Abstract
Featured Article
Lymphangiogenesis plays an important role in promoting cancer metastasis to sentinel lymph nodes and beyond and also promotes organ transplant rejection. We used human lymphatic endothelial cells to establish a reliable three-dimensional lymphangiogenic sprouting assay with automated image acquisition and analysis for inhibitor screening. This high-content phenotype-based assay quantifies sprouts by automated fluorescence microscopy and newly developed analysis software. We identified signaling pathways involved in lymphangiogenic sprouting by screening the Library of Pharmacologically Active Compounds (LOPAC)(1280) collection of pharmacologically relevant compounds. Hit characterization revealed that mitogen-activated protein kinase kinase (MEK) 1/2 inhibitors substantially block lymphangiogenesis in vitro and in vivo. Importantly, the drug class of statins, for the first time, emerged as potent inhibitors of lymphangiogenic sprouting in vitro and of corneal and cutaneous lymphangiogenesis in vivo. This effect was mediated by inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and subsequently the isoprenylation of Rac1. Supplementation with the enzymatic products of HMG-CoA reductase functionally rescued lymphangiogenic sprouting and the recruitment of Rac1 to the plasma membrane.
In this manuscript, the authors identify anti-lymphangiogenic compounds in an automated “ in vitro phenotype-based lymphangiogenic screening assay” utilizing a 3-D human lymphatic endothelial cell (LEC) sprouting assay developed by this team. Using reproducible methods, they studied the Library of Pharmacologically Active Compounds (LOPAC) and identified 31 substances which were classified as anti-lymphangiogenic, then focused on the statin class for further characterization of effect in vivo and in vitro. They observed Simvastatin as the most effective in inhibiting LEC sprouting (3-D sprouting assay) and postnatal lymphangiogenesis (mouse-Matrigel plug assay and mouse cornea assay). The presumed mechanism of action is via 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibition. The implication that statins may indeed provide a pharmacologic avenue to inhibit unwanted lymphangiogenesis is indeed intriguing and if further studies support this observation, statins may be an important addition to pharmacotherapy in malignancies and many other diseases.
Basic Science
Bazigou, E. and T. Makinen (2012). “Flow control in our vessels: vascular valves make sure there is no way back.” Cell Mol Life Sci.
Betterman, K. L., et al. (2012). “Remodeling of the lymphatic vasculature during mouse mammary gland morphogenesis is mediated via epithelial-derived lymphangiogenic stimuli.” Am J Pathol.
Bronneke, S., et al. (2012). “DNA methylation regulates lineage-specifying genes in primary lymphatic and blood endothelial cells.” Angiogenesis 15(2): 317–329.
During embryonic development, the lymphatic system emerges by transdifferentiation from the cardinal vein. Although lymphatic and blood vasculature share a close molecular and developmental relationship, they display distinct features and functions. However, even after terminal differentiation, transitions between blood endothelial cells (BEC) and lymphatic endothelial cells (LEC) have been reported. Since phenotypic plasticity and cellular differentiation processes frequently involve epigenetic mechanisms, we hypothesized that DNA methylation might play a role in regulating cell type-specific expression in endothelial cells. By analyzing global gene expression and methylation patterns of primary human dermal LEC and BEC, we identified a highly significant set of genes, which were differentially methylated and expressed. Pathway analyses of the differentially methylated and upregulated genes in LEC revealed involvement in developmental and transdifferentiation processes. We further identified a set of novel genes, which might be implicated in regulating BEC-LEC plasticity and could serve as therapeutic targets and/or biomarkers in vascular diseases associated with alterations in the endothelial phenotype.
Chen, C. Y., et al. (2012). “Blood flow reprograms lymphatic vessels to blood vessels.” J Clin Invest 122(6): 2006–2017.
Human vascular malformations cause disease as a result of changes in blood flow and vascular hemodynamic forces. Although the genetic mutations that underlie the formation of many human vascular malformations are known, the extent to which abnormal blood flow can subsequently influence the vascular genetic program and natural history is not. Loss of the SH2 domain-containing leukocyte protein of 76 kDa (SLP76) resulted in a vascular malformation that directed blood flow through mesenteric lymphatic vessels after birth in mice. Mesenteric vessels in the position of the congenital lymphatic in mature Slp76-null mice lacked lymphatic identity and expressed a marker of blood vessel identity. Genetic lineage tracing demonstrated that this change in vessel identity was the result of lymphatic endothelial cell reprogramming rather than replacement by blood endothelial cells. Exposure of lymphatic vessels to blood in the absence of significant flow did not alter vessel identity in vivo, but lymphatic endothelial cells exposed to similar levels of shear stress ex vivo rapidly lost expression of PROX1, a lymphatic fate-specifying transcription factor. These findings reveal that blood flow can convert lymphatic vessels to blood vessels, demonstrating that hemodynamic forces may reprogram endothelial and vessel identity in cardiovascular diseases associated with abnormal flow.
Cheng, J., et al. (2012). “Renal lymphatic ligation aggravates renal dysfunction through induction of tubular epithelial cell apoptosis in mononephrectomized rats.” Clin Nephrol.
Choi, I., et al. (2012). “Interleukin-8 reduces post-surgical lymphedema formation by promoting lymphatic vessel regeneration.” Angiogenesis.
Davis, M. J., et al. (2012). “Intrinsic increase in lymphangion muscle contractility in response to elevated afterload.” Am J Physiol Heart Circ Physiol 303(7): H795–808.
Fukuhara, J., et al. (2012). “Expression of vascular endothelial growth factor C in human pterygium.” Histochem Cell Biol.
Girling, J. E. and P. A. Rogers (2012). “The endometrial lymphatic vasculature: Function and dysfunction.” Rev Endocr Metab Disord.
