To see the other types of publications on this topic, follow the link: Lung dividing cells.
Journal articles on the topic 'Lung dividing cells'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Lung dividing cells.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Liu, Shan-Lu, Christine L. Halbert, and A. Dusty Miller. "Jaagsiekte Sheep Retrovirus Envelope Efficiently Pseudotypes Human Immunodeficiency Virus Type 1-Based Lentiviral Vectors." Journal of Virology 78, no. 5 (March 1, 2004): 2642–47. http://dx.doi.org/10.1128/jvi.78.5.2642-2647.2003.
Full textAbstract:
ABSTRACT Jaagsiekte sheep retrovirus (JSRV) infects lung epithelial cells in sheep, and oncoretroviral vectors bearing JSRV Env can mediate transduction of human cells, suggesting that such vectors might be useful for lung-directed gene therapy. Here we show that JSRV Env can also efficiently pseudotype a human immunodeficiency virus type 1-based lentiviral vector, a more suitable vector for transduction of slowly dividing lung epithelial cells. We created several chimeric Env proteins that, unlike the parental Env, do not transform rodent fibroblasts but are still capable of pseudotyping lentiviral and oncoretroviral vectors.
2
Hyde, Dallas M., David J. Magliano, and Charles G. Plopper. "Morphometric Assessment of Pulmonary Toxicity in the Rodent Lung." Toxicologic Pathology 19, no. 4_part_1 (November 1991): 428–46. http://dx.doi.org/10.1177/0192623391019004-112.
Full textAbstract:
An overview of the epithelial and interstitial composition of rat respiratory airways shows complexity and variability. Airway epithelium varies in 1) different airway levels; 2) the types and ultrastructure of cells present; and 3) the abundance, type, and composition of stored secretory product. Unbiased sampling of airways is done using airway microdissection with a specific binary numbering system for airway generation. Vertical sections of selected airways are used to sample epithelium and interstitium. We determine the ratios of the volume of epithelial or interstitial cells to the total epithelial or interstitial volume (Vv). The surface of the epithelial basal lamina to the total epithelial or interstitial volume (Sv) is determined using point and intersection counting with a cycloid grid. Using the selector method on serial plastic sections, we determine the number of epithelial or interstitial cells per volume (Nv) of total epithelium or interstitium. We calculate the number of epithelial or interstitial cells per surface of epithelial basal lamina (Ns) by dividing Nv by Sv where the volumes are the same compartment. We calculate average cell volumes (v̄) for specific epithelial and interstitial cells by dividing the absolute nuclear volume by the ratio of the nucleus to cell volume (Vv). By multiplying the average cell volume (v̄) by the ratio of organellar volume to cell volume (Vv), we calculate the average organellar volume per cell. These unbiased stereological approaches are critical in a quantitative evaluation of toxicological injury of rat tracheobronchial airways.
3
Wagner, Elizabeth M., Irina Petrache, Brian Schofield, and Wayne Mitzner. "Pulmonary ischemia induces lung remodeling and angiogenesis." Journal of Applied Physiology 100, no. 2 (February 2006): 587–93. http://dx.doi.org/10.1152/japplphysiol.00029.2005.
Full textAbstract:
Cellular remodeling during angiogenesis in the lung is poorly described. Furthermore, it is the systemic vasculature of the lung and surrounding the lung that is proangiogenic when the pulmonary circulation becomes impaired. In a mouse model of chronic pulmonary thromboembolism, after left pulmonary artery ligation (LPAL), the intercostal vasculature, in proximity to the ischemic lung, proliferates and invades the lung ( 12 ). In the present study, we performed a detailed investigation of the kinetics of remodeling using histological sections of the left lung of C57Bl/6J mice after LPAL (4 h to 20 days) or after sham surgery. New vessels were seen within the thickened visceral pleura 4 days after LPAL predominantly in the upper portion of the left lung. Connections between new vessels within the pleura and pulmonary capillaries were clearly discerned by 7 days after LPAL. The visceral pleura and the lung parenchyma showed intense tissue remodeling, as evidenced by markedly elevated levels of both proliferating cell nuclear antigen and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive cells. Rapidly dividing cells were predominantly macrophages and type II pneumocytes. The increased apoptotic activity was further quantified by caspase-3 activity, which showed a sixfold increase relative to naive lungs, by 24 h after LPAL. Because sham surgeries had little effect on measured parameters, we conclude that both thoracic wound healing and pulmonary ischemia are required for systemic neovascularization.
4
Choi, Y. W., I. C. Lee, and S. R. Ross. "Requirement for the simian virus 40 small tumor antigen in tumorigenesis in transgenic mice." Molecular and Cellular Biology 8, no. 8 (August 1988): 3382–90. http://dx.doi.org/10.1128/mcb.8.8.3382-3390.1988.
Full textAbstract:
To examine the role of simian virus 40 (SV40) large T and small t antigens in tumorigenesis in animals, we generated transgenic mice which expressed either both the SV40 large T and small t antigens or the SV40 large T antigen alone under the control of the mouse mammary tumor virus long terminal repeat. The mouse mammary tumor virus long terminal repeat directs the expression of transgenes in ductal epithelial cells of several organs, including the mammary gland, lung, and kidney, and in lymphoid cells. The mice which expressed both the T and t tumor antigens developed lung and kidney adenocarcinomas, while those which expressed large T alone did not. Both types of mice developed malignant lymphomas with similar frequencies and latency periods. Our results show that the SV40 small t antigen cooperates with the large T antigen in inducing tumors in slowly dividing epithelial cells in the lung and kidney.
5
Choi, Y. W., I. C. Lee, and S. R. Ross. "Requirement for the simian virus 40 small tumor antigen in tumorigenesis in transgenic mice." Molecular and Cellular Biology 8, no. 8 (August 1988): 3382–90. http://dx.doi.org/10.1128/mcb.8.8.3382.
Full textAbstract:
To examine the role of simian virus 40 (SV40) large T and small t antigens in tumorigenesis in animals, we generated transgenic mice which expressed either both the SV40 large T and small t antigens or the SV40 large T antigen alone under the control of the mouse mammary tumor virus long terminal repeat. The mouse mammary tumor virus long terminal repeat directs the expression of transgenes in ductal epithelial cells of several organs, including the mammary gland, lung, and kidney, and in lymphoid cells. The mice which expressed both the T and t tumor antigens developed lung and kidney adenocarcinomas, while those which expressed large T alone did not. Both types of mice developed malignant lymphomas with similar frequencies and latency periods. Our results show that the SV40 small t antigen cooperates with the large T antigen in inducing tumors in slowly dividing epithelial cells in the lung and kidney.
6
Fry, Jeffrey R., Alison H. Hammond, Michael J. Garle, and Kishan Lal. "Comparison of Xenobiotic-mediated Cytotoxicity in Rat Cultured Hepatocytes and the V79 Chinese Hamster Lung Fibroblast Cell Line: Can Metabolically-activated Hepatotoxins be Identified by Selective Cytotoxicity to Hepatocytes?" Alternatives to Laboratory Animals 21, no. 1 (January 1993): 8–12. http://dx.doi.org/10.1177/026119299302100103.
Full textAbstract:
The effects of 17 xenobiotics on rat hepatocytes and V79 cells were evaluated under identical exposure conditions (confluent monolayer for 24 hours) and endpoint measurement (MTT reduction). The data indicated that the majority of metabolically-activated rat hepatotoxins could be identified by greater cytotoxicity to rat hepatocytes relative to V79 cells, but that direct-acting hepatotoxins (galactosamine and ethionine) and a group of eight compounds likely to act through interference of basal functions in non-dividing and dividing cells produced similar toxicity in each cell type. It is possible that the greater water-solubility of the direct-acting hepatotoxins relative to the indirect-acting hepatotoxins may contribute to the lack of effect seen with the former group under the conditions of the assay (top concentration of 1mM).
7
Willart, Monique A. M., Hendrik Jan de Heer, Hamida Hammad, Thomas Soullié, Kim Deswarte, Björn E. Clausen, Louis Boon, Henk C. Hoogsteden, and Bart N. Lambrecht. "The lung vascular filter as a site of immune induction for T cell responses to large embolic antigen." Journal of Experimental Medicine 206, no. 12 (October 26, 2009): 2823–35. http://dx.doi.org/10.1084/jem.20082401.
Full textAbstract:
The bloodstream is an important route of dissemination of invading pathogens. Most of the small bloodborne pathogens, like bacteria or viruses, are filtered by the spleen or liver sinusoids and presented to the immune system by dendritic cells (DCs) that probe these filters for the presence of foreign antigen (Ag). However, larger pathogens, like helminths or infectious emboli, that exceed 20 µm are mostly trapped in the vasculature of the lung. To determine if Ag trapped here can be presented to cells of the immune system, we used a model of venous embolism of large particulate Ag (in the form of ovalbumin [OVA]-coated Sepharose beads) in the lung vascular bed. We found that large Ags were presented and cross-presented to CD4 and CD8 T cells in the mediastinal lymph nodes (LNs) but not in the spleen or liver-draining LNs. Dividing T cells returned to the lungs, and a short-lived infiltrate consisting of T cells and DCs formed around trapped Ag. This infiltrate was increased when the Toll-like receptor 4 was stimulated and full DC maturation was induced by CD40 triggering. Under these conditions, OVA-specific cytotoxic T lymphocyte responses, as well as humoral immunity, were induced. The T cell response to embolic Ag was severely reduced in mice depleted of CD11chi cells or Ly6C/G+ cells but restored upon adoptive transfer of Ly6Chi monocytes. We conclude that the lung vascular filter represents a largely unexplored site of immune induction that traps large bloodborne Ags for presentation by monocyte-derived DCs.
8
Bassett, D. J., and J. L. Rabinowitz. "Incorporation of glucose carbons into rat lung lipids after exposure to 0.6 ppm ozone." American Journal of Physiology-Endocrinology and Metabolism 248, no. 5 (May 1, 1985): E553—E559. http://dx.doi.org/10.1152/ajpendo.1985.248.5.e553.
Full textAbstract:
Continuous exposure to low concentrations of ozone has previously been associated with proliferation of lung alveolar type II epithelial cells. In this study, 14C incorporation into tissue lipids was determined in isolated rat lungs by perfusion with [U-14C]glucose, at a time of maximal hyperplasia brought about by 3 days continuous exposure to 0.6 ppm ozone. Ozone exposed lungs exhibited increased rates of glycolytic energy production, indicated by an 89% increase in 3H2O generation on perfusion with [5-3H]glucose, from a control value of 17.5 +/- 2.1 mumol X h-1 X g-1 X dry wt-1 (+/- SE, n = 4). Ozone exposure resulted in enhanced 14C incorporations into glyceride-glycerol and fatty acid moieties of lung lipids of 95 and 180%, respectively, with a greater proportion of label being recovered in shorter chain fatty acids. Although increased labeling was observed in both neutral and phospholipids, the pattern of 14C recovery suggested a relative increased glucose carbon incorporation into lung free fatty acids, phosphatidic acid, and such membrane associated lipids as phosphatidylinositol and those containing sphingosine. These results are consistent with the needs of a dividing cell population for enhanced energy production and synthesis of new lipids.
9
Yurkevich, Mariya Yu, Pavel V. Alchovik, Anastasia A. Tsarik, and Marina A. Kokhniuk. "CULTURES OF ALVEOLOCYTES I AND II TYPE FOR MEDICAL AND ECOLOGICAL RESEARCH." JOURNAL OF THE BELARUSIAN STATE UNIVERSITY ECOLOGY 2 (2021): 67–73. http://dx.doi.org/10.46646/2521-683x/2021-2-67-73.
Full textAbstract:
The alveolar epithelium is a dynamic tissue, consisting of cells of types I and II, covering more than 99 % of the lung inner surface and actively responding to various endogenous and exogenous stimuli. The technology of alveolocyte isolation is presented, which consists in mechanical disaggregation of tissue with subsequent processing of the resulting explants with 0.25 % trypsin solution in combination with filtration of the cell suspension through pores with a diameter of 100 µm and 50 µm. In two-dimensional static culture viable actively dividing rounded cells and large alveolar epithelial cells with cuboid or polygonal morphology, producing surfactant proteins, were visualized.
10
Sorokin, S. P., N. A. McNelly, and R. F. Hoyt. "CFU-rAM, the origin of lung macrophages, and the macrophage lineage." American Journal of Physiology-Lung Cellular and Molecular Physiology 263, no. 3 (September 1, 1992): L299—L307. http://dx.doi.org/10.1152/ajplung.1992.263.3.l299.
