cancer.Methods From January 2005 to August 2008, 297 consecutive lung cancer patients underwent conventional PFTs (spirometry + single-breath carbon monoxide diffusing capacity of the lungs (DLCOsb) for diffusion capacity) and CPET preoperatively. The correlation of postoperative cardiopulmonary complications with the parameters of PFT and CPET was retrospectively analyzed using the chi-square test, independent sample t test and binary Logistic regression analysis.Results Of the 297 patients, 78 did not receive operation due to advanced disease stage or poor cardiopulmonary function. The remaining 219 underwent different modes of operations. Twenty-one cases were excluded from this study due to exploration alone (15 cases) and operation-related complications (6 cases). Thus, 198 cases were eligible for evaluation. Fifty of the 198 patients (25.2%) had postoperative cardiopulmonary complications. Three patients (1.5%)died of complications within 30 postoperative days. The patients were stratified into groups based on VO2max/pred respectively. The rate of postoperative cardiopulmonary complications was significantly higher in the group with cardiopulmonary complications were significantly correlated with age, comorbidities, and poor PFT and CPET results.used to stratify the patients' cardiopulmonary function status and to predict the risk of postoperative cardiopulmonary predicting perioperative risk. If available, cardiopulmonary exercise testing is strongly suggested for high-risk lung cancer patients in

  19. Tumorigenicity of acrylamide and its metabolite glycidamide in the neonatal mouse bioassay

    Science.gov (United States)

    Von Tungeln, Linda S.; Doerge, Daniel R.; da Costa, Gonçalo Gamboa; Marques, M. Matilde; Witt, William M.; Koturbash, Igor; Pogribny, Igor P.; Beland, Frederick A.

    2012-01-01

    Acrylamide is a high-volume industrial chemical, a component of cigarette smoke, and a product formed in certain foods prepared at high temperatures. Previously, we compared the extent of DNA adduct formation and mutations in B6C3F1/Tk mice treated neonatally with acrylamide or glycidamide to obtain information concerning the mechanism of acrylamide genotoxicity. We have now examined the tumorigenicity of acrylamide and glycidamide in mice treated neonatally. Male B6C3F1 mice were injected intraperitoneally on postnatal days 1, 8, and 15 with 0.0, 0.14, or 0.70 mmol acrylamide or glycidamide per kg body weight per day and the tumorigenicity was assessed after one year. Survival in each of the groups was >87%, there were no differences in body weights among the groups, and the only treatment-related neoplasms involved the liver. The incidence of combined hepatocellular adenoma or carcinoma was 3.8% in the control group, 8.3% in the 0.14 mmol acrylamide and glycidamide per kg body weight groups, 4.2% in the 0.70 mmol acrylamide per kg body weight group, and 71.4% in the 0.70 mmol glycidamide per kg body weight group. Analysis of the hepatocellular tumors indicated that the increased incidence observed in mice administered 0.70 mmol glycidamide per kg body weight was associated with A→ G and A → T mutations at codon 61 of H-ras. These results, combined with our previous data on DNA adduct formation and mutation induction, suggest that the carcinogenicity of acrylamide is dependent upon its metabolism to glycidamide, a pathway that is deficient in neonatal mice. PMID:22336951

  20. Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells.

    Science.gov (United States)

    Barszczyk, Mark; Buczkowicz, Pawel; Castelo-Branco, Pedro; Mack, Stephen C; Ramaswamy, Vijay; Mangerel, Joshua; Agnihotri, Sameer; Remke, Marc; Golbourn, Brian; Pajovic, Sanja; Elizabeth, Cynthia; Yu, Man; Luu, Betty; Morrison, Andrew; Adamski, Jennifer; Nethery-Brokx, Kathleen; Li, Xiao-Nan; Van Meter, Timothy; Dirks, Peter B; Rutka, James T; Taylor, Michael D; Tabori, Uri; Hawkins, Cynthia

    2014-12-01

    Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 ± 11 vs 64 ± 18 %; p = 0.03) and overall survival (58 ± 12 vs 83 ± 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.

  1. Drug-induced lung disease: High-resolution CT and histological findings

    Energy Technology Data Exchange (ETDEWEB)

    Cleverley, Joanne R.; Screaton, Nicholas J.; Hiorns, Melanie P.; Flint, Julia D.A.; Mueller, Nestor L

    2002-04-01

    AIM: To compare the parenchymal high-resolution computed tomography (HRCT) appearances with histological findings in patients with drug-induced lung disease and to determine the prognostic value of HRCT. MATERIALS AND METHODS: Drug history, HRCT features, histological findings and outcome at 3 months in 20 patients with drug induced-lung disease were reviewed retrospectively. The HRCT images were assessed for the pattern and distribution of abnormalities and classified as most suggestive of interstitial pneumonitis/fibrosis, diffuse alveolar damage (DAD), organizing pneumonia (OP) reaction, or a hypersensitivity reaction. RESULTS: On histopathological examination there were eight cases of interstitial pneumonitis/fibrosis, five of DAD, five of OP reactions, one of hypersensitivity reaction and one of pulmonary eosinophilia. The most common abnormalities on HRCT were ground-glass opacities (n = 17), consolidation (n = 14), interlobular septal thickening (n = 15) and centrilobular nodules (n 8). HRCT interpretation and histological diagnosis were concordant in only nine (45%) of 20 patients. The pattern, distribution, and extent of HRCT abnormalities were of limited prognostic value: all eight patients with histological findings of OP, hypersensitivity reaction, or eosinophilic infiltrate improved on follow-up compared to only five of 13 patients with interstitial pneumonitis/fibrosis or DAD. CONCLUSION: In many cases of drug-induced lung injury HRCT is of limited value in determining the histological pattern and prognosis. Cleverly, J.R. et al.

  2. High Lung Allocation Score Is Associated With Increased Morbidity and Mortality Following Transplantation

    Science.gov (United States)

    Russo, Mark J.; Iribarne, Alexander; Hong, Kimberly N.; Davies, Ryan R.; Xydas, Steve; Takayama, Hiroo; Ibrahimiye, Ali; Gelijns, Annetine C.; Bacchetta, Matthew D.; D’Ovidio, Frank; Arcasoy, Selim

    2010-01-01

    Background: The lung allocation score (LAS) was initiated in May 2005 to allocate lungs based on medical urgency and posttransplant survival. The purpose of this study was to determine if there is an association between an elevated LAS at the time of transplantation and increased postoperative morbidity and mortality. Methods: The United Network for Organ Sharing provided de-identified patient-level data. Analysis included lung transplant recipients aged ≥ 12 years who received transplants between April 5, 2006, and December 31, 2007 (n = 3,836). Recipients were stratified into three groups: LAS < 50 (n = 3,161, 83.87%), LAS 50 to 75 (n = 411, 10.9%), and LAS ≥ 75 (n = 197, 5.23%), referred to as low LAS (LLAS), intermediate LAS (ILAS), and high LAS (HLAS), respectively. The primary outcome was posttransplant graft survival at 1 year. Secondary outcomes included length of stay and in-hospital complications. Results: HLAS recipients had significantly worse actuarial survival at 90 days and 1 year compared with LLAS recipients. When transplant recipients were stratified by disease etiology, a trend of decreased survival with elevated LAS was observed across all major causes of lung transplant. HLAS recipients were more likely to require dialysis or to have infections compared with LLAS recipients (P < .001). In addition, length of stay was higher in the HLAS group when compared with the LLAS group (P < .001). Conclusions: HLAS is associated with decreased survival and increased complications during the transplant hospitalization. Whereas the LAS has improved organ allocation through decreased waiting list deaths and waiting list times, lower survival and higher morbidity among HLAS recipients suggests that continued review of LAS scoring is needed to ensure optimal long-term transplant survival. PMID:19820072

  3. AS30D Model of Hepatocellular Carcinoma: Tumorigenicity and Preliminary Characterization by Imaging, Histopathology, and Immunohistochemistry

    Energy Technology Data Exchange (ETDEWEB)

    Thompson, Scott M. [Mayo Clinic, Medical Scientist Training Program (United States); Callstrom, Matthew R. [Mayo Clinic, Department of Radiology (United States); Knudsen, Bruce [Mayo Clinic, Department of Laboratory Medicine and Pathology (United States); Anderson, Jill L. [Mayo Clinic, Division of Physiology and Bioengineering (United States); Butters, Kim A.; Grande, Joseph P. [Mayo Clinic, Department of Laboratory Medicine and Pathology (United States); Roberts, Lewis R. [Mayo Clinic, Division of Gastroenterology and Hepatology (United States); Woodrum, David A., E-mail: woodrum.david@mayo.edu [Mayo Clinic, Department of Radiology (United States)

    2013-02-15

    This study was designed to determine the tumorigenicity of the AS30D HCC cell line following orthotopic injection into rat liver and preliminarily characterize the tumor model by both magnetic resonance imaging (MRI) and ultrasound (US) as well as histopathology and immunohistochemistry.MaterialsAS30D cell line in vitro proliferation was assessed by using MTT assay. Female rats (N = 5) underwent injection of the AS30D cell line into one site in the liver. Rats subsequently underwent MR imaging at days 7 and 14 to assess tumor establishment and volume. One rat underwent US of the liver at day 7. Rats were euthanized at day 7 or 14 and livers were subjected to gross, histopathologic (H and E), and immunohistochemical (CD31) analysis to assess for tumor growth and neovascularization. AS30D cell line demonstrated an in vitro doubling time of 33.2 {+-} 5.3 h. MR imaging demonstrated hyperintense T2-weighted and hypointense T1-weighted lesions with tumor induction in five of five and three of three sites at days 7 and 14, respectively. The mean (SD) tumor volume was 126.1 {+-} 36.2 mm{sup 3} at day 7 (N = 5). US of the liver demonstrated a well-circumscribed, hypoechoic mass and comparison of tumor dimensions agreed well with MRI. Analysis of H and E- and CD31-stained sections demonstrated moderate-high grade epithelial tumors with minimal tumor necrosis and evidence of diffuse intratumoral and peritumoral neovascularization by day 7. AS30D HCC cell line is tumorigenic following orthotopic injection into rat liver and can be used to generate an early vascularizing, slower-growing rat HCC tumor model.

  4. Monitoring of experimental rat lung transplants by high-resolution flat-panel volumetric computer tomography (fpVCT).

    Science.gov (United States)

    Greschus, Susanne; Kuchenbuch, Tim; Plötz, Christian; Obert, Martin; Traupe, Horst; Padberg, Winfried; Grau, Veronika; Hirschburger, Markus

    2009-01-01

    Noninvasive assessment of experimental lung transplants with high resolution would be favorable to exclude technical failure and to follow up graft outcome in the living animal. Here we describe a flat-panel Volumetric Computed Tomography (fpVCT) technique using a prototype scanner. Lung transplantation was performed in allogeneic as well as in corresponding syngeneic rat strain combinations. At different time points post-transplantation, fpVCT was performed. Lung transplants can be visualized in the living rat with high-spatial resolution. FpVCT allows a detailed analysis of the lung and the bronchi. Infiltrates developing during rejection episodes can be diagnosed and follow-up studies can easily be performed. With fpVCT it is possible to control the technical success of the surgical procedure. Graft rejection can be visualized individually in the living animal noninvasively, which is highly advantageous for studying the pathogenesis of chronic rejection or to monitor new therapies.

  5. Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy.

    Science.gov (United States)

    Mastorakos, Panagiotis; da Silva, Adriana L; Chisholm, Jane; Song, Eric; Choi, Won Kyu; Boyle, Michael P; Morales, Marcelo M; Hanes, Justin; Suk, Jung Soo

    2015-07-14

    Gene therapy has emerged as an alternative for the treatment of diseases refractory to conventional therapeutics. Synthetic nanoparticle-based gene delivery systems offer highly tunable platforms for the delivery of therapeutic genes. However, the inability to achieve sustained, high-level transgene expression in vivo presents a significant hurdle. The respiratory system, although readily accessible, remains a challenging target, as effective gene therapy mandates colloidal stability in physiological fluids and the ability to overcome biological barriers found in the lung. We formulated highly stable DNA nanoparticles based on state-of-the-art biodegradable polymers, poly(β-amino esters) (PBAEs), possessing a dense corona of polyethylene glycol. We found that these nanoparticles efficiently penetrated the nanoporous and highly adhesive human mucus gel layer that constitutes a primary barrier to reaching the underlying epithelium. We also discovered that these PBAE-based mucus-penetrating DNA nanoparticles (PBAE-MPPs) provided uniform and high-level transgene expression throughout the mouse lungs, superior to several gold standard gene delivery systems. PBAE-MPPs achieved robust transgene expression over at least 4 mo following a single administration, and their transfection efficiency was not attenuated by repeated administrations, underscoring their clinical relevance. Importantly, PBAE-MPPs demonstrated a favorable safety profile with no signs of toxicity following intratracheal administration.

  6. High fluence laser irradiation induces reactive oxygen species generation in human lung adenocarcinoma cells

    Science.gov (United States)

    Wang, Fang; Xing, Da; Chen, Tong-Sheng

    2006-09-01

    Low-power laser irradiation (LPLI) has been used for therapies such as curing spinal cord injury, healing wound et al. Yet, the mechanism of LPLI remains unclear. Our previous study showed that low fluences laser irradiation induces human lung adenocarcinoma cells (ASTC-a-1) proliferation, but high fluences induced apoptosis and caspase-3 activation. In order to study the mechanism of apoptosis induced by high fluences LPLI further, we have measured the dynamics of generation of reactive oxygen species (ROS) using H IIDCFDA fluorescence probes during this process. ASTC-a-1 cells apoptosis was induced by He-Ne laser irradiation at high fluence of 120J/cm2. A confocal laser scanning microscope was used to perform fluorescence imaging. The results demonstrated that high fluence LPLI induced the increase of mitochondria ROS. Our studies contribute to clarify the biological mechanism of high fluence LPLI-induced cell apoptosis.

  7. High Frequency/Small Tidal Volume Differential Lung Ventilation”: A Technique of Ventilating the Nondependent Lung of One Lung Ventilation for Robotically Assisted Thoracic Surgery

    OpenAIRE

    Shoman, Bassam M.; Hany O. Ragab; Ammar Mustafa; Rashid Mazhar

    2015-01-01

    With the introduction of new techniques and advances in the thoracic surgery fields, challenges to the anesthesia techniques had became increasingly exponential. One of the great improvements that took place in the thoracic surgical field was the use of the robotically assisted thoracic surgical procedure and minimally invasive endoscopic thoracic surgery. One lung ventilation technique represents the core anesthetic management for the success of those surgical procedures. Even with the use o...

  8. Fluorescence polarization of amniotic fluid to assess fetal lung maturity in high risk pregnancies

    Directory of Open Access Journals (Sweden)

    Tadeu Gantus Simão Stefano

    2006-06-01

    Full Text Available Objective: To assess the accuracy, sensitivity, specificity, and thepositive and negative predictive values of amniotic fluidfluorescence polarization for neonatal respiratory distresssyndrome in high risk pregnancies. Methods: A prospectivedescriptive study of 54 patients with high risk pregnancies. Fetallung maturity was assessed using amniotic fluid florescencepolarization obtained by amniocentesis up to 72 hours beforedelivery. Respiratory distress syndrome, stratified by gestationalage at birth, was the primary outcome analyzed. Amniotic fluidfluorescence polarization values equal to or over 50 mg/g (indicatingfetal lung maturity were considered as negative results. Results:The mean gestational age at birth was 35 weeks (SD 2.0.Respiratory distress syndrome was seen in 14 newborns(24%. Amniotic fluid fluorescence polarization had high sensitivity(86% and specificity (81%, with 14% false-negative and 19% falsepositiveresults. The positive predictive value was 60% and thenegative predictive value was 94%. The area under the ROC curveindicated the 50 mg/g albumin/surfactant ratio as the best cutoffpoint (85% sensitivity and 81% specificity. Conclusion: A negativevalue in amniotic fluid fluorescence polarization (results equal toor over 50 mg/g confirms lung maturity which translates into avery low risk of a newborn developing respiratory distresssyndrome in high risk pregnancies.

  9. Expression Changes of Early Response Genes in Lung Due to High Volume Ventilation

    Institute of Scientific and Technical Information of China (English)

    WANG Yuelan; YAO Shanglong; XIONG Ping

    2005-01-01

    Summary: The expression changes of early response genes due to ventilation with high volume in adult rats in vivo were observed. Forty SD male rats were randomly divided into control and 30, 60, 90 and 120 min ventilation groups, respectively (n=8 in each group). The animals were ventilated with tidal volume of 42 ml/kg and a PEEP level of 0 cmH2O at a rate of 40 breaths per minute in room air with a ventilator was given to the small animals. The expression of Egr-1, C-jun and IL-1β mRNA and proteins was detected by RT-PCR and immunohistochemical technique, respectively. The pathological changes in lung tissues were examined by HE staining. The results indicated that the expression of Egr-1, C-jun and IL-1β mRNA was detectable at 30th min after overventilation, but there was no significant difference in comparison with that in control group until overventilation for 60 min. However, at 90 and 120 min there was a significent increase as compared with 30 min or control group (P<0.05). The expression of Egr-1, C-jun and IL-1β deteced by immunohistochemical assay also showed a similar tendency of the gradual increase. In the 120 min ventilation group, the expression intensity of Egr-1, C-jun and IL-1β proteins in lung cells was the strongest and the nuclear translocation was increased markedly in comparison with any other groups (P<0.05). HE staining suggested that the degree of lung injury was aggravated gradually with the ventialtion going on and had a similar tendency to the expression of these early response genes and proteins. The current data suggested that overventilation activated and upregulated the expression of early response genes and the expression of these genes may be taken as the early signal to predict the onset and degree of lung injury. These results may demonstrated partially that the expression of early response genes induced by the mechanical stretch is associated with biochamic lung injury.

  10. High spatiotemporal resolution measurement of regional lung air volumes from 2D phase contrast x-ray images

    Energy Technology Data Exchange (ETDEWEB)

    Leong, Andrew F. T.; Islam, M. Sirajul; Kitchen, Marcus J. [School of Physics, Monash University, Victoria 3800 (Australia); Fouras, Andreas [Division of Biological Engineering, Monash University, Victoria 3800 (Australia); Wallace, Megan J.; Hooper, Stuart B. [Ritchie Centre and Department of Obstetrics and Gynaecology, Monash Institute of Medical Research, Monash University, Victoria 3168 (Australia)

    2013-04-15

    Purpose: Described herein is a new technique for measuring regional lung air volumes from two-dimensional propagation-based phase contrast x-ray (PBI) images at very high spatial and temporal resolution. Phase contrast dramatically increases lung visibility and the outlined volumetric reconstruction technique quantifies dynamic changes in respiratory function. These methods can be used for assessing pulmonary disease and injury and for optimizing mechanical ventilation techniques for preterm infants using animal models. Methods: The volumetric reconstruction combines the algorithms of temporal subtraction and single image phase retrieval (SIPR) to isolate the image of the lungs from the thoracic cage in order to measure regional lung air volumes. The SIPR algorithm was used to recover the change in projected thickness of the lungs on a pixel-by-pixel basis (pixel dimensions {approx}16.2 {mu}m). The technique has been validated using numerical simulation and compared results of measuring regional lung air volumes with and without the use of temporal subtraction for removing the thoracic cage. To test this approach, a series of PBI images of newborn rabbit pups mechanically ventilated at different frequencies was employed. Results: Regional lung air volumes measured from PBI images of newborn rabbit pups showed on average an improvement of at least 20% in 16% of pixels within the lungs in comparison to that measured without the use of temporal subtraction. The majority of pixels that showed an improvement was found to be in regions occupied by bone. Applying the volumetric technique to sequences of PBI images of newborn rabbit pups, it is shown that lung aeration at birth can be highly heterogeneous. Conclusions: This paper presents an image segmentation technique based on temporal subtraction that has successfully been used to isolate the lungs from PBI chest images, allowing the change in lung air volume to be measured over regions as small as the pixel size. Using

  11. Offering Lung Cancer Screening to High-Risk Medicare Beneficiaries Saves Lives and Is Cost-Effective: An Actuarial Analysis

    Science.gov (United States)

    Pyenson, Bruce S.; Henschke, Claudia I.; Yankelevitz, David F.; Yip, Rowena; Dec, Ellynne

    2014-01-01

    Background By a wide margin, lung cancer is the most significant cause of cancer death in the United States and worldwide. The incidence of lung cancer increases with age, and Medicare beneficiaries are often at increased risk. Because of its demonstrated effectiveness in reducing mortality, lung cancer screening with low-dose computed tomography (LDCT) imaging will be covered without cost-sharing starting January 1, 2015, by nongrandfathered commercial plans. Medicare is considering coverage for lung cancer screening. Objective To estimate the cost and cost-effectiveness (ie, cost per life-year saved) of LDCT lung cancer screening of the Medicare population at high risk for lung cancer. Methods Medicare costs, enrollment, and demographics were used for this study; they were derived from the 2012 Centers for Medicare & Medicaid Services (CMS) beneficiary files and were forecast to 2014 based on CMS and US Census Bureau projections. Standard life and health actuarial techniques were used to calculate the cost and cost-effectiveness of lung cancer screening. The cost, incidence rates, mortality rates, and other parameters chosen by the authors were taken from actual Medicare data, and the modeled screenings are consistent with Medicare processes and procedures. Results Approximately 4.9 million high-risk Medicare beneficiaries would meet criteria for lung cancer screening in 2014. Without screening, Medicare patients newly diagnosed with lung cancer have an average life expectancy of approximately 3 years. Based on our analysis, the average annual cost of LDCT lung cancer screening in Medicare is estimated to be $241 per person screened. LDCT screening for lung cancer in Medicare beneficiaries aged 55 to 80 years with a history of ≥30 pack-years of smoking and who had smoked within 15 years is low cost, at approximately $1 per member per month. This assumes that 50% of these patients were screened. Such screening is also highly cost-effective, at <$19,000 per life

  12. High-grade primary myxoid lung sarcoma presenting as recurrent hemorrhagic pleural effusions in a young woman

    Directory of Open Access Journals (Sweden)

    Hassan Tahir

    2015-12-01

    Full Text Available Primary lung sarcomas are rare but aggressive tumors accounting for less than 0.5% of all lung tumors. The diagnosis of primary lung sarcoma should only be considered after exclusion of other sites. A 32-year-old female presented with recurrent hemorrhagic pleural effusions, shortness of breath and persistent cough. Pleural effusion was drained twice, and each time its analysis was normal. Patient developed atelectasis of left lung with hemothorax for which she underwent video-assisted thoracoscopic surgery. A large mass was found compressing the entire lower lobe of left lung with extension into mediastinum, the biopsy of which showed myxoid sarcoma. The tumor was inoperable and options of chemotherapy or radiotherapy were discussed with the patient. Primary lung sarcoma can rarely present with recurrent hemorrhagic pleural effusion. A high degree of suspicion is required for early diagnosis as large hemothorax on computed tomography or chest X-ray may obscure lung mass and make its diagnosis difficult.

  13. Post-mortem high-resolution computed tomography of the lung: radiologic-morphologic correlation. Postmortale hochaufloesende Computertomographie der Lunge: Radiologisch-morphologische Korrelationen

    Energy Technology Data Exchange (ETDEWEB)

    Roos, N.; Diederich, X.; Lenzen, H.; Wiesmann, J.; Peters, P.E. (Muenster Univ. (Germany). Radiologische Klinik und Poliklinik); Fahrenkamp, A.; Puskas, Z. (Muenster Univ. (Germany). Gerhard-Domagk-Institut fuer Pathologie); Holst, D. (Muenster Univ. (Germany). Klinik und Poliklinik fuer Anaesthesiologie und Operative Intensivmedizin); Lunkenheimer, P.P. (Muenster Univ. (Germany). Klinik und Poliklinik fuer Thorax-, Herz- und Gefaesschirurgie)

    1993-03-01

    To establish precise correlations between high-resolution computed tomography (CT) and normal pulmonary anatomy and pulmonary pathology, 49 lungs affected by different diseases were analysed. Post-mortem high-resolution CT scans were compared with the corresponding macroscopic and microscopic pathological findings. For scanning, lungs were inflated and fixed, which avoided any decrease in the structural resolution of pulmonary parenchyma and allowed a topographically exact correlation between CT appearances and morphological changes. After demonstration of the structural details relevant for CT in normal pulmonary parenchyma, an attempt is made to establish the morphological basis of the following CT phenomena: thickening of interlobular septae, increase in pulmonary translucency, consolidation of the non-nodular alveolar and of the nodular type, and changes in the pleural region. Although CT findings in pulmonary lesions are mainly non-specific, knowledge of the corresponding morphological basis is helpful in diagnostic evaluation. (orig.).

  14. Acetylsalicylic Acid Compared to Placebo in Treating High-Risk Patients With Subsolid Lung Nodules | Division of Cancer Prevention

    Science.gov (United States)

    This randomized phase II trial studies acetylsalicylic acid compared to placebo in treating high-risk patients with subsolid lung nodules. A nodule is a growth or lump that may be malignant (cancer) or benign (not cancer). Chemoprevention is the use of drugs to keep cancer from forming or coming back. The use of acetylsalicylic acid may keep cancer from forming in patients with subsolid lung nodules. |

  15. Lung pressures and gas transport during high-frequency airway and chest wall oscillation.

    Science.gov (United States)

    Khoo, M C; Ye, T H; Tran, N H

    1989-09-01

    The major goal of this study was to compare gas exchange, tidal volume (VT), and dynamic lung pressures resulting from high-frequency airway oscillation (HFAO) with the corresponding effects in high-frequency chest wall oscillation (HFCWO). Eight anesthetized paralyzed dogs were maintained eucapnic with HFAO and HFCWO at frequencies ranging from 1 to 16 Hz in the former and 0.5 to 8 Hz in the latter. Tracheal (delta Ptr) and esophageal (delta Pes) pressure swings, VT, and arterial blood gases were measured in addition to respiratory impedance and static pressure-volume curves. Mean positive pressure (25-30 cmH2O) in the chest cuff associated with HFCWO generation decreased lung volume by approximately 200 ml and increased pulmonary impedance significantly. Aside from this decrease in functional residual capacity (FRC), no change in lung volume occurred as a result of dynamic factors during the course of HFCWO application. With HFAO, a small degree of hyperinflation occurred only at 16 Hz. Arterial PO2 decreased by 5 Torr on average during HFCWO. VT decreased with increasing frequency in both cases, but VT during HFCWO was smaller over the range of frequencies compared with HFAO. delta Pes and delta Ptr between 1 and 8 Hz were lower than the corresponding pressure swings obtained with conventional mechanical ventilation (CMV) applied at 0.25 Hz. delta Pes was minimized at 1 Hz during HFCWO; however, delta Ptr decreased continuously with decreasing frequency and, below 2 Hz, became progressively smaller than the corresponding values obtained with HFAO and CMV.

  16. A microRNA signature for tumorigenic conazoles in mouse liver.

    Science.gov (United States)

    Triadimefon, propiconazole and myclobutanil are conazoles, an important class of agricultural and therapeutic fungicides. Triadimefon and propiconazole are mouse liver tumorigens, while myclobutanil is not. As part of a coordinated study to understand the molecular determinants o...

  17. Altered microRNA expression induced by tumorigenic conazoles in mouse liver.

    Science.gov (United States)

    Triadimefon, propiconazole, and myclobutanil are conazoles, an important class of agricultural and therapeutic fungicides. Triadimefon and propiconazole are mouse liver tumorigens, while myclobutanil is not. As part of a coordinated study to understand the molecular determinants ...

  18. A potential microRNA signature for tumorigenic conazoles in mouse liver

    Science.gov (United States)

    Triadimefon, propiconazole and myclobutanil are conazoles, an important class of agricultural fungicides. Triadimefon and propiconazole are mouse liver tumorigens, while myclobutanil is not. As part of a coordinated study to understand the molecular determinants of conazole tumor...

  19. Application of a high throughput method of biomarker discovery to improvement of the EarlyCDT(®-Lung Test.

    Directory of Open Access Journals (Sweden)

    Isabel K Macdonald

    Full Text Available BACKGROUND: The National Lung Screening Trial showed that CT screening for lung cancer led to a 20% reduction in mortality. However, CT screening has a number of disadvantages including low specificity. A validated autoantibody assay is available commercially (EarlyCDT®-Lung to aid in the early detection of lung cancer and risk stratification in patients with pulmonary nodules detected by CT. Recent advances in high throughput (HTP cloning and expression methods have been developed into a discovery pipeline to identify biomarkers that detect autoantibodies. The aim of this study was to demonstrate the successful clinical application of this strategy to add to the EarlyCDT-Lung panel in order to improve its sensitivity and specificity (and hence positive predictive value, (PPV. METHODS AND FINDINGS: Serum from two matched independent cohorts of lung cancer patients were used (n = 100 and n = 165. Sixty nine proteins were initially screened on an abridged HTP version of the autoantibody ELISA using protein prepared on small scale by a HTP expression and purification screen. Promising leads were produced in shake flask culture and tested on the full assay. These results were analyzed in combination with those from the EarlyCDT-Lung panel in order to provide a set of re-optimized cut-offs. Five proteins that still displayed cancer/normal differentiation were tested for reproducibility and validation on a second batch of protein and a separate patient cohort. Addition of these proteins resulted in an improvement in the sensitivity and specificity of the test from 38% and 86% to 49% and 93% respectively (PPV improvement from 1 in 16 to 1 in 7. CONCLUSION: This is a practical example of the value of investing resources to develop a HTP technology. Such technology may lead to improvement in the clinical utility of the EarlyCDT--Lung test, and so further aid the early detection of lung cancer.

  20. Application of a high throughput method of biomarker discovery to improvement of the EarlyCDT(®)-Lung Test.

    Science.gov (United States)

    Macdonald, Isabel K; Murray, Andrea; Healey, Graham F; Parsy-Kowalska, Celine B; Allen, Jared; McElveen, Jane; Robertson, Chris; Sewell, Herbert F; Chapman, Caroline J; Robertson, John F R

    2012-01-01

    The National Lung Screening Trial showed that CT screening for lung cancer led to a 20% reduction in mortality. However, CT screening has a number of disadvantages including low specificity. A validated autoantibody assay is available commercially (EarlyCDT®-Lung) to aid in the early detection of lung cancer and risk stratification in patients with pulmonary nodules detected by CT. Recent advances in high throughput (HTP) cloning and expression methods have been developed into a discovery pipeline to identify biomarkers that detect autoantibodies. The aim of this study was to demonstrate the successful clinical application of this strategy to add to the EarlyCDT-Lung panel in order to improve its sensitivity and specificity (and hence positive predictive value, (PPV)). Serum from two matched independent cohorts of lung cancer patients were used (n = 100 and n = 165). Sixty nine proteins were initially screened on an abridged HTP version of the autoantibody ELISA using protein prepared on small scale by a HTP expression and purification screen. Promising leads were produced in shake flask culture and tested on the full assay. These results were analyzed in combination with those from the EarlyCDT-Lung panel in order to provide a set of re-optimized cut-offs. Five proteins that still displayed cancer/normal differentiation were tested for reproducibility and validation on a second batch of protein and a separate patient cohort. Addition of these proteins resulted in an improvement in the sensitivity and specificity of the test from 38% and 86% to 49% and 93% respectively (PPV improvement from 1 in 16 to 1 in 7). This is a practical example of the value of investing resources to develop a HTP technology. Such technology may lead to improvement in the clinical utility of the EarlyCDT--Lung test, and so further aid the early detection of lung cancer.

  1. Flooded Lung Generates a Suitable Acoustic Pathway for Transthoracic Application of High Intensity Focused Ultrasound in Liver

    Science.gov (United States)

    Lesser, Thomas Günther; Boltze, Carsten; Schubert, Harald; Wolfram, Frank

    2016-01-01

    Background: In recent years, high intensity focused ultrasound (HIFU) has gained increasing clinical interest as a non-invasive method for local therapy of liver malignancies. HIFU treatment of tumours and metastases in the liver dome is limited due to the adjacent ultrasound blocking lung. One-lung flooding (OLF) enables complete sonography of lung and adjoining organs including liver. HIFU liver ablation passing through the flooded lung could enable a direct intercostal beam path and thus improve dose deposition in liver. In this study, we evaluate the feasibility of an ultrasound guided transthoracic, transpulmonary HIFU ablation of liver using OLF. Methods: After right-side lung flooding, ultrasound guided HIFU was applied transthoracic- transpulmonary into liver to create thermal lesions in three pigs. The HIFU beam was targeted five times into liver, two times at the liver surface and three times deeper into the tissue. During autopsy examinations of lung, diaphragm and liver located in the HIFU path were performed. The focal liver lesions and lung tissue out of the beam path were examined histologically. Results: Fifteen thermal liver lesions were generated by transpulmonary HIFU sonication in all targeted regions. The lesions appeared well-demarcated in grey color with a cigar-shaped configuration. The mean length and width of the superficial and deeper lesions were 15.8 mm (range: 13-18 mm) and 5.8 mm (range: 5-7 mm), and 10.9 mm (range: 9-13 mm) and 3.3 mm (range: 2-5 mm), respectively. Histopathological, all liver lesions revealed a homogeneous thermal necrosis lacking vitality. There were no signs of damage of the overlying diaphragm and lung tissue. Conclusions: Flooded lung is a suitable pathway for applying HIFU to the liver, thus enabling a transthoracic, transpulmonary approach. The enlarged acoustic window could enhance the ablation speed for targets in the hepatic dome. PMID:27766022

  2. Slit-Robo Repulsive Signaling Extrudes Tumorigenic Cells from Epithelia.

    Science.gov (United States)

    Vaughen, John; Igaki, Tatsushi

    2016-12-19

    Cells dynamically interact throughout animal development to coordinate growth and deter disease. For example, cell-cell competition weeds out aberrant cells to enforce homeostasis. In Drosophila, tumorigenic cells mutant for the cell polarity gene scribble (scrib) are actively eliminated from epithelia when surrounded by wild-type cells. While scrib cell elimination depends critically on JNK signaling, JNK-dependent cell death cannot sufficiently explain scrib cell extirpation. Thus, how JNK executed cell elimination remained elusive. Here, we show that repulsive Slit-Robo2-Ena signaling exerts an extrusive force downstream of JNK to eliminate scrib cells from epithelia by disrupting E-cadherin. While loss of Slit-Robo2-Ena in scrib cells potentiates scrib tumor formation within the epithelium, Robo2-Ena hyperactivation surprisingly triggers luminal scrib tumor growth following excess extrusion. This extrusive signaling is amplified by a positive feedback loop between Slit-Robo2-Ena and JNK. Our observations provide a potential causal mechanism for Slit-Robo dysregulation in numerous human cancers.

  3. Glycerol-3-phosphate acyltranferase-2 behaves as a cancer testis gene and promotes growth and tumorigenicity of the breast cancer MDA-MB-231 cell line.

    Directory of Open Access Journals (Sweden)

    Magali Pellon-Maison

    Full Text Available The de novo synthesis of glycerolipids in mammalian cells begins with the acylation of glycerol-3-phosphate, catalyzed by glycerol-3-phosphate acyltransferase (GPAT. GPAT2 is a mitochondrial isoform primarily expressed in testis under physiological conditions. Because it is aberrantly expressed in multiple myeloma, it has been proposed as a novel cancer testis gene. Using a bioinformatics approach, we found that GPAT2 is highly expressed in melanoma, lung, prostate and breast cancer, and we validated GPAT2 expression at the protein level in breast cancer by immunohistochemistry. In this case GPAT2 expression correlated with a higher histological grade. 5-Aza-2' deoxycytidine treatment of human cells lines induced GPAT2 expression suggesting epigenetic regulation of gene expression. In order to evaluate the contribution of GPAT2 to the tumor phenotype, we silenced its expression in MDA-MB-231 cells. GPAT2 knockdown diminished cell proliferation, anchorage independent growth, migration and tumorigenicity, and increased staurosporine-induced apoptosis. In contrast, GPAT2 over-expression increased cell proliferation rate and resistance to staurosporine-induced apoptosis. To understand the functional role of GPAT2, we performed a co-expression analysis in mouse and human testis and found a significant association with semantic terms involved in cell cycle, DNA integrity maintenance, piRNA biogenesis and epigenetic regulation. Overall, these results indicate the GPAT2 would be directly associated with the control of cell proliferation. In conclusion, we confirm GPAT2 as a cancer testis gene and that its expression contributes to the tumor phenotype of MDA-MB-231 cells.

  4. Apoptosis inducing ability of silver decorated highly reduced graphene oxide nanocomposites in A549 lung cancer.

    Science.gov (United States)

    Khan, Merajuddin; Khan, Mujeeb; Al-Marri, Abdulhadi H; Al-Warthan, Abdulrahman; Alkhathlan, Hamad Z; Siddiqui, Mohammed Rafiq H; Nayak, Vadithe Lakshma; Kamal, Ahmed; Adil, Syed F

    2016-01-01

    Recently, graphene and graphene-based materials have been increasingly used for various biological applications due to their extraordinary physicochemical properties. Here, we demonstrate the anticancer properties and apoptosis-inducing ability of silver doped highly reduced graphene oxide nanocomposites synthesized by employing green approach. These nano composites (PGE-HRG-Ag) were synthesized by using Pulicaria glutinosa extract (PGE) as a reducing agent and were evaluated for their anticancer properties against various human cancer cell lines with tamoxifen as the reference drug. A correlation between the amount of Ag nanoparticles on the surface of highly reduced graphene oxide (HRG) and the anticancer activity of nanocomposite was observed, wherein an increase in the concentration of Ag nanoparticles on the surface of HRG led to the enhanced anticancer activity of the nanocomposite. The nanocomposite PGE-HRG-Ag-2 exhibited more potent cytotoxicity than standard drug in A549 cells, a human lung cancer cell line. A detailed investigation was undertaken and Fluorescence activated cell sorting (FACS) analysis demonstrated that the nanocomposite PGE-HRG-Ag-2 showed G0/G1 phase cell cycle arrest and induced apoptosis in A549 cells. Studies such as, measurement of mitochondrial membrane potential, generation of reactive oxygen species (ROS) and Annexin V-FITC staining assay suggested that this compound induced apoptosis in human lung cancer cells.

  5. Lung transplantation

    Science.gov (United States)

    Afonso, José Eduardo; Werebe, Eduardo de Campos; Carraro, Rafael Medeiros; Teixeira, Ricardo Henrique de Oliveira Braga; Fernandes, Lucas Matos; Abdalla, Luis Gustavo; Samano, Marcos Naoyuki; Pêgo-Fernandes, Paulo Manuel

    2015-01-01

    ABSTRACT Lung transplantation is a globally accepted treatment for some advanced lung diseases, giving the recipients longer survival and better quality of life. Since the first transplant successfully performed in 1983, more than 40 thousand transplants have been performed worldwide. Of these, about seven hundred were in Brazil. However, survival of the transplant is less than desired, with a high mortality rate related to primary graft dysfunction, infection, and chronic graft dysfunction, particularly in the form of bronchiolitis obliterans syndrome. New technologies have been developed to improve the various stages of lung transplant. To increase the supply of lungs, ex vivo lung reconditioning has been used in some countries, including Brazil. For advanced life support in the perioperative period, extracorporeal membrane oxygenation and hemodynamic support equipment have been used as a bridge to transplant in critically ill patients on the waiting list, and to keep patients alive until resolution of the primary dysfunction after graft transplant. There are patients requiring lung transplant in Brazil who do not even come to the point of being referred to a transplant center because there are only seven such centers active in the country. It is urgent to create new centers capable of performing lung transplantation to provide patients with some advanced forms of lung disease a chance to live longer and with better quality of life. PMID:26154550

  6. Silencing the mannose 6-phosphate/IGF-II receptor differentially affects tumorigenic properties of normal breast epithelial cells.

    Science.gov (United States)

    Caixeiro, Nicole J; Martin, Janet L; Scott, Carolyn D

    2013-12-01

    Although loss of the mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF-IIR) in breast cancer is believed to play a role in tumorigenesis, it has not been demonstrated that M6P/IGF-IIR loss is sufficient to confer a malignant phenotype in an untransformed cell. We investigated the impact of M6P/IGF-IIR silencing using phenotypically normal (MCF-10A) and oncogenically transformed (MCF-10T, the c-Ha-ras transformed derivative of MCF-10A) human breast epithelial cell lines as model systems. In both cell lines, silencing of M6P/IGF-IIR increased cell proliferation and motility, with the effects being more pronounced in MCF-10A cells. Although anchorage-independent growth was increased by M6P/IGF-IIR silencing in MCF-10T cells, MCF-10A cells did not acquire the ability to grow in soft agar. Conversely, reduced M6P/IGF-IIR expression increased the invasive potential of MCF-10A cells, but did not enhance the already high rate of invasion of MCF-10T cells. M6P/IGF-IIR silencing had no effect on basal or IGF-II-stimulated IGF-I receptor (IGF-IR) or AKT phosphorylation in either cell line, but both were abrogated by IGF-IR kinase inhibition, which also reduced the stimulatory effect of M6P/IGF-IIR silencing on proliferation under basal and IGF-II-stimulated conditions in both cell lines. However, cell motility was neither stimulated by IGF-II nor reduced by IGF-IR inhibition, suggesting that potentiation of specific tumorigenic features in response to M6P/IGF-IIR silencing involves IGF-II- dependent and -independent mechanisms. Collectively, these data suggest that M6P/IGF-IIR silencing alone is insufficient to confer a tumorigenic phenotype, but can enhance tumorigenicity in an already transformed cell.

  7. High-inflation pressure and positive end-expiratory pressure. Injurious to the lung? No.

    Science.gov (United States)

    Nelson, L D

    1996-07-01

    Survival rates in ARDS with conventional ventilation using high oxygen fractions and low PEEP levels have been reported to be less than 10%. In three prospective evaluations of ARDS in the 1980s, mortality rates remained greater than 60%. Early studies using high-level PEEP therapy in severe ARDS by Douglas, Downs, Kirby, and Civetta showed improved survival rates with ranges between 60% and 80%. In 1979 Gallagher reviewed 59 patients with ARDS who were treated with PEEP greater than 15 cm H2O titrated to improve FRC by achieving an intrapulmonary shunt fraction of 15%. The overall survival was 65%, with only 5% of the patients dying secondary to respiratory failure. In the more recent study by Miller in trauma patients and later by DiRusso in a variety of surgical patients, the overall mortality rate for those patients receiving PEEP greater than 15 cm H2O was 20% to 30%. Of the 14 patients who died, only seven (10% of the total) succumbed to respiratory failure. The remaining patients died from the primary underlying disease with normal oxygenation or after significant weaning from high PEEP levels. By using a goal-oriented approach to the management of patients with severe ARDS, we have found that high-level PEEP therapy was effective in lowering the intrapulmonary shunt and improving the SaO2 at acceptable levels of inspired oxygen. All of these patients were ventilated with traditional high tidal volumes (10 to 15 mL/kg) and therefore exhibited high peak inspiratory airway pressures. This support method did not seem to cause lung injury or an excessive amount of barotrauma in these patients, but in fact, was associated with a lower mortality rate (30%) than reported in other studies of patients with lesser degrees of lung oxygenation dysfunction and extrapulmonary organ system dysfunction. Currently available information indicates that increases in mean airway pressure (induced with PEEP or other modes of ventilatory support to restore losses in FRC that occur

  8. Frequent attenuation of the WWOX tumor suppressor in osteosarcoma is associated with increased tumorigenicity and aberrant RUNX2 expression.

    Science.gov (United States)

    Kurek, Kyle C; Del Mare, Sara; Salah, Zaidoun; Abdeen, Suhaib; Sadiq, Hussain; Lee, Suk-Hee; Gaudio, Eugenio; Zanesi, Nicola; Jones, Kevin B; DeYoung, Barry; Amir, Gail; Gebhardt, Mark; Warman, Matthew; Stein, Gary S; Stein, Janet L; Lian, Jane B; Aqeilan, Rami I

    2010-07-01

    The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that is deleted or attenuated in most human tumors. Wwox-deficient mice develop osteosarcoma (OS), an aggressive bone tumor with poor prognosis that often metastasizes to lung. On the basis of these observations, we examined the status of WWOX in human OS specimens and cell lines. In human OS clinical samples, WWOX expression was absent or reduced in 58% of tumors examined (P < 0.0001). Compared with the primary tumors, WWOX levels frequently increased in tumors resected following chemotherapy. In contrast, tumor metastases to lung often exhibited reduced WWOX levels relative to the primary tumor. In human OS cell lines having reduced WWOX expression, ectopic expression of WWOX inhibited proliferation and attenuated invasion in vitro, and suppressed tumorigenicity in nude mice. Expression of WWOX was associated with reduced RUNX2 expression in OS cell lines, whereas RUNX2 levels were elevated in femurs of Wwox-deficient mice. Furthermore, WWOX reconstitution in HOS cells was associated with downregulation of RUNX2 levels and RUNX2 target genes, consistent with the ability of WWOX to suppress RUNX2 transactivation activity. In clinical samples, RUNX2 was expressed in the majority of primary tumors and undetectable in most tumors resected following chemotherapy, whereas most metastases were RUNX2 positive. Our results deepen the evidence of a tumor suppressor role for WWOX in OS, furthering its prognostic and therapeutic significance in this disease. Copyright 2010 AACR.

  9. Changes in lung parenchyma after acute respiratory distress syndrome (ARDS): assessment with high-resolution computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Noebauer-Huhmann, I.-M.; Eibenberger, K.; Schaefer-Prokop, C.; Herold, C.J. [Vienna Univ. (Austria). Inst. fuer Radiologie; Steltzer, H.; Strasser, K.; Fridrich, P. [Dept. of General Anesthesia and Intensive Care, Univ. of Vienna (Austria); Schlick, W. [Dept. of Cardio-Thoracic Surgery, Univ. of Vienna (Austria)

    2001-12-01

    The aim of this study was to evaluate the appearance, extent, and distribution of parenchymal changes in the lung after acute respiratory distress syndrome (ARDS) as a function of disease severity and therapeutic procedures. High-resolution computed tomography (HRCT), clinical examination, and lung function tests were performed in 15 patients, 6-10 months after ARDS. The appearance and extent of parenchymal changes were compared with the severity of ARDS, as well as with clinical and therapeutic data. Lung parenchymal changes resembling those found in the presence of pulmonary fibrosis were observed in 13 of 15 patients (87%). The changes were significantly more frequent and more pronounced in the ventral than in the dorsal portions of the lung (p<0.01). A significant correlation was observed between the extent of lung alterations and the severity of ARDS (p<0.01), and the duration in which patients had received mechanical ventilation either with a peak inspiratory pressure greater than 30 mmHg (p<0.05), or with more than 70% oxygen (p<0.01). Acute respiratory distress syndrome frequently is followed by fibrotic changes in lung parenchyma. The predominantly ventral distribution of these changes indicates that they may be caused by the ventilation regimen and the oxygen therapy rather than by the ARDS. (orig.)

  10. High-density Lipoproteins and Apolipoprotein A-I: Potential New Players in the Prevention and Treatment of Lung Disease

    Directory of Open Access Journals (Sweden)

    Elizabeth M. Gordon

    2016-09-01

    Full Text Available Apolipoprotein A-I (apoA-I and high-density lipoproteins (HDL mediate reverse cholesterol transport out of cells. Furthermore, HDL has additional protective functions, which include anti-oxidative, anti-inflammatory, anti-apoptotic, and vasoprotective effects. In contrast, HDL can become dysfunctional with a reduction in both cholesterol efflux and anti-inflammatory properties in the setting of disease or the acute phase response. These paradigms are increasingly being recognized to be active in the pulmonary system, where apoA-I and HDL have protective effects in normal lung health, as well as in a variety of disease states, including acute lung injury, asthma, chronic obstructive pulmonary disease, lung cancer, pulmonary arterial hypertension, pulmonary fibrosis, and viral pneumonia. Similar to observations in cardiovascular disease, however, HDL may become dysfunctional and contribute to disease pathogenesis in respiratory disorders. Furthermore, synthetic apoA-I mimetic peptides have been shown to have protective effects in animal models of acute lung injury, asthma, pulmonary hypertension, and influenza pneumonia. These findings provide evidence to support the concept that apoA-I mimetic peptides might be developed into a new treatment that can either prevent or attenuate the manifestations of lung diseases, such as asthma. Thus, the lung is positioned to take a page from the cardiovascular disease playbook and utilize the protective properties of HDL and apoA-I as a novel therapeutic approach.

  11. Identifying high risk individuals for targeted lung cancer screening: Independent validation of the PLCOm2012 risk prediction tool.

    Science.gov (United States)

    Weber, Marianne; Yap, Sarsha; Goldsbury, David; Manners, David; Tammemagi, Martin; Marshall, Henry; Brims, Fraser; McWilliams, Annette; Fong, Kwun; Kang, Yoon Jung; Caruana, Michael; Banks, Emily; Canfell, Karen

    2017-07-15

    Lung cancer screening with computerised tomography holds promise, but optimising the balance of benefits and harms via selection of a high risk population is critical. PLCOm2012 is a logistic regression model based on U.S. data, incorporating sociodemographic and health factors, which predicts 6-year lung cancer risk among ever-smokers, and thus may better predict those who might benefit from screening than criteria based solely on age and smoking history. We aimed to validate the performance of PLCOm2012 in predicting lung cancer outcomes in a cohort of Australian smokers. Predicted risk of lung cancer was calculated using PLCOm2012 applied to baseline data from 95,882 ever-smokers aged ≥45 years in the 45 and Up Study (2006-2009). Predictions were compared to lung cancer outcomes captured to June 2014 via linkage to population-wide health databases; a total of 1,035 subsequent lung cancer diagnoses were identified. PLCOm2012 had good discrimination (area under the receiver-operating-characteristic-curve; AUC 0.80, 95%CI 0.78-0.81) and excellent calibration (mean and 90th percentiles of absolute risk difference between observed and predicted outcomes: 0.006 and 0.016, respectively). Sensitivity (69.4%, 95%CI, 65.6-73.0%) of the PLCOm2012 criteria in the 55-74 year age group for predicting lung cancers was greater than that using criteria based on ≥30 pack-years smoking and ≤15 years quit (57.3%, 53.3-61.3%; p cancer screening using PLCOm2012 might improve the balance of benefits versus harms, and cost-effectiveness of lung cancer screening. © 2017 UICC.

  12. High resolution computed tomography of the lung in neutropenic febrile patients; Hochaufloesende Computertomographie der Lunge bei neutropenischen Patienten mit Fieber

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    Heussel, C.P. [Mainz Univ. (Germany). Klinik fuer Radiologie; Kauczor, H.U. [Mainz Univ. (Germany). Klinik fuer Radiologie; Matzke, G. [Mainz Univ. (Germany). Abt. fuer Haematologie; Fischer, B. [Mainz Univ. (Germany). Abt. fuer Pneumologie; Mildenberger, P. [Mainz Univ. (Germany). Klinik fuer Radiologie

    1996-05-01

    Chest X-ray and HRCT were prospectively performed to exclude pneumonia in 34 patients (53 examinations) suffering from febrile neutropenia following antitumorous therapy. Diagnosis was confirmed by bronchoalveolar lavage or sputum cultures. Cest X-ray showed pneumonia in 13/53 examinations, in 12/13 a micro-organism was found. HRCT demonstrated pneumonia in 39/53, in 31/39 a mirco-organism was found. All cases with positive cultures showed suspicious HRCT findings. Changes in antibiotical treatment resulted in findings suspicious for pneumonia and evidence of a new or a just treated micro-organism (chest X-ray 8/53, HRCT 31/53); the search for the source of fever was escalated in cases without evidence of micro-organisms and without suspicion of pneumonia findings 14/53. (orig./MG) [Deutsch] Prospektiv wurden bei 34 Patienten (53 Untersuchungen), bei denen im Rahmen einer antitumoroesen Therapie eine Neutropenie und Fieber aufgetreten waren, zum Pneumonieausschluss eine konventionelle Thoraxaufnahme und eine hochaufloesende Computertomographie (HRCT) durchgefuehrt. Die Sicherung der Diagnose erfolgte durch bronchoalveolaere Lavage sowie durch Routinesputumkulturen. In der konventionellen Roentgenuntersuchung der Lunge zeigte sich ein pneumonisches Infiltrat in 13/53 Faellen, ein Keimnachweis war in 12/13 Faellen zu fuehren. Die HRCT zeigte in 39/53 Faellen pneumonieverdaechtige Veraenderungen. In 31/39 Faellen liess sich ein Keim aus der Lunge nachweisen. Alle Faelle mit Keimnachweis waren in der HRCT pneumonieverdaechtig. Eine Aenderung des Antibiotikakonzeptes ergab sich durch pneumonieverdaechtige Befunde und den mikrobiologischen Nachweis eines nicht oder kurzzeitig abgedeckten Keimes (Roentgenthorax: 8/53, HRCT 31/53); aus dem fehlenden Keimnachweis bei unauffaelliger Lungenuntersuchung resultierte eine Ausdehnung der Suche nach der Fieberursache 14/53. (orig./MG)

  13. CdSe magic-sized quantum dots incorporated in biomembrane models at the air-water interface composed of components of tumorigenic and non-tumorigenic cells.

    Science.gov (United States)

    Goto, Thiago E; Lopes, Carla C; Nader, Helena B; Silva, Anielle C A; Dantas, Noelio O; Siqueira, José R; Caseli, Luciano

    2016-07-01

    Cadmium selenide (CdSe) magic-sized quantum dots (MSQDs) are semiconductor nanocrystals with stable luminescence that are feasible for biomedical applications, especially for in vivo and in vitro imaging of tumor cells. In this work, we investigated the specific interaction of CdSe MSQDs with tumorigenic and non-tumorigenic cells using Langmuir monolayers and Langmuir-Blodgett (LB) films of lipids as membrane models for diagnosis of cancerous cells. Surface pressure-area isotherms and polarization modulation reflection-absorption spectroscopy (PM-IRRAS) showed an intrinsic interaction between the quantum dots, inserted in the aqueous subphase, and Langmuir monolayers constituted either of selected lipids or of tumorigenic and non-tumorigenic cell extracts. The films were transferred to solid supports to obtain microscopic images, providing information on their morphology. Similarity between films with different compositions representing cell membranes, with or without the quantum dots, was evaluated by atomic force microscopy (AFM) and confocal microscopy. This study demonstrates that the affinity of quantum dots for models representing cancer cells permits the use of these systems as devices for cancer diagnosis.

  14. SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells

    Science.gov (United States)

    Wuebben, Erin L.; Wilder, Phillip J.; Cox, Jesse L.; Grunkemeyer, James A.; Caffrey, Thomas; Hollingsworth, Michael A.; Rizzino, Angie

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly deadly malignancy. Expression of the stem cell transcription factor SOX2 increases during progression of PDAC. Knockdown of SOX2 in PDAC cell lines decreases growth in vitro; whereas, stable overexpression of SOX2 in one PDAC cell line reportedly increases growth in vitro. Here, we reexamined the role of SOX2 in PDAC cells, because inducible SOX2 overexpression in other tumor cell types inhibits growth. In this study, four PDAC cell lines were engineered for inducible overexpression of SOX2 or inducible knockdown of SOX2. Remarkably, inducible overexpression of SOX2 in PDAC cells inhibits growth in vitro and reduces tumorigenicity. Additionally, inducible knockdown of SOX2 in PDAC cells reduces growth in vitro and in vivo. Thus, growth and tumorigenicity of PDAC cells is highly dependent on the expression of optimal levels of SOX2 – a hallmark of molecular rheostats. We also determined that SOX2 alters the responses of PDAC cells to drugs used in PDAC clinical trials. Increasing SOX2 reduces growth inhibition mediated by MEK and AKT inhibitors; whereas knockdown of SOX2 further reduces growth when PDAC cells are treated with these inhibitors. Thus, targeting SOX2, or its mode of action, could improve the treatment of PDAC. PMID:27145457

  15. Tumorigenicity of cellulose fibers injected into the rat peritoneal cavity.

    Science.gov (United States)

    Cullen, R T; Miller, B G; Clark, S; Davis, J M G

    2002-07-01

    Cellulose fibers, along with many other organic fibers, are durable. Therefore, if inhaled, they have the potential to persist within the lung, and may then cause disease. Here we report the effects of injecting high-purity cellulose fibers into the abdominal cavity of rats. A respirable fraction of cellulose fiber was collected from an aerosol of a thermo-mechanically-processed wood pulp. A sample of respirable crocidolite asbestos, known to produce mesotheliomas in rats, was used as a positive control. Total doses of 10(6), 10(7), 10(8), or 10(9) WHO fibers were injected intraperitoneally as 3 weekly aliquots. A negative control was provided by phosphate-buffered saline used to suspend the fibers for injection. There were 50 rats per treatment group except for the 10(8) and 10(9) fibers crocidolite groups which were reduced to 26 rats because of the expectation of high tumor incidence in these groups. The two higher doses of crocidolite asbestos caused greatly reduced survival compared to the saline controls. With cellulose there was a much less marked effect on survival. In the highest dose cellulose group, multiple large nodules (granulomas) and widespread adhesions (bands of new tissue connecting organs to each other and to the abdominal wall) were present in all animals. Granulomas were not observed in the 10(9) fibers crocidolite group. More than 80% of animals in the 10(8) and 10(9) crocidolite asbestos groups had mesotheliomas, a type of tumor sometimes observed in people exposed to asbestos. In contrast, there were only 2 animals in the cellulose groups with mesothelioma tumors, 1 in the 10(7) and 1 in the 10(8) groups. However, 9 (18%) of the 10(9) cellulose group had malignant tumors that, in contrast to the usual pattern of mesothelioma development following treatment with mineral fibers in rats, showed no obvious involvement of mesothelial tissues, were not associated with blood-stained ascites fluid, and were thus classified as sarcomas. This study

  16. Dietary energy restriction reduces high-fat diet-enhanced metastasis of Lewis lung carcinoma in mice

    Science.gov (United States)

    Obesity is a risk factor for cancer. The objective of this study was to determine the effects of dietary energy restriction on high-fat diet-enhanced spontaneous metastasis of Lewis lung carcinoma (LLC) in mice. Male C57BL/6 mice were fed an AIN93G diet or a high-fat diet (16% or 45% of energy fro...

  17. Cancer-associated fibroblasts from lung tumors maintain their immunosuppressive abilities after high-dose irradiation.

    Science.gov (United States)

    Gorchs, Laia; Hellevik, Turid; Bruun, Jack-Ansgar; Camilio, Ketil-Andre; Al-Saad, Samer; Stuge, Tor-Brynjar; Martinez-Zubiaurre, Inigo

    2015-01-01

    Accumulating evidence supports the notion that high-dose (>5 Gy) radiotherapy (RT) regimens are triggering stronger pro-immunogenic effects than standard low-dose (2 Gy) regimens. However, the effects of RT on certain immunoregulatory elements in tumors remain unexplored. In this study, we have investigated the effects of high-dose radiotherapy (HD-RT) on the immunomodulating functions of cancer-associated fibroblasts (CAFs). Primary CAF cultures were established from lung cancer specimens derived from patients diagnosed for non-small cell lung cancer. Irradiated and non-irradiated CAFs were examined for immunomodulation in experiments with peripheral blood mononuclear cells from random, healthy donors. Regulation of lymphocytes behavior was checked by lymphocyte proliferation assays, lymphocyte migration assays, and T-cell cytokine production. Additionally, CAF-secreted immunoregulatory factors were studied by multiplex protein arrays, ELISAs, and by LC-MS/MS proteomics. In all functional assays, we observed a powerful immunosuppressive effect exerted by CAF-conditioned medium on activated T-cells (p > 0.001), and this effect was sustained after a single radiation dose of 18 Gy. Relevant immunosuppressive molecules such as prostaglandin E2, interleukin-6, and -10, or transforming growth factor-β were found in CAF-conditioned medium, but their secretion was unchanged after irradiation. Finally, immunogenic cell death responses in CAFs were studied by exploring the release of high motility group box-1 and ATP. Both alarmins remained undetectable before and after irradiation. In conclusion, CAFs play a powerful immunosuppressive effect over activated T-cells, and this effect remains unchanged after HD-RT. Importantly, CAFs do not switch on immunogenic cell death responses after exposure to HD-RT.