Hagendoorn, J., et al. (2005). “Molecular regulation of microlymphatic formation and function: role of nitric oxide.” Trends Cardiovasc Med 15(5): 169–173.
Harvey, N. L. and E. J. Gordon (2012). “Deciphering the roles of macrophages in developmental and inflammation stimulated lymphangiogenesis.” Vasc Cell 4(1): 15.
He, G. Z., et al. (2012). “The effects of n-3 PUFA and intestinal lymph drainage on high-mobility group box 1 and Toll-like receptor 4 mRNA in rats with intestinal ischaemia-reperfusion injury.” Br J Nutr 108(5): 883–892.
Hoffman, S. J., et al. (2012). “An in vivo method to quantify lymphangiogenesis in zebrafish.” PLoS One 7(9): e45240.
BACKGROUND: Lymphangiogenesis is a highly regulated process involved in the pathogenesis of disease. Current in vivo models to assess lymphangiogenesis are largely unphysiologic. The zebrafish is a powerful model system for studying development, due to its rapid growth and transparency during early stages of life. Identification of a network of trunk lymphatic capillaries in zebrafish provides an opportunity to quantify lymphatic growth in vivo. METHODS AND RESULTS: Late-phase microangiography was used to detect trunk lymphatic capillaries in zebrafish 2- and 3-days post-fertilization. Using this approach, real-time changes in lymphatic capillary development were measured in response to modulators of lymphangiogenesis. Recombinant human vascular endothelial growth factor (VEGF)-C added directly to the zebrafish aqueous environment as well as human endothelial and mouse melanoma cell transplantation resulted in increased lymphatic capillary growth, while morpholino-based knockdown of vegfc and chemical inhibitors of lymphangiogenesis added to the aqueous environment resulted in decreased lymphatic capillary growth. CONCLUSION: Lymphatic capillaries in embryonic and larval zebrafish can be quantified using late-phase microangiography. Human activators and small molecule inhibitors of lymphangiogenesis, as well as transplanted human endothelial and mouse melanoma cells, alter lymphatic capillary development in zebrafish. The ability to rapidly quantify changes in lymphatic growth under physiologic conditions will allow for broad screening of lymphangiogenesis modulators, as well as help define cellular roles and elucidate pathways of lymphatic development.
Hoopes, S. L., et al. (2012). “Characteristics of multi-organ lymphangiectasia resulting from temporal deletion of calcitonin receptor-like receptor in adult mice.” PLoS One 7(9): e45261.
Jalili, A. (2013). “Chemokine overexpression in the skin by biolistic DNA delivery.” Methods Mol Biol 940: 175–188.
Kaji, C., et al. (2012). “Immunohistochemical Examination of Novel Rat Monoclonal Antibodies against Mouse and Human Podoplanin.” Acta Histochem Cytochem 45(4): 227–237.
Kosaka, N., et al. (2013). “In vivo real-time lymphatic draining using quantum-dot optical imaging in mice.” Contrast Media Mol Imaging 8(1): 96–100.
Lee, K. M., et al. (2012). “D6: the ‘crowd controller’ at the immune gateway.” Trends Immunol.
Li, C., et al. (2012). “Crosstalk between Platelets and the Immune System: Old Systems with New Discoveries.” Adv Hematol 2012: 384685.
Platelets are small anucleate cells circulating in the blood. It has been recognized for more than 100 years that platelet adhesion and aggregation at the site of vascular injury are critical events in hemostasis and thrombosis; however, recent studies demonstrated that, in addition to these classic roles, platelets also have important functions in inflammation and the immune response. Platelets contain many proinflammatory molecules and cytokines (e.g., P-selectin, CD40L, IL-1beta, etc.), which support leukocyte trafficking, modulate immunoglobulin class switch, and germinal center formation. Platelets express several functional Toll-like receptors (TLRs), such as TLR-2, TLR-4, and TLR-9, which may potentially link innate immunity with thrombosis. Interestingly, platelets also contain multiple anti-inflammatory molecules and cytokines (e.g., transforming growth factor-beta and thrombospondin-1). Emerging evidence also suggests that platelets are involved in lymphatic vessel development by directly interacting with lymphatic endothelial cells through C-type lectin-like receptor 2. Besides the active contributions of platelets to the immune system, platelets are passively targeted in several immune-mediated diseases, such as autoimmune thrombocytopenia, infection-associated thrombocytopenia, and fetal and neonatal alloimmune thrombocytopenia. These data suggest that platelets are important immune cells and may contribute to innate and adaptive immunity under both physiological and pathological conditions.
Liu, Z. Y., et al. (2012). “Suppression of lymphangiogenesis in human lymphatic endothelial cells by simultaneously blocking VEGF-C and VEGF-D/VEGFR-3 with norcantharidin.” Int J Oncol.
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Marin-Padilla, M. (2012). “The human brain intracerebral microvascular system: development and structure.” Front Neuroanat 6: 38.
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Mendez, U., et al. (2012). “Functional recovery of fluid drainage precedes lymphangiogenesis in acute murine foreleg lymphedema.” Am J Physiol Heart Circ Physiol 302(11): H2250–2256.
Mendez, U., et al. (2012). “A chronic and latent lymphatic insufficiency follows recovery from acute lymphedema in the rat foreleg.” Am J Physiol Heart Circ Physiol.
Mkonyi, L. E., et al. (2012). “Gingival lymphatic drainage protects against porphyromonas gingivalis-induced bone loss in mice.” Am J Pathol 181(3): 907–916.
Nagaoka, F., et al. (2012). “Visual detection of filaria-specific IgG4 in urine using red-colored high density latex beads.” Parasitol Int.
Negrini, D. and A. Moriondo (2012). “Pleural function and lymphatics.” Acta Physiol (Oxf).