Full textAbstract:
Macrophage precursors and their progeny have been identified in early rat embryos with the use of a peroxidase-coupled marker, isolectin B4 of Griffonia simplicifolia (GSA I-B4). The macrophage lineage can be traced back to actively dividing GSA-positive angular cells present in the mesenchyme of late neurulas. These increase in number and establish residence successively in rudiments of the central nervous system, liver, and lungs. In organ-cultured fetal lungs they transform directly into a self-replicating population of macrophages responsive to colony-stimulating factors. The angular cell therefore can be seen as the source of lung macrophages during prenatal life. The extent to which this manner of production continues in postnatal life is unclear, but it appears that central hematopoietic tissues (bone marrow, spleen) may generate macrophages by a direct pathway from early-committed progenitors as well as indirectly through a series of intermediate stem cells. Considering the wealth of new information available from diverse studies in specialized culture environments and to a lesser extent from studies in vivo, it is time to integrate these findings into a more comprehensive theory of macrophage origin and fate than we have at present.
11
Zhang, Naming, Ziang Wang, Shuya Ning, Shuhong Wang, Song Wang, and Hao Qiu. "Non-Thermal Intervention of Lung Tumor by Core-Shell Magnetic Nanoparticles in a Magnetic Field." Applied Sciences 11, no. 5 (February 24, 2021): 2003. http://dx.doi.org/10.3390/app11052003.
Full textAbstract:
K-Ras mutations result in normal cells dividing uncontrollably and becoming cancerous. The prognosis is currently poor for patients due to the lack of drugs that can effectively target these mutations. In this study, magnetic nanoparticles (MNPs) were prepared, characterized, and cooperated with a magnetic field to intervene in the growth of lung tumor cells. The rise in temperature of a stimulation coil was studied by numerical calculation. The non-thermal effects of MNPs under a magnetic force were analyzed. The cell experiments showed that the growth of A549 tumor cells slowed down. The result of a wound-healing assay also indicated that the migration of tumor cells was suppressed. Compared with magnetic stimulation without MNPs, MNPs enhanced the inhibitory effects of a magnetic field. This study suggests a new way to treat K-Ras driven lung tumors using non-thermal effects of MNPs without the side effects caused by thermal effects.
12
Hoyt, R. F., N. A. McNelly, E. M. McDowell, and S. P. Sorokin. "Neuroepithelial bodies stimulate proliferation of airway epithelium in fetal hamster lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 260, no. 4 (April 1, 1991): L234—L240. http://dx.doi.org/10.1152/ajplung.1991.260.4.l234.
Full textAbstract:
Autoradiographs were prepared from lungs of a newborn Syrian golden hamster exposed continuously to [3H]thymidine throughout the final 4.5 days of gestation. Silver grains were counted over nuclei of 1,145 nonendocrine airway epithelial cells adjacent to 28 mature neuroepithelial bodies (NEBs). Generally, accumulated label was greater in cells nearer a NEB than in those further away. Diminution of label with increasing distance from the closet NEB was confirmed statistically. In 24 of 28 instances, both rank-order correlation and linear regression were significant (P less than 0.001-0.05); in two others, only one test was significant; in another two, neither test was significant. The pattern was consistent and widespread. Rank-order correlations and linear regressions were significant (P less than 0.001) in populations pooled separately from left lung, right upper, and right lower lobes, and the three regression lines were superimposable. Confirmation was obtained in another animal by labeling S-phase cells with a 2-h transplacental pulse of bromodeoxyuridine (BrdU) on fetal day 15. Of 322 BrdU-positive cells counted in 270,204 microns 2 of bronchial epithelium, 174 (54%) lay within 20 microns of a neuroepithelial body. This concentration of dividing cells was significant by chi-square test: chi 2[1] = 101.62; P less than 0.001. We conclude that established NEBs promote growth of the developing airway by stimulating proliferation of local endoderm. A few daughter cells may enter NEBs; most move away to join the expanding nonendocrine airway lining.
13
Jurin, A., T. Jukić, S. Ivanković, and Mislav Jurin. "Metastases Development Following Local Tumour Treatment." Folia Biologica 55, no. 5 (2009): 177–82. http://dx.doi.org/10.14712/fb2009055050177.
Full textAbstract:
Transplantable mouse methylcholanthrene-induced fibrosarcoma (CMC4 tumour growing in CBA/HZgr mice), characterized by lung metastases developing shortly after local tumour cell transplantation, was used as an experimental model to investigate the problem of tumour metastases after local tumour treatment. Surgery and/or irradiation were performed on locally growing tumour of particular size. Further, heavily irradiated, viable but not dividing tumour cells, imitating the situation in treated tumour-bearing organism, were injected intraperitoneally in a parallel group of treated tumour-bearing mice. The animals were killed 35 days after tumour transplantation and the number and volume of lung metastases were determined. Depending on the treatment performed, when the tumour mass was reduced or even eliminated, the number of lung metastases and their volume were significantly lower than in control mice, but the addition of tumour mass (injection of heavily irradiated tumour cells) resulted in a significant increase in lung metastases parameters, pointing to a possible role of the host’s immune reaction against the tumour. Further, the release of a simple molecule, such as nitric oxide, from tumour mass seems to be detrimental for the survival of tumour cells and subsequently their metastases through the induction of angiogenesis and possible suppression of immune reaction. Thus, complex mechanisms could be involved when a locally growing tumour is exposed to a particular therapeutic approach.
14
Fortoul, Teresa I., Maria-Rosa Ávila-Costa, Guadalupe Espejel-Maya, Patricia Mussali-Galante, Maria del Carmen Ávila-Casado, Maria Isidra Hernández-Serrato, and Liliana Saldivar-Osorio. "Metal mixture inhalation (Cd-Pb) and its effects on the bronchiolar epithelium. An ultrastructural approach." Toxicology and Industrial Health 20, no. 1-5 (February 2004): 69–75. http://dx.doi.org/10.1191/0748233704th196oa.
Full textAbstract:
The current study explores the effects of the inhalation of lead (Pb), Cd and its mixture (Pb-Cd) in a mice model, analysing metal concentrations in the lung, and the morphological modifications in the bronchiolar epithelium identified by scanning electron microscopy after eight weeks of inhalation. Our results indicate that metal concentrations in lung were higher compared to controls; however, Pb concentrations drastically decrease in the mixture. This reduction was also observed in the inhalation chamber. The main changes observed in the bronchiole were mostly in the mixture. The modifications were mainly given by Cd alone and in the mixture, with a decreased number of nonciliated bronchiolar cells and an increased number of bundles of dividing cells. The additive effect of Pb-Cd is suggested, as the extensive damage observed was more evident when mice were exposed to the mixture, and the results endured more research in the area of inhaled mixtures.
15
Yan, Yunfeng, Li Liu, Hu Xiong, Jason B. Miller, Kejin Zhou, Petra Kos, Kenneth E. Huffman, et al. "Functional polyesters enable selective siRNA delivery to lung cancer over matched normal cells." Proceedings of the National Academy of Sciences 113, no. 39 (September 12, 2016): E5702—E5710. http://dx.doi.org/10.1073/pnas.1606886113.
Full textAbstract:
Conventional chemotherapeutics nonselectively kill all rapidly dividing cells, which produces numerous side effects. To address this challenge, we report the discovery of functional polyesters that are capable of delivering siRNA drugs selectively to lung cancer cells and not to normal lung cells. Selective polyplex nanoparticles (NPs) were identified by high-throughput library screening on a unique pair of matched cancer/normal cell lines obtained from a single patient. Selective NPs promoted rapid endocytosis into HCC4017 cancer cells, but were arrested at the membrane of HBEC30-KT normal cells during the initial transfection period. When injected into tumor xenografts in mice, cancer-selective NPs were retained in tumors for over 1 wk, whereas nonselective NPs were cleared within hours. This translated to improved siRNA-mediated cancer cell apoptosis and significant suppression of tumor growth. Selective NPs were also able to mediate gene silencing in xenograft and orthotopic tumors via i.v. injection or aerosol inhalation, respectively. Importantly, this work highlights that different cells respond differentially to the same drug carrier, an important factor that should be considered in the design and evaluation of all NP carriers. Because no targeting ligands are required, these functional polyester NPs provide an exciting alternative approach for selective drug delivery to tumor cells that may improve efficacy and reduce adverse side effects of cancer therapies.
16
Rice, Pamela L., Stephanie E. Porter, Kelli M. Koski, Gayatri Ramakrishna, Aaron Chen, David Schrump, Andrius Kazlauskas, and Alvin M. Malkinson. "Reduced receptor expression for platelet-derived growth factor and epidermal growth factor in dividing mouse lung epithelial cells." Molecular Carcinogenesis 25, no. 4 (August 1999): 285–94. http://dx.doi.org/10.1002/(sici)1098-2744(199908)25:4<285::aid-mc7>3.0.co;2-f.
Full text
17
Hassert, Mariah, Mohammad Heidarian, Vladimir P. Badovinac, and John T. Harty. "Ionizing radiation induces lasting changes to the tissue resident memory T cell compartment." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 156.10. http://dx.doi.org/10.4049/jimmunol.210.supp.156.10.
Full textAbstract:
Abstract Exposure to sublethal ionizing radiation can occur through various mechanisms, including purposeful medical exposure, nuclear accidents, and acts of nuclear terrorism, making the development of effective medical countermeasures a high public health priority. The induction of DNA damage through reactive oxygen species makes rapidly dividing cells, such as naïve T cells highly sensitive to radiation induced depletion. A previous study demonstrated that broadly, circulating memory T cells are more resistant to numerical loss following radiation exposure compared to naïve T cells. However, the effects of radiation on the more recently described memory T cell subset, tissue resident memory T cells (T RM) remain unknown. T RMhave been identified as a critical T cell subset in protection from a number of infections including influenza, respiratory syncytial virus and malaria. In particular, lung T RMare critical for strain-transcending heterosubtypic immunity to influenza virus. In a murine model of influenza infection (IAV), we have found that sublethal thorax targeted radiation resulted in the rapid numerical decline of lung T RMwithout major alterations in circulating IAV-specific memory CD8+ T cells. The depletion of anti-IAV lung T RMwas long-lasting, and resulted in the loss of heterosubtypic immunity to IAV. Interestingly, any surviving T RMdisplay elevated granzyme B expression, indicating functional consequences for T RMfollowing radiation exposure, which could have implications for immune-mediated pathology. Designing effective vaccination strategies to reinvigorate this critical T cell subset will be an important step in combating the immunological effects of radiation exposure. 1F32AI174382-01
18
Wiriansya, Edward Pandu, Asyifah Andari Syarif, Muhammad Naufal Zuhair, Syamsu Rijal, Dzul Ikram, Ismail Ismail, Muhammad Azka Al Atsari, and Andi Nurdahlia. "Exploring Lung Histopathology in White Rats After Cigarette Smoke Exposure." Jurnal Berkala Kesehatan 9, no. 2 (November 30, 2023): 123. http://dx.doi.org/10.20527/jbk.v9i2.17400.
Full textAbstract:
Smoking-induced respiratory epithelium changes, driven by nicotine and smoke components, can lead to severe lung alterations with prolonged exposure. However, until now, no one has examined the histopathological appearance of bronchioles and alveoli in Wistar rats following exposure to cigarette smoke. This study aimed to assessed lung histopathological changes in white rats (Rattus norvegicus) exposed to cigarette smoke. A descriptive study used a post-test group control design, exposing Rattus norvegicus to cigarette smoke and dividing them into control, 1-week, 2-week, and 4-week groups. Histopathological findings revealed that the control group had intact bronchioles; the one-week group showed lymphocyte infiltration and typical alveolar structure; the two-week group had increased respiratory epithelial cells; the four-week group displayed dominant bronchiole changes; the one-week group had varying alveolar septal thickness; the two-week group had narrowed alveolar lumens; four-week group showed thickened septa and pronounced pigmented macrophages. Cigarette smoke exposure affects changes to Rattus norvegicus lung histology. Prolonged exposure to cigarette smoke induces damage to the structure of the bronchioles and alveoli.
19
Yu, Qin, Bryan P. Toole, and Ivan Stamenkovic. "Induction of Apoptosis of Metastatic Mammary Carcinoma Cells In Vivo by Disruption of Tumor Cell Surface CD44 Function." Journal of Experimental Medicine 186, no. 12 (December 15, 1997): 1985–96. http://dx.doi.org/10.1084/jem.186.12.1985.