  18. Establishment and Characterization of a Novel Chinese Human Lung Adenocarcinoma Cell Line CPA-Yang2 in Immunodeficient Mice

    Directory of Open Access Journals (Sweden)

    Shunfang YANG

    2009-10-01

    Full Text Available Background and objective The recurrence, metastasis and multidrug resistance (MDR in lung cancer are the tough problems worldwide. This study was to establish a novel chinese lung adenocarcinoma cell line with high metastasis potential for exploring the mechanism of reccurrence, development and MDR in lung cancer. Methods The cell came from the abdominal dropsy of a fifty-six years old female patient with lung adenocarcinoma and the tumor markers CA125, CYFRA21-1, CEA, NSE were detected to be higher secretion by radioimmunoassay in the abdominal dropsy. Tumorigenicity of immunodeficient mice was confirmed in 8th passage. The cell growth curve was mapped. Analysis of chromosome karyotype was tested. The gene expression was measured by real-time quantitative PCR. Results The tumorigenesis rate started at 8th passage in 3/10 immunodeficient mice via subcutaneously and the fully tumorigenicity was at 11th passage as well as later passages. Under the microscope, the cell showed oval-shap and adherence. The chromosome karyotype analysis of the cells was sub-triploid. Approximately 1×106 and 1.5×106 cancerous cells were injected into left cardiac ventricle and tail vein of immunodeficient mice respectively. The results showed multiorgan metastasis in the mice after three-four weeks, including mandible, scapula, humerus, vertebral column, femur, rib and brain, liver, adrenal gland, pulmonary in the mice after inoculation. The bone metastasis rate was 100% in the tumor bearing mice by bone scintigraphy and pathology. Quantitative real-time PCR was used to examined and compared with SPC-A-1 lung adenocarcinoma, ESM1, VEGF-C, IL-6, IL-8, AR genes were overexpressed. The novel cell was named CPA-Yang2. Conclusion The characteristics of novel strain CPA-Yang2 is a highly metastasis cell line of Chinese lung adenocarcinoma. It has stable traits, highly metastasis ability and maybe is a MDR lung cancerous cell line. Of course, it’s a good experimental

  19. CT scan screening for lung cancer: risk factors for nodules and malignancy in a high-risk urban cohort.

    Directory of Open Access Journals (Sweden)

    Alissa K Greenberg

    Full Text Available BACKGROUND: Low-dose computed tomography (CT for lung cancer screening can reduce lung cancer mortality. The National Lung Screening Trial reported a 20% reduction in lung cancer mortality in high-risk smokers. However, CT scanning is extremely sensitive and detects non-calcified nodules (NCNs in 24-50% of subjects, suggesting an unacceptably high false-positive rate. We hypothesized that by reviewing demographic, clinical and nodule characteristics, we could identify risk factors associated with the presence of nodules on screening CT, and with the probability that a NCN was malignant. METHODS: We performed a longitudinal lung cancer biomarker discovery trial (NYU LCBC that included low-dose CT-screening of high-risk individuals over 50 years of age, with more than 20 pack-year smoking histories, living in an urban setting, and with a potential for asbestos exposure. We used case-control studies to identify risk factors associated with the presence of nodules (n=625 versus no nodules (n=557, and lung cancer patients (n=30 versus benign nodules (n=128. RESULTS: The NYU LCBC followed 1182 study subjects prospectively over a 10-year period. We found 52% to have NCNs >4 mm on their baseline screen. Most of the nodules were stable, and 9.7% of solid and 26.2% of sub-solid nodules resolved. We diagnosed 30 lung cancers, 26 stage I. Three patients had synchronous primary lung cancers or multifocal disease. Thus, there were 33 lung cancers: 10 incident, and 23 prevalent. A sub-group of the prevalent group were stable for a prolonged period prior to diagnosis. These were all stage I at diagnosis and 12/13 were adenocarcinomas. CONCLUSIONS: NCNs are common among CT-screened high-risk subjects and can often be managed conservatively. Risk factors for malignancy included increasing age, size and number of nodules, reduced FEV1 and FVC, and increased pack-years smoking. A sub-group of screen-detected cancers are slow-growing and may contribute to over

  20. Mutagenicity and tumorigenicity of the four enantiopure bay-region 3,4-diol-1,2-epoxide isomers of dibenz[a,h]anthracene.

    Science.gov (United States)

    Chang, Richard L; Wood, Alexander W; Huang, Mou Tuan; Xie, Jian Guo; Cui, Xiao Xing; Reuhl, Kenneth R; Boyd, D R; Lin, Yong; Shih, Weichung Joe; Balani, Suresh K; Yagi, Haruhiko; Jerina, Donald M; Conney, Allan H

    2013-09-01

    Each enantiomer of the diastereomeric pair of bay-region dibenz[a,h]anthracene 3,4-diol-1,2-epoxides in which the benzylic 4-hydroxyl group and epoxide oxygen are either cis (isomer 1) or trans (isomer 2) were evaluated for mutagenic activity. In strains TA 98 and TA 100 of Salmonella typhimurium, the diol epoxide with (1S,2R,3S,4R) absolute configuration [(-)-diol epoxide-1] had the highest mutagenic activity. In Chinese hamster V-79 cells, the diol epoxide with (1R,2S,3S,4R) absolute configuration [(+)-diol epoxide-2] had the highest mutagenic activity. The (1R,2S,3R,4S) diol epoxide [(+)-diol epoxide-1] also had appreciable activity, whereas the other two bay-region diol epoxide enantiomers had very low activity. In tumor studies, the (1R,2S,3S,4R) enantiomer was the only diol epoxide isomer tested that had strong activity as a tumor initiator on mouse skin and in causing lung and liver tumors when injected into newborn mice. This stereoisomer was about one-third as active as the parent hydrocarbon, dibenz[a,h]anthracene as a tumor initiator on mouse skin; it was several-fold more active than dibenz[a,h]anthracene as a lung and liver carcinogen when injected into newborn mice. (-)-(3R,4R)-3β,4α-dihydroxy-3,4-dihydro-dibenz[a,h]anthracene [(-)-3,4-dihydrodiol] was slightly more active than dibenz[a,h]anthracene as a tumor initiator on mouse skin, whereas (+)-(3S,4S)-3α,4β-dihydroxy-3,4-dihydro-dibenz[a,h]anthracene [(+)-3,4-dihydrodiol] had only very weak activity. The present investigation and previous studies with the corresponding four possible enantiopure bay-region diol epoxide enantiomers/diastereomers of benzo[a]pyrene, benz[a]anthracene, chrysene, benzo[c]phenanthrene, dibenz[c,h]acridine, dibenz[a,h]acridine and dibenz[a,h]anthracene indicate that the bay-region diol epoxide enantiomer with [R,S,S,R] absolute stereochemistry has high tumorigenic activity on mouse skin and in newborn mice.

  1. Squamous cell carcinoma of the lung with highly proliferating fibromatosis-like stroma: a rare phenomenon.

    Science.gov (United States)

    Tajima, Shogo; Takanashi, Yusuke; Koda, Kenji

    2015-01-01

    Few cases of carcinoma with exuberant stromal proliferation have been documented, apart from scirrhous carcinoma. To the best of our knowledge, previous cases of carcinoma exhibiting exuberant stromal proliferation have exclusively been reported in the thyroid gland, specifically as papillary carcinoma. The exuberant stromal proliferation has been recognized to be similar to either fibromatosis or nodular fasciitis. Herein, we report a case of a 74-year-old Japanese man whose tumor in the upper lobe of his right lung displayed highly proliferating stroma with dispersed, poorly differentiated squamous cell carcinoma nests. The stromal spindle cells (fibroblasts/myofibroblasts) had similar molecular profiles to those typically observed in fibromatosis rather than nodular fasciitis, resulting in the designation of "fibromatosis-like" stroma. The presence of carcinoma cells, along with stromal cells, expressing TGF-β in this case likely fostered continuous stromal proliferation, presumably in conjunction with the unique microenvironment in which the carcinoma cells were present.

  2. Investigating the expression, effect and tumorigenic pathway of PADI2 in tumors

    Directory of Open Access Journals (Sweden)

    Guo W

    2017-03-01

    Full Text Available Wei Guo,1,2,* Yabing Zheng,2,* Bing Xu,1 Fang Ma,1 Chang Li,3 Xiaoqian Zhang,4 Yao Wang,1 Xiaotian Chang1 1Medical Research Center, Shandong Provincial Qianfoshan Hospital, 2Obstetrical Department, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, 3Pathology Department, Tengzhou Central People’s Hospital, Tengzhou, 4Clinical Laboratory, PKU Care Luzhong Hospital, Zibo, Shandong, People’s Republic of China *These authors contributed equally to this work Background: Peptidylarginine deiminase (PAD catalyzes the conversion of arginine residues to citrulline residues, termed citrullination. Recent studies have suggested that PAD isoform 2 (PADI2 plays an important role in tumors, although its tumorigenic effect and mechanism are largely unknown. Materials and methods: Immunohistochemistry and enzyme-linked immunosorbent assay (ELISA were used to investigate the expression level of PADI2 in various tumor tissues and patient blood samples, respectively. MNK-45 and Bel-7402 tumor cell lines originating from gastric and liver tumors, respectively, were treated with anti-PADI2 siRNA, and the subsequent cell proliferation, apoptosis and migration were observed. Polymerase chain reaction (PCR arrays, including Cancer PathwayFinder, Oncogenes and Tumor Suppressor Genes, p53 Signaling Pathway, Signal Transduction Pathway and Tumor Metastasis PCR arrays, were used to investigate the tumorigenic pathway of PADI2 in the siRNA-treated tumor cells. This analysis was verified by real-time PCR. Results: Immunohistochemistry detected significantly increased expression of PADI2 in invasive breast ductal carcinoma, cervical squamous cell carcinoma, colon adenocarcinoma, liver hepatocellular carcinoma, lung cancer, ovarian serous papillary adenocarcinoma and papillary thyroid carcinoma samples. ELISA detected a twofold increase in PADI2 expression in the blood of 48.3% of patients with liver cancer, 38% of patients with cervical

  3. Apoptosis inducing ability of silver decorated highly reduced graphene oxide nanocomposites in A549 lung cancer

    Directory of Open Access Journals (Sweden)

    Khan M

    2016-03-01

    Full Text Available Merajuddin Khan,1 Mujeeb Khan,1 Abdulhadi H Al-Marri,1 Abdulrahman Al-Warthan,1 Hamad Z Alkhathlan,1 Mohammed Rafiq H Siddiqui,1 Vadithe Lakshma Nayak,2 Ahmed Kamal,2 Syed F Adil1 1Department of Chemistry, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia; 2Department of Medicinal Chemistry and Pharmacology, CSIR – Indian Institute of Chemical Technology, Hyderabad, India Abstract: Recently, graphene and graphene-based materials have been increasingly used for various biological applications due to their extraordinary physicochemical properties. Here, we demonstrate the anticancer properties and apoptosis-inducing ability of silver doped highly reduced graphene oxide nanocomposites synthesized by employing green approach. These nano­composites (PGE-HRG-Ag were synthesized by using Pulicaria glutinosa extract (PGE as a reducing agent and were evaluated for their anticancer properties against various human cancer cell lines with tamoxifen as the reference drug. A correlation between the amount of Ag nanoparticles on the surface of highly reduced graphene oxide (HRG and the anticancer activity of nanocomposite was observed, wherein an increase in the concentration of Ag nanoparticles on the surface of HRG led to the enhanced anticancer activity of the nanocomposite. The nanocomposite PGE-HRG-Ag-2 exhibited more potent cytotoxicity than standard drug in A549 cells, a human lung cancer cell line. A detailed investigation was undertaken and Fluorescence activated cell sorting (FACS analysis demonstrated that the nanocomposite PGE-HRG-Ag-2 showed G0/G1 phase cell cycle arrest and induced apoptosis in A549 cells. Studies such as, measurement of mitochondrial membrane potential, generation of reactive oxygen species (ROS and Annexin V-FITC staining assay suggested that this compound induced apoptosis in human lung cancer cells. Keywords: plant extract, graphene/silver nanocomposites, anticancer, apoptosis

  4. Lung metastases

    Science.gov (United States)

    Metastases to the lung; Metastatic cancer to the lung; Lung cancer - metastases ... Metastatic tumors in the lungs are cancers that developed at other places in the body (or other parts of the lungs). They then spread through ...

  5. Highly Efficient Labeling of Human Lung Cancer Cells Using Cationic Poly-L-lysine-Assisted Magnetic Iron Oxide Nanoparticles

    Institute of Scientific and Technical Information of China (English)

    Xueqin Wang; Huiru Zhang; Hongjuan Jing; Liuqing Cui

    2015-01-01

    Cell labeling with magnetic iron oxide nanoparticles (IONPs) is increasingly a routine approach in the cell-based cancer treatment. However, cell labeling with magnetic IONPs and their leading effects on the biological properties of human lung carcinoma cells remain scarcely reported. Therefore, in the present study the magnetic c-Fe2O3 nanoparticles (MNPs) were firstly synthesized and surface-modified with cationic poly-L-lysine (PLL) to construct the PLL-MNPs, which were then used to magnetically label human A549 lung cancer cells. Cell viability and proliferation were evaluated with propidium iodide/fluorescein diacetate double staining and standard 3-(4,5-dimethylthiazol-2-diphe-nyl-tetrazolium) bromide assay, and the cytoskeleton was immunocytochemically stained. The cell cycle of the PLL-MNP-labeled A549 lung cancer cells was analyzed using flow cytometry. Apoptotic cells were fluorescently analyzed with nuclear-specific staining after the PLL-MNP labeling. The results showed that the constructed PLL-MNPs efficiently magnetically labeled A549 lung cancer cells and that, at low concentrations, labeling did not affect cellular viability, proliferation capability, cell cycle, and apoptosis. Furthermore, the cytoskeleton in the treated cells was detected intact in comparison with the untreated counterparts. However, the results also showed that at high concentration (400 lg mL-1), the PLL-MNPs would slightly impair cell viability, proliferation, cell cycle, and apoptosis and disrupt the cytoskeleton in the treated A549 lung cancer cells. Therefore, the present results indicated that the PLL-MNPs at adequate concentrations can be efficiently used for labeling A549 lung cancer cells and could be considered as a feasible approach for magnetic targeted anti-cancer drug/gene delivery, targeted diagnosis, and therapy in lung cancer treatment.

  6. Generation of dendritic cell-based vaccine using high hydrostatic pressure for non-small cell lung cancer immunotherapy

    Science.gov (United States)

    Hradilova, Nada; Sadilkova, Lenka; Palata, Ondrej; Mysikova, Dagmar; Mrazkova, Hana; Lischke, Robert; Spisek, Radek; Adkins, Irena

    2017-01-01

    High hydrostatic pressure (HHP) induces immunogenic death of tumor cells which confer protective anti-tumor immunity in vivo. Moreover, DC pulsed with HHP-treated tumor cells induced therapeutic effect in mouse cancer model. In this study, we tested the immunogenicity, stability and T cell stimulatory activity of human monocyte-derived dendritic cell (DC)-based HHP lung cancer vaccine generated in GMP compliant serum free medium using HHP 250 MPa. DC pulsed with HHP-killed lung cancer cells and poly(I:C) enhanced DC maturation, chemotactic migration and production of pro-inflammatory cytokines after 24h. Moreover, DC-based HHP lung cancer vaccine showed functional plasticity after transfer into serum-containing media and stimulation with LPS or CD40L after additional 24h. LPS and CD40L stimulation further differentially enhanced the expression of costimulatory molecules and production of IL-12p70. DC-based HHP lung cancer vaccine decreased the number of CD4+CD25+Foxp3+ T regulatory cells and stimulated IFN-γ-producing tumor antigen-specific CD4+ and CD8+ T cells from non-small cell lung cancer (NSCLC) patients. Tumor antigen specific CD8+ and CD4+ T cell responses were detected in NSCLC patient’s against a selected tumor antigens expressed by lung cancer cell lines used for the vaccine generation. We also showed for the first time that protein antigen from HHP-killed lung cancer cells is processed and presented by DC to CD8+ T cells. Our results represent important preclinical data for ongoing NSCLC Phase I/II clinical trial using DC-based active cellular immunotherapy (DCVAC/LuCa) in combination with chemotherapy and immune enhancers. PMID:28187172

  7. SOX9-mediated upregulation of LGR5 is important for glioblastoma tumorigenicity

    Energy Technology Data Exchange (ETDEWEB)

    Hiraoka, Koji; Hayashi, Tomoatsu; Kaneko, Ryusuke; Nasu-Nishimura, Yukiko; Koyama-Nasu, Ryo; Kawasaki, Yoshihiro; Akiyama, Tetsu, E-mail: akiyama@iam.u-tokyo.ac.jp

    2015-05-01

    LGR5 plays an important role in the self-renewal of stem cells and is used as a marker identifying self-renewing stem cells in small intestine and hair follicles. Moreover, LGR5 has been reported to be overexpressed in several cancers. SOX9 is a transcription factor that plays a key role in development, differentiation and lineage commitment in various tissues. It has also been reported that SOX9 is overexpressed in a variety of cancers and contributes to their malignant phenotype. Here we show that LGR5 is required for the tumorigenicity of glioblastoma cells. We further show that SOX9 is upregulated in glioblastoma cells and directly enhances the expression of LGR5. We also demonstrate that knockdown of SOX9 suppresses the proliferation and tumorigenicity of glioblastoma cells. These results suggest that SOX9-mediated transcriptional regulation of LGR5 is critical for the tumorigenicity of glioblastoma cells. We speculate that the SOX9-LGR5 pathway could be a potentially promising target for the therapy of glioblastoma. - Highlights: • LGR5 is required for the tumorigenicity of glioblastoma cells. • SOX9 directly enhances the expression of LGR5. • SOX9 is required for the tumorigenicity of glioblastoma cells.

  8. Development of a highly metastatic model that reveals a crucial role of fibronectin in lung cancer cell migration and invasion

    Directory of Open Access Journals (Sweden)

    He Xianghuo

    2010-07-01

    Full Text Available Abstract Background The formation of metastasis is the most common cause of death in patients with lung cancer. A major implement to understand the molecular mechanisms involved in lung cancer metastasis has been the lack of suitable models to address it. In this study, we aimed at establishing a highly metastatic model of human lung cancer and characterizing its metastatic properties and underlying mechanisms. Methods The human lung adeno-carcinoma SPC-A-1 cell line was used as parental cells for developing of highly metastatic cells by in vivo selection in NOD/SCID mice. After three rounds of selection, a new SPC-A-1sci cell line was established from pulmonary metastatic lesions. Subsequently, the metastatic properties of this cell line were analyzed, including optical imaging of in vivo metastasis, immunofluorescence and immunohistochemical analysis of several epithelial mesenchymal transition (EMT makers and trans-well migration and invasion assays. Finally, the functional roles of fibronectin in the invasive and metastatic potentials of SPC-A-1sci cells were determined by shRNA analysis. Results A spontaneously pulmonary metastatic model of human lung adeno-carcinoma was established in NOD/SCID mice, from which a new lung cancer cell line, designated SPC-A-1sci, was isolated. Initially, the highly metastatic behavior of this cell line was validated by optical imaging in mice models. Further analyses showed that this cell line exhibit phenotypic and molecular alterations consistent with EMT. Compared with its parent cell line SPC-A-1, SPC-A-1sci was more aggressive in vitro, including increased potentials for cell spreading, migration and invasion. Importantly, fibronectin, a mesenchymal maker of EMT, was found to be highly expressed in SPC-A-1sci cells and down-regulation of it can decrease the in vitro and in vivo metastatic abilities of this cell line. Conclusions We have successfully established a new human lung cancer cell line with

  9. Lung function and breathing pattern in subjects developing high altitude pulmonary edema.

    Directory of Open Access Journals (Sweden)

    Christian F Clarenbach

    Full Text Available INTRODUCTION: The purpose of the study was to comprehensively evaluate physiologic changes associated with development of high altitude pulmonary edema (HAPE. We tested whether changes in pulmonary function and breathing pattern would herald clinically overt HAPE at an early stage. METHODS: In 18 mountaineers, spirometry, diffusing capacity, nitrogen washout, nocturnal ventilation and pulse oximetry were recorded at 490 m and during 3 days after rapid ascent to 4559 m. Findings were compared among subjects developing HAPE and those remaining well (controls. RESULTS: In 8 subjects subsequently developing radiographically documented HAPE at 4559 m, median FVC declined to 82% of low altitude baseline while closing volume increased to 164% of baseline (P<0.05, both instances. In 10 controls, FVC decreased slightly (to 93% baseline, P<0.05 but significantly less than in subjects with HAPE and closing volume remained unchanged. Sniff nasal pressure was reduced in both subjects with and without subsequent HAPE. During nights at 4559 m, mean nocturnal oxygen saturation dropped to lower values while minute ventilation, the number of periodic breathing cycles and heart rate were higher (60%; 8.6 L/min; 97 cycles/h; 94 beats/min, respectively in subjects subsequently developing HAPE than in controls (73%; 5.1 L/min; 48 cycles/h; 79 beats/min; P<0.05 vs. HAPE, all instances. CONCLUSION: The results comprehensively represent the pattern of physiologic alterations that precede overt HAPE. The changes in lung function are consistent with reduced lung compliance and impaired gas exchange. Pronounced nocturnal hypoxemia, ventilatory control instability and sympathetic stimulation are further signs of subsequent overt HAPE.

  10. High-resolution computed tomographic findings of Aspergillus infection in lung transplant patients

    Energy Technology Data Exchange (ETDEWEB)

    Gazzoni, Fernando Ferreira, E-mail: gazzoni4@gmail.com [Hospital de Clínicas de Porto Alegre, Av. Cristovão Colombo 4105, ap.603-C, Post Code: 90560-005, Porto Alegre, RS (Brazil); Hochhegger, Bruno, E-mail: brunohochhegger@gmail.com [Santa Casa de Porto Alegre, Rua 24 de outubro 925/903, Post Code: 90510-002, Porto Alegre, RS (Brazil); Severo, Luiz Carlos, E-mail: severo@santacasa.tche.br [Federal University of Rio Grande do Sul, Rua Ramiro Barcelos, 2400, 2° andar, Post Code: 90035-003, Porto Alegre, RS (Brazil); Marchiori, Edson, E-mail: edmarchiori@gmail.com [Federal University of Rio de Janeiro, Radiology Department, Av. Pedro Calmon, n° 550 – Cidade Universitária, Post Code: 21941-901, Rio de Janeiro, RJ (Brazil); Pasqualotto, Alessandro, E-mail: acpasqualotto@hotmail.com [Santa Casa de Porto Alegre, Rua 24 de outubro 925/903, Post Code: 90510-002, Porto Alegre, RS (Brazil); Sartori, Ana Paula Garcia, E-mail: ana_sartori@hotmail.com [Santa Casa de Porto Alegre, Rua 24 de outubro 925/903, Post Code: 90510-002, Porto Alegre, RS (Brazil); Schio, Sadi, E-mail: smschio@hotmail.com [Santa Casa de Porto Alegre, Rua 24 de outubro 925/903, Post Code: 90510-002, Porto Alegre, RS (Brazil); Camargo, José, E-mail: jjcamargo@terra.com.br [Santa Casa de Porto Alegre, Rua 24 de outubro 925/903, Post Code: 90510-002, Porto Alegre, RS (Brazil)

    2014-01-15

    Objective: The aim of this study was to assess high-resolution computed tomographic (HRCT) findings at presentation in lung transplant patients diagnosed with pulmonary Aspergillus infection. Materials and methods: We retrospectively reviewed HRCT findings from 23 patients diagnosed with pulmonary aspergillosis. Imaging studies were performed 2–5 days after the onset of symptoms. The patient sample comprised 12 men and 11 women aged 22–59 years (mean age, 43.6 years). All patients had dyspnea, tachypnea, and cough. Diagnoses were established with Platelia Aspergillus enzyme immunoassays for galactomannan antigen detection in bronchoalveolar lavage and recovery of symptoms, and HRCT findings after voriconazole treatment. The HRCT scans were reviewed independently by two observers who reached a consensus decision. Results: The main HRCT pattern, found in 65% (n = 15) of patients, was centrilobular tree-in-bud nodules associated with bronchial thickening. This pattern was described in association with areas of consolidation and ground-glass opacities in 13% (n = 3) of patients. Consolidation and ground-glass opacities were the main pattern in 22% (n = 5) of patients. The pattern of large nodules with and without the halo sign was observed in 13% (n = 3) of patients, and were associated with consolidation and ground-glass opacities in one case. Conclusion: The predominant HRCT findings in lung transplant patients with pulmonary aspergillosis were bilateral bronchial wall thickening and centrilobular opacities with the tree-in-bud pattern. Ground-glass opacities and/or bilateral areas of consolidation were also common findings. Pulmonary nodules with the halo sign were found in only 13% of patients.

  11. The subclinical involvement of the lung in rheumatoid arthritis: evaluation by high-resolution computed tomography

    Directory of Open Access Journals (Sweden)

    E. Bichi Secchi

    2011-09-01

    Full Text Available Pulmonary involvement is one of the most frequent extra-articular manifestations of rheumatoid arthritis (RA and represents a serious complication, being the second cause of death after infection. High-resolution computed tomography (HRCT, owing to its increased sensitivity and diagnostic accuracy respect to the conventional chest radiograph (CXR, allows to detect pulmonary abnormalities in RA patients more frequently than CXR. The aim of this study was to assess pulmonary involvement by HRCT in lifelong non-smoking RA patients without symptoms and clinical signs of pulmonary disease. Seventy-two patients (54 women and 18 men with a mean age of 56.8±10.4 years (range, 40- 77 years and mean duration of disease of 6.9±4.7 years (range, 2-12 years entered the study. 52/72 (72% were positive for rheumatoid factor (> 20 UI/ml. Standard CXR and HRCT were carried out in each patient. CXR showed a mild interstitial fibrosis in 7 patients (9.7%, whereas HRCT demonstrated pulmonary abnormalities in an higher number of them (22/72 = 30.5%. The most frequent abnormal findings on HRCT were irregular pleural margins (13.8% and septal/subpleural lines (18%, both compatible with pulmonary fibrosis. Ground-glass opacities were found in 8.3% of the patients. Pulmonary nodules (diameter, range 0,5-2 cm predominantly located in the subpleural portions of the lung, were demonstrated in the same percentage (8.3% of patients. Small airway involvement, represented by bronchiectasis/bronchioloectasis, was shown in 15.2% of patients. Subpleural cysts were present in two cases (2.8%. No patient had evidence of honeycombing on HRCT. In conclusion, HRCT is an accurate, non-invasive and safe method of diagnosing lung abnormalities in RA patients without signs and clinical symptoms of pulmonary disease...

  12. High Resolution Ultrasound and Photoacoustic Imaging of Orthotopic Lung Cancer in Mice: New Perspectives for Onco-Pharmacology

    Science.gov (United States)

    Sobilo, Julien; Le Mée, Marilyne; Rétif, Stéphanie; Natkunarajah, Sharuja; Lerondel, Stéphanie; Le Pape, Alain

    2016-01-01

    Objectives We have developed a relevant preclinical model associated with a specific imaging protocol dedicated to onco-pharmacology studies in mice. Materials and Methods We optimized both the animal model and an ultrasound imaging procedure to follow up longitudinally the lung tumor growth in mice. Moreover we proposed to measure by photoacoustic imaging the intratumoral hypoxia, which is a crucial parameter responsible for resistance to therapies. Finally, we compared ultrasound data to x-ray micro computed tomography and volumetric measurements to validate the relevance of this approach on the NCI-H460 human orthotopic lung tumor. Results This study demonstrates the ability of ultrasound imaging to detect and monitor the in vivo orthotopic lung tumor growth by high resolution ultrasound imaging. This approach enabled us to characterize key biological parameters such as oxygenation, perfusion status and vascularization of tumors. Conclusion Such an experimental approach has never been reported previously and it would provide a nonradiative tool for assessment of anticancer therapeutic efficacy in mice. Considering the absence of ultrasound propagation through the lung parenchyma, this strategy requires the implantation of tumors strictly located in the superficial posterior part of the lung. PMID:27070548

  13. Effect of high-frequency oscillation on blood flow to an atelectatic lung in closed-chest dogs.

    Science.gov (United States)

    Hall, S M; Strawn, W B; Levitzky, M G

    1984-05-01

    Seven dogs with electromagnetic flow probes implanted on their main (QT) and left (QL) pulmonary arteries, had catheters placed in their left atria and pulmonary artery, and were ventilated via Carlen's double-lumen endotracheal tubes. The effect of high-frequency oscillation (HFO) on the redistribution of pulmonary blood flow away from unilaterally atelectatic lungs was determined. During bilateral ventilation with 100% O2, using either a Harvard respirator (PPV) or an Emerson airway vibrator (HFO), the fraction of cardiac output perfusing the left lung (QL/QT) was 0.45 +/- .01 and 0.43 +/- .01, respectively, whereas PaO2 was 465 +/- 40 and 334 +/- 34 torr, respectively. With left lung atelectasis during right lung ventilation with PPV at 10 to 15 cycle/min, QL/QT fell to 0.37 +/- .01 and PaO2 was 56 +/- 5 torr. During HFO at 100 cycle/min, QL/QT fell to 0.32 +/- .02 whereas PaO2 rose to 102 +/- 23 torr. Mean transpulmonary pressure was 10.0 +/- 1.5 torr with PPV and 7.3 +/- 1.2 torr during HFO; intrapleural pressures were -3.2 +/- 1.6 and -5.7 +/- 1.4 mm Hg, respectively. Thus, the diversion of blood away from unilaterally atelectatic lungs was better maintained during HFO.

  14. Genome-wide identification of bone metastasis-related microRNAs in lung adenocarcinoma by high-throughput sequencing.

    Directory of Open Access Journals (Sweden)

    Lin Xie

    Full Text Available BACKGROUND: MicroRNAs (miRNAs are a class of small noncoding RNAs that regulate gene expression at the post-transcriptional level. They participate in a wide variety of biological processes, including apoptosis, proliferation and metastasis. The aberrant expression of miRNAs has been found to play an important role in many cancers. RESULTS: To understand the roles of miRNAs in the bone metastasis of lung adenocarcinoma, we constructed two small RNA libraries from blood of lung adenocarcinoma patients with and without bone metastasis. High-throughput sequencing combined with differential expression analysis identified that 7 microRNAs were down-regulated and 21 microRNAs were up-regulated in lung adenocarcinoma with bone metastasis. A total of 797 target genes of the differentially expressed microRNAs were identified using a bioinformatics approach. Functional annotation analysis indicated that a number of pathways might be involved in bone metastasis, survival of the primary origin and metastatic angiogenesis of lung adenocarcinoma. These include the MAPK, Wnt, and NF-kappaB signaling pathways, as well as pathways involving the matrix metalloproteinase, cytoskeletal protein and angiogenesis factors. CONCLUSIONS: This study provides some insights into the molecular mechanisms that underlie lung adenocarcinoma development, thereby aiding the diagnosis and treatment of the disease.

  15. Smoking-promoted oxidative DNA damage response is highly correlated to lung carcinogenesis.

    Science.gov (United States)

    Cao, Chao; Lai, Tianwen; Li, Miao; Zhou, Hongbin; Lv, Dan; Deng, Zaichun; Ying, Songmin; Chen, Zhihua; Li, Wen; Shen, Huahao

    2016-04-05

    Oxidative stress induced by tobacco smoking is one of the main causes of DNA damage and is known to be involved in various cancers. Smoking is the leading cause of lung cancer, while the role of cigarette smoke-induced oxidative DNA damage response during lung carcinogenesis is largely unknown. In this study, we investigated oxidative DNA damage response levels in smoking and nonsmoking patients with lung cancer, and evaluated the potential diagnostic value of 8-OHdG for lung cancer. We observed a higher level of 8-OHdG expression and secretion in airways of lung cancer patients than that of noncancer controls. 8-OHdG expression was associated with the TNM stages. Additionally, cigarette smoke-induced oxidative DNA damage response was observed in bronchial epithelial cells in vitro and in vivo. A statistical significance correlation was found between the levels of 8-OHdG and smoking index. With a cut-off value of 2.86 ng/ml, 8-OHdG showed a sensitivity and specificity of 70.0% and 73.7%, respectively, to identify a patient with lung cancer. These findings not only underscore the importance of smoking in oxidative DNA damage response of lung cancer patients, but also suggest 8-OHdG as a potential diagnostic biomarker for lung cancer.

  16. No relationship between lung function and high-sensitive C-reactive protein in adolescence

    DEFF Research Database (Denmark)

    Nybo, Mads; Hansen, Henrik Steen; Siersted, Hans Christian

    2010-01-01

      Several studies on adults have indicated that lower spirometric lung function may be associated with increased systemic inflammation, but no studies have investigated if this association is already present in adolescence. Objective:  We explored the temporal relationship between changes in lung...

  17. High NOTCH activity induces radiation resistance in non small cell lung cancer

    NARCIS (Netherlands)

    Theys, J.; Yahyanejad, S.; Habets, R.; Span, P.N.; Dubois, L.; Paesmans, K.; Kattenbeld, B.; Cleutjens, J.; Groot, A.J.; Schuurbiers, O.C.J.; Lambin, P.; Bussink, J.; Vooijs, M.

    2013-01-01

    BACKGROUND AND PURPOSE: Patients with advanced NSCLC have survival rates <15%. The NOTCH pathway plays an important role during lung development and physiology but is often deregulated in lung cancer, making it a potential therapeutic target. We investigated NOTCH signaling in NSCLC and hypothesi

  18. T24 HRAS transformed NIH/3T3 mouse cells (GhrasT-NIH/3T3) in serial tumorigenic in vitro/in vivo passages give rise to increasingly aggressive tumorigenic cell lines T1-A and T2-A and metastatic cell lines T3-HA and T4-PA.

    Science.gov (United States)

    Ray, Durwood B; Merrill, Gerald A; Brenner, Frederic J; Lytle, Laurie S; Lam, Tan; McElhinney, Aaron; Anders, Joel; Rock, Tara Tauber; Lyker, Jennifer Kier; Barcus, Scott; Leslie, Kara Hust; Kramer, Jill M; Rubenstein, Eric M; Pryor Schanz, Karen; Parkhurst, Amy J; Peck, Michelle; Good, Kimberly; Granath, Kristi Lemke; Cifra, Nicole; Detweiler, Jessalee Wantz; Stevens, Laura; Albertson, Richard; Deir, Rachael; Stewart, Elisabeth; Wingard, Katherine; Richardson, Micah Rose; Blizard, Sarah B; Gillespie, Lauren E; Kriley, Charles E; Rzewnicki, Daniel I; Jones, David H

    2016-01-01

    Cancer cells often arise progressively from "normal" to "pre-cancer" to "transformed" to "local metastasis" to "metastatic disease" to "aggressive metastatic disease". Recent whole genome sequencing (WGS) and spectral karyotyping (SKY) of cancer cells and tumorigenic models have shown this progression involves three major types of genome rearrangements: ordered small step-wise changes, more dramatic "punctuated evolution" (chromoplexy), and large catastrophic steps (chromothripsis) which all occur in random combinations to generate near infinite numbers of stochastically rearranged metastatic cancer cell genomes. This paper describes a series of mouse cell lines developed sequentially to mimic this type of progression. This starts with the new GhrasT-NIH/Swiss cell line that was produced from the NIH/3T3 cell line that had been transformed by transfection with HRAS oncogene DNA from the T24 human bladder carcinoma. These GhrasT-NIH/Swiss cells were injected s.c. into NIH/Swiss mice to produce primary tumors from which one was used to establish the T1-A cell line. T1-A cells injected i.v. into the tail vein of a NIH/Swiss mouse produced a local metastatic tumor near the base of the tail from which the T2-A cell line was established. T2-A cells injected i.v. into the tail vein of a nude NIH/Swiss mouse produced metastases in the liver and one lung from which the T3-HA (H=hepatic) and T3-PA (P=pulmonary) cell lines were developed, respectively. T3-HA cells injected i.v. into a nude mouse produced a metastasis in the lung from which the T4-PA cell line was established. PCR analysis indicated the human T24 HRAS oncogene was carried along with each in vitro/in vivo transfer step and found in the T2-A and T4-PA cell lines. Light photomicrographs indicate that all transformed cells are morphologically similar. GhrasT-NIH/Swiss cells injected s.c. produced tumors in 4% of NIH/Swiss mice in 6-10 weeks; T1-A cells injected s.c. produced tumors in 100% of NIH/Swiss mice in 7

  19. High-frequency oscillatory ventilation is not superior to conventional mechanical ventilation in surfactant-treated rabbits with lung injury

    NARCIS (Netherlands)

    D.A.M.P.J. Gommers (Diederik); A. Hartog (Anneke); R. Schnabel; A. de Jaegere (Anne); B.F. Lachmann (Burkhard)

    1999-01-01

    textabstractThe aim of this study was to compare high-frequency oscillatory ventilation (HFOV) with conventional mechanical ventilation (CMV) with and without surfactant in the treatment of surfactant-deficient rabbits. A previously described saline lung lavage model of

  20. Improvement of lung mechanics by exogenous surfactant: effect of prior application of high positive end-expiratory pressure

    NARCIS (Netherlands)

    A. Hartog (Anneke); D.A.M.P.J. Gommers (Diederik); J.J. Haitsma (Jack); B.F. Lachmann (Burkhard)

    2000-01-01

    textabstractThe use of a ventilation strategy with high positive end-expiratory pressure (PEEP) that is intended to recruit collapsed alveoli and to prevent recurrent collapse can reduce alveolar protein influx in experimental acute lung injury (ALI). This could affect

  1. Cancer-targeted BikDD gene therapy elicits protective antitumor immunity against lung cancer.

    Science.gov (United States)

    Sher, Yuh-Pyng; Liu, Shih-Jen; Chang, Chun-Mien; Lien, Shu-Pei; Chen, Chien-Hua; Han, Zhenbo; Li, Long-Yuan; Chen, Jin-Shing; Wu, Cheng-Wen; Hung, Mien-Chie

    2011-04-01

    Targeted cancer-specific gene therapy is a promising strategy for treating metastatic lung cancer, which is a leading cause of lung cancer-related deaths. Previously, we developed a cancer-targeted gene therapy expression system with high tumor specificity and strong activity that selectively induced lung cancer cell killing without affecting normal cells in immunocompromised mice. Here, we found this cancer-targeted gene therapy, SV-BikDD, composed of the survivin promoter in the VP16-GAL4-WPRE integrated systemic amplifier system to drive the apoptotic gene BikDD, not only caused cytotoxic effects in cancer cells but also elicited a cancer-specific cytotoxic T lymphocyte response to synergistically increase the therapeutic effect and further develop an effective systemic antitumoral immunity against rechallenges of tumorigenic dose of parental tumor cells inoculated at distant sites in immunocompetent mice. In addition, this cancer-targeted gene therapy does not elicit an immune response against normal tissues, but CMV-BikDD treatment does. The therapeutic vector could also induce proinflammatory cytokines to activate innate immunity and provide some benefits in antitumor gene therapy. Thus, this study provides a promising strategy with benefit of antitumoral immune response worthy of further development in clinical trials for treating lung cancer via cancer-targeted gene therapy.

  2. Mutant p53 attenuates the anti-tumorigenic activity of fibroblasts-secreted interferon beta.

    Directory of Open Access Journals (Sweden)

    Shalom Madar

    Full Text Available Mutations in the p53 tumor suppressor protein are highly frequent in tumors and often endow cells with tumorigenic capacities. We sought to examine a possible role for mutant p53 in the cross-talk between cancer cells and their surrounding stroma, which is a crucial factor affecting tumor outcome. Here we present a novel model which enables individual monitoring of the response of cancer cells and stromal cells (fibroblasts to co-culturing. We found that fibroblasts elicit the interferon beta (IFNβ pathway when in contact with cancer cells, thereby inhibiting their migration. Mutant p53 in the tumor was able to alleviate this response via SOCS1 mediated inhibition of STAT1 phosphorylation. IFNβ on the other hand, reduced mutant p53 RNA levels by restricting its RNA stabilizer, WIG1. These data underscore mutant p53 oncogenic properties in the context of the tumor microenvironment and suggest that mutant p53 positive cancer patients might benefit from IFNβ treatment.

  3. Tafazzin (TAZ) promotes the tumorigenicity of cervical cancer cells and inhibits apoptosis

    Science.gov (United States)

    Chen, Mei; Zhang, Yuan; Zheng, Peng-Sheng

    2017-01-01

    Tafazzin (TAZ) is often aberrantly expressed in some cancers, including rectal cancer and thyroid neoplasms. However, the function of TAZ in cervical cancer cells remains unknown. This study aims to explore the expression and function of TAZ in cervical cancer cells. Here, we determined the expression of TAZ protein in normal cervical tissue (NC, n = 27), high-grade squamous intraepithelial lesions (HSIL, n = 26) and squamous cervical carcinoma (SCC, n = 41) by immunohistochemistry, the expression of TAZ protein gradually increased from NC to HSIL to SCC. TAZ was overexpressed or down-regulated in cervical cancer cells by stably transfecting a TAZ-expressing plasmid or a shRNA plasmid targeting TAZ. In vitro, the cell growth curves and MTT assays showed that TAZ may promote the growth and viability of cervical cancer cells. In vivo, xenografts experiment showed that TAZ may increase tumor-forming ability. The percentage of apoptosis cells analyzed by FACS and TUNEL assays consistently showed that TAZ inhibits apoptosis in cervical cancer cells. Furthermore, the Cleaved Caspase 9 and Cleaved Caspase 3 were down-regulated by TAZ in cervical cancer cells. Taken together, this study demonstrated that TAZ is overexpressed in cervical cancer and may promote tumorigenicity of cervical cancer cells and inhibit apoptosis. PMID:28489874

  4. Dkk-3, a Secreted Wnt Antagonist, Suppresses Tumorigenic Potential and Pulmonary Metastasis in Osteosarcoma

    Directory of Open Access Journals (Sweden)

    Carol H. Lin

    2013-01-01

    Full Text Available Osteosarcoma (OS is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis. Despite current multidisciplinary treatments, there has not been a drastic change in overall prognosis within the past 2 decades. Dickkopf-3 protein (Dkk-3/REIC has been known to inhibit canonical Wnt/β-catenin pathway, and its expression has been shown to be downregulated in OS cell lines. Using in vivo and in vitro studies, we demonstrated that Dkk-3-transfected 143B cells inhibited tumorigenesis and metastasis in an orthotopic xenograft model of OS. Inoculation of Dkk-3-transfected 143B cell lines into nude mice showed significant decreased tumor growth and less metastatic pulmonary nodules (88.7% compared to the control vector. In vitro experiments examining cellular motility and viability demonstrated less anchorage-independent growth and decreased cellular motility for Dkk-3-transfected 143B and SaOS2 cell lines compared to the control vector. Downstream expressions of Met, MAPK, ALK, and S1004A were also downregulated in Dkk-3-transfected SaOS2 cells, suggesting the ability of Dkk-3 to inhibit tumorigenic potential of OS. Together, these data suggest that Dkk-3 has a negative impact on the progression of osteosarcoma. Reexpressing Dkk-3 in Dkk-3-deficient OS tumors may prove to be of benefit as a preventive or therapeutic strategy.

  5. Differential epigenetic regulation of TOX subfamily high mobility group box genes in lung and breast cancers.

    Directory of Open Access Journals (Sweden)

    Mathewos Tessema

    Full Text Available Aberrant cytosine methylation affects regulation of hundreds of genes during cancer development. In this study, a novel aberrantly hypermethylated CpG island in cancer was discovered within the TOX2 promoter. TOX2 was unmethylated in normal cells but 28% lung (n = 190 and 23% breast (n = 80 tumors were methylated. Expression of two novel TOX2 transcripts identified was significantly reduced in primary lung tumors than distant normal lung (p<0.05. These transcripts were silenced in methylated lung and breast cancer cells and 5-Aza-2-deoxycytidine treatment re-expressed both. Extension of these assays to TOX, TOX3, and TOX4 genes that share similar genomic structure and protein homology with TOX2 revealed distinct methylation profiles by smoking status, histology, and cancer type. TOX was almost exclusively methylated in breast (43% than lung (5% cancer, whereas TOX3 was frequently methylated in lung (58% than breast (30% tumors. TOX4 was unmethylated in all samples and showed the highest expression in normal lung. Compared to TOX4, expression of TOX, TOX2 and TOX3 in normal lung was 25, 44, and 88% lower, respectively, supporting the premise that reduced promoter activity confers increased susceptibility to methylation during lung carcinogenesis. Genome-wide assays revealed that siRNA-mediated TOX2 knockdown modulated multiple pathways while TOX3 inactivation targeted neuronal development and function. Although these knockdowns did not result in further phenotypic changes of lung cancer cells in vitro, the impact on tissue remodeling, inflammatory response, and cell differentiation pathways suggest a potential role for TOX2 in modulating tumor microenvironment.

  6. In vitro growth environment produces lipidomic and electron transport chain abnormalities in mitochondria from non-tumorigenic astrocytes and brain tumours

    Directory of Open Access Journals (Sweden)

    Thomas N Seyfried

    2009-05-01

    Full Text Available The mitochondrial lipidome influences ETC (electron transport chain and cellular bioenergetic efficiency. Brain tumours are largely dependent on glycolysis for energy due to defects in mitochondria and oxidative phosphorylation. In the present study, we used shotgun lipidomics to compare the lipidome in highly purified mitochondria isolated from normal brain, from brain tumour tissue, from cultured tumour cells and from non-tumorigenic astrocytes. The tumours included the CT-2A astrocytoma and an EPEN (ependymoblastoma, both syngeneic with the C57BL/6J (B6 mouse strain. The mitochondrial lipidome in cultured CT-2A and EPEN tumour cells were compared with those in cultured astrocytes and in solid tumours grown in vivo. Major differences were found between normal tissue and tumour tissue and between in vivo and in vitro growth environments for the content or composition of ethanolamine glycerophospholipids, phosphatidylglycerol and cardiolipin. The mitochondrial lipid abnormalities in solid tumours and in cultured cells were associated with reductions in multiple ETC activities, especially Complex I. The in vitro growth environment produced lipid and ETC abnormalities in cultured non-tumorigenic astrocytes that were similar to those associated with tumorigenicity. It appears that the culture environment obscures the boundaries of the Crabtree and the Warburg effects. These results indicate that in vitro growth environments can produce abnormalities in mitochondrial lipids and ETC activities, thus contributing to a dependency on glycolysis for ATP production.

  7. JB/MS murine melanoma: a new model for studies on the modulation of differentiation and of tumorigenic and metastatic potential.

    Science.gov (United States)

    Hearing, V J; Cannon, G B; Vieira, W D; Jiménez-Atiénzar, M; Kameyama, K; Law, L W

    1988-02-15

    The recently obtained JB/MS melanoma (induced by DMBA in C57Bl/6 mice) has been successfully established in culture, and characterization of various parameters of these cells, as they have been serially passaged in vivo and in vitro, has begun. The culture lines were initially highly dendritic and melanotic, growing slowly in vitro and extremely slowly in vivo. During serial passage in vivo and in vitro the cell lines have gradually evolved into less melanotic, but more proliferative, tumorigenic and metastatic cells. We have been able to demonstrate that the JB/MS melanoma shares the common melanoma TSTA previously reported for B16, K1735 and JB/RH melanomas, but does not cross-react with the S91 melanoma or with other non-melanoma cell lines used as specificity controls. The JB/MS cells can be induced to differentiate in vitro by alpha-melanocyte stimulating hormone, a physiologically relevant agent, and studies have been initiated to detail the level at which this induction occurs. These sublines should prove to be excellent models for study of the progression of transformed cells from non-tumorigenic to tumorigenic phenotypes, and for progression through stages of varying metastatic potential, immunogenicity and differentiation.

  8. Human lung cancer cell line SPC-A1 contains cells with characteristics of cancer stem cells.

    Science.gov (United States)

    Zhou, C H; Yang, S F; Li, P Q

    2012-01-01

    Cancer stem cells (CSCs) play important roles in occurrence, development, recurrence and metastasis of cancer. Isolation and identification of CSCs have been performed from some cancer tissues or cells. In this paper, human lung adenocarcinoma stem cells were induced and isolated from SPC-A1 cells and their characteristics were determined. SPC-A1 cells were cultured in serum-free medium and epidermal growth factor and basic fibroblast growth factor were added into the medium to induce the formation of multicellular tumor spheroids. The results showed that floating multicellular tumor spheroids (named pulmospheres) were formed 5-10 d after the induction of SPC-A1 cells. Real-time PCR analysis showed that in the pulmospheres, the marker of bronchioalveolar stem cells, Clara cell secretary protein and the marker of AT2 cells, alveolar surfactant protein C were highly expressed. Furthermore, such embryonic stem cell markers as octamer-binding transcription factor 4 (OCT-4), Bmi-1, and thyroid transcription factor -1 (TTF-1) were also highly expressed. Some miRNAs as hsa-miR-126, hsa-miR-145, hsa-let-7g, hsa-let-7d, hsa-let-7c, hsa-let-7e and hsa-miR-98, which were lowly expressed in SPC-A1 cells, were not expressed in the pulmospheres. Cell cycle analysis showed that 94.29 % of the pulmosphere cells were in G1 stages. Further study showed that these cells possessed higher proliferation and invasion activity than SPC-A1 cells. Tumorigenicity activity experiments on BALB/c nude mice showed that 1 × 103 of the pulmosphere cells could form tumors with similar pathological features with lung adenocarcinoma. In conclusion, lung adenocarcinoma stem cells were enriched in the pulmosphere cells and were with high tumorigenicity.

  9. Clinical study of rheumatoid interstitial lung disease evaluated by high resolution CT

    Energy Technology Data Exchange (ETDEWEB)

    Okuda, Yasuaki; Takasugi, Kiyoshi; Imai, Atsuko; Oyama, Tetsu; Oyama, Hiroko (Dohgo Spa Hospital, Matsuyama (Japan)); Kawamura, Sachiko

    1993-02-01

    High resolution computed tomographic (HRCT) scans were obtained in 215 patients with rheumatoid arthritis to assess pulmonary fibrosis (PF). We classified the HRCT appearances as five-point scale (0-4) based on the degrees of PF. We found 117 cases (54.4%) of PF on HRCT. Patients with PF (grade 1-4) showed significantly increased leucocyte cell counts and significantly worsened pulmonary function test than patients without PF (grade 0). Patients with advanced articular involvement had significantly higher prevalence of PF than others without them. Patients who were previously or currently receiving gold sodium thiomalate (GST) injection or administration of methotrexate had higher prevalence of PF than others. However, patients who were receiving long term GST therapy (1 year long or [Sigma]1000 mg) had slightly lower prevalence of PF than others. This finding suggests that dose-dependent lung injury is not related to GST therapy. Patients with advanced PF (grade 3, 4) had high prevalence of male sex, smoker, extraarticular manifestation. (author).

  10. An Appreciation for the Rabbit Ladderlike Modeling of Radiation-induced Lung Injury with High-energy X-Ray

    Directory of Open Access Journals (Sweden)

    Xiang-Ming Fang

    2015-01-01

    Full Text Available Background: To evaluate the utility of rabbit ladderlike model of radiation-induced lung injury (RILI for the future investigation of computed tomography perfusion. Methods: A total of 72 New Zealand rabbits were randomly divided into two groups: 36 rabbits in the test group were administered 25 Gy of single fractionated radiation to the whole lung of unilateral lung; 36 rabbits in the control group were sham-radiated. All rabbits were subsequently sacrificed at 1, 6, 12, 24, 48, 72 h, and 1, 2, 4, 8,1 6, 24 weeks after radiation, and then six specimens were extracted from the upper, middle and lower fields of the bilateral lungs. The pathological changes in these specimens were observed with light and electron microscopy; the expression of tumor necrosis factor-α (TNF-a and transforming growth factor-β1 (TGF-β1 in local lung tissue was detected by immunohistochemistry. Results: (1 Radiation-induced lung injury occurred in all rabbits in the test group. (2 Expression of TNF-a and TGF-β1 at 1 h and 48 h after radiation, demonstrated a statistically significant difference between the test and control groups (each P 0.05. At greater than 48 h postradiation the relative amount of collagen fibers in the test groups significantly differ from the control groups (each P < 0.05, correlating well with the time postradiation (r = 0.99318. Conclusions: A consistent and reliable rabbit model of RILI can be generated in gradient using 25 Gy of high-energy X-ray, which can simulate the development and evolution of RILI.

  11. VEGF Production by Ly6C+high Monocytes Contributes to Ventilator-Induced Lung Injury

    National Research Council Canada - National Science Library

    Shi, Chung-Sheng; Huang, Tzu-Hsiung; Lin, Chin-Kuo; Li, Jhy-Ming; Chen, Mei-Hsin; Tsai, Mei-Ling; Chang, Chih-Ching

    2016-01-01

      Background Mechanical ventilation is a life-saving procedure for patients with acute respiratory failure, although it may cause pulmonary vascular inflammation and leakage, leading to ventilator-induced lung injury (VILI). Ly6C...

  12. High procedure volume is strongly associated with improved survival after lung cancer surgery

    DEFF Research Database (Denmark)

    Lüchtenborg, Margreet; Riaz, Sharma P; Coupland, Victoria H

    2013-01-01

    Studies have reported an association between hospital volume and survival for non-small-cell lung cancer (NSCLC). We explored this association in England, accounting for case mix and propensity to resect.......Studies have reported an association between hospital volume and survival for non-small-cell lung cancer (NSCLC). We explored this association in England, accounting for case mix and propensity to resect....

  13. Safe Distances From a High-Energy Capacitor Bank for Ear and Lung Protection

    Science.gov (United States)

    2014-06-01

    Fontaine, M. D.; Walsh, P. DC Arc Calculations – Arc -In-Open-Air & Arc -In-A- Box – Using A Simplified Approach (Multiplication Factor Method), IEEE Paper...banks may have a significant amount of residual energy after a test or malfunction. This presents distinct hazards from shock, arc flash, projectile...danger to the ear and lung from the over-pressure of an arc blast has not been satisfactorily established. This lung and ear danger is addressed in

  14. High-frequency chest compression system to aid in clearance of mucus from the lung.

    Science.gov (United States)

    Hansen, L G; Warwick, W J

    1990-01-01

    The authors developed a high-frequency chest compression (HFCC) device to aid in mucous clearance for patients with obstructive lung disease. The device, designed for self-therapy, consists of a large-volume variable-frequency air-pulse delivery system and a nonstretchable inflatable vest worn by the patient. Pressure pulses are controlled by the patient and applied during expiration. Pulse frequency is tunable from 5 to 25 Hz. Maximum vest pressure is 39 mmHg (5.2 kPa), with patient-controlled vest inflation and deflation time constants of 0.5 s. Vest pressure increases from 28 mmHg (3.7 kPa) at 5 Hz to 39 mmHg (5.2 kPa) at 25 Hz. Preliminary clinical trials have shown the HFCC device to be more effective than standard chest physical therapy. The HFCC device yielded a mean volume of cleared mucus of 3.3 cc per session, compared with 1.8 cc for a conventional therapy session.

  15. Increased prevalence of high anti-Cladosporium antibody titers in interstitial lung diseases.

    Science.gov (United States)

    Watanuki, Zenta; Okada, Shinji; Chiba, Shigeki; Kamei, Katsuhiko; Suzuki, Yasuko; Yamada, Norihiro

    2012-01-01

    Interstitial lung diseases (ILDs) represent a large group of different diseases, with a large part comprising idiopathic interstitial pneumonias. Differentiating hypersensitivity pneumonitis (HP), especially its chronic form and other ILDs, is difficult because of similarities in radiological manifestation and clinical course, and the difficulty of identifying causative antigens. We recently experienced a patient with Cladosporium-induced chronic HP that developed in a household environment, but the cause had been misdiagnosed as idiopathic interstitial pneumonia for several years. This case highlighted the need for measures differentiating HP from idiopathic interstitial pneumonia. In this study, we examined fungal exposure in ILDs using an antibody titer in serum to identify possible fungus-related HP. We measured the antibody titer to Cladosporium spp. in 34 patients with various ILDs, 17 patients with bronchial asthma, and 21 control subjects using an immunofluorescence assay. ILDs included HP (5 patients), idiopathic interstitial pneumonias (21 patients), and ILDs with collagen vascular diseases (8 patients). Results showed a significantly higher tendency for high anti-Cladosporium antibody titers in ILD groups (12 patients out of 34 patients), compared to patients with bronchial asthma (0/17) or control subjects (0/21). This increase in antibody titers was observed not only in patients with HP, but also in those with idiopathic interstitial pneumonias and those exhibiting collagen vascular diseases with ILDs. This report highlights the pathogenic role of fungal antigens in various ILDs. In conclusion, fungi commonly observed in our living environment such as Cladosporium could be involved in the development of ILDs.

  16. High Expression of PHGDH Predicts Poor Prognosis in Non–Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Jinhong Zhu

    2016-12-01

    Full Text Available Tumors have exceptionally high demands for energy and anabolism because of their rapid growth. The de novo serine synthesis pathway initiated by phosphoglycerate dehydrogenase (PHGDH has been recognized as a hallmark of metabolic adaption in carcinogenesis. The oncogenic role and prognostic value of PHGDH have been investigated in multiple cancer types, including breast cancer, melanoma, cervical cancer, and colon cancer. Due to the importance of PHGDH in cancer, we attempted to determine the clinical significance of PHGDH in 319 patients with non–small cell lung cancer (NSCLC. We evaluated the mRNA and protein expression levels of PHGDH gene, using quantitative reverse transcriptase polymerase chain reaction and tissue array–based immunohistochemistry, respectively. Significantly increased PHGDH expression in mRNA and protein levels was identified in tumor tissues versus matched adjacent nontumor tissues. More interestingly, immunohistochemical expression of PHGDH was significantly associated with lymph node metastasis (P = .021 and TNM stage (P = .016. Kaplan-Meier survival analysis indicated that NSCLC patients with low levels of PHGDH outperformed patients with high levels of PHGDH regarding 5-year overall survival. Significantly longer survival in the former suggested the prognostic implication of PHGDH in NSCLC. Multivariate survival analysis using Cox regression model demonstrated that high PHGDH levels and advanced TNM stage (III + IV were independent predictors of prognosis in NSCLC. Moreover, bioinformatics analysis confirmed the increase in PHGDH transcripts (data from The Cancer Genome Atlas and its prognostic value (Kaplan-Meier plotter in NSCLC. In conclusion, this study suggested the clinical implication of PHGDH in NSCLC. PHGDH may be a promising therapeutic target in NSCLC.

  17. Frequency dependence of lung volume changes during superimposed high-frequency jet ventilation and high-frequency jet ventilation.