Olsnes, C., et al. (2012). “OK-432-stimulated chemokine secretion from human monocytes depends on MEK1/2, and involves p38 MAPK and NF-kappaB phosphorylation, in vitro.” APMIS.
Planas-Paz, L., et al. (2012). “Mechanoinduction of lymph vessel expansion.” EMBO J 31(4): 788–804.
Ran, S. and K. E. Montgomery (2012). “Macrophage-mediated lymphangiogenesis: the emerging role of macrophages as lymphatic endothelial progenitors.” Cancers (Basel) 4(3): 618–657.
Regenfu, B., et al. (2012). “Corneal angiogenesis and lymphangiogenesis.” Curr Opin Allergy Clin Immunol 12(5): 548–554.
Scallan, J. P., et al. (2012). “Constriction of isolated collecting lymphatic vessels in response to acute increases in downstream pressure.” J Physiol.
Scallan, J. P., et al. (2012). “Independent and interactive effects of preload and afterload on the pump function of the isolated lymphangion.” Am J Physiol Heart Circ Physiol 303(7): H809–824.
Sun, Q. N., et al. (2012). “Reconstitution of myocardial lymphatic vessels after acute infarction of rat heart.” Lymphology 45(2): 80–86.
Tewalt, E. F., et al. (2012). “Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells.” Blood.
Thomas, S. N., et al. (2012). “Impaired humoral immunity and tolerance in K14-VEGFR-3-Ig mice that lack dermal lymphatic drainage.” J Immunol 189(5): 2181–2190.
Yao, L. C., et al. (2012). “Plasticity of button-like junctions in the endothelium of airway lymphatics in development and inflammation.” Am J Pathol 180(6): 2561–2575.
Endothelial cells of initial lymphatics have discontinuous button-like junctions (buttons), unlike continuous zipper-like junctions (zippers) of collecting lymphatics and blood vessels. Buttons are thought to act as primary valves for fluid and cell entry into lymphatics. To learn when and how buttons form during development and whether they change in disease, we examined the appearance of buttons in mouse embryos and their plasticity in sustained inflammation. We found that endothelial cells of lymph sacs at embryonic day (E)12.5 and tracheal lymphatics at E16.5 were joined by zippers, not buttons. However, zippers in initial lymphatics decreased rapidly just before birth, as buttons appeared. The proportion of buttons increased from only 6% at E17.5 and 12% at E18.5 to 35% at birth, 50% at postnatal day (P)7, 90% at P28, and 100% at P70. In inflammation, zippers replaced buttons in airway lymphatics at 14 and 28 days after Mycoplasma pulmonis infection of the respiratory tract. The change in lymphatic junctions was reversed by dexamethasone but not by inhibition of vascular endothelial growth factor receptor-3 signaling by antibody mF4-31C1. Dexamethasone also promoted button formation during early postnatal development through a direct effect involving glucocorticoid receptor phosphorylation in lymphatic endothelial cells. These findings demonstrate the plasticity of intercellular junctions in lymphatics during development and inflammation and show that button formation can be promoted by glucocorticoid receptor signaling in lymphatic endothelial cells.
Zhuo, W., et al. (2012). “The CXCL12-CXCR4 chemokine pathway: a novel axis regulates lymphangiogenesis.” Clin Cancer Res.
PURPOSE: Lymphangiogenesis, the growth of lymphatic vessels, contributes to lymphatic metastasis. However, the precise mechanism underlying lymphangiogenesis remains poorly understood. This study aimed to examine chemokine/chemokine receptors that directly contribute to chemoattraction of activated lymphatic endothelial cells (LEC) and tumor lymphangiogenesis. EXPERIMENTAL DESIGN: We used quantitative RT-PCR to analyze specifically expressed chemokine receptors in activated LECs upon stimulation of vascular endothelial growth factor-C (VEGF-C). Subsequently, we established in vitro and in vivo models to show lymphangiogenic functions of the chemokine axis. Effects of targeting the chemokine axis on tumor lymphangiogenesis and lymphatic metastasis were determined in an orthotopic breast cancer model. RESULTS: VEGF-C specifically upregulates CXCR4 expression on lymphangiogenic endothelial cells. Moreover, hypoxia-inducible factor-1alpha (HIF-1alpha) mediates the CXCR4 expression induced by VEGF-C. Subsequent analyses identify the ligand CXCL12 as a chemoattractant for LECs. CXCL12 induces migration, tubule formation of LECs in vitro, and lymphangiogenesis in vivo. CXCL12 also stimulates the phosphorylation of intracellular signaling Akt and Erk, and their specific antagonists impede CXCL12-induced chemotaxis. In addition, its level is correlated with lymphatic vessel density in multiple cancer tissues microarray. Furthermore, the CXCL12-CXCR4 axis is independent of the VEGFR-3 pathway in promoting lymphangiogenesis. Intriguingly, combined treatment with anti-CXCL12 and anti-VEGF-C antibodies results in additive inhibiting effects on tumor lymphangiogenesis and lymphatic metastasis. CONCLUSIONS: These results show the role of the CXCL12-CXCR4 axis as a novel chemoattractant for LECs in promoting lymphangiogenesis, and support the potential application of combined targeting of both chemokines and lymphangiogenic factors in inhibiting lymphatic metastasis. Clin Cancer Res; 1–12. (c)2012 AACR.
Oncology
Astarita, J. L., et al. (2012). “Podoplanin: emerging functions in development, the immune system, and cancer.” Front Immunol 3: 283.