Full textAbstract:
To understand how the hyaluronan receptor CD44 regulates tumor metastasis, the murine mammary carcinoma TA3/St, which constitutively expresses cell surface CD44, was transfected with cDNAs encoding soluble isoforms of CD44 and the transfectants (TA3sCD44) were compared with parental cells (transfected with expression vector only) for growth in vivo and in vitro. Local release of soluble CD44 by the transfectants inhibited the ability of endogenous cell surface CD44 to bind and internalize hyaluronan and to mediate TA3 cell invasion of hyaluronan-producing cell monolayers. Mice intravenously injected with parental TA3/St cells developed massive pulmonary metastases within 21–28 d, whereas animals injected with TA3sCD44 cells developed few or no tumors. Tracing of labeled parental and transfectant tumor cells revealed that both cell types initially adhered to pulmonary endothelium and penetrated the interstitial stroma. However, although parental cells were dividing and forming clusters within lung tissue 48 h following injection, >80% of TA3sCD44 cells underwent apoptosis. Although sCD44 transfectants displayed a marked reduction in their ability to internalize and degrade hyaluronan, they elicited abundant local hyaluronan production within invaded lung tissue, comparable to that induced by parental cells. These observations provide direct evidence that cell surface CD44 function promotes tumor cell survival in invaded tissue and that its suppression can induce apoptosis of the invading tumor cells, possibly as a result of impairing their ability to penetrate the host tissue hyaluronan barrier.
20
Hogg, J. C., H. O. Coxson, M. L. Brumwell, N. Beyers, C. M. Doerschuk, W. MacNee, and B. R. Wiggs. "Erythrocyte and polymorphonuclear cell transit time and concentration in human pulmonary capillaries." Journal of Applied Physiology 77, no. 4 (October 1, 1994): 1795–800. http://dx.doi.org/10.1152/jappl.1994.77.4.1795.
Full textAbstract:
Pulmonary capillary transit times were examined in patients who required lung resection by use of 99mTc-labeled macroaggregates (99Tc-MAA) and chromium-labeled erythrocytes (51Cr-RBC) to measure regional blood flow and volume in the resected lung. Cell flow (cells.ml-1.s-1) to each resected lung sample was determined by multiplying the number of polymorphonuclear leukocytes (PMN) per milliliter of circulating blood by the blood flow to that sample. Capillary blood volume was obtained by multiplying the morphometrically determined fraction of pulmonary blood in capillaries by the total 51Cr-RBC volume in each sample. Cell concentrations (cells/ml) in capillary blood were calculated morphometrically, and capillary transit times were obtained by dividing cell concentration by cell flow. The results show that PMN transit times were 60–100 times longer than the RBC transit times, with a 22% overlap between their distributions. We conclude that PMN are concentrated with respect to RBC in pulmonary capillary blood because of differences in their transit times and that these long transit times provide an opportunity for PMN-endothelial interactions.
21
Littlefield, Katherine M., Renée O. Watson, Jennifer M. Schneider, Charles P. Neff, Eiko Yamada, Min Zhang, Thomas B. Campbell, et al. "SARS-CoV-2-specific T cells associate with inflammation and reduced lung function in pulmonary post-acute sequalae of SARS-CoV-2." PLOS Pathogens 18, no. 5 (May 26, 2022): e1010359. http://dx.doi.org/10.1371/journal.ppat.1010359.
Full textAbstract:
As of January 2022, at least 60 million individuals are estimated to develop post-acute sequelae of SARS-CoV-2 (PASC) after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While elevated levels of SARS-CoV-2-specific T cells have been observed in non-specific PASC, little is known about their impact on pulmonary function which is compromised in the majority of these individuals. This study compares frequencies of SARS-CoV-2-specific T cells and inflammatory markers with lung function in participants with pulmonary PASC and resolved COVID-19 (RC). Compared to RC, participants with respiratory PASC had between 6- and 105-fold higher frequencies of IFN-γ- and TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells in peripheral blood, and elevated levels of plasma CRP and IL-6. Importantly, in PASC participants the frequency of TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells, which exhibited the highest levels of Ki67 indicating they were activity dividing, correlated positively with plasma IL-6 and negatively with measures of lung function, including forced expiratory volume in one second (FEV1), while increased frequencies of IFN-γ-producing SARS-CoV-2-specific T cells associated with prolonged dyspnea. Statistical analyses stratified by age, number of comorbidities and hospitalization status demonstrated that none of these factors affect differences in the frequency of SARS-CoV-2 T cells and plasma IL-6 levels measured between PASC and RC cohorts. Taken together, these findings demonstrate elevated frequencies of SARS-CoV-2-specific T cells in individuals with pulmonary PASC are associated with increased systemic inflammation and decreased lung function, suggesting that SARS-CoV-2-specific T cells contribute to lingering pulmonary symptoms. These findings also provide mechanistic insight on the pathophysiology of PASC that can inform development of potential treatments to reduce symptom burden.
22
Zhang, Haiyun, Weidong Han, Haimei Liu, and Haijun Chen. "lncRNA UBE2R2-AS1 Had Anti-Tumor Effects in Non-Small Cell Lung Cancer." Journal of Biomaterials and Tissue Engineering 9, no. 12 (December 1, 2019): 1685–92. http://dx.doi.org/10.1166/jbt.2019.2200.
Full textAbstract:
Background: The purpose of our work was to discuss anti-tumor effects and mechanisms of lncRNA UBE2R2-AS1 in NSCLC. Methods : lncRNA UBE2R2-AS1 gene level was measured by RT-qPCR in BEAS-2B, A549, H1975, H1650 and HCC827. Dividing A549 and H1650 cells into NC, Vector and UBE2R2-AS1. Measuring the cell proliferation by CCK-8 assay; Using flow cytometer to evaluate cell apoptosis, using transwell and wound healing methods to evaluate invasion and migration abilities. The relative protein expressions were measured by WB assay. Results: UBE2R2-AS1 mRNA expression of A549 and H1650 were the lowest in all cells lines. With UBE2R2-AS1 transfection, the cell proliferation rates were significantly down-regulation with cell apoptosis significantly increasing (P < 0 001). Meanwhile, the invasion cell number and wound healing rates of UBE2R2-AS1 groups were significantly depressed (P < 0 001). Bcl-2, TLR4 and MyD88 proteins expressions were significantly down-regulation and Caspase-3 and Caspase-8 proteins levels were significantly upregulation in UBE2R2-AS1 groups (P < 0 001). Conclusion: UBE2R2-AS1 overexpression had antitumor in NSCLC, the mechanisms might be correlation with regulation Bcl-2, caspase-3, caspase-8, TLR4 and MyD88 protein levels.
23
Pańczyszyn, Anna, and Ewa Boniewska-Bernacka. "Telomeropathies: rare disease syndromes." Medical Science Pulse 12, no. 2 (June 30, 2018): 47–50. http://dx.doi.org/10.5604/01.3001.0012.1165.
Full textAbstract:
Telomeres are located at the end of the chromosomes. They protect chromosomes from fusion and degradation. Every cell division causes a shortening of the telomeres. A special enzymatic complex called telomerase is responsible for maintaining telomere length in intensively dividing cells, such as epithelial cells and bone marrow cells. The enzymatic complex includes the TERT subunit, which has reverse transcriptase activity, and the TERC subunit, which acts as a template. Other important components of telomerase are the proteins that are responsible for structural stability. Telomerase remains active only in the dividing cells of the body. The rate of telomere shortening depends on many factors including age, sex, and comorbidities. Faster shortening of telomeres is caused by gene defects, which have an impact on telomerase action. Collectively, these are called telomeropathies. Common causes of telomeropathies are mutations in the TERT and TERC telomerase genes. Types of telemeropathies include dyskeratosis congenita, idiopathic pulmonary fibrosis, and aplastic anaemia, among others. Clinical manifestations and prognoses depend on the type and quantity of mutated genes. Diagnosis of telomeropathies is often problematic because they present with the same symptoms as other diseases. So far, no effective therapeutic methods have been developed for telomeropathies. A therapeutic method for patients with bone marrow failure may be the transplantation of hematopoietic stem cells. For patients with idiopathic pulmonary fibrosis, treatments include immunosuppressive therapy, lung transplantation, or palliative care. In the future, gene therapy may be an effective treatment strategy for telomeropathies. Lifestyle changes may also have a positive impact on the person. Physical activity combined with a healthy diet rich in antioxidants and unsaturated fatty acids can decrease the oxidative stress levels in cells and lead to a slower shortening of the telomeres.
24
Zhang, Wei, Xin Huang, yueming Li, yingxuan Gong, and xiuzhi Li. "Abstract 5836: SMC4 promotes prostate cancer organ-specific metastasis by modifying cancer cell metabolism." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5836. http://dx.doi.org/10.1158/1538-7445.am2022-5836.
Full textAbstract:
Abstract Structural maintenance of chromosomes 4 (SMC4), one subunit of condensin complexes, is a key structural component of mitotic chromosomes. Accumulating evidence has suggested that SMC4 regulates prostate carcinogenesis. However, its roles on regulation of prostate cancer development remain unclear. Our previous studies showed that the expression of SMC4 is increased in highly lung-metastatic prostate cancer cells, RM1-LM, an organ-specific metastasis cell line that we developed. To investigate the function of SMC4, SMC4 gene was knockdown in RM1-LM cells by CRISPR/Cas9 system. Knockdown of SMC4 significantly diminished the cancer cell growth in RM1-LM. In addition, transwell assay results showed that SMC4 knockdown in RM1-LM suppressed the cell migration and invasion. Furthermore, we observed that SMC4 protein is important in the non-dividing phase of the cell cycle. In particular, cell cycle flow cytometry analysis indicated that SMC4 knockdown leaded to cell arrest in S phase. Finally, RM1-LM cells showed increased lung metastases compared with RM1-SMC4+/- cells in a murine model. The H&E and IHC results confirmed that RM1-LM cells induced greater number of lung metastases and colonization than RM1-SMC4+/-cells, suggesting the loss of SMC4 suppressed prostate cancer metastasis. The interactome of SMC4 was uncovered through IP-MS and revealed that SMC4 may interacted with GLUT1, a key protein in glycolysis pathway. The ATP rate assay and Glycolysis rate assay illustrated a significantly metabolic switch existing in RM1-SMC4+/-cells compared with their parental cells. Collectively, our study suggested that the interaction between SMC4 and GLUT1, confirmed by Co-IP, promotes prostate cancer cells metastasis via modifying the cell metabolism. This work was supported by NSFC projects 81802949, 81773146, 81972766, 81972420, 82173336; Shenzhen Science and Technology Commission Project JCYJ20190809161811237, JCYJ2021032410424040; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research (2017B030301018);and College students' innovative entrepreneurial training program (S202114325028) Citation Format: Wei Zhang, Xin Huang, yueming Li, yingxuan Gong, xiuzhi Li. SMC4 promotes prostate cancer organ-specific metastasis by modifying cancer cell metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5836.
25
De Man, Ruben, Taylor Adams, John McDonough, Juan Cala-Garcia, Benjamin Moss, Xiting Yan, Ivan Rosas, and Naftali Kaminski. "SINGLE-CELL ANALYSIS OF SOMATIC MUTATIONS IN HUMAN LUNG REVEALS ASSOCIATION WITH TRANSCRIPTIONAL CHANGES IN AGING." Innovation in Aging 8, Supplement_1 (December 2024): 571–72. https://doi.org/10.1093/geroni/igae098.1872.
Full textAbstract:
Abstract Age is a major risk factor for lung disease. Accumulation of somatic mutations has been implicated in both aging and cellular senescence. We analyzed somatic mutations called from single-cell RNAseq (scRNAseq) data. scRNAseq was performed on lung parenchyma samples from healthy donors (32 samples, 11-72 years, 21M/11F). Following standard pre-processing and cell type annotation, mutations were called using SComatic with the default parameters. Mutation burden was calculated for each cell type-sample combination by dividing the number of mutations by the number of callable sites. Our resulting scRNAseq dataset consisted of 199,400 cells, comprising 25 distinct cell types. Mutation burden was highest in alveolar type 1 (AT1) cells (93.6 mutations/MB), alveolar macrophages (79.1), and general capillary (gCap) cells (62.1). Mutation burden was positively correlated with age (r=0.28, p< 0.001). Globally, the top genes correlated with mutation burden included ubiquitin ligase genes (AMBRA1, ANAPC1, SEL1L, USP25, USP33) and DNA damage response genes (RAD50, PRKDC). Notably, mutation burden also correlated with expression of senescence marker CDKN2A (r=0.48, p< 0.05). In AT1 cells, mutation burden correlated with decreased expression of cell marker genes such as AGER (r=-0.64, p< 0.05) and HOPX (r=-0.83, p< 0.05). Similarly, gCap cells exhibited decreased expression of marker genes Il7R (r=-0.54) and VIPR1 (r=-0.64), while MAPK/ERK signaling genes were increased (p < 0.05). These genes were also significantly correlated with age in the same direction (p < 0.05). These results suggest that somatic mutation accumulation may contribute to age-associated transcriptional changes and loss of cell function, with cell types of the alveoli and endothelium experiencing the greatest effects.