    Science.gov (United States)

    Sütterlin, R; Priori, R; Larsson, A; LoMauro, A; Frykholm, P; Aliverti, A

    2014-01-01

    Superimposed high-frequency jet ventilation (SHFJV) has proved to be safe and effective in clinical practice. However, it is unclear which frequency range optimizes ventilation and gas exchange. The aim of this study was to systematically compare high-frequency jet ventilation (HFJV) with HFJV by assessing chest wall volume variations (ΔEEV(CW)) and gas exchange in relation to variable high frequency. SHFJV or HFJV were used alternatively to ventilate the lungs of 10 anaesthetized pigs (21-25 kg). The low-frequency component was kept at 16 min(-1) in SHFJV. In both modes, high frequencies ranging from 100 to 1000 min(-1) were applied in random order and ventilation was maintained for 5 min in all modalities. Chest wall volume variations were obtained using opto-electronic plethysmography. Airway pressures and arterial blood gases were measured repeatedly. SHFJV increased ΔEEV(CW) compared with HFJV; the difference ranged from 43 to 68 ml. Tidal volume (V(T)) was always >240 ml during SHFJV whereas during HFJV ranged from 92 ml at the ventilation frequency of 100 min(-1) to negligible values at frequencies >300 min(-1). We observed similar patterns for Pa(O₂) and Pa(CO₂). SHFJV provided generally higher, frequency-independent oxygenation (Pa(O₂) at least 32.0 kPa) and CO₂ removal (Pa(CO₂) ∼5.5 kPa), whereas HFJV led to hypoxia and hypercarbia at higher rates (Pa(O₂) 10 kPa at f(HF)>300 min(-1)). In a porcine model, SHFJV was more effective in increasing end-expiratory volume than single-frequency HFJV, but both modes may provide adequate ventilation in the absence of airway obstruction and respiratory disease, except for HFJV at frequencies ≥300 min(-1).

  18. Lung nodule detection in a high-risk population: Comparison of magnetic resonance imaging and low-dose computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Sommer, Gregor, E-mail: gregor.sommer@usb.ch [Department of Radiology (E010), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg (Germany); Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research, Heidelberg (Germany); Clinic of Radiology and Nuclear Medicine, University of Basel Hospital, Basel (Switzerland); Tremper, Jan, E-mail: j.tremper@dkfz.de [Department of Radiology (E010), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg (Germany); Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research, Heidelberg (Germany); Koenigkam-Santos, Marcel, E-mail: marcelk46@yahoo.com.br [Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research, Heidelberg (Germany); Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik Heidelberg gGmbH, Amalienstr. 5, 69126 Heidelberg (Germany); Department of Radiology, University Hospital of the School of Medicine of Ribeirao Preto – University of Sao Paulo, Av. Bandeirantes 3900, Campus Universitario Monte Alegre, 14048 900 Ribeirao Preto, SP (Brazil); Delorme, Stefan, E-mail: s.delorme@dkfz.de [Department of Radiology (E010), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg (Germany); Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research, Heidelberg (Germany); Becker, Nikolaus, E-mail: n.becker@dkfz.de [Division of Cancer Epidemiology (C020), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg (Germany); Biederer, Jürgen, E-mail: juergen.biederer@uni-heidelberg.de [Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research, Heidelberg (Germany); Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg (Germany); and others

    2014-03-15

    Objective: To investigate the potential of MRI for lung nodule detection in a high-risk population in comparison to low-dose CT. Methods: 49 participants (31 men, 18 women, 51–71 years) of the German Lung Cancer Screening and Intervention Trial (LUSI) with a cancer-suspicious lung lesion in CT were examined with non-contrast-enhanced MRI of the lung at 1.5 T. Data were pseudonymized and presented at random order together with 30 datasets (23 in men, 7 in women, 18–64 years) from healthy volunteers. Two radiologists read the data for the presence of nodules. Sensitivity and specificity were calculated. Gold standard was either histology or long-term follow-up. Contrast-to-Noise-Ratio (CNR) was measured for all detected lesions in all MRI sequences. Results: Average maximum diameter of the lesions was 15 mm. Overall sensitivity and specificity of MRI were 48% (26/54) and 88% (29/33) compared to low-dose CT. Sensitivity of MRI was significantly higher for malignant nodules (78% (12.5/16)) than for benign ones (36% (13.5/38); P = 0.007). There was no statistically significant difference in sensitivity between nodules (benign and malignant) larger or smaller than 10 mm (P = 0.7). Inter observer agreement was 84% (κ = 0.65). Lesion-to-background CNR of T2-weighted single-shot turbo-spin-echo was significantly higher for malignant nodules (89 ± 27) than for benign ones (56 ± 23; P = 0.002). Conclusion: The sensitivity of MRI for detection of malignant pulmonary nodules in a high-risk population is 78%. Due to its inherent soft tissue contrast, MRI is more sensitive to malignant nodules than to benign ones. MRI may therefore represent a useful test for early detection of lung cancer.

  19. Monocyte chemotactic protein-1 deficiency attenuates and high-fat diet exacerbates bone loss in mice with Lewis lung carcinoma.

    Science.gov (United States)

    Yan, Lin; Nielsen, Forrest H; Sundaram, Sneha; Cao, Jay

    2017-04-04

    Bone loss occurs in obesity and cancer-associated complications including wasting. This study determined whether a high-fat diet and a deficiency in monocyte chemotactic protein-1 (MCP-1) altered bone structural defects in male C57BL/6 mice with Lewis lung carcinoma (LLC) metastases in lungs. Compared to non-tumor-bearing mice, LLC reduced bone volume fraction, connectivity density, trabecular number, trabecular thickness and bone mineral density and increased trabecular separation in femurs. Similar changes occurred in vertebrae. The high-fat diet compared to the AIN93G diet exacerbated LLC-induced detrimental structural changes; the exacerbation was greater in femurs than in vertebrae. Mice deficient in MCP-1 compared to wild-type mice exhibited increases in bone volume fraction, connectivity density, trabecular number and decreases in trabecular separation in both femurs and vertebrae, and increases in trabecular thickness and bone mineral density and a decrease in structure model index in vertebrae. Lewis lung carcinoma significantly decreased osteocalcin but increased tartrate-resistant acid phosphatase 5b (TRAP 5b) in plasma. In LLC-bearing mice, the high-fat diet increased and MCP-1 deficiency decreased plasma TRAP 5b; neither the high-fat diet nor MCP-1 deficiency resulted in significant changes in plasma concentration of osteocalcin. In conclusion, pulmonary metastasis of LLC is accompanied by detrimental bone structural changes; MCP-1 deficiency attenuates and high-fat diet exacerbates the metastasis-associated bone wasting.

  20. MORPHOLOGICAL CHARACTERISTICS OF POTENTIALLY MALIGNANT PULMONARY NODULES IN HIGH-RISK MALE SMOKERS DETECTED IN LUNG CANCER SCREENING TRIAL IN CRACOW, POLAND

    NARCIS (Netherlands)

    Kiszka, Kinga; Rudnicka-Sosin, Lucyna; Tomaszewska, Romana; Urbanczyk-Zawadzka, Malgorzata; Krupinski, Maciej; Pikul, Patrycja; Podsiadlo, Kaja; Pasowicz, Mieczyslaw; Vliegenthart, Rozemarijn; Oudkerk, Matthijs; Miszalski-Jamka, Tomasz

    2013-01-01

    The purpose of this paper was to present morphological characteristics of potentially malignant nodules revealed in a group of male smokers aged 50-74 with a very high risk for developing lung cancer estimated in the study for lung cancer screening in Cracow (Poland). Nine hundred male smokers aged

  1. Decellularized matrix from tumorigenic human mesenchymal stem cells promotes neovascularization with galectin-1 dependent endothelial interaction

    DEFF Research Database (Denmark)

    Burns, Jorge S; Kristiansen, Malthe; Kristensen, Lars P

    2011-01-01

    . Histological analysis showed that cells of the most vascularized tumorigenic clone, -BD11 had a pericyte-like alpha smooth muscle actin (ASMA+) and CD146+ positive phenotype. Upon serum withdrawal in culture, -BD11 cells formed cord-like structures mimicking capillary morphogenesis. In contrast, cells...

  2. Morphogenic and tumorigenic potentials of the mammary growth hormone/growth hormone receptor system.

    NARCIS (Netherlands)

    Garderen, E. van; Schalken, J.A.

    2002-01-01

    Due to the characteristics of the luteal phase of the ovarian cycle in the dog, which spans a prolonged time period, this species is a suitable model to study the role of progestins in both normal morphogenic and abnormal tumorigenic processes in the mammary gland. It has been convincingly shown tha

  3. Sonic hedgehog (Shh) signaling promotes tumorigenicity and stemness via activation of epithelial-to-mesenchymal transition (EMT) in bladder cancer.

    Science.gov (United States)

    Islam, S S; Mokhtari, R B; Noman, A S; Uddin, M; Rahman, M Z; Azadi, M A; Zlotta, A; van der Kwast, T; Yeger, H; Farhat, W A

    2016-05-01

    Activation of the sonic hedgehog (Shh) signaling pathway controls tumorigenesis in a variety of cancers. Here, we show a role for Shh signaling in the promotion of epithelial-to-mesenchymal transition (EMT), tumorigenicity, and stemness in the bladder cancer. EMT induction was assessed by the decreased expression of E-cadherin and ZO-1 and increased expression of N-cadherin. The induced EMT was associated with increased cell motility, invasiveness, and clonogenicity. These progression relevant behaviors were attenuated by treatment with Hh inhibitors cyclopamine and GDC-0449, and after knockdown by Shh-siRNA, and led to reversal of the EMT phenotype. The results with HTB-9 were confirmed using a second bladder cancer cell line, BFTC905 (DM). In a xenograft mouse model TGF-β1 treated HTB-9 cells exhibited enhanced tumor growth. Although normal bladder epithelial cells could also undergo EMT and upregulate Shh with TGF-β1 they did not exhibit tumorigenicity. The TGF-β1 treated HTB-9 xenografts showed strong evidence for a switch to a more stem cell like phenotype, with functional activation of CD133, Sox2, Nanog, and Oct4. The bladder cancer specific stem cell markers CK5 and CK14 were upregulated in the TGF-β1 treated xenograft tumor samples, while CD44 remained unchanged in both treated and untreated tumors. Immunohistochemical analysis of 22 primary human bladder tumors indicated that Shh expression was positively correlated with tumor grade and stage. Elevated expression of Ki-67, Shh, Gli2, and N-cadherin were observed in the high grade and stage human bladder tumor samples, and conversely, the downregulation of these genes were observed in the low grade and stage tumor samples. Collectively, this study indicates that TGF-β1-induced Shh may regulate EMT and tumorigenicity in bladder cancer. Our studies reveal that the TGF-β1 induction of EMT and Shh is cell type context dependent. Thus, targeting the Shh pathway could be clinically beneficial in the

  4. ADAM28: a potential oncogene involved in asbestos-related lung adenocarcinomas.

    Science.gov (United States)

    Wright, Casey M; Larsen, Jill E; Hayward, Nicholas K; Martins, Maria U; Tan, Maxine E; Davidson, Morgan R; Savarimuthu, Santiyagu M; McLachlan, Rebecca E; Passmore, Linda H; Windsor, Morgan N; Clarke, Belinda E; Duhig, Edwina E; Yang, Ian A; Bowman, Rayleen V; Fong, Kwun M

    2010-08-01

    Asbestos-related lung cancer accounts for 4-12% of all lung cancers worldwide. Since putative mechanisms of carcinogenesis differ between asbestos and tobacco induced lung cancers, tumors induced by the two agents may be genetically distinct. To identify gene expression biomarkers associated with asbestos-related lung tumorigenicity we performed gene expression array analysis on tumors of 36 patients with primary lung adenocarcinoma, comparing 12 patients with lung asbestos body counts above levels associated with urban dwelling (ARLC-AC: asbestos-related lung cancer-adenocarcinoma) with 24 patients with no asbestos bodies (NARLC-AC: non-asbestos related lung cancer-adenocarcinoma). Genes differentially expressed between ARLC-AC and NARLC-AC were identified on fold change and P value, and then prioritized using gene ontology. Candidates included ZNRF3, ADAM28, PPP1CA, IRF6, RAB3D, and PRDX1. Expression of these six genes was technically and biologically replicated by qRT-PCR in the training set and biologically validated in three independent test sets. ADAM28, encoding a disintegrin and metalloproteinase domain protein that interacts with integrins, was consistently upregulated in ARLC across all four datasets. Further studies are being designed to investigate the possible role of this gene in asbestos lung tumorigenicity, its potential utility as a marker of asbestos related lung cancer for purposes of causal attribution, and its potential as a treatment target for lung cancers arising in asbestos exposed persons.

  5. Lung Emergencies

    Science.gov (United States)

    ... Emergencies Cardiac Emergencies Eye Emergencies Lung Emergencies Surgeries Lung Emergencies People with Marfan syndrome can be at ... should be considered an emergency. Symptoms of sudden lung collapse (pneumothorax) Symptoms of a sudden lung collapse ...

  6. Ultra-High-Resolution Computed Tomography of the Lung: Image Quality of a Prototype Scanner.

    Directory of Open Access Journals (Sweden)

    Ryutaro Kakinuma

    Full Text Available The image noise and image quality of a prototype ultra-high-resolution computed tomography (U-HRCT scanner was evaluated and compared with those of conventional high-resolution CT (C-HRCT scanners.This study was approved by the institutional review board. A U-HRCT scanner prototype with 0.25 mm x 4 rows and operating at 120 mAs was used. The C-HRCT images were obtained using a 0.5 mm x 16 or 0.5 mm x 64 detector-row CT scanner operating at 150 mAs. Images from both scanners were reconstructed at 0.1-mm intervals; the slice thickness was 0.25 mm for the U-HRCT scanner and 0.5 mm for the C-HRCT scanners. For both scanners, the display field of view was 80 mm. The image noise of each scanner was evaluated using a phantom. U-HRCT and C-HRCT images of 53 images selected from 37 lung nodules were then observed and graded using a 5-point score by 10 board-certified thoracic radiologists. The images were presented to the observers randomly and in a blinded manner.The image noise for U-HRCT (100.87 ± 0.51 Hounsfield units [HU] was greater than that for C-HRCT (40.41 ± 0.52 HU; P < .0001. The image quality of U-HRCT was graded as superior to that of C-HRCT (P < .0001 for all of the following parameters that were examined: margins of subsolid and solid nodules, edges of solid components and pulmonary vessels in subsolid nodules, air bronchograms, pleural indentations, margins of pulmonary vessels, edges of bronchi, and interlobar fissures.Despite a larger image noise, the prototype U-HRCT scanner had a significantly better image quality than the C-HRCT scanners.

  7. TAZ induces lung cancer stem cell properties and tumorigenesis by up-regulating ALDH1A1.

    Science.gov (United States)

    Yu, Jihang; Alharbi, Adel; Shan, Hongchao; Hao, Yawei; Snetsinger, Brooke; Rauh, Michael J; Yang, Xiaolong

    2017-06-13

    Recent studies suggest that lung cancer stem cells (CSCs) may play major roles in lung cancer. Therefore, identification of lung CSC drivers may provide promising targets for lung cancer. TAZ is a transcriptional co-activator and key downstream effector of the Hippo pathway, which plays critical roles in various biological processes. TAZ has been shown to be overexpressed in lung cancer and involved in tumorigenicity of lung epithelial cells. However, whether TAZ is a driver for lung CSCs and tumor formation in vivo is unknown. In addition, the molecular mechanism underlying TAZ-induced lung tumorigenesis remains to be determined. In this study, we provided evidence that constitutively active TAZ (TAZ-S89A) is a driver for lung tumorigenesis in vivo in mice and formation of lung CSC. Further RNA-seq and qRT-PCR analysis identified Aldh1a1, a well-established CSC marker, as critical TAZ downstream target and showed that TAZ induces Aldh1a1 transcription by activating its promoter activity through interaction with the transcription factor TEAD. Most significantly, inhibition of ALDH1A1 with its inhibitor A37 or CRISPR gene knockout in lung cancer cells suppressed lung tumorigenic and CSC phenotypes in vitro, and tumor formation in mice in vivo. In conclusion, this study identified TAZ as a novel inducer of lung CSCs and the first transcriptional activator of the stem cell marker ALDH1A1. Most significantly, we identified ALDH1A1 as a critical meditator of TAZ-induced tumorigenic and CSC phenotypes in lung cancer. Our studies provided preclinical data for targeting of TAZ-TEAD-ALDH1A1 signaling to inhibit CSC-induced lung tumorigenesis in the future.

  8. Effect of high dose steroids on oleic acid-induced lung injury in rabbits: CT findings

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hwa Yeon; Yoo, Seung Min [Chung-Ang University Hospital, Seoul (Korea, Republic of)

    2006-02-15

    The purpose of this study is to evaluate the therapeutic efficacy, on the basis of CT findings, of high dose methyl prednisolone for treating acute lung injury that was induced by oleic acid injection. A total of 30 healthy rabbits (1.8-2.2 kg) were included in this study. Group I included 10 rabbits in which 0.2 mL oleic acid was injected through their ear veins. Group IIa included 10 rabbits in which 30 mg/kg methyl prednisolone and 0.2 mL oleic acid were intravenously injected at the same time. Group IIb included 5 rabbits in which 30 mg/kg methyl prednisolone was injected 6 hours prior to the 0.2 mL oleic acid intravenous injection. The other 5 rabbits (Group III) were injected intravenously with 30 mg/kg methyl prednisolone without the oleic acid. After that, 30 mg/kg methyl prednisolone per every 12 hours was injected in the non-sacrificed rabbits of Group II and Group III. Nonenhanced Chest CT scans were performed prior to the 30 minutes, 4 hours, 24 hours, 48 hours, and 72 hours after the intravenous injection of oleic acid or methyl prednisolone. We randomly sacrificed one rabbit of groups I, II and III 30 minutes, 4 hours, 24 hours, 48 hours and 72 hours after CT scanning. The distribution, extent, and pattern of the lesions on the CT scan were analyzed. The analyzed pattern of the lesions was ground glass attenuation, consolidation and interstitial thickening. Pathologic correlation was then done. The main CT findings of Group I were peripheral, wedge shaped, ill-defined ground glass attenuations and /or consolidations. The pathologic findings of Group I were interstitial or intraalveolar edema, intraalveolar hemorrhage and coagulation necrosis. Diffuse ground glass opacities with interstitial thickening were noted in 20% (n=2/10) of Group I and in 60% (n=9/15) of Group II at the 30 minute CT; however, there was no statistical difference between the two groups ({rho} = 0.09). Consolidations with air bronchogram were noted in 22.2% (2/9) of Group I and in

  9. DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2

    Science.gov (United States)

    Poirier, John T.; Gardner, Eric E.; Connis, Nick; Moreira, Andre L.; de Stanchina, Elisa; Hann, Christine L.; Rudin, Charles M.

    2015-01-01

    Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis, rapid development of resistance to chemotherapy, and genetic instability. This study profiles DNA methylation in SCLC, patient-derived xenografts (PDXs) and cell lines at single nucleotide resolution. DNA methylation patterns of primary samples are distinct from those of cell lines, while PDXs maintain a pattern closely consistent with primary samples. Clustering of DNA methylation and gene expression of primary SCLC revealed distinct disease subtypes among histologically indistinguishable primary patient samples with similar genetic alterations. SCLC is notable for dense clustering of high-level methylation in discrete promoter CpG islands, in a pattern clearly distinct from other lung cancers and strongly correlated with high expression of the E2F target and histone methyltransferase gene EZH2. Pharmacologic inhibition of EZH2 in a SCLC PDX markedly inhibited tumor growth. PMID:25746006

  10. DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2.

    Science.gov (United States)

    Poirier, J T; Gardner, E E; Connis, N; Moreira, A L; de Stanchina, E; Hann, C L; Rudin, C M

    2015-11-26

    Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis, rapid development of resistance to chemotherapy and genetic instability. This study profiles DNA methylation in SCLC, patient-derived xenografts (PDX) and cell lines at single-nucleotide resolution. DNA methylation patterns of primary samples are distinct from those of cell lines, whereas PDX maintain a pattern closely consistent with primary samples. Clustering of DNA methylation and gene expression of primary SCLC revealed distinct disease subtypes among histologically indistinguishable primary patient samples with similar genetic alterations. SCLC is notable for dense clustering of high-level methylation in discrete promoter CpG islands, in a pattern clearly distinct from other lung cancers and strongly correlated with high expression of the E2F target and histone methyltransferase gene EZH2. Pharmacologic inhibition of EZH2 in a SCLC PDX markedly inhibited tumor growth.

  11. Humidification of Base Flow Gas during Adult High-Frequency Oscillatory Ventilation:An Experimental Study Using a Lung Model

    Directory of Open Access Journals (Sweden)

    Shiba,Naoki

    2012-08-01

    Full Text Available In adult high-frequency oscillatory ventilation (HFOV with an R100 artificial ventilator, exhaled gas from patientʼs lung may warm the temperature probe and thereby disturb the humidification of base flow (BF gas. We measured the humidity of BF gas during HFOV with frequencies of 6, 8 and 10Hz, maximum stroke volumes (SV of 285, 205, and 160ml at the respective frequencies, and, BFs of 20, 30, 40l/min using an original lung model. The R100 device was equipped with a heated humidifier, HummaxⅡ, consisting of a porous hollow fiber in circuit. A 50-cm length of circuit was added between temperature probe (located at 50cm proximal from Y-piece and the hollow fiber. The lung model was made of a plastic container and a circuit equipped with another HummaxⅡ. The lung model temperature was controlled at 37℃. The HummaxⅡ of the R100 was inactivated in study-1 and was set at 35℃ or 37℃ in study-2. The humidity was measured at the distal end of the added circuit in study-1 and at the proximal end in study-2. In study-1, humidity was detected at 6Hz (SV 285ml and BF 20l/min, indicating the direct reach of the exhaled gas from the lung model to the temperature probe. In study-2 the absolute humidity of the BF gas decreased by increasing SV and by increasing BF and it was low with setting of 35℃. In this study setting, increasing the SV induced significant reduction of humidification of the BF gas during HFOV with R100.

  12. Consequences of a Maternal High-Fat Diet and Late Gestation Diabetes on the Developing Rat Lung

    OpenAIRE

    Michelle L Baack; Forred, Benjamin J.; Larsen, Tricia D.; Jensen, Danielle N.; Wachal, Angela L.; Khan, Muhammad Ali; Vitiello, Peter F.

    2016-01-01

    Rationale Infants born to diabetic or obese mothers are at risk of respiratory distress and persistent pulmonary hypertension of the newborn (PPHN), conceivably through fuel-mediated pathogenic mechanisms. Prior research and preventative measures focus on controlling maternal hyperglycemia, but growing evidence suggests a role for additional circulating fuels including lipids. Little is known about the individual or additive effects of a maternal high-fat diet on fetal lung development. Objec...

  13. Reader Accuracy and Confidence in Diagnosing Diffuse Lung Disease on High-Resolution Computed Tomography of the Lungs: Impact of Sampling Frequency

    Energy Technology Data Exchange (ETDEWEB)

    Sundaram, B.; Gross, B.H.; Oh, E.; Mueller, N.; Myles, J.D.; Kazerooni, E.A. (Dept. of Radiology, Michigan Institute for Clinical Health Research, Univ. of Michigan Health System, Ann Arbor, Michigan (United States))

    2008-10-15

    Background: The accuracy of the number of high-resolution computed tomography (HRCT) images necessary to diagnose diffuse lung disease (DLD) is not well established. Purpose: To evaluate the impact of HRCT sampling frequency on reader confidence and accuracy for diagnosing DLD. Material and Methods: HRCT images of 100 consecutive patients with proven DLD were reviewed. They were: 48 usual interstitial pneumonia, 22 sarcoidosis, six hypersensitivity pneumonitis, five each of desquamative interstitial pneumonitis, eosinophilic granulomatosis, and lymphangioleiomyomatosis, and nine others. Inspiratory images at 1-cm increments throughout the lungs and three specified levels formed complete and limited examinations. In random order, three experts (readers 1, 2, and 3) ranked their top three diagnoses and rated confidence for their top diagnosis, independently and blinded to clinical information. Results: Using the complete versus limited examinations for correct first-choice diagnosis, accuracy for reader 1 (R1) was 81% versus 80%, respectively, for reader 2 (R2) 70% versus 70%, and for reader 3 (R3) 64% versus 59%. Reader accuracy within their top three choices for complete versus limited examinations was: R1 91% versus 91% of cases, respectively, R2 84% versus 83%, and R3 79% versus 72% of cases. No statistically significant differences were found between the diagnosis methods (P=0.28 for first diagnosis and P=0.17 for top three choices). The confidence intervals for individual raters showed considerable overlap, and the point estimates are almost identical. The mean interreader agreement for complete versus limited HRCT for both top and top three diagnoses were the same (moderate and fair, respectively). The mean intrareader agreement between complete and limited HRCT for top and top three diagnoses were substantial and moderate, respectively. Conclusion: Overall reader accuracy and confidence in diagnosis did not significantly differ when fewer or more HRCT images

  14. Lung parenchyma changes in ankylosing spondylitis: demonstration with high resolution CT and correlation with disease duration

    Energy Technology Data Exchange (ETDEWEB)

    Senocak, Oezlem E-mail: emine.senocak@deu.edu.tr; Manisali, Metin; Oezaksoy, Dinc; Sevinc, Can; Akalin, Elif

    2003-02-01

    Objective: To analyze the spectrum of the lung parenchyma changes in ankylosing spondylitis (AS) with high resolution computed tomography (HRCT) and correlate the findings with disease duration. Material and methods: Twenty patients (18 male, 2 female) with the diagnosis of AS according to New York criteria were included in the study. None of the patients had history of tuberculosis, prolonged inorganic dust exposure and hospitalization for pneumonia. Seven of the patients were smokers, three patients were ex-smokers, and 10 patients were nonsmokers. The patients were assigned to three groups depending on disease duration. Group 1: patients with disease duration {<=}5 years (n: four patients), group 2: patients with disease duration {>=}6 years but {<=}10 years (n: four patients), group 3: patients with disease duration {>=}11 years (n: 12 patients). HRCT and pulmonary function tests (PFT) were performed in all patients. Results: HRCT demonstrated pathology in 17 patients (85%). Two patients in group 1, 4 patients in group 2 and 11 patients in group 3 had pulmonary parenchyma changes. Emphysema (9/20), septal thickening (9/20) and pleural thickening (9/20) were the most common changes followed by nodule (8/20) and subpleural band formation (7/20). Three patients had apical fibrosis (AF). Septal and pleural thickening (both 4/10) were the most common changes when only nonsmokers were considered. Among nine patients with emphysema three were nonsmokers. Conclusion: There is a wide spectrum in pulmonary parenchyma changes in AS. These changes begin in early stages of the disease and increase with disease duration. Although smoking complicates the spectrum of changes in pulmonary parenchyma, they are predominately in the form of interstitial inflammation.

  15. High-throughput library screening identifies two novel NQO1 inducers in human lung cells.

    Science.gov (United States)

    Tan, Xiang-Lin; Marquardt, Gaby; Massimi, Aldo B; Shi, Miao; Han, Weiguo; Spivack, Simon D

    2012-03-01

    Many phytochemicals possess antioxidant and cancer-preventive properties, some putatively through antioxidant response element-mediated phase II metabolism, entailing mutagen/oxidant quenching. In our recent studies, however, most candidate phytochemical agents were not potent in inducing phase II genes in normal human lung cells. In this study, we applied a messenger RNA (mRNA)-specific gene expression-based high throughput in vitro screening approach to discover new, potent plant-derived phase II inducing chemopreventive agents. Primary normal human bronchial epithelial (NHBE) cells and immortalized human bronchial epithelial cells (HBECs) were exposed to 800 individual compounds in the MicroSource Natural Products Library. At a level achievable in humans by diet (1.0 μM), 2,3-dihydroxy-4-methoxy-4'-ethoxybenzophenone (DMEBP), triacetylresveratrol (TRES), ivermectin, sanguinarine sulfate, and daunorubicin induced reduced nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 (NQO1) mRNA and protein expression in NHBE cells. DMEBP and TRES were the most attractive agents as coupling potency and low toxicity for induction of NQO1 (mRNA level, ≥3- to 10.8-fold that of control; protein level, ≥ two- to fourfold that of control). Induction of glutathione S-transferase pi mRNA expression was modest, and none was apparent for glutathione S-transferase pi protein expression. Measurements of reactive oxygen species and glutathione/oxidized glutathione ratio showed an antioxidant effect for DMEBP, but no definite effect was found for TRES in NHBE cells. Exposure of NHBE cells to H(2)O(2) induced nuclear translocation of nuclear factor erythroid 2-related factor 2, but this translocation was not significantly inhibited by TRES and DMEBP. These studies show that potency and low toxicity may align for two potential NQO1-inducing agents, DMEBP and TRES.

  16. High resolution lung airway cast segmentation with proper topology suitable for computational fluid dynamic simulations.

    Science.gov (United States)

    Carson, James P; Einstein, Daniel R; Minard, Kevin R; Fanucchi, Michelle V; Wallis, Christopher D; Corley, Richard A

    2010-10-01

    Developing detailed lung airway models is an important step towards understanding the respiratory system. While modern imaging and airway casting approaches have dramatically improved the potential detail of such models, challenges have arisen in image processing as the demand for greater detail pushes the image processing approaches to their limits. Airway segmentations with proper topology have neither loops nor invalid voxel-to-voxel connections. Here we describe a new technique for segmenting airways with proper topology and apply the approach to an image volume generated by magnetic resonance imaging of a silicone cast created from an excised monkey lung.

  17. History of lung disease and risk of lung cancer in a population with high household fuel combustion exposures in rural China.

    Science.gov (United States)

    Hosgoodiii, H Dean; Chapman, Robert S; He, Xingzhou; Hu, Wei; Tian, Linwei; Liu, Larry Z; Lai, Hong; Chen, Wei; Rothman, Nathaniel; Lan, Qing

    2013-09-01

    History of chronic lung diseases and household coal use for heating and cooking are established risk factors of lung cancer; however, few studies have been able to explore these risk factors simultaneously. Xuanwei, China, has some of the highest rates of lung cancer in China and most residents experience substantial in-home coal smoke exposures. Using a population-based case-control study of 498 lung cancer cases and 498 age-matched controls, we evaluated the risk of lung cancer in relation to coal smoke exposure and history of chronic lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, tuberculosis (TB), chronic bronchitis, and emphysema. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by conditional logistic regression adjusting for potential confounders. We observed an increased risk of lung cancer with history of any chronic lung disease among males (OR = 14.2; 95%CI = 4.3-46.9), females (OR = 2.6; 95%CI = 1.1-6.3), smokers (OR = 12.7; 95%CI = 3.5-45.8), and nonsmokers (OR = 2.6; 95%CI = 1.1-6.4). Specifically, TB (OR = 83.7; 95%CI = 11.0-634.7), COPD (OR = 3.2; 95%CI = 1.7-6.0), and emphysema and chronic bronchitis (OR = 3.3; 95%CI = 1.7-6.4) were associated with increased risks. These findings suggest that history of chronic lung diseases may also increase risk of lung cancer in populations with indoor coal smoke exposures. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  18. Properties of lewis lung carcinoma cells surviving curcumin toxicity.

    Science.gov (United States)

    Yan, Dejun; Geusz, Michael E; Jamasbi, Roudabeh J

    2012-01-01

    The anti-inflammatory agent curcumin can selectively eliminate malignant rather than normal cells. The present study examined the effects of curcumin on the Lewis lung carcinoma (LLC) cell line and characterized a subpopulation surviving curcumin treatments. Cell density was measured after curcumin was applied at concentrations between 10 and 60 μM for 30 hours. Because of the high cell loss at 60 μM, this dose was chosen to select for surviving cells that were then used to establish a new cell line. The resulting line had approximately 20% slower growth than the original LLC cell line and based on ELISA contained less of two markers, NF-κB and ALDH1A, used to identify more aggressive cancer cells. We also injected cells from the original and surviving lines subcutaneously into syngeneic C57BL/6 mice and monitored tumor development over three weeks and found that the curcumin surviving-line remained tumorigenic. Because curcumin has been reported to kill cancer cells more effectively when administered with light, we examined this as a possible way of enhancing the efficacy of curcumin against LLC cells. When LLC cells were exposed to curcumin and light from a fluorescent lamp source, cell loss caused by 20 μM curcumin was enhanced by about 50%, supporting a therapeutic use of curcumin in combination with white light. This study is the first to characterize a curcumin-surviving subpopulation among lung cancer cells. It shows that curcumin at a high concentration either selects for an intrinsically less aggressive cell subpopulation or generates these cells. The findings further support a role for curcumin as an adjunct to traditional chemical or radiation therapy of lung and other cancers.

  19. Pluridirectional High-Energy Agile Scanning Electron Radiotherapy (PHASER): Extremely Rapid Treatment for Early Lung Cancer

    Science.gov (United States)

    2015-09-01

    of 4 different body regions with varying tissue characteristics – head/neck, thorax (lung), abdomen (liver), and pelvis (prostate) – using repre...by joint inventors and one of the inventors is a Government employee, the Government’s rights in such an inventor’s interest in the invention will

  20. Establishment and characterization of primary lung cancer cell lines from Chinese population

    Institute of Scientific and Technical Information of China (English)

    Chao ZHENG; Yi-hua SUN; Xiao-lei YE; Hai-quan CHEN; Hong-bin JI

    2011-01-01

    Aim: To establish and characterize primary lung cancer cell lines from Chinese population.Methods: Lung cancer specimens or pleural effusions were collected from Chinese lung cancer patients and cultured in vitro with ACL4 medium (for non-small cell lung carcinomas (NSCLC)) or HITES medium (for small cell lung carcinomas (SCLC)) supplemented with 5%FBS. All cell lines were maintained in culture for more than 25 passages. Most of these cell lines were further analyzed for oncogenic mutations, karyotype, cell growth kinetics, and tumorigenicity in nude mice.Results: Eight primary cell lines from Chinese lung cancer patients were established and characterized, including seven NSCLC cell lines and one SCLC cell line. Five NSCLC cell lines were found to harbor epidermal growth factor receptor (EGFR) kinase domain mutations.Conclusion: These well-characterized primary lung cancer cell lines from Chinese population provide a unique platform for future studies of the ethnic differences in lung cancer biology and drug response.

  1. High-resolution CT of the lung (HRCT) in collagen diseases: A prospective study of 73 patients. Hochaufloesende Computertomographie der Lunge (HRCT) bei Kollagenosen: eine prospektive Untersuchung an 73 Patienten

    Energy Technology Data Exchange (ETDEWEB)

    Mueller-Leisse, C. (Klinik fuer Radiologische Diagnostik, RWTH Aachen (Germany)); Bussmann, A.; Mayer, O. (Klinik fuer Radiologische Diagnostik, RWTH Aachen (Germany)); Genth, E.; Guenther, R.W. (Klinik fuer Radiologische Diagnostik, RWTH Aachen (Germany))

    1994-07-01

    To determine pulmonary features of collagenous vascular diseases as assessed by high resolution computed tomography (HRCT) we performed a prospective study of 73 consecutive patients, 44 with rheumatoid arthritis (ra), 11 with progressive systemic sclerosis (pss), 8 with systemic lupus erythematosus (sle), 5 with sjoegren's syndrome, 3 with dermato-/polymyositis and 2 with mixed connective-tissue disease. Pathological lung changes were demonstrated in 70% of patients with ra, 91% with pss, 63% with sle and 60% with the rest. HRCT features included: Intralobular thickening (48%) with a predominance in posterior lower and middle lung areas, pleural thickening (48%) with a predominance in upper lung areas, prominent interlobular septa (37%), subpleural lines (33%), parenchymal bands (33%) with a predominance in lower and anterior lung areas, honeycombing (33%), groundglass pattern (29%) with a predominance in upper and middle, micronodules (18%) with a predominance in upper lung areas and bronchiectasis (14%). HRCT is an important means for the assessment of lung changes associated with collagenous vascular diseases and a definite diagnosis is possible in most cases. (orig.)

  2. The effect of rib and lung heterogeneities on the computed dose to lung in Ir-192 high-dose-rate breast brachytherapy: Monte Carlo versus a treatment planning system.

    Science.gov (United States)

    Yazdi, Hossein Salehi; Shamsaei, Mojtaba; Jaberi, Ramin; Shabani, Hamid Reza; Allahverdi, Mahmoud; Vaezzadeh, Seyed Ali

    2012-01-01

    This study investigates to what extent the dose received by lungs from a commercially available treatment planning system, Ir-192 high-dose-rate (HDR), in breast brachytherapy, is accurate, with the emphasis on tissue heterogeneities, and taking into account the presence of ribs, in dose delivery to the lung. A computed tomography (CT) scan of a breast was acquired and transferred to the 3-D treatment planning system and was also used to construct a patient-equivalent phantom. An implant involving 13 plastic catheters and 383 programmed source dwell positions were simulated, using the Monte Carlo N-Particle eXtended (MCNPX) code. The Monte Carlo calculations were compared with the corresponding commercial treatment planning system (TPS) in the form of percentage isodose and cumulative dose-volume histogram (DVH) in the breast, lungs, and ribs. The comparison of the Monte Carlo results and the TPS calculations showed that a percentage of isodose greater than 75% in the breast, which was located rather close to the implant or away from the breast curvature surface and lung boundary, were in good agreement. TPS calculations overestimated the dose to the lung for lower isodose contours that were lying near the breast surface and the boundary of breast and lung and were relatively away from the implant. Taking into account the ribs and entering the actual data for breasts, ribs, and lungs, revealed an average overestimation of the dose by a factor of 8% in the lung for TPS calculations. Therefore, the accuracy of the TPS results may be limited to regions near the implants where the treatment is planned, and is a more conservative approach for regions at boundaries with curvatures or tissues with a different material than that in the breast.

  3. Lung involvement in systemic sclerosis: role of high resolution computed tomography and its relationship with other pulmonary and clinico-serological features.

    Science.gov (United States)

    Colaci, M; Sebastiani, M; Manfredi, A; Giuggioli, D; Cassone, G; Manzini, C U; Ghizzoni, C; Cerri, S; Ferri, C

    2014-01-01

    The study investigated the characteristic of interstitial lung disease in a large series of systemic sclerosis (SSc) patients by means of HRCT and the correlations between functional lung parameters, serological features and the extent of lung involvement evaluated by high-resolution computed tomography (HRCT). One hundred and seven SSc patients, consecutively investigated by means of HRCT, standard chest X-ray, and pulmonary function tests, were retrospectively evaluated. Chest radiogram and HRCT scores were strongly associated (Pearson’'s r=0.82, p involvement in SSc evaluated with HRCT is directly proportional to functional lung parameters. HRCT, spirometry and DLco should be considered essential in the core-set of non-invasive diagnostic tools for the first-line assessment of scleroderma lung involvement.

  4. An Appreciation for the Rabbit Ladderlike Modeling of Radiation-induced Lung Injury with High-energy X-Ray

    Institute of Scientific and Technical Information of China (English)

    Xiang-Ming Fang; Chun-Hong Hu; Xiao-Yun Hu; Xuan-Jun Yao; Ping-Yan Qian; Ju-Ying Zhou; Jian Guo

    2015-01-01

    Background:To evaluate the utility of rabbit ladderlike model of radiation-induced lung injury (RILI) for the future investigation of computed tomography perfusion.Methods:A total of 72 New Zealand rabbits were randomly divided into two groups:36 rabbits in the test group were administered 25 Gy of single fractionated radiation to the whole lung of unilateral lung;36 rabbits in the control group were sham-radiated.All rabbits were subsequently sacrificed at 1,6,12,24,48,72 h,and 1,2,4,8,1 6,24 weeks after radiation,and then six specimens were extracted from the upper,middle and lower fields of the bilateral lungs.The pathological changes in these specimens were observed with light and electron microscopy;the expression of tumor necrosis factor-α (TNF-a) and transforming growth factor-βl (TGF-β1) in local lung tissue was detected by immunohistochemistry.Results:(1) Radiation-induced lung injury occurred in all rabbits in the test group.(2) Expression of TNF-a and TGF-β1 at 1 h and 48 h after radiation,demonstrated a statistically significant difference between the test and control groups (each P < 0.05).(3) Evaluation by light microscopy demonstrated statistically significant differences between the two groups in the following parameters (each P < 0.05):thickness of alveolar wall,density of pulmonary interstitium area (1 h after radiation),number offibroblasts and fibrocytes in interstitium (24 h after radiation).The test group metrics also correlated well with the time ofpostradiation.(4) Evaluation by electron microscopy demonstrated statistically significant differences in the relative amounts of collagen fibers at various time points postradiation in the test group (P < 0.005),with no significant differences in the control group (P > 0.05).At greater than 48 h postradiation the relative amount of collagen fibers in the test groups significantly differ from the control groups (each P < 0.05),correlating well with the time postradiation (r =0

  5. Lung parenchymal change after the resolution of adenovirus pneumonia : chest radiographs and high-resolution CT findings

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Jung Hee; Kim, Joung Sook; Kim, Chang Kuen; Kang, Seung Pyung; Lee, Soo Hyun; Hur Gham [Inje Univ. Sanggye Paik Hospital, Seoul (Korea, Republic of)

    1998-07-01

    To evaluate lung parenchymal change as seen on chest radiographs and high-resolution CT (HRCT) after the resolution of adenovirus pneumonia (a common cause of lower respiratory infection in infants and children),and the usefulness of HRCT during follow-up. Material and Methods : Four to 13(mean, 8) months after recovery, ten patients infected with adenovirus pneumonia underwent HRCT and chest radiographs. Eight were boys and two were girls, and their mean age was 26(range, 14-45) months. Adenovirus pneumonia had been confirmed by viral isolation in culture or serologic test. CT scanning was performed during quiet breathing ; collimation was 2 mm and the interval from apex to diaphragm was 5-10 mm. Lung settings were 1600 HU (window width) and -700 HU(level). CT findings were assessed and compared with chest radiographs by two chest radiologists, who reached a consensus. The patients were clinically followed up for one year. Result : On chest radiographs, hyperlucent lung was seen in 8 of 10 patients (80%) ; in one other there was partial collapse, and in one, findings were normal. The most common HRCT finding was a mosaic pattern of lung attenuation with decreased pulmonary vascularity in the area of lower attenuation ; this was seen in 8 of 10 patients (80%). Other findings were partial collapse, bronchiectasis, and bronchial wall thickening, each seen in two patients, and reticulonodular density, seen in one. In two patients HRCT findings were normal ; in one of these, chest findings were normal but a mosaic pattern of lung attenuation was found in all lobes. During follow-up, three patients wheezed continuously. Conclusion : In cases of adenovirus pneumonia, HRCT demonstrated more specific parenchymal change than did chest radiographs ; a mosaic pattern of lung attenuation was seen, with decreased pulmonary vascularity in areas of lower attenuation ; bronchiectasis,bronchial wall thickening, and reticulo-odular density were also noted. These findings were

  6. Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes - A Meta-Analysis.

    Science.gov (United States)

    Chen, Li-Shiun; Baker, Timothy; Hung, Rayjean J; Horton, Amy; Culverhouse, Robert; Hartz, Sarah; Saccone, Nancy; Cheng, Iona; Deng, Bo; Han, Younghun; Hansen, Helen M; Horsman, Janet; Kim, Claire; Rosenberger, Albert; Aben, Katja K; Andrew, Angeline S; Chang, Shen-Chih; Saum, Kai-Uwe; Dienemann, Hendrik; Hatsukami, Dorothy K; Johnson, Eric O; Pande, Mala; Wrensch, Margaret R; McLaughlin, John; Skaug, Vidar; van der Heijden, Erik H; Wampfler, Jason; Wenzlaff, Angela; Woll, Penella; Zienolddiny, Shanbeh; Bickeböller, Heike; Brenner, Hermann; Duell, Eric J; Haugen, Aage; Brüske, Irene; Kiemeney, Lambertus A; Lazarus, Philip; Le Marchand, Loic; Liu, Geoffrey; Mayordomo, Jose; Risch, Angela; Schwartz, Ann G; Teare, M Dawn; Wu, Xifeng; Wiencke, John K; Yang, Ping; Zhang, Zuo-Feng; Spitz, Margaret R; Amos, Christopher I; Bierut, Laura J

    2016-09-01

    Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N=12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium. Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR=0.48, 95%CI=0.30-0.75, p=0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR=0.68, 95%CI=0.61-0.77, p=4.9∗10(-10)). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype. We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke. Copyright © 2016

  7. Plasma marker proteins associated with the progression of lung cancer in obese mice fed a high-fat diet.

    Science.gov (United States)

    Choi, Jung-Won; Liu, Hao; Song, Hyerim; Park, Jung Han Yoon; Yun, Jong Won

    2012-06-01

    Recent studies have indicated that obesity increases the risk of developing several types of cancers including lung cancer, which is the leading cause of cancer death worldwide. In the present study, we attempted to discover marker proteins associated with lung cancer progression mediated by treatment of a high-fat diet (HFD) using 2DE combined with MALDI-TOF-MS. Image analysis and further statistical analysis allowed for the detection and identification of 14 proteins, which consequently were classified into two groups based on their regulation patterns in response to diet and tumor. Interestingly, the protein abundances of ten proteins exhibited a synergistic effect when treated with HFD in tumor-bearing mice (Group I). Proteins that had a higher abundance in the plasma of tumor-bearing mice included FGB, Tf, Hpx, Cp, and Hp and the proteins that had a lower abundance included A1AT precursor, PON1, TTRt, and α2-M. These proteins can be used as molecular markers that contribute simultaneously to both obesity and cancer. Four other proteins showed an increase (complement C3 and FGA) or decrease (Apo H and AT III precursor) in the only tumor-bearing mice independently of diet (Group II). The marker proteins identified here may lead to the development of new therapeutics for obesity-causative treatment of lung cancer. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Role of high-resolution CT in the diagnosis of small pulmonary nodules coexisting with potentially operable lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yuan, Yue; Matsumoto, Tsuneo; Hiyama, Atsuto; Miura, Goji; Tanaka, Nobuyuki; Matsunaga, Naofumi [Yamaguchi Univ., Ube (Japan). School of Medicine

    2002-10-01

    The purpose of this study was to evaluate whether high-resolution CT (HRCT) could facilitate the preoperative diagnosis of one or two small nodules of 1 cm or less coexisting with a lung cancer, i.e., coexisting small nodule. This study included 27 coexisting small nodules in 24 potentially operable lung cancer patients. An observer study was performed by five radiologists. The observer performances in differentiating malignant from benign coexisting small nodules were evaluated on conventional CT and HRCT using receiver operating characteristic (ROC) analysis. The area under the ROC curve of five observers was 0.731 on HRCT and 0.578 on conventional CT in the differential diagnosis of coexisting small nodules. A significant diagnostic improvement was found on HRCT (p=0.031). This was especially evident for nodules of ground-glass attenuation (p=0.005). HRCT plays an important role in determining the treatment of potentially operable lung cancer patients with coexisting small nodules. (author)

  9. Changes in structural lung disease in cystic fibrosis children over 4 years as evaluated by high-resolution computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Carpio, Carlos; Alvarez-Sala, Rodolfo; Prados, Concepcion [University Hospital La Paz, La Paz Hospital Research Institute, Department of Respiratory Medicine, Madrid (Spain); Albi, Gustavo [Nino de Jesus Children' s Hospital, Department of Radiology, Madrid (Spain); Rayon-Aledo, Jose Carlos; Caballero, Paloma [University Hospital La Princesa, Department of Radiology, Madrid (Spain); Giron, Rosa [University Hospital La Princesa, Department of Respiratory Medicine, Madrid (Spain)

    2015-12-15

    To compare the worsening of structural lung disease on high-resolution computed tomography (HRCT) with changes in spirometry results in cystic fibrosis (CF) patients, and analyse factors associated with the worsening of structural lung disease over time. A total of 31 CF subjects (mean age 11.03 ± 3.67 years old) were prospectively evaluated by two HRCT and spirometry tests performed 4 years apart. HRCT abnormalities were scored using the Bhalla scoring system. Comparisons between changes on HRCT and spirometry were made for all patients, and also for groups categorized by age, sex, genotypic alterations and lung obstruction. The mean HRCT Bhalla scoring, forced expiratory volume in 1 s (FEV{sub 1} %pred.) and forced vital capacity (FVC %pred.) were 7.92 ± 3.59, 87.76 ± 20.52 and 96.54 ± 15.12, respectively. There was a significant deterioration in the Bhalla score (p < 0.01) and in certain categories: severity of bronchiectasis, peribronchial thickening, mucous plugging and bronchial divisions. Females had a more pronounced worsening of the Bhalla score than males (p = 0.048). No change over time was found in FEV{sub 1} and FVC. Only sex was associated with a deterioration in HRCT. HRCT Bhalla scoring changes statistically significantly over 4 years, but spirometry results do not. Worsening on HRCT is more evident in females. (orig.)

  10. Inhibition of heregulin expression blocks tumorigenicity and metastasis of breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Tsai, Miaw-Sheue; Shamon-Taylor, Lisa A.; Mehmi, Inderjit; Tang, Careen K.; Cardillo, Marina; Lupu, Ruth

    2001-12-20

    The growth factor Heregulin (HRG) is expressed in 30% of breast cancer tumors. HRG induces tumorigenicity and metastasis of breast cancer cells. Our investigation into whether blockage of HRG reduces the aggressiveness of breast cancer cells demonstrated that transfection of MDA-MB-231 with an HRG antisense cDNA suppressed proliferation, tumorigenicity, and metastasis. Blockage of the aggressive phenotype is mediated possibly through inactivation of the erbB signaling pathways and a decrease in MMP-9 activity. Our study is the first to report that HRG is a key promoter of breast cancer progression and should be deemed as a potential target in developing therapies for the treatment of breast carcinomas.

  11. The splicing factor SRSF6 is amplified and is an oncoprotein in lung and colon cancers

    DEFF Research Database (Denmark)

    Cohen-Eliav, Michal; Golan-Gerstl, Regina; Siegfried, Zahava;

    2013-01-01

    An increasing body of evidence connects alterations in the process of alternative splicing with cancer development and progression. However, a direct role of splicing factors as drivers of cancer development is mostly unknown. We analyzed the gene copy number of several splicing factors in colon...... and lung tumors and found that the gene encoding for the splicing factor SRSF6 is amplified and overexpressed in these cancers. Moreover, overexpression of SRSF6 in immortal lung epithelial cells enhanced proliferation, protected them from chemotherapy-induced cell death and converted them...... to be tumorigenic in mice. In contrast, knockdown of SRSF6 in lung and colon cancer cell lines inhibited their tumorigenic abilities. SRSF6 up- or down regulation altered the splicing of several tumor suppressors and oncogenes to generate the oncogenic isoforms and reduce the tumor suppressive isoforms. Our data...

  12. High throughput determination of TGFβ1/SMAD3 targets in A549 lung epithelial cells.

    Directory of Open Access Journals (Sweden)

    Yingze Zhang

    Full Text Available BACKGROUND: Transforming growth factor beta 1 (TGFβ1 plays a major role in many lung diseases including lung cancer, pulmonary hypertension, and pulmonary fibrosis. TGFβ1 activates a signal transduction cascade that results in the transcriptional regulation of genes in the nucleus, primarily through the DNA-binding transcription factor SMAD3. The objective of this study is to identify genome-wide scale map of SMAD3 binding targets and the molecular pathways and networks affected by the TGFβ1/SMAD3 signaling in lung epithelial cells. METHODOLOGY: We combined chromatin immunoprecipitation with human promoter region microarrays (ChIP-on-chip along with gene expression microarrays to study global transcriptional regulation of the TGFβ1/SMAD3 pathway in human A549 alveolar epithelial cells. The molecular pathways and networks associated with TGFβ1/SMAD3 signaling were identified using computational approaches. Validation of selected target gene expression and direct binding of SMAD3 to promoters were performed by quantitative real time RT-PCR and electrophoretic mobility shift assay on A549 and human primary lung epithelial cells. RESULTS AND CONCLUSIONS: Known TGFβ1 target genes such as SERPINE1, SMAD6, SMAD7, TGFB1 and LTBP3, were found in both ChIP-on-chip and gene expression analyses as well as some previously unrecognized targets such as FOXA2. SMAD3 binding of FOXA2 promoter and changed expression were confirmed. Computational approaches combining ChIP-on-chip and gene expression microarray revealed multiple target molecular pathways affected by the TGFβ1/SMAD3 signaling. Identification of global targets and molecular pathways and networks associated with TGFβ1/SMAD3 signaling allow for a better understanding of the mechanisms that determine epithelial cell phenotypes in fibrogenesis and carcinogenesis as does the discovery of the direct effect of TGFβ1 on FOXA2.

  13. Isolation of stem-like cells from spontaneous feline mammary carcinomas: Phenotypic characterization and tumorigenic potential

    Energy Technology Data Exchange (ETDEWEB)

    Barbieri, Federica; Wurth, Roberto [Section of Pharmacology, Dept. of Internal Medicine Di.M.I., and Center of Excellence for Biomedical Research - University of Genova, Viale Benedetto XV, 2, 16132 Genova (Italy); Ratto, Alessandra; Campanella, Chiara; Vito, Guendalina [Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D' Aosta, National Reference Center of Veterinary and Comparative Oncology (CEROVEC), Piazza Borgo Pila, 16129, Genova (Italy); Thellung, Stefano [Section of Pharmacology, Dept. of Internal Medicine Di.M.I., and Center of Excellence for Biomedical Research - University of Genova, Viale Benedetto XV, 2, 16132 Genova (Italy); Daga, Antonio [Laboratory of Translational Oncology, IRCCS Azienda Ospedaliera Universitaria San Martino - IST- Istituto Nazionale Ricerca sul Cancro, L.go R. Benzi, 10, 16132 Genova Italy (Italy); Cilli, Michele [Animal Facility, IRCCS Azienda Ospedaliera Universitaria San Martino - IST- Istituto Nazionale Ricerca sul Cancro, L.go R. Benzi, 10, 16132 Genova Italy (Italy); Ferrari, Angelo [Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D' Aosta, National Reference Center of Veterinary and Comparative Oncology (CEROVEC), Piazza Borgo Pila, 16129, Genova (Italy); Florio, Tullio, E-mail: tullio.florio@unige.it [Section of Pharmacology, Dept. of Internal Medicine Di.M.I., and Center of Excellence for Biomedical Research - University of Genova, Viale Benedetto XV, 2, 16132 Genova (Italy)

    2012-04-15

    Current carcinogenesis theory states that only a small subset of tumor cells, the cancer stem cells or tumor initiating cells (TICs), are responsible for tumor formation and progression. Human breast cancer-initiating cells have been identified as CD44-expressing cells, which retain tumorigenic activity and display stem cell-like properties. Spontaneous feline mammary carcinoma (FMC) is an aggressive cancer, which shows biological similarities to the human tumor counterpart. We report the isolation and phenotypic characterization of FMC-derived stem/progenitor cells, showing in vitro self-renewal, long-lasting proliferation and in vivo tumorigenicity. Twenty-one FMC samples were collected, histologically classified and characterized for the expression of Ki67, EGFR, ER-{alpha} and CD44, by immunohistochemistry. By culture in stem cell permissive conditions, we isolated, from 13 FMCs, a CD44-positive subpopulation able to survive and proliferate in vitro as mammospheres of different sizes and morphologies. When injected in NOD/SCID mice, FMC stem-like cells initiate tumors, generating cell heterogeneity and recapitulating the original histotype. In serum-containing medium, spheroid cells showed differentiation properties as shown by morphological changes, the loss of CD44 expression and tumorigenic potential. These data show that stem-defined culture of FMC enriches for TICs and validate the use of these cells as a suitable model for comparative oncology studies of mammary biology and testing therapeutic strategies aimed at eradicating TICs. -- Highlights: Black-Right-Pointing-Pointer Feline mammary carcinoma contain a sub-population of stem-like cells expressing CD44 Black-Right-Pointing-Pointer These grow as spheres in serum-free medium and self-renew Black-Right-Pointing-Pointer Isolated stem-like cancer cells initiate tumor in immunodeficient mice Black-Right-Pointing-Pointer Xenografted tumors are phenotypically similar to the original tumor Black

  14. Genotoxic Pyrrolizidine Alkaloids — Mechanisms Leading to DNA Adduct Formation and Tumorigenicity

    OpenAIRE

    2002-01-01

    Abstract: Plants that contain pyrrolizidine alkaloids are widely distributed in the world. Although pyrrolizidine alkaloids have been shown to be genotoxic and tumorigenic in experimental animals, the mechanisms of actions have not been fully understood. The results of our recent mechanistic studies suggest that pyrrolizidine alkaloids induce tumors via a genotoxic mechanism mediated by 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5Hpyrrolizine (DHP)-derived DNA adduct formation. This mechanism may ...

  15. Knockdown of E2F2 inhibits tumorigenicity, but preserves stemness of human embryonic stem cells.

    Science.gov (United States)

    Suzuki, Daniela Emi; Nakahata, Adriana Miti; Okamoto, Oswaldo Keith

    2014-06-01

    Tumorigenicity of human pluripotent stem cells is a major threat limiting their application in cell therapy protocols. It remains unclear, however, whether suppression of tumorigenic potential can be achieved without critically affecting pluripotency. A previous study has identified hyperexpressed genes in cancer stem cells, among which is E2F2, a gene involved in malignant transformation and stem cell self-renewal. Here we tested whether E2F2 knockdown would affect the proliferative capacity and tumorigenicity of human embryonic stem cells (hESC). Transient E2F2 silencing in hESC significantly inhibited expression of the proto-oncogenes BMI1 and HMGA1, in addition to proliferation of hESC, indicated by a higher proportion of cells in G1, fewer cells in G2/M phase, and a reduced capacity to generate hESC colonies in vitro. Nonetheless, E2F2-silenced cells kept expression of typical pluripotency markers and displayed differentiation capacity in vitro. More importantly, E2F2 knockdown in hESC significantly inhibited tumor growth in vivo, which was considerably smaller than tumors generated from control hESC, although displaying typical teratoma traits, a major indicator of pluripotency retention in E2F2-silenced cells. These results suggest that E2F2 knockdown can inhibit hESC proliferation and tumorigenicity without significantly harming stemness, providing a rationale to future protocols aiming at minimizing risks related to therapeutic application of cells and/or products derived from human pluripotent cells.

  16. Deviation of tracheal pressure from airway opening pressure during high-frequency oscillatory ventilation in a porcine lung model.

    Science.gov (United States)

    Johannes, Amélie; Zollhoefer, Bernd; Eujen, Ulrike; Kredel, Markus; Rauch, Stefan; Roewer, Norbert; Muellenbach, Ralf M

    2013-04-01

    Oxygenation during high-frequency oscillatory ventilation is secured by a high level of mean airway pressure. Our objective was to identify a pressure difference between the airway opening of the respiratory circuit and the trachea during application of different oscillatory frequencies. Six female Pietrain pigs (57.1 ± 3.6 kg) were first ventilated in a conventional mechanical ventilation mode. Subsequently, the animals were switched to high-frequency oscillatory ventilation by setting mean airway opening pressure 5 cmH(2)O above the one measured during controlled mechanical ventilation. Measurements at the airway opening and at tracheal levels were performed in healthy lungs and after induction of acute lung injury by surfactant depletion. During high-frequency oscillatory ventilation, the airway opening pressure was set at a constant level. The pressure amplitude was fixed at 90 cmH(2)O. Starting from an oscillatory frequency of 3 Hz, the frequency was increased in steps of 3 Hz to 15 Hz and then decreased accordingly. At each frequency, measurements were performed in the trachea through a side-lumen of the endotracheal tube and the airway opening pressure was recorded. The pressure difference was calculated. At every oscillatory frequency, a pressure loss towards the trachea could be shown. This pressure difference increased with higher oscillatory frequencies (3 Hz 2.2 ± 2.1 cmH(2)O vs. 15 Hz 7.5 ± 1.8 cmH(2)O). The results for healthy and injured lungs were similar. Tracheal pressures decreased with higher oscillatory frequencies. This may lead to pulmonary derecruitment. This has to be taken into consideration when increasing oscillatory frequencies and differentiated pressure settings are mandatory.