Podoplanin (PDPN) is a well-conserved, mucin-type transmembrane protein expressed in multiple tissues during ontogeny and in adult animals, including the brain, heart, kidney, lungs, osteoblasts, and lymphoid organs. Studies of PDPN-deficient mice have demonstrated that this molecule plays a critical role in development of the heart, lungs, and lymphatic system. PDPN is widely used as a marker for lymphatic endothelial cells and fibroblastic reticular cells of lymphoid organs and for lymphatics in the skin and tumor microenvironment. Much of the mechanistic insight into PDPN biology has been gleaned from studies of tumor cells; tumor cells often upregulate PDPN as they undergo epithelial-mesenchymal transition and this upregulation is correlated with increased motility and metastasis. The physiological role of PDPN that has been most studied is its ability to aggregate and activate CLEC-2-expressing platelets, as PDPN is the only known endogenous ligand for CLEC-2. However, more recent studies have revealed that PDPN also plays crucial roles in the biology of immune cells, including T cells and dendritic cells. This review will provide a comprehensive overview of the diverse roles of PDPN in development, immunology, and cancer.
Babu, S. and T. B. Nutman (2012). “Immunopathogenesis of lymphatic filarial disease.” Semin Immunopathol.
Biaoxue, R., et al. (2012). “Upregulation of Hsp90-beta and annexin A1 correlates with poor survival and lymphatic metastasis in lung cancer patients.” J Exp Clin Cancer Res 31(1): 70.
Biedka, M., et al. (2012). “Labeling of microvessel density, lymphatic vessel density and potential role of proangiogenic and lymphangiogenic factors as a predictive/prognostic factors after radiotherapy in patients with cervical cancer.” Eur J Gynaecol Oncol 33(4): 399–405.
Bracher, A., et al. (2012). “Epidermal growth factor facilitates melanoma lymph node metastasis by influencing tumor lymphangiogenesis.” J Invest Dermatol.
Cao, R., et al. (2012). “Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis.” Proc Natl Acad Sci U S A.
Chang, D. W. (2012). “Lymphaticovenular bypass surgery for lymphedema management in breast cancer patients.” Handchir Mikrochir Plast Chir.
Ding, M., et al. (2012). “The effect of vascular endothelial growth factor C expression in tumor-associated macrophages on lymphangiogenesis and lymphatic metastasis in breast cancer.” Mol Med Report.
Elsir, T., et al. (2012). “Transcription factor PROX1: its role in development and cancer.” Cancer Metastasis Rev.
The homeobox gene PROX1 is critical for organ development during embryogenesis. The Drosophila homologue, known as prospero has been shown to act as a tumor suppressor by controlling asymmetric cell division of neuroblasts. Likewise, alterations in PROX1 expression and function are associated with a number of human cancers including hematological malignancies, carcinomas of the pancreas, liver and the biliary system, sporadic breast cancer, Kaposiform hemangioendothelioma, colon cancer, and brain tumors. PROX1 is involved in cancer development and progression and has been ascribed both tumor suppressive and oncogenic properties in a variety of different cancer types. However, the exact mechanisms through which PROX1 regulates proliferation, migration, and invasion of cancer cells are by large unknown. This review provides an update on the role of PROX1 in organ development and on its emerging functions in cancer, with special emphasis on the central nervous system and glial brain tumors.
Finas, D., et al. (2012). “Detection and distribution of superparamagnetic nanoparticles in lymphatic tissue in a breast cancer model for magnetic particle imaging.” Biomed Tech (Berl).
Hayashi, T., et al. (2012). “Uterine angiosarcoma associated with lymphangioleiomyomatosis in a patient with tuberous sclerosis complex: an autopsy case report with immunohistochemical and genetic analysis.” Hum Pathol 43(10): 1777–1784.
Karamanou, M., et al. (2012). “The quarrel between iatromechanists and animists about the cause of cancer: lymph's role in oncogenesis.” J BUON 17(3): 605–608.
Karnezis, T., et al. (2012). “The connection between lymphangiogenic signalling and prostaglandin biology: A missing link in the metastatic pathway.” Oncotarget 3(8): 890–903.
Substantial evidence supports important independent roles for lymphangiogenic growth factor signaling and prostaglandins in the metastatic spread of cancer. The significance of the lymphangiogenic growth factors, vascular endothelial growth factor (VEGF)-C and VEGF-D, is well established in animal models of metastasis, and a strong correlation exits between an increase in expression of VEGF-C and VEGF-D, and metastatic spread in various solid human cancers. Similarly, key enzymes that control the production of prostaglandins, cyclooxygenases (COX-1 and COX-2, prototypic targets of Non-steroidal anti-inflammatory drugs (NSAIDs)), are frequently over-expressed or de-regulated in the progression of cancer. Recent data have suggested an intersection of lymphangiogenic growth factor signaling and the prostaglandin pathways in the control of metastatic spread via the lymphatic vasculature. Furthermore, this correlates with current clinical data showing that some NSAIDs enhance the survival of cancer patients through reducing metastasis. Here, we discuss the potential biochemical and cellular basis for such anti-cancer effects of NSAIDs through the prostaglandin and VEGF signaling pathways.
Kudo, Y., et al. (2012). “Periostin directly and indirectly promotes tumor lymphangiogenesis of head and neck cancer.” PLoS One 7(8): e44488.
Li, W., et al. (2012). “Protein predictive signatures for lymph node metastasis of gastric cancer.” Int J Cancer.
Liersch, R., et al. (2012). “Induced lymphatic sinus hyperplasia in sentinel lymph nodes by VEGF-C as the earliest premetastatic indicator.” Int J Oncol.
