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Query: UNIPROT:P06889 (Mol)
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Titanium dioxide (TiO2) has been used extensively in the manufacturing of white pigment and has generally been regarded as a nuisance dust in animals and man. After inhalation exposure, little is known about transmigration routes and potential toxic effects of translocated particles in other organs. In order to answer these questions, rats were exposed to TiO2 by inhalation exposure at concentrations of 0, 10, 50, and 250 mg/m3 for 2 years. A few free particles were retained in the nasal and tracheobronchial epithelium without any cellular damage, but aggregates of dust-laden macrophages (dust cells) were found in the lymphoid tissue of the submucosa. Inhaled particles were mostly engulfed by alveolar macrophages and confined sharply to the alveolar duct region at 10 and 50 mg/m3, while dust cells were scattered throughout alveoli at 250 mg/m3. A fraction of the inhaled particles was retained in the membranous pneumocytes and interstitial macrophages. A dense accumulation of dust cells was found in the perivascular and peribronchial lymphoid tissue. Some dust cells entered peribronchial lymphatics or pulmonary blood vessels and the general circulation. Dust cells in the hyperplastic peribronchial lymphoid tissue were exposed directly in the luminal surface of the airways and were subsequently eliminated via airways. Massive dust deposition was observed in the tracheobronchial lymph nodes. Dust transmigration was markedly reduced in the cervical lymph nodes, and only a trace amount of dust particles was found in the mesenteric lymph nodes. Some dust cells entered either blood or lymphatic vessels in the lymph nodes and then migrated into the general circulation. The incidence of extrapulmonary dust deposition in the liver or spleen was increased in a dose-related fashion similar to the lung dust burden. Since there was no tissue response to translocated particles in the lymph nodes, spleen, or liver, potential adverse health effects appear to be negligible.
Exp Mol Pathol 1985 Jun
PMID:Transmigration of titanium dioxide (TiO2) particles in rats after inhalation exposure. 399 54

Vasculogenesis and angiogenesis are the mechanisms responsible for the development of the blood vessels. Angiogenesis refers to the formation of capillaries from pre-existing vessels in the embryo and adult organism, while vasculogenesis is the development of new blood vessels from the differentiation of endothelial precursors (angioblasts) in situ. Vascular endothelial growth factor (VEGF) family members are major mediators of vasculogenesis and angiogenesis both during development and in pathological conditions. VEGF has a variety of effects on vascular endothelium, including the ability to promote endothelial cell viability, mitogenesis, chemotaxis, and vascular permeability. It mediates its activity mainly via two tyrosine kinase receptors, VEGFR-1 (flt-1) and VEGFR-2 (flk-1/KDR), although other receptors, such as neuropilin-1 and -2, can also bind VEGF. Another tyrosine kinase receptor, VEGFR-3 (flt-4) binds VEGF-C and VEGF-D and is more important in the development of lymphatic vessels. While the functional effects of VEGF on endothelial cells has been well studied, not as much is known about VEGF signaling. This review summarizes the different pathways known to be involved in VEGF signal transduction and the biological responses triggered by the VEGF signaling cascade.
Int J Mol Med 2000 May
PMID:Signaling pathways induced by vascular endothelial growth factor (review). 1076 46

Cyclin D1 is a G1 cyclin that controls the transition of the cell cycle from G1 phase to S phase, and its gene is located on chromosome 11q13. We evaluated the expression of cyclin D1 mRNA in surgically resected specimens of gastric and colorectal cancers using quantitative RT-PCR. In this method, cDNA derived from cyclin D1 mRNA was amplified in a tube together with an internal control. The expression of cyclin D1 mRNA was high in 8 of 36 gastric cancer tissues (22%) and 9 of 27 (33%) colorectal cancer tissues, compared to normal mucosal tissues. In gastric cancers, the rate of cyclin D1 mRNA expression (an index of the density of DNA bands) was significantly higher in patients with tumors invading beyond the submucosal layer, regional lymph nodes and lymphatic vessels (i.e., patients with stage III or IV). In colorectal cancers, the rate of cyclin D1 mRNA expression was significantly higher in patients with venous invasion. Moreover, in patients with colorectal cancer, the survival rate of high-expression group was significantly lower than in low-expression group. Our results suggested that overexpression of cyclin D1 mRNA reflected the severity of gastric cancer and poor prognosis of colorectal cancer.
Res Commun Mol Pathol Pharmacol 1999
PMID:Evaluation of cyclin D1 mRNA expression in gastric and colorectal cancers. 1095 28