  17. High-dose corticosteroid therapy for erlotinib-induced interstitial lung disease in Japanese patient with advanced pancreatic cancer.

    Science.gov (United States)

    Yoshioka, Masato; Watanabe, Go; Uchinami, Hiroshi; Ise, Norihito; Nakagawa, Yasuhiko; Kudoh, Kazuhiro; Morita, Ryo; Andoh, Hideaki; Yamamoto, Yuzo

    2014-11-28

    Erlotinib is a selective epidermal growth factor receptor tyrosine kinase inhibitor used as a target therapy against non-small lung cancer and advanced pancreatic cancer. A regimen of erlotinib plus gemcitabine has been proven to prolong overall survival in the patient with advanced pancreatic cancer. In addition to common adverse effects, such as diarrhea, mucositis and skin rash (acne form eruptions), acute interstitial lung disease (ILD) has been reported as an infrequent but potentially fatal complication. We here report a case of a Japanese patient with erlotinib-induced ILD in whom high-dose corticosteroid therapy was successful. A fifty-five-year-old male with cancer of the head of the pancreas with multiple liver metastases started treatment with gemcitabine plus erlotinib. On the 13th day of erlotinib treatment, he had high fever. Chest computed tomography (CT) scan showed a diffuse ground-glass like infiltration of both lungs. He was diagnosed with ILD, and high-dose corticosteroid therapy was started. Two weeks after the introduction of steroid therapy, the reticular shadow faded away on CT. He was successfully treated with corticosteroid for erlotinib-induced acute ILD although he died 6 months after the initiation of chemotherapy owing to disease progression. we showed a case of a successfully treated Japanese patient of erlotinib-induced ILD. Because erlotinib-induced ILD would frequently occur in Japanese patients, closer attention to ILD should be paid for Japanese patients than in Western populations. If erlotinib-induced ILD occurs, a high-dose corticosteroid therapy would be a useful option of treatment.

  18. Human Muse cells, non-tumorigenic pluripotent-like stem cells, have the capacity for liver regeneration by specific homing and replenishment of new hepatocytes in liver fibrosis mouse model.

    Science.gov (United States)

    Iseki, Masahiro; Kushida, Yoshihiro; Wakao, Shohei; Akimoto, Takahiro; Mizuma, Masamichi; Motoi, Fuyuhiko; Asada, Ryuta; Shimizu, Shinobu; Unno, Michiaki; Chazenbalk, Gregorio; Dezawa, Mari

    2016-11-02

    Muse cells, a novel type of non-tumorigenic pluripotent-like stem cells reside in the bone marrow, skin and adipose tissue, are collectable as cells positive for pluripotent surface marker SSEA-3. They are able to differentiate into cells representative of all three germ layers. The capacity of intravenously injected human bone marrow-Muse cells to repair the liver fibrosis model of immunodeficient mice was evaluated in this study. They exhibited the ability for differentiation spontaneously into hepatoblast/hepatocyte-lineage cells and high migration toward the serum and liver tissue of carbon tetrachloride-treated mice in vitro. In vivo, they specifically accumulated into the liver, but not into other organs except the lower rate in the lung at 2 weeks after intravenous injection into the liver fibrosis model. After homing, Muse cells spontaneously differentiated in vivo into HepPar-1 (71.1±15.2%), human albumin (54.3±8.2%) and anti-trypsin (47.9±4.6%)-positive cells without fusing with host hepatocytes, and expressed mature functional markers such as human-CYP1A2, and human-Glc-6-Pase, at 8 weeks. Recovery in serum total bilirubin and albumin, and significant attenuation of fibrosis were recognized with statistical differences between the Muse group and control groups which received the vehicle or the same number of non-Muse cells, namely cells other than Muse cells in bone marrow mesenchymal stem cells. Thus, unlike ES and iPS cells, Muse cells are unique in their efficient migration and integration into damaged liver only by intravenous injection, nontumorigenicity, and spontaneous differentiation into hepatocytes, rendering induction into hepatocytes prior to transplantation unnecessary. They are suggested to repair liver fibrosis in two simple steps; expansion after collection from the bone marrow and intravenous injection. Such feasible strategy might provide impressive regenerative performance to liver disease patients.

  19. TNP-470 Suppresses the Tumorigenicity of HT1080 Fibrosarcoma Tumor Through the Inhibition of VEGF Secretion From the Tumor Cells

    OpenAIRE

    Mitsunori Kaya; Takuro Wada; Satoshi Nagoya; Satoshi Kawaguchi; Toshihiko Yamashita; Nobuyuki Yamamoto; Mitsunori Yoshimoto; Futoshi Okada; Seiichi Ishii

    2001-01-01

    Angiogenesis inhibitors are a novel class of promising therapeutic agents for treating cancer. TNP-470, a systemic analogue of fumagillin, is an angiogenesis inhibitor capable of suppressing the tumorigenicity in several animal models even though the mechanisms of action have not been completely clarified. In the current study, we investigated the effects of TNP-470 on human fibrosarcoma cells in vivo and in vitro. The administration of TNP-470 could suppress the tumorigenicity of HT1080 fibr...

  20. EMT-induced stemness and tumorigenicity are fueled by the EGFR/Ras pathway.

    Directory of Open Access Journals (Sweden)

    Dominic Chih-Cheng Voon

    Full Text Available Recent studies have revealed that differentiated epithelial cells would acquire stem cell-like and tumorigenic properties following an Epithelial-Mesenchymal Transition (EMT. However, the signaling pathways that participate in this novel mechanism of tumorigenesis have not been fully characterized. In Runx3 (-/- p53 (-/- murine gastric epithelial (GIF-14 cells, EMT-induced plasticity is reflected in the expression of the embryonal proto-oncogene Hmga2 and Lgr5, an exclusive gastrointestinal stem cell marker. Here, we report the concurrent activation of an EGFR/Ras gene expression signature during TGF-β1-induced EMT in GIF-14 cells. Amongst the altered genes was the induction of Egfr, which corresponded with a delayed sensitization to EGF treatment in GIF-14. Co-treatment with TGF-β1 and EGF or the expression of exogenous KRas led to increased Hmga2 or Lgr5 expression, sphere initiation and colony formation in soft agar assay. Interestingly, the gain in cellular plasticity/tumorigenicity was not accompanied by increased EMT. This uncoupling of EMT and the induction of plasticity reveals an involvement of distinct signaling cues, whereby the EGFR/Ras pathway specifically promotes stemness and tumorigenicity in EMT-altered GIF-14 cells. These data show that the EGFR/Ras pathway requisite for the sustenance of gastric stem cells in vivo and in vitro is involved in the genesis and promotion of EMT-induced tumor-initiating cells.

  1. Genomic instability and tumorigenic induction in immortalized human bronchial epithelial cells by heavy ions

    Science.gov (United States)

    Hei, T. K.; Piao, C. Q.; Wu, L. J.; Willey, J. C.; Hall, E. J.

    1998-11-01

    Carcinogenesis is postulated to be a progressive multistage process characterized by an increase in genomic instability and clonal selection with each mutational event endowing a selective growth advantage. Genomic instability as manifested by the amplification of specific gene fragments is common among tumor and transformed cells. In the present study, immortalized human bronchial (BEP2D) cells were irradiated with graded doses of either 1GeV/nucleon 56Fe ions or 150 keV/μm alpha particles. Transformed cells developed through a series of successive steps before becoming tumorigenic in nude mice. Tumorigenic cells showed neither ras mutations nor deletion in the p16 tumor suppressor gene. In contrast, they harbored mutations in the p53 gene and over-expressed cyclin D1. Genomic instability among transformed cells at various stage of the carcinogenic process was examined based on frequencies of PALA resistance. Incidence of genomic instability was highest among established tumor cell lines relative to transformed, non-tumorigenic and control cell lines. Treatment of BEP2D cells with a 4 mM dose of the aminothiol WR-1065 significantly reduced their neoplastic transforming response to 56Fe particles. This model provides an opportunity to study the cellular and molecular mechanisms involved in malignant transformation of human epithelial cells by heavy ions.

  2. Tumorigenicity of hypoxic respiring cancer cells revealed by a hypoxia–cell cycle dual reporter

    Science.gov (United States)

    Le, Anne; Stine, Zachary E.; Nguyen, Christopher; Afzal, Junaid; Sun, Peng; Hamaker, Max; Siegel, Nicholas M.; Gouw, Arvin M.; Kang, Byung-hak; Yu, Shu-Han; Cochran, Rory L.; Sailor, Kurt A.; Song, Hongjun; Dang, Chi V.

    2014-01-01

    Although aerobic glycolysis provides an advantage in the hypoxic tumor microenvironment, some cancer cells can also respire via oxidative phosphorylation. These respiring (“non-Warburg”) cells were previously thought not to play a key role in tumorigenesis and thus fell from favor in the literature. We sought to determine whether subpopulations of hypoxic cancer cells have different metabolic phenotypes and gene-expression profiles that could influence tumorigenicity and therapeutic response, and we therefore developed a dual fluorescent protein reporter, HypoxCR, that detects hypoxic [hypoxia-inducible factor (HIF) active] and/or cycling cells. Using HEK293T cells as a model, we identified four distinct hypoxic cell populations by flow cytometry. The non-HIF/noncycling cell population expressed a unique set of genes involved in mitochondrial function. Relative to the other subpopulations, these hypoxic “non-Warburg” cells had highest oxygen consumption rates and mitochondrial capacity consistent with increased mitochondrial respiration. We found that these respiring cells were unexpectedly tumorigenic, suggesting that continued respiration under limiting oxygen conditions may be required for tumorigenicity. PMID:25114222

  3. Lung disease

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000066.htm Lung disease To use the sharing features on this page, ... fibrosis and sarcoidosis are examples of lung tissue disease. Lung circulation diseases -- These diseases affect the blood vessels ...

  4. Lung transplant

    Science.gov (United States)

    Solid organ transplant - lung ... the chance that the body will reject the transplant . Lungs can also be given by living donors. ... the person who is receiving it. During lung transplant surgery, you are asleep and pain-free (under ...

  5. Collapsed Lung

    Science.gov (United States)

    A collapsed lung happens when air enters the pleural space, the area between the lung and the chest wall. If it is a ... is called pneumothorax. If only part of the lung is affected, it is called atelectasis. Causes of ...

  6. A computer-assisted 3D model for analyzing the aggregation of tumorigenic cells reveals specialized behaviors and unique cell types that facilitate aggregate coalescence.

    Directory of Open Access Journals (Sweden)

    Amanda Scherer

    Full Text Available We have developed a 4D computer-assisted reconstruction and motion analysis system, J3D-DIAS 4.1, and applied it to the reconstruction and motion analysis of tumorigenic cells in a 3D matrix. The system is unique in that it is fast, high-resolution, acquires optical sections using DIC microscopy (hence there is no associated photoxicity, and is capable of long-term 4D reconstruction. Specifically, a z-series at 5 μm increments can be acquired in less than a minute on tissue samples embedded in a 1.5 mm thick 3D Matrigel matrix. Reconstruction can be repeated at intervals as short as every minute and continued for 30 days or longer. Images are converted to mathematical representations from which quantitative parameters can be derived. Application of this system to cancer cells from established lines and fresh tumor tissue has revealed unique behaviors and cell types not present in non-tumorigenic lines. We report here that cells from tumorigenic lines and tumors undergo rapid coalescence in 3D, mediated by specific cell types that we have named "facilitators" and "probes." A third cell type, the "dervish", is capable of rapid movement through the gel and does not adhere to it. These cell types have never before been described. Our data suggest that tumorigenesis in vitro is a developmental process involving coalescence facilitated by specialized cells that culminates in large hollow spheres with complex architecture. The unique effects of select monoclonal antibodies on these processes demonstrate the usefulness of the model for analyzing the mechanisms of anti-cancer drugs.

  7. Tumor-associated MUC5AC stimulates in vivo tumorigenicity of human pancreatic cancer.

    Science.gov (United States)

    Hoshi, Hirotaka; Sawada, Tetsuji; Uchida, Motoyuki; Saito, Hikaru; Iijima, Hiroko; Toda-Agetsuma, Mikako; Wada, Tsutomu; Yamazoe, Sadaaki; Tanaka, Hiroaki; Kimura, Kenjiro; Kakehashi, Anna; Wei, Min; Hirakawa, Kosei; Wanibuchi, Hideki

    2011-03-01

    MUC5AC, a high molecular weight glycoprotein, is overexpressed in the ductal region of human pancreatic cancer but is not detectable in the normal pancreas, suggesting its association with disease development. In the present study, we investigated the in vitro and in vivo effects of MUC5AC knockdown by short interfering RNA (siRNA) in the MUC5AC-overexpressing SW1990 and BxPC3 human pancreatic cancer cell lines in order to clarify its function. Significant decreases in the expression levels of MUC5AC mRNA and protein were observed in SW1990 and BxPC3 cells that had been stably transfected with a MUC5AC siRNA expression vector (SW1990/si-MUC5AC and BxPC3/si-MUC5AC cells) compared to those in cells transfected with an si-mock vector (SW1990/si-mock and BxPC3/si-mock cells). In in vitro studies, neither type of MUC5AC-knockdown cell showed any difference in cell survival, proliferation, or morphology from the si-mock cells or parental cells. However, in vivo xenograft studies demonstrated that MUC5AC knockdown significantly reduced the tumorigenicity and suppressed the tumor growth of si-MUC5AC cells compared to those of the si-mock cells. Immunohistochemical analysis revealed that CD45R/B220+ and Gr-1+ cells had infiltrated into the tumor tissue of the SW1990/si-MUC5AC cells. Furthermore, cancer-associated antigen specific antibodies were detected at high levels in the sera from the SW1990/si-MUC5AC cell-bearing mice. These results suggest that tumor-associated MUC5AC expressed on the surface of pancreatic cancer cells supports the escape of pancreatic cancer cells from immunosurveillance. The present findings highlight a new dimension of MUC5AC as a functional immunosuppressive agent and its important role in pancreatic cancer progression.

  8. Effects of High-Intensity Swimming on Lung Inflammation and Oxidative Stress in a Murine Model of DEP-Induced Injury.

    Science.gov (United States)

    Ávila, Leonardo C M; Bruggemann, Thayse R; Bobinski, Franciane; da Silva, Morgana Duarte; Oliveira, Regiane Carvalho; Martins, Daniel Fernandes; Mazzardo-Martins, Leidiane; Duarte, Marta Maria Medeiros Frescura; de Souza, Luiz Felipe; Dafre, Alcir; Vieira, Rodolfo de Paula; Santos, Adair Roberto Soares; Bonorino, Kelly Cattelan; Hizume Kunzler, Deborah de C

    2015-01-01

    Studies have reported that exposure to diesel exhaust particles (DEPs) induces lung inflammation and increases oxidative stress, and both effects are susceptible to changes via regular aerobic exercise in rehabilitation programs. However, the effects of exercise on lungs exposed to DEP after the cessation of exercise are not clear. Therefore, the aim of this study was to evaluate the effects of high-intensity swimming on lung inflammation and oxidative stress in mice exposed to DEP concomitantly and after exercise cessation. Male Swiss mice were divided into 4 groups: Control (n = 12), Swimming (30 min/day) (n = 8), DEP (3 mg/mL-10 μL/mouse) (n = 9) and DEP+Swimming (n = 8). The high-intensity swimming was characterized by an increase in blood lactate levels greater than 1 mmoL/L between 10th and 30th minutes of exercise. Twenty-four hours after the final exposure to DEP, the anesthetized mice were euthanized, and we counted the number of total and differential inflammatory cells in the bronchoalveolar fluid (BALF), measured the lung homogenate levels of IL-1β, TNF-α, IL-6, INF-ϫ, IL-10, and IL-1ra using ELISA, and measured the levels of glutathione, non-protein thiols (GSH-t and NPSH) and the antioxidant enzymes catalase and glutathione peroxidase (GPx) in the lung. Swimming sessions decreased the number of total cells (pswimming groups compared with the control groups, as did the CAT lung levels (p = 0.0001). Simultaneously, swimming resulted in an increase in the GSH-t and NPSH lung levels in the DEP group (p = 0.0001 and pswimming sessions decreased the lung inflammation and oxidative stress status during DEP-induced lung inflammation in mice.

  9. TGF-β1 in bronchoalveolar lavage fluid in diffuse parenchymal lung diseases and high-resolution computed tomography score

    Directory of Open Access Journals (Sweden)

    Artur Szlubowski

    2010-07-01

    Full Text Available INTRODUCTION: In the pathogenesis of diffuse parenchymal lung diseases (DPLDs, growth factors, including transforming growth factor β1 (TGF-β1, are responsible for cell proliferation, apoptosis, chemotaxis, and angiogenesis, and also for the production and secretion of some components of the extracellular matrix. OBJECTIVES: The aim of the study was to evaluate correlations in DPLDs between TGF-β1 levels in bronchoalveolar lavage (BAL fluid and high-resolution computed tomography (HRCT score. PATIENTS AND METHODS: The study was performed in 31 DPLD patients in whom a selection of lung segments with high and low intensity of abnormalities was estimated by HRCT score. All patients underwent BAL with TGF-β1 measured by an enzyme immunoassay in BAL fluid and video-assisted thoracic surgery lung biopsy from both selected segments. RESULTS: All 31 patients were diagnosed, and based on histopathology, they were classified into 2 groups: idiopathic interstitial pneumonia (usual interstitial pneumonia – 12, nonspecific interstitialpneumonia – 2, cryptogenic organizing pneumonia – 2, and desquamative interstitial pneumonia – 1 and granulomatous disease (sarcoidosis – 7, extrinsic allergic alveolitis – 5, and histiocytosis X – 2. The final analysis was performed in 28 patients who showed nonhomogenous distribution on HRCT. TGF-β1 levels in BAL fluid were significantly higher in the areas with high intensity of abnormalities assessed by HRCT score (P = 0.018, analysis of variance. These levels were not different between the groups, but a trend towards higher levels in idiopathic interstitial pneumonia was observed. CONCLUSIONS: The results confirm that TGF-β1 may be a good but not specific marker of fibrosis in DPLDs. A significant positive correlation between TGF-β1 levels in BAL fluid and the HRCT score was observed.

  10. Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes — A Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Li-Shiun Chen

    2016-09-01

    Conclusion: We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7 years for those who develop it. These results: 1 underscore the potential value of smoking cessation for all smokers, 2 suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3 have potential value for framing preventive interventions for those who smoke.

  11. Two-stage induced differentiation of OCT4+/Nanog+ stem-like cells in lung adenocarcinoma.

    Science.gov (United States)

    Li, Rong; Huang, Jinsu; Ma, Meili; Lou, Yuqing; Zhang, Yanwei; Wu, Lixia; Chang, David W; Zhao, Picheng; Dong, Qianggang; Wu, Xifeng; Han, Baohui

    2016-10-18

    Stem-like cells in solid tumors are purported to contribute to cancer development and poor treatment outcome. The abilities to self-renew, differentiate, and resist anticancer therapies are hallmarks of these rare cells, and steering them into lineage commitment may be one strategy to curb cancer development or progression. Vitamin D is a prohormone that can alter cell growth and differentiation and may induce the differentiation cancer stem-like cells. In this study, octamer-binding transcription factor 4 (OCT4)-positive/Nanog homeobox (Nanog)- positive lung adenocarcinoma stem-like cells (LACSCs) were enriched from spheroid cultured SPC-A1 cells and differentiated by a two-stage induction (TSI) method, which involved knockdown of hypoxia-inducible factor 1-alpha (HIF1α) expression (first stage) followed by sequential induction with 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3, VD3) and suberoylanilide hydroxamic acid (SAHA) treatment (second stage). The results showed the HIF1α-knockdowned cells displayed diminished cell invasion and clonogenic activities. Moreover, the TSI cells highly expressed tumor suppressor protein p63 (P63) and forkhead box J1 (FOXJ1) and lost stem cell characteristics, including absent expression of OCT4 and Nanog. These cells regained sensitivity to cisplatin in vitro while losing tumorigenic capacity and decreased tumor cell proliferation in vivo. Our results suggest that induced transdifferentiation of LACSCs by vitamin D and SAHA may become novel therapeutic avenue to alter tumor cell phenotypes and improve patient outcome.The development and progression of lung cancer may involve rare population of stem-like cells that have the ability to grow, differentiate, and resist drug treatment. However, current therapeutic strategies have mostly focused on tumor characteristics and neglected the potential source of cells that may contribute to poor clinical outcome. We generated lung adenocarcinoma stem-like cells from spheroid culture and

  12. Frameless high dose rate stereotactic lung radiotherapy: intrafraction tumor position and delivery time.

    Science.gov (United States)

    Peguret, Nicolas; Dahele, Max; Cuijpers, Johan P; Slotman, Ben J; Verbakel, Wilko F A R

    2013-06-01

    Intrafraction change in tumor position (Δ) was evaluated for stereotactic lung radiotherapy delivered with flattening filter free volumetric modulated arc therapy. In 140 fractions from 32 patients mean Δ (±SD) was -0.7±1.4 mm (vertical), -0.7±1.3 mm (longitudinal) and +0.2±1.2 mm (lateral) with mean vector 2.1±1.2 mm. Mean delivery time was 4.4±3.4 min (mean beam-on 1.9±0.4 min). Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  13. High-fat Diet Enhances and Plasminogen Activator Inhibitor-1 Deficiency Attenuates Bone Loss in Mice with Lewis Lung Carcinoma.

    Science.gov (United States)

    Yan, Lin; Nielsen, Forrest H; Sundaram, Sneha; Cao, Jay

    2015-07-01

    This study determined the effects of a high-fat diet and plasminogen activator inhibitor-1 deficiency (Pai1(-/-)) on the bone structure in male C57BL/6 mice bearing Lewis lung carcinoma (LLC) in lungs. Significant reduction in bone volume fraction (BV/TV), trabecular number (Tb.N) and bone mineral density (BMD) in femurs and vertebrae were found in LLC-bearing mice compared to non-tumor-bearing mice. In LLC-bearing mice, the high-fat diet compared to the AIN93G control diet significantly reduced BV/TV, Tb.N and BMD in femurs and BV/TV in vertebrae. The high-fat diet significantly reduced BMD in vertebrae in wild-type mice but not in Pai1(-/-) mice. Compared to wild-type mice, PAI1 deficiency significantly increased BV/TV and Tb.N in femurs. The plasma concentration of osteocalcin was significantly lower and that of tartrate-resistant acid phosphatase 5b (TRAP5b) was significantly higher in LLC-bearing mice. The high-fat diet significantly reduced plasma osteocalcin and increased TRAP5b. Deficiency in PAI1 prevented the high-fat diet-induced increases in plasma TRAP5b. These findings demonstrate that a high-fat diet enhances, whereas PAI1 deficiency, attenuates metastasis-associated bone loss, indicating that a high-fat diet and PAI1 contribute to metastasis-associated bone deterioration. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  14. Low-versus high-energy photon beams in radiotherapy for lung cancer.

    Science.gov (United States)

    Foote, R L; Robinow, J S; Shaw, E G; Kline, R W; Suman, V J; Ilstrup, D M; Lee, R E

    1993-01-01

    This retrospective study analyzed the outcome of lung cancer patients who were treated with either 4-MV or 10-MV photons. From October 1979 through December 1982, 126 patients with locally advanced, unresectable or medically inoperable, nonmetastatic non-small cell lung cancer were treated in a prospective trial in which they were randomly assigned to one of three chemotherapy combinations and thoracic radiotherapy. The patients were stratified by cell type, extent of operation, age, sex, and status of supraclavicular lymph nodes. All patients were followed until death or for a minimum of 4.8 years. Of the 102 evaluable patients, 98 were treated with either 4-MV or 10-MV photons (49 patients in each group). Outcomes examined included best primary tumor response, time to first local (in-field) recurrence, disease-free survival, and overall survival. No significant differences were detected between the patients treated with 4-MV or 10-MV photons for several important prognostic and treatment factors or for any of the study outcomes, including first local (in-field) recurrence, disease-free survival, and overall survival. For the group of 98 patients treated with either 4-MV or 10-MV photons, the estimated 2-year freedom from first local (in-field) recurrence was 47.7%. The estimated 2-year disease-free and overall survivals were 21.6% and 28.6%, respectively.

  15. Preparation of cell blocks for lung cancer diagnosis and prediction: protocol and experience of a high-volume center.

    Science.gov (United States)

    Kossakowski, Claudia A; Morresi-Hauf, Alicia; Schnabel, Philipp A; Eberhardt, Ralf; Herth, Felix J F; Warth, Arne

    2014-01-01

    Minimally invasive diagnostic techniques are increasingly being used to obtain specimens for pathological diagnosis and prediction. Referring to lung cancer, both endobronchial and endoesophageal ultrasound are used worldwide as diagnostic routine methods. Consequently, an increasing number of pathological samples are cytological and fewer are histological. On the other hand, the requirements for specific and sensitive tumor subtyping complemented by predictive analyses are steadily increasing and are an essential basis for evidence-based treatment decisions. In this article we focus on the cell block method as a helpful tool for diagnostic and predictive analyses in lung cancer and point out its advantages and disadvantages in comparison to conventional cytological and biopsy specimens. Furthermore, we retrospectively analyze the diagnostic results of the cell block method in a high-volume center over 5 years. The main advantages of cell blocks are the availability of established and validated protocols, archiving and the opportunity to have serial sections from the same specimens to provide or repeat molecular analyses. Actually, in case of tumor progression, even additional biomarkers can be tested using the original cell block when re-biopsies are not feasible. The cell block method should be considered as a reliable, complimentary approach to conventional cytological or biopsy procedures, which is helpful to fulfill the increasing requirements of high-quality diagnostics and prediction.

  16. Lung disease assessment in primary ciliary dyskinesia: a comparison between chest high-field magnetic resonance imaging and high-resolution computed tomography findings

    Directory of Open Access Journals (Sweden)

    Iacotucci Paola

    2009-08-01

    Full Text Available Abstract Background Primary ciliary dyskinesia (PCD is associated with pulmonary involvement that requires periodical assessment. Chest high-resolution computed tomography (HRCT has become the method of choice to evaluate chronic lung disease, but entails exposure to ionizing radiation. Magnetic resonance imaging (MRI has been proposed as a potential radiation-free technique in several chest disorders. Aim of our study is to evaluate whether high-field MRI is as effective as HRCT in identifying PCD pulmonary abnormalities. We also analyzed the relationships between the severity and extension of lung disease, and functional data. Methods Thirteen PCD patients (8 children/5 adults; median age, 15.2 yrs underwent chest HRCT and high-field 3T MRI, spirometry, and deep throat or sputum culture. Images were scored using a modified version of the Helbich system. Results HRCT and MRI total scores were 12 (range, 6–20 and 12 (range, 5–17, respectively. Agreement between HRCT and MRI scores was good or excellent (r > 0.8. HRCT and MRI total scores were significantly related to forced vital capacity (r = -0.5, p = 0.05; and r = -0.7, p = 0.009, respectively and forced expiratory volume at 1 second (r = -0.6, p = 0.03; and r = -0.7, p = 0.009, respectively. Conclusion Chest high-field 3T MRI appears to be as effective as HRCT in assessing the extent and severity of lung abnormalities in PCD. MRI scores might be used for longitudinal assessment and be an outcome surrogate in future studies.

  17. Lung ultrasound in systemic sclerosis: correlation with high-resolution computed tomography, pulmonary function tests and clinical variables of disease.

    Science.gov (United States)

    Gigante, Antonietta; Rossi Fanelli, Filippo; Lucci, Silvio; Barilaro, Giuseppe; Quarta, Silvia; Barbano, Biagio; Giovannetti, Antonello; Amoroso, Antonio; Rosato, Edoardo

    2016-03-01

    Interstitial lung disease (ILD) is a hallmark of systemic sclerosis (SSc). Although high-resolution computed tomography (HRCT) is the gold standard to diagnose ILD, recently lung ultrasound (LUS) has emerged in SSc patients as a new promising technique for the ILD evaluation, noninvasive and radiation-free. The aim of this study was to evaluate if there is a correlation between LUS, chest HRCT, pulmonary function tests findings and clinical variables of the disease. Thirty-nine patients (33 women and 6 men; mean age 51 ± 15.2 years) underwent clinical examination, HRCT, pulmonary function tests and LUS for detection of B-lines. A positive correlation exists between the number of B-lines and the HRCT score (r = 0.81, p < 0.0001), conversely a negative correlation exists between the number of B-lines and diffusing capacity of the lung for carbon monoxide (DLCO) (r = -0.63, p < 0.0001). The number of B-lines increases along with the progression of the capillaroscopic damage. A statistically significant difference in the number of B-lines was found between patients with and without digital ulcers [42 (3-84) vs 16 (4-55)]. We found that the number of B-lines increased with the progression of both HRCT score and digital vascular damage. LUS may therefore, be a useful tool to determine the best timing for HRCT execution, thus, preventing for many patients a continuous and useless exposure to ionizing radiation.

  18. Lung membrane conductance and capillary volume derived from the NO and CO transfer in high-altitude newcomers.

    Science.gov (United States)

    Martinot, Jean-Benoît; Mulè, Massimiliano; de Bisschop, Claire; Overbeek, Maria J; Le-Dong, Nhat-Nam; Naeije, Robert; Guénard, Hervé

    2013-07-15

    Acute exposure to high altitude may induce changes in carbon monoxide (CO) membrane conductance (DmCO) and capillary lung volume (Vc). Measurements were performed in 25 lowlanders at Brussels (D0), at 4,300 m after a 2- or 3-day exposure (D2,3) without preceding climbing, and 5 days later (D7,8), before and after an exercise test, under a trial with two arterial pulmonary vasodilators or a placebo. The nitric oxide (NO)/CO transfer method was used, assuming both infinite and finite values to the NO blood conductance (θNO). Doppler echocardiography provided hemodynamic data. Compared with sea level, lung diffusing capacity for CO increased by 24% at D2,3 and is returned to control at D7,8. The acute increase in lung diffusing capacity for CO resulted from increases in DmCO and Vc with finite and infinite θNO assumptions. The alveolar volume increased by 16% at D2,3 and normalized at D7,8. The mean increase in systolic arterial pulmonary pressure at rest at D2,3 was minimal. In conclusion, the acute increase in Vc may be related to the increase in alveolar volume and to the increase in capillary pressure. Compared with the infinite θNO value, the use of a finite θNO value led to about a twofold increase in DmCO value and to a persistent increase in DmCO at D7,8 compared with D0. After exercise, DmCO decreased slightly less in subjects treated by the vasodilators, suggesting a beneficial effect on interstitial edema.

  19. pp-GalNAc-T13 induces high metastatic potential of murine Lewis lung cancer by generating trimeric Tn antigen

    Energy Technology Data Exchange (ETDEWEB)

    Matsumoto, Yasuyuki; Zhang, Qing [Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065 (Japan); Akita, Kaoru; Nakada, Hiroshi [Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-Motoyama, Kita-ku, Kyoto 603-8555 (Japan); Hamamura, Kazunori; Tokuda, Noriyo [Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065 (Japan); Tsuchida, Akiko [Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065 (Japan); Noguchi Institute, 1-8-1 Kaga, Itabashi, Tokyo 173-0003 (Japan); Matsubara, Takeshi; Hori, Tomoko; Okajima, Tetsuya [Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065 (Japan); Furukawa, Keiko [Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065 (Japan); Department of Biomedical Sciences, Chubu University College of Life and Health Sciences, 1200 Matsumoto-cho, Kasugai 487-8501 (Japan); Urano, Takeshi [Department of Biochemistry, Shimane University School of Medicine, Izumo 693-8501 (Japan); Furukawa, Koichi, E-mail: koichi@med.nagoya-u.ac.jp [Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065 (Japan)

    2012-03-02

    Highlights: Black-Right-Pointing-Pointer ppGalNAc-T13 was up-regulated in high metastatic sublines of Lewis lung cancer. Black-Right-Pointing-Pointer ppGalNAc-T13 expression enhanced cell invasion activity in low metastatic sublines. Black-Right-Pointing-Pointer Trimeric Tn antigen was induced in the transfectant cells of ppGalNAc-T13 cDNA. Black-Right-Pointing-Pointer A major protein carrying trimeric Tn structure was identified as Syndecan-1. Black-Right-Pointing-Pointer Silencing of ppGalNAc-T13 resulted in the reduction of invasion and of metastasis.. -- Abstract: In order to analyze the mechanisms for cancer metastasis, high metastatic sublines (H7-A, H7-Lu, H7-O, C4-sc, and C4-ly) were obtained by repeated injection of mouse Lewis lung cancer sublines H7 and C4 into C57BL/6 mice. These sublines exhibited increased proliferation and invasion activity in vitro. Ganglioside profiles exhibited lower expression of GM1 in high metastatic sublines than the parent lines. Then, we established GM1-Si-1 and GM1-Si-2 by stable silencing of GM1 synthase in H7 cells. These GM1-knockdown clones exhibited increased proliferation and invasion. Then, we explored genes that markedly altered in the expression levels by DNA microarray in the combination of C4 vs. C4-ly or H7 vs. H7 (GM1-Si). Consequently, pp-GalNAc-T13 gene was identified as up-regulated genes in the high metastatic sublines. Stable transfection of pp-GalNAc-T13 cDNA into C4 (T13-TF) resulted in increased invasion and motility. Then, immunoblotting and flow cytometry using various antibodies and lectins were performed. Only anti-trimeric Tn antibody (mAb MLS128), showed increased expression levels of trimeric Tn antigen in T13-TF clones. Moreover, immunoprecipitation/immunoblotting was performed by mAb MLS128, leading to the identification of an 80 kDa band carrying trimeric Tn antigen, i.e. Syndecan-1. Stable silencing of endogenous pp-GalNAc-T13 in C4-sc (T13-KD) revealed that primary tumors generated by

  20. Lung and skeleton malignant tumor induction due to high let emitters

    Energy Technology Data Exchange (ETDEWEB)

    Buldakov, L.A.; Lyubchansky, E.R.; Kalmikova, Z.I.; Buhtoyarova, Z.M. [Institute of biophysics, Moscow (Russian Federation)] [and others

    1992-06-01

    Experimental studies show that malignant tumor induction is of primary importance in regard to the biological action of transuranium elements on the animal body. Clarification of quantitative relationship between these parameters for low-level radiation is aproblem to be solved by health physics. This report aims at analysis of the dose-response relationship following rat exposure to PU-239, Am-241, and NP-237 over a wide range of doses, and also at comparison between risk fact obtained experimentally and tose recommended by the ICRP. The biological effect of transuranium elements was investigated regarding malignant tumor incidence in rat bone for all the pathways of intake covered and in the lung for intakes of radionuclides into the respiratory system.

  1. High-resolution computed tomography (HRCT) of lung infections in non-AIDS immunocompromised patients

    Energy Technology Data Exchange (ETDEWEB)

    Franquet, Tomas [Universitat Autonoma de Barcelona, Department of Radiology, Thoracic Radiology Section, Hospital de Sant Pau, Barcelona (Spain)

    2006-03-15

    Non-AIDS immunocompromised patients are susceptible to infections by a wide range of organisms. In the past several decades, advances in the treatment of cancer, organ transplantation, and immunosuppressive therapy have resulted in large numbers of patients who develop abnormalities in their immune system. Moreover, mildly impaired host immunity as it occurs in chronic debilitating illness, diabetes mellitus, malnutrition, alcoholism, advanced age, prolonged corticosteroid administration, and chronic obstructive lung disease have also been regarded as predisposing factors of pulmonary infections. Imaging plays a crucial role in the detection and management of patients with pulmonary infectious diseases. When pulmonary infection is suspected, knowledge of the varied radiographic manifestations will narrow the differential diagnosis, helping to direct additional diagnostic measures and serving as an ideal tool for follow-up examinations. Combination of pattern recognition with knowledge of the clinical setting is the best approach to pulmonary infection occurring in the immunocompromised patients. (orig.)

  2. Comparative Proteomic Analysis of Proteins Involved in the Tumorigenic Process of Seminal Vesicle Carcinoma in Transgenic Mice

    Directory of Open Access Journals (Sweden)

    Wei-Chao Chang

    2010-01-01

    Full Text Available We studied the seminal vesicle secretion (SVS of transgenic mice by using one-dimensional gel electrophoresis combined with LTQ-FT ICR MS analysis to explore protein expression profiles. Using unique peptide numbers as a cut-off criterion, 79 proteins were identified with high confidence in the SVS proteome. Label-free quantitative analysis was performed by using the IDEAL_Q software program. Furthermore, western blot assays were performed to validate the expression of seminal vesicle proteins. Sulfhydryl oxidase 1, glia-derived nexin, SVS1, SVS3, and SVS6 showed overexpression in SVS during cancer development. With high sequence similarity to human semenogelin, SVS2 is the most abundance protein in SVS and is dramatically decreased during the tumorigenic process. Our results indicate that these protein candidates could serve as potential targets for monitoring seminal vesicle carcinoma. Moreover, this information can provide clues for investigating seminal vesicle secretion-containing seminal plasma for related human diseases.

  3. High pretreatment neutrophil-lymphocyte ratio predicts recurrence and poor prognosis for combined small cell lung cancer.

    Science.gov (United States)

    Shao, N; Cai, Q

    2015-10-01

    Compared to pure small cell lung cancer (SCLC), combined small cell lung cancer (C-SCLC) has its own characteristics. High neutrophil to lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have been shown to be related to poor prognosis in several types of tumors. The aim of this study was to explore the prognosis value of NLR and PLR in patients with C-SCLC. A total of 112 patients diagnosed with C-SCLC between January 2000 and March 2009 were enrolled in the study. The clinicopathological parameters, laboratory analyses, and survival time were collected and analyzed. The correlation between NLR, PLR, and clinicopathological characters was analyzed. Univariate and multivariate analyses were performed to investigate the prognostic significance of these parameters for C-SCLC. The pretreatment NLR was elevated in 37.5 % patients (NLR ≥ 4.15; n = 42; H-NLR). NLR was significantly related to disease stage (p = 0.033) and tumor recurrence (p = 0.014). The median overall survival (OS) and progression-free survival (PFS) were significantly worse in the H-NLR group (OS: 22.0 months vs 11.7 months, p = 0.001; PFS: 11.1 vs 6.0 months, p recurrence and predicts a poor long-term prognosis for C-SCLC, which should be considered in defining the prognosis with other well-known prognosticators in C-SCLC patients.

  4. Human embryonic stem cell microenvironment suppresses the tumorigenic phenotype of aggressive cancer cells.

    Science.gov (United States)

    Postovit, Lynne-Marie; Margaryan, Naira V; Seftor, Elisabeth A; Kirschmann, Dawn A; Lipavsky, Alina; Wheaton, William W; Abbott, Daniel E; Seftor, Richard E B; Hendrix, Mary J C

    2008-03-18

    Embryonic stem cells sustain a microenvironment that facilitates a balance of self-renewal and differentiation. Aggressive cancer cells, expressing a multipotent, embryonic cell-like phenotype, engage in a dynamic reciprocity with a microenvironment that promotes plasticity and tumorigenicity. However, the cancer-associated milieu lacks the appropriate regulatory mechanisms to maintain a normal cellular phenotype. Previous work from our laboratory reported that aggressive melanoma and breast carcinoma express the embryonic morphogen Nodal, which is essential for human embryonic stem cell (hESC) pluripotency. Based on the aberrant expression of this embryonic plasticity gene by tumor cells, this current study tested whether these cells could respond to regulatory cues controlling the Nodal signaling pathway, which might be sequestered within the microenvironment of hESCs, resulting in the suppression of the tumorigenic phenotype. Specifically, we discovered that metastatic tumor cells do not express the inhibitor to Nodal, Lefty, allowing them to overexpress this embryonic morphogen in an unregulated manner. However, exposure of the tumor cells to a hESC microenvironment (containing Lefty) leads to a dramatic down-regulation in their Nodal expression concomitant with a reduction in clonogenicity and tumorigenesis accompanied by an increase in apoptosis. Furthermore, this ability to suppress the tumorigenic phenotype is directly associated with the secretion of Lefty, exclusive to hESCs, because it is not detected in other stem cell types, normal cell types, or trophoblasts. The tumor-suppressive effects of the hESC microenvironment, by neutralizing the expression of Nodal in aggressive tumor cells, provide previously unexplored therapeutic modalities for cancer treatment.

  5. pp-GalNAc-T13 induces high metastatic potential of murine Lewis lung cancer by generating trimeric Tn antigen.

    Science.gov (United States)

    Matsumoto, Yasuyuki; Zhang, Qing; Akita, Kaoru; Nakada, Hiroshi; Hamamura, Kazunori; Tokuda, Noriyo; Tsuchida, Akiko; Matsubara, Takeshi; Hori, Tomoko; Okajima, Tetsuya; Furukawa, Keiko; Urano, Takeshi; Furukawa, Koichi

    2012-03-01

    In order to analyze the mechanisms for cancer metastasis, high metastatic sublines (H7-A, H7-Lu, H7-O, C4-sc, and C4-ly) were obtained by repeated injection of mouse Lewis lung cancer sublines H7 and C4 into C57BL/6 mice. These sublines exhibited increased proliferation and invasion activity in vitro. Ganglioside profiles exhibited lower expression of GM1 in high metastatic sublines than the parent lines. Then, we established GM1-Si-1 and GM1-Si-2 by stable silencing of GM1 synthase in H7 cells. These GM1-knockdown clones exhibited increased proliferation and invasion. Then, we explored genes that markedly altered in the expression levels by DNA microarray in the combination of C4 vs. C4-ly or H7 vs. H7 (GM1-Si). Consequently, pp-GalNAc-T13 gene was identified as up-regulated genes in the high metastatic sublines. Stable transfection of pp-GalNAc-T13 cDNA into C4 (T13-TF) resulted in increased invasion and motility. Then, immunoblotting and flow cytometry using various antibodies and lectins were performed. Only anti-trimeric Tn antibody (mAb MLS128), showed increased expression levels of trimeric Tn antigen in T13-TF clones. Moreover, immunoprecipitation/immunoblotting was performed by mAb MLS128, leading to the identification of an 80 kDa band carrying trimeric Tn antigen, i.e. Syndecan-1. Stable silencing of endogenous pp-GalNAc-T13 in C4-sc (T13-KD) revealed that primary tumors generated by subcutaneous injection of T13-KD clones showed lower coalescence to fascia and peritoneum, and significantly reduced lung metastasis than control clones. These data suggested that high expression of pp-GalNAc-T13 gene generated trimeric Tn antigen on Syndecan-1, leading to the enhanced metastasis.

  6. Effects of High-Intensity Swimming on Lung Inflammation and Oxidative Stress in a Murine Model of DEP-Induced Injury.

    Directory of Open Access Journals (Sweden)

    Leonardo C M Ávila

    Full Text Available Studies have reported that exposure to diesel exhaust particles (DEPs induces lung inflammation and increases oxidative stress, and both effects are susceptible to changes via regular aerobic exercise in rehabilitation programs. However, the effects of exercise on lungs exposed to DEP after the cessation of exercise are not clear. Therefore, the aim of this study was to evaluate the effects of high-intensity swimming on lung inflammation and oxidative stress in mice exposed to DEP concomitantly and after exercise cessation. Male Swiss mice were divided into 4 groups: Control (n = 12, Swimming (30 min/day (n = 8, DEP (3 mg/mL-10 μL/mouse (n = 9 and DEP+Swimming (n = 8. The high-intensity swimming was characterized by an increase in blood lactate levels greater than 1 mmoL/L between 10th and 30th minutes of exercise. Twenty-four hours after the final exposure to DEP, the anesthetized mice were euthanized, and we counted the number of total and differential inflammatory cells in the bronchoalveolar fluid (BALF, measured the lung homogenate levels of IL-1β, TNF-α, IL-6, INF-ϫ, IL-10, and IL-1ra using ELISA, and measured the levels of glutathione, non-protein thiols (GSH-t and NPSH and the antioxidant enzymes catalase and glutathione peroxidase (GPx in the lung. Swimming sessions decreased the number of total cells (p<0.001, neutrophils and lymphocytes (p<0.001; p<0.05 in the BALF, as well as lung levels of IL-1β (p = 0.002, TNF-α (p = 0.003, IL-6 (p = 0.0001 and IFN-ϫ (p = 0.0001. However, the levels of IL-10 (p = 0.01 and IL-1ra (p = 0.0002 increased in the swimming groups compared with the control groups, as did the CAT lung levels (p = 0.0001. Simultaneously, swimming resulted in an increase in the GSH-t and NPSH lung levels in the DEP group (p = 0.0001 and p<0.002. We concluded that in this experimental model, the high-intensity swimming sessions decreased the lung inflammation and oxidative stress status during DEP-induced lung

  7. miR-150 suppresses the proliferation and tumorigenicity of leukemia stem cells by targeting the Nanog signaling pathway

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    Dan-dan Xu

    2016-11-01

    Full Text Available Proliferation, a key feature of cancer cells, accounts for the majority of cancer-related diseases resulting in mortality. MicroRNAs (miRNAs plays important post-transcriptional modulation roles by acting on multiple signaling pathways, but the underlying mechanism in proliferation and tumorigenicity is unclear. Here, we identified the role of miR-150 in proliferation and tumorigenicity in leukemia stem cells (LSCs (CD34+CD38- cells. miR-150 expression was significantly down-regulated in LSCs from leukemia cell lines and clinical samples. Functional assays demonstrated that increased miR-150 expression inhibited proliferation and clonal and clonogenic growth, enhanced chemosensitivity, and attenuated tumorigenic activity of LSCs in vitro. Transplantation animal studies revealed that miR-150 overexpression progressively abrogates tumour growth. Immunohistochemistry assays demonstrated that miR-150 overexpression enhanced caspase-3 level and reduced Ki-67 level. Moreover, luciferase reporter assays indicated Nanog is a direct and functional target of miR-150. Nanog silencing using small interfering RNA recapitulated anti-proliferation and tumorigenicity inhibition effects. Furthermore, miR-150 directly down-regulated the expression of other cancer stem cell factors including Notch2 and CTNNB1. These results provide insights into the specific biological behaviour of miR-150 in regulating LSC proliferation and tumorigenicity. Targeting this miR-150/Nanog axis would be a helpful therapeutic strategy to treat acute myeloid leukemia.

  8. Cancer-Associated Fibroblasts from lung tumors maintain their immuno-suppressive abilities after high-dose irradiation

    Directory of Open Access Journals (Sweden)

    Laia eGorchs

    2015-05-01

    Full Text Available Accumulating evidence supports the notion that high-dose (>5 Gy radiotherapy (RT regimens are triggering stronger pro-immunogenic effects than standard low-dose (2 Gy regimens. However, the effects of RT on certain immunoregulatory elements in tumors remain unexplored. In this study we have investigated the effects of high-dose irradiation (HD-RT on the immunomodulating functions of cancer-associated fibroblasts (CAFs. Primary CAF cultures were established from lung cancer specimens derived from patients diagnosed for non-small cell lung cancer. Irradiated and non-irradiated CAFs were examined for immunomodulation in experiments with peripheral blood mononuclear cells from random, healthy donors. Regulation of lymphocytes behavior was checked by lymphocyte proliferation assays, lymphocyte migration assays and T-cell cytokine production. Additionally, CAF-secreted immuno-regulatory factors were studied by multiplex protein arrays, ELISAs and by LC-MS/MS proteomics. In all functional assays we observed a powerful immuno-suppressive effect exerted by CAF-conditioned medium on activated T-cells (p>0,001, and this effect was sustained after a single radiation dose of 18 Gy. Relevant immuno-suppressive molecules such as prostaglandin E2, interleukin-6 and -10, or transforming growth factor-β were found in CAF conditioned medium, but their secretion was unchanged after irradiation. Finally, immunogenic cell death responses in CAFs were studied by exploring the release of high motility group box-1 and ATP. Both alarmins remained undetectable before and after irradiation. In conclusion, CAFs play a powerful immuno-suppressive effect over activated T-cells, and this effect remains unchanged after HD-RT. Importantly, CAFs do not switch on immunogenic cell death responses after exposure to HD-RT.

  9. High expression of Y-box-binding protein 1 correlates with poor prognosis and early recurrence in patients with small invasive lung adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Zhao S

    2016-05-01

    Full Text Available Shilei Zhao,1,* Wei Guo,1,* Jinxiu Li,1 Wendan Yu,1 Tao Guo,1 Wuguo Deng,2,3 Chundong Gu1 1The First Affiliated Hospital, Institute of Cancer Stem Cell, Lung Cancer Diagnosis and Treatment Center, Dalian Medical University, Dalian, 2Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University, Guangzhou, 3State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, People’s Republic of China *These authors contributed equally to this work Background: Prognosis of small (≤2 cm invasive lung adenocarcinoma remains poor, and identification of high-risk individuals from the patients after complete surgical resection of lung adenocarcinoma has become an urgent problem. YBX1 has been reported to be able to predict prognosis in many cancers (except lung adenocarcinoma that are independent of TNM (tumor, nodes, metastases staging, especially small invasive lung adenocarcinoma. Therefore, we examined the significance of YBX1 expression on prognosis and recurrence in patients with small invasive lung adenocarcinoma. Material and methods: A total of 75 patients with small invasive lung adenocarcinoma after complete resection were enrolled from January 2008 to December 2010. Immunohistochemical staining was used to detect the expression of YBX1, and receiver operating characteristic curve analysis was performed to precisely assess the overall expression of YBX1. Meanwhile, primary lesions were identified based on the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society’s classification of lung adenocarcinoma. The effect of different clinicopathological factors on patients’ survival was examined. Furthermore, Western blot analysis was used to show the expression of YBX1 in vitro. Results: Sensitivity and specificity of YBX1 for detecting small

  10. The Effects of High Frequency Oscillatory Flow on Particles' Deposition in Upper Human Lung Airways

    Science.gov (United States)

    Bonifacio, Jeremy; Rahai, Hamid; Taherian, Shahab

    2016-11-01

    The effects of oscillatory inspiration on particles' deposition in upper airways of a human lung during inhalation/exhalation have been numerically investigated and results of flow characteristics, and particles' deposition pattern have been compared with the corresponding results without oscillation. The objective of the investigation was to develop an improved method for drug delivery for Asthma and COPD patients. Previous clinical investigations of using oral airway oscillations have shown enhanced expectoration in cystic fibrosis (CF) patients, when the frequency of oscillation was at 8 Hz with 9:1 inspiratory/expiratory (I:E) ratio. Other investigations on oscillatory ventilation had frequency range of 0.5 Hz to 2.5 Hz. In the present investigations, the frequency of oscillation was changed between 2 Hz to 10 Hz. The particles were injected at the inlet and particle velocity was equal to the inlet air velocity. One-way coupling of air and particles was assumed. Lagrangian phase model was used for transport and depositions of solid 2.5 micron diameter round particles with 1200 kg/m3 density. Preliminary results have shown enhanced PM deposition with oscillatory flow with lower frequency having a higher deposition rate Graduate Assistant.

  11. Assessment of impact of high particulate concentration on peak expiratory flow rate of lungs of sand stone quarry workers.

    Science.gov (United States)

    Singh, Suresh Kumar; Chowdhary, G R; Purohit, Gopal

    2006-12-01

    This study was designed to assess the impact of high particulate concentration on peak expiratory flow rate of lungs of sand stone quarry workers. The workers were engaged in different types of activities such as drilling, loading and dressing. These different working conditions had different concentrations of RSPM, leading to different exposure levels in workers. It was found that exposure duration and exposure concentrations were the main factors responsible for damage to the respiratory tracts of the workers. The particles were deposited at various areas of the respiratory system and reduced the peak flow rate. It was also revealed from the study that most of the workers suffered from silicosis if the exposure duration was more than 20 years.

  12. High interferon type I responses in the lung, plasma and spleen during highly pathogenic H5N1 infection of chicken

    Directory of Open Access Journals (Sweden)

    Moulin Hervé R

    2011-01-01

    Full Text Available Abstract This study shows that high pathogenic H5N1 influenza virus infection of chicken induced high levels of bioactive interferon type I in the lung (4.3 × 105 U/mg tissue, plasma (1.1 × 105 U/mL, and spleen (9.1 × 105 U/mg tissue. In contrast, a low pathogenic attenuated H5N1 vaccine strain only induced approximately 24 times less IFN in the lung, 441 times less in the spleen and 649 less in the plasma. This was in the same range as a reassortant carrying the HA from the vaccine strain and the remaining genes from the high pathogenic virus. On the other hand, a reassortant virus with the HA from the high pathogenic H5N1 with the remaining genes from the vaccine strain had intermediate levels of IFN. The level of interferon responses related to the viral load, and those in the spleen and blood to the spread of virus to lymphoid tissue, as well as disease severity. In vitro, the viruses did not induce interferon in chicken embryonic fibroblasts, but high levels in splenocytes, with not clear relationship to pathogenicity and virulence. This, and the responses also with inactivated viruses imply the presence of plasmacytoid dendritic cell-like leukocytes within the chicken immune system, possibly responsible for the high interferon responses during H5N1 infection. Our data also indicate that the viral load as well as the cleavability of the HA enabling systemic spread of the virus are two major factors controlling systemic IFN responses in chicken.

  13. NELSON lung cancer screening study

    NARCIS (Netherlands)

    Y. Zhao (Yingru); X. Xie (Xueqian); H.J. de Koning (Harry); W.P. Mali (Willem); R. Vliegenthart (Rozemarijn); M. Oudkerk (Matthijs)

    2011-01-01

    textabstractThe Dutch-Belgian Randomized Lung Cancer Screening Trial (Dutch acronym: NELSON study) was designed to investigate whether screening for lung cancer by low-dose multidetector computed tomography (CT) in high-risk subjects will lead to a decrease in 10-year lung cancer mortality of at

  14. FGFR2 promotes breast tumorigenicity through maintenance of breast tumor-initiating cells.

    Directory of Open Access Journals (Sweden)

    Sungeun Kim

    Full Text Available Emerging evidence suggests that some cancers contain a population of stem-like TICs (tumor-initiating cells and eliminating TICs may offer a new strategy to develop successful anti-cancer therapies. As molecular mechanisms underlying the maintenance of the TIC pool are poorly understood, the development of TIC-specific therapeutics remains a major challenge. We first identified and characterized TICs and non-TICs isolated from a mouse breast cancer model. TICs displayed increased tumorigenic potential, self-renewal, heterogeneous differentiation, and bipotency. Gene expression analysis and immunostaining of TICs and non-TICs revealed that FGFR2 was preferentially expressed in TICs. Loss of FGFR2 impaired self-renewal of TICs, thus resulting in marked decreases in the TIC population and tumorigenic potential. Restoration of FGFR2 rescued the defects in TIC pool maintenance, bipotency, and breast tumor growth driven by FGFR2 knockdown. In addition, pharmacological inhibition of FGFR2 kinase activity led to a decrease in the TIC population which resulted in suppression of breast tumor growth. Moreover, human breast TICs isolated from patient tumor samples were found enriched in a FGFR2+ population that was sufficient to initiate tumor growth. Our data suggest that FGFR2 is essential in sustaining the breast TIC pool through promotion of self-renewal and maintenance of bipotent TICs, and raise the possibility of FGFR2 inhibition as a strategy for anti-cancer therapy by eradicating breast TICs.

  15. Molecular Imaging of Stem Cells: Tracking Survival, Biodistribution, Tumorigenicity, and Immunogenicity

    Directory of Open Access Journals (Sweden)

    Eugene Gu, Wen-Yi Chen, Jay Gu, Paul Burridge, Joseph C. Wu

    2012-01-01

    Full Text Available Being able to self-renew and differentiate into virtually all cell types, both human embryonic stem cells (hESCs and induced pluripotent stem cells (iPSCs have exciting therapeutic implications for myocardial infarction, neurodegenerative disease, diabetes, and other disorders involving irreversible cell loss. However, stem cell biology remains incompletely understood despite significant advances in the field. Inefficient stem cell differentiation, difficulty in verifying successful delivery to the target organ, and problems with engraftment all hamper the transition from laboratory animal studies to human clinical trials. Although traditional histopathological techniques have been the primary approach for ex vivo analysis of stem cell behavior, these postmortem examinations are unable to further elucidate the underlying mechanisms in real time and in vivo. Fortunately, the advent of molecular imaging has led to unprecedented progress in understanding the fundamental behavior of stem cells, including their survival, biodistribution, immunogenicity, and tumorigenicity in the targeted tissues of interest. This review summarizes various molecular imaging technologies and how they have advanced the current understanding of stem cell survival, biodistribution, immunogenicity, and tumorigenicity.

  16. Etk/Bmx tyrosine kinase activates Pak1 and regulates tumorigenicity of breast cancer cells.

    Science.gov (United States)

    Bagheri-Yarmand, R; Mandal, M; Taludker, A H; Wang, R A; Vadlamudi, R K; Kung, H J; Kumar, R

    2001-08-03

    Etk/Bmx, a member of the Tec family of nonreceptor protein-tyrosine kinases, is characterized by an N-terminal pleckstrin homology domain and has been shown to be a downstream effector of phosphatidylinositol 3-kinase. P21-activated kinase 1 (Pak1), another well characterized effector of phosphatidylinositol 3-kinase, has been implicated in the progression of breast cancer cells. In this study, we characterized the role of Etk in mammary development and tumorigenesis and explored the functional interactions between Etk and Pak1. We report that Etk expression is developmentally regulated in the mammary gland. Using transient transfection, coimmunoprecipitation and glutathione S-transferase-pull down assays, we showed that Etk directly associates with Pak1 via its N-terminal pleckstrin homology domain and also phosphorylates Pak1 on tyrosine residues. The expression of wild-type Etk in a non-invasive human breast cancer MCF-7 cells significantly increased proliferation and anchorage-independent growth of epithelial cancer cells. Conversely, expression of kinase-inactive mutant Etk-KQ suppressed the proliferation, anchorage-independent growth, and tumorigenicity of human breast cancer MDA-MB435 cells. These results indicate that Pak1 is a target of Etk and that Etk controls the proliferation as well as the anchorage-independent and tumorigenic growth of mammary epithelial cancer cells.

  17. Human lung natural killer cells are predominantly comprised of highly differentiated hypofunctional CD69(-)CD56(dim) cells.