Research on tumor-induced lymphangiogenesis has predominantly focused on alterations and abnormal growth of peritumoral and intratumoral lymphatic vessels. However, recent evidence indicates that lymphangiogenesis of sentinel lymph nodes might also contribute to cancer progression. In clinical oncology, the sentinel lymph nodes play an important role in diagnosis, staging and management of disease. The prognostic value that may be placed in the analysis of various parameters in tumor-free lymph nodes is still under debate. We, therefore, chose to investigate genetically fluorescent MDA-MB-435/green fluorescent protein human cancer cells transfected to overexpress VEGF-C in a nude mouse model and investigated metastasis, lymph node lymphangiogenesis, lymph node angiogenesis and size of sentinel lymph nodes. The nature of MDA-MB-435, identified as a breast cancer cell line for several decades, has recently been reidentified as being from melanoma origin. Vascular endothelial growth factor-C overexpression induced early metastasis and significantly increased the lymphatic vessel area in sentinel lymph nodes even before the tumor metastasis. At early time-points, expansion of the lymphatic network was observed even though no difference of blood vessel area and lymph node size was detected. These results suggest that primary tumors -via secretion of VEGF-C- can induce hyperplasia of the sentinel lymph node lymphatic vessel network and thereby promote their further spread. In cases of tumor-free lymph nodes the increased lymphatic network of sentinel lymph nodes is a very early premetastatic sign and may provide a new prognostic indicator and target for aggressive diseases.
Lo, P. K., et al. (2012). “Cytoplasmic mislocalization of overexpressed FOXF1 is associated with the malignancy and metastasis of colorectal adenocarcinomas.” Exp Mol Pathol.
Our previous studies have revealed that the human FOXF1 gene, encoding a transcription factor member of the forkhead box (FOX) family, functions as a tumor suppressor and its expression is frequently silenced in breast cancer via DNA hypermethylation. Moreover, we recently reported that FOXF1 expression is preferentially silenced in colorectal cancer cell lines with inactive p53 and knockdown of FOXF1 caused genomic instability in FOXF1-expressing colorectal cancer cells with a defect in the p53-p21(WAF1) checkpoint, suggesting that FOXF1 plays a key role in colorectal tumorigenesis. Given that the in vivo role of FOXF1 in colorectal cancer remains unknown, the study here was aimed at delineating the clinical relevance of FOXF1 in colorectal adenocarcinomas. To characterize FOXF1 protein expression in colorectal cancer, designed tissue microarrays, comprising 50 cases of primary colorectal adenocarcinoma paired with matched adjacent normal tissue, were utilized in the immunohistochemistry (IHC) study. The IHC results showed that for adjacent normal colorectal tissue, the FOXF1 protein was only detected in stroma, not in epithelium, with either cytoplasmic staining (70% of total cases) or a mix of cytoplasmic and nuclear staining (6%). In contrast, for colorectal adenocarcinomas, FOXF1 staining was predominately identified in the cytoplasm of tumor epithelial cells (40% of total cases) and tumor-associated stromal cells of some cases (10%) also exhibited FOXF1 positivity in their cytoplasm. Cytoplasmic FOXF1 protein expression in tumor epithelial cells positively correlated with the histologic grade, depth of invasion, stage and lymphatic metastasis of colorectal adenocarcinomas (p<0.05). Moreover, in silico meta-analysis of Oncomine's cancer microarray database indicates that FOXF1 mRNA is overexpressed in a significant subset of colorectal adenocarcinoma tumors compared with normal colorectal tissue and other types of cancers. Our findings for the first time have revealed that the FOXF1 protein is overexpressed as well as mislocalized in cancerous epithelial cells and underexpressed/lost in tumor-associated stromal fibroblasts of colorectal adenocarcinomas, and suggest that FOXF1 is a potential prognostic marker due to its association with the malignancy and metastasis of colorectal cancer.
Mattavelli, F., et al. (2012). “Neoplastic lymphangiosis of the upper aerodigestive tract simulating field cancerization: histopathological analysis, surgical limits and literature review.” Tumori 98(4): 115e-117e.
Mihara, M., et al. (2012). “Pathological steps of cancer-related lymphedema: histological changes in the collecting lymphatic vessels after lymphadenectomy.” PLoS One 7(7): e41126.
Mihara, M., et al. (2012). “Antegrade and retrograde lymphatico-venous anastomosis for cancer-related lymphedema with lymphatic valve dysfuction and lymphatic varix.” Microsurgery.
Oashi, K., et al. (2012). “Pathophysiological characteristics of melanoma in-transit metastasis in a lymphedema mouse model.” J Invest Dermatol.
Ozasa, R., et al. (2012). “Tumor-induced lymphangiogenesis in cervical lymph nodes in oral melanoma-bearing mice.” J Exp Clin Cancer Res 31(1): 83.
Schito, L., et al. (2012). “Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells.” Proc Natl Acad Sci U S A 109(40): E2707–2716.
Shiozawa, M., et al. (2012). “Magnetic resonance lymphography of sentinel lymph nodes in patients with breast cancer using superparamagnetic iron oxide: a feasibility study.” Breast Cancer.
Sun, J. J., et al. (2012). “New model of in-situ xenograft lymphangiogenesis by a human colonic adenocarcinoma cell line in nude mice.” Asian Pac J Cancer Prev 13(6): 2823–2828.
Viola, K., et al. (2012). “Bay11-7082 inhibits the disintegration of the lymphendothelial barrier triggered by MCF-7 breast cancer spheroids; the role of ICAM-1 and adhesion.” Br J Cancer.
Wada, H., et al. (2012). “Lymphatic invasion identified with D2-40 immunostaining as a risk factor of nodal metastasis in T1 colorectal cancer.” Int J Clin Oncol.
Wiig, H. and M. A. Swartz (2012). “Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer.” Physiol Rev 92(3): 1005–1060.
Xu, X. Y., et al. (2012). “Aberrant SERCA3 expression is closely linked to pathogenesis, invasion, metastasis, and prognosis of gastric carcinomas.” Tumour Biol.
Yanagawa, T., et al. (2012). “Vascular endothelial growth factor-D is a key molecule that enhances lymphatic metastasis of soft tissue sarcomas.” Exp Cell Res 318(7): 800–808.
Yang, Q., et al. (2012). “A clinical study on regional lymphatic chemotherapy using an activated carbon nanoparticle-epirubicin in patients with breast cancer.” Tumour Biol.