The aim of this study was to investigate the feasibility of lymphoscintigraphy for sentinel node identification in testicular cancer. Five patients with clinical stage I testicular cancer were prospectively included. A single dose of technetium-99m nanocolloid (mean dose 99 MBq, volume 0.2 ml) was injected into the funiculus in the first patient and into the testicular parenchyma in the following four patients. Dynamic lymphoscintigraphy was performed over 10 min, followed by early and late static images after 15 min and 2 to 24 h, respectively. Lymphoscintigraphy was followed by laparoscopic sentinel node biopsy on the same day in the last two patients using patent blue dye and an endoscopic gamma probe. The funicular administration route showed five hot spots in the right inguinal region after 2 h. Intratesticular administration resulted in sentinel node visualisation in three of the four patients. Dynamic images showed afferent lymphatic vessels to one sentinel node in the left para-aortic region in two patients and two sentinel nodes in the left para-aortic region in another patient. Sentinel nodes were intraoperatively identified in one of two patients who underwent laparoscopic exploration. It is concluded that lymphoscintigraphy for sentinel node identification is feasible in stage I testicular cancer using intratesticular radiocolloid administration.
Eur J Nucl Med Mol Imaging 2002 May
PMID:Feasibility of sentinel node lymphoscintigraphy in stage I testicular cancer. 1253 6

Brugia malayi is a filarial nematode parasite that causes lymphatic filariasis, a disease that affects millions of people in the tropics. Sexual reproduction of filarial worms occurs within the lymphatic vessels of the human host and is crucial for transmission of the parasite to the mosquito vector. We have previously identified several B. malayi genes that exhibit apparent gender-specific expression. One of these had significant sequence similarity to the Ascaris suum embryo-associated fatty acid binding protein, As-p18. The full length cDNA for the B. malayi female-associated fatty acid binding protein (Bm-FAB-1) encodes a 17.8 kDa protein (excluding a signal peptide) with 70% sequence identity with mature As-p18 and significant similarity to Caenorhabditis elegans and mammalian fatty acid-binding proteins (FABPs). Antibodies raised to Bm-FAB-1 bound to developing embryos within female worms, especially around early embryo cells and the surfaces of immature worms within eggs. Functional studies showed that recombinant Bm-FAB-1 binds to several long chain fatty acids including oleate, but not retinol. Taken together, these results demonstrate that Bm-FAB-1 is a member of an unusual nematode-specific, secreted lipid binding protein family. The existence of a novel class of lipid binding proteins in nematode embryos raises the possibility that drugs targeting these proteins could be developed with broad activity against nematode parasites of medical and veterinary importance.
Mol Biochem Parasitol
PMID:An embryo-associated fatty acid-binding protein in the filarial nematode Brugia malayi. 1238 45

The ability to determine various functions of genes in an intact host will be an important advance in the postgenomic era. Intravital imaging of gene regulation and the physiological effect of the gene products can play a powerful role in this pursuit. Intravital epifluorescence microscopy has provided powerful insight into gene expression, tissue pH, tissue pO2, angiogenesis, blood vessel permeability, leukocyte-endothelial (L-E) interaction, molecular diffusion, convection and binding, and barriers to the delivery of molecular and cellular medicine. Multiphoton laser scanning microscopy (MPLSM) has recently been applied in vivo to overcome three drawbacks associated with traditional epifluorescence microscopy: (i) limited depth of imaging due to scattering of excitation and emission light; (ii) projection of three-dimensional structures onto a two-dimensional plane; and (iii) phototoxicity. Here, we use MPLSM for the first time to obtain high-resolution images of deep tissue lymphatic vessels and show an increased accuracy in quantifying lymphatic size. We also demonstrate the use of MPLSM to perform accurate calculations of the volume density of angiogenic vessels and discuss how this technique may be used to assess the potential of antiangiogenic treatments. Finally, high-speed MPLSM, applied for the first time in vivo, is used to compare L-E interactions in normal tissue and a rhabdomyosarcoma tumor. Our work demonstrates the potential of MPLSM to noninvasively monitor physiology and pathophysiology both at the tissue and cellular level. Future applications will include the use of MPLSM in combination with fluorescent reporters to give novel insight into the regulation and function of genes.
Mol Imaging
PMID:Conventional and high-speed intravital multiphoton laser scanning microscopy of microvasculature, lymphatics, and leukocyte-endothelial interactions. 1292 Aug 56

Lymphatic vessels in the colon are normally distributed beneath the muscularis mucosae with rare branches reaching through the muscularis mucosae to the most basal aspect of the colonic crypts. In chronic inflammatory bowel disease demonstrating acute inflammation and architectural disarray, lymph vessel proliferation is seen within the lamina propria and within the submucosa. We analyzed the number and distribution of lymphatic vessels within the lamina propria and submucosa in chronic active and treated ulcerative colitis with restoration of architecture by immunostaining with D2-40, a specific monoclonal antibody against lymphatic vessels. We found significantly increased numbers of lymph vessels in chronic active ulcerative colitis both within the lamina propria and the submucosa as compared to normal mucosa. Numbers of lymph vessels in lamina propria were highest in severe chronic active ulcerative colitis and less in moderate and minimal residual disease with minimal architectural disarray (p<0.05). Lymph vessels in the submucosa were increased significantly above normal values in both severe, moderate and minimal residual disease. We conclude that lymph vessel distribution in chronic active ulcerative colitis extends into the lamina propria. With restoration of architectural morphology, the integrity of the lamina propria in regards to the distribution of lymph vessels is restored.
Int J Mol Med 2004 Feb
PMID:Proliferation of D2-40-expressing intestinal lymphatic vessels in the lamina propria in inflammatory bowel disease. 1471 25