    Science.gov (United States)

    Marquardt, Nicole; Kekäläinen, Eliisa; Chen, Puran; Kvedaraite, Egle; Wilson, Jennifer N; Ivarsson, Martin A; Mjösberg, Jenny; Berglin, Lena; Säfholm, Jesper; Manson, Martijn L; Adner, Mikael; Al-Ameri, Mamdoh; Bergman, Per; Orre, Ann-Charlotte; Svensson, Mattias; Dahlén, Barbro; Dahlén, Sven-Erik; Ljunggren, Hans-Gustaf; Michaëlsson, Jakob

    2017-04-01

    In contrast to the extensive knowledge about human natural killer (NK) cells in peripheral blood, relatively little is known about NK cells in the human lung. Knowledge about the composition, differentiation, and function of human lung NK cells is critical to better understand their role in diseases affecting the lung, including asthma, chronic obstructive pulmonary disease, infections, and cancer. We sought to analyze and compare the phenotypic and functional characteristics of NK cells in the human lung and peripheral blood at the single-cell level. NK cells in human lung tissue and matched peripheral blood from 132 subjects were analyzed by using 16-color flow cytometry and confocal microscopy. CD56(dim)CD16(+) NK cells made up the vast majority of NK cells in human lungs, had a more differentiated phenotype, and more frequently expressed educating killer cell immunoglobulin-like receptors compared with NK cells in peripheral blood. Despite this, human lung NK cells were hyporesponsive toward target cell stimulation, even after priming with IFN-α. Furthermore, we detected a small subset of NK cells expressing CD69, a marker of tissue residency. These CD69(+) NK cells in the lung consisted predominantly of immature CD56(bright)CD16(-) NK cells and less differentiated CD56(dim)CD16(+) NK cells. Here, we characterize the major NK cell populations in the human lung. Our data suggest a model in which the majority of NK cells in the human lung dynamically move between blood and the lung rather than residing in the lung as bona fide tissue-resident CD69(+) NK cells. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  18. Single particle aerosol mass spectrometry of coal combustion particles associated with high lung cancer rates in Xuanwei and Fuyuan, China.

    Science.gov (United States)

    Lu, Senlin; Tan, Zhengying; Liu, Pinwei; Zhao, Hui; Liu, Dingyu; Yu, Shang; Cheng, Ping; Win, Myat Sandar; Hu, Jiwen; Tian, Linwei; Wu, Minghong; Yonemochi, Shinich; Wang, Qingyue

    2017-11-01

    Coal combustion particles (CCPs) are linked to the high incidence of lung cancer in Xuanwei and in Fuyuan, China, but studies on the chemical composition of the CCPs are still limited. Single particle aerosol mass spectrometry (SPAMS) was recently developed to measure the chemical composition and size of single particles in real-time. In this study, SPAMS was used to measure individual combustion particles emitted from Xuanwei and Fuyuan coal samples and the results were compared with those by ICP-MS and transmission electron microscopy (TEM). The total of 38,372 particles mass-analyzed by SPAMS can be divided into 9 groups based on their chemical composition and their number percentages: carbonaceous, Na-rich, K-rich, Al-rich, Fe-rich, Si-rich, Ca-rich, heavy metal-bearing, and PAH-bearing particles. The carbonaceous and PAH-bearing particles are enriched in the size range below 0.56 μm, Fe-bearing particles range from 0.56 to 1.0 μm in size, and heavy metals such as Ti, V, Cr, Cu, Zn, and Pb have diameters below 1 μm. The TEM results show that the particles from Xuanwei and Fuyuan coal combustion can be classified into soot aggregates, Fe-rich particles, heavy metal containing particles, and mineral particles. Non-volatile particles detected by SPAMS could also be observed with TEM. The number percentages by SPAMS also correlate with the mass concentrations measured by ICP-MS. Our results could provide valuable insight for understanding high lung cancer incidence in the area. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Lung surgery

    Science.gov (United States)

    ... Pneumonectomy; Lobectomy; Lung biopsy; Thoracoscopy; Video-assisted thoracoscopic surgery; VATS ... You will have general anesthesia before surgery. You will be asleep and unable to feel pain. Two common ways to do surgery on your lungs are thoracotomy and video- ...

  20. Clinical, pathological, and radiological characteristics of solitary ground-glass opacity lung nodules on high-resolution computed tomography

    Directory of Open Access Journals (Sweden)

    Qiu ZX

    2016-09-01

    Full Text Available Zhi-Xin Qiu,1 Yue Cheng,1 Dan Liu,1 Wei-Ya Wang,2 Xia Wu,2 Wei-Lu Wu,2 Wei-Min Li1,2 1Department of Respiratory Medicine, 2Department of Pathology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China Background: Lung nodules are being detected at an increasing rate year by year with high-resolution computed tomography (HRCT being widely used. Ground-glass opacity nodule is one of the special types of pulmonary nodules that is confirmed to be closely associated with early stage of lung cancer. Very little is known about solitary ground-glass opacity nodules (SGGNs. In this study, we analyzed the clinical, pathological, and radiological characteristics of SGGNs on HRCT.Methods: A total of 95 resected SGGNs were evaluated with HRCT scan. The clinical, pathological, and radiological characteristics of these cases were analyzed.Results: Eighty-one adenocarcinoma and 14 benign nodules were observed. The nodules included 12 (15% adenocarcinoma in situ (AIS, 14 (17% minimally invasive adenocarcinoma (MIA, and 55 (68% invasive adenocarcinoma (IA. No patients with recurrence till date have been identified. The positive expression rates of anaplastic lymphoma kinase and ROS-1 (proto-oncogene tyrosine-protein kinase ROS were only 2.5% and 8.6%, respectively. The specificity and accuracy of HRCT of invasive lung adenocarcinoma were 85.2% and 87.4%. The standard uptake values of only two patients determined by 18F-FDG positron emission tomography/computed tomography (PET/CT were above 2.5. The size, density, shape, and pleural tag of nodules were significant factors that differentiated IA from AIS and MIA. Moreover, the size, shape, margin, pleural tag, vascular cluster, bubble-like sign, and air bronchogram of nodules were significant determinants for mixed ground-glass opacity nodules (all P<0.05.Conclusion: We analyzed the clinical, pathological, and radiological characteristics of SGGNs on HRCT and found that the size, density

  1. Enrichment and Function Research of Large Cell Lung Cancer Stem Cell-like Cells

    Directory of Open Access Journals (Sweden)

    Wenke YUE

    2011-06-01

    Full Text Available Background and objective There are no universal method to recognize and screen for lung cancer stem cell markers and indicators. Commonly used methods are flow Cytometry and learning from other cancer stem cell sorting tags to sort lung cancer stem cells. But this method has low specificity screening, the workload is huge. In this study, Serum-free suspension culture was used to enrich lung cancer stem cells, and explore method for lung cancer stem cell screening. Methods Human large lung cancer cell line-L9981 was cultured in serum-free and growth factors added medium, and spheres were obtained. Then the morphological differences of sphere cells and adherent L9981 cells cultured in serum-containing mediums are observed. Cell proliferation was analyzed by Vi-cell viability analyzer; invasion ability was tested by transwell assay; and in vivo tumorigenicity of the two groups of cells was studied in nude mouse. Results Compared with adherent L9981 cells cultured in serum-containing mediums, cells cultured in serum-free medium display sphere appearance. Doubling time of adherent cells and sphere cells are (56.05±1.95 h and (33.00±1.44 h respectively; Spheroid cells had higher invasion and tumorigenicity ability, 5 times and 20 times respectively, than adherent cells. Conclusion Suspension cultured L9981 in Serum-free medium could form spheroid populations. Cells in spheres had higher ability of invasion and Tumorigenicity than adherent L9981 cells. These results indicated spheroid L9981 cells contained enriched lung cancer stem cells, and Serum-free suspension culture can be a candidate method for enriching lung cancer stem cell.

  2. Nanoquartz in Late Permian C1 coal and the high incidence of female lung cancer in the Pearl River Origin area: a retrospective cohort study

    Directory of Open Access Journals (Sweden)

    Zhou Yiping

    2008-12-01

    Full Text Available Abstract Background The Pearl River Origin area, Qujing District of Yunnan Province, has one of the highest female lung cancer mortality rates in China. Smoking was excluded as a cause of the lung cancer excess because almost all women were non-smokers. Crystalline silica embedded in the soot emissions from coal combustion was found to be associated with the lung cancer risk in a geographical correlation study. Lung cancer rates tend to be higher in places where the Late Permian C1 coal is produced. Therefore, we have hypothesized the two processes: C1 coal combustion --> nanoquartz in ambient air --> lung cancer excess in non-smoking women. Methods/Design We propose to conduct a retrospective cohort study to test the hypothesis above. We will search historical records and compile an inventory of the coal mines in operation during 1930–2009. To estimate the study subjects' retrospective exposure, we will reconstruct the historical exposure scenario by burning the coal samples, collected from operating or deserted coal mines by coal geologists, in a traditional firepit of an old house. Indoor air particulate samples will be collected for nanoquartz and polycyclic aromatic hydrocarbons (PAHs analyses. Bulk quartz content will be quantified by X-ray diffraction analysis. Size distribution of quartz will be examined by electron microscopes and by centrifugation techniques. Lifetime cumulative exposure to nanoquartz will be estimated for each subject. Using the epidemiology data, we will examine whether the use of C1 coal and the cumulative exposure to nanoquartz are associated with an elevated risk of lung cancer. Discussion The high incidence rate of lung cancer in Xuan Wei, one of the counties in the current study area, was once attributed to high indoor air concentrations of PAHs. The research results have been cited for qualitative and quantitative cancer risk assessment of PAHs by the World Health Organization and other agencies. If

  3. Sox9 regulates self-renewal and tumorigenicity by promoting symmetrical cell division of cancer stem cells in hepatocellular carcinoma.

    Science.gov (United States)

    Liu, Chungang; Liu, Limei; Chen, Xuejiao; Cheng, Jiamin; Zhang, Heng; Shen, Junjie; Shan, Juanjuan; Xu, Yanmin; Yang, Zhi; Lai, Maode; Qian, Cheng

    2016-07-01

    Hepatocellular carcinoma (HCC) is a highly aggressive liver tumor containing cancer stem cells (CSCs) that participate in tumor propagation, resistance to conventional therapy, and promotion of tumor recurrence, causing poor patient outcomes. The protein SRY (sex determining region Y)-box 9 (Sox9) is a transcription factor expressed in some solid tumors, including HCC. However, the molecular mechanisms underlying Sox9 function in liver CSCs remain unclear. Here, we show that Sox9 is highly expressed in liver CSCs and that high levels of Sox9 predict a decreased probability of survival in HCC patients. We demonstrate that Sox9 is required for maintaining proliferation, self-renewal, and tumorigenicity in liver CSCs. Overexpression of exogenous Sox9 in liver non-CSCs restored self-renewal capacity. Additionally, a reduction in the asymmetrical cell division of spheroid-cultured liver CSCs was observed when compared with differentiated cancer cells or liver CSCs with inhibited Notch signaling. Furthermore, we demonstrate that Sox9 is responsible for the asymmetrical-to-symmetrical cell division switch in liver CSCs. Sox9 also negatively regulates Numb expression, contributing to a feedback circuit that maintains Notch activity and directs symmetrical cell division. Clinical analyses revealed that the Sox9(High) Numb(Low) profile is associated with poor prognosis in human HCC patients. We demonstrate that Sox9 plays a critical role in self-renewal and tumor propagation of liver CSCs and identify the molecular mechanisms regulated by Sox9 that link tumor initiation and cell division. (Hepatology 2016;64:117-129). © 2016 by the American Association for the Study of Liver Diseases.

  4. Role of TGF-β-induced Claudin-4 expression through c-Jun signaling in non-small cell lung cancer.

    Science.gov (United States)

    Rachakonda, Girish; Vu, Trung; Jin, Lin; Samanta, Debangshu; Datta, Pran K

    2016-10-01

    Claudin-4 has been identified as an integral member of tight junctions and has been found to be upregulated in various types of cancers especially in metastatic cancers. However, the molecular mechanism of the upregulation of Claudin-4 and its role in lung tumorigenesis are unknown. The aim of the present study is to investigate the role of Claudin-4 on migration and tumorigenicity of lung cancer cells and to examine the regulatory effects of TGF-β on Claudin-4 expression. We have observed that TGF-β induces the expression of Claudin-4 dramatically in lung cell lines in a time dependent manner. TGF-β-induced Smad signaling is important for enhancing Claudin-4 mRNA level through inducing its promoter activity. Treatment with curcumin, a c-Jun inhibitor, or stable knockdown of c-Jun abrogates TGF-β-induced Claudin-4 expression suggesting an involvement of the c-Jun pathway. Notably, TGF-β-induced Claudin-4 expression through c-Jun pathway plays a role in TGF-β-mediated motility and tumorigenicity of these cells. In support of these observations, we have uncovered that Claudin-4 is upregulated in 14 of 24 (58%) lung tumors when compared with normal lung tissue. This is the first study to show how TGF-β regulates the expression of Claudin-4 through c-Jun signaling and how this pathway contributes to the migratory and tumorigenic phenotype of lung tumor cells.

  5. Diffuse lung neoplasms. Correlation between high resolution computerized tomography and anatomopathology; Neoplasias pulmonares difusas: correlacao da tomografia computadorizada de alta resolucao com a anatomopatologia

    Energy Technology Data Exchange (ETDEWEB)

    Marchiori, Edson [Universidade Federal Fluminense, Niteroi, RJ (Brazil). Dept. de Radiologia; Irion, Klaus L. [Complexo Hospitalar Santa Casa de Porto Alegre, RS (Brazil). Servico de Radiologia do Pavilhao Pereira Filho; Souza Junior, Arthur Soares [Faculdade de Medicina de Sao Jose do Rio Preto, SP (Brazil)]. E-mail: edmarchiori@zipmail.com.br

    2002-08-01

    A short comparative evaluation study between high resolution computerized tomography and anatomopathologic findings is presented. The association of these two diagnostic techniques is discussed as a factor to enhance the accuracy of diffuse lung diseases, such as carcinomatous lymphangitis, Kaposi's Sarcoma, lymphomas, hematogenic metastases, bronchiole-alveolar carcinoma and leukemia. (MAC)

  6. Effects of a high-fat diet on spontaneous metastasis of Lewis lung carcinoma in plasminogen activator inhibitor-1 deficient and wild-type mice

    Science.gov (United States)

    We investigated the effects of plasminogen activator inhibitor-1 (PAI-1) deficiency on spontaneous metastasis of Lewis lung carcinoma (LLC) in PAI-1 deficient (PAI-1-/-) and wildtype mice (C57BL/6J background) fed the AIN93G diet or that diet modified with 45% calories from fat. The high-fat diet i...

  7. Consumption of a high-fat diet abrogates inhibitory effects of methylseleninic acid on spontaneous metastasis of Lewis lung carcinoma in mice

    Science.gov (United States)

    We investigated the effect of dietary supplementation with selenium (Se) on spontaneous metastasis of Lewis lung carcinoma (LLC) in male C57BL/6 mice fed a high-fat diet. Mice were fed the AIN93G diet or that diet modified with 45% calories from fat supplemented with or without 2.5 mg Se/4029 kCal ...

  8. Monocyte chemotactic protein-1 attenuates and high-fat diet exacerbates bone loss in mice with pulmonary metastasis of Lewis lung carcinoma

    Science.gov (United States)

    Bone can be adversely affected by obesity and cancer-associated complications including wasting. The objective of this study was to determine whether a high-fat diet and a deficiency in monocyte chemotactic protein-1 (MCP-1) altered bone structural defects found in male C57BL/6 mice with Lewis lung...

  9. Dyspnoea assessed by visual analogue scale in patients with chronic obstructive lung disease during progressive and high intensity exercise.

    Science.gov (United States)

    Noseda, A; Carpiaux, J P; Schmerber, J; Yernault, J C

    1992-01-01

    BACKGROUND: A study was carried out to determine whether rating of dyspnoea by means of a visual analogue scale during a progressive exercise test is affected by the subject's awareness of the progressive nature of the protocol. METHODS: Nineteen patients with chronic obstructive lung disease (FEV1 mean (SE) 1.06 (0.07) 1) were studied. A preliminary incremental test was carried out with a work rate increasing by 10 watts every minute until the subject could no longer exercise, to determine the maximum work load (Wmax) and to anchor the upper end of the visual analogue scale. This was followed by two exercise tests performed one day apart in randomised sequence, with two different protocols. One was a 12 minute protocol that included two sudden bursts of three minute high intensity exercise, up to the subject's Wmax, each preceded by three minutes of low level exercise. The other test was a conventional three minute incremental test lasting 12 minutes. On both study days the only information given to the subject about the temporal profile of load was that a change would be made every three minutes. The relation between dyspnoea, as assessed by the visual analogue scale, and ventilation, measured during high intensity or progressive exercise, was studied. RESULTS: The mean (SE) rates of increase of dyspnoea with increasing ventilation (% of line length 1(-1) min) obtained by linear regression analysis were similar for the two tests (2.86 (0.20) for progressive exercise and 2.87 (0.25) for high intensity exercise); it was 2.59 (0.25) for the initial burst of high intensity exercise when the data on this were analysed separately. In six subjects with stable disease studied again two months later the reproducibility of the rating of dyspnoea was reasonably good for both protocols. CONCLUSION: The results suggest that in most patients with chronic obstructive lung disease the assessment of exercise induced dyspnoea by means of a visual analogue scale during a

  10. Lung function

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    2005200 The effect of body position changes on lung function, lung CT imaging and pathology in an oleic acid induced acute lung injury model. JI Xin-ping (戢新平), et al. Dept Emergency, 1st Affili Hosp, China Med Univ, Shenyang 110001. Chin J Tuberc Respir Dis, 2005;28(1) :33-36. Objective: To study the effect of body position changes on lung mechanics, oxygenation, CT images and pathology in an oleic acid-induced acute lung injury (ALl) model. Methods: The study groups con-

  11. Exposure to 9,10-phenanthrenequinone accelerates malignant progression of lung cancer cells through up-regulation of aldo-keto reductase 1B10

    Energy Technology Data Exchange (ETDEWEB)

    Matsunaga, Toshiyuki, E-mail: matsunagat@gifu-pu.ac.jp [Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196 (Japan); Morikawa, Yoshifumi; Haga, Mariko; Endo, Satoshi [Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196 (Japan); Soda, Midori; Yamamura, Keiko [Laboratory of Clinical Pharmacy, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650 (Japan); El-Kabbani, Ossama [Monash Institute of Pharmaceutical Sciences, Monash University, Victoria 3052 (Australia); Tajima, Kazuo [Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1181 (Japan); Ikari, Akira [Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196 (Japan); Hara, Akira [Faculty of Engineering, Gifu University, Gifu 501-1193 (Japan)

    2014-07-15

    Inhalation of 9,10-phenanthrenequinone (9,10-PQ), a major quinone in diesel exhaust, exerts fatal damage against a variety of cells involved in respiratory function. Here, we show that treatment with high concentrations of 9,10-PQ evokes apoptosis of lung cancer A549 cells through production of reactive oxygen species (ROS). In contrast, 9,10-PQ at its concentrations of 2 and 5 μM elevated the potentials for proliferation, invasion, metastasis and tumorigenesis, all of which were almost completely inhibited by addition of an antioxidant N-acetyl-L-cysteine, inferring a crucial role of ROS in the overgrowth and malignant progression of lung cancer cells. Comparison of mRNA expression levels of six aldo-keto reductases (AKRs) in the 9,10-PQ-treated cells advocated up-regulation of AKR1B10 as a major cause contributing to the lung cancer malignancy. In support of this, the elevation of invasive, metastatic and tumorigenic activities in the 9,10-PQ-treated cells was significantly abolished by the addition of a selective AKR1B10 inhibitor oleanolic acid. Intriguingly, zymographic and real-time PCR analyses revealed remarkable increases in secretion and expression, respectively, of matrix metalloproteinase 2 during the 9,10-PQ treatment, and suggested that the AKR1B10 up-regulation and resultant activation of mitogen-activated protein kinase cascade are predominant mechanisms underlying the metalloproteinase induction. In addition, HPLC analysis and cytochrome c reduction assay in in vitro 9,10-PQ reduction by AKR1B10 demonstrated that the enzyme catalyzes redox-cycling of this quinone, by which ROS are produced. Collectively, these results suggest that AKR1B10 is a key regulator involved in overgrowth and malignant progression of the lung cancer cells through ROS production due to 9,10-PQ redox-cycling. - Highlights: • 9,10-PQ promotes invasion, metastasis and tumorigenicity in lung cancer cells. • The 9,10-PQ-elicited promotion is possibly due to AKR1B10 up

  12. Tumorigenic lung tumorospheres exhibit stem-like features with significantly increased expression of CD133 and ABCG2

    OpenAIRE

    Zhao, Wensi; Luo, Yi; Li, Boyi; Zhang, Tao

    2016-01-01

    Accumulating evidence supports the existence of cancer stem cells (CSCs) in human tumors, and the successful certification of CSCs may lead to the identification of therapeutic targets, which are more effective for the treatment of cancer. The use of spherical cancer models has increased in popularity in cancer stem cell investigations. Tumorospheres, which are used as a model of CSCs and are established in serum-free medium supplemented with growth factors under non-adherent conditions, are ...

  13. Lung Organogenesis

    Science.gov (United States)

    Warburton, David; El-Hashash, Ahmed; Carraro, Gianni; Tiozzo, Caterina; Sala, Frederic; Rogers, Orquidea; De Langhe, Stijn; Kemp, Paul J.; Riccardi, Daniela; Torday, John; Bellusci, Saverio; Shi, Wei; Lubkin, Sharon R; Jesudason, Edwin

    2011-01-01

    Developmental lung biology is a field that has the potential for significant human impact: lung disease at the extremes of age continues to cause major morbidity and mortality worldwide. Understanding how the lung develops holds the promise that investigators can use this knowledge to aid lung repair and regeneration. In the decade since the “molecular embryology” of the lung was first comprehensively reviewed, new challenges have emerged—and it is on these that we focus the current review. Firstly, there is a critical need to understand the progenitor cell biology of the lung in order to exploit the potential of stem cells for the treatment of lung disease. Secondly, the current familiar descriptions of lung morphogenesis governed by growth and transcription factors need to be elaborated upon with the reinclusion and reconsideration of other factors, such as mechanics, in lung growth. Thirdly, efforts to parse the finer detail of lung bud signaling may need to be combined with broader consideration of overarching mechanisms that may be therapeutically easier to target: in this arena, we advance the proposal that looking at the lung in general (and branching in particular) in terms of clocks may yield unexpected benefits. PMID:20691848

  14. Lung density

    DEFF Research Database (Denmark)

    Garnett, E S; Webber, C E; Coates, G

    1977-01-01

    The density of a defined volume of the human lung can be measured in vivo by a new noninvasive technique. A beam of gamma-rays is directed at the lung and, by measuring the scattered gamma-rays, lung density is calculated. The density in the lower lobe of the right lung in normal man during quiet...... breathing in the sitting position ranged from 0.25 to 0.37 g.cm-3. Subnormal values were found in patients with emphsema. In patients with pulmonary congestion and edema, lung density values ranged from 0.33 to 0.93 g.cm-3. The lung density measurement correlated well with the findings in chest radiographs...... but the lung density values were more sensitive indices. This was particularly evident in serial observations of individual patients....

  15. Inhibitory effects of silibinin on proliferation and lung metastasis of human high metastasis cell line of salivary gland adenoid cystic carcinoma via autophagy induction

    Directory of Open Access Journals (Sweden)

    Jiang C

    2016-10-01

    Full Text Available Canhua Jiang,1 Shufang Jin,1 Zhisheng Jiang,1 Jie Wang2 1Department of Oral and Maxillofacial Surgery, Xiangya Hospital, 2Department of Immunology, Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China Objective: To investigate the possible mechanisms and effects of silibinin (SIL on the proliferation and lung metastasis of human lung high metastasis cell line of salivary gland adenoid cystic carcinoma (ACC-M.Methods: A methyl thiazolyl tetrazolium assay was performed to detect the inhibitory effects of SIL on the proliferation of ACC-M cells in vitro. Fluorescence microscopy and transmission electron microscopy were used to observe the autophagic process. Western blot was performed to detect the expression of microtube-related protein 1 light-chain 3 (LC3. An experimental adenoid cystic carcinoma (ACC lung metastasis model was established in nude mice to detect the impacts of SIL on lung weight and lung cancer nodules. Immunohistochemistry was used to detect the expressions of LC3 in human ACC samples and normal salivary gland tissue samples.Results: SIL inhibited the proliferation of ACC-M cells in a dose- and time-dependent manner, and inductively increased the autophagic bodies in ACC-M cells. Furthermore, SIL could increase the expression of LC3 in ACC-M cells and promote the conversion of LC3-I into LC3-II in a dose- and time-dependent manner. In the ACC lung metastasis model, the lung weight and left and right lung nodules in the SIL-treated group were significantly less than those in the control group (P<0.05. The expressions of LC3-I and LC3-II as well as the positive expression rate of LC3 (80% significantly increased, but the positive expression of LC3 in human ACC (42.22% reduced significantly.Conclusion: SIL could inhibit the proliferation and lung metastasis of ACC-M cells by possibly inducing tumor cells autophagy. Keywords: silibinin, adenoid cystic carcinoma, ACC-M cells, autophagy

  16. Tumorigenic potential of pituitary tumor transforming gene (PTTG in vivo investigated using a transgenic mouse model, and effects of cross breeding with p53 (+/− transgenic mice

    Directory of Open Access Journals (Sweden)

    Fong Miranda Y

    2012-11-01

    Full Text Available Abstract Background Pituitary tumor-transforming gene (PTTG is an oncogene that is overexpressed in variety of tumors and exhibits characteristics of a transforming gene. Previous transgenic mouse models to access the tumorigenic potential in the pituitary and ovary have resulted in dysplasia without formation of visible tumors, possibly due to the insufficient expression of PTTG. PTTG expression level is critical for ovarian tumorigenesis in a xenograft model. Therefore, the tumorigenic function of PTTG in vivo remains unclear. We generated a transgenic mouse that overexpresses PTTG driven by the CMV promoter to determine whether PTTG functions as a transforming oncogene that is capable of initiating tumorigenesis. Methods Transgenic animals were generated by microinjection of PTTG transgene into the male pronucleus of FVB 0.5 day old embryos. Expression levels of PTTG in tissues of transgenic animals were analyzed using an immunohistochemical analysis. H&E staining and immunohistostaining were performed to examine the type of tumor in transgenic and PTTG transgenic/p53+/- animals. Results PTTG transgenic offspring (TgPTTG were monitored for tumor development at various ages. H&E analysis was performed to identify the presence of cancer and hyperplastic conditions verified with the proliferation marker PCNA and the microvessel marker CD31. Immunohistochemistry was performed to determine transgene expression, revealing localization to the epithelium of the fallopian tube, with more generalized expression in the liver, lung, kidney, and spleen. At eight months of age, 2 out of 15 TgPTTG developed ovarian cancer, 2 out of 15 developed benign tumors, 2 out of 15 developed cervical dysplasia, and 3 out of 15 developed adenomyosis of the uterus. At ten months of age, 2 out of 10 TgPTTG developed adenocarcinoma of the ovary, 1 out of 10 developed a papillary serous adenocarcinoma, and 2 out of 10 presented with atypia of ovarian epithelial cells

  17. Scaffold-Free Coculture Spheroids of Human Colonic Adenocarcinoma Cells and Normal Colonic Fibroblasts Promote Tumorigenicity in Nude Mice

    Directory of Open Access Journals (Sweden)

    Jong-il Park

    2016-02-01

    Full Text Available The aim of this study was to form a scaffold-free coculture spheroid model of colonic adenocarcinoma cells (CACs and normal colonic fibroblasts (NCFs and to use the spheroids to investigate the role of NCFs in the tumorigenicity of CACs in nude mice. We analysed three-dimensional (3D scaffold-free coculture spheroids of CACs and NCFs. CAC Matrigel invasion assays and tumorigenicity assays in nude mice were performed to examine the effect of NCFs on CAC invasive behaviour and tumorigenicity in 3D spheroids. We investigated the expression pattern of fibroblast activation protein-α (FAP-α by immunohistochemical staining. CAC monocultures did not form densely-packed 3D spheroids, whereas cocultured CACs and NCFs formed 3D spheroids. The 3D coculture spheroids seeded on a Matrigel extracellular matrix showed higher CAC invasiveness compared to CACs alone or CACs and NCFs in suspension. 3D spheroids injected into nude mice generated more and faster-growing tumors compared to CACs alone or mixed suspensions consisting of CACs and NCFs. FAP-α was expressed in NCFs-CACs cocultures and xenograft tumors, whereas monocultures of NCFs or CACs were negative for FAP-α expression. Our findings provide evidence that the interaction between CACs and NCFs is essential for the tumorigenicity of cancer cells as well as for tumor propagation.

  18. The transcriptional regulators TAZ and YAP direct transforming growth factor β-induced tumorigenic phenotypes in breast cancer cells.

    Science.gov (United States)

    Hiemer, Samantha E; Szymaniak, Aleksander D; Varelas, Xaralabos

    2014-05-09

    Uncontrolled transforming growth factor-β (TGFβ) signaling promotes aggressive metastatic properties in late-stage breast cancers. However, how TGFβ-mediated cues are directed to induce tumorigenic events is poorly understood, particularly given that TGFβ has clear tumor suppressing activity in other contexts. Here, we demonstrate that the transcriptional regulators TAZ and YAP (TAZ/YAP), key effectors of the Hippo pathway, are necessary to promote and maintain TGFβ-induced tumorigenic phenotypes in breast cancer cells. Interactions between TAZ/YAP, TGFβ-activated SMAD2/3, and TEAD transcription factors reveal convergent roles for these factors in the nucleus. Genome-wide expression analyses indicate that TAZ/YAP, TEADs, and TGFβ-induced signals coordinate a specific pro-tumorigenic transcriptional program. Importantly, genes cooperatively regulated by TAZ/YAP, TEAD, and TGFβ, such as the novel targets NEGR1 and UCA1, are necessary for maintaining tumorigenic activity in metastatic breast cancer cells. Nuclear TAZ/YAP also cooperate with TGFβ signaling to promote phenotypic and transcriptional changes in nontumorigenic cells to overcome TGFβ-repressive effects. Our work thus identifies cross-talk between nuclear TAZ/YAP and TGFβ signaling in breast cancer cells, revealing novel insight into late-stage disease-driving mechanisms.

  19. Silencing of Kv4.1 potassium channels inhibits cell proliferation of tumorigenic human mammary epithelial cells

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    Jang, Soo Hwa [Laboratories of Veterinary Pharmacology, College of Veterinary Medicine, Seoul National University, San 56-1 Sillim-Dong Kwanak-Gu, Seoul 151-742 (Korea, Republic of); Choi, Changsun [Department of Food and Nutrition, College of Human Ecology, Chung-Ang University, Anseong, Gyeonggi (Korea, Republic of); Hong, Seong-Geun; Yarishkin, Oleg V. [Department of Physiology, College of Medicine, Gyeongsang National University, Jinju (Korea, Republic of); Bae, Young Min; Kim, Jae Gon [Department of Physiology, College of Medicine, Konkuk University, Seoul (Korea, Republic of); O' Grady, Scott M. [Department of Physiology, 495 Animal Science/Veterinary Medicine Bldg., St. Paul, University of Minnesota, MN (United States); Yoon, Kyong-Ah [Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi (Korea, Republic of); Kang, Kyung-Sun [Veterinary Public Health, College of Veterinary Medicine, Seoul National University, San 56-1 Sillim-Dong Kwanak-Gu, Seoul (Korea, Republic of); Ryu, Pan Dong [Laboratories of Veterinary Pharmacology, College of Veterinary Medicine, Seoul National University, San 56-1 Sillim-Dong Kwanak-Gu, Seoul 151-742 (Korea, Republic of); Lee, So Yeong, E-mail: leeso@snu.ac.kr [Laboratories of Veterinary Pharmacology, College of Veterinary Medicine, Seoul National University, San 56-1 Sillim-Dong Kwanak-Gu, Seoul 151-742 (Korea, Republic of)

    2009-06-26

    Potassium channel activity has been shown to facilitate cell proliferation in cancer cells. In the present study, the role of Kv4.1 channels in immortal and tumorigenic human mammary epithelial cells was investigated. Kv4.1 protein expression was positively correlated with tumorigenicity. Moreover, transfection with siRNAs targeting Kv4.1 mRNA suppressed proliferation of tumorigenic mammary epithelial cells. Experiments using mRNA isolated from human breast cancer tissues revealed that the level of Kv4.1 mRNA expression varied depending on the stage of the tumor. Kv4.1 protein expression increased during stages T2 and T3 compared to normal tissue. These results demonstrated that Kv4.1 plays a role in proliferation of tumorigenic human mammary epithelial cells. In addition, elevated Kv4.1 expression may be useful as a diagnostic marker for staging mammary tumors and selective blockers of Kv4.1 may serve to suppress tumor cell proliferation.

  20. Side population rather than CD133+ cells distinguishes enriched tumorigenicity in hTERT-immortalized primary prostate cancer cells

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    Wolcott Karen

    2011-09-01

    Full Text Available Abstract Background Subpopulations of cancer cells with the capacity of generating solid tumors have been characterized. In various cancer types, including prostate cancer cells, a side population (SP and CD133-expressing cells have been proposed as containing a population cancer cells with stem-like ability. Therefore the aim of this work was to determine, in prostate cancer cell lines, the frequency and tumorigenic potential of SP and CD133+ cells. Results In vitro 2D colony-forming assay and sphere-forming assay, Flow cytometry analysis and magnetic cell sorting were utilized to sort CD133+, CD133- and Side population (SP cells. Our findings indicate that CD44 and integrin α-6 are uniformly expressed in the hTERT cell lines; however, CD133 is expressed only in a small population (in vitro and in vivo. Additionally, for the hTERT cells, SP rather than CD133 expression showed an 8-fold enhanced tumorigenic potential. The data suggest that SP cells, rather than those with CD133 marker, contain the rare population of CSC capable of producing prostate tumors. Conclusion Collectively, our data suggest that although CD133 is expressed only in a small population of hTERT-immortalized prostate cancer cells, it is not likely to be associated with stem cells, as CD133- and CD133+ cells exhibited similar tumorigenicity. However, SP isolated cells, appear to be enriched with tumorigenic stem-like cells capable of generating palpable tumors.

  1. Cytogenetic Evolution of Human Ovarian Cell Lines Associated with Chemoresistance and Loss of Tumorigenicity

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    Stéphanie Struski

    2003-01-01

    Full Text Available In order to identify genomic changes associated with a resistant phenotype acquisition, we used comparative genomic hybridization (CGH to compare a human ovarian cell line, Igrov1, and four derived subcell lines, resistant to vincristine and presenting a reversion of malignant properties. Multicolor FISH (Multiplex‐FISH and Spectral Karyotype and conventional FISH are also used to elucidate the karyotype of parental cell line. The drug‐resistant subcell lines displayed many chromosomal abnormalities suggesting the implication of different pathways leading to a multidrug resistance phenotype. However, these cell lines shared two common rearrangements: an unbalanced translocation der(8t(8;13(p22;q? and a deletion of the 11p. These chromosomal imbalances could reflected the acquisition of the chemoresistance (der(8 or the loss of tumorigenicity properties (del(11p. Colour figure can be viewed on http://www.esacp.org/acp/2003/25‐3/struski.htm.

  2. Differentiation and tumorigenicity of neural stem cells from human cord blood mesenchymal stem cells

    Institute of Scientific and Technical Information of China (English)

    Jing Xiang; Changming Wang; Jingzhou Wang

    2009-01-01

    BACKGROUND:Mesenchymal stem cells (MSCs) are capable of differentiating into a variety of tissues and exhibit low immunogenicity.OBJECTIVE:To investigate isolation and in vitro cultivation methods of human cord blood MSCs,to observe expression of neural stem cell (NSC) marker mRNA under induction,and to detect tumorigenicity in animals.DESIGN,TIME AND SETTING:A cell biological,in vitro trial and a randomized,controlled,in vivo experiment were performed at the Department of Neurology,Daping Hospital at the Third Military Medical University of Chinese PLA from August 2006 to May 2008.MATERIALS:Umbilical cord blood was collected from full-term-delivery fetus at the Department of Gynecology and Obstetrics of DapJng Hospital,China.Eighteen BALB/C nu/nu nude mice were randomly assigned to three groups:back subcutaneous,cervical subcutaneous,and control,with 6 mice in each group.METHODS:Monocytes were isolated from heparinized human cord blood samples by density gradient centrifugation and then adherent cultivated in vitro to obtain MSC clones.After the cord blood MSCs were cultured for 7 days with nerve growth factor and retinoic acid to induce differentiation into NSCs,the cells (adjusted density of 1×10~7/mL) were prepared into cell suspension.In the back subcutaneous and cervical subcutaneous groups,nude mice were hypodermically injected with a 0.5-mL cell suspension into the back and cervical regions,respectively.In the control group,nude mice received a subcutaneous injection of 0.5 mL physiological saline into the back or cervical regions,respectively.MAIN OUTCOME MEASURES:Cellular morphology was observed by inverted microscopy,cultured cord blood MSCs were examined by flow cytometry,expression of nestin and musashi-1 mRNA was detected by reverse-transcriptase polymerase chain reaction prior to and after induction,and tumorigenicity following cord blood MSC transplantation was assayed by hematoxylin-eosin staining.RESULTS:Following adherent cultivation

  3. Severe lung contusion and death after high-velocity behind-armor blunt trauma: relation to protection level.

    Science.gov (United States)

    Gryth, Dan; Rocksén, David; Persson, Jonas K E; Arborelius, Ulf P; Drobin, Dan; Bursell, Jenny; Olsson, Lars-Gunnar; Kjellström, Thomas B

    2007-10-01

    The most-used safety recommendation for protective vests is that the impact should not cause more than a 44-mm impression in plasticine. The aim of this study was to investigate whether this criterion was sufficient if the vest was exposed to a high-velocity projectile. We tested the hypothesis with pigs divided into a 40-mm group (n = 10) and a 34-mm group (n = 8) protected by a vest allowing a 40-mm or 34-mm impression in plasticine, respectively. Five (50%) of 10 animals in the 40-mm group and 2 (25%) of 8 in the 34-mm group died due to the trauma. We observed severe lung hematoma, impaired circulation, desaturation, and electroencephalogram changes. These effects were more aggravated in the 40-mm group compared to the 34-mm group. Based on our results, the overall judgment is that the safety criterion of 44-mm impression is insufficient when a vest is exposed to a high-velocity projectile.

  4. 99mTc-MIBI Lung Scintigraphy in the Assessment of Pulmonary Involvement in Interstitial Lung Disease and Its Comparison With Pulmonary Function Tests and High-Resolution Computed Tomography: A Preliminary Study.

    Science.gov (United States)

    Bahtouee, Mehrzad; Saberifard, Jamshid; Javadi, Hamid; Nabipour, Iraj; Raeisi, Alireza; Assadi, Majid; Eftekhari, Mohammad

    2015-11-01

    The differentiation of active inflammatory processes from an inactive form of the disease is of great value in the management of interstitial lung disease (ILD). The aim of this investigation was to assess the efficacy of 99mTc-methoxy-isobutyl-isonitrile (99mTc-MIBI) scans in distinguishing the severity of the disease compared to radiological and clinical parameters.In total, 19 known cases of ILD were included in this study and were followed up for 1 year. Five patients without lung disease were considered as the control group. The patients underwent pulmonary function tests (PFTs) and high-resolution computed tomography scans, followed by 99mTc-MIBI scanning. The 99mTc-MIBI scans were analyzed either qualitatively (subjectively) or semiquantitatively.All 19 ILD patients demonstrated a strong increase in 99mTc-MIBI uptake in the lungs compared to the control group. The 99mTc-MIBI scan scores were higher in the patient group in both the early phase (0.24[0.19-0.31] vs 0.11[0.10-0.15], P 0.14). The 99mTc-MIBI scan scores were not significantly correlated with the PFT findings (P > 0.05). In total, 5 patients died and 14 patients were still alive over the 1-year follow-up period. There was also a significant difference between the uptake intensity of 99mTc-MIBI and the outcome in the early phase (dead: 0.32[0.29-0.43] vs alive: 0.21[0.18-0.24], P pulmonary involvement in early views, which were well correlated with HRCT findings. These results also revealed that 99mTc-MIBI lung scans might be used as a complement to other diagnostic and clinical examinations in terms of functional information in ILD; however, further investigations are strongly required.

  5. Open lung biopsy

    Science.gov (United States)

    ... CT scan Disseminated tuberculosis Granulomatosis with polyangiitis Lung cancer - small cell Lung disease Lung needle biopsy Malignant mesothelioma Pulmonary tuberculosis Rheumatoid lung disease Sarcoidosis Simple pulmonary eosinophilia ...

  6. Tumorigenic risk of human induced pluripotent stem cell explants cultured on mouse SNL76/7 feeder cells

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    Kamada, Mizuna; Mitsui, Youji, E-mail: y-mitsui8310@hb.tp1.jp; Kumazaki, Tsutomu; Kawahara, Yuta; Matsuo, Taira; Takahashi, Tomoko, E-mail: t-takahashi@kph.bunri-u.ac.jp

    2014-10-24

    Highlights: • hiPS cell explants formed malignant tumors when SNL76/7 feeder cells were used. • Multi type tumors developed by interaction of SNL76/7 feeder cells with hiPS cells. • Tumorigenic risk occurs by co-culture of hiPS cells with SNL76/7 feeder cells. - Abstract: The potential for tumor formation from transplanted human induced pluripotent stem cell (hiPSC) derivatives represents a high risk in their application to regenerative medicine. We examined the genetic origin and characteristics of tumors, that were formed when 13 hiPSC lines, established by ourselves, and 201B7 hiPSC from Kyoto University were transplanted into severe combined immune-deficient (SCID) mice. Though teratomas formed in 58% of mice, five angiosarcomas, one malignant solitary fibrous tumor and one undifferentiated pleomorphic sarcoma formed in the remaining mice. Three malignant cell lines were established from the tumors, which were derived from mitomycin C (MMC)-treated SNL76/7 (MMC-SNL) feeder cells, as tumor development from fusion cells between MMC-SNL and hiPSCs was negative by genetic analysis. While parent SNL76/7 cells produced malignant tumors, neither MMC-SNL nor MMC-treated mouse embryo fibroblast (MEF) produced malignant tumors. When MMC-SNL feeder cells were co-cultured with hiPSCs, growing cell lines were generated, that expressed genes similar to the parent SNL76/7 cells. Thus, hiPSCs grown on MMC-SNL feeder cells have a high risk of generating feeder-derived malignant tumors. The possible mechanism(s) of growth restoration and the formation of multiple tumor types are discussed with respect of the interactions between MMC-SNL and hiPSC.

  7. Tumorigenicity of IL-1α– and IL-1β–Deficient Fibrosarcoma Cells

    Directory of Open Access Journals (Sweden)

    Irina Nazarenko

    2008-06-01

    Full Text Available Analyzing the growth of fibrosarcoma lines derived from IL-1α–, IL-1β–, or IL-1αβ–knockout (−/− mice in the immunocompetent host revealed that tumor-derived IL-1α and IL-1β exert strong and opposing effects on immune response induction, which prohibited the evaluation of a potential impact on tumorigenicity. Therefore, in vivo growth of IL-1–deficient tumor lines was evaluated in nu/nu mice and was compared with in vitro growth characteristics. All IL-1–deficient fibrosarcoma lines grow in immunocompromised mice. However, IL-1α−/−β–competent (comp lines grow more aggressively, efficiently induce angiogenesis, and recruit inflammatory cells. Despite stronger tumorigenicity of IL-1βcomp lines, IL-1α strengthens anchorage-independent growth, but both IL-1α and IL-1β support drug resistance. Corresponding to the aggressive growth, IL-1βcomp cells display increased matrix adhesion, motility, and cable formation on matrigel, likely supported by elevated αv/β3 and matrix metalloproteinase expression. Recruitment of myeloid cells requires IL-1β but is regulated by IL-1α, because inflammatory chemokine and cytokine expression is stronger in IL-1α−/−βcomp than in IL-1wt lines. This regulatory effect of tumorderived IL-1α is restricted to the tumor environment and does not affect systemic inflammatory response induction by tumor-derived IL-1β. Both sarcoma cell–derived IL-1α and IL-1β promote tumor growth. However, IL-1α exerts regulatory activity on the tumor cell–matrix cross-talk, and only IL-1β initiates systemic inflammation.

  8. Pro-Tumorigenic Phosphorylation of p120 Catenin in Renal and Breast Cancer.

    Directory of Open Access Journals (Sweden)

    Antonis Kourtidis

    Full Text Available Altered protein expression and phosphorylation are common events during malignant transformation. These perturbations have been widely explored in the context of E-cadherin cell-cell adhesion complexes, which are central in the maintenance of the normal epithelial phenotype. A major component of these complexes is p120 catenin (p120, which binds and stabilizes E-cadherin to promote its adhesive and tumor suppressing function. However, p120 is also an essential mediator of pro-tumorigenic signals driven by oncogenes, such as Src, and can be phosphorylated at multiple sites. Although alterations in p120 expression have been extensively studied by immunohistochemistry (IHC in the context of tumor progression, little is known about the status and role of p120 phosphorylation in cancer. Here we show that tyrosine and threonine phosphorylation of p120 in two sites, Y228 and T916, is elevated in renal and breast tumor tissue samples. We also show that tyrosine phosphorylation of p120 at its N-terminus, including at the Y228 site is required for its pro-tumorigenic potential. In contrast, phosphorylation of p120 at T916 does not affect this p120 function. However, phosphorylation of p120 at T916 interferes with epitope recognition of the most commonly used p120 antibody, namely pp120. As a result, this antibody selectively underrepresents p120 levels in tumor tissues, where p120 is phosphorylated. Overall, our data support a role of p120 phosphorylation as a marker and mediator of tumor transformation. Importantly, they also argue that the level and localization of p120 in human cancer tissues immunostained with pp120 needs to be re-evaluated.

  9. High-Frequency Oscillatory Ventilation in Pediatric Acute Lung Injury: A Multicenter International Experience.

    Science.gov (United States)

    Rettig, Jordan S; Smallwood, Craig D; Walsh, Brian K; Rimensberger, Peter C; Bachman, Thomas E; Bollen, Casper W; Duval, Els L; Gebistorf, Fabienne; Markhorst, Dick G; Tinnevelt, Marcel; Todd, Mark; Zurakowski, David; Arnold, John H

    2015-12-01

    We aim to describe current clinical practice, the past decade of experience and factors related to improved outcomes for pediatric patients receiving high-frequency oscillatory ventilation. We have also modeled predictive factors that could help stratify mortality risk and guide future high-frequency oscillatory ventilation practice. Multicenter retrospective, observational questionnaire study. Seven PICUs. Demographic, disease factor, and ventilatory and outcome data were collected, and 328 patients from 2009 to 2010 were included in this analysis. None. Patients were classified into six cohorts based on underlying diagnosis. We used univariate analysis to identify factors associated with mortality risk and multivariate logistic regression to identify independent predictors of mortality risk. An oxygenation index greater than 35 and immunocompromise exhibited the greatest predictive power (p highly dependent on primary underlying condition. A trend toward an increase in oscillator amplitude and frequency was observed when compared with historical data. Given the number of centers and subjects included in the database, these findings provide a robust description of current practice regarding the use of high-frequency oscillatory ventilation for pediatric hypoxic respiratory failure. Patients with severe hypoxic respiratory failure and immunocompromise had the highest mortality risk, and those with respiratory syncytial virus had the lowest. A means of identifying the risk of 30-day mortality for subjects can be obtained by identifying the underlying disease and oxygenation index on conventional ventilation preceding the initiation of high-frequency oscillatory ventilation.

  10. Bazex Syndrome in Lung Squamous Cell Carcinoma: High Expression of Epidermal Growth Factor Receptor in Lesional Keratinocytes with Th2 Immune Shift

    Science.gov (United States)

    Amano, Maki; Hanafusa, Takaaki; Chikazawa, Sakiko; Ueno, Makiko; Namiki, Takeshi; Igawa, Ken; Miura, Keiko; Yokozeki, Hiroo

    2016-01-01

    An 82-year-old Japanese man was referred for detailed examination of hyperkeratotic erythematous plaques on his palms and soles for 6 months. Two weeks before his first visit, he had undergone lung lobectomy for right lung squamous cell carcinoma (SCC). Laboratory findings showed elevations of eosinophil counts, serum IgE, thymus and activation-regulated chemokine, SCC antigen, and soluble interleukin-2 receptor levels. Histological results of a skin biopsy involving the left palm showed psoriasiform dermatitis. Before lung lobectomy, the hyperkeratotic erythematous plaques on the palms and soles and the erythemas on the trunk and extremities were difficult to treat with topical steroids. After lobectomy, the skin symptoms dramatically and rapidly subsided with topical steroids. Therefore, we diagnosed Bazex syndrome (BS), also known as acrokeratosis paraneoplastica, as a paraneoplastic cutaneous disease in lung SCC. The mild eosinophilia subsided and levels of SCC antigen, IgE, and soluble interleukin-2 receptor were reduced. BS is a paraneoplastic cutaneous disease characterized by acral psoriasiform lesions associated with an underlying neoplasm. In a previous report, a shift to the Th2 immune condition was found in patients with non-small cell lung cancer, as shown in our patient. Epidermal growth factor receptor (EGFR) is also known as tumor growth factor-α receptor; it is increased in psoriatic keratinocytes. In our case, EGFR expression increased in lesional keratinocytes 2 weeks after surgery and decreased 4 weeks after surgery. We speculate that a shift to Th2 immune reactions in lung SCC may be the pathogenesis of BS, whereby lesional keratinocytes highly express EGFR in parallel with disease activity. PMID:28101024

  11. Sensitive Tumorigenic Potential Evaluation of Adult Human Multipotent Neural Cells Immortalized by hTERT Gene Transduction.

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    Kee Hang Lee

    Full Text Available Stem cells and therapeutic genes are emerging as a new therapeutic approach to treat various neurodegenerative diseases with few effective treatment options. However, potential formation of tumors by stem cells has hampered their clinical application. Moreover, adequate preclinical platforms to precisely test tumorigenic potential of stem cells are controversial. In this study, we compared the sensitivity of various animal models for in vivo stem cell tumorigenicity testing to identify the most sensitive platform. Then, tumorigenic potential of adult human multipotent neural cells (ahMNCs immortalized by the human telomerase reverse transcriptase (hTERT gene was examined as a stem cell model with therapeutic genes. When human glioblastoma (GBM cells were injected into adult (4-6-week-old Balb/c-nu, adult NOD/SCID, adult NOG, or neonate (1-2-week-old NOG mice, the neonate NOG mice showed significantly faster tumorigenesis than that of the other groups regardless of intracranial or subcutaneous injection route. Two kinds of ahMNCs (682TL and 779TL were primary cultured from surgical samples of patients with temporal lobe epilepsy. Although the ahMNCs were immortalized by lentiviral hTERT gene delivery (hTERT-682TL and hTERT-779TL, they did not form any detectable masses, even in the most sensitive neonate NOG mouse platform. Moreover, the hTERT-ahMNCs had no gross chromosomal abnormalities on a karyotype analysis. Taken together, our data suggest that neonate NOG mice could be a sensitive animal platform to test tumorigenic potential of stem cell therapeutics and that ahMNCs could be a genetically stable stem cell source with little tumorigenic activity to develop regenerative treatments for neurodegenerative diseases.

  12. High-Frequency Oscillatory Ventilation in Pediatric Acute Lung Injury : A Multicenter International Experience

    NARCIS (Netherlands)

    Rettig, Jordan S; Smallwood, Craig D; Walsh, Brian K; Rimensberger, Peter C; Bachman, Thomas E; Bollen, Casper W.; Duval, Els L; Gebistorf, Fabienne; Markhorst, Dick G; Tinnevelt, Marcel; Todd, Mark; Zurakowski, David; Arnold, John H

    2015-01-01

    OBJECTIVE: We aim to describe current clinical practice, the past decade of experience and factors related to improved outcomes for pediatric patients receiving high-frequency oscillatory ventilation. We have also modeled predictive factors that could help stratify mortality risk and guide future hi

  13. High-Frequency Oscillatory Ventilation in Pediatric Acute Lung Injury : A Multicenter International Experience

    NARCIS (Netherlands)

    Rettig, Jordan S; Smallwood, Craig D; Walsh, Brian K; Rimensberger, Peter C; Bachman, Thomas E; Bollen, Casper W.|info:eu-repo/dai/nl/304813362; Duval, Els L; Gebistorf, Fabienne; Markhorst, Dick G; Tinnevelt, Marcel; Todd, Mark; Zurakowski, David; Arnold, John H

    2015-01-01

    OBJECTIVE: We aim to describe current clinical practice, the past decade of experience and factors related to improved outcomes for pediatric patients receiving high-frequency oscillatory ventilation. We have also modeled predictive factors that could help stratify mortality risk and guide future hi

  14. Involvement of highly sulfated chondroitin sulfate in the metastasis of the Lewis lung carcinoma cells.

    NARCIS (Netherlands)

    Li, F.; Dam, G.B. ten; Murugan, S.; Yamada, S.; Hashiguchi, T.; Mizumoto, S.; Oguri, K.; Okayama, M.; Kuppevelt, A.H.M.S.M. van; Sugahara, K.

    2008-01-01

    The altered expression of cell surface chondroitin sulfate (CS) and dermatan sulfate (DS) in cancer cells has been demonstrated to play a key role in malignant transformation and tumor metastasis. However, the functional highly sulfated structures in CS/DS chains and their involvement in the process

  15. High-Frequency Oscillatory Ventilation in Pediatric Acute Lung Injury : A Multicenter International Experience

    NARCIS (Netherlands)

    Rettig, Jordan S; Smallwood, Craig D; Walsh, Brian K; Rimensberger, Peter C; Bachman, Thomas E; Bollen, Casper W.; Duval, Els L; Gebistorf, Fabienne; Markhorst, Dick G; Tinnevelt, Marcel; Todd, Mark; Zurakowski, David; Arnold, John H

    2015-01-01

    OBJECTIVE: We aim to describe current clinical practice, the past decade of experience and factors related to improved outcomes for pediatric patients receiving high-frequency oscillatory ventilation. We have also modeled predictive factors that could help stratify mortality risk and guide future

  16. CYP1A1 gene polymorphisms increase lung cancer risk in a high-incidence region of Spain: a case control study

    Directory of Open Access Journals (Sweden)

    San Jose Carmen

    2010-08-01

    Full Text Available Abstract Background A rural region in south-west Spain has one of the highest lung cancer incidence rates of the country, as revealed by a previous epidemiological 10-year follow-up study. The present work was undertaken to ascertain the role of CYP1A1 gene polymorphisms and their interaction with tobacco smoking in the development of the disease in this location. Methods One-hundred-and-three cases of lung cancer and 265 controls participated in the study. The participants were screened for the presence of four CYP1A1 polymorphisms, namely MspI, Ile462Val, T3205C, and Thr461Asn. Lung cancer risk was estimated as odds ratios (OR and 95% confidence intervals (CI using unconditional logistic regression models adjusting for age, sex, and smoking. Results The distribution of the variant CYP1A1 alleles was different from that described for other Caucasian populations, with CYP1A1*2A showing an uncommonly high frequency (p CYP1A1*2B allele (carrying MspI and Ile462Val mutations was strongly associated with high lung cancer risk (OR = 4.59, CI:1.4-12.6, p p p = 0.04. Moreover, the Thr461Asn polymorphism was found to be associated with SCLC in a Caucasian population for the first time to our knowledge (OR = 8.33, CI: 1.3-15.2, p = 0.04. Conclusion The results suggest that CYP1A1 polymorphisms contribute to increase lung cancer susceptibility in an area with an uncommon high incidence rate.

  17. Acute respiratory distress syndrome and lung fibrosis after ingestion of a high dose of ortho-phenylphenol.

    Science.gov (United States)

    Cheng, Shih-Lung; Wang, Hao-Chien; Yang, Pan-Chyr

    2005-08-01

    Ortho-phenylphenol (OPP) and its sodium salt are used as fungicides and antibacterial agents, ingestion of which has been found to cause liver toxicity, renal toxicity and carcinomas in the urinary tract of rats. Lung damage due to OPP ingestion has not been reported in humans. We report a suicidal 39-year-old woman with stage II cervical cancer who drank a potentially lethal dose of OPP in the form of a commercial antiseptic, which led to the complication of liver and renal function impairment, severe lung damage with acute respiratory distress syndrome and subsequent severe lung fibrosis. Open lung biopsy showed diffuse alveolar damage. She was discharged after 34 days of hospitalization with continuing domiciliary oxygen therapy.

  18. MRGD, a MAS-related G-protein coupled receptor, promotes tumorigenisis and is highly expressed in lung cancer.

    Directory of Open Access Journals (Sweden)

    Satoko Nishimura

    Full Text Available To elucidate the function of MAS-related GPCR, member D (MRGD in cancers, we investigated the in vitro and in vivo oncogenic function of MRGD using murine fibroblast cell line NIH3T3 in which MRGD is stably expressed. The expression pattern of MRGD in clinical samples was also analyzed. We found that overexpression of MRGD in NIH3T3 induced focus formation and multi-cellular spheroid formation, and promoted tumors in nude mice. In other words, overexpression of MRGD in NIH3T3 induced the loss of contact inhibition, anchorage-independent growth and in vivo tumorigenesis. Furthermore, it was found that the ligand of MRGD, beta-alanine, enhanced spheroid formation in MRGD-expressing NIH3T3 cells. From investigation of clinical cancer tissues, we found high expression of MRGD in several lung cancers by immunohistochemistry as well as real time PCR. Based on these results, MRGD could be involved in tumorigenesis and could also be a novel anticancer drug target.

  19. Progressing features of atypical mycobacterial infection in the lung on conventional and high resolution CT (HRCT) images

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    Tanaka, Daizo; Niwatsukino, Hiroshi; Nakajo, Masayuki [Kagoshima Univ. (Japan). Faculty of Medicine; Oyama, Takao

    2001-10-01

    The aim of this study was to clarify the localization of abnormalities within secondary pulmonary lobules and the changes in follow-up studies of pulmonary atypical mycobacterial infection (AMI) by conventional and high-resolution computed tomography (HRCT). Forty-six patients (16 men and 30 women; 43-84 years) with pulmonary AMI (M. intracellulare 36; M. avium 10) in the lung were examined by conventional and HRCT. In peripheral zones, all patients had the nodule located in the terminal or lobular bronchiole, and most of the patients also had nodules accompanied with a wedge-shaped or linear shadow connected with the pleura. In the follow-up scans, new centrilobular nodules appeared in other segments, and consolidation or ground-glass pattern appeared newly and was preceded by nodules. Bronchiectasis became more severe in five of 38 follow-up patients. The common HRCT findings of AMI were centrilobular, peribronchovascular nodules, bronchiectasis, consolidation, and pleural thickening/adhesion. The nodules frequently connected with the pleura. The initial and follow-up studies suggest that the disease may begin in the terminal bronchiole or as preexisting bronchiectasis and spread transbronchially along the draining bronchus or towards the pleura to produce lesions such as new nodules, cavities, consolidation, pleuritis, and bronchiectasis, or more severe bronchiectasis. (author)

  20. 99mTc-MIBI Lung Scintigraphy in the Assessment of Pulmonary Involvement in Interstitial Lung Disease and Its Comparison With Pulmonary Function Tests and High-Resolution Computed Tomography

    Science.gov (United States)

    Bahtouee, Mehrzad; Saberifard, Jamshid; Javadi, Hamid; Nabipour, Iraj; Raeisi, Alireza; Assadi, Majid; Eftekhari, Mohammad

    2015-01-01

    Abstract The differentiation of active inflammatory processes from an inactive form of the disease is of great value in the management of interstitial lung disease (ILD). The aim of this investigation was to assess the efficacy of 99mTc-methoxy-isobutyl-isonitrile (99mTc-MIBI) scans in distinguishing the severity of the disease compared to radiological and clinical parameters. In total, 19 known cases of ILD were included in this study and were followed up for 1 year. Five patients without lung disease were considered as the control group. The patients underwent pulmonary function tests (PFTs) and high-resolution computed tomography scans, followed by 99mTc-MIBI scanning. The 99mTc-MIBI scans were analyzed either qualitatively (subjectively) or semiquantitatively. All 19 ILD patients demonstrated a strong increase in 99mTc-MIBI uptake in the lungs compared to the control group. The 99mTc-MIBI scan scores were higher in the patient group in both the early phase (0.24[0.19–0.31] vs 0.11[0.10–0.15], P  0.14). The 99mTc-MIBI scan scores were not significantly correlated with the PFT findings (P > 0.05). In total, 5 patients died and 14 patients were still alive over the 1-year follow-up period. There was also a significant difference between the uptake intensity of 99mTc-MIBI and the outcome in the early phase (dead: 0.32[0.29–0.43] vs alive: 0.21[0.18–0.24], P lung scans might distinguish the severity of pulmonary involvement in early views, which were well correlated with HRCT findings. These results also revealed that 99mTc-MIBI lung scans might be used as a complement to other diagnostic and clinical examinations in terms of functional information in ILD; however, further investigations are strongly required. PMID:26632717

  1. Ex-vivo ultra-high-resolution optical coherence tomography imaging of fine lung structure by use of a high-power Gaussian-like supercontinuum at 0.8-μm wavelength

    Science.gov (United States)

    Nishizawa, N.; Ishida, S.; Ohta, T.; Itoh, K.; Kitatsuji, M.; Ohshima, H.; Hasegawa, Y.; Matsushima, M.; Kawabe, T.