Yang, Y., et al. (2012). “Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos.” Blood.
Yin, Y. X., et al. (2012). “Increased expression of Rab25 in breast cancer correlates with lymphatic metastasis.” Tumour Biol.
Yokoyama, J., et al. (2012). “Impact of lymphatic chemotherapy targeting metastatic lymph nodes in patients with tongue cancer (cT3N2bM0) using intra-arterial chemotherapy.” Head Neck Oncol 4(2): 64.
INTRODUCTION: We have reported that our novel drug-delivery system is feasible for lymphatic chemotherapy targeting sentinel lymph nodes (SLNs) in patients with cT3N0M0 tongue cancer with occult metastasis in SLNs. Neck metastasis is a significant prognostic factor of tongue cancer. It is, therefore, imperative that intra-arterial chemotherapy is performed in order to preserve organs and to control neck metastasis when treating oral cancer. OBJECTIVE: Evaluate lymphatic chemotherapy targeting neck metastases in patients with tongue cancer (cT3N2bM0) using intra-arterial chemotherapy. METHODS: Seven patients with tongue cancer (cT3N2bM0) were treated by intra-arterial chemotherapy as neoadjuvant chemotherapy. After a week of chemotherapy, patients underwent surgical treatment. Intra-arterial chemotherapy was administered at 75 mg/m2 of cis-diamminedichloroplatinum (CDDP) two times weekly. At the beginning of surgery, 5 mg of indocyanine green (ICG) was administered to the lingual artery. SLNs were detected using ICG fluorescence imaging and a conventional radioactive method. The effect of lymphatic chemotherapy was evaluated by apoptosis using Trevigen's apoptosis detection kit. RESULTS: The mean CDDP concentrations in the metastasis and non-SLNs were 2.35 mg/g and 1.08 mg/g, respectively (p=0.034). Of 27 metastatic nodes, 24 (89%) were identified by ICG fluorescence imaging; however, only 18 (67%) were identified by the conventional method (p=0.043). Of 22 measurable metastatic nodes, eight responded (partial response) and 14 did not respond (stable disease). Apoptosis was detected in all metastatic nodes. CONCLUSION: The CDDP concentrations in metastatic nodes were significantly higher than those in non-SLNs. This novel drug-delivery system is feasible for lymphatic chemotherapy targeting metastatic nodes in patients with cT3N2bM0 tongue cancer.
Yokoyama, J., et al. (2012). “A feasibility study of lymphatic chemotherapy targeting sentinel lymph nodes of patients with tongue cancer (cT3N0M0) using intra-arterial chemotherapy.” Head Neck Oncol 4(2): 60.
Zhang, B., et al. (2012). “M2-polarized macrophages promote metastatic behavior of Lewis lung carcinoma cells by inducing vascular endothelial growth factor-C expression.” Clinics (Sao Paulo) 67(8): 901–906.
Zheng, N. N., et al. (2012). “Targeting rictor inhibits mouse vascular tumor cell proliferation and invasion in vitro and tumor growth in vivo.” Neoplasma.
Vascular tumor is an abnormal buildup of blood vessels in the skin or internal organs that can lead to disfigurement and/or life-threatening consequences. The mechanism of hemangiogenesis remains unknown. The aim of this study was to assess the role of rapamycin-insensitive companion of mTOR (Rictor) in control of vascular tumor malignant biological behavior and cell signaling mechanism in Mouse Hemangioendothelioma Endothelial Cells (EOMA cells) and nude mouse model. Knocking down rictor was mediated by lentivirus shRNA. The role and mechanism of rictor in vascular tumor were assessed by western blotting, wst-1 proliferation assay, matrigel invasion assay and xenograft vascular tumor growth. Our results in vitro showed that loss of rictor down-regulated phosphorylation of AKT and S6 by which EOMA cells growth and proliferation were greatly suppressed. Knock down of rictor also inhibited the invasion of EOMA cells. Furthermore, we demonstrated that knock down of rictor inhibited xenograft vascular tumor growth in nude mice. Taken together, we purpose that rictor contributed to vascular tumor growth and progression. Targeting rictor becomes an effective strategy in vascular tumor treatment. Keywords: AKT, mTOR2, rictor, vascular tumor, hemangioma.
Clinical
Ayestaray, B., et al. (2012). “pi-Shaped lymphaticovenular anastomosis for head and neck lymphoedema: A preliminary study.” J Plast Reconstr Aesthet Surg.
Becker, C., et al. (2012). “Surgical treatment of congenital lymphedema.” Clin Plast Surg 39(4): 377–384.
Boland, J. M., et al. (2012). “Diffuse pulmonary lymphatic disease presenting as interstitial lung disease in adulthood: report of 3 cases.” Am J Surg Pathol 36(10): 1548–1554.
Boneti, C., et al. (2012). “Axillary reverse mapping (ARM): initial results of phase II trial in preventing lymphedema after lymphadenectomy.” Minerva Ginecol 64(5): 421–430.
Bucher, F., et al. (2012). “Topical Ranibizumab inhibits inflammatory corneal hem- and lymphangiogenesis.” Acta Ophthalmol.
Campisi, C. C., et al. (2012). “Immunodeficiency due to chylous dysplasia: diagnostic and therapeutic considerations.” Lymphology 45(2): 58–62.
Chachaj, A., et al. (2012). “Chyloperitoneum, chylothorax and lower extremity lymphedema in woman with sporadic lymphangioleiomyomatosis successfully treated with sirolimus: a case report.” Lymphology 45(2): 53–57.
Han, K. E., et al. (2012). “Removal of Lymphangiectasis Using High-Frequency Radio Wave Electrosurgery.” Cornea.