26
Cruz-Collazo, Ailed M., Nilmary Grafals, Luis D. Borrero, and Suranganie Dharmawardhane. "Abstract 2680: Combination of the Rac/Cdc42 inhibitor MBQ-167 with paclitaxel reduces metastasis in triple negative breast cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2680. http://dx.doi.org/10.1158/1538-7445.am2023-2680.
Full textAbstract:
Abstract Metastasis represents a therapeutic challenge, especially in the case of triple negative breast cancer (TNBC), where patients often show recurrence and metastasis due to resistance to chemotherapy. The frontline therapy in TNBC is Paclitaxel, which targets actively dividing cells inducing subsequent apoptosis. Since dormant cells or metastatic cancer cells are not targeted by Paclitaxel, this strategy selects for non-dividing stem cells or more motile metastatic cells. Therefore, targeted treatment options are needed to overcome the recurrence and spreading of metastatic cells. We recently reported on MBQ-167, a Rac/Cdc42 inhibitor, which is highly effective in reducing tumor growth and metastasis in mouse models of TNBC (Cruz-Collazo et al., 2021, Molecular Cancer Therapeutics). Unpublished data show that in the MDA-MB-231 human TNBC model, MBQ-167 is as effective as Paclitaxel in reducing tumor growth and is more effective in metastasis prevention. Therefore, we hypothesize that MBQ-167 is a viable candidate for combined therapy with Paclitaxel and will reduce metastasis in TNBC. The purpose of this study is to test MBQ-167 in combination with Paclitaxel in the EGFR overexpressing MDA-MB-468 human TNBC cell line, which is highly malignant and also expresses the Rac1.B oncogenic splice variant. We found that MBQ-167 inhibits Rac, Rac1.B, and Cdc42 activation in this cell line. Next, we tested individual or combined MBQ-167 (50 mg/kg 5X a week) via oral administration and Paclitaxel (10 mg/kg 1X a week) via intraperitoneal administration in SCID mice bearing luciferase-tagged MDA-MB-468 tumors. Tumor growth and metastases were analyzed by chemiluminescence imaging followed by H&E staining of extracted lungs at necropsy. Similar to our studies with the syngeneic 4T-1/Balb/C model, in this MDA-MB-468 model, Paclitaxel increased metastasis while single agent MBQ-167 significantly reduced metastasis. MBQ-167 in combination with Paclitaxel reduced the enhanced lung metastasis in response to Paclitaxel. In conclusion, this study validates the clinical testing of MBQ-167 in combination with Paclitaxel as a potential combination therapy for TNBC. Citation Format: Ailed M. Cruz-Collazo, Nilmary Grafals, Luis D. Borrero, Suranganie Dharmawardhane. Combination of the Rac/Cdc42 inhibitor MBQ-167 with paclitaxel reduces metastasis in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2680.
27
Sherwin, R. P., V. Richters, and A. Richters. "Image Analysis Quantitation of Type 2 Cells and Alveolar Walls Part II: Influence of 0.3 ppm Nitrogen Dioxide Exposure on the Developing Mouse Lung." Journal of the American College of Toxicology 4, no. 1 (January 1985): 27–43. http://dx.doi.org/10.3109/10915818509014502.
Full textAbstract:
Newborn male mice (45 control and 45 experimental) were tested after 6 weeks of 0.3 ppm nitrogen dioxide (NO2) exposure and at postexposure periods of 4 and 10 weeks. After 6 weeks of exposure, there was a 12.9% increase in type 2 cell number that was statistically significant (P < 0.025) and an 11% increase in mean type 2 cell area that fell short of statistical significance. The ratio of cell area to alveolar wall area was also statistically significant (P = 0.05). The latter ratio, dividing a combined measurement of numbers and area of type 2 cells (type 2 cell field area) by the alveolar wall area, serves to control for lung volume. Although increases in type 2 cell number were not statistically significant for the 2 postexposure test periods, a significant increase (P < 0.05) was found by analysis of variance for all 3 test periods. NO2 exposure also resulted in a significant interaction (group x time; P < 0.05) of the type 2 cell field area:alveolar wall area ratio, i.e., a progressive fall for the exposed animals vs. a progressive rise for the control group. The interaction is believed to be the result of NO2-induced type 2 cell swelling followed by impairment of normal type 2 cell growth. The increase in type 2 cell numbers most likely reflects damage to the type 1 cell population since type 2 cell hyperplasia is a common denominator for diverse kinds of human lung disease where damaged type 1 cells are replaced by type 2 cells. The finding of a statistically significant interaction of the type 2 cell field area:wall area ratio and the persistence of increased alveolar wall area imply that the effects of NO2 on type 2 cells and alveolar walls were not completely reversed 10 weeks after exposure. Should the effects be irreversible, there would be the further implication of a commensurate depletion of structural and functional reserves of the lung.
28
Tawfik, Haytham O., Anwar A. El-Hamaky, Eman A. El-Bastawissy, Kirill A. Shcherbakov, Alexander V. Veselovsky, Yulia A. Gladilina, Dmitry D. Zhdanov, and Mervat H. El-Hamamsy. "New Genetic Bomb Trigger: Design, Synthesis, Molecular Dynamics Simulation, and Biological Evaluation of Novel BIBR1532-Related Analogs Targeting Telomerase against Non-Small Cell Lung Cancer." Pharmaceuticals 15, no. 4 (April 14, 2022): 481. http://dx.doi.org/10.3390/ph15040481.
Full textAbstract:
Telomeres serve a critical function in cell replication and proliferation at every stage of the cell cycle. Telomerase is a ribonucleoprotein, responsible for maintaining the telomere length and chromosomal integrity of frequently dividing cells. Although it is silenced in most human somatic cells, telomere restoration occurs in cancer cells because of telomerase activation or alternative telomere lengthening. The telomerase enzyme is a universal anticancer target that is expressed in 85–95% of cancers. BIBR1532 is a selective non-nucleoside potent telomerase inhibitor that acts by direct noncompetitive inhibition. Relying on its structural features, three different series were designed, and 30 novel compounds were synthesized and biologically evaluated as telomerase inhibitors using a telomeric repeat amplification protocol (TRAP) assay. Target compounds 29a, 36b, and 39b reported the greatest inhibitory effect on telomerase enzyme with IC50 values of 1.7, 0.3, and 2.0 μM, respectively, while BIBR1532 displayed IC50 = 0.2 μM. Compounds 29a, 36b, and 39b were subsequently tested using a living-cell TRAP assay and were able to penetrate the cell membrane and inhibit telomerase inside living cancer cells. Compound 36b was tested for cytotoxicity against 60 cancer cell lines using the NCI (USA) procedure, and the % growth was minimally impacted, indicating telomerase enzyme selectivity. To investigate the interaction of compound 36b with the telomerase allosteric binding site, molecular docking and molecular dynamics simulations were used.
29
Boesteanu, Alina C., Douglas V. Dolfi, Caspian H. Oliai, Annie Borowski, and Peter D. Katsikis. "CD28 costimulation is required by effector and memory CD8+ T cells (43.2)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S36. http://dx.doi.org/10.4049/jimmunol.178.supp.43.2.
Full textAbstract:
Abstract CD28 costimulation is crucial for priming of CD8+ T cell responses to pathogens, however its role in the later phase of the primary and in the secondary immune responses is not clear. To dissect the role of CD28, C57Bl/6 mice were primed intranasally with influenza virus and then treated with a non-depleting blocking anti CD28 antibody at days 6 and 8 post infection. The frequency and absolute number of virus-specific CD8+ T cells were reduced in anti CD28 treated (3.9±0.4%; 1.9±0.5x105) vs. untreated mice (11.5±1.2%; 7.4±1.7 x105). We found that anti-CD28 treatment induces apoptosis of virus-specific CD8+ cells while it did not affect the number of actively dividing cells. To study the role of CD28 during secondary CD8+ T cell responses, C57Bl/6 mice were primed with flu virus strain PR8 and day 60 memory cells were transferred into C57Bl/6 or CD80−/−CD86−/− deficient mice. Mice were then rechallenged with flu virus strain X31 and 7 days post rechallenge CD80−/−CD86−/− deficient mice exhibited a reduction in virus-specific CD8+ T cells in the lung, compared to C57Bl/6 mice (1.2±0.7x106 vs. 5.8±1.1x106, respectively). Failure of memory CD8+ T cells to expand in the absence of CD28 costimulation is due to a failure to downregulate Bcl-2 and to cell cycle arrest. Thus, effector and memory CD8+ T cells require CD28 costimulation to generate optimal immune responses against pathogens.
30
Marciniec, Krzysztof, Zuzanna Rzepka, Elwira Chrobak, Stanisław Boryczka, Małgorzata Latocha, Dorota Wrześniok, and Artur Beberok. "Design, Synthesis and Biological Evaluation of Quinoline-8-Sulfonamides as Inhibitors of the Tumor Cell-Specific M2 Isoform of Pyruvate Kinase: Preliminary Study." Molecules 28, no. 6 (March 9, 2023): 2509. http://dx.doi.org/10.3390/molecules28062509.
Full textAbstract:
Cancer cells need to carefully regulate their metabolism to keep them growing and dividing under the influence of different nutrients and oxygen levels. Muscle isoform 2 of pyruvate kinase (PKM2) is a key glycolytic enzyme involved in the generation of ATP and is critical for cancer metabolism. PKM2 is expressed in many human tumors and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various modulators regulate PKM2, shifting it between highly active and less active states. In the presented work, a series of 8-quinolinesulfonamide derivatives of PKM2 modulators were designed using molecular docking and molecular dynamics techniques. New compounds were synthesized using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Compound 9a was identified in in silico studies as a potent modulator of muscle isoform 2 of pyruvate kinase. The results obtained from in vitro experiments confirmed the ability of compound 9a to reduce the intracellular pyruvate level in A549 lung cancer cells with simultaneous impact on cancer cell viability and cell-cycle phase distribution. Moreover, compound 9a exhibited more cytotoxicity on cancer cells than normal cells, pointing to high selectivity in the mode of action. These findings indicate that the introduction of another quinolinyl fragment to the modulator molecule may have a significant impact on pyruvate levels in cancer cells and provides further directions for future research to find novel analogs suitable for clinical applications in cancer treatment.
31
Petrillo, Laura A., Ashley Zhou, Ryan J. Sullivan, Angelo E. Volandes, Joseph A. Greer, Jennifer S. Temel, and Areej El-Jawahri. "Knowledge about risks, benefits, and curative potential of immunotherapy among patients with advanced lung cancer or melanoma." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 6579. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.6579.
Full textAbstract:
6579 Background: Immunotherapy is a novel treatment paradigm that has improved survival for patients with advanced melanoma and lung cancer and poses new risks of immune-related adverse events, which are important for patients to recognize promptly. We aimed to describe patients’ knowledge about the risks and benefits of immunotherapy, and their understanding of the goal of treatment with immunotherapy. Methods: We conducted a cross-sectional study of patients at a single institution who had initiated therapy with an immune checkpoint inhibitor for advanced melanoma, small cell lung cancer, or non-small cell lung cancer in the past 12 weeks. We assessed patients’ knowledge about immunotherapy with a 9-item knowledge questionnaire (score range 0-100; higher score represents greater knowledge). We used the Perception of Treatment and Prognosis Questionnaire to assess patients’ understanding of the goal of their treatment. We used the two-sample t-test to compare knowledge scores and chi-square test to compare goals of therapy between patients with melanoma and lung cancer. Results: A total of 105 patients (57 with melanoma, 48 with lung cancer) completed the study questionnaire. Participants had a median age of 69 years (range 36-89), and 33% (35/105) were female. Participants’ mean knowledge score was 69.0 (SD = 23.3). Overall, 91% (96/105) of patients endorsed that immunotherapy works by turning on the body’s immune system to recognize and attack cancer cells and 33% (35/105) correctly identified that immunotherapy does not kill all rapidly dividing cells. With respect to immunotherapy side effects, 68% (71/105) of patients reported that immunotherapy side effects can affect any organ in the body and 65% (68/105) endorsed that side effects from immunotherapy can occur at any time, even after the treatment ends. Overall, 34% (36/105) of participants reported that the primary goal of their treatment is to cure their cancer. Participants with melanoma had higher mean knowledge scores compared to those with lung cancer (74.7 vs. 62.3, P = 0.003). Participants with melanoma were also more likely to report that the goal of their immunotherapy was to cure compared to those with lung cancer (58% [33/57] vs. 6% [3/48], P < 0.001) and that their oncologist had said that immunotherapy would cure their cancer (19% [11/57] vs. 0% [0/48], p = 0.005). Conclusions: We observed substantial knowledge deficits about immunotherapy and perceptions that immunotherapy is a cure for advanced cancer, particularly among patients with melanoma. These findings underscore the need for interventions to enhance patients’ knowledge about immunotherapy and to help them understand the goal of immunotherapy for patients with advanced cancer.