    2011-03-01

    Optical coherence tomography (OCT) is an emerging technology for non-invasive cross-sectional imaging of biological tissue and material with um resolution. Recently, non-invasive high resolution cross-sectional imaging is desired for investigation of diseases in lung in the field of pulmonary medicine. So far, a few works have been reported about OCT imaging of lung. Since the lung consists of alveoli separated by thin wall, ultrahigh resolution (UHR) OCT is supposed to be effective for the imaging of fine structure in lung tissue. In this work, ex vivo cross-sectional imaging of isolated rat lungs was demonstrated using UHR-OCT. A 120 nm-wide, high-power, Gaussian-like supercontinuum (SC) was generated at wavelength of 0.8 um region and it was used as the light source in time domain UHR-OCT. An ultrahigh resolution of 2.1 um in tissue was obtained and the achieved sensitivity was 105 dB. For the UHR-OCT imaging of trachea, the detailed structures of the tracheal cartilage and tracheal mucosa overlying the cartilage were observed clearly. The epithelium and lamina propria were also distinguishable. For the imaging of visceral pleura and alveoli, when saline was instilled into the lung, the penetration depth was improved, and clear images of the fine structure of the lung, including alveoli, were observed owing to the index matching effect. The clear images of up to about 4 alveoli were observed below the visceral pleura. The shape of the alveolar septum was clearly observed, and the alveolar sac was clearly visible.

  2. Doxycycline-Regulated p16(MTS1) Expression Suppresses the Anchorage-Independence and Tumorigenicity of Breast Cancer Cell Lines that Lack Endogenous p16.

    Science.gov (United States)

    Todd, Maria C; Langan, Thomas A; Sclafani, Robert A

    2017-01-01

    The RB pathway controls the critical transition from G1 into S phase of the mammalian cell cycle. Deregulation of the RB pathway by means of RB or p16 inactivation has been implicated in the development of virtually all human cancers. Such findings have led to the view that the loss of RB-mediated regulation at the G1/S checkpoint is a precondition for human malignancy. Our analysis of the RB-positive MCF-7 and ZR75.1 breast cancer cell lines revealed a lack of endogenous p16 protein expression as a result of the homozygous deletion and methylation of the p16 gene at the CDKN2A locus, respectively. We employed the TET-OFF inducible expression system to investigate the effects of non-growth inhibitory levels of functional p16 protein upon the in vitro and in vivo transformed properties of the MCF-7 and ZR75.1 cell lines. Stable transfectants of MCF-7 and ZR75.1 cells were isolated that expressed different levels of p16 protein in the absence of doxycycline (DOX) but continued to proliferate in culture. Transfectants that expressed modest levels of p16 (relative to SV40 T antigen-transformed HBL-100 breast epithelial cells) demonstrated a marked suppression of anchorage-independent growth in soft agar. Further, the induction of moderate and high levels of p16 (relative to HBL-100) resulted in the suppression of tumorigenicity of both MCF-7 and ZR75.1 cells as assayed by injection into nude mice. From these data, we concluded that RB pathway restoration by non-growth inhibitory levels of p16 protein was sufficient to revert breast cancer cells to a non-transformed and non-tumorigenic state.

  3. Doxycycline-Regulated p16MTS1 Expression Suppresses the Anchorage-Independence and Tumorigenicity of Breast Cancer Cell Lines that Lack Endogenous p16

    Science.gov (United States)

    Todd, Maria C; Langan, Thomas A; Sclafani, Robert A

    2017-01-01

    The RB pathway controls the critical transition from G1 into S phase of the mammalian cell cycle. Deregulation of the RB pathway by means of RB or p16 inactivation has been implicated in the development of virtually all human cancers. Such findings have led to the view that the loss of RB-mediated regulation at the G1/S checkpoint is a precondition for human malignancy. Our analysis of the RB-positive MCF-7 and ZR75.1 breast cancer cell lines revealed a lack of endogenous p16 protein expression as a result of the homozygous deletion and methylation of the p16 gene at the CDKN2A locus, respectively. We employed the TET-OFF inducible expression system to investigate the effects of non-growth inhibitory levels of functional p16 protein upon the in vitro and in vivo transformed properties of the MCF-7 and ZR75.1 cell lines. Stable transfectants of MCF-7 and ZR75.1 cells were isolated that expressed different levels of p16 protein in the absence of doxycycline (DOX) but continued to proliferate in culture. Transfectants that expressed modest levels of p16 (relative to SV40 T antigen-transformed HBL-100 breast epithelial cells) demonstrated a marked suppression of anchorage-independent growth in soft agar. Further, the induction of moderate and high levels of p16 (relative to HBL-100) resulted in the suppression of tumorigenicity of both MCF-7 and ZR75.1 cells as assayed by injection into nude mice. From these data, we concluded that RB pathway restoration by non-growth inhibitory levels of p16 protein was sufficient to revert breast cancer cells to a non-transformed and non-tumorigenic state.

  4. High-frequency ultrasonic atomization for drug delivery to rodent animal models - optimal particle size for lung inhalation of difluoromethyl ornithine.

    Science.gov (United States)

    Zhang, Guifang; Fandrey, Chris; Naqwi, Amir; Wiedmann, Timothy Scott

    2008-06-01

    A high-(8-MHz) and a low-(1.7-MHz) frequency ultrasonic transducer were compared for delivering aerosols to mouse lung. The aerosol concentration (mass of dry particles/volume of air) rose nonlinearly with solution concentration of difluoromethyl ornithine for both transducers. The particle size was linear with the cube root of the solution concentration, and the slope of the low-frequency transducer was 8 times greater than that of the high-frequency transducer. The deposition fraction assessed by the assayed mass in the lung relative to the calculated inhaled mass was found to decline exponentially with particle size. The lower-frequency transducer provided a higher dose despite a lower deposition fraction, but the high-frequency transducer was more efficient and provides a more selective deposition in the lower respiratory tract while operating with significantly less demands on aerosol drying.

  5. The Affection of High-fat Diet on CTGF of Rat Lung Tissue%高脂饮食对大鼠肺组织CTGF的影响

    Institute of Scientific and Technical Information of China (English)

    于洪志

    2013-01-01

    Objective To explore the relation between high-fat diet and interstitial lung damage by detecting the content of SOD, MDA, HYP and CTGF in lung tissue with the set-up rat model of high-fat diet. Methods 20 SD rats were randomly divided into 2 groups:high-fat diet and control group, 10 in each, and high-fat diet and Lieber-Decarli liquid were provided respectively every day;all rats were single-caged with no water feeding;rats in both groups were killed after feeding for 12 weeks;HE staining was applied to ob-serve the structure of lung tissues while Masson staining to observe the collagen deposition of interstitial lung, colorimetry to detect the content of SOD, MDA and HYP in lung tissues and enzyme linked immunoassay to detect the content of CTGF in lung tissues. Results Pathological study suggested that, in high-fat diet group, there was an inflammatory cell infiltration in alveolar and alveolar septum, some alveolar walls were damaged or collapsed, collagen deposition among alveolar septum increased and the septum became wider;the content of MDA, HYP and CTGF in lung homogenate in high-fat diet group was higher than that in control group while its content of SOD was lower than that in control group. Conclusions High-fat diet leads to the increase of the expression of CTGF in lung tissues of rats, the damage of alveolar structure and the increase of interstitial collagen, it may be one of the factors in causing interstitial lung damage.%目的建立高脂饮食大鼠模型,测定肺组织中超氧化物歧化酶(SOD)、丙二醛(MDA)、羟脯氨酸(HYP)和结缔组织生长因子(CTGF)含量,探讨高脂饮食与肺间质损伤的关系。方法 SD大鼠20只,随机分为高脂饮食组与对照组各10只,每日分别给予高脂(脂肪占71%总热量)和对照(脂肪占35%总热量)Lieber-De-Carli液体饲料单笼喂养,不再提供饮水。各组动物均于12周后处死,HE染色观察肺组织结构;Masson染色观察

  6. Identification of early-stage usual interstitial pneumonia from low-dose chest CT scans using fractional high-density lung distribution

    Science.gov (United States)

    Xie, Yiting; Salvatore, Mary; Liu, Shuang; Jirapatnakul, Artit; Yankelevitz, David F.; Henschke, Claudia I.; Reeves, Anthony P.

    2017-03-01

    A fully-automated computer algorithm has been developed to identify early-stage Usual Interstitial Pneumonia (UIP) using features computed from low-dose CT scans. In each scan, the pre-segmented lung region is divided into N subsections (N = 1, 8, 27, 64) by separating the lung from anterior/posterior, left/right and superior/inferior in 3D space. Each subsection has approximately the same volume. In each subsection, a classic density measurement (fractional high-density volume h) is evaluated to characterize the disease severity in that subsection, resulting in a feature vector of length N for each lung. Features are then combined in two different ways: concatenation (2*N features) and taking the maximum in each of the two corresponding subsections in the two lungs (N features). The algorithm was evaluated on a dataset consisting of 51 UIP and 56 normal cases, a combined feature vector was computed for each case and an SVM classifier (RBF kernel) was used to classify them into UIP or normal using ten-fold cross validation. A receiver operating characteristic (ROC) area under the curve (AUC) was used for evaluation. The highest AUC of 0.95 was achieved by using concatenated features and an N of 27. Using lung partition (N = 27, 64) with concatenated features had significantly better result over not using partitions (N = 1) (p-value < 0.05). Therefore this equal-volume partition fractional high-density volume method is useful in distinguishing early-stage UIP from normal cases.

  7. High lung-metastatic variant of human osteosarcoma cells, selected by passage of lung metastasis in nude mice, is associated with increased expression of α(v)β(3) integrin.

    Science.gov (United States)

    Tome, Yasunori; Kimura, Hiroaki; Maehara, Hiroki; Sugimoto, Naotoshi; Bouvet, Michael; Tsuchiya, Hiroyuki; Kanaya, Fuminori; Hoffman, Robert M

    2013-09-01

    Altered expression of αvβ3 integrin is associated with tumor progression and metastasis in several types of cancer, including metastatic osteosarcoma. In this study, we demonstrate that in vivo passaging of lung metastasis in nude mice can generate an aggressive variant of human osteosarcoma cells. Experimental metastases were established by injecting 143B human osteosarcoma cells, expressing green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm, in the tail vein of nude mice. Lung metastases were harvested under fluorescence microscopy from nude mice to establish cell lines which were then injected via the tail vein of additional nude mice. This procedure was repeated for four passages in order to isolate highly metastatic variant sublines. When the parental and metastatic variants were transplanted orthotopically into the tibia of nude mice, the 143B-LM4 variant had the highest metastatic rate, approximately 18-fold higher than the parent (plung metastases created a highly metastatic variant of human osteosarcoma cells which had increased expression of αvβ3 integrin, suggesting that αvβ3 integrin plays an essential role in osteosarcoma metastasis. With this highly metastatic variant overexpressing αvβ3 integrin, it will now be possible to further investigate the mechanism by which αvβ3 integrin facilitates metastasis.

  8. 99mTc-IgG-Lung Scintigraphy in the Assessment of Pulmonary Involvement in Interstitial Lung Disease and Its Comparison With Pulmonary Function Tests and High-Resolution Computed Tomography: A Preliminary Study

    Directory of Open Access Journals (Sweden)

    Bahtouee

    2015-08-01

    Full Text Available Background The discrimination of inactive inflammatory processes from the active form of the disease is of great importance in the management of interstitial lung disease (ILD. Objectives The aim of this study was to determine the efficacy of 99mTc-IgG scan for the detection of severity of disease compared to high-resolution computed tomography (HRCT and pulmonary function test (PFT. Patients and Methods Eight known cases of ILD including four cases of Mustard gas (MG intoxication and four patients with ILD of unknown cause were included in this study. A population of six patients without lung disease was considered as the control group. The patients underwent PFT and high-resolution computed tomography, followed by 99mTc-IgG scan. They were followed up for one year. 99mTc-IgG scan assessment of IgG uptake was accomplished both qualitatively (subjectively and semiquantitatively. Results All eight ILD patients demonstrated a strong increase in 99mTc-IgG uptake in the lungs, compared to the control patients. The 99mTc-IgG scan scores were higher in the patient group (0.64[95% confidence interval(CI=0.61-0.69] than the control group (0.35 (0.35[95% CI=0.28-0.40], (P 0.05. There were no significant correlations between 99mTc-IgG score and HRCT patterns including ground glass opacity, reticular fibrosis and honeycombing (P value > 0.05. Conclusion The present results confirmed that 99mTc-IgG scan could be applied to detect the severity of pulmonary involvement, which was well correlated with HRCT findings. This data also showed that the 99mTc-IgG scan might be used as a complement to HRCT in the functional evaluation of the clinical status in ILD; however, further studies are recommended.

  9. Incomplete and accessory fissures of the lung evaluated by high-resolution computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Heřmanová, Zuzana, E-mail: zuzana.hermanova2@fnol.cz; Čtvrtlík, Filip, E-mail: filip.ctvrtlik@fnol.cz; Heřman, Miroslav, E-mail: herman@fnol.cz

    2014-03-15

    Purpose: The aim of our study was to assess incomplete and accessory interlobar fissures using volumetric thin-section high-resolution computed tomography (HRCT). Materials and methods: Retrospective assessment of HRCT examinations of 250 patients was performed. We assessed the localization, extension, and type of the incompleteness of fissures as well as the presence and localization of accessory fissures. We searched for possible correlation among the localization of interlobar fissures, the presence of incompleteness, and accessory fissures. Results: On the left side, an incomplete oblique fissure was found in 24%. The discontinuity was present in the parahilar region and the area of the incompleteness was most frequently between 21% and 40%. The right oblique fissure was incomplete in 35%, mostly parahilarly, with the most frequent discontinuity below 20%. An incomplete horizontal fissure was found in 74%. Accessory fissures were identified in 16% of patients, with the same frequency on both sides. The most frequent finding was accessory horizontal fissure with 8.0% on the left side, superior accessory fissure (7.2%) and inferior accessory fissure (5.2%) on the right side. No correlation was found among the localization of interlobar fissures, the presence of incompleteness, and accessory fissures. Conclusion: Incomplete and accessory fissures are frequent anatomic variations of interlobar fissures.

  10. Analysis of the crow lung transcriptome in response to infection with highly pathogenic H5N1 avian influenza virus.

    Science.gov (United States)

    Vijayakumar, Periyasamy; Mishra, Anamika; Ranaware, Pradip B; Kolte, Atul P; Kulkarni, Diwakar D; Burt, David W; Raut, Ashwin Ashok

    2015-03-15

    The highly pathogenic avian influenza (HPAI) H5N1 virus, currently circulating in Asia, causes severe disease in domestic poultry as well as wild birds like crow. However, the molecular pathogenesis of HPAIV infection in crows and other wild birds is not well known. Thus, as a step to explore it, a comprehensive global gene expression analysis was performed on crow lungs, infected with HPAI H5N1 crow isolate (A/Crow/India/11TI11/2011) using high throughput next generation sequencing (NGS) (GS FLX Titanium XLR70). The reference genome of crow is not available, so RNA seq analysis was performed on the basis of a de novo assembled transcriptome. The RNA seq result shows, 4052 genes were expressed uniquely in noninfected, 6277 genes were expressed uniquely in HPAIV infected sample and of the 6814 genes expressed in both samples, 2279 genes were significantly differentially expressed. Our transcriptome profile data allows for the ability to understand the molecular mechanism behind the recent lethal HPAIV outbreak in crows which was, until recently, thought to cause lethal infections only in gallinaceous birds such as chickens, but not in wild birds. The pattern of differentially expressed genes suggest that this isolate of H5N1 virus evades the host innate immune response by attenuating interferon (IFN)-inducible signalling possibly by down regulating the signalling from type I IFN (IFNAR1 and IFNAR2) and type II IFN receptors, upregulation of the signalling inhibitors suppressor of cytokine signalling 1 (SOCS1) and SOCS3 and altering the expression of toll-like receptors (TLRs). This may be the reason for disease and mortality in crows. Copyright © 2015. Published by Elsevier B.V.

  11. Lung Cancer

    Science.gov (United States)

    Lung cancer is one of the most common cancers in the world. It is a leading cause of cancer death in men and women in the United States. Cigarette smoking causes most lung cancers. The more cigarettes you smoke per day and ...

  12. Lung Diseases

    Science.gov (United States)

    When you breathe, your lungs take in oxygen from the air and deliver it to the bloodstream. The cells in your body need oxygen to ... you breathe nearly 25,000 times. People with lung disease have difficulty breathing. Millions of people in ...

  13. Asbestos Surveillance Program Aachen (ASPA): initial results from baseline screening for lung cancer in asbestos-exposed high-risk individuals using low-dose multidetector-row CT.

    Science.gov (United States)

    Das, Marco; Mühlenbruch, Georg; Mahnken, Andreas H; Hering, K G; Sirbu, H; Zschiesche, W; Knoll, Lars; Felten, Michael K; Kraus, Thomas; Günther, Rolf W; Wildberger, Joachim E

    2007-05-01

    The purpose of this study was to assess the prevalence of lung cancer in a high-risk asbestos-exposed cohort using low-dose MDCT. Of a population of 5,389 former power-plant workers, 316 were characterized as individuals at highest risk for lung cancer according to a lung-cancer risk model including age, asbestos exposure and smoking habits. Of these 316, 187 (mean age: 66.6 years) individuals were included in a prospective trial. Mean asbestos exposure time was 29.65 years and 89% were smokers. Screening was performed on a 16-slice MDCT (Siemens) with low-dose technique (10/20 mAs(eff.); 1 mm/0.5 mm increment). In addition to soft copy PACS reading analysis on a workstation with a dedicated lung analysis software (LungCARE; Siemens) was performed. One strongly suspicious mass and eight cases of histologically proven lung cancer were found plus 491 additional pulmonary nodules (average volume: 40.72 ml, average diameter 4.62 mm). Asbestos-related changes (pleural plaques, fibrosis) were visible in 80 individuals. Lung cancer screening in this high-risk cohort showed a prevalence of lung cancer of 4.28% (8/187) at baseline screening with an additional large number of indeterminate pulmonary nodules. Low-dose MDCT proved to be feasible in this highly selected population.

  14. A Nomogram to Predict Recurrence and Survival of High-Risk Patients Undergoing Sublobar Resection for Lung Cancer: An Analysis of a Multicenter Prospective Study (ACOSOG Z4032).

    Science.gov (United States)

    Kent, Michael S; Mandrekar, Sumithra J; Landreneau, Rodney; Nichols, Francis; Foster, Nathan R; DiPetrillo, Thomas A; Meyers, Bryan; Heron, Dwight E; Jones, David R; Tan, Angelina D; Starnes, Sandra; Putnam, Joe B; Fernando, Hiran C

    2016-07-01

    Individualized prediction of outcomes may help with therapy decisions for patients with non-small cell lung cancer. We developed a nomogram by analyzing 17 clinical factors and outcomes from a randomized study of sublobar resection for non-small cell lung cancer in high-risk operable patients. The study compared sublobar resection alone with sublobar resection with brachytherapy. There were no differences in primary and secondary outcomes between the study arms, and they were therefore combined for this analysis. The clinical factors of interest (considered as continuous variables) were assessed in a univariate Cox proportional hazards model for significance at the 0.10 level for their impact on overall survival (OS), local recurrence-free survival (LRFS), and any recurrence-free survival (RFS). The final multivariable model was developed using a stepwise model selection. Of 212 patients, 173 had complete data on all 17 risk factors. Median follow-up was 4.94 years (range, 0.04 to 6.22). The 5-year OS, LRFS, and RFS were 58.4%, 53.2%, and 47.4%, respectively. Age, baseline percent diffusing capacity of lung for carbon monoxide, and maximum tumor diameter were significant predictors for OS, LRFS, and RFS in the multivariable model. Nomograms were subsequently developed for predicting 5-year OS, LRFS, and RFS. Age, baseline percent diffusing capacity of lung for carbon monoxide, and maximum tumor diameter significantly predicted outcomes after sublobar resection. Such nomograms may be helpful for treatment planning in early stage non-small cell lung cancer and to guide future studies. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  15. High resolution computed tomography findings on the lung of early breast-cancer patients treated by postoperative breast irradiation with a hypofractionated radiotherapy schedule

    Directory of Open Access Journals (Sweden)

    Plataniotis G

    2005-01-01

    Full Text Available Context: Hypofractionated breast radiotherapy (RT, although convenient for patients and health care systems, could have a negative impact on normal tissues such as lung. Aims: To evaluate radiation-induced lung toxicity in early breast-cancer patients treated by hypofractionated RT. Settings and Design: We have been using the 42.5 Gy/16 fractions RT schedule since May 2003. As large fraction size is related to increased normal tissue toxicity we intended to investigate the possible radiation-induced lung toxicity to these patients, by performing high-resolution computed tomography (HRCT 6 months after the completion of the treatment. Methods and Material: A group of 30 consecutive early breast cancer patients (T1-2N0M0 have been treated by the above-mentioned RT schedule, using a pair of opposing tangential fields. The impact of chemotherapy and hormonotherapy and various breast size-related parameters on HRCT lung changes were investigated. Acute skin and breast tissue reactions were also recorded. Statistical analysis: used Correlation of numerical variables was investigated by Pearson correlation coefficient. Logistic regression analysis was used to investigate correlation between HRCT findings (present vs absent with other variables. Results: Minimal HRCT findings were evident in 15/30 patients. These included small septal lines, linear and subpleural opacities and to a lesser extend, focal-ground glass opacification. The HRCT findings were positively correlated only to field separation (distance between the entrance points of the tangential beams on the breast (H.R.=1.33, 95% CI: 1.013-1.75. Conclusions: The short 16-fraction RT schedule for early breast-cancer patients appears to have a minor effect on the underlying lung parenchyma.

  16. Lung Cancer Prevention

    Science.gov (United States)

    ... Treatment Lung Cancer Prevention Lung Cancer Screening Research Lung Cancer Prevention (PDQ®)–Patient Version What is prevention? ... to keep cancer from starting. General Information About Lung Cancer Key Points Lung cancer is a disease ...

  17. Lung Cancer Screening

    Science.gov (United States)

    ... Treatment Lung Cancer Prevention Lung Cancer Screening Research Lung Cancer Screening (PDQ®)–Patient Version What is screening? Go ... These are called diagnostic tests . General Information About Lung Cancer Key Points Lung cancer is a disease in ...

  18. What Is Lung Cancer?

    Science.gov (United States)

    ... Graphics Infographic Stay Informed Cancer Home What Is Lung Cancer? Language: English Español (Spanish) Recommend on Facebook Tweet ... cancer starts in the lungs, it is called lung cancer. Lung cancer begins in the lungs and may ...

  19. Multi-detector CT (MDCT) evaluation in interstitial lung disease (ILD): Comparison of MinIP and volumetric high resolution CT (HRCT) images

    OpenAIRE

    Youssriah Y. Sabri; Iman M. Hamdy Ibrahim; Shady Mohamed Tarek Gamal; Hebatallah H. Assal

    2017-01-01

    The aim of the study: Is to compare the role of minimum intensity projection (MinIP) images with that of volumetric high resolution computed tomography (HRCT) images in the diagnosis of interstitial lung diseases (ILD). Patients and methods: 180 patients (149 females and 31 males) were included in this prospective study that took place over a duration of two and half years. All patients underwent HRCT and MinIP images. The positive findings were compared recording which technique was bette...

  20. Decellularized matrix from tumorigenic human mesenchymal stem cells promotes neovascularization with galectin-1 dependent endothelial interaction.

    Directory of Open Access Journals (Sweden)

    Jorge S Burns

    Full Text Available BACKGROUND: Acquisition of a blood supply is fundamental for extensive tumor growth. We recently described vascular heterogeneity in tumours derived from cell clones of a human mesenchymal stem cell (hMSC strain (hMSC-TERT20 immortalized by retroviral vector mediated human telomerase (hTERT gene expression. Histological analysis showed that cells of the most vascularized tumorigenic clone, -BD11 had a pericyte-like alpha smooth muscle actin (ASMA+ and CD146+ positive phenotype. Upon serum withdrawal in culture, -BD11 cells formed cord-like structures mimicking capillary morphogenesis. In contrast, cells of the poorly tumorigenic clone, -BC8 did not stain for ASMA, tumours were less vascularized and serum withdrawal in culture led to cell death. By exploring the heterogeneity in hMSC-TERT20 clones we aimed to understand molecular mechanisms by which mesenchymal stem cells may promote neovascularization. METHODOLOGY/PRINCIPAL FINDINGS: Quantitative qRT-PCR analysis revealed similar mRNA levels for genes encoding the angiogenic cytokines VEGF and Angiopoietin-1 in both clones. However, clone-BD11 produced a denser extracellular matrix that supported stable ex vivo capillary morphogenesis of human endothelial cells and promoted in vivo neovascularization. Proteomic characterization of the -BD11 decellularized matrix identified 50 extracellular angiogenic proteins, including galectin-1. siRNA knock down of galectin-1 expression abrogated the ex vivo interaction between decellularized -BD11 matrix and endothelial cells. More stable shRNA knock down of galectin-1 expression did not prevent -BD11 tumorigenesis, but greatly reduced endothelial migration into -BD11 cell xenografts. CONCLUSIONS: Decellularized hMSC matrix had significant angiogenic potential with at least 50 angiogenic cell surface and extracellular proteins, implicated in attracting endothelial cells, their adhesion and activation to form tubular structures. hMSC -BD11 surface galectin-1

  1. Mutations in BALB mitochondrial DNA induce CCL20 up-regulation promoting tumorigenic phenotypes

    Energy Technology Data Exchange (ETDEWEB)

    Sligh, James [Department of Medicine—Dermatology Division, University of Arizona, Tucson, AZ 857 24 (United States); University of Arizona Cancer Center, Tucson, AZ 85724 (United States); Janda, Jaroslav [University of Arizona Cancer Center, Tucson, AZ 85724 (United States); Jandova, Jana, E-mail: jjandova@email.arizona.edu [Department of Medicine—Dermatology Division, University of Arizona, Tucson, AZ 857 24 (United States); University of Arizona Cancer Center, Tucson, AZ 85724 (United States)

    2014-11-15

    Highlights: • Alterations in mitochondrial DNA are commonly found in various human cancers. • Mutations in BALB mitochondrial DNA induce up-regulation of chemokine CCL20. • Increased growth and motility of mtBALB cells is associated with CCL20 levels. • mtDNA changes in BALB induce in vivo tumor growth through CCL20 up-regulation. • Mutations in mitochondrial DNA play important roles in keratinocyte neoplasia. - Abstract: mtDNA mutations are common in human cancers and are thought to contribute to the process of neoplasia. We examined the role of mtDNA mutations in skin cancer by generating fibroblast cybrids harboring a mutation in the gene encoding the mitochondrial tRNA for arginine. This somatic mutation (9821insA) was previously reported in UV-induced hyperkeratotic skin tumors in hairless mice and confers specific tumorigenic phenotypes to mutant cybrids. Microarray analysis revealed and RT-PCR along with Western blot analysis confirmed the up-regulation of CCL20 and its receptor CCR6 in mtBALB haplotype containing the mt-Tr 9821insA allele compared to wild type mtB6 haplotype. Based on reported role of CCL20 in cancer progression we examined whether the hyper-proliferation and enhanced motility of mtBALB haplotype would be associated with CCL20 levels. Treatment of both genotypes with recombinant CCL20 (rmCCL20) resulted in enhanced growth and motility of mtB6 cybrids. Furthermore, the acquired somatic alteration increased the in vivo tumor growth of mtBALB cybrids through the up-regulation of CCL20 since neutralizing antibody significantly decreased in vivo tumor growth of these cells; and tumors from anti-CCL20 treated mice injected with mtBALB cybrids showed significantly decreased CCL20 levels. When rmCCL20 or mtBALB cybrids were used as chemotactic stimuli, mtB6 cybrids showed increased motility while anti-CCL20 antibody decreased the migration and in vivo tumor growth of mtBALB cybrids. Moreover, the inhibitors of MAPK signaling and NF

  2. Antisense Oligonucleotide Targeting TGF-β1 Abrogates Tumorigenicity of Rhabdomyosarcoma in vivo

    Institute of Scientific and Technical Information of China (English)

    Shouli Wang; Huihua Yao; Lingling Guo; Liang Dong; Shigang Li; Haizhen Deng; Maomin Sun

    2008-01-01

    OBJECTIVE Over-expression of transforming growth factor β1 (TGF-β1) has been observed in many advanced cancers.The present study was aimed at developing potential antisense oligonucleotides (ASONs) to repress TGF-β1 expression in rhabdomyosarcoma (RMS) RD cells, and to examine their effect on tumorigenicity of RD cells in vivo.METHODS ASONs targeting the region surrounding the start codon of TGF-β1 were synthesized and transferred into cells in the form of complexes with Lipofectamine 2000. The TGF-β1 protein was determined by immunofluorescence and ELISA.The cell viability and cell cycle were examined by MTT and flow cytometry. The RD cells, with or without TGF-β1ASON, in 50 μl of serum-free EMDM medium were injected subcutaneously into the right flank of nude mice. The tumors were then measured and weighed.RESULTS The ASON sequence targeting the first start site at bases 841-855 of the human TGF-β1 gene had the greatest effect on attenuating the expression of TGF-β1 (P<0.05). The ASONs induced a decrease in OD values after 6 d (P<0.05). Analysis of the cell cycle revealed that the ASON induced a significant decrease in cells in the S phase and an increase in cells in the G1 phase (P<0.05). In the nude mice model, the mean tumor volume, after 2 weeks of treatment with Lipofectamine or ASON,decreased to 88.5% or 55% respectively, compared to the control tumor size, resulting in a significant difference (P<0.01).CONCLUSION The sequence of the ASON, which targeted the start condon at the bases 841-855 of the human TGF-β1 gene, was demonstrated to be a useful agent for studying the regulation of TGF-β1 over-expression in RD cells, and has important therapeutic potential for suppressing the tumorigenicity of human RMS in vivo.

  3. High-resolution computed tomography to differentiate chronic diffuse interstitial lung diseases with predominant ground-glass pattern using logical analysis of data

    Energy Technology Data Exchange (ETDEWEB)

    Martin, Sophie Grivaud; Brauner, Michel W.; Rety, Frederique [Universite Paris 13, Assistance Publique-Hopitaux de Paris, Hopital Avicenne, UPRES EA 2363, Department of Radiology, Bobigny (France); Kronek, Louis-Philippe; Brauner, Nadia [Universite Joseph Fourier, Laboratoire G-SCOP, Grenoble (France); Valeyre, Dominique; Nunes, Hilario [Universite Paris 13, Assistance Publique-Hopitaux de Paris, Hopital Avicenne, UPRES EA 2363, Department of Pneumology, Bobigny (France); Brillet, Pierre-Yves [Universite Paris 13, Assistance Publique-Hopitaux de Paris, Hopital Avicenne, UPRES EA 2363, Department of Radiology, Bobigny (France); Hopital Avicenne, Service de Radiologie, Bobigny Cedex (France)

    2010-06-15

    We evaluated the performance of high-resolution computed tomography (HRCT) to differentiate chronic diffuse interstitial lung diseases (CDILD) with predominant ground-glass pattern by using logical analysis of data (LAD). A total of 162 patients were classified into seven categories: sarcoidosis (n = 38), connective tissue disease (n = 32), hypersensitivity pneumonitis (n = 18), drug-induced lung disease (n = 15), alveolar proteinosis (n = 12), idiopathic non-specific interstitial pneumonia (n = 10) and miscellaneous (n = 37). First, 40 CT attributes were investigated by the LAD to build up patterns characterising a category. From the association of patterns, LAD determined models specific to each CDILD. Second, data were recomputed by adding eight clinical attributes to the analysis. The 20 x 5 cross-folding method was used for validation. Models could be individualised for sarcoidosis, hypersensitivity pneumonitis, connective tissue disease and alveolar proteinosis. An additional model was individualised for drug-induced lung disease by adding clinical data. No model was demonstrated for idiopathic non-specific interstitial pneumonia and the miscellaneous category. The results showed that HRCT had a good sensitivity ({>=}64%) and specificity ({>=}78%) and a high negative predictive value ({>=}93%) for diseases with a model. Higher sensitivity ({>=}78%) and specificity ({>=}89%) were achieved by adding clinical data. The diagnostic performance of HRCT is high and can be increased by adding clinical data. (orig.)

  4. Treatment of small cell carcinoma of lung with combined high dose mediastinal irradiation, whole brain prophylaxis and chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Shank, B.; Natale, R.B.; Hilaris, B.S.; Wittes, R.E.

    1981-04-01

    Survival of patients with small cell carcinoma of lung, treated on a new combined radiotherapy-chemotherapy protocol, compares favorably with other regimens in the literature and our own previous combined approaches. Radiation, given after induction chemotherapy, consisted of whole brain prophylaxis in all 44 evaluable patients. Patients with limited disease were also treated to the primary and mediastinum to a high dose (5000 rad equivalent) using multiple fields. The new chemotherapy regimen consisted of induction with cyclophosphamide, doxorubicin, and vincristine alternated with cis-platinum and VP-16 (an epipodophyllotoxin) for two cycles, followed by consolidation with low dose cyclophosphamide and vincristine concurrent with irradiation. Patients with limited disease who achieved less than complete response, and all patients with extensive disease were not continued on maintenance chemotherapy. Out of 24 evaluable patients with limited disease, there was 73% survival at 1 year by life-table analysis, measured from treatment initiation. After induction, 16/24 of these limited disease patients were CR (complete responders): 20/24 were CR at completion of their irradiation. Out of 20 evaluable patients with extensive disease, there was 59% survival at 1 year by life-table analysis. Only 4/44 (9%) brain parenchymal relapses occurred, one at 3 months and one at 6 months after local failure and two in patients who did not become CRs, implicating a possible re-seeding mechanism. Five patients had central nervous system relapses outside of brain parenchyma (spinal epidural and leptomeningeal); in three patients this was the initial site of failure. Significant complications included leukopenia (50%) and thrombocytopenia (24%) primarily during induction, and chronic pulmonary fibrosis (25%), possibly contributing to two deaths.

  5. High Resolution Melting Analysis for Detecting p53 Gene Mutations in Patients with Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Zhihong CHEN

    2011-10-01

    Full Text Available Background and objective It has been proven that p53 gene was related to many human cancers. The mutations in p53 gene play an important role in carcinogensis and mostly happened in exon 5-8. The aim of this study is to establish a high resolution melting (HRM assay to detect p53 mutations from patients with non-small cell lung cancer (NSCLC, to investigate the characteristics of p53 gene mutations, and to analyze the relationship between p53 mutations and evolution regularity of pathogenesis. Methods p53 mutations in exon 5-8 were detected by HRM assay on DNA insolated from 264 NSCLC samples derived from tumor tissues and 54 control samples from pericancerous pulmonary tissues. The mutation samples by the HRM assay were confirmed by sequencing technique. Samples which were positive by HRM but wild type by sequencing were further confirmed by sub-clone and sequencing. Results No mutation was found in 54 pericancerous pulmonary samples by HRM assay. 104 of the 264 tumor tissues demonstrated mutation curves by HRM assay, 102 samples were confirmed by sequencing, including 95 point mutations and 7 frame shift mutations by insertion or deletion. The mutation rate of p53 gene was 39.4%. The mutation rate from exon 5-8 were 11.7%, 8%, 12.5% and 10.6%, respectively and there was no statistically significant difference between them (P=0.35. p53 mutations were significantly more frequent in males than that in females, but not related to the other clinicopathologic characteristics. Conclusion The results indicate that HRM is a sensitive in-tube methodology to detect for mutations in clinical samples. The results suggest that the arising p53 mutations in NSCLC may be due to spontaneous error in DNA synthesis and repair.

  6. Pulmonary Artery Invasion, High-Dose Radiation, and Overall Survival in Patients With Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Han, Cheng-Bo [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Department of Oncology, Shengjing Hospital of China Medical University, Shenyang (China); Wang, Wei-Li [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Department of Radiation Oncology, Fourth Hospital of China Medical University, Shenyang (China); Quint, Leslie [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Xue, Jian-Xin [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu (China); Matuszak, Martha; Ten Haken, Randall [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Kong, Feng-Ming, E-mail: fkong@gru.edu [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States)

    2014-06-01

    Purpose: To investigate whether high-dose radiation to the pulmonary artery (PA) affects overall survival (OS) in patients with non-small cell lung cancer (NSCLC). Methods and Materials: Patients with medically inoperable/unresectable NSCLC treated with definitive radiation therapy in prospective studies were eligible for this study. Pulmonary artery involvement was defined on the basis of pretreatment chest CT and positron emission tomography/CT fusion. Pulmonary artery was contoured according to the Radiation Therapy Oncology Group protocol 1106 atlas, and dose-volume histograms were generated. Results: A total of 100 patients with a minimum follow-up of 1 year for surviving patients were enrolled: 82.0% underwent concurrent chemoradiation therapy. Radiation dose ranged from 60 to 85.5 Gy in 30-37 fractions. Patients with PA invasion of grade ≤2, 3, 4, and 5 had 1-year OS and median survival of 67% and 25.4 months (95% confidence interval [CI] 15.7-35.1), 62% and 22.2 months (95% CI 5.8-38.6), 90% and 35.8 months (95% CI 28.4-43.2), and 50% and 7.0 months, respectively (P=.601). Two of the 4 patients with grade 5 PA invasion died suddenly from massive hemorrhage at 3 and 4.5 months after completion of radiation therapy. Maximum and mean doses to PA were not significantly associated with OS. The V45, V50, V55, and V60 of PA were correlated significantly with a worse OS (P<.05). Patients with V45 >70% or V60 >37% had significantly worse OS (13.3 vs 37.9 months, P<.001, and 13.8 vs 37.9 months, P=.04, respectively). Conclusions: Grade 5 PA invasion and PA volume receiving more than 45-60 Gy may be associated with inferior OS in patients with advanced NSCLC treated with concurrent chemoradiation.

  7. Different expression of EZH2, BMI1 and Ki67 in low and high grade neuroendocrine tumors of the lung

    DEFF Research Database (Denmark)

    Bondgaard, Anna-Louise Reinert Ørsum; Poulsen, Thomas Tuxen; Poulsen, Hans Skovgaard

    2012-01-01

    Enhancer of Zeste Homolog 2 (EZH2) and B lymphoma Mo-MLV Insertion region 1 polycomb ring finger (BMI1) are involved in malignant transformation of many human carcinomas. Still, in neuroendocrine tumors of the lung (NELT) their expression pattern is largely unknown. This study evaluated their exp......Enhancer of Zeste Homolog 2 (EZH2) and B lymphoma Mo-MLV Insertion region 1 polycomb ring finger (BMI1) are involved in malignant transformation of many human carcinomas. Still, in neuroendocrine tumors of the lung (NELT) their expression pattern is largely unknown. This study evaluated...

  8. Risk of tumorigenicity in mesenchymal stromal cell-based therapies--bridging scientific observations and regulatory viewpoints.

    Science.gov (United States)

    Barkholt, Lisbeth; Flory, Egbert; Jekerle, Veronika; Lucas-Samuel, Sophie; Ahnert, Peter; Bisset, Louise; Büscher, Dirk; Fibbe, Willem; Foussat, Arnaud; Kwa, Marcel; Lantz, Olivier; Mačiulaitis, Romaldas; Palomäki, Tiina; Schneider, Christian K; Sensebé, Luc; Tachdjian, Gérard; Tarte, Karin; Tosca, Lucie; Salmikangas, Paula

    2013-07-01

    In the past decade, the therapeutic value of mesenchymal stromal cells (MSCs) has been studied in various indications, thereby taking advantage of their immunosuppressive properties. Easy procurement from bone marrow, adipose tissue or other sources and conventional in vitro expansion culture have made their clinical use attractive. Bridging the gap between current scientific knowledge and regulatory prospects on the transformation potential and possible tumorigenicity of MSCs, the Cell Products Working Party and the Committee for Advanced Therapies organized a meeting with leading European experts in the field of MSCs. This meeting elucidated the risk of potential tumorigenicity related to MSC-based therapies from two angles: the scientific perspective and the regulatory point of view. The conclusions of this meeting, including the current regulatory thinking on quality, nonclinical and clinical aspects for MSCs, are presented in this review, leading to a clearer way forward for the development of such products.

  9. Genotoxic Pyrrolizidine Alkaloids — Mechanisms Leading to DNA Adduct Formation and Tumorigenicity

    Directory of Open Access Journals (Sweden)

    Ming W. Chou

    2002-09-01

    Full Text Available Abstract: Plants that contain pyrrolizidine alkaloids are widely distributed in the world. Although pyrrolizidine alkaloids have been shown to be genotoxic and tumorigenic in experimental animals, the mechanisms of actions have not been fully understood. The results of our recent mechanistic studies suggest that pyrrolizidine alkaloids induce tumors via a genotoxic mechanism mediated by 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5Hpyrrolizine (DHP-derived DNA adduct formation. This mechanism may be general to most carcinogenic pyrrolizidine alkaloids, including the retronecine-, heliotridine-, and otonecinetype pyrrolizidine alkaloids. It is hypothesized that these DHP-derived DNA adducts are potential biomarkers of pyrrolizidine alkaloid tumorigenicity. The mechanisms that involve the formation of DNA cross-linking and endogenous DNA adducts are also discussed.

  10. Lung cancer screening: Update

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hyea Young [Dept. of Radiology, Center for Lung Cancer, National Cancer Center, Goyang (Korea, Republic of)

    2015-09-15

    Lung cancer is the leading cause of cancer deaths worldwide as well as in Korea. A recent National Lung Screening Trial in U.S. revealed that low-dose CT (LDCT) screening reduced lung cancer specific mortality by 20% in high risk individuals as compared to chest radiograph screening. Based on this evidence, several expert societies in U.S. and Korean multisociety collaborative committee developed guidelines for recommendation of lung cancer screening using annual LDCT in high risk populations. In most of the societies high risk groups are defined as persons aged 55 to 74 years, who are current smokers with history of smoking of more than 30 packs per year or ex-smokers, who quit smoking up to 15 or more years ago. The benefits of LDCT screening are modestly higher than the harms in high risk individuals. The harms included a high rate of false-positive findings, over-diagnosis and radiation-related deaths. Invasive diagnostic procedure due to false positive findings may lead to complications. LDCT should be performed in qualified hospitals and interpreted by expert radiologists. Recently, the American College of Radiology released the current version of Lung cancer CT screening Reporting and Data Systems. Education and actions to stop smoking must be offered to current smokers.

  11. Effect of doxorubicin/pluronic SP1049C on tumorigenicity, aggressiveness, DNA methylation and stem cell markers in murine leukemia.

    Directory of Open Access Journals (Sweden)

    Daria Y Alakhova

    Full Text Available PURPOSE: Pluronic block copolymers are potent sensitizers of multidrug resistant cancers. SP1049C, a Pluronic-based micellar formulation of doxorubicin (Dox has completed Phase II clinical trial and demonstrated safety and efficacy in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction. This study elucidates the ability of SP1049C to deplete cancer stem cells (CSC and decrease tumorigenicity of cancer cells in vivo. EXPERIMENTAL DESIGN: P388 murine leukemia ascitic tumor was grown in BDF1 mice. The animals were treated with: (a saline, (b Pluronics alone, (c Dox or (d SP1049C. The ascitic cancer cells were isolated at different passages and examined for 1 in vitro colony formation potential, 2 in vivo tumorigenicity and aggressiveness, 3 development of drug resistance and Wnt signaling activation 4 global DNA methylation profiles, and 5 expression of CSC markers. RESULTS: SP1049C treatment reduced tumor aggressiveness, in vivo tumor formation frequency and in vitro clonogenic potential of the ascitic cells compared to drug, saline and polymer controls. SP1049C also prevented overexpression of BCRP and activation of Wnt-β-catenin signaling observed with Dox alone. Moreover, SP1049C significantly altered the DNA methylation profiles of the cells. Finally, SP1049C decreased CD133(+ P388 cells populations, which displayed CSC-like properties and were more tumorigenic compared to CD133(- cells. CONCLUSIONS: SP1049C therapy effectively suppresses the tumorigenicity and aggressiveness of P388 cells in a mouse model. This may be due to enhanced activity of SP1049C against CSC and/or altered epigenetic regulation restricting appearance of malignant cancer cell phenotype.

  12. Study on interleukin-18 gene transfer into human breast cancer cells to prevent tumorigenicity

    Institute of Scientific and Technical Information of China (English)

    韩明勇; 郑树; 于金明; 彭佳萍; 郭其森; 王家林

    2004-01-01

    To study the effect of interleukin-18 gene transfection on the tumorigenesis of breast cancer cell line Bacp37, human breast cancer cell line Bcap37 were transfected with Lipofectamine and selected by G418. The biological expression of rhIL-18 was tested by RT-PCR and ELISA method; nude mice were injected with Bcap37 cell with or without the hIL-18 gene. The hIL-18 cDNA was successfully integrated into Bcap37 cell; 126.3±4.5 pg hIL-18 secreted by one million transduced cells in 24 hours. Nude mice injected with IL-18 gene engineered Bcap37 cell had no tumor growth. These findings indicated that human breast cancer cells were successfully modified by the gene of IL-18 cytokine; the IL-18 gene engineered Bcap37 cells secreted hIL-18 and lost their tumorigenicity. The Bcap37 cells transduced with IL-18 gene may be used as breast cancer vaccine.

  13. Muse cells, newly found non-tumorigenic pluripotent stem cells, reside in human mesenchymal tissues.

    Science.gov (United States)

    Wakao, Shohei; Akashi, Hideo; Kushida, Yoshihiro; Dezawa, Mari

    2014-01-01

    Mesenchymal stem cells (MSCs) have been presumed to include a subpopulation of pluripotent-like cells as they differentiate not only into the same mesodermal-lineage cells but also into ectodermal- and endodermal-lineage cells and exert tissue regenerative effects in a wide variety of tissues. A novel type of pluripotent stem cell, Multilineage-differentiating stress enduring (Muse) cells, was recently discovered in mesenchymal tissues such as the bone marrow, adipose tissue, dermis and connective tissue of organs, as well as in cultured fibroblasts and bone marrow-MSCs. Muse cells are able to differentiate into all three germ layers from a single cell and to self-renew, and yet exhibit non-tumorigenic and low telomerase activities. They can migrate to and target damaged sites in vivo, spontaneously differentiate into cells compatible with the targeted tissue, and contribute to tissue repair. Thus, Muse cells may account for the wide variety of differentiation abilities and tissue repair effects that have been observed in MSCs. Muse cells are unique in that they are pluripotent stem cells that belong in the living body, and are thus assumed to play an important role in 'regenerative homeostasis' in vivo.

  14. Mitochondrial NADP(+)-dependent isocitrate dehydrogenase knockdown inhibits tumorigenicity of melanoma cells.

    Science.gov (United States)

    Kim, Sung Hwan; Yoo, Young Hyun; Lee, Jin Hyup; Park, Jeen-Woo

    2014-08-22

    The potent cytotoxicity of reactive oxygen species (ROS) can cause various diseases but may also serve as a powerful weapon capable of destroying cancer cells. Although the balance between generation and elimination of ROS is maintained by the proper function of antioxidative systems, the severe disturbance of cellular redox status may cause various damages, leading to cell death. Mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2), an NADPH-generating enzyme, is one of the major antioxidant and redox regulators in mitochondria. To assess the effect of IDH2 knockdown in the malignancy process, we generated B16F10 melanoma cells stably transfected either with the cDNA for mouse IDH2 cloned in antisense orientation or with a control vector. Mice injected with B16F10 cells harboring IDH2 downregulation showed a dramatic reduction in tumor progression in comparison to mice administered control cells. This effect might be secondary to a shift from a reducing to an oxidative state in tumor cells. The tumor tissue of mice administered B16F10 cells transfected with the IDH2 cDNA exhibited induction of apoptosis and downregulation of angiogenesis markers. These observations demonstrate that reduction of IDH2 levels in malignant cells has anti-tumorigenic effects and suggest that IDH2 is a potential target for cancer therapy.

  15. Loss of Cell Adhesion Increases Tumorigenic Potential of Polarity Deficient Scribble Mutant Cells.

    Directory of Open Access Journals (Sweden)

    Indrayani Waghmare

    Full Text Available Epithelial polarity genes are important for maintaining tissue architecture, and regulating growth. The Drosophila neoplastic tumor suppressor gene scribble (scrib belongs to the basolateral polarity complex. Loss of scrib results in disruption of its growth regulatory functions, and downregulation or mislocalization of Scrib is correlated to tumor growth. Somatic scribble mutant cells (scrib- surrounded by wild-type cells undergo apoptosis, which can be prevented by introduction of secondary mutations that provide a growth advantage. Using genetic tools in Drosophila, we analyzed the phenotypic effects of loss of scrib in different growth promoting backgrounds. We investigated if a central mechanism that regulates cell adhesion governs the growth and invasive potential of scrib mutant cells. Here we show that increased proliferation, and survival abilities of scrib- cells in different genetic backgrounds affect their differentiation, and intercellular adhesion. Further, loss of scrib is sufficient to cause reduced cell survival, activation of the JNK pathway and a mild reduction of cell adhesion. Our data show that for scrib cells to induce aggressive tumor growth characterized by loss of differentiation, cell adhesion, increased proliferation and invasion, cooperative interactions that derail signaling pathways play an essential role in the mechanisms leading to tumorigenesis. Thus, our study provides new insights on the effects of loss of scrib and the modification of these effects via cooperative interactions that enhance the overall tumorigenic potential of scrib deficient cells.

  16. β-Catenin Does Not Confer Tumorigenicity When Introduced into Partially Transformed Human Mesenchymal Stem Cells

    Directory of Open Access Journals (Sweden)

    Sajida Piperdi

    2012-01-01

    Full Text Available Although osteosarcoma is the most common primary malignant bone tumor in children and adolescents, its cell of origin and the genetic alterations are unclear. Previous studies have shown that serially introducing hTERT, SV40 large TAg, and H-Ras transforms human mesenchymal stem cells into two distinct sarcomas cell populations, but they do not form osteoid. In this study, β-catenin was introduced into mesenchymal stem cells already containing hTERT and SV40 large TAg to analyze if this resulted in a model which more closely recapitulated osteosarcoma. Results. Regardless of the level of induced β-catenin expression in the stable transfectants, there were no marked differences induced in their phenotype or invasion and migration capacity. Perhaps more importantly, none of them formed tumors when injected into immunocompromised mice. Moreover, the resulting transformed cells could be induced to osteogenic and chondrogenic differentiation but not to adipogenic differentiation. Conclusions. β-catenin, although fostering osteogenic differentiation, does not induce the malignant features and tumorigenicity conveyed by oncogenic H-RAS when introduced into partly transformed mesenchymal stem cells. This may have implications for the role of β-catenin in osteosarcoma pathogenesis. It also may suggest that adipogenesis is an earlier branch point than osteogenesis and chondrogenesis in normal mesenchymal differentiation.

  17. The stem cell factor SOX2 regulates the tumorigenic potential in human gastric cancer cells.

    Science.gov (United States)

    Hütz, Katharina; Mejías-Luque, Raquel; Farsakova, Katarina; Ogris, Manfred; Krebs, Stefan; Anton, Martina; Vieth, Michael; Schüller, Ulrich; Schneider, Marlon R; Blum, Helmut; Wagner, Ernst; Jung, Andreas; Gerhard, Markus

    2014-04-01

    Gastric cancer (GC) is still one of the most common causes of cancer-related death worldwide, which is mainly attributable to late diagnosis and poor treatment options. Infection with Helicobacter pylori, different environmental factors and genetic alterations are known to influence the risk of developing gastric tumors. However, the molecular mechanisms involved in gastric carcinogenesis are still not fully understood, making it difficult to design targeted therapeutic approaches. Aberrant expression of the specific gastric differentiation marker SOX2 has been observed in stomach cancer. However, the role of SOX2 in gastric tumors has not been well established to date. To elucidate the role of SOX2 in gastric tumorigenesis, SOX2 transcriptional activity was blocked in AZ-521 cells. Interestingly, inhibition of SOX2 reduced cell proliferation and migration, increased apoptosis and induced changes in cell cycle. Blocking of SOX2 also reduced the tumorigenic potential of AZ-521 cells in vivo. In addition, correlation of SOX2 expression and proliferation was observed in a subset of human gastric tumors. Finally, target genes of SOX2 were for the first time identified by RNA microarray in GC cells. Taken together, the results presented here indicate that SOX2 controls several aspects related to GC development and progression by regulating the expression of members of important signaling pathways. These findings could provide new therapeutic options for a subset of GCs exhibiting SOX2 deregulation.

  18. Study on interleukin-18 gene transfer into human breast cancer cells to prevent tumorigenicity

    Institute of Scientific and Technical Information of China (English)

    韩明勇; 郑树; 于金明; 彭佳萍; 郭其森; 王家林

    2004-01-01

    To study the effect of interleukin-18 gene transfection on the tumorigenesis of breast cancer cell line Bacp37,human breast cancer cell line Bcap37 were transfected with Lipofectamine and selected by G418.The biological expression of rhIL-18 was tested by RT-PCR and ELISA method;nude mice were injected with Bcap37 cell with or without the hIL-18 gene.The hIL-18 cDNA was successfully integrated into Bcap37 cell; 126.3±4.5pg hIL-18 secreted by one million transduced cells in 24 hours. Nude mice injected with IL-18 gene engineered Bcap37 cell had no tumor growth.These findings indicated that human breast cancer cells were successfully modified by the gene of IL-18 cytokine;the IL-18 gene engineered Bcap37 cells secreted hIL-18 and lost their tumorigenicity.The Bcap37 cells transduced with IL-18 gene may be used as breast cancer vaccine.

  19. Elasticity and tumorigenic characteristics of cells in a monolayer after nanosecond pulsed electric field exposure.

    Science.gov (United States)

    Steuer, A; Wende, K; Babica, P; Kolb, J F

    2017-09-01

    Nanosecond pulsed electric fields (nsPEFs) applied to cells can induce different biological effects depending on pulse duration and field strength. One known process is the induction of apoptosis whereby nsPEFs are currently investigated as a novel cancer therapy. Another and probably related change is the breakdown of the cytoskeleton. We investigated the elasticity of rat liver epithelial cells WB-F344 in a monolayer using atomic force microscopy (AFM) with respect to the potential of cells to undergo malignant transformation or to develop a potential to metastasize. We found that the elastic modulus of the cells decreased significantly within the first 8 min after treatment with 20 pulses of 100 ns and with a field strength of 20 kV/cm but was still higher than the elasticity of their tumorigenic counterpart WB-ras. AFM measurements and immunofluorescent staining showed that the cellular actin cytoskeleton became reorganized within 5 min. However, both a colony formation assay and a cell migration assay revealed no significant changes after nsPEF treatment, implying that cells seem not to adopt malignant characteristics associated with metastasis formation despite the induced transient changes to elasticity and cytoskeleton that can be observed for up to 1 h.

  20. miR-17* suppresses tumorigenicity of prostate cancer by inhibiting mitochondrial antioxidant enzymes.

    Directory of Open Access Journals (Sweden)

    Yong Xu

    Full Text Available Aberrant micro RNA (miRNA expression has been implicated in the pathogenesis of cancer. Recent studies have shown that the miR-17-92 cluster is overexpressed in many types of cancer. The oncogenic function of mature miRNAs encoded by the miR-17-92 cluster has been identified from the 5' arm of six precursors. However, the function of the miRNAs produced from the 3' arm of these precursors remains unknown. The present study demonstrates that miR-17* is able to suppress critical primary mitochondrial antioxidant enzymes, such as manganese superoxide dismutase (MnSOD, glutathione peroxidase-2 (GPX2 and thioredoxin reductase-2 (TrxR2. Transfection of miR-17* into prostate cancer PC-3 cells significantly reduces levels of the three antioxidant proteins and activity of the luciferase reporter under the control of miR-17* binding sequences located in the 3'-untranslated regions of the three target genes. Disulfiram (DSF, a dithiolcarbomate drug shown to have an anticancer effect, induces the level of mature miR-17* and cell death in PCa cells, which can be attenuated by transfection of antisense miR-17*. Increasing miR-17* level in PC-3 cells by a Tet-on based conditional expression system markedly suppresses its tumorigencity. These results suggest that miR-17* may suppress tumorigenicity of prostate cancer through inhibition of mitochondrial antioxidant enzymes.

  1. Long-term stable expression of antisense cDNA of cyclin B1 profoundly inhibits the proliferation of tumor cells and suppresses tumorigenicity in implanted mice

    Institute of Scientific and Technical Information of China (English)

    ZHANG Tao; SU Xiao-mei; ZHANG Ling; LI Ji-cheng; WEI Dong; WEI Yu-quan; ZHANG Ru; CHENG Peng; CHEN Xian-cheng; LIU Huan-yi

    2008-01-01

    Background Cyclin B1 (CLB1) is necessary for mitotic initiation in mammalian cells and plays important roles in cancer development. Therefore, a potential strategy in cancer therapy is to suppress the activity of CLB1 by delivering antisense constructs of CLB1 into tumor cells. In previous CLB1 studies, antisense constructs with a short half life were often used and these constructs might not persistently inhibit CLB1.Methods We successfully created a recombinant plasmid encoding the full-length antisense cDNA of mouse cyclin B1 (AS-mCLB1) and transfected this construct to the murine Lewis lung carcinoma (LL/2) and CT-26 colon carcinoma (CT-26) cells. We isolated clones of LL/2 and CT-26 transfectants with stable expression of AS-mGLB1. Reverse transcriptional polymerase chain reaction (RT-PCR) and Western blot were applied to detect the expression of the mRNA and protein levels of CLB1. To further test the efficacy of this strategy in vivo, AS-mCLBl-expressing LL/2 and CT-26 transfectants were implanted into mice.Results We found the expression of the mRNA and protein levels of CLB1 decrease in these trensfectants. The inhibition of CLB1 caused prominent G1 arrest, abnormal morphology, retarded cell growth and an increase in apoptosis. In AS-mCLB1-expressing LL/2 and CT-26 transfectants implanted mice, tumorigenicity was effectively suppressed compared with the controls. In addition, the expression of AS-mCLB1 also significantly increases the survival duration of implanted animals.Conclusion AS-mCLB1 is likely to be useful in future cancer therapy, which may be associated with its ability to down-regulate the expression of CLB1 and then induce G1 arrest and apoptosis in tumor cells.