Hara, H., et al. (2012). “Idiopathic portal hypertension and lower limb lymphedema.” Lymphology 45(2): 63–70.
Hara, H., et al. (2012). “Presence of thoracic duct abnormalities in patients with primary lymphoedema of the extremities.” J Plast Reconstr Aesthet Surg 65(11): e305–310.
Hardavella, G., et al. (2012). “Lymphangiogenesis in COPD: another link in the pathogenesis of the disease.” Respir Med 106(5): 687–693.
BACKGROUND: New lymphatic vessels are associated with tissue injury and repair. Recent studies have shown increased lymphatic follicles formation in the lungs of COPD patients. We hypothesized that lymphatic vascular remodeling could be part of COPD pathogenesis. AIM: To investigate the lymphangiogenetic process in COPD we measured the lymphatic microvessel density (LMVD), the lymphatic invasion (L.I), and their correlation with clinical and laboratory parameters. METHODS: Lung tissue from 20 COPD patients and 20 non-COPD smokers was immunohistochemically stained for D2-40 (lymphatic endothelial cell marker), and LYVE-1 (lymphatic endothelial hyaluronan receptor 1). Both groups had similar age and smoking history. RESULTS: D2-40 and LYVE-1 were expressed in all specimens. Lymphatic invasion was presented only in COPD specimens. Lymphatic microvessel density (LMVD) as revealed by D2-40 and LYVE-1 markers was statistically significantly higher in COPD patients when compared with non-COPD smokers. Both markers (D2-40, LYVE-1) were correlated with FEV1 (% pred) (R(2)=0.415, R(2)=0.605, respectively). CONCLUSIONS: We report for the first time high lymphatic microvessel density and lymphatic invasion in COPD patients, related to the degree of airway obstruction. Our findings could provide novel insights in the pathogenesis of the disease.
Henske, E. P. and F. X. McCormack (2012). “Lymphangioleiomyomatosis - a wolf in sheep's clothing.” J Clin Invest 122(11): 3807–3816.
Honkonen, K. M., et al. (2012). “Lymph Node Transfer and Perinodal Lymphatic Growth Factor Treatment for Lymphedema.” Ann Surg.
Iskender, C., et al. (2012). “Fetal axillary cystic hygroma: A novel association with triple X syndrome.” Birth Defects Res A Clin Mol Teratol.
Kaburagi, T., et al. (2012). “Intraoperative fluorescence lymphography using indocyanine green in a patient with chylothorax after esophagectomy: report of a case.” Surg Today.
Lee, A. S., et al. (2012). “Vascular endothelial growth factor-C and -D are involved in lymphangiogenesis in mouse unilateral ureteral obstruction.” Kidney Int.
Lee, S., et al. (2012). “Massive localized lymphedema of the male external genitalia: a clinicopathologic study of 6 cases.” Hum Pathol.
Maamer, A. B., et al. (2012). “Primary intestinal lymphangiectasia or Waldmann's disease: A rare cause of lower gastrointestinal bleeding.” Arab J Gastroenterol 13(2): 97–98.
Maeda, S., et al. (2012). “Lymphangiomatosis of the Systemic Skin in an Old Dog.” J Vet Med Sci.
Mand, S., et al. (2012). “Doxycycline improves filarial lymphedema independent of active filarial infection: a randomized controlled trial.” Clin Infect Dis 55(5): 621–630.
Olivieri, C., et al. (2012). “Successful management of congenital chylous ascites with early octreotide and total parenteral nutrition in a newborn.” BMJ Case Rep 2012.
Ostergaard, P., et al. (2012). “Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy.” Am J Hum Genet 90(2): 356–362.
We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a microcephaly-lymphedema-chorioretinal-dysplasia cohort. Subsequent Sanger sequencing of KIF11 in a further 15 unrelated microcephalic probands with lymphedema and/or chorioretinopathy identified additional heterozygous mutations in 12 of them. KIF11 encodes EG5, a homotetramer kinesin motor. The variety of mutations we have found (two nonsense, two splice site, four missense, and six indels causing frameshifts) are all predicted to have an impact on protein function. EG5 has previously been shown to play a role in spindle assembly and function, and these findings highlight the critical role of proteins necessary for spindle formation in CNS development. Moreover, identification of KIF11 mutations in patients with chorioretinopathy and lymphedema suggests that EG5 is involved in the development and maintenance of retinal and lymphatic structures.
Rodriguez-Alarcon, C. A., et al. (2012). “Protein-losing enteropathy in a dog with lymphangiectasia, lymphoplasmacytic enteritis and pancreatic exocrine insufficiency.” Vet Q.
Scholl, J., et al. (2012). “First-trimester cystic hygroma: relationship of nuchal translucency thickness and outcomes.” Obstet Gynecol 120(3): 551–559.
Tosi, L. L., et al. (2011). “Assessment and management of the orthopedic and other complications of Proteus syndrome.” J Child Orthop 5(5): 319–327.
Udare, A., et al. (2012). “A rare demonstration of the filarial dance sign in the upper limb lymphatic vessels mimicking deep venous thrombosis.” J Ultrasound Med 31(9): 1464–1465.
Vignes, S., et al. (2012). “Primary upper-limb lymphedema.” Br J Dermatol.
Yamamoto, T., et al. (2012). “A modified side-to-end lymphaticovenular anastomosis.” Microsurgery.
Zeldenryk, L., et al. (2012). “Disability measurement for lymphatic filariasis: a review of generic tools used within morbidity management programs.” PLoS Negl Trop Dis 6(9): e1768.
Vascular Anomalies
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Alniemi ST, Griepentrog GJ, Diehl N, Mohney BG. Incidence and clinical characteristics of periocular infantile hemangiomas. Archives of ophthalmology. Jul 1 2012;130(7):889–893.