32
Rober, R. A., K. Weber, and M. Osborn. "Differential timing of nuclear lamin A/C expression in the various organs of the mouse embryo and the young animal: a developmental study." Development 105, no. 2 (February 1, 1989): 365–78. http://dx.doi.org/10.1242/dev.105.2.365.
Full textAbstract:
In mouse embryos, acquisition of the nuclear lamin polypeptides A/C varies according to developmental stage and tissue type. In order to determine the precise time points and cell types in which lamin A/C are first observed, we have used two monoclonal antibodies in immunofluorescence studies of different tissues of developing mouse embryos and of young mice. One antibody (mAB346) is specific for lamins A and C, while the other (PKB8) detects lamins A, B and C. Dividing uterine development into three phases—germ layer formation, organogenesis and tissue differentiation—our results show that lamin A/C expression in the embryo proper is not observed until the third phase of development. Lamin A/C first appears at embryonic day 12 in muscle cells of the trunk, head and the appendages. Three days later it is also seen in cells of the epidermis where its appearance coincides with the time of stratification. In the simple epithelial of lung, liver, kidney and intestine, as well as in heart and brain, lamins A/C do not appear until well after birth. Embryonal carcinoma (EC) cells express lamin B but not lamin A/C. Lamin A/C expression is noted in some EC cells after they are induced to differentiate and in several differentiated teratocarcinoma cell lines. Our results suggest that commitment of a cell to a particular pathway of differentiation (assayed by cell-type-specific expression of intermediate filament proteins) usually occurs prior to the time that lamin A/C can be detected. Thus lamin A/C expression may serve as a limit on the plasticity of cells for further developmental events.
33
Skarin, A. T., F. Vekeman, F. Laliberté, O. Afonja, M. Lafeuille, V. Barghout, and M. S. Duh. "Pattern of utilization of pegfilgrastim in patients with chemotherapy-induced neutropenia: A retrospective analysis of administrative claims data." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 9624. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.9624.
Full textAbstract:
9624 Background: Pegfilgrastim is a long-acting granulocyte colony-stimulating factor (G-CSF) used to prevent or treat febrile neutropenia associated with myelosuppressive anticancer therapies. According to the prescribing information, pegfilgrastim should not be administered within 14 days before or 24 hours after cytotoxic chemotherapy because of the potential for myeloid toxicity. This study examined use patterns of pegfilgrastim in real-life practice. Methods: Analysis of health insurance claims data in 2000- 2007 from > 35 large health plans across the US was conducted. Patients who had a cancer diagnosis and chemotherapy within 120 days of their first pegfilgrastim injection were identified. The proportion of pegfilgrastim injections that were followed by administration of chemotherapy within 11 and 9 days was calculated. Analysis was also stratified by cancer type [Non-Hodgkin's lymphoma (NHL), lung, breast]. Results: A total of 13,526 cancer patients received 57,118 pegfilgrastim injections. NHL, lung, and breast cohorts comprised 2,722, 2,772, and 4,955 patients, respectively. Mean age (SD) was 55.0 (11.6) and women represented 65.9% of study population. Among all cancer types, 19.2% of pegfilgrastim injections had a chemotherapy claim within the following 11 days. This pattern of use was the highest in NHL (18.9%), followed by lung (17.1%), and breast (16.2%). Similar results were observed in the 9-day sensitivity analysis (see Table ). Conclusions: Based on the retrospective analysis of this administrative claims database, the use of pegfilgrastim within 11 days of an administration of chemotherapy was observed in 15–20% of cases which is inconsistent with the recommended guidelines. Pegfilgrastim use in these situations may have the potential to increase sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy. Further research is being conducted to assess the related clinical and economic impact of this pattern of usage. [Table: see text] [Table: see text]
34
Evans, Angela C., Kelly A. Martin, Manoj Saxena, Sandra Bicher, Elizabeth Wheeler, Emilio J. Cordova, Christopher D. Porada, et al. "Curcumin Nanodiscs Improve Solubility and Serve as Radiological Protectants against Ionizing Radiation Exposures in a Cell-Cycle Dependent Manner." Nanomaterials 12, no. 20 (October 15, 2022): 3619. http://dx.doi.org/10.3390/nano12203619.
Full textAbstract:
Curcumin, a natural polyphenol derived from the spice turmeric (Curcuma longa), contains antioxidant, anti-inflammatory, and anti-cancer properties. However, curcumin bioavailability is inherently low due to poor water solubility and rapid metabolism. Here, we further refined for use curcumin incorporated into “biomimetic” nanolipoprotein particles (cNLPs) consisting of a phospholipid bilayer surrounded by apolipoprotein A1 and amphipathic polymer scaffolding moieties. Our cNLP formulation improves the water solubility of curcumin over 30-fold and produces nanoparticles with ~350 µg/mL total loading capacity for downstream in vitro and in vivo applications. We found that cNLPs were well tolerated in AG05965/MRC-5 human primary lung fibroblasts compared to cultures treated with curcumin solubilized in DMSO (curDMSO). Pre-treatment with cNLPs of quiescent G0/G1-phase MRC-5 cultures improved cell survival following 137Cs gamma ray irradiations, although this finding was reversed in asynchronously cycling log-phase cell cultures. These findings may be useful for establishing cNLPs as a method to improve curcumin bioavailability for administration as a radioprotective and/or radiomitigative agent against ionizing radiation (IR) exposures in non-cycling cells or as a radiosensitizing agent for actively dividing cell populations, such as tumors.
35
Aneja, Ritu, Jun Zhou, Surya N. Vangapandu, Binfei Zhou, Ramesh Chandra, and Harish C. Joshi. "Drug-resistant T-lymphoid tumors undergo apoptosis selectively in response to an antimicrotubule agent, EM011." Blood 107, no. 6 (March 15, 2006): 2486–92. http://dx.doi.org/10.1182/blood-2005-08-3516.
Full textAbstract:
AbstractWe have shown previously that EM011, a synthetic compound, binds tubulin with a higher affinity than the founding compound, noscapine, without changing total microtubule polymer mass. Now we show that EM011 is potently effective against vinblastine-resistant human lymphoblastoid line CEM/VLB100 and its parental vinblastine-sensitive line CEM. The cytotoxicity is mediated by cell cycle arrest at G2/M phase and subsequent apoptosis, as indicated by altered plasma membrane asymmetry, loss of mitochondrial transmembrane potential, activation of caspase-3, and increased DNA fragmentation. Furthermore, oral EM011 treatment of nude mice bearing human lymphoma xenografts results in pronounced tumor regression by triggering apoptosis and significantly lengthens the survival time of mice. EM011 treatment does not have obvious side effects in tissues with frequently dividing cells, such as the spleen and duodenum. In addition, EM011 does not show any toxicity in the liver, lung, heart, brain, and sciatic nerve. More importantly, EM011 does not affect hematopoiesis as determined by complete blood count profiles. These findings suggest that EM011 may be a safe and effective chemotherapeutic agent for oral treatment of drug-resistant human lymphomas. (Blood. 2006;107:2486-2492)
36
Maiti, Priyanka, Priyanka Sharma, Mahesha Nand, Indra D. Bhatt, Muthannan Andavar Ramakrishnan, Shalini Mathpal, Tushar Joshi, et al. "Integrated Machine Learning and Chemoinformatics-Based Screening of Mycotic Compounds against Kinesin Spindle ProteinEg5 for Lung Cancer Therapy." Molecules 27, no. 5 (March 2, 2022): 1639. http://dx.doi.org/10.3390/molecules27051639.
Full textAbstract:
Among the various types of cancer, lung cancer is the second most-diagnosed cancer worldwide. The kinesin spindle protein, Eg5, is a vital protein behind bipolar mitotic spindle establishment and maintenance during mitosis. Eg5 has been reported to contribute to cancer cell migration and angiogenesis impairment and has no role in resting, non-dividing cells. Thus, it could be considered as a vital target against several cancers, such as renal cancer, lung cancer, urothelial carcinoma, prostate cancer, squamous cell carcinoma, etc. In recent years, fungal secondary metabolites from the Indian Himalayan Region (IHR) have been identified as an important lead source in the drug development pipeline. Therefore, the present study aims to identify potential mycotic secondary metabolites against the Eg5 protein by applying integrated machine learning, chemoinformatics based in silico-screening methods and molecular dynamic simulation targeting lung cancer. Initially, a library of 1830 mycotic secondary metabolites was screened by a predictive machine-learning model developed based on the random forest algorithm with high sensitivity (1) and an ROC area of 0.99. Further, 319 out of 1830 compounds screened with active potential by the model were evaluated for their drug-likeness properties by applying four filters simultaneously, viz., Lipinski’s rule, CMC-50 like rule, Veber rule, and Ghose filter. A total of 13 compounds passed from all the above filters were considered for molecular docking, functional group analysis, and cell line cytotoxicity prediction. Finally, four hit mycotic secondary metabolites found in fungi from the IHR were screened viz., (−)-Cochlactone-A, Phelligridin C, Sterenin E, and Cyathusal A. All compounds have efficient binding potential with Eg5, containing functional groups like aromatic rings, rings, carboxylic acid esters, and carbonyl and with cell line cytotoxicity against lung cancer cell lines, namely, MCF-7, NCI-H226, NCI-H522, A549, and NCI H187. Further, the molecular dynamics simulation study confirms the docked complex rigidity and stability by exploring root mean square deviations, root mean square fluctuations, and radius of gyration analysis from 100 ns simulation trajectories. The screened compounds could be used further to develop effective drugs against lung and other types of cancer.
37
Wang, Jinjie, Jiaqi Zhu, Yijie Tang, Anping Zhang, Tingting Zhou, Youlang Zhou, and Jiahai Shi. "Characteristic of Molecular Subtypes in Lung Squamous Cell Carcinoma Based on Autophagy-Related Genes and Tumor Microenvironment Infiltration." Journal of Oncology 2022 (September 13, 2022): 1–18. http://dx.doi.org/10.1155/2022/3528142.
Full textAbstract:
Background. Recently, a large number of studies have sought personalized treatment for lung squamous cell carcinoma (LUSC) by dividing patients into different molecular subtypes. Autophagy plays an important role in maintaining the tumor microenvironment and immune-related biological processes. However, the molecular subtypes mediated by autophagy in LUSC are not clear. Methods. Based on 490 LUSC samples, we systematically analyzed the molecular subtype modification patterns mediated by autophagy-related genes. The ssGSEA and CIBERSORT algorithm were utilized to quantify the relative abundance of TME cell infiltration. Principal component analysis was used to construct autophagy prognostic score (APS) model. Results. We identified three autophagy subtypes in LUSC, and their clinical outcomes and TME cell infiltration had significant heterogeneity. Cluster A was rich in immune cell infiltration. The enrichment of EMT stromal pathways and immune checkpoint molecules were significantly enhanced, which may lead to its immunosuppression. Cluster B was characterized by relative immunosuppression and relative stromal activation. Cluster C was activated in biological processes related to repair. Patients with high APS were significantly positively correlated with TME stromal activity and poor survival. Meanwhile, high APS showed an advantage in response to anti-PD1 and anti-CTLA4 immunotherapy. Conclusion. This study explored the autophagy molecular subtypes in LUSC. We also discovered the heterogeneity of TME cell infiltration driven by autophagy-related genes. The established APS model is of great significance for evaluating the prognosis of LUSC patients, the infiltration of TME cells, and the effect of immunotherapy.