  2. Usp9x regulates Ets-1 ubiquitination and stability to control NRAS expression and tumorigenicity in melanoma.

    Science.gov (United States)

    Potu, Harish; Peterson, Luke F; Kandarpa, Malathi; Pal, Anupama; Sun, Hanshi; Durham, Alison; Harms, Paul W; Hollenhorst, Peter C; Eskiocak, Ugur; Talpaz, Moshe; Donato, Nicholas J

    2017-02-15

    ETS transcription factors are commonly deregulated in cancer by chromosomal translocation, overexpression or post-translational modification to induce gene expression programs essential in tumorigenicity. Targeted destruction of these proteins may have therapeutic impact. Here we report that Ets-1 destruction is regulated by the deubiquitinating enzyme, Usp9x, and has major impact on the tumorigenic program of metastatic melanoma. Ets-1 deubiquitination blocks its proteasomal destruction and enhances tumorigenicity, which could be reversed by Usp9x knockdown or inhibition. Usp9x and Ets-1 levels are coincidently elevated in melanoma with highest levels detected in metastatic tumours versus normal skin or benign skin lesions. Notably, Ets-1 is induced by BRAF or MEK kinase inhibition, resulting in increased NRAS expression, which could be blocked by inactivation of Usp9x and therapeutic combination of Usp9x and MEK inhibitor fully suppressed melanoma growth. Thus, Usp9x modulates the Ets-1/NRAS regulatory network and may have biologic and therapeutic implications.

  3. Neural Stem Cell Tumorigenicity and Biodistribution Assessment for Phase I Clinical Trial in Parkinson’s Disease

    Science.gov (United States)

    Garitaonandia, Ibon; Gonzalez, Rodolfo; Christiansen-Weber, Trudy; Abramihina, Tatiana; Poustovoitov, Maxim; Noskov, Alexander; Sherman, Glenn; Semechkin, Andrey; Snyder, Evan; Kern, Russell

    2016-01-01

    Human pluripotent stem cells (PSC) have the potential to revolutionize regenerative medicine. However undifferentiated PSC can form tumors and strict quality control measures and safety studies must be conducted before clinical translation. Here we describe preclinical tumorigenicity and biodistribution safety studies that were required by the US Food and Drug Administration (FDA) and Australian Therapeutic Goods Administration (TGA) prior to conducting a Phase I clinical trial evaluating the safety and tolerability of human parthenogenetic stem cell derived neural stem cells ISC-hpNSC for treating Parkinson’s disease (ClinicalTrials.gov Identifier NCT02452723). To mitigate the risk of having residual PSC in the final ISC-hpNSC population, we conducted sensitive in vitro assays using flow cytometry and qRT-PCR analyses and in vivo assays to determine acute toxicity, tumorigenicity and biodistribution. The results from these safety studies show the lack of residual undifferentiated PSC, negligible tumorigenic potential by ISC-hpNSC and provide additional assurance to their clinical application. PMID:27686862

  4. Further Report on Carcinogenesis or Tumorigenicity of MDCK Canine Kidney Cell(CKC) Lines and Analysis of Their Chromosome Karyotypes

    Institute of Scientific and Technical Information of China (English)

    ZHANG De-li; FANG Fu-de; XIA Geng-tian; HE Xu-yu; GAO Bu-xian; BAI Xiao-hong; LI Liu-jin; HUANG Gao-sheng; LIU Shang-gao; YEN Lung-fei

    2002-01-01

    Using Hela cell cultures as positive control and primary canine kidney cell (CKC) or feline kidney cell (FKC) cultures purified in vitro on passage 3 as negative control, the tumorigenicity of Madin-Darby canine kidney (MDCK) cells was tested in >273 nude mice, and colony formation in soft agarose and haemagglutination under different concentration of plant lectins of these cells were carried out at the same time. Subsequently, very low tumorigenicity strains of MDCK line were successfully selected; these were evaluated for the production of canine or feline combination viral vaccines, free of infectious agents, and of known cytogenetic and tumorigenic. It is thus evident that MDCK cell of M, JB, JC, WB or H strain can be approved as substrate for the preparation of attenuated viral vaccines, but MDCK cell of YA, YB and KA strains can not be approved as substrate for the preparation of attenuated viral vaccines. The heritable character of these cell sub-lines is comparatively stable, and shows little significant difference between passages.

  5. Usp9x regulates Ets-1 ubiquitination and stability to control NRAS expression and tumorigenicity in melanoma

    Science.gov (United States)

    Potu, Harish; Peterson, Luke F.; Kandarpa, Malathi; Pal, Anupama; Sun, Hanshi; Durham, Alison; Harms, Paul W.; Hollenhorst, Peter C.; Eskiocak, Ugur; Talpaz, Moshe; Donato, Nicholas J.

    2017-01-01

    ETS transcription factors are commonly deregulated in cancer by chromosomal translocation, overexpression or post-translational modification to induce gene expression programs essential in tumorigenicity. Targeted destruction of these proteins may have therapeutic impact. Here we report that Ets-1 destruction is regulated by the deubiquitinating enzyme, Usp9x, and has major impact on the tumorigenic program of metastatic melanoma. Ets-1 deubiquitination blocks its proteasomal destruction and enhances tumorigenicity, which could be reversed by Usp9x knockdown or inhibition. Usp9x and Ets-1 levels are coincidently elevated in melanoma with highest levels detected in metastatic tumours versus normal skin or benign skin lesions. Notably, Ets-1 is induced by BRAF or MEK kinase inhibition, resulting in increased NRAS expression, which could be blocked by inactivation of Usp9x and therapeutic combination of Usp9x and MEK inhibitor fully suppressed melanoma growth. Thus, Usp9x modulates the Ets-1/NRAS regulatory network and may have biologic and therapeutic implications. PMID:28198367

  6. Cyclophosphamide-refractory scleroderma-associated interstitial lung disease: remarkable clinical and radiological response to a single course of rituximab combined with high-dose corticosteroids.

    LENUS (Irish Health Repository)

    Haroon, Muhammad

    2011-10-01

    We would like to report our experience of using rituximab in cyclophosphamide refractory, rapidly progressive interstitial lung disease (ILD) in a patient with limited scleroderma. A 40-year-old man presented with 10-week history of inflammatory polyarthritis, which responded to a short course of oral corticosteroids. However, 3 weeks later, he developed new onset of exertional dyspnoea. High-resolution CT of the thorax was suggestive of early ILD. Surgical lung biopsy showed features of fibrotic non-specific interstitial pneumonia. He was diagnosed with scleroderma on the basis of: presence of anticentromere antibodies, Raynaud\\'s phenomenon, pulmonary fibrosis, digital oedema and hypomotility along with a dilated oesophagus. He was treated aggressively with pulse doses of corticosteroids and cyclophosphamide; however, his ILD continued to deteriorate. At this stage, he received rituximab (two pulses of 1 g each), which led to a gradual clinical improvement. Now, 12 months since his rituximab infusion, he walks 2 miles daily without any exertional dyspnoea.

  7. High-definition imaging of circulating tumor cells and associated cellular events in non-small cell lung cancer patients: a longitudinal analysis

    Science.gov (United States)

    Nieva, Jorge; Wendel, Marco; Luttgen, Madelyn S.; Marrinucci, Dena; Bazhenova, Lyudmila; Kolatkar, Anand; Santala, Roger; Whittenberger, Brock; Burke, James; Torrey, Melissa; Bethel, Kelly; Kuhn, Peter

    2012-02-01

    Sampling circulating tumor cells (CTCs) from peripheral blood is ideally accomplished using assays that detect high numbers of cells and preserve them for downstream characterization. We sought to evaluate a method using enrichment free fluorescent labeling of CTCs followed by automated digital microscopy in patients with non-small cell lung cancer. Twenty-eight patients with non-small cell lung cancer and hematogenously seeded metastasis were analyzed with multiple blood draws. We detected CTCs in 68% of analyzed samples and found a propensity for increased CTC detection as the disease progressed in individual patients. CTCs were present at a median concentration of 1.6 CTCs ml-1 of analyzed blood in the patient population. Higher numbers of detected CTCs were associated with an unfavorable prognosis.

  8. Fatal interstitial lung disease associated with high erlotinib and metabolite levels. A case report and a review of the literature.

    NARCIS (Netherlands)

    Heine, R. ter; Bosch, R.T. van den; Schaefer-Prokop, C.M.; Lankheet, N.A.; Beijnen, J.H.; Staaks, G.H.; Westerlaken, M.M. van der; Malingre, M.M.; Brand, J.J. van den

    2012-01-01

    INTRODUCTION: Erlotinib is an agent in the class of oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Although this class of agents is considered to be relatively safe, the most serious, but rare, adverse reaction is drug-associated interstitial lung disease (ILD). This potent

  9. Rapid test for lung maturity, based on spectroscopy of gastric aspirate, predicted respiratory distress syndrome with high sensitivity

    DEFF Research Database (Denmark)

    Verder, Henrik; Heiring, Christian; Clark, Howard

    2017-01-01

    for targeting surfactant supplementation. METHODS: Concentrations of the most surface-active lung phospholipid dipalmitoylphosphatidylcholine and sphingomyelin in gastric aspirates from premature infants were measured by mass spectrometry and expressed as the lecithin/sphingomyelin ratio (L/S). The same...

  10. Rapid test for lung maturity, based on spectroscopy of gastric aspirate, predicted respiratory distress syndrome with high sensitivity

    DEFF Research Database (Denmark)

    Verder, Henrik; Heiring, Christian; Clark, Howard

    2017-01-01

    AIM: Respiratory distress syndrome (RDS) is a major cause of mortality and morbidity in premature infants. By the time symptoms appear, it may already be too late to prevent a severe course, with bronchopulmonary dysplasia or mortality. We aimed to develop a rapid test of lung maturity for target...

  11. Buffer optimization for high resolution of human lung cancer tissue proteins by two-dimensional gel electrophoresis.

    Science.gov (United States)

    Lee, Kibeom; Pi, Kyungbae; Lee, Keeman

    2009-01-01

    A problem in proteomic analysis of lung cancer tissue is the presence of complex components of different histological backgrounds (squamous cell carcinoma, small cell lung carcinoma, and adenocarcinoma). The efficient solubilization of protein components before two-dimensional electrophoresis (2-DE) is a very critical. Poor solubilization has been associated with a failure to detect proteins and diffuse, streaked and/or trailing protein spots. Here, we have optimized the solubilization of human lung cancer tissue to increase protein resolution. Isoelectric focusing (IEF) rehydration buffer containing a thiourea-urea mixture provided superior resolution, whereas a buffer without thiourea yielded consistently poor results. In addition, IEF rehydration buffers containing CHAPS and DTT gave superior resolution, whereas buffers containing Nonidet P-40 (NP-40) and/or Triton X-100 did not. A tributylphosphine-containing buffer gave consistently poor results. Using optimized conditions, we used 2-D gel analysis of human lung cancer tissue to identify 11 differentially-expressed protein spots by MALDI-mass spectrometry. This study provides a methodological tool to study the complex mammalian proteomes.

  12. Qualitative assessment of general movements in high-risk preterm infants with chronic lung disease requiring dexamethasone therapy

    NARCIS (Netherlands)

    Bos, AF; Martijn, A; van Asperen, RM; Hadders-Algra, M; Okken, A; Prechtl, HFR

    1998-01-01

    Objective: The objective of this study was to determine in preterm infants al risk for severe chronic lung disease (1) the quality of general movements (GMs) and (2) the effect of dexamethasone treatment on spontaneous motor activity. Study design: In 15 very low birth weight infants the quality of

  13. Tumor Expression of the Carcinoembryonic Antigen Correlates with High Mitotic Activity and Cell Pleomorphism Index in Lung Carcinoma

    Directory of Open Access Journals (Sweden)

    Rancés Blanco

    2013-01-01

    Full Text Available At present, some research efforts are focusing on the evaluation of a variety of tumor associated antigens (TAAs for a better understanding of tumor biology and genetics of lung tumors. For this reason, we evaluated the tissue expression of carcinoembryonic antigen (CEA and ior C2 (a cell surface O-linked glycoprotein carbohydrate chain TAA in lung carcinomas, as well as its correlation with a variety of clinicopathological features. The tissue expression of CEA was evidenced in 22/43 (51.16% lung carcinomas and it was correlated with mitotic activity, cell pleomorphism indexes, and age of patients. The expression of ior C2 was observed in 15/43 (34.88% tumors but no correlation with the clinicopathological features mentioned above was obtained. No correlation between both CEA and ior C2 antigens expression and the overall survival (OS of non-small-cell lung cancer patients was also observed. However, CEA-negative patients displayed higher OS rates as compared with positive ones (69.74 versus 58.26 months. Our results seem to be in agreement with the role of CEA expression in tumor cell proliferation, inhibition of cell polarizations and tissue architecture distortion. The significance of ior C2 antigen in these malignancies and it potential use in diagnosis, prognosis, and/or immunotherapy must be reevaluated.

  14. High specificity but low sensitivity of mutation-specific antibodies against EGFR mutations in non-small-cell lung cancer

    DEFF Research Database (Denmark)

    Bondgaard, Anna-Louise; Høgdall, Estrid; Mellemgaard, Anders;

    2014-01-01

    Determination of epidermal growth factor receptor (EGFR) mutations has a pivotal impact on treatment of non-small-cell lung cancer (NSCLC). A standardized test has not yet been approved. So far, Sanger DNA sequencing has been widely used. Its rather low sensitivity has led to the development...

  15. CLINICAL EVALUATION OF THE MANIFESTATIONS OF INTERSTITIAL LUNG INJURYIN SYSTEMIC SCLERODERMA FROM HIGH-RESOLUTION COMPUTER T OMOGRAPHY DATA

    Directory of Open Access Journals (Sweden)

    L P Anan'eva

    2011-01-01

    Conclusion. Chest HRCT reveals the characteristic symptoms of ILI and reflects different phases of a fibrosing process in the lung. It is essential to make an in-depth examination using HRCT in all patients with SDD, irrespective of its clinical form in the earliest periods for the timely detection and treatment of ILI.

  16. Monocyte chemotactic protein-1 deficiency reduces spontaneous metastasis of Lewis lung carcinoma in mice fed a high-fat diet

    Science.gov (United States)

    Obesity is a risk factor for cancer. Adipose tissue produces pro-inflammatory adipokines that contribute obesity-related malignant progression. This study investigated the effects of monocyte chemotactic protein-1 (MCP-1) deficiency on pulmonary metastasis of Lewis lung carcinoma (LLC) in male C57...

  17. Acrylamide-induced carcinogenicity in mouse lung involves mutagenicity: cII gene mutations in the lung of big blue mice exposed to acrylamide and glycidamide for up to 4 weeks.

    Science.gov (United States)

    Manjanatha, Mugimane G; Guo, Li-Wu; Shelton, Sharon D; Doerge, Daniel R

    2015-06-01

    Potential health risks for humans from exposure to acrylamide (AA) and its epoxide metabolite glycidamide (GA) have garnered much attention lately because substantial amounts of AA are present in a variety of fried and baked starchy foods. AA is tumorigenic in rodents, and a large number of in vitro and in vivo studies indicate that AA is genotoxic. A recent cancer bioassay on AA demonstrated that the lung was one of the target organs for tumor induction in mice; however, the mutagenicity of AA in this tissue is unclear. Therefore, to investigate whether or not gene mutation is involved in the etiology of AA- or GA-induced mouse lung carcinogenicity, we screened for cII mutant frequency (MF) in lungs from male and female Big Blue (BB) mice administered 0, 1.4, and 7.0 mM AA or GA in drinking water for up to 4 weeks (19-111 mg/kg bw/days). Both doses of AA and GA produced significant increases in cII MFs, with the high doses producing responses 2.7-5.6-fold higher than the corresponding controls (P ≤ 0.05; control MFs = 17.2 ± 2.2 and 15.8 ± 3.5 × 10(-6) in males and females, respectively). Molecular analysis of the mutants from high doses indicated that AA and GA produced similar mutation spectra and that these spectra were significantly different from the spectra in control mice (P ≤ 0.01). The predominant types of mutations in the lung cII gene from AA- and GA-treated mice were A:T → T:A, and G:C → C:G transversions, and -1/+1 frameshifts at a homopolymeric run of Gs. The MFs and types of mutations induced by AA and GA in the lung are consistent with AA exerting its genotoxicity via metabolism to GA. These results suggest that AA is a mutagenic carcinogen in mouse lungs and therefore further studies on its potential health risk to humans are warranted. Environ. Mol. Mutagen. 56:446-456, 2015. © 2015 Wiley Periodicals, Inc.

  18. Multiple cystic lung disease

    Directory of Open Access Journals (Sweden)

    Flavia Angélica Ferreira Francisco

    2015-12-01

    Full Text Available Multiple cystic lung disease represents a diverse group of uncommon disorders that can present a diagnostic challenge due to the increasing number of diseases associated with this presentation. High-resolution computed tomography of the chest helps to define the morphological aspects and distribution of lung cysts, as well as associated findings. The combination of appearance upon imaging and clinical features, together with extrapulmonary manifestations, when present, permits confident and accurate diagnosis of the majority of these diseases without recourse to open-lung biopsy. The main diseases in this group that are discussed in this review are lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis and folliculin gene-associated syndrome (Birt–Hogg–Dubé; other rare causes of cystic lung disease, including cystic metastasis of sarcoma, are also discussed. Disease progression is unpredictable, and understanding of the complications of cystic lung disease and their appearance during evolution of the disease are essential for management. Correlation of disease evolution and clinical context with chest imaging findings provides important clues for defining the underlying nature of cystic lung disease, and guides diagnostic evaluation and management.

  19. Targeting the Renin–Angiotensin System Combined With an Antioxidant Is Highly Effective in Mitigating Radiation-Induced Lung Damage

    Energy Technology Data Exchange (ETDEWEB)

    Mahmood, Javed [Ontario Cancer Institute and the Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Radiation Medicine Program, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Ontario (Canada); Jelveh, Salomeh [Radiation Medicine Program, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Ontario (Canada); Zaidi, Asif [Ontario Cancer Institute and the Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Doctrow, Susan R. [Pulmonary Center, Department of Medicine, Boston University, Boston, Massachusetts (United States); Medhora, Meetha [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Hill, Richard P., E-mail: hill@uhnres.utoronto.ca [Ontario Cancer Institute and the Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Departments of Medical Biophysics and Radiation Oncology, University of Toronto, Toronto, Ontario (Canada)

    2014-07-15

    Purpose: To investigate the outcome of suppression of the renin angiotensin system using captopril combined with an antioxidant (Eukarion [EUK]-207) for mitigation of radiation-induced lung damage in rats. Methods and Materials: The thoracic cavity of female Sprague-Dawley rats was irradiated with a single dose of 11 Gy. Treatment with captopril at a dose of 40 mg/kg/d in drinking water and EUK-207 given by subcutaneous injection (8 mg/kg daily) was started 1 week after irradiation (PI) and continuing until 14 weeks PI. Breathing rate was monitored until the rats were killed at 32 weeks PI, when lung fibrosis was assessed by lung hydroxyproline content. Lung levels of the cytokine transforming growth factor-β1 and macrophage activation were analyzed by immunohistochemistry. Oxidative DNA damage was assessed by 8-hydroxy-2-deoxyguanosine levels, and lipid peroxidation was measured by a T-BARS assay. Results: The increase in breathing rate in the irradiated rats was significantly reduced by the drug treatments. The drug treatment also significantly decreased the hydroxyproline content, 8-hydroxy-2-deoxyguanosine and malondialdehyde levels, and levels of activated macrophages and the cytokine transforming growth factor-β1 at 32 weeks. Almost complete mitigation of these radiation effects was observed by combining captopril and EUK-207. Conclusion: Captopril and EUK-207 can provide mitigation of radiation-induced lung damage out to at least 32 weeks PI after treatment given 1-14 weeks PI. Overall the combination of captopril and EUK-207 was more effective than the individual drugs used alone.

  20. Lung Transplant

    Science.gov (United States)

    ... will recover in the hospital’s intensive care unit (ICU) before moving to a hospital room for one to three weeks. Your doctor may recommend pulmonary rehabilitation after your lung transplant surgery to help you ...

  1. BRCA1 regulation on β-hCG: a mechanism for tumorigenicity in BRCA1 defective breast cancer.

    Science.gov (United States)

    Sengodan, S K; Nadhan, R; Nair, R S; Hemalatha, S K; Somasundaram, V; Sushama, R R; Rajan, A; Latha, N R; Varghese, G R; Thankappan, R K; Kumar, J M; Chil, A; Anilkumar, T V; Srinivas, P

    2017-09-04

    Human chorionic gonadotropin β (β-hCG) has been implicated in breast tumorigenesis. However, the role of this hormone is highly controversial as certain studies suggest it has anti-tumor properties while others have found it to be pro-tumorigenic. To unveil the truth, we have analyzed the expression of β-hCG in breast cancer. We identified for the first time that β-hCG expression is linked to BRCA1 status and its overexpression is seen in BRCA1 mutated breast cancer cells, BRCA1 conditional knockout mouse breast cancer tissues and BRCA1 floxed basal cell carcinoma (BCC) tissues. An analysis of three large, transcriptomic data sets from TCGA (The Cancer Genome Atlas) expression profile confirmed the inverse correlation between BRCA1 and β-hCG in human breast cancer. Using ChIP and luciferase assays, we also demonstrated that the cancer cells with wild-type but not mutant BRCA1 directly repress the expression of β-hCG by binding to its promoter. Further, β-hCG promotes migration and invasion predominantly in BRCA1 mutant breast cancer cells. Interestingly, stable overexpression of β-hCG in BRCA1 mutant but not wild-type breast cancer cells results in the formation of spheres even on monolayer cultures. The cells of these spheres show high expression of both EMT and stem cell markers. Since β-hCG belongs to a cysteine knot family of proteins like TGFβ and TGFβ signaling is deregulated in BRCA1 defective tumors, we checked whether β-hCG can mediate signaling through TGFβRII in BRCA1 mutated cells. We found for the first time that β-hCG can bind and phosphorylate TGFβRII, irrespective of LHCGR status and induce proliferation in BRCA1 defective cells. Our results confirmed that there exists a transcriptional regulation of BRCA1 on β-hCG and BRCA1 mutation promotes β-hCG mediated tumorigenesis through TGFβRII signaling. Thus inhibiting β-hCG-TGFβRII could prove an effective treatment strategy for BRCA1 mutated tumors.

  2. Activation of PPARγ in myeloid cells promotes lung cancer progression and metastasis.

    Directory of Open Access Journals (Sweden)

    Howard Li

    Full Text Available Activation of peroxisome proliferator-activated receptor-γ (PPARγ inhibits growth of cancer cells including non-small cell lung cancer (NSCLC. Clinically, use of thiazolidinediones, which are pharmacological activators of PPARγ is associated with a lower risk of developing lung cancer. However, the role of this pathway in lung cancer metastasis has not been examined well. The systemic effect of pioglitazone was examined in two models of lung cancer metastasis in immune-competent mice. In an orthotopic model, murine lung cancer cells implanted into the lungs of syngeneic mice metastasized to the liver and brain. As a second model, cancer cells injected subcutaneously metastasized to the lung. In both models systemic administration of pioglitazone increased the rate of metastasis. Examination of tissues from the orthotopic model demonstrated increased numbers of arginase I-positive macrophages in tumors from pioglitazone-treated animals. In co-culture experiments of cancer cells with bone marrow-derived macrophages, pioglitazone promoted arginase I expression in macrophages and this was dependent on the expression of PPARγ in the macrophages. To assess the contribution of PPARγ in macrophages to cancer progression, experiments were performed in bone marrow-transplanted animals receiving bone marrow from Lys-M-Cre+/PPARγ(flox/flox mice, in which PPARγ is deleted specifically in myeloid cells (PPARγ-Mac(neg, or control PPARγ(flox/flox mice. In both models, mice receiving PPARγ-Mac(neg bone marrow had a marked decrease in secondary tumors which was not significantly altered by treatment with pioglitazone. This was associated with decreased numbers of arginase I-positive cells in the lung. These data support a model in which activation of PPARγ may have opposing effects on tumor progression, with anti-tumorigenic effects on cancer cells, but pro-tumorigenic effects on cells of the microenvironment, specifically myeloid cells.

  3. Diagnostic Imaging of Lung Cancer

    Directory of Open Access Journals (Sweden)

    Kemal Kara

    2012-12-01

    Full Text Available Lung cancer is the most common cause of cancer related death in men and women. It is frequently seen among men than in women and male-female ratio is 1.5:1. Common epidemiological factors that increase risk of lung cancer is smoking. Early age to start smoking, high number of smoking cigarettes per a day and depth of inhalation increase risk of lung cancer. 25% of patients with lung cancer are nonsmokers that passively exposed to cigarette smoke. Occupational exposure to substances such as asbestos, arsenic, nickel, beryllium, mustard gas increases the risk of lung cancer. The well defined risk factor is exposure to asbestos. In addition advanced age, diffuse pulmonary fibrosis, chronic obstructive pulmonary disease (COPD and genetic predisposition are the risk factors that increases lung cancer. [TAF Prev Med Bull 2012; 11(6.000: 749-756

  4. Neutrophils support lung colonization of metastasis-initiating breast cancer cells.

    Science.gov (United States)

    Wculek, Stefanie K; Malanchi, Ilaria

    2015-12-17

    Despite progress in the development of drugs that efficiently target cancer cells, treatments for metastatic tumours are often ineffective. The now well-established dependency of cancer cells on their microenvironment suggests that targeting the non-cancer-cell component of the tumour might form a basis for the development of novel therapeutic approaches. However, the as-yet poorly characterized contribution of host responses during tumour growth and metastatic progression represents a limitation to exploiting this approach. Here we identify neutrophils as the main component and driver of metastatic establishment within the (pre-)metastatic lung microenvironment in mouse breast cancer models. Neutrophils have a fundamental role in inflammatory responses and their contribution to tumorigenesis is still controversial. Using various strategies to block neutrophil recruitment to the pre-metastatic site, we demonstrate that neutrophils specifically support metastatic initiation. Importantly, we find that neutrophil-derived leukotrienes aid the colonization of distant tissues by selectively expanding the sub-pool of cancer cells that retain high tumorigenic potential. Genetic or pharmacological inhibition of the leukotriene-generating enzyme arachidonate 5-lipoxygenase (Alox5) abrogates neutrophil pro-metastatic activity and consequently reduces metastasis. Our results reveal the efficacy of using targeted therapy against a specific tumour microenvironment component and indicate that neutrophil Alox5 inhibition may limit metastatic progression.

  5. Navigated Percutaneous Lung Ablation under High-Frequency Jet Ventilation of a Metastasis from a Wilms’ Tumour: A Paediatric Case Report

    Directory of Open Access Journals (Sweden)

    Jacob Freedman

    2016-07-01

    Full Text Available This is a case report of microwave energy being used to ablate an inoperable metastasis of a Wilms’ tumour in a 6-year-old boy using state-of-the-art navigated computed tomography targeting and high-frequency jet ventilation to reduce organ displacement and the potential risk of procedure-related pneumothorax. After the ablation, the young boy had high-dose chemotherapy followed by an autologous stem cell transplantation with rapid reduction of three recurrent right-sided lung metastases.

  6. Rapid Response to High-Dose, Pulsatile Erlotinib in Afatinib-Refractory Leptomeningeal Carcinomatosis from Adenocarcinoma of the Lung: A Case Report

    Directory of Open Access Journals (Sweden)

    Frank S. Fan

    2016-09-01

    Full Text Available Leptomeningeal carcinomatosis occurred in an old female patient who was on a standard dose of afatinib for the treatment of her non-small cell lung cancer harboring an epidermal growth factor receptor gene mutation sensitive to tyrosine kinase inhibitors when extracranial lesions were still under control. Shifting to high-dose, pulsatile erlotinib dramatically saved her from the devastating condition in a very short period of time. Inadequate afatinib concentration in cerebrospinal fluid is reasonably suspected, and there is a call for clinical trials testing high-dose afatinib in leptomeningeal carcinomatosis.

  7. Humidity and Inspired Oxygen Concentration During High-Flow Nasal Cannula Therapy in Neonatal and Infant Lung Models.

    Science.gov (United States)

    Chikata, Yusuke; Ohnishi, Saki; Nishimura, Masaji

    2017-05-01

    High-flow nasal cannula therapy (HFNC) for neonate/infants can deliver up to 10 L/min of heated and humidified gas, and FIO2 can be adjusted to between 0.21 and 1.0. With adults, humidification and actual FIO2 are known to vary according to inspiratory and HFNC gas flow, tidal volume (VT), and ambient temperature. There have been few studies focused on humidification and FIO2 in HFNC settings for neonates/infants, so we performed a bench study to investigate the influence of gas flow, ambient temperature, and respiratory parameters on humidification and actual FIO2 in a neonate/infant simulation. HFNC gas flow was set at 3, 5, and 7 L/min, and FIO2 was set at 0.3, 0.5, and 0.7. Spontaneous breathing was simulated using a 2-bellows-in-a-box model of a neonate lung. Tests were conducted with VT settings of 20, 30, and 40 mL and breathing frequencies of 20 and 30 breaths/min. Inspiratory time was 0.8 s with decelerating flow waveform. The HFNC tube was placed in an incubator, which was either set at 37°C or turned off. Absolute humidity (AH) and actual FIO2 were measured for 1 min using a hygrometer and an oxygen analyzer, and data for the final 3 breaths were extracted. At all settings, when the incubator was turned on, AH was greater than when it was turned off (P incubator was turned off, as gas flow increased, AH increased (P < .001); however, VT did not affect AH (P = .16). As gas flow increased, actual FIO2 more closely corresponded to set FIO2 . When gas flow was 3 L/min, measured FIO2 decreased proportionally more at each FIO2 setting increment (P < .001). AH was affected by ambient temperature and HFNC gas flow. Actual FIO2 depended on VT when gas flow was 3 L/min. Copyright © 2017 by Daedalus Enterprises.

  8. Rheumatoid lung disease

    Science.gov (United States)

    Lung disease - rheumatoid arthritis; Rheumatoid nodules; Rheumatoid lung ... They often cause no symptoms. The cause of lung disease associated with rheumatoid arthritis is unknown. Sometimes, the ...

  9. PA-X-associated early alleviation of the acute lung injury contributes to the attenuation of a highly pathogenic H5N1 avian influenza virus in mice.

    Science.gov (United States)

    Hu, Jiao; Mo, Yiqun; Gao, Zhao; Wang, Xiaoquan; Gu, Min; Liang, Yanyan; Cheng, Xin; Hu, Shunlin; Liu, Wenbo; Liu, Huimou; Chen, Sujuan; Liu, Xiaowen; Peng, Daxing; Liu, Xiufan

    2016-08-01

    PA-X is a novel discovered accessory protein encoded by the PA mRNA. Our previous study demonstrated that PA-X decreases the virulence of a highly pathogenic H5N1 strain A/Chicken/Jiangsu/k0402/2010 in mice. However, the underlying mechanism of virulence attenuation associated with PA-X is still unknown. In this study, we compared two PA-X-deficient mutant viruses and the parental virus in terms of induction of pathology and manipulation of host response in the mouse lung, stimulation of cell death and PA nuclear accumulation. We first found that down-regulated PA-X expression markedly aggravated the acute lung injury of the infected mice early on day 1 post-infection (p.i.). We then determined that loss of PA-X expression induced higher levels of cytokines, chemokines and complement-derived peptides (C3a and C5a) in the lung, especially at early time point's p.i. In addition, in vitro assays showed that the PA-X-deficient viruses enhanced cell death and increased expression of reactive oxygen species (ROS) in mammalian cells. Moreover, we also found that PA nuclear accumulation of the PA-X-null viruses accelerated in MDCK cells. These results demonstrate that PA-X decreases the level of complement components, ROS, cell death and inflammatory response, which may together contribute to the alleviated lung injury and the attenuation of the virulence of H5N1 virus in mice.

  10. Feasibility of Automated Quantification of Regional Disease Patterns Depicted on High-Resolution Computed Tomography in Patients with Various Diffuse Lung Diseases

    Energy Technology Data Exchange (ETDEWEB)

    Park, Sang Ok; Seo, Joon Beom; Kim, Nam Kug; Park, Bum Woo; Sung, Yu Sub; Lee, Young Joo [Asan Medical Center, Seoul (Korea, Republic of); Park, Seong Hoon [Wonkwang University Hospital, Iksan (Korea, Republic of); Lee, Young Kyung [East-West Neo Medical Center of Kyunghee University, Seoul (Korea, Republic of); Lee, Jeong Jin [The Catholic University of Korea, Seoul (Korea, Republic of); Kang, Suk Ho [Seoul National University, Seoul (Korea, Republic of)

    2009-10-15

    This study was designed to develop an automated system for quantification of various regional disease patterns of diffuse lung diseases as depicted on high-resolution computed tomography (HRCT) and to compare the performance of the automated system with human readers. A total of 600 circular regions-of-interest (ROIs), 10 pixels in diameter, were utilized. The 600 ROIs comprised 100 ROIs that represented six typical regional patterns (normal, ground-glass opacity, reticular opacity, honeycombing, emphysema, and consolidation). The ROIs were used to train the automated classification system based on the use of a Support Vector Machine classifier and 37 features of texture and shape. The performance of the classification system was tested with a 5-fold cross-validation method. An automated quantification system was developed with a moving ROI in the lung area, which helped classify each pixel into six categories. A total of 92 HRCT images obtained from patients with different diseases were used to validate the quantification system. Two radiologists independently classified lung areas of the same CT images into six patterns using the manual drawing function of dedicated software. Agreement between the automated system and the readers and between the two individual readers was assessed. The overall accuracy of the system to classify each disease pattern based on the typical ROIs was 89%. When the quantification results were examined, the average agreement between the system and each radiologist was 52% and 49%, respectively. The agreement between the two radiologists was 67%. An automated quantification system for various regional patterns of diffuse interstitial lung diseases can be used for objective and reproducible assessment of disease severity.

  11. Dentin sialophosphoprotein (DSPP gene-silencing inhibits key tumorigenic activities in human oral cancer cell line, OSC2.

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    Rajeshree Joshi

    Full Text Available BACKGROUND: We determined recently that dentin sialophosphoprotein (DSPP, a member of the SIBLING (Small integrin-binding ligand N-linked glycoproteins family of phosphoglycoproteins, is highly upregulated in human oral squamous cell carcinomas (OSCCs where upregulation is associated with tumor aggressiveness. To investigate the effects of DSPP-silencing on the tumorigenic profiles of the oral cancer cell line, OSC2, short-hairpin RNA (shRNA interference was employed to silence DSPP in OSC2 cells. METHODOLOGY/PRINCIPAL FINDINGS: Multiple regions of DSPP transcript were targeted for shRNA interference using hDSP-shRNA lentiviral particles designed to silence DSPP gene expression. Control shRNA plasmid encoding a scrambled sequence incapable of degrading any known cellular mRNA was used for negative control. Following puromycin selection of stable lines of DSSP-silenced OSC2 cells, phenotypic hallmarks of oral carcinogenesis were assayed by western blot and RT-PCR analyses, MTT (cell-viability, colony-formation, modified Boyden-Chamber (migration and invasion, and flow cytometry (cell-cycle and apoptosis analyses. DSPP-silenced OSC2 cells showed altered cell morphology, reduced viability, decreased colony-formation ability, decreased migration and invasion, G0/G1 cell-cycle arrest, and increased tumor cell sensitivity to cisplatin-induced apoptosis. Furthermore, MMP-2, MMP-3, MMP-9, VEGF, Ki-67, p53, and EGFR were down-regulated. There was a direct correlation between the degree of DSPP-silencing and MMP suppression, as indicated by least squares regression: MMP-2 {(y = 0.850x, p<0.001 (y = 1.156x, p<0.001}, MMP-3 {(y = 0.994x, p<0.001 (y = 1.324x, p = 0.004}, and MMP-9 {(y = 1.248x, p = 0.005, y = 0.809, p = 0.013}. CONCLUSIONS/SIGNIFICANCE: DSPP-silencing in OSC2 cell decreased salient hallmarks of oral tumorigenesis and provides the first functional evidence of a potential key role for DSPP in oral cancer

  12. Bortezomib reduces the tumorigenicity of multiple myeloma via downregulation of upregulated targets in clonogenic side population cells.

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    Miho Nara

    Full Text Available Side population (SP cells in cancers, including multiple myeloma, exhibit tumor-initiating characteristics. In the present study, we isolated SP cells from human myeloma cell lines and primary tumors to detect potential therapeutic targets specifically expressed in SP cells. We found that SP cells from myeloma cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11 express CD138 and that non-SP cells include a CD138-negative population. Serial transplantation of SP and non-SP cells into NOD/Shi-scid IL-2γnul mice revealed that clonogenic myeloma SP cells are highly tumorigenic and possess a capacity for self-renewal. Gene expression analysis showed that SP cells from five MM cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11, JJN3 express genes involved in the cell cycle and mitosis (e.g., CCNB1, CDC25C, CDC2, BIRC5, CENPE, SKA1, AURKB, KIFs, TOP2A, ASPM, polycomb (e.g., EZH2, EPC1 and ubiquitin-proteasome (e.g., UBE2D3, UBE3C, PSMA5 more strongly than do non-SP cells. Moreover, CCNB1, AURKB, EZH2 and PSMA5 were also upregulated in the SPs from eight primary myeloma samples. On that basis, we used an aurora kinase inhibitor (VX-680 and a proteasome inhibitor (bortezomib with RPMI 8226 and AMO1 cells to determine whether these agents could be used to selectively target the myeloma SP. We found that both these drugs reduced the SP fraction, though bortezomib did so more effectively than VX-680 due to its ability to reduce levels of both phospho-histone H3 (p-hist. H3 and EZH2; VX-680 reduced only p-hist. H3. This is the first report to show that certain oncogenes are specifically expressed in the myeloma SP, and that bortezomib effectively downregulates expression of their products. Our approach may be useful for screening new agents with which to target a cell population possessing strong tumor initiating potential in multiple myeloma.

  13. Lung transplantation for cystic fibrosis

    NARCIS (Netherlands)

    Adler, Frederick R; Aurora, Paul; Barker, David H; Barr, Mark L; Blackwell, Laura S; Bosma, Otto H; Brown, Samuel; Cox, D R; Jensen, Judy L; Kurland, Geoffrey; Nossent, George D; Quittner, Alexandra L; Robinson, Walter M; Romero, Sandy L; Spencer, Helen; Sweet, Stuart C; van der Bij, Wim; Vermeulen, J; Verschuuren, Erik A M; Vrijlandt, Elianne J L E; Walsh, William; Woo, Marlyn S; Liou, Theodore G

    2009-01-01

    Lung transplantation is a complex, high-risk, potentially life-saving therapy for the end-stage lung disease of cystic fibrosis (CF). The decision to pursue transplantation involves comparing the likelihood of survival with and without transplantation as well as assessing the effect of wait-listing

  14. High-Resolution Computed Tomography and Chest X-Ray Findings of Interstitial Lung Disease Related to Systemic Sclerosis

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    V. Sheikh

    2012-07-01

    Full Text Available Introduction & Objective: Interstitial lung disease is the leading cause of mortality and morbidity in patients with scleroderma. For this reason an early diagnosis of lung involvement is warranted. The best approach to detect pulmonary disease particularly alveolitis (inflammatory NSIP as a reversible phase is controversial. The aim of this study is estimating the advantage of HRCT as a noninvasive screening test to detect the pattern of ILD related to systemic sclerosis.Materials & Methods: In this cross sectional study, 52 patients with scleroderma who referred to rheumatologic medical center from 2010 to 2011 were evaluated for ILD by the use of history, physical examination, CXR and HRCT. Finally, all the data were analyzed using SPSS13 software.Results: HRCT was normal in 21 patients (40.4%, and NSIP in 19 patients (36.5% and UIP in 12 patients (23.1% were reported. CXR was normal in 19 (36.5% and mild reticular pattern in 15 (28.8%, overt reticular pattern in 14 (26.9% and honey combing in 4 (7.7% were seen. HRCT findings were abnormal in 6(11.5% patients without dyspnea, 22(42.3% without cough, 20(38.4% without crackle in lung auscultation and 26(50% without clubbing in physical examination. In 2(3.8% patients no pulmonary signs and symptoms UIP were reported.Conclusion: HRCT is a noninvasive method to detect lung involvement in early phases independent of presence or absence of pulmonary signs and symptoms.(Sci J Hamadan Univ Med Sci 2012;19(2:16-22

  15. Chrysotile effects on the expression of anti-oncogene P53 and P16 and oncogene C-jun and C-fos in Wistar rats' lung tissues.

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    Cui, Yan; Wang, Yuchan; Deng, Jianjun; Hu, Gongli; Dong, Faqin; Zhang, Qingbi

    2017-09-13

    Chrysotile is the most widely used form of asbestos worldwide. China is the world's largest consumer and second largest producer of chrysotile. The carcinogenicity of chrysotile has been extensively documented, and accumulative evidence has shown that chrysotile is capable of causing lung cancer and other forms of cancer. However, molecular mechanisms underlying the tumorigenic effects of chrysotile remained poorly understood. To explore the carcinogenicity of chrysotile, Wistar rats were administered by intratracheal instillation (by an artificial route of administration) for 0, 0.5, 2, or 8 mg/ml of natural chrysotile (from Mangnai, Qinghai, China) dissolved in saline, repeated once a month for 6 months (a repeated high-dose exposure which may have little bearing on the effects following human exposure). The lung tissues were analyzed for viscera coefficients and histopathological alterations. Expression of P53, P16, C-JUN, and C-FOS was measured by western blotting and qRT-PCR. Our results found that chrysotile exposure leads the body weight to grow slowly and lung viscera coefficients to increase in a dose-dependent manner. General sample showed white nodules, punctiform asbestos spots, and irregular atrophy; moreover, HE staining revealed inflammatory infiltration, damage of alveolar structures, agglomerations, and pulmonary fibrosis. In addition, chrysotile can induce inactivation of the anti-oncogene P53 and P16 and activation of the proto-oncogenes C-JUN and C-FOS both in the messenger RNA and protein level. In conclusion, chrysotile induced an imbalanced expression of cancer-related genes in rats' lung tissue. These results contribute to our understanding of the carcinogenic mechanism of chrysotile.

  16. Lung Cancer Stem Cells

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    Sharon R. Pine

    2008-01-01

    Full Text Available Lung cancer remains a major cause of cancer-related lethality because of high incidence and recurrence in spite of significant advances in staging and therapies. Recent data indicates that stem cells situated throughout the airways may initiate cancer formation. These putative stem cells maintain protumorigenic characteristics including high proliferative capacity, multipotent differentiation, drug resistance and long lifespan relative to other cells. Stem cell signaling and differentiation pathways are maintained within distinct cancer types, and destabilization of this machinery may participate in maintenance of cancer stem cells. Characterization of lung cancer stem cells is an area of active research and is critical for developing novel therapies. This review summarizes the current knowledge on stem cell signaling pathways and cell markers used to identify the lung cancer stem cells.

  17. Highly expressed N1-acetylpolyamine oxidase detoxifies polyamine analogue N1-cyclopropylmethyl-N11-ethylnorspermine in human lung cancer cell line A549

    Institute of Scientific and Technical Information of China (English)

    HAN Yu; REN Yu-san; CAO Chun-yu; REN Dong-ming; ZHOU Yong-qin; WANG Yan-lin

    2009-01-01

    Background The critical roles of polyamines in cell growth and differentiation have made polyamine metabolic pathway a promising target for antitumor therapy. Recent studies have demonstrated in vitro that some antitumor polyamine analogues could be used as substrates and oxidized by purified recombinant human N1-acetylpolyamine oxidase (APAO, an enzyme that catabolizes natural polyamines), indicating a potential role of APAO in determining the sensitivity of cancer cells to specific antitumor analogues. This study evaluated, in vivo, the effect of APAO on cytotoxicity of antitumor polyamine analogue, N1-cyclopropylmethyI-N11-ethylnorspermine (CPENS) and its mechanism when highly expressed in human lung cancer line A549.Methods A clone with high expression of APAO was obtained by transfecting A549 lung cancer cell line with pcDNA3.1/APAO plasmid and selecting with quantitative realtime PCR and APAO activity assay. Cell proliferation was determined by MTT method and apoptosis related events were evaluated by DNA fragmentation, sub-G1/flow cytometric assay, western blotting (for cytochrome C and Bax) and colorimetric assay (for casapse-3 activity). Results A clone highly expressing APAO was obtained. High expression of APAO in A549 cells inhibited accumulation of CPENS, decreased their sensitivity to the toxicity of CPENS and prevented CPENS induced apoptosis. Conclusion These results indicate a new drug resisting, mechanism in the tumor cells. High expression of APAO can greatly decrease the sensitivity of tumor cells to the specific polyamine analogues by detoxitying those analogues and prevent analogue induced apoptosis.

  18. High-frequency percussive ventilation and initial biomarker levels of lung injury in patients with minor burns after smoke inhalation injury.

    Science.gov (United States)

    Reper, P; Heijmans, W

    2015-02-01

    Several biological markers of lung injury are predictors of morbidity and mortality in patients with acute respiratory distress syndrome (ARDS). Some lung-protective ventilation strategies, such as low tidal volume, are associated with a significant decrease in plasma biomarker levels compared to the high tidal volume ventilation strategy. The primary objective of this study was to test whether the institution of high-frequency percussive ventilation (HFPV) to patients with respiratory distress after smoke inhalation injury influenced initial biomarker levels of lung injury (just before and after using percussive ventilation). A prospective observational cohort study was conducted in the intensive care unit of the Brussels Burn Center. Fifteen intubated, mechanically ventilated patients with minor burns and ARDS following smoke inhalation were enrolled in our study. Physiologic data and serum samples were collected before intubation and at four different time points within the first 48h after intubation to measure the concentration of interleukin (IL)-6, IL-8, and tumor necrosis factor-α (TNF alpha). The differences in biomarker levels before and after starting HFPV were analyzed using repeated measure analysis of variance and a paired t test with correction for multiple comparisons. Before starting HFPV under endotracheal intubation, all biological markers (IL-6, IL-8, and TNF alpha) were elevated in the spontaneously breathing patients with acute lung injury (ALI). After intubation and institution of a positive pressure ventilation with HFPV (tidal volume 5.6-6.6ml/kg per ideal body weight), none of the biological markers were increased significantly at either an early (3±2h) or a later point in time. However, the levels of IL-8 had decreased significantly after intubation at a later point in time. During the post-intubation period, the PaO2/FiO2 (partial pressure of arterial oxygen/fraction of the inspired oxygen) ratio increased significantly and the plateau

  19. Loss of HSulf-1 expression enhances tumorigenicity by inhibiting Bim expression in ovarian cancer.

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    He, Xiaoping; Khurana, Ashwani; Roy, Debarshi; Kaufmann, Scott; Shridhar, Viji

    2014-10-15

    The expression of human Sulfatase1 (HSulf-1) is downregulated in the majority of primary ovarian cancer tumors, but the functional consequence of this downregulation remains unclear. Using two different shRNAs (Sh1 and Sh2), HSulf-1 expression was stably downregulated in ovarian cancer OV202 cells. We found that HSulf-1-deficient OV202 Sh1 and Sh2 cells formed colonies in soft agar. In contrast, nontargeting control (NTC) shRNA-transduced OV202 cells did not form any colonies. Moreover, subcutaneous injection of OV202 HSulf-1-deficient cells resulted in tumor formation in nude mice, whereas OV202 NTC cells did not. Also, ectopic expression of HSulf-1 in ovarian cancer SKOV3 cells significantly suppressed tumor growth in nude mice. Here, we show that HSulf-1-deficient OV202 cells have markedly decreased expression of proapoptotic Bim protein, which can be rescued by restoring HSulf-1 expression in OV202 Sh1 cells. Enhanced expression of HSulf-1 in HSulf-1-deficient SKOV3 cells resulted in increased Bim expression. Decreased Bim levels after loss of HSulf-1 were due to increased p-ERK, because inhibition of ERK activity with PD98059 resulted in increased Bim expression. However, treatment with a PI3 kinase/AKT inhibitor, LY294002, failed to show any change in Bim protein level. Importantly, rescuing Bim expression in HSulf-1 knockdown cells significantly retarded tumor growth in nude mice. Collectively, these results suggest that loss of HSulf-1 expression promotes tumorigenicity in ovarian cancer through regulating Bim expression.

  20. Integrin-linked kinase overexpression and its oncogenic role in promoting tumorigenicity of hepatocellular carcinoma.

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    Jenny Chan

    Full Text Available BACKGROUND: Integrin-linked kinase (ILK was first discovered as an integrin β1-subunit binding protein. It localizes at the focal adhesions and is involved in cytoskeleton remodeling. ILK overexpression and its dysregulated signaling cascades have been reported in many human cancers. Aberrant expression of ILK influenced a wide range of signaling pathways and cellular functions. Although ILK has been well characterized in many malignancies, its role in hepatocellular carcinoma (HCC is still largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Quantitative PCR analysis was used to examine ILK mRNA expression in HCC clinical samples. It was shown that ILK was overexpressed in 36.9% (21/57 of HCC tissues when compared to the corresponding non-tumorous livers. The overall ILK expression level was significantly higher in tumorous tissues (P = 0.004, with a significant stepwise increase in expression level along tumor progression from tumor stage I to IV (P = 0.045. ILK knockdown stable clones were established in two HCC cell lines, BEL7402 and HLE, and were subjected to different functional assays. Knockdown of ILK significantly suppressed HCC cell growth, motility and invasion in vitro and inhibited tumorigenicity in vivo. Western blot analysis revealed a reduced phosphorylated-Akt (pAkt at Serine-473 expression in ILK knockdown stable clones when compared to control clones. CONCLUSION/SIGNIFICANCE: This study provides evidence about the clinical relevance of ILK in hepatocarcinogenesis. ILK was found to be progressively elevated along HCC progression. Here our findings also provide the first validation about the oncogenic capacity of ILK in vivo by suppressing its expression in HCC cells. The oncogenic role of ILK is implicated to be mediated by Akt pathway.

  1. Neogenin expression may be inversely correlated to the tumorigenicity of human breast cancer

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    Kim Sung-Won

    2005-12-01

    Full Text Available Abstract Background Neogenin is expressed in cap cells that have been suggested to be mammary stem or precursor cells. Neogenin is known to play an important role in mammary morphogenesis; however its relationship to tumorigenesis remains to be elucidated. Methods To compare the expression levels of neogenin in cells with different tumorigenicity, the expression levels in M13SV1, M13SV1R2 and M13SV1R2N1 cells, which are immortalized derivatives of type I human breast epithelial cells, were evaluated. Then we measured the expression level of neogenin in paired normal and cancer tissues from eight breast cancer patients. Tissue array analysis was performed for 54 human breast tissue samples with different histology, and the results were divided into four categories (none, weak, moderate, strong by a single well-trained blinded pathologist and statistically analyzed. Results The nontumorigenic M13SV1 cells and normal tissues showed stronger expression of neogenin than the M13SV1R2N1 cells and the paired cancer tissues. In the tissue array, all (8/8 of the normal breast tissues showed strong neogenin expression, while 93.5% (43/46 of breast cancer tissues had either no expression or only moderate levels of neogenin expression. There was a significant difference, in the expression level of neogenin, in comparisons between normal and infiltrating ductal carcinoma (p Conclusion Neogenin may play a role in mammary carcinogenesis as well as morphogenesis, and the expression may be inversely correlated with mammary carcinogenicity. The value of neogenin as a potential prognostic factor needs further evaluation.

  2. Role of mitogen activated protein kinases in skin tumorigenicity of Patulin

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    Saxena, Neha; Ansari, Kausar M.; Kumar, Rahul; Chaudhari, Bhushan P.; Dwivedi, Premendra D.; Das, Mukul, E-mail: mditrc@rediffmail.com

    2011-12-15

    WHO has highlighted the need to evaluate dermal toxicity of mycotoxins including Patulin (PAT), detected in several fruits. In this study the skin carcinogenic potential of topically applied PAT was investigated. Single topical application of PAT (400 nmol) showed enhanced cell proliferation ({approx} 2 fold), along with increased generation of ROS and activation of ERK, p38 and JNK MAPKs, in mouse skin. PAT exposure also showed activation of downstream target proteins, c-fos, c-Jun and NF-{kappa}B transcription factors. Further, single topical application of PAT (400 nmol) followed by twice weekly application of TPA resulted in tumor formation after 14 weeks, indicating the tumor initiating activity of PAT. However no tumors were observed when PAT was used either as a complete carcinogen (80 nmol) or as a tumor promoter (20 nmol and 40 nmol) for 25 weeks. Histopathological findings of tumors found in PAT/TPA treated mice showed that these tumors were of squamous cell carcinoma type and similar to those found in the positive control group (DMBA/TPA) along with significant increase of lipid peroxidation and decrease in free sulfydryls, catalase, superoxide dismutase and glutathione reductase activities. The results suggest the possible role of free radicals in PAT mediated dermal tumorigenicity involving MAPKs. -- Highlights: Black-Right-Pointing-Pointer Single topical application of Patulin showed enhanced cell proliferation. Black-Right-Pointing-Pointer Patulin activate MAPKs, c-fos, c-Jun and NF-{kappa}B transcription factors. Black-Right-Pointing-Pointer Patulin showed skin tumor initiating potential. Black-Right-Pointing-Pointer We could not detect skin tumor promoting potential of Patulin at the tested dose. Black-Right-Pointing-Pointer However prolonged exposure of Patulin at a higher dose may promote tumor.

  3. Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure.

    Science.gov (United States)

    Fernández-Sánchez, María Elena; Barbier, Sandrine; Whitehead, Joanne; Béalle, Gaëlle; Michel, Aude; Latorre-Ossa, Heldmuth; Rey, Colette; Fouassier, Laura; Claperon, Audrey; Brullé, Laura; Girard, Elodie; Servant, Nicolas; Rio-Frio, Thomas; Marie, Hélène; Lesieur, Sylviane; Housset, Chantal; Gennisson, Jean-Luc; Tanter, Mickaël; Ménager, Christine; Fre, Silvia; Robine, Sylvie; Farge, Emmanuel

    2015-07-02

    The tumour microenvironment may contribute to tumorigenesis owing to mechanical forces such as fibrotic stiffness or mechanical pressure caused by the expansion of hyper-proliferative cells. Here we explore the contribution of the mechanical pressure exerted by tumour growth onto non-tumorous adjacent epithelium. In the early stage of mouse colon tumour development in the Notch(+)Apc(+/1638N) mouse model, we observed mechanistic pressure stress in the non-tumorous epithelial cells caused by hyper-proliferative adjacent crypts overexpressing active Notch, which is associated with increased Ret and β-catenin signalling. We thus developed a method that allows the delivery of a defined mechanical pressure in vivo, by subcutaneously inserting a magnet close to the mouse colon. The implanted magnet generated a magnetic force on ultra-magnetic liposomes, stabilized in the mesenchymal cells of the connective tissue surrounding colonic crypts after intravenous injection. The magnetically induced pressure quantitatively mimicked the endogenous early tumour growth stress in the order of 1,200 Pa, without affecting tissue stiffness, as monitored by ultrasound strain imaging and shear wave elastography. The exertion of pressure mimicking that of tumour growth led to rapid Ret activation and downstream phosphorylation of β-catenin on Tyr654, imparing its interaction with the E-cadherin in adherens junctions, and which was followed by β-catenin nuclear translocation after 15 days. As a consequence, increased expression of β-catenin-target genes was observed at 1 month, together with crypt enlargement accompanying the formation of early tumorous aberrant crypt foci. Mechanical activation of the tumorigenic β-catenin pathway suggests unexplored modes of tumour propagation based on mechanical signalling pathways in healthy epithelial cells surrounding the tumour, which may contribute to tumour heterogeneity.

  4. Nitric oxide-releasing nanoparticles: synthesis, characterization, and cytotoxicity to tumorigenic cells

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    Pelegrino, Milena T.; Silva, Letícia C.; Watashi, Carolina M.; Haddad, Paula S.; Rodrigues, Tiago; Seabra, Amedea B.

    2017-02-01

    Nitric oxide (NO) is involved in several biological processes, including toxicity against tumor cells. The aim of this study was to synthesize, characterize, and evaluate the cytotoxicity of NO-releasing chitosan nanoparticles. A thiol-containing molecule, mercaptosuccinic acid (MSA), was encapsulated (encapsulation efficiency of 99%) in chitosan/sodium tripolyphosphate nanoparticles (CS NPs). The obtained nanoparticles showed an average hydrodynamic size of 108.40 ± 0.96 nm and polydispersity index of 0.26 ± 0.01. MSA-CS NPs were nitrosated leading to S-nitroso-MSA-CS NPs, which act as NO donor. The cytotoxicity of CS NPs, MSA-CS NPs, and S-nitroso-MSA-CS NPs were evaluated in several tumor cells, including human hepatocellular carcinoma (HepG2), mouse melanoma (B16F10), and human chronic myeloid leukemia (K562) cell lines and Lucena-1, a vincristine-resistant K562 cell line. Both CS NPs and MSA-CS NPs did not cause toxic effects in these cells, whereas S-nitroso-MSA-CS NPs caused potent cytotoxic effects in all the tested tumor cell lines. The half-maximal inhibitory concentration values of S-nitroso-MSA-CS NPs were 19.7, 10.5, 22.8, and 27.8 μg·mL-1 for HepG2, B16F10, K562, and Lucena-1 cells, respectively. In contrast, S-nitroso-MSA-CS NPs exhibited lower cytotoxic to non-tumorigenic melanocytes (Melan-A) when compared with melanoma B16F10. Therefore, the results highlight the potential use of NO-releasing CS NPs in antitumor chemotherapy.

  5. β-Catenin is required for the tumorigenic behavior of triple-negative breast cancer cells.

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    Jinhua Xu

    Full Text Available Our previous data illustrated that activation of the canonical Wnt signaling pathway was enriched in triple-negative breast cancer and associated with reduced overall survival in all patients. To determine whether Wnt signaling may be a promising therapeutic target for triple-negative breast cancer, we investigated whether β-catenin was necessary for tumorigenic behaviors in vivo and in vitro. β-catenin expression level was significantly reduced in two human triple-negative breast cancer cell lines, MDA-MB-231 and HCC38, using lentiviral delivery of β-catenin-specific small hairpin RNAs (shRNAs. Upon implantation of the cells in the mammary fat pad of immunocompromised mice, we found that β-catenin shRNA HCC38 cells formed markedly smaller tumors than control cells and grew much more slowly. In in vitro assays, β-catenin silencing significantly reduced the percentage of Aldefluor-positive cells, a read-out of the stem-like cell population, as well as the expression of stem cell-related target genes including Bmi-1 and c-Myc. β-catenin-knockdown cells were also significantly impaired in their ability to migrate in wound-filling assays and form anchorage-independent colonies in soft agar. β-catenin-knockdown cells were more sensitive to chemotherapeutic agents doxorubicin and cisplatin. Collectively, these data suggest that β-catenin is required for triple-negative breast cancer development by controlling numerous tumor-associated properties, such as migration, stemness, anchorage-independent growth and chemosensitivity.

  6. β-Catenin is required for the tumorigenic behavior of triple-negative breast cancer cells.