Lymphoscintigraphy involves interstitial injection of radiolabelled particulate materials or radioproteins. Although several variations in the technique have been described, their place in clinical practice remains controversial. Traditional diagnostic criteria are based primarily on lymph node appearances but in situations such as breast cancer, where lymph nodes may have been excised, these criteria are of limited use. In these circumstances, lymphatic vessel morphology takes on greater importance as a clinical endpoint, so a method that gives good definition of lymphatic vessels would be useful. In patients with breast cancer, for example, such a method, used before and after lymph node resection, may assist in predicting the development of breast cancer-related lymphoedema. The aim of this study was to optimise a method for the visualisation of lymphatic vessels. Subcutaneous (sc) and intradermal (id) injection sites were compared, and technetium-99m nanocolloid, a particulate material, was compared with (99m)Tc-human immunoglobulin (HIG), which is a soluble macromolecule. Twelve normal volunteers were each studied on two occasions. In three subjects, id (99m)Tc-HIG was compared with sc (99m)Tc-HIG, in three id (99m)Tc-nanocolloid was compared with sc (99m)Tc-nanocolloid, in three id (99m)Tc-HIG was compared with id (99m)Tc-nanocolloid and in three sc (99m)Tc-HIG was compared with sc (99m)Tc-nanocolloid. Endpoints were quality of lymphatic vessel definition, the time after injection at which vessels were most clearly visualised, the rate constant of depot disappearance ( k) and the systemic blood accumulation rate as measured by gamma camera imaging over the liver or cardiac blood pool. Excellent definition of lymphatic vessels was obtained following id injection of either radiopharmaceutical, an injection route that was clearly superior to sc. Differences between radiopharmaceuticals were less clear, although after id injection, (99m)Tc-HIG gave images that were marginally but significantly better than those given by (99m)Tc-nanocolloid. Image quality correlated inversely with time after injection at which the best image was obtained, consistent with the notion that good vessel definition was dependent on a "narrow" bolus width. k was approximately three times higher after id injection than after sc injection but it was not significantly different between radiopharmaceuticals for either injection route. Intradermal (99m)Tc-HIG gave a cardiac blood pool signal that, over the first 60 min, increased about five times faster than that with sc (99m)Tc-HIG, but no clear difference was observed in the rate of increase in hepatic activity between id (99m)Tc-nanocolloid and sc (99m)Tc-nanocolloid. We conclude that id injection provides rapid access of radiotracers to lymphatic vessels, which is ideal for imaging lymphatic vessel morphology. (99m)Tc-HIG is marginally superior to nanocolloid for this purpose and, in drainage basins from which lymph nodes have been excised, is not handicapped by a potentially inferior ability, compared with radiocolloid, to image lymph nodes.
Eur J Nucl Med Mol Imaging 2004 Apr
PMID:Finding an optimal method for imaging lymphatic vessels of the upper limb. 1472 73

In the absence of antibodies specific for lymphatic vessels, analysis of lymphatic vessels within different tissues has been widely performed with light microscopic and, most importantly, electron microscopic techniques. In regard to lymphatic vessels in the ocular globe and the periocular structures, controversy remains about the specific distribution of lymphatic channels. It is postulated that bulbar and retrobulbar tissues are devoid of lymphatic vessels, but lymphatic vessels have been demonstrated in lacrimal gland and epibulbar conjunctiva. In this study, we analyzed orbital fat for the presence of lymphatic tissue using D2-40, a monoclonal antibody, specific for lymphatic vessels. We found lymphatic vessels present within bulbar conjunctiva extending to the level of the ciliary apparatus. No lymphatics were identified in healthy anterior orbital adipose tissue. In two cases of orbital mucor-mycosis and one case of panendophthalmitis, significant lymphovascular proliferation was present within granulation tissue associated with the acute inflammation. We conclude that lymph vessel proliferation may be induced in inflammatory conditions in tissues which are normally devoid of lymph channels.
Int J Mol Med 2004 May
PMID:Observation of lymphatic vessels in orbital fat of patients with inflammatory conditions: a form fruste of lymphangiogenesis? 1506 70

Endothelial cells line the inside of blood and lymphatic vessels, and cancer cells must cross this barrier, first to gain access to the circulation, and, second, to exit and metastasize. How this occurs is incompletely understood. We now demonstrate that human cancer cells are able to fuse with endothelial cells to form hybrid cells displaying proteins and chromosomal markers characteristic of both parent cells. The hybrid cells are viable and capable of undergoing mitosis. Fusions between cancer cells and endothelial cells were shown to occur both in vitro, in co-cultures of human breast cancer cells and endothelial cells, and in vivo, following intravascular dissemination of human breast cancer cells in nude mice. These observations demonstrate a new type of cancer-endothelial cell interaction that may be of fundamental importance to the process of metastasis.
Cell Mol Life Sci 2004 Aug
PMID:Spontaneous fusion between cancer cells and endothelial cells. 1531 61


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