38
Cruz-Collazo, Ailed M., Olga Katsara, Elizabeth Salvo, Jean Ruiz, Robert Schneider, and Suranganie Dharmawardhane. "Abstract 4065: Efficacy of the Rac/Cdc42 inhibitor MBQ-167 in combination therapy with Paclitaxel." Cancer Research 82, no. 12_Supplement (June 15, 2022): 4065. http://dx.doi.org/10.1158/1538-7445.am2022-4065.
Full textAbstract:
Abstract Triple negative breast cancer (TNBC) represents a challenge because of its aggressiveness and resistance to standard chemotherapy. Since TNBC lacks targeted therapy options, the frontline therapy is Paclitaxel, which targets actively dividing cells inducing subsequent apoptosis. Since dormant cells or metastatic cancer cells are not targeted by Paclitaxel, more targeted treatment options are needed. MBQ-167, a small molecule developed by us to target the metastasis drivers Rac and Cdc42, is highly effective in reducing tumor growth and metastasis in mouse models of TNBC (Cruz-Collazo et al., 2021, Molecular Cancer Therapeutics). The purpose of this study is to test the hypothesis that MBQ-167 is a viable candidate for combined therapy with Paclitaxel in TNBC. Therefore, we tested the efficacy of MBQ-167 in combination with Paclitaxel in MDA-MB-231 human TNBC cells via MTT viability assays and caspase 3/7 apoptosis, using effective concentrations of MBQ-167 and/or Paclitaxel for 24, 48, 96 & 120 hrs. We found that individual MBQ-167 or the combination therapy was more effective at 48-120 hrs at reducing cell viability by ~80% compared to ~60% by Paclitaxel treatment alone and significatively increasing apoptosis. Next, we tested individual or combined MBQ-167 (5 mg/kg 5X a week) and Paclitaxel (10 mg/kg 1X a week) on SCID mice bearing MDA-MB-231 tumors, via intraperitoneal administration. We report a significant reduction in tumor growth and lung metastasis in response to combined MBQ-167 and Paclitaxel compared to either treatment alone. A more aggressive syngeneic model of 4T-1 mouse breast cancer cells in BALB/c immunocompetent model was used to determine the direct effect of MBQ-167 and Paclitaxel on metastasis. When 4T-1 tumors were surgically removed and MBQ-167, Paclitaxel, or the combination administered for 17 days, the combination treatment, but not individual compounds, significantly reduced lung metastases by ~80%. In conclusion, this study validates the clinical testing of MBQ-167 in combination with Paclitaxel as a potential therapeutic for TNBC. Citation Format: Ailed M. Cruz-Collazo, Olga Katsara, Elizabeth Salvo, Jean Ruiz, Robert Schneider, Suranganie Dharmawardhane. Efficacy of the Rac/Cdc42 inhibitor MBQ-167 in combination therapy with Paclitaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4065.
39
Goto, Yukinobu, James C. Hogg, Chih-Horng Shih, Hiroshi Ishii, Renaud Vincent, and Stephan F. van Eeden. "Exposure to ambient particles accelerates monocyte release from bone marrow in atherosclerotic rabbits." American Journal of Physiology-Lung Cellular and Molecular Physiology 287, no. 1 (July 2004): L79—L85. http://dx.doi.org/10.1152/ajplung.00425.2003.
Full textAbstract:
Exposure to air pollution [particulate matter, particles <10 μm (PM10)] causes a systemic inflammatory response that includes stimulation of the bone marrow (BM) and progression of atherosclerosis. Monocytes are known to play a key role in atherogenesis by migration into subendothelial lesions where they appear as foam cells. The present study was designed to quantify the BM monocyte response in Watanabe heritable hyperlipidemic (WHHL) rabbits after PM10exposure. WHHL rabbits were given twice weekly intrapharyngeal instillations of 5 mg of PM10for 4 wk to a total of 40 mg and compared with control WHHL or New Zealand White (NZW) rabbits. The thymidine analog 5′-bromo-2′-deoxyuridine was used to label dividing cells in the BM and a monoclonal antibody to identify monocytes in peripheral blood. The transit time of monocytes through the BM was faster in WHHL than in NZW rabbits (30.4 ± 1.9 h vs. 35.2 ± 0.9 h, WHHL vs. NZW; P < 0.05). PM10instillation exposure increased circulating band cell counts, caused rapid release of monocytes from the BM, and further shortened their transit time through the BM to 23.2 ± 1.6 h ( P < 0.05). The percentage of alveolar macrophages containing particles in the lung correlated with the BM transit time of monocytes (r2= 0.45, P <0.05). We conclude that atherosclerosis increases the release of monocytes from the BM, and PM10exposure accelerates this process in relation to the amount of particles phagocytosed by alveolar macrophages.
40
Goliwas, Kayla F., Anthony M. Wood, Young-il Kim, Joel L. Berry, James M. Donahue, and Jessy S. Deshane. "Abstract B33: Tumor-stromal response to immune checkpoint blockade within patient tissue derived three-dimensional lung tumor models." Cancer Immunology Research 10, no. 12_Supplement (December 1, 2022): B33. http://dx.doi.org/10.1158/2326-6074.tumimm22-b33.
Full textAbstract:
Abstract The tumor microenvironment is a key regulator of tumor biology and response to therapeutic intervention, with intercellular communication between tumor and stromal cells regulating growth and progression. While two dimensional cultures are commonly utilized for in vitro preclinical studies, they do not recapitulate the tissue microenvironment or three dimensional tissue architecture. Herein, we utilize tissue engineering strategies and patient-derived specimen to develop ex vivo non-small cell lung tumor models. These models allow for evaluation of tumor-stromal interactions and response to immune directed therapies while keeping the native tissue microenvironment intact. For this study, tumor models were generated utilizing remnant lung tumor specimen from consented patients undergoing surgical tumor resection. 5 mm diameter tissue cores were placed in a volume of extracellular matrix within a perfusion bioreactor platform, and through-channels were generated to provide nutrient circulation during ex vivo culture. Spatial profiling using the Nanostring GeoMx platform, multiplex cytokine analysis, histologic and flow cytometric analyses were performed following culture. Primary human tumor specimens cultured ex vivo maintain histologic architecture and representative cell populations following 14 days culture. Tissues treated with an anti-programmed cell death protein 1 (PD-1) blocking antibody showed reduced IL-6 (380.8 ±133.9 pg/mL) levels within the circulating media when compared to IgG control treated tissues (1119 ±382.9 pg/mL, p=0.08). Spatial profiling showed increased proportions of dividing T cells (2.27 ± 1.02 IgG vs. 8.28 ± 1.171 anti-PD-1; p=0.02) and CD8+ memory T cells (0.09 ± 0.09 IgG vs. 1.74 ± 0.64 anti-PD-1; p=0.04) and a trend towards more natural killer cells (3.88 ± 0.73 IgG vs. 6.56 ± 3.14 anti-PD-1; p=0.067), along with decreased proportions of macrophages (14.33 ± 2.16 IgG vs. 6.44 ± 0.59 anti-PD-1; p=0.004) near the tumor in tissues treated with anti-PD-1 when compared to control. Additionally, genes within the tumor immune signature associated with programmed cell death ligand 1 suppression, anti-tumor cytotoxicity and T cell response, including CXCR6, CCL3, NKG7, CMKLR1, CD27 & PSMB10, were upregulated and genes associated with immune suppression, including IDO and HLA-E, were downregulated with anti-PD-1 treatment when compared to IgG control. Moving forward, this platform will allow for extensive characterization of tumor-stromal interactions, response to therapeutic intervention, and therapeutic resistance in a patient specific manner. Funding: Nanostring DSP Cancer Transcriptome Atlas Award; 1R21 CA263365-01A1; Respiratory Health Association Lung Cancer Award (RHA2022-01-LC). Citation Format: Kayla F. Goliwas, Anthony M. Wood, Young-il Kim, Joel L. Berry, James M. Donahue, Jessy S. Deshane. Tumor-stromal response to immune checkpoint blockade within patient tissue derived three-dimensional lung tumor models [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B33.
41
Zicha, D., E. Genot, G. A. Dunn, and I. M. Kramer. "TGFbeta1 induces a cell-cycle-dependent increase in motility of epithelial cells." Journal of Cell Science 112, no. 4 (February 15, 1999): 447–54. http://dx.doi.org/10.1242/jcs.112.4.447.
Full textAbstract:
We have previously shown that addition of type 1 transforming growth factor-beta (TGFbeta1) to an exponentially growing population of mink lung CCl64 cells increases their average intermitotic time from 14.4 to 20.3 hours, predominantly by extending G1 from 7.5 to 13.5 hours. Here we have used the DRIMAPS system (digitally recorded interference microscopy with automatic phase-shifting) for obtaining data on cellular mass distribution, cell motility and morphology. We found no significant change in the cells' rate of mass increase following TGFbeta1 treatment, which implies that the treated cells attained a higher mass during their extended cell cycle and this was confirmed by direct measurement of cell size. However, the cells showed a dramatic motile response to treatment: TGFbeta1-treated cells had a significantly higher time-averaged speed of 36.2 microm hour-1 compared to 14.5 microm hour-1 for the control cells. The time course of the response was gradual, reaching a maximum mean speed of 52.6 microm hour-1 after 15 hours exposure. We found that the gradual onset of the response was probably not due to a slow accumulation of a secondary factor but because cells were dividing throughout the experiment and most of the response to TGFbeta1 occurred only after the first cell division in its presence. Thus, taking only those cells that had not yet divided, the time-averaged speed of treated cells (26.1 micrometer hour-1) was only moderately higher than that of untreated cells (14.9 micrometer hour-1) whereas, for those cells that had divided, the difference in speed between treated cells (45.1 micrometer hour-1) and untreated cells (14.1 microm hour-1) was much greater. Increased speed was a consequence of enhanced protrusion and retraction of the cell margin coupled with an increase in cell polarity. TGFbeta1 also increased the mean spreading of the cells, measured as area-to-mass ratio, from 3.2 to 4.4 micrometer2 pg-1, and the intracellular mass distribution became more asymmetric. The observations indicate that a G2 signal may be necessary to reach maximal motility in the presence of TGFbeta1.
42
Doronin, Konstantin, Karoly Toth, Mohan Kuppuswamy, Peter Ward, Ann E. Tollefson, and William S. M. Wold. "Tumor-Specific, Replication-Competent Adenovirus Vectors Overexpressing the Adenovirus Death Protein." Journal of Virology 74, no. 13 (July 1, 2000): 6147–55. http://dx.doi.org/10.1128/jvi.74.13.6147-6155.2000.
Full textAbstract:
ABSTRACT We have constructed two novel adenovirus (Ad) replication-competent vectors, named KD1 and KD3, that may have use in anticancer therapy. The vectors have two key features. First, they markedly overexpress the Ad death protein (ADP), an Ad nuclear membrane glycoprotein required at late stages of infection for efficient cell lysis and release of Ad from cells. Overexpression of ADP was achieved by deleting the E3 region and reinserting the adp gene. Because ADP is overexpressed, KD1 and KD3 are expected to spread more rapidly and effectively through tumors. Second, KD1 and KD3 have two E1A mutations (from the mutant dl1101/1107) that prevent efficient replication in nondividing cells but allow replication in dividing cancer cells. These E1A mutations preclude binding of E1A proteins to p300 and pRB. As a result, the virus should not be able to drive cells from G0 to S phase and therefore should not be able to replicate in normal tissues. We show that KD1 and KD3 do not replicate well in quiescent HEL-299 cells or in primary human bronchial epithelial cells, small airway epithelial cells, or endothelial cells; however, they replicate well in proliferating HEL-299 cells and human A549 lung carcinoma cells. In cultured A549 cells, KD1 and KD3 lyse cells and spread from cell to cell more rapidly than their control virus, dl1101/1107, or wild-type Ad. They are also more efficient than dl1101/1107 or wild-type Ad in complementing the spread from cell to cell of an E1− E3−replication-defective vector expressing β-galactosidase. A549 cells form rapidly growing solid tumors when injected into the hind flanks of immunodeficient nude mice; however, when A549 cells were infected with 10−4 PFU of KD3/cell prior to injection into mice, tumor formation was nearly completely suppressed. When established A549 tumors in nude mice were examined, tumors injected with buffer grew 13.3-fold over 5 weeks, tumors injected with dl1101/1107 grew 8-fold, and tumors injected with KD1 or KD3 grew 2.6-fold. Hep 3B tumors injected with buffer grew 12-fold over 3.5 weeks, whereas tumors injected with KD1 or KD3 grew 4-fold. We conclude that KD1 and KD3 show promise as anticancer therapeutics.