    Science.gov (United States)

    Xu, Jinhua; Prosperi, Jenifer R; Choudhury, Noura; Olopade, Olufunmilayo I; Goss, Kathleen H

    2015-01-01

    Our previous data illustrated that activation of the canonical Wnt signaling pathway was enriched in triple-negative breast cancer and associated with reduced overall survival in all patients. To determine whether Wnt signaling may be a promising therapeutic target for triple-negative breast cancer, we investigated whether β-catenin was necessary for tumorigenic behaviors in vivo and in vitro. β-catenin expression level was significantly reduced in two human triple-negative breast cancer cell lines, MDA-MB-231 and HCC38, using lentiviral delivery of β-catenin-specific small hairpin RNAs (shRNAs). Upon implantation of the cells in the mammary fat pad of immunocompromised mice, we found that β-catenin shRNA HCC38 cells formed markedly smaller tumors than control cells and grew much more slowly. In in vitro assays, β-catenin silencing significantly reduced the percentage of Aldefluor-positive cells, a read-out of the stem-like cell population, as well as the expression of stem cell-related target genes including Bmi-1 and c-Myc. β-catenin-knockdown cells were also significantly impaired in their ability to migrate in wound-filling assays and form anchorage-independent colonies in soft agar. β-catenin-knockdown cells were more sensitive to chemotherapeutic agents doxorubicin and cisplatin. Collectively, these data suggest that β-catenin is required for triple-negative breast cancer development by controlling numerous tumor-associated properties, such as migration, stemness, anchorage-independent growth and chemosensitivity.

  7. Lung Injury After One-Lung Ventilation: A Review of the Pathophysiologic Mechanisms Affecting the Ventilated and the Collapsed Lung.

    Science.gov (United States)

    Lohser, Jens; Slinger, Peter

    2015-08-01

    Lung injury is the leading cause of death after thoracic surgery. Initially recognized after pneumonectomy, it has since been described after any period of 1-lung ventilation (OLV), even in the absence of lung resection. Overhydration and high tidal volumes were thought to be responsible at various points; however, it is now recognized that the pathophysiology is more complex and multifactorial. All causative mechanisms known to trigger ventilator-induced lung injury have been described in the OLV setting. The ventilated lung is exposed to high strain secondary to large, nonphysiologic tidal volumes and loss of the normal functional residual capacity. In addition, the ventilated lung experiences oxidative stress, as well as capillary shear stress because of hyperperfusion. Surgical manipulation and/or resection of the collapsed lung may induce lung injury. Re-expansion of the collapsed lung at the conclusion of OLV invariably induces duration-dependent, ischemia-reperfusion injury. Inflammatory cytokines are released in response to localized injury and may promote local and contralateral lung injury. Protective ventilation and volatile anesthesia lessen the degree of injury; however, increases in biochemical and histologic markers of lung injury appear unavoidable. The endothelial glycocalyx may represent a common pathway for lung injury creation during OLV, because it is damaged by most of the recognized lung injurious mechanisms. Experimental therapies to stabilize the endothelial glycocalyx may afford the ability to reduce lung injury in the future. In the interim, protective ventilation with tidal volumes of 4 to 5 mL/kg predicted body weight, positive end-expiratory pressure of 5 to 10 cm H2O, and routine lung recruitment should be used during OLV in an attempt to minimize harmful lung stress and strain. Additional strategies to reduce lung injury include routine volatile anesthesia and efforts to minimize OLV duration and hyperoxia.

  8. Screening for Lung Cancer

    Science.gov (United States)

    Mazzone, Peter J.; Naidich, David P.; Bach, Peter B.

    2013-01-01

    Background: Lung cancer is by far the major cause of cancer deaths largely because in the majority of patients it is at an advanced stage at the time it is discovered, when curative treatment is no longer feasible. This article examines the data regarding the ability of screening to decrease the number of lung cancer deaths. Methods: A systematic review was conducted of controlled studies that address the effectiveness of methods of screening for lung cancer. Results: Several large randomized controlled trials (RCTs), including a recent one, have demonstrated that screening for lung cancer using a chest radiograph does not reduce the number of deaths from lung cancer. One large RCT involving low-dose CT (LDCT) screening demonstrated a significant reduction in lung cancer deaths, with few harms to individuals at elevated risk when done in the context of a structured program of selection, screening, evaluation, and management of the relatively high number of benign abnormalities. Whether other RCTs involving LDCT screening are consistent is unclear because data are limited or not yet mature. Conclusions: Screening is a complex interplay of selection (a population with sufficient risk and few serious comorbidities), the value of the screening test, the interval between screening tests, the availability of effective treatment, the risk of complications or harms as a result of screening, and the degree with which the screened individuals comply with screening and treatment recommendations. Screening with LDCT of appropriate individuals in the context of a structured process is associated with a significant reduction in the number of lung cancer deaths in the screened population. Given the complex interplay of factors inherent in screening, many questions remain on how to effectively implement screening on a broader scale. PMID:23649455

  9. Lung cancer - small cell

    Science.gov (United States)

    Cancer - lung - small cell; Small cell lung cancer; SCLC ... About 15% of all lung cancer cases are SCLC. Small cell lung cancer is slightly more common in men than women. Almost all cases of SCLC are ...

  10. Lung Involvement in TSC

    Science.gov (United States)

    ... Privacy Policy Sitemap Learn Engage Donate About TSC Lungs Lung involvement in tuberous sclerosis complex (TSC) has ... testing. (Krueger et al., 2013) What Are the Lung Features of TSC? Two forms of lung involvement ...

  11. Lung Nodules: Overview

    Science.gov (United States)

    ... Research & Science Education & Training Home Conditions Lung Nodules Lung Nodules Make an Appointment Find a Doctor Ask ... Kern, MD (June 01, 2016) What is a lung nodule? A lung nodule is also called a ...

  12. The effects of using high-fidelity simulators and standardized patients on the thorax, lung, and cardiac examination skills of undergraduate nursing students.

    Science.gov (United States)

    Tuzer, Hilal; Dinc, Leyla; Elcin, Melih

    2016-10-01

    Existing research literature indicates that the use of various simulation techniques in the training of physical examination skills develops students' cognitive and psychomotor abilities in a realistic learning environment while improving patient safety. The study aimed to compare the effects of the use of a high-fidelity simulator and standardized patients on the knowledge and skills of students conducting thorax-lungs and cardiac examinations, and to explore the students' views and learning experiences. A mixed-method explanatory sequential design. The study was conducted in the Simulation Laboratory of a Nursing School, the Training Center at the Faculty of Medicine, and in the inpatient clinics of the Education and Research Hospital. Fifty-two fourth-year nursing students. Students were randomly assigned to Group I and Group II. The students in Group 1 attended the thorax-lungs and cardiac examination training using a high-fidelity simulator, while the students in Group 2 using standardized patients. After the training sessions, all students practiced their skills on real patients in the clinical setting under the supervision of the investigator. Knowledge and performance scores of all students increased following the simulation activities; however, the students that worked with standardized patients achieved significantly higher knowledge scores than those that worked with the high-fidelity simulator; however, there was no significant difference in performance scores between the groups. The mean performance scores of students on real patients were significantly higher compared to the post-simulation assessment scores (pthorax-lungs and cardiac examinations; however, practice on real patients increased performance scores of all students without any significant difference in two groups. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Muramyl dipeptide induces NOD2-dependent Ly6C(high monocyte recruitment to the lungs and protects against influenza virus infection.

    Directory of Open Access Journals (Sweden)

    François Coulombe

    Full Text Available Bacterial peptidoglycan-derived muramyl dipeptide (MDP and derivatives have long-recognized antiviral properties but their mechanism of action remains unclear. In recent years, the pattern-recognition receptor NOD2 has been shown to mediate innate responses to MDP. Here, we show that MDP treatment of mice infected with Influenza A virus (IAV significantly reduces mortality, viral load and pulmonary inflammation in a NOD2-dependent manner. Importantly, the induction of type I interferon (IFN and CCL2 chemokine was markedly increased in the lungs following MDP treatment and correlated with a NOD2-dependent enhancement in circulating monocytes. Mechanistically, the protective effect of MDP could be explained by the NOD2-dependent transient increase in recruitment of Ly6C(high "inflammatory" monocytes and, to a lesser extent, neutrophils to the lungs. Indeed, impairment in both Ly6C(high monocyte recruitment and survival observed in infected Nod2-/- mice treated with MDP was recapitulated in mice deficient for the chemokine receptor CCR2 required for CCL2-mediated Ly6C(high monocyte migration from the bone marrow into the lungs. MDP-induced pulmonary monocyte recruitment occurred normally in IAV-infected and MDP-treated Ips-1-/- mice. However, IPS-1 was required for improved survival upon MDP treatment. Finally, mycobacterial N-glycolyl MDP was more potent than N-acetyl MDP expressed by most bacteria at reducing viral burden while both forms of MDP restored pulmonary function following IAV challenge. Overall, our work sheds light on the antiviral mechanism of a clinically relevant bacterial-derived compound and identifies the NOD2 pathway as a potential therapeutic target against IAV.

  14. Inhalational Lung Disease

    Directory of Open Access Journals (Sweden)

    S Kowsarian

    2010-01-01

    Full Text Available Inhalational lung diseases are among the most important occupational diseases. Pneumoconiosis refers to a group of lung diseases result from inhalation of usually inorganic dusts such as silicon dioxide, asbestos, coal, etc., and their deposition in the lungs. The resultant pulmonary disorders depend on the susceptibility of lungs; size, concentration, solubility and fibrogenic properties of the inhaled particles; and duration of exposure. Radiographic manifestations of pneumoconiosis become apparent several years after exposure to the particles. However, for certain types of dusts, e.g., silicone dioxide crystal and beryllium, heavy exposure within a short period can cause an acute disease. Pulmonary involvement in asbestosis is usually in the lower lobes. On the contrary, in silicosis and coal worker pneumoconiosis, the upper lobes are involved predominantly. For imaging evaluation of pneumoconiosis, high-resolution computed tomography (CT is superior to conventional chest x-ray. Magnetic resonance imaging (MRI and positron emission tomography (PET scan are helpful in those with suspected tumoral lesions. In this essay, we reviewed the imaging aspects of inhalational lung disease.

  15. Evaluation of tumorigenic potential of CeO2 and Fe2O3 engineered nanoparticles by a human cell in vitro screening model.

    Science.gov (United States)

    Stueckle, Todd A; Davidson, Donna C; Derk, Raymond; Kornberg, Tiffany G; Schwegler-Berry, Diane; Pirela, Sandra V; Deloid, Glen; Demokritou, Philip; Luanpitpong, Sudjit; Rojanasakul, Yon; Wang, Liying

    2017-04-01

    With rapid development of novel nanotechnologies that incorporate engineered nanomaterials (ENMs) into manufactured products, long-term, low dose ENM exposures in occupational settings is forecasted to occur with potential adverse outcomes to human health. Few ENM human health risk assessment efforts have evaluated tumorigenic potential of ENMs. Two widely used nano-scaled metal oxides (NMOs), cerium oxide (nCeO2) and ferric oxide (nFe2O3) were screened in the current study using a sub-chronic exposure to human primary small airway epithelial cells (pSAECs). Multi-walled carbon nanotubes (MWCNT), a known ENM tumor promoter, was used as a positive control. Advanced dosimetry modeling was employed to ascertain delivered vs. administered dose in all experimental conditions. Cells were continuously exposed in vitro to deposited doses of 0.18 μg/cm(2) or 0.06 μg/cm(2) of each NMO or MWCNT, respectively, over 6 and 10 weeks, while saline- and dispersant-only exposed cells served as passage controls. Cells were evaluated for changes in several cancer hallmarks, as evidence for neoplastic transformation. At 10 weeks, nFe2O3- and MWCNT-exposed cells displayed a neoplastic-like transformation phenotype with significant increased proliferation, invasion and soft agar colony formation ability compared to controls. nCeO2-exposed cells showed increased proliferative capacity only. Isolated nFe2O3 and MWCNT clones from soft agar colonies retained their respective neoplastic-like phenotypes. Interestingly, nFe2O3-exposed cells, but not MWCNT cells, exhibited immortalization and retention of the neoplastic phenotype after repeated passaging (12 - 30 passages) and after cryofreeze and thawing. High content screening and protein expression analyses in acute exposure ENM studies vs. immortalized nFe2O3 cells, and isolated ENM clones, suggested that long-term exposure to the tested ENMs resulted in iron homeostasis disruption, an increased labile ferrous iron pool, and subsequent

  16. A new scheme for real-time high-contrast imaging in lung cancer radiotherapy: a proof-of-concept study

    Science.gov (United States)

    Yan, Hao; Tian, Zhen; Shao, Yiping; Jiang, Steve B.; Jia, Xun

    2016-03-01

    Visualization of anatomy in real time is of critical importance for motion management in lung cancer radiotherapy. To achieve real-time, and high-contrast in-treatment imaging, we propose a novel scheme based on the measurement of Compton scatter photons. In our method, a slit x-ray beam along the superior-inferior direction is directed to the patient, (intersecting the lung region at a 2D plane) containing most of the tumor motion trajectory. X-ray photons are scattered off this plane primarily due to the Compton interaction. An imager with a pinhole or a slat collimator is placed at one side of the plane to capture the scattered photons. The resulting image, after correcting for incoming fluence inhomogeneity, x-ray attenuation, scatter angle variation, and outgoing beam geometry, represents the linear attenuation coefficient of Compton scattering. This allows the visualization of the anatomy on this plane. We performed Monte Carlo simulation studies both on a phantom and a patient for proof-of-principle purposes. In the phantom case, a small tumor-like structure could be clearly visualized. The contrast-resolution calculated using tumor/lung as foreground/background for kV fluoroscopy, cone beam computed tomography (CBCT), and scattering image were 0.037, 0.70, and 0.54, respectively. In the patient case, tumor motion could be clearly observed in the scatter images. Imaging dose to the voxels directly exposed by the slit beam was ~0.4 times of that under a single CBCT projection. These studies demonstrated the potential feasibility of the proposed imaging scheme to capture the instantaneous anatomy of a patient on a 2D plane with a high image contrast. Clear visualization of the tumor motion may facilitate marker-less tumor tracking.

  17. Metabolic pathways of lung inflammation revealed by high-resolution metabolomics (HRM) of H1N1 influenza virus infection in mice.

    Science.gov (United States)

    Chandler, Joshua D; Hu, Xin; Ko, Eun-Ju; Park, Soojin; Lee, Young-Tae; Orr, Michael; Fernandes, Jolyn; Uppal, Karan; Kang, Sang-Moo; Jones, Dean P; Go, Young-Mi

    2016-11-01

    Influenza is a significant health concern worldwide. Viral infection induces local and systemic activation of the immune system causing attendant changes in metabolism. High-resolution metabolomics (HRM) uses advanced mass spectrometry and computational methods to measure thousands of metabolites inclusive of most metabolic pathways. We used HRM to identify metabolic pathways and clusters of association related to inflammatory cytokines in lungs of mice with H1N1 influenza virus infection. Infected mice showed progressive weight loss, decreased lung function, and severe lung inflammation with elevated cytokines [interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ] and increased oxidative stress via cysteine oxidation. HRM showed prominent effects of influenza virus infection on tryptophan and other amino acids, and widespread effects on pathways including purines, pyrimidines, fatty acids, and glycerophospholipids. A metabolome-wide association study (MWAS) of the aforementioned inflammatory cytokines was used to determine the relationship of metabolic responses to inflammation during infection. This cytokine-MWAS (cMWAS) showed that metabolic associations consisted of distinct and shared clusters of 396 metabolites highly correlated with inflammatory cytokines. Strong negative associations of selected glycosphingolipid, linoleate, and tryptophan metabolites with IFN-γ contrasted strong positive associations of glycosphingolipid and bile acid metabolites with IL-1β, TNF-α, and IL-10. Anti-inflammatory cytokine IL-10 had strong positive associations with vitamin D, purine, and vitamin E metabolism. The detailed metabolic interactions with cytokines indicate that targeted metabolic interventions may be useful during life-threatening crises related to severe acute infection and inflammation. Copyright © 2016 the American Physiological Society.

  18. Downregulation of β-catenin decreases the tumorigenicity, but promotes epithelial-mesenchymal transition in breast cancer cells

    Directory of Open Access Journals (Sweden)

    Kai Cai

    2014-01-01

    Full Text Available Background: Wnt/β-catenin signaling pathway plays a key role in human breast cancer progression. In this study, we down regulated β-catenin expression in human breast cancer MDA-MB-231 cells and investigated the effect of β-catenin knockdown on the cell biological characteristics. Materials and Methods: The recombinant plasmids of pSUPER-enhancement green fluorescent protein 1 (EGFP1-scrabble-β-catenin-short hairpin ribonucleic acid (shRNA and pSUPER-EGFP1-β-catenin-shRNA-1 were transfected into MDA-MB-231 cells, respectively, and the stably transfected cells were isolated from G418 selected clones. The β-catenin gene silenced efficiency was measured by quantitative reverse transcriptase polymerase chain reaction (QRT-PCR and Western blot. The biological characteristics of MDA-MB-231 cells with down regulated β-catenin were evaluated by analyzing cell proliferation, clonogenicity, cell mobility and tumorigenicity. The expression of E-cadherin and Vimentin was concurrently detected by QRT-PCR. Results: The β-catenin-shRNA-1 stably transfected MDA-MB-231 cells significantly decreased β-catenin expression, cell proliferation, clonogenicity, and tumorigenicity in Balb/c nude mice compared with the MDA-MB-231 cells transfected with pSUPER-EGFP1-scrabble-β-catenin-shRNA. Interestingly, knockdown of β-catenin led to the reduction of epithelial E-cadherin expression, the increase of cell mobility and mesenchymal vimentin expression in MDA-MB-231 cells, indicating an epithelial to mesenchymal transition. Conclusion: Knockdown of β-catenin expression in human breast cancer MDA-MB-231 cells inhibits cell tumorigenicity in mice, but promotes cell epithelial-mesenchymal transition.

  19. Mineralogical and compositional characteristics of Late Permian coals from an area of high lung cancer rate in Xuan Wei, Yunnan, China: Occurrence and origin of quartz and chamosite

    Science.gov (United States)

    Dai, S.; Tian, L.; Chou, C.-L.; Zhou, Y.; Zhang, M.; Zhao, L.; Wang, Jingyuan; Yang, Z.; Cao, H.; Ren, D.

    2008-01-01

    Some townships in Xuan Wei County, Yunnan Province, have one of the highest lung cancer mortality rates in China and the epidemic disease in the area has generally been attributed to the polycyclic aromatic hydrocarbons (PAHs) released from domestic coal burning. However, the cancer-causing culprit is not settled as Tian [Tian, L., 2005. Coal Combustion Emissions and Lung Cancer in Xuan Wei, China. Ph.D. thesis, University of California, Berkeley.] found nanometer quartz in these coals, soot emissions, and lung cancer tissues. We have conducted mineralogical and geochemical studies of the coals from Xuan Wei for the purpose of shedding light on the minerals which may be related to the epidemic lung cancer. In this paper, abundances, modes of occurrence, and origins of minerals and elements in the coals from two mines in Xuan Wei have been studied using optical microscope, low-temperature ashing, X-ray diffraction analysis, scanning electron microscope equipped with energy-dispersive X-ray spectrometer, and inductively-coupled plasma mass spectrometry. The minerals in the coals are mainly composed of quartz, chamosite, kaolinite, and calcite. The particle size of quartz is rather small, mostly less than 20????m and it is of authigenic origin. Chamosite occurs mainly as cell-fillings. The occurrence of quartz and chamosite indicates that they were derived from the hydrothermal fluids. Epigenetic calcite is derived from calcic fluids. Kaolinite is derived mainly from sediment source region of Kangdian Oldland to the west of coal basin. The composition of Xuan Wei coal is high in SiO2, Fe2O3, TiO2, CaO, MnO, V, Co, Ni, Cu, and Zn. The high SiO2 content is attributed to quartz, and the Fe2O3 content to chamosite. The high Mn and low Mg contents in the coal indicate the inputs of hydrothermal fluids. CaO occurs mainly in epigenetic calcite. Elements Ti, Co, Ni, Cu, Zn, and rare earth elements were derived from the basaltic rocks at sediment source region. ?? 2008

  20. Pyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity.

    Science.gov (United States)

    Xia, Qingsu; Zhao, Yuewei; Von Tungeln, Linda S; Doerge, Daniel R; Lin, Ge; Cai, Lining; Fu, Peter P

    2013-09-16

    Pyrrolizidine alkaloid-containing plants are the most common poisonous plants affecting livestock, wildlife, and humans. The U.S. National Toxicology Program (NTP) classified riddelliine, a tumorigenic pyrrolizidine alkaloid, as "reasonably anticipated to be a human carcinogen" in the NTP 12th Report on Carcinogens in 2011. We previously determined that four DNA adducts were formed in rats dosed with riddelliine. The structures of the four DNA adducts were elucidated as (i) a pair of epimers of 7-hydroxy-9-(deoxyguanosin-N(2)-yl)dehydrosupinidine adducts (termed as DHP-dG-3 and DHP-dG-4) as the predominant adducts; and (ii) a pair of epimers of 7-hydroxy-9-(deoxyadenosin-N(6)-yl)dehydrosupinidine adducts (termed as DHP-dA-3 and DHP-dA-4 adducts). In this study, we selected a nontumorigenic pyrrolizidine alkaloid, platyphylliine, a pyrrolizidine alkaloid N-oxide, riddelliine N-oxide, and nine tumorigenic pyrrolizidine alkaloids (riddelliine, retrorsine, monocrotaline, lycopsamine, retronecine, lasiocarpine, heliotrine, clivorine, and senkirkine) for study in animals. Seven of the nine tumorigenic pyrrolizidine alkaloids, with the exception of lycopsamine and retronecine, are liver carcinogens. At 8-10 weeks of age, female F344 rats were orally gavaged for 3 consecutive days with 4.5 and 24 μmol/kg body weight test article in 0.5 mL of 10% DMSO in water. Twenty-four hours after the last dose, the rats were sacrificed, livers were removed, and liver DNA was isolated for DNA adduct analysis. DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4 adducts were formed in the liver of rats treated with the individual seven hepatocarcinogenic pyrrolizidine alkaloids and riddelliine N-oxide. These DNA adducts were not formed in the liver of rats administered retronecine, the nontumorigenic pyrrolizidine alkaloid, platyphylliine, or vehicle control. These results indicate that this set of DNA adducts, DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4, is a common biological biomarker of

  1. [Humidifier lung].

    Science.gov (United States)

    Gerber, P; de Haller, R; Pyrozynski, W J; Sturzenegger, E R; Brändli, O

    1981-02-07

    Breathing air from a humidifier or an air conditioning unit contaminated by various microorganisms can cause an acute lung disease involving fever, cough and dyspnea, termed "humidifier fever". This type of hypersensitivity pneumonitis was first described in 1959 by PESTALOZZI in the Swiss literature and subsequently by BANASZAK et al. in the Anglo-American. Here a chronic form of this disease which led to pulmonary fibrosis is described: A 37-year-old woman who works in a cheese shop presented with dyspnea which had been progressive over two years, weight loss, a diffuse reticular pattern radiographically and a severe restrictive defect in lung function tests. Open lung biopsy revealed chronic interstitial and alveolar inflammation with non-caseating granulomas and fibrotic changes. Circulating immune complexes and precipitins against the contaminated humidifier water and cheese mites were found, but no antibodies suggesting legionnaires' disease. Two out of five otherwise healthy employees of this cheese shop, where a new humidifying system had been installed 7 years earlier, also had precipitins against the contaminated water from the humidifier and the cheese mites. Despite ending of exposure and longterm steroid and immunosuppressive therapy, the signs and symptoms of pulmonary fibrosis persisted. Contrary to the acute disease, this chronic form is termed "humidifier lung". The importance is stressed of investigating the possibility of exposure to contaminated humidifiers or air conditioning units in all cases of newly detected pulmonary fibrosis.

  2. Welders’ lung

    Directory of Open Access Journals (Sweden)

    Izidor Kern

    2010-02-01

    Conclusions: h is study coni rms that longterm welders may have symptoms with no functional disorders, but with prominent morphological changes. h e key to correct diagnosis is an occupational history of the patient. Diagnostic work-up includes funda-mental procedures in suspected interstitial lung disease. h e best therapy is cessation of exposure.

  3. Lung cancer

    DEFF Research Database (Denmark)

    Hansen, H H; Rørth, M

    1999-01-01

    The results of the many clinical trials published in 1997 had only modest impact on the treatment results using either cytostatic agents alone or combined with radiotherapy in lung cancer. In SCLC, combination chemotherapy including platin-compounds (cisplatin, carboplatin) and the podophyllotoxins...

  4. Lung cancer

    DEFF Research Database (Denmark)

    Hansen, H H; Rørth, M

    1999-01-01

    The results of the many clinical trials published in 1997 had only modest impact on the treatment results using either cytostatic agents alone or combined with radiotherapy in lung cancer. In SCLC, combination chemotherapy including platin-compounds (cisplatin, carboplatin) and the podophyllotoxins...

  5. Diagnostic Value of Soluble Suppression of Tumorigenicity-2 for Heart Failure

    Institute of Scientific and Technical Information of China (English)

    Dong-Hui Huang; Hao Sun; Jing-Pu Shi

    2016-01-01

    Background:Many studies have explored the diagnostic performance of soluble suppression of tumorigenicity-2 (sST2) for heart failure (HF),but the results are inconsistent.Here,we performed a meta-analysis to assess the role of sST2 in the diagnosis of HF.Methods:We searched PubMed,Web of Science,Cochrane Library,China National Knowledge Infrastructure,and Wanfang Database from inception to April 2015.Studies that investigated the diagnostic role of sST2 for HF were reviewed.The numbers of true-positive,false-positive,false-negative,and true-negative results were extracted to calculate pooled diagnostic odds ratio (DOR) with 95% confidence interval (CI) and the summary receiver operating characteristic curve and area under the curve (AUC).The Spearman correlation coefficient was used to check the threshold effect.The Cochran Q statistic (P < 0.05) and the inconsistency index (I2 > 50%) were used to assess the nonthreshold effect.Meta-regression was conducted to explore the source of heterogeneity;subgroup analysis showed the results in different subgroups.Finally,the Deeks' test was performed to assess the publication bias.Results:Nine articles including 10 studies were included in the meta-analysis.The pooled sensitivity was 0.84 (95% CI:0.81-0.86),and pooled specificity was 0.74 (95% CI:0.72-0.76).The summary DOR was 8.49 (95% CI:4.54-15.86),and AUC was 0.81 (standard error:0.03).The Spearman correlation coefficient identified the nonsignificant threshold effect (coefficient =0.49,P =0.148),but the nonthreshold effect heterogeneity was significant (Cochran Q =58.52,P < 0.0001;I2 =84.6%).Meta-regression found that characteristics of controls might be the suggestive source ofnonthreshold effect heterogeneity (P =0.095).Subgroup analysis found that DOR was 5.65 and 7.86,respectively for the controls of hospital patients and healthy populations.Deeks' test demonstrated that there was no publication bias (P =0.616).Conclusion:The meta

  6. Prevalence and Characteristics of Lung Involvement on High Resolution Computed Tomography in Patients with Ankylosing Spondylitis: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Abdellah El Maghraoui

    2012-01-01

    Full Text Available To determine the prevalence of lung involvement and the spectrum of abnormalities revealed on HRCT in patients with AS, a systematic literature review was conducted in the Medline database up to May 2009 and in the abstracts of rheumatology scientific meetings (2006–2008. A hand search of references was also performed. Among the 264 selected articles, 10 articles (303 patients allowed a calculation of the prevalence of lung abnormalities on thoracic HRCT in AS. A total of 185 patients (61% had an abnormal thoracic HRCT: upper lobe fibrosis in 21 (6.9%, emphysema in 55 (18.1%, bronchiectasis in 33 (10.8%, and ground glass attenuation in 34 (11.2%. Non specific interstitial abnormalities were observed in 101 (33% patients. The most common observed abnormalities were pleural thickening (52%, parenchymal bands (45% and interlobular septal thickening (30%. Only the prevalence of upper lobe fibrosis increased significantly with disease duration (3 studies. Mild and non-specific interstitial abnormalities on thoracic HRCT are common in patients with AS, even in patients with early disease and without respiratory symptoms.

  7. Prevalence and characteristics of lung involvement on high resolution computed tomography in patients with ankylosing spondylitis: a systematic review.

    Science.gov (United States)

    El Maghraoui, Abdellah; Dehhaoui, Mohamed

    2012-01-01

    To determine the prevalence of lung involvement and the spectrum of abnormalities revealed on HRCT in patients with AS, a systematic literature review was conducted in the Medline database up to May 2009 and in the abstracts of rheumatology scientific meetings (2006-2008). A hand search of references was also performed. Among the 264 selected articles, 10 articles (303 patients) allowed a calculation of the prevalence of lung abnormalities on thoracic HRCT in AS. A total of 185 patients (61%) had an abnormal thoracic HRCT: upper lobe fibrosis in 21 (6.9%), emphysema in 55 (18.1%), bronchiectasis in 33 (10.8%), and ground glass attenuation in 34 (11.2%). Non specific interstitial abnormalities were observed in 101 (33%) patients. The most common observed abnormalities were pleural thickening (52%), parenchymal bands (45%) and interlobular septal thickening (30%). Only the prevalence of upper lobe fibrosis increased significantly with disease duration (3 studies). Mild and non-specific interstitial abnormalities on thoracic HRCT are common in patients with AS, even in patients with early disease and without respiratory symptoms.

  8. High probability and frequency of EGFR mutations in non-small cell lung cancer with brain metastases.

    Science.gov (United States)

    Ge, Mengxi; Zhuang, Yingjie; Zhou, Xinli; Huang, Ruofan; Liang, Xiaohua; Zhan, Qiong

    2017-08-05

    Lung cancer is the leading cause of cancer death in men and women worldwide. Brain metastasis (BMs) of non-small cell lung cancer (NSCLC) is the most important cause of death. This study aimed to explore the association of epidermal growth factor receptor (EGFR) mutations and BMs in NSCLC. We analyzed 50 NSCLC patients with BMs and 50 match-paired NSCLC patients with no brain metastases (NBMs). The EGFR mutation status of primary lesions was detected using the amplification refractory mutation system polymerase chain reaction. The BMs patients had a higher frequency of EGFR mutations than the NBMs patients (52.0 vs. 22.0% respectively, P < 0.001), in both adenocarcinoma (60.5 vs. 30.6%, P = 0.003) and squamous carcinoma (37.5 vs. 0%, P = 0.04). The incidence of BMs in patients with EGFR mutations was higher than in patients with wild-type EGFR (70.3 vs. 38.1%, P = 002). NSCLC patients with BMs had a higher incidence of EGFR mutations and those with mutant EGFR had a higher frequency of BMs. EGFR mutations may promote brain metastasis growth of NSCLC.

  9. Establishment of an experimental human lung adenocarcinoma cell line SPC-A-1BM with high bone metastases potency by {sup 99m}Tc-MDP bone scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Yang Shunfang [Department of Nuclear Medicine, Shanghai Chest Hospital of Shanghai Jiaotong University, Shanghai 200030 (China)], E-mail: yzyg@sh163.net; Dong Qianggang [Laboratory of Mol-diagnosis, Shanghai Cancer Institute of Shanghai Jiaotong University, Shanghai 200032 (China); Yao Ming [Laboratory of Pathology, Shanghai Cancer Institute of Shanghai Jiaotong University, Shanghai 200032 (China); Shi Meiping [Department of Pathology, Shanghai Chest Hospital of Shanghai Jiaotong University, Shanghai 200030 (China); Ye Jianding [Department of Radiology, Shanghai Chest Hospital of Shanghai Jiaotong University, Shanghai 200030 (China); Zhao Langxiang [Department of Pathology, Shanghai Chest Hospital of Shanghai Jiaotong University, Shanghai 200030 (China); Su Jianzhong; Gu Weiyong [Shanghai Thoracic Tumor Institute, Shanghai Chest Hospital of Shanghai Jiaotong University, Shanghai 200030 (China); Xie Wenhui [Department of Nuclear Medicine, Shanghai Chest Hospital of Shanghai Jiaotong University, Shanghai 200030 (China); Wang Kankan; Du Yanzhi [State Key Laboratory of Medical Genomics, Ruijin Hospital of Shanghai Jiaotong University, Shanghai 200025 (China); Li Yao [State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai 200433 (China); Huang Yan [State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai 200433 (China)], E-mail: huangyan@fudan.edu.cn

    2009-04-15

    Background: Bone metastasis is one of the most common clinical phenomena of late stage lung cancer. A major impediment to understanding the pathogenesis of bone metastasis has been the lack of an appropriate animal and cell model. This study aims to establish human lung adenocarcinoma cell line with highly bone metastases potency with {sup 99m}Tc-MDP bone scintigraphy. Methods: The human lung adenocarcinoma cancer cells SPC-A-1 were injected into the left cardiac ventricle of NIH-Beige-Nude-XID (NIH-BNX) immunodeficient mice. The metastatic lesions of tumor-bearing mice were imaged with {sup 99m}Tc-MDP bone scintigraphy on a Siemens multi-single photon emission computed tomography. Pinhole images were acquired on a GZ-B conventional gamma camera with a self-designed pinhole collimator. The mice with bone metastasis were sacrificed under deep anesthesia, and the lesions were resected. Bone metastatic cancer cells in the resected lesions were subjected for culture and then reinoculated into the NIH-BNX mice through left cardiac ventricle. The process was repeated for eight cycles to obtain a novel cell subline SPC-A-1BM. Real-time polymerase chain reaction (PCR) was used to compare the gene expression differences in the parental and SPC-A-1BM cells. Results: The bone metastasis sites were successfully revealed by bone scintigraphy. The established bone metastasis cell line SPC-A-1BM had a high potential to metastasize in bone, including mandible, humerus, thoracic vertebra, lumbar, femur, patella, ilium and cartilage rib. The expression level of vascular endothelial growth factor gene family, Bcl-2 and cell adhesion-related genes ECM1, ESM1, AF1Q, SERPINE2 and FN1 were examined. Gene expression difference was found between parental and bone-seeking metastasis cell SPC-A-1BM, which indicates SPC-A-1BM has metastatic capacity vs. its parental cells. Conclusion: SPC-A-1BM is a bone-seeking metastasis human lung adenocarcinoma cell line. Bone scintigraphy may be used as

  10. Establishment of an experimental human lung adenocarcinoma cell line SPC-A-1BM with high bone metastases potency by (99m)Tc-MDP bone scintigraphy.

    Science.gov (United States)

    Yang, Shunfang; Dong, Qianggang; Yao, Ming; Shi, Meiping; Ye, Jianding; Zhao, Langxiang; Su, Jianzhong; Gu, Weiyong; Xie, Wenhui; Wang, Kankan; Du, Yanzhi; Li, Yao; Huang, Yan

    2009-04-01

    Bone metastasis is one of the most common clinical phenomena of late stage lung cancer. A major impediment to understanding the pathogenesis of bone metastasis has been the lack of an appropriate animal and cell model. This study aims to establish human lung adenocarcinoma cell line with highly bone metastases potency with (99m)Tc-MDP bone scintigraphy. The human lung adenocarcinoma cancer cells SPC-A-1 were injected into the left cardiac ventricle of NIH-Beige-Nude-XID (NIH-BNX) immunodeficient mice. The metastatic lesions of tumor-bearing mice were imaged with (99m)Tc-MDP bone scintigraphy on a Siemens multi-single photon emission computed tomography. Pinhole images were acquired on a GZ-B conventional gamma camera with a self-designed pinhole collimator. The mice with bone metastasis were sacrificed under deep anesthesia, and the lesions were resected. Bone metastatic cancer cells in the resected lesions were subjected for culture and then reinoculated into the NIH-BNX mice through left cardiac ventricle. The process was repeated for eight cycles to obtain a novel cell subline SPC-A-1BM. Real-time polymerase chain reaction (PCR) was used to compare the gene expression differences in the parental and SPC-A-1BM cells. The bone metastasis sites were successfully revealed by bone scintigraphy. The established bone metastasis cell line SPC-A-1BM had a high potential to metastasize in bone, including mandible, humerus, thoracic vertebra, lumbar, femur, patella, ilium and cartilage rib. The expression level of vascular endothelial growth factor gene family, Bcl-2 and cell adhesion-related genes ECM1, ESM1, AF1Q, SERPINE2 and FN1 were examined. Gene expression difference was found between parental and bone-seeking metastasis cell SPC-A-1BM, which indicates SPC-A-1BM has metastatic capacity vs. its parental cells. SPC-A-1BM is a bone-seeking metastasis human lung adenocarcinoma cell line. Bone scintigraphy may be used as an accurate, sensitive, noninvasive tool to detect

  11. Distinct population of highly malignant cells in a head and neck squamous cell carcinoma cell line established by xenograft model

    Directory of Open Access Journals (Sweden)

    Jan Chia-Ing

    2009-11-01

    Full Text Available Abstract The progression and metastasis of solid tumors, including head and neck squamous cell carcinoma (HNSCC, have been related to the behavior of a small subpopulation of cancer stem cells. Here, we have established a highly malignant HNSCC cell line, SASVO3, from primary tumors using three sequential rounds of xenotransplantation. SASVO3 possesses enhanced tumorigenic ability both in vitro and in vivo. Moreover, SASVO3 exhibits properties of cancer stem cells, including that increased the abilities of sphere-forming, the number of side population cells, the potential of transplanted tumor growth and elevated expression of the stem cell marker Bmi1. Injection of SASVO3 into the tail vein of nude mice resulted in lung metastases. These results are consistent with the postulate that the malignant and/or metastasis potential of HNSCC cells may reside in a stem-like subpopulation.

  12. Comparison of exogenous surfactant therapy, mechanical ventilation with high end-expiratory pressure and partial liquid ventilation in a model of acute lung injury

    NARCIS (Netherlands)

    A. Hartog (Anneke); G.F. Vazquez de Anda; D.A.M.P.J. Gommers (Diederik); U. Kaisers; S.J.C. Verbrugge (Serge); R. Schnabel; B.F. Lachmann (Burkhard)

    1999-01-01

    textabstractWe have compared three treatment strategies, that aim to prevent repetitive alveolar collapse, for their effect on gas exchange, lung mechanics, lung injury, protein transfer into the alveoli and surfactant system, in a model of acute lung injury. In adult r

  13. Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy for locally advanced non-small cell lung cancer.

    Science.gov (United States)

    Dickhoff, C; Dahele, M; Paul, M A; van de Ven, P M; de Langen, A J; Senan, S; Smit, E F; Hartemink, K J

    2016-04-01

    Curative intent treatment options for locoregional recurrence or persistent tumor after radical chemoradiotherapy for locally-advanced non-small cell lung cancer (NSCLC) are limited. In selected patients, surgery can be technically feasible, although it is widely believed to be hazardous. As data regarding the outcome of this approach is sparse, we evaluated our institutional experience with salvage surgery. Patients with a pulmonary resection for in-field locoregional recurrence or persistent tumor after high dose chemoradiotherapy (≥60 Gy) for the treatment of non-small cell lung cancer, were identified and retrospectively analyzed. A total of 15 patients treated between January 2007 and August 2015 were eligible for evaluation. In 13 patients (87%), the indication for surgery was a locoregional recurrence, while 2 patients had persistent tumor. The prior median radiotherapy dose was 66 Gy (range 60-70). All patients underwent an anatomical resection, with 8 patients having a pneumonectomy, and all pathological specimens revealed the presence of viable tumor. The in-hospital morbidity rate was 40% (6 patients), and the 90-day mortality rate was 6.7% (1 patient). Median follow-up was 12.1 months. The estimated median overall and event-free survivals were 46 months and 43.6 months, respectively. Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy, resulted in acceptable morbidity, mortality and promising outcome. It should be considered as a treatment option for selected patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. Determination of SGK1 mRNA in non-small cell lung cancer samples underlines high expression in squamous cell carcinomas

    Directory of Open Access Journals (Sweden)

    Abbruzzese Claudia

    2012-01-01

    Full Text Available Abstract Background Lung cancer represents the most frequent cause of death for cancer. In non-small cell lung cancer (NSCLC, which accounts for the vast majority of this disease, only early detection and treatment, when possible, may significantly affect patient's prognosis. An important role in NSCLC malignancy is attributed to the signal transduction pathways involving PI3Kinase, with consequent activation of the AKT family factors. The serum and glucocorticoid kinase (SGK factors, which share high structural and functional homologies with the AKT factors, are a family of ubiquitously expressed serine/threonine kinases under the control of cellular stress and hormones. SGK1 is the most represented SGK member. Methods By means of immunohistochemistry and quantitative real-time PCR, we determined SGK1 protein and mRNA expression in a cohort of 66 formalin-fixed, paraffin-embedded NSCLC surgical samples. All samples belonged to patients with a well-documented clinical history. Results mRNA expression was significantly higher in squamous cell carcinomas, and correlated with several clinical prognostic indicators, being elevated in high-grade tumors and in tumors with bigger size and worse clinical stage. No correlation was found between SGK1 protein expression and these clinical parameters. Conclusions This explorative analysis of SGK1 expression in NSCLC samples highlights the potential role of this factor in NSCLC patients' prognosis. Moreover, the higher expression in the squamous cell carcinoma subtype opens new therapeutic possibilities in this NSCLC subtype by designing specific kinase inhibitors.

  15. Radiation Therapy for Lung Cancer

    Science.gov (United States)

    ... of the lung cancer and your overall health. Radiation Therapy Radiation is a high-energy X-ray that can ... surgery, chemotherapy or both depending upon the circumstances. Radiation therapy works within cancer cells by damaging their ...

  16. Hyperpolarized {sup 3}helium magnetic resonance ventilation imaging of the lung in cystic fibrosis: comparison with high resolution CT and spirometry

    Energy Technology Data Exchange (ETDEWEB)

    McMahon, Colm J.; Dodd, Jonathan D.; Skehan, Stephen J.; Masterson, James B. [St. Vincent' s University Hospital, Department of Radiology, Dublin (Ireland); Hill, Catherine; Woodhouse, Neil; Wild, Jim M.; Fichele, Stan [Royal Hallamshire Hospital, The Unit of Academic Radiology, University of Sheffield, Sheffield (United Kingdom); Gallagher, Charles G. [St. Vincent' s University Hospital, Department of National Referral Centre for Adult Cystic Fibrosis, Dublin (Ireland); Beek, Edwin J.R. van [Royal Hallamshire Hospital, The Unit of Academic Radiology, University of Sheffield, Sheffield (United Kingdom); University of Iowa, Department of Radiology, Carver College of Medicine, Iowa City, IA (United States)

    2006-11-15

    The purpose of this study was to compare hyperpolarized {sup 3}helium magnetic resonance imaging ({sup 3}He MRI) of the lungs in adults with cystic fibrosis (CF) with high-resolution computed tomography (HRCT) and spirometry. Eight patients with stable CF prospectively underwent {sup 3}He MRI, HRCT, and spirometry within 1 week. Three-dimensional (3D) gradient-echo sequence was used during an 18-s breath-hold following inhalation of hyperpolarized {sup 3}He. Each lung was divided into six zones; {sup 3}He MRI was scored as percentage ventilation per lung zone. HRCT was scored using a modified Bhalla scoring system. Univariate (Spearman rank) and multivariate correlations were performed between {sup 3}He MRI, HRCT, and spirometry. Results are expressed as mean{+-}SD (range). Spirometry is expressed as percent predicted. There were four men and four women, mean age=31.9{+-}9 (20-46). Mean forced expiratory volume in 1 s (FEV){sub 1}=52%{+-}29 (27-93). Mean {sup 3}He MRI score=74%{+-}25 (55-100). Mean HRCT score=48.8{+-}24 (13.5-83). The correlation between {sup 3}He MRI and HRCT was strong (R={+-}0.89, p<0.001). Bronchiectasis was the only independent predictor of {sup 3}He MRI; {sup 3}He MRI correlated better with FEV{sub 1} and forced vital capacity (FVC) (R=0.86 and 0.93, p<0.01, respectively) than HRCT (R={+-}0.72 and {+-}0.81, p<0.05, respectively). This study showed that {sup 3}He MRI correlates strongly with structural HRCT abnormalities and is a stronger correlate of spirometry than HRCT in CF. (orig.)

  17. Hyperglycemia enhances the proliferation of non-tumorigenic and malignant mammary epithelial cells through increased leptin/IGF1R signaling and activation of AKT/mTOR.

    Directory of Open Access Journals (Sweden)

    Rebecca Lopez

    Full Text Available Obesity and diabetes are associated with increased breast cancer risk and worse disease progression once cancer is diagnosed; however, the exact etiology behind these observations remains to be fully elucidated. Due to the global obesity/diabetes pandemic, it is imperative to understand how these diseases promote and enhance breast cancer and other common cancers. In this study we demonstrate that hyperglycemia promotes breast cancer by altering leptin/IGF1R and AKT/mTOR signaling. To our knowledge, we show for the first time that in breast epithelial cells, hyperglycemia alone directly impacts leptin signaling. Hyperglycemia increased proliferation of both non-tumorigenic and malignant mammary epithelial cells. These observations coincided with increased leptin receptor and IGF1R receptor, as well as, increased levels of GRB2, pJAK2, pSTAT3, pIRS1/2, pAKT, and p-mTOR. Moreover, pJAK2 was almost completely colocalized with leptin receptor under high glucose conditions. These results demonstrate how hyperglycemia can potentially increase the risk of breast cancer in premalignant lesions and enhance cancer progression in malignant cells.

  18. SIV Infection of Lung Macrophages.

    Directory of Open Access Journals (Sweden)

    Yue Li

    Full Text Available HIV-1 depletes CD4+ T cells in the blood, lymphatic tissues, gut and lungs. Here we investigated the relationship between depletion and infection of CD4+ T cells in the lung parenchyma. The lungs of 38 Indian rhesus macaques in early to later stages of SIVmac251 infection were examined, and the numbers of CD4+ T cells and macrophages plus the frequency of SIV RNA+ cells were quantified. We showed that SIV infected macrophages in the lung parenchyma, but only in small numbers except in the setting of interstitial inflammation where large numbers of SIV RNA+ macrophages were detected. However, even in this setting, the number of macrophages was not decreased. By contrast, there were few infected CD4+ T cells in lung parenchyma, but CD4+ T cells were nonetheless depleted by unknown mechanisms. The CD4+ T cells in lung parenchyma were depleted even though they were not productively infected, whereas SIV can infect large numbers of macrophages in the setting of interstitial inflammation without depleting them. These observations point to the need for future investigations into mechanisms of CD4+ T cell depletion at this mucosal site, and into mechanisms by which macrophage populations are maintained despite high levels of infection. The large numbers of SIV RNA+ macrophages in lungs in the setting of interstitial inflammation indicates that lung macrophages can be an important source for SIV persistent infection.

  19. The application of High-resolution CT scanning in the diagnosis of interstitial lung disease%高分辨CT扫描技术在肺间质性病变中的应用价值

    Institute of Scientific and Technical Information of China (English)

    苏毅; 倪傲; 李源

    2012-01-01

    目的 探讨高分辨CT扫描技术,对肺间质性病变的诊断价值.方法 采用Philips MX8000 Dual 螺旋CT机对30例肺间质性病变患者,行高分辨CT技术扫描.结果 高分辨CT可清晰显示肺间质性病变的各种征象,肺间质性病变的高分辨CT主要表现为:(1)磨玻璃样密度影;(2)肺小叶间隔增厚;(3)小叶内间质增生;(4)网格状影;(5)胸膜下弧线影;(6)蜂窝肺;(7)牵拉支气管扩张;(8)胸膜增厚.病变分布以两肺中外带、胸膜下为主,病灶自肺尖向肺底逐渐加重,两肺基底部病变明显.结论 高分辨CT扫描具有良好的空间分辨率,能细致、准确地反映肺间质病变的影像特征,对肺间质性病变具有重要的诊断价值.%Objective To study the value of HRCT scanning technology in improving the diagnosis of interstitial lung disease. Methods 30 cases of interstitial lung disease were scanned throng high-resolution CT with Philips MX8000 Dual CT machine. Results High-resolution CT can clearly show various signs of interstitial lung disease. The Interstitial lung disease of High-resolution CT Perform-ance:( 1 ) ground-glass opacity;( 2 ) pulmonary interlobular septal thickening; ( 3 ) intralobular interstitial thickening;( 4 ) grid-like shadow ;( 5 ) pleural shadow off the assembly line;( 6 ) cell lung;( 7 ) traction bronchiectasis; ( 8 ) pleural thickening. The lesion mainly distributes in lateral and under pleural of two lungs. The infection aggravates gradually from lung' s point to lung' s bottom. Conclusion The application of high-resolution CT scan in the interstitial lung disease has important diagnostic value. As the high-resolution CT scan with a good spatial resolution, can detail, accurately reflect the images of interstitial lung disease characterized.

  20. TMPRSS4 induces cancer stem cell-like properties in lung cancer cells and correlates with ALDH expression in NSCLC patients.

    Science.gov (United States)

    de Aberasturi, Arrate L; Redrado, Miriam; Villalba, Maria; Larzabal, Leyre; Pajares, Maria J; Garcia, Javier; Evans, Stephanie R; Garcia-Ros, David; Bodegas, Maria Elena; Lopez, Lissett; Montuenga, Luis; Calvo, Alfonso

    2016-01-28

    Metastasis involves a series of changes in cancer cells that promote their escape from the primary tumor and colonization to a new organ. This process is related to the transition from an epithelial to a mesenchymal phenotype (EMT). Recently, some authors have shown that migratory cells with an EMT phenotype share properties of cancer stem cells (CSCs), which allow them to form a new tumor mass. The type II transmembrane serine protease TMPRSS4 is highly expressed in some solid tumors, promotes metastasis and confers EMT features to cancer cells. We hypothesized that TMPRSS4 could also provide CSC properties. Overexpression of TMPRSS4 reduces E-cadherin and induces N-cadherin and vimentin in A549 lung cancer cells, supporting an EMT phenotype. These changes are accompanied by enhanced migration, invasion and tumorigenicity in vivo. TMPRSS4 expression was highly increased in a panel of lung cancer cells cultured as tumorspheres (a typical assay to enrich for CSCs). H358 and H441 cells with knocked-down TMPRSS4 levels were significantly less able to form primary and secondary tumorspheres than control cells. Moreover, they showed a lower proportion of ALDH+ cells (examined by FACS analysis) and lower expression of some CSC markers than controls. A549 cells overexpressing TMPRSS4 conferred the opposite phenotype and were also more sensitive to the CSC-targeted drug salinomycin than control cells, but were more resistant to regular chemotherapeutic drugs (cisplatin, gemcitabine and 5-fluorouracil). Analysis of 70 NSCLC samples from patients revealed a very significant correlation between TMPRSS4 expression and CSC markers ALDH (p = 0.0018) and OCT4 (p = 0.0004), suggesting that TMPRSS4 is associated with a CSC phenotype in patients' tumors. These results show that TMPRSS4, in addition to inducing EMT, can also promote CSC features in lung cancer; therefore, CSC-targeting drugs could be an appropriate treatment for TMPRSS4+ tumors.

  1. EGFR gene mutant tested by high resolution melting method in lung cancer%HRM法检测肺癌EGFR基因突变

    Institute of Scientific and Technical Information of China (English)

    高菲; 师建国; 魏金花; 王弢; 秦勇; 时凯

    2011-01-01

    Objective :To research EGFR - TKI molecular target therapy by detecting lung cancer EGFR gene mutant with high resolution melting method in different areas of China, and analyze the ratio of mutations type. Methods : To detect gene mutation of EGFR with HRM method in 253 surgical resection paraffin specimens of lung cancer and verify with gene sequencing method. Results: Mutation rate of EGFR gene was 42% in 253 cases with lung cance specimen using HRM method, while the mutation rate was 40% using sequencing method. There was no significant difference between two methods. At the same time, 2 cases of T790M mutations, 11 cases of multi - point mutations and 2 cases E18 new sites mutations were found using HRM method, there was no significant difference between the rates of the eastern region and the non - eastern region of patients with lung cancer EGFR mutation. The sensitivity of HRM was higher than gene sequencing method, and the specificity of HRM method was 100%. Conclusion : HRM technology has the characteristics of high sensitivity, high accuracy and high specificity. It is simpler and more cost - effective than gene sequencing method. It' s necessary to specify the mutations types and to use for clinical EGFR - TKI which can provide important basis for molecular target therapy. EGFR gene mutations of the lung specimen which collect by the labs have no regional variations.%目的:HRM法检测中国不同区域肺癌患者的EGFR基因突变,统计突变类型间比率,为临床EGFR-TKI分子靶向治疗提供依据,并验证HRM法的临床适用性.方法:收集2010年手术切除的肺癌石蜡标本253例,HRM法检测EGFR基因突变情况,并用基因测序法进行验证.结果:在253例肺癌标本中,HRM法检测出EGFR基因突变率为42%,与基因测序法检测出的突变率40%无显著性差异,并检测出2例T790M突变,11例多点突变和2例E18新位点突变.将本实验中收集的东部地区和非东部地区肺癌患者的EGFR基

  2. Dissecting the oncogenic and tumorigenic potential of differentiated human induced pluripotent stem cells and human embryonic stem cells.

    Science.gov (United States)

    Ghosh, Zhumur; Huang, Mei; Hu, Shijun; Wilson, Kitchener D; Dey, Devaveena; Wu, Joseph C

    2011-07-15

    Pluripotent stem cells, both human embryonic stem cells (hESC) and human-induced pluripotent stem cells (hiPSC), can give rise to multiple cell types and hence have tremendous potential for regenerative therapies. However, the tumorigenic potential of these cells remains a great concern, as reflected in the formation of teratomas by transplanted pluripotent cells. In clinical practice, most pluripotent cells will be differentiated into useful therapeutic cell types such as neuronal, cardiac, or endothelial cells prior to human transplantation, drastically reducing their tumorigenic potential. Our work investigated the extent to which these differentiated stem cell derivatives are truly devoid of oncogenic potential. In this study, we analyzed the gene expression patterns from three sets of hiPSC- and hESC-derivatives and the corresponding primary cells, and compared their transcriptomes with those of five different types of cancer. Our analysis revealed a significant gene expression overlap of the hiPSC- and hESC-derivatives with cancer, whereas the corresponding primary cells showed minimum overlap. Real-time quantitative PCR analysis of a set of cancer-related genes (selected on the basis of rigorous functional and pathway analyses) confirmed our results. Overall, our findings suggested that pluripotent stem cell derivatives may still bear oncogenic properties even after differentiation, and additional stringent functional assays to purify these cells should be done before they can be used for regenerative therapy.

  3. Targeting PPM1D by lentivirus-mediated RNA interference inhibits the tumorigenicity of bladder cancer cells

    Directory of Open Access Journals (Sweden)

    W. Wang

    2014-12-01

    Full Text Available Protein phosphatase magnesium/manganese-dependent 1D (PPM1D is a p53-induced phosphatase that functions as a negative regulator of stress response pathways and has oncogenic properties. However, the functional role of PPM1D in bladder cancer (BC remains largely unknown. In the present study, lentivirus vectors carrying small hairpin RNA (shRNA targeting PPM1D were used to explore the effects of PPM1D knockdown on BC cell proliferation and tumorigenesis. shRNA-mediated knockdown of PPM1D significantly inhibited cell growth and colony forming ability in the BC cell lines 5637 and T24. Flow cytometric analysis showed that PPM1D silencing increased the proportion of cells in the G0/G1 phase. Downregulation of PPM1D also inhibited 5637 cell tumorigenicity in nude mice. The results of the present study suggest that PPM1D plays a potentially important role in BC tumorigenicity, and lentivirus-mediated delivery of shRNA against PPM1D might be a promising therapeutic strategy for the treatment of BC.

  4. Targeting PPM1D by lentivirus-mediated RNA interference inhibits the tumorigenicity of bladder cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, W. [Institute of Urology, Huashan Hospital, Fudan University, Shanghai (China); Department of the Intensive Care Unit, Huashan Hospital, Fudan University, Shanghai (China); Zhu, H. [Department of the Intensive Care Unit, Huashan Hospital, Fudan University, Shanghai (China); Zhang, H.; Zhang, L. [Department of Urology, Huashan Hospital, Fudan University, Shanghai (China); Ding, Q.; Jiang, H. [Institute of Urology, Huashan Hospital, Fudan University, Shanghai (China); Department of Urology, Huashan Hospital, Fudan University, Shanghai (China)

    2014-09-23

    Protein phosphatase magnesium/manganese-dependent 1D (PPM1D) is a p53-induced phosphatase that functions as a negative regulator of stress response pathways and has oncogenic properties. However, the functional role of PPM1D in bladder cancer (BC) remains largely unknown. In the present study, lentivirus vectors carrying small hairpin RNA (shRNA) targeting PPM1D were used to explore the effects of PPM1D knockdown on BC cell proliferation and tumorigenesis. shRNA-mediated knockdown of PPM1D significantly inhibited cell growth and colony forming ability in the BC cell lines 5637 and T24. Flow cytometric analysis showed that PPM1D silencing increased the proportion of cells in the G0/G1 phase. Downregulation of PPM1D also inhibited 5637 cell tumorigenicity in nude mice. The results of the present study suggest that PPM1D plays a potentially important role in BC tumorigenicity, and lentivirus-mediated delivery of shRNA against PPM1D might be a promising therapeutic strategy for the treatment of BC.

  5. Long non-coding RNA MALAT1 promotes gastric cancer tumorigenicity and metastasis by regulating vasculogenic mimicry and angiogenesis.

    Science.gov (United States)

    Li, Yue; Wu, Zhenzhen; Yuan, Jia; Sun, Li; Lin, Li; Huang, Na; Bin, Jianping; Liao, Yulin; Liao, Wangjun

    2017-06-01

    MALAT1 is an oncogenic long non-coding RNA that has been found to promote the proliferation of many malignant cell types and non-malignant human umbilical vein endothelial cells (HUVECs). However, the functions of MALAT1 in vasculogenic mimicry (VM) and angiogenesis and the potential mechanisms responsible have not yet been investigated in any malignancy. Here, in situ hybridization and CD31/periodic acid-Schiff double staining of 150 gastric cancer (GC) clinical specimens revealed that MALAT1 expression was tightly associated with densities of VM and endothelial vessels. MALAT1 knockdown markedly reduced GC cell migration, invasion, tumorigenicity, metastasis, and VM, while restricting HUVEC angiogenesis and increasing vascular permeability. Moreover, MALAT1 was found to regulate expression of VE-cadherin, β-catenin, MMPs 2 and 9, MT1-MMP, p-ERK, p-FAK, and p-paxillin, which have been established as classical markers of VM and angiogenesis and components of associated signaling pathways. Consistent with this, the p-ERK inhibitors U0126 and PD98059 both effectively blocked GC cell VM. In conclusion, MALAT1 can promote tumorigenicity and metastasis in GC by facilitating VM and angiogenesis via the VE-cadherin/β-catenin complex and ERK/MMP and FAK/paxillin signaling pathways.

  6. Interstitial lung disease - adults - discharge

    Science.gov (United States)

    Diffuse parenchymal lung disease - discharge; Alveolitis - discharge; Idiopathic pulmonary pneumonitis - discharge; IPP - discharge; Chronic interstitial lung - discharge; Chronic respiratory interstitial lung - discharge; Hypoxia - interstitial lung - discharge

  7. The effect of rib and lung heterogeneities on the computed dose to lung in Ir-192 High-Dose-Rate breast brachytherapy: Monte Carlo versus a treatment planning system

    Directory of Open Access Journals (Sweden)

    Hossein Salehi Yazdi

    2012-01-01

    Conclusions: Taking into account the ribs and entering the actual data for breasts, ribs, and lungs, revealed an average overestimation