43
Xiang, Huihui, Rika Kasajima, Hiroyuki Ito, Tomoyuki Yokose, Takashi Oshima, Tetsuro Sasada, and Yohei Miyagi. "Abstract 2200: Transcriptomic profiling identifies an amino acid metabolism-related prognostic gene signature in lung adenocarcinoma patients." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2200. http://dx.doi.org/10.1158/1538-7445.am2023-2200.
Full textAbstract:
Abstract Lung cancer is by far the most common cancer-related fatality. In addition to the existing standard treatment methods, it is urgent to develop new therapy methods to improve the survival rate of patients. Amino acid metabolism plays a crucial role in tumor development. Cancer cells rely on amino acids for replication, energy source, redox homeostasis, and release metabolites that recruit and stimulate immunosuppressive cells. This study constructed a novel prognostic signature model of lung adenocarcinoma (LUAD) composed of amino acid metabolism-related genes and assessed immune cell infiltration characteristics and predictive value for patient therapy. We screened differentially expressed genes involved in amino acid metabolic pathways in LUAD tumor tissues versus normal tissues from RNA-seq data of The Cancer Genome Atlas. Then we performed a multivariate cox analysis of 9 genes significantly associated with patients’ overall survival, which established a new prognostic signature. Dividing the patients into high- and low-risk groups using a cutoff value of -0.36, the outcome showed that the risk score of this model could predict survival of LUAD patients with relatively high accuracy (ROC-AUC (max)=0.73). Subsequently, we utilized the ssGSEA method to quantify the infiltration of immune cells. We found that several immune cell subpopulations were significantly altered abundance between the high- and low-risk patients. Immune cell subpopulations, such as mast cell, plasmacytoid dendritic cell, and central memory CD4 T cell, were significantly abundant in the low-risk patients. After ESTIMATE algorithm evaluation, a method for estimating the proportion of stromal and immune cells in tumor tissues based on gene expression profiles, we observed that immune and stroma scores were markedly upregulated in low-risk patients, suggesting that the immune and stromal activity were increased. The key molecules of this signature exhibited a significant correlation with the expression of immune checkpoint molecules. Moreover, multivariate cox regression model analysis was performed with patients’ age, gender, clinical stage, T stage, M stage, N stage and risk score. The results indicated that the risk score signature was a significant and independent prognostic biomarker for the prognostic prevision of LUAD patients.Finally, the risk score based on the amino acid metabolism-related signature was successfully validated by the data of LUAD patients in the GEO dataset GES30219.These findings suggest that the prognostic signature based on the expression of genes involved in amino acid metabolism may be useful and effective. We further characterized one of the 9 genes involved in tryptophan metabolism for its biological implications in tumor progression and construction of immuno-suppressive tumor microenvironment by experimental procedures with human LUAD cell lines. Citation Format: Huihui Xiang, Rika Kasajima, Hiroyuki Ito, Tomoyuki Yokose, Takashi Oshima, Tetsuro Sasada, Yohei Miyagi. Transcriptomic profiling identifies an amino acid metabolism-related prognostic gene signature in lung adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2200.
44
Choi, Yoon-La, Sehhoon Park, Sergio Pereira, Seonwook Park, Minuk Ma, Jiwon Shin, Jisoo Shin, et al. "Distinct subset of immune cells assessed by multiplex immunohistochemistry correlates with immune phenotype classified by an artificial intelligence-powered tissue analyzer in advanced non-small cell lung cancer." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e21012-e21012. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e21012.
Full textAbstract:
e21012 Background: Pathologic classification of immune phenotype is challenging since there is no consensus on how to assess spatial relations of tumor-infiltrating lymphocyte (TIL) on cancer epithelium (CE) and cancer stroma (CS) in whole-slide images (WSI). We previously suggested that the artificial intelligence (AI)-powered tissue analyzer, Lunit SCOPE IO, can classify immune phenotype, and that its predictions are correlated with the clinical outcome of immune checkpoint inhibitor (ICI) in non-small cell lung cancer (NSCLC). In this study, we designed a pathologic validation of immune phenotype using multiplex immunohistochemistry. Methods: Lunit SCOPE IO was developed based on a 2.8 x 109 micrometer2 area of CE or CS, and 5.9 x 106 TILs from 3,166 H&E Whole-Slide Image (WSI) of multiple cancer types, annotated by board-certified pathologists. H&E WSIs were divided into 1 mm2-sized tiles, where we classified immune phenotype (IP) based on TIL density on CE and TIL density on CS. Representative IP was determined based on the overall proportion of tile-level IPs in each WSI. Multiplex immunohistochemistry (mIHC) staining with CD3, CD8, CD20, CD68, FOXP3, CK, and DAPI was performed in NSCLC tumor tissues (n = 99) treated with immune checkpoint inhibitors (ICI) at the Samsung Medical Center. A normalized number of cells expressing each marker was calculated by dividing the total number of marker-positive cells by the number of DAPI-positive cells in each WSI. Results: The proportions of inflamed IP, immune-excluded IP, and immune desert IP in the analysis set were 46.5%, 29.3%, and 24.2%. respectively. Median progression-free survival of ICI was 6.4 m in inflamed IP, 1.9 m in immune-excluded IP, and 1.6 m in immune-desert IP (hazard ratio of inflamed versus others: 0.43, confidence interval 0.27-0.68, P = 0.000188). Multiplex IHC results showed that the normalized CD3-positive cells and CD8-positive cells, which play a role of anti-tumor activity, were highly enriched in inflamed IP compared to those in other IPs (CD3: fold change [FC] 1.57, P = 0.0182; CD8: FC 1.24, P = 0.0697), whereas FOXP3-positive cells, linked to the immunosuppressive activity, were enriched in immune-excluded IP (FC 1.26, P = 0.0656). We also noted that CD68-positive cells were significantly enriched in immune-desert IP (FC 1.76, P = 0.00467). Conclusions: The immune cell subset in WSI is distinct according to the immune phenotype, as CD3- or CD8-positive cells are enriched in inflamed IP rather than immune-excluded IP as classified by AI-powered TIL analysis of H&E image.
45
Hossain, Mohammad S., and Ned Waller. "Mechanisms of Migration and Generation of Allo-Reactive Donor T Cells That Cause Organ Specific Acute GvHD in Allogeneic BMT Recipients." Blood 110, no. 11 (November 16, 2007): 3270. http://dx.doi.org/10.1182/blood.v110.11.3270.3270.
Full textAbstract:
Background: Allo-reactive donor T cells are primarily responsible for GvHD in allogeneic BMT. A number of studies have shown that increased allo-reactivity is found among the CD62L+ subset of donor T-cells, but the mechanisms for organ specific allo-reactivity are poorly defined. Our hypothesis is that rapid proliferation and migration of CD62L+ naive donor CD4+ and CD8+ T cells to specific organs leads to acute GvHD. Methods: We used a parent (C57BL/6) to (C57BL/6 × BALB/c) CB6F1 allogeneic BMT model with a combination of T cell depleted BM (TCD BM) and splenocytes. 30 × 106 congeneic donor splenocytes labeled with CFSE were transplanted with 5 × 106 TCD congeneic BM into lethally irradiated (11Gy) CB6F1 mice. Recipients were sacrificed within 3.5 days of transplant and FACS was used to measure proliferation of CFSE-labeled donor T-cells isolated from blood, spleen, liver, lungs, thymus, BM, lymph nodes, and peritoneal exudates cells (PEC). Syngeneic C57BL/6 recipients served as controls. At least 5 mice per group were used in each experiment. Results: There was increased homing of CFSE-labeled donor T-cells to most organs in allogeneic compared to syngeneic BMT recipients. CD45.1+ donor cells were 4-fold higher in spleen, p=0.01; 9-fold higher in liver, p=0.002; 14-fold higher in PEC, p=0.017; 136-fold higher in lung, p=0.0006; 126-fold higher in BM, P=0.002, 1482-fold higher in thymus p=0.002 compared to syngeneic recipients. Allogeneic and syngeneic recipients had equivalent numbers of donor CFSE-labeled lymphocytes in PBMC and lymph nodes. The tissue specific homing of CD4+ and CD8+ donor T-cells was also found significantly higher in most organs except the PBMC and LNs. Donor splenocytes were 80% CD62L+ before transplant, but the frequency of CD62L+ donor T-cells had declined to 15–16% in BM, 4–10% in liver, 17–30% in spleen and 10 to 25% in the thymus within 3.5 days post-transplant. In syngeneic recipients, 80% of donor T-cells remained CD62L+ within 3.5 days post-transplant. Most donor T-cells that divided rapidly lost expression of CD62L, while non-replicating donor CD4+ and CD8+ T cells remained predominately CD62L+. The expression of CD44 on donor T-cells were the opposite, with CD44+ cells undergoing less, and CD44− cells dividing more in allogeneic transplant recipients. In syngeneic BMT, donor CD4+ and CD8+ T-cells underwent minimal proliferation within the first 3.5 days post-transplant. Intracellular cytokine staining showed that high levels of IFN-g and TNF-a synthesis was seen among CD62L+ CD4+ and CD8+ T cells that had yet to divide (and had un-diluted CFSE staining). Conclusion: Migration of allogeneic donor T cells to tissues and local proliferation occurs rapidly after allogeneic BMT compared to recipients of syngeneic transplants. The dissociation of CD62L expression from lymph node homing suggests lack of the CD62L-receptor expression in lymph node HEV following irradiation, or a dominant effect of other chemokine receptors in directing donor T-cell preferentially to other organs. The marked and preferential homing of donor T-cells to the recipient thymus and bone marrow may play a role in achieving donor hematopoietic and T-cell chimerism in recipients of allogeneic BMT. Tissue specific homing of naive CD62L+ donor T-cells, with a high proliferative capacity, is likely responsible for the initiation of acute GvHD at these sites.
46
Miyata, Ryohei, Ni Bai, Renaud Vincent, Don D. Sin, and Stephan F. Van Eeden. "Novel properties of statins: suppression of the systemic and bone marrow responses induced by exposure to ambient particulate matter (PM10) air pollution." American Journal of Physiology-Lung Cellular and Molecular Physiology 303, no. 6 (September 15, 2012): L492—L499. http://dx.doi.org/10.1152/ajplung.00154.2012.
Full textAbstract:
Exposure to ambient particulate matter (PM10) elicits systemic inflammatory responses that include the stimulation of bone marrow and progression of atherosclerosis. The present study was designed to assess the effect of repeated exposure of PM10on the turnover and release of polymorphonuclear leukocytes (PMNs) from the bone marrow into the circulation and the effect of lovastatin on the PM10-induced bone marrow stimulation. Rabbits exposed to PM10three times a week for 3 wk, were given a bolus of 5′-bromo-2′-deoxyuridine to label dividing cells in the marrow to calculate the transit time of PMNs in the mitotic or postmitotic pool. PM10exposure accelerated the turnover of PMNs by shortening their transit time through the marrow (64.8 ± 1.9 h vs. 34.3 ± 7.4 h, P < 0.001, control vs. PM10). This was predominantly due to a rapid transit of PMNs through the postmitotic pool (47.9 ± 0.7 h vs. 21.3 ± 4.3 h, P < 0.001, control vs. PM10) but not through the mitotic pool. Lovastatin delayed the transit time of postmitotic PMNs (38.2 ± 0.5 h, P < 0.001 vs. PM10) and shifted the postmitotic PMN release peak from 30 h to 48 h. PM10exposure induced the prolonged retention of newly released PMNs in the lung, which was reduced by lovastatin ( P < 0.01). PM10exposure increased plasma interleukin-6 levels with significant reduction by lovastatin ( P < 0.01). We conclude that lovastatin downregulates the PM10-induced overactive bone marrow by attenuating PM10-induced systemic inflammatory responses.
47
Zhang, X. D., Y. Zhang, X. Liu, Y. S. Li, J. P. Ding, X. R. Zhang, and Y. H. Zhang. "132 REFERENCE GENE SCREENING FOR ANALYZING GENE EXPRESSION ACROSS FEMALE GOAT TISSUE." Reproduction, Fertility and Development 26, no. 1 (2014): 179. http://dx.doi.org/10.1071/rdv26n1ab132.
Full textAbstract:
Quantitative RT-PCR (RT-qPCR) is an important method for investigating changes in mRNA expression levels in cells and tissues. Selection of the proper reference genes is very important when calibrating the results of RT-qPCR. Studies on the selection of reference genes in goat tissues are limited, despite the economic importance of their meat and dairy products. We applied absolute quantification using the standard curve method to the detection of the expression levels of 8 reference gene candidates (18S, TBP, YWHAZ, HMBS, ACTB, HPRT1, GAPDH, and EEF1A2) in 10 different tissue types (heart, liver, spleen, lung, kidney, stomach, uterus, ovary, small intestine, and muscle) sourced from a 5-month-old female Boer goat. All the experiments were performed using 3 biological replicates and technical triplicates of each cDNA sample. The optimal reference gene combination was selected according to the results determined by geNorm, NormFinder, and Bestkeeper software packages. The analyses showed that tissue is an important variability factor in gene expression stability. When all tissues were considered, 18S, TBP, and HMBS with the smallest paired variation coefficient is the optimal reference combination for calibrating RT-qPCR analysis of gene expression from goat tissues. The stability of each gene was evaluated, taking into account all of the data. The stability values (M) for these genes were 0.643/0.634/0.799, 0.156/0.467/0.584, and 0.396/0.445/0.566 by geNorm, NormFinder, and Bestkeeper, respectively. Dividing the dataset by different tissues, ACTB was the most stable in stomach, small intestine, and ovary, 18S in heart and spleen, HMBS in uterus and lung, TBP in liver, HPRT1 in kidney, and GAPDH in muscle. Overall, this study provided valuable information about the female goat reference genes that can be used in order to perform a proper normalisation when relative quantification by RT-qPCR studies is undertaken. This work was supported by National ‘863’ Program (2011AA100307-4), the Technology Innovation Project – Special Program and the Science and Technology Program of Anhui Province (11Z0101095 and 11010302108).
48
Davidi, Shiri, Roni Blat, Mijal Munster, Anna Shteingauz, Shay Cahal, Moshe Giladi, Uri Weinberg, Yoram Palti, and Moshe Giladi. "176 Evaluating the safety of tumor treating fields (TTFields) application to the torso – in vivo studies." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A190. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0176.
Full textAbstract:
BackgroundTumor Treating Fields (TTFields) are a noninvasive, antineoplastic treatment delivered locoregionally to tumor bed via low intensity (1–3 V/cm), intermediate frequency (100–500 kHz), alternating electric fields. This treatment modality has been shown to be cytotoxic to rapidly dividing cells, with highest efficacy demonstrated at different optimal frequencies depending on tumor cell-type. TTFields therapy is FDA-approved for the treatment of newly diagnosed and recurrent glioblastoma (GBM), with the overall tolerable safety profile (EF-11 and EF-14 clinical trials) attributed to the low rate of mitotic events in normal, quiescent brain cells. Further evaluation of the safety profile of TTFields is needed for treating cancer in different body regions where there are high rates of cellular proliferation, i.e. torso. Many solid malignant tumors may reside in the torso region – mesothelioma and non-small cell lung carcinoma (NSCLC) in the thoracic segment; pancreatic cancer, hepatocellular carcinoma, and gastric cancer in the abdomen; and ovarian cancer in the pelvis. Hence, we investigated the safety of delivering TTFields to the torso of healthy rats at conditions previously deemed effective for treating the aforementioned cancer cell types.MethodsTTFields were applied using the Novo-TTF100L system at frequencies of 150 or 200 kHz and intensities of 1–2 V/cm RMS to torsos of Sprague Dawley (SD) female rats for a duration of 2 weeks. Throughout treatment, animals underwent daily clinical examinations. Blood samples and comparative histological evaluation of major internal organs were performed at treatment cessation.ResultsNo significant differences were observed for the TTFields treated groups in comparison to control groups for the following parameters: activity level, food and water intake, stools, motor neurological status, respiration, weight, complete blood count, blood biochemistry, and pathological findings.ConclusionsThese results demonstrate the safety of 150 and 200 kHz TTFields when delivered to torsos of healthy rats, where there are normal tissues with high cellular proliferation rates. Overall, TTFields delivery to the torso demonstrated safety and feasibility for the treatment of thoracic and other abdominal and pelvic cancers. TTFields are currently being investigated in clinical studies for the treatment of solid tumors located in the torso, including locally advanced pancreatic cancer (PANOVA-3 Study, NCT03377491), ovarian cancer (INNOVATE-3 Study, NCT03940196), lung cancer (LUNAR Study, NCT02973789), hepatocellular carcinoma (HEPANOVA Study, NCT03606590) and gastric cancer.
49
Miller, Jeffrey, Nicholas Zorko, Behiye Kodal, Zachary Davis, Alexander Lenvik, Todd Lenvik, Joshua Walker, et al. "470 Targeting Pan-Tumor Associated Antigen B7H3 via Combination of Tri-specific Killer Engager and Off-the-shelf NK Cell Therapy Enhances Specificity and Function Against a Broad Range of Solid Tumors." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A500. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0470.
Full textAbstract:
BackgroundB7H3 is a tumor associated antigen (TAA), found on numerous malignancies including prostate, lung, and breast cancers. High levels of B7H3 expression are correlated with late stage disease and poor prognosis. Furthermore, B7H3 is minimally expressed on normal tissue, making it an ideal TAA for broad cancer treatment strategy. We developed a tri-specific killer engager (TriKETM) consisting of a nanobody anti-CD16, IL-15, and nanobody anti-B7H3 joined by flexible linkers (camB7H3 TriKE) (figure 1A). The combination of B7H3 TriKE with an off-the-shelf NK cell therapy presents an appealing therapeutic strategy for the treatment of solid tumors with decreased risk of toxicity in allogeneic settings compared to T-cell derived products.MethodsAn anti-B7H3 nanobody was developed via biopanning and cloned into a TriKE vector. TriKE was produced in Expi293 cells and affinity purified using poly-His tag. NK cells were co-incubated with cell lines exhibiting a range of B7H3 expression and with 3nM of camelid B7H3 TriKE or control. We have previously derived NK cells expressing high affinity non-cleavable hnCD16, CD38 KO, and IL-15/IL-15R fusion from clonal master engineered iPSC lines. Engineered iNK cells were tested in conjunction with the TriKE. A repeated measures ANOVA was used for statistical comparisons as noted in figure legendsResultsEngineered iNK cells co-incubated with camB7H3 TriKE and C4-2 prostate cells significantly increased degranulation (CD107a) and cytokine production (IFN-gamma) compared to controls (figure 1B/C, P<0.05, n=3). camB7H3 TriKE directly bound C4-2 cells with an estimated EC50 of approximately 3nM. camB7H3 TriKE increased percentages of engineered iNK cells dividing robustly (3 or more times) compared to corresponding IL-15 doses at 3 nM (figure 1D, P<0.001, n=3). Furthermore, camB7H3 TriKE enhanced cytotoxic activity of engineered iNK cells against a variety of tumor cells in 2D and spheroid format independent of cytokine support (figure 1E-F). Engineered iNK cells incorporating an anti-B7H3 chimeric antigen receptor (CAR) is also being developed and will be discussed.Abstract 470 Figure 1A) Schematic of TriKE molecule demonstrating spatial relationship of anti-CD16 nanobody, IL-15, and anti-B7H3 nanobody with flexible linker regions. B) Percent of PB NK cells CD107a as a marker of NK degranulation. Unselected PBMCs were stimulated with 3nM camB7H3 TriKE, 3nM IL-15, or no treatment with B7H3-expressing C4-2 prostate cancer cell lines Cells were stimulated for 5 hours and evaluated for degranulation (surface CD107a) by flow cytometry, gating on the NK (CD56+CD3-) population (displayed). Graphs display mean ± SEM. P<0.05 using repeated measures ANOVA. C) Percent of PB NK cells expressing intracellular interferon-gamma. Unselected PBMCs were stimulated with 3nM camB7H3 TriKE, 3nM IL-15, or no treatment with B7H3-expressing C4-2 prostate cancer cell lines Cell were stimulated for 5 hours and evaluated for degranulation (surface CD107a) by flow cytometry, gating on the NK (CD56+CD3-) population (displayed). Graphs display mean ± SEM. P<0.05 using repeated measures ANOVA. D) Percent of PB NK cells dividing robustly (3 or more times) over a 7 day stimulation with 3nM camB7H3 TriKE, 3nM IL-15, or no treatment. PBMCs were incubated with Cell-Trace Violet reagent prior to stimulation. Graphs display mean ± SEM. P<0.001 using repeated measures ANOVA. E) Representative 2D IncuCyte images of PC3 prostate cancer cell lines transduced with NucLight Red. Cells were co-incubated with iNK alone, iNK with 3nM IL-15 or iNK with 3 nM antiB7H3 TriKE. Images represent remaining NucLight Red transduced PC3 cells after 72 hours of co-incubation as noted above. F) Representative microspheriod IncuCyte images of PC3 prostate cancer lines transduced with NucLight Red. Cells were co-incubated with iNK cells alone, iNK with 3 nM IL-15 or iNK with 3 nM antiB7H3 TriKE. Images represent remaining NucLight Red transduced PC3 cells after 72 hours of co-incubation as noted aboveConclusionscamB7H3 TriKE dramatically increases function and activation on endogenous NK cells as well as engineered iNK cell, which can be adoptively transferred to patients with a broad range of cancers, including prostate cancer. TriKE activity was potent across a broad concentration spectrum and corresponded directly with B7H3 target expression. These studies represent the proof-of-concept of a novel pairing of off-the-shelf, engineered iNK cells with B7H3-directed pan-cancer engager molecules (TriKEs and CARs) to enhance specificity, persistence and anti-tumor function.
50
Mazur, Grzegorz, Ilona Kryczek, Tomasz Wrobel, Dorota Dlubek, Aleksandra Klimczak, Emilia Jaskula, Michal Jelen, Andrzej Lange, and Kazimierz Kuliczkowski. "CCL2 Chemokine Gene Expression in Lymph Nodes May Have Prognostic Value in Non-Hodgkin’s Lymphoma." Blood 108, no. 11 (November 16, 2006): 4644. http://dx.doi.org/10.1182/blood.v108.11.4644.4644.
Full textAbstract:
Abstract Background: Non-Hodgkin’s lymphomas (nHL) constitute complex group of lymphoproliferative disorders in which clinical outcome is difficult to predict at the moment of diagnosis. Formation of International Prognostic Index has provided criteria dividing patients into groups of risk, but still new prognostic factors are being searched. There are several reports that some chemokines including CCL2 play a role in progression of solid tumours (bladder, ovarian, non-small cell lung cancer) and increased level of CCL2 has been found in myeloma multiple. CCL2 is the chemokine produced by tumour cells and some stromal cells, such as: fibroblasts, endothelial cells and monocytes. CCL2 is chemoattractant for monocytes, T, NK and dendritic cells and basophlis. CCL2 has also angiogenic activity and is necessary for tumour growth and metastatic process. Aim: The purpose of this study was to evaluate gene expression of CCL2 chemokine in lymphoma and reactive lymph nodes. Material and methods: CCL2 gene expression was determined in 37 lymph nodes of lymphoma patients (26 B-cell lymphoma: 12 females and 14 males aged 26–73 years; 4 T-cell lymphoma: males aged 41–81 years; 7 Hodgkin’s lymphoma: 4 females and 3 males aged 21–58 years) and 25 reactive lymph nodes (15 females, 10 males, aged 18–59 years, median age 32 years). Gene expression was determined by the reverse transcription (RT)-polymerase chain reaction method. Scale of expression was 0–3 AU. Statistical analysis was performed using Kruskall-Wallis and Mann-Witney tests (p<0,05). Results: In lymphoma lymph nodes CCL2 expression was significantly higher (2–3 AU) than in reactive lymph nodes (p=0,0008). Increased CCL2 expression was detected in 19/26 (73%) B-cell lymphoma lymph nodes and all (4/4, 100%) T-cell lymphomas. In reactive lymph nodes 2 AU expression was observed in 7/25 cases (28%). Particularly high expression characterized diffuse large B-cell lymphomas and Burkitt lymphomas. Patients with high CCL2 expression had significantly shorter survival than those with low expression (p=0,004). There was positive correlation between CCL2 expression and Ki-67 proliferation marker (p<0,05; coefficient 0,39). Conclusions: CCL2 expression is higher in B-cell lymphoma lymph nodes than in reactive lymph nodes. Multivariate analysis has proved CCL2 as independent prognostic factor in nHL.