Aman J, Thunnissen E, Paul MA, van Nieuw Amerongen GP, Vonk-Noordegraaf A. Successful treatment of diffuse pulmonary lymphangiomatosis with bevacizumab. Annals of internal medicine. Jun 5 2012;156(11):839–840.
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Annagur A, Altunhan H, Konak M, Ors R. Successful use of topical “Ankaferd Blood Stopper” for repetitive bleedings in an infant with infantile hemangioma. International journal of clinical and experimental medicine. 2012;5(4):342–345.
Balma-Mena A, Chakkittakandiyil A, Weinstein M, et al. Propranolol in the management of infantile hemangiomas: clinical response and predictors. Journal of cutaneous medicine and surgery. May-Jun 2012;16(3):169–173.
Barranco-Pons R, Burrows PE, Landrigan-Ossar M, Trenor CC, 3rd, Alomari AI. Gross hemoglobinuria and oliguria are common transient complications of sclerotherapy for venous malformations: review of 475 procedures. AJR. American journal of roentgenology. Sep 2012;199(3):691–694.
Bingham MM, Saltzman B, Vo NJ, Perkins JA. Propranolol reduces infantile hemangioma volume and vessel density. Otolaryngology–head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. Aug 2012;147(2):338–344.
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Catala A, Roe E, Vikkula M, Baselga E. Capillary Malformation-Arteriovenous Malformation Syndrome: A Report of 2 Cases, Diagnostic Criteria, and Management. Actas dermo-sifiliograficas. Aug 21 2012.
Chang CS, Wong A, Rohde CH, Ascherman JA, Wu JK. Management of lip hemangiomas: Minimizing peri-oral scars. Journal of plastic, reconstructive & aesthetic surgery : JPRAS. Feb 2012;65(2):163–168.
Drolet BA, Pope E, Juern AM, et al. Gastrointestinal bleeding in infantile hemangioma: a complication of segmental, rather than multifocal, infantile hemangiomas. The Journal of pediatrics. Jun 2012;160(6):1021–1026 e1023.
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Frigerio A, Stevenson DA, Grimmer JF. The genetics of vascular anomalies. Current opinion in otolaryngology & head and neck surgery. Aug 21 2012.
Garabedian MJ, Wallerstein D, Medina N, Byrne J, Wallerstein RJ. Prenatal Diagnosis of Cystic Hygroma related to a Deletion of 16q24.1 with Haploinsufficiency of FOXF1 and FOXC2 Genes. Case reports in genetics. 2012;2012:490408.
Godfraind C, Calicchio ML, Kozakewich H. Pyogenic granuloma, an impaired wound healing process, linked to vascular growth driven by FLT4 and the nitric oxide pathway. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc. Sep 7 2012.
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Handra-Luca A, Montgomery E. Vascular malformations and hemangiolymphangiomas of the gastrointestinal tract: morphological features and clinical impact. International journal of clinical and experimental pathology. Jun 20 2011;4(5):430–443.
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Itinteang T, Tan ST, Brasch HD, et al. Infantile haemangioma expresses embryonic stem cell markers. J Clin Pathol. May 2012;65(5):394–398.
Jahnel J, Lackner H, Reiterer F, Urlesberger B, Urban C. Kaposiform Hemangioendothelioma with Kasabach-Merritt Phenomenon: From Vincristine to Sirolimus. Klinische Padiatrie. Oct 15 2012.
Kida A, Matsuda K, Hirai S, et al. A pedunculated polyp-shaped small-bowel lymphangioma causing gastrointestinal bleeding and treated by double-balloon enteroscopy. World journal of gastroenterology: WJG. Sep 14 2012;18(34):4798–4800.
Kleiman A, Keats EC, Chan NG, Khan ZA. Elevated IGF2 prevents leptin induction and terminal adipocyte differentiation in hemangioma stem cells. Experimental and molecular pathology. Oct 6 2012.
Kumar V, Kumar P, Pandey A, et al. Intralesional bleomycin in lymphangioma: an effective and safe non-operative modality of treatment. Journal of cutaneous and aesthetic surgery. Apr 2012;5(2):133–136.
Kupeli S. Use of propranolol for infantile hemangiomas. Pediatric hematology and oncology. Apr 2012;29(3):293–298.
Kurek KC, Luks VL, Ayturk UM, et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet. Jun 8 2012;90(6):1108–1115.
Lanoel A, Tosi V, Bocian M, et al. Perianal Ulcers on a Segmental Hemangioma With Minimal or Arrested Growth. Actas dermo-sifiliograficas. Oct 22 2012.
Liu NF, Yan ZX, Wu XF. Classification of lymphatic-system malformations in primary lymphoedema based on MR lymphangiography. European journal of vascular and endovascular surgery: the official journal of the European Society for Vascular Surgery. Sep 2012;44(3):345–349.
Lopez V, Lopez I, Ricart JM. Temporary alopecia after embolization of an arteriovenous malformation. Dermatology online journal. 2012;18(9):14.
Lv MM, Fan XD, Su LX. Propranolol for problematic head and neck hemangiomas: an analysis of 37 consecutive patients. International journal of pediatric otorhinolaryngology. Apr 2012;76(4):574–578.
McCarthy C, Kaliaperumal C, O'Sullivan M. Recurrence of a paediatric arteriovenous malformation 9 years postcomplete excision: case report and review of literature. BMJ case reports. 2012;2012.
Medici D, Olsen BR. Rapamycin Inhibits Proliferation of Hemangioma Endothelial Cells by Reducing HIF-1-Dependent Expression of VEGF. PLoS One. 2012;7(8):e42913.
Meijer-Jorna LB, van der Loos CM, Teeling P, et al. Proliferation and maturation of microvessels in arteriovenous malformations–expression patterns of angiogenic and cell cycle-dependent factors. Journal of cutaneous pathology. Jun 2012;39(6):610–620.
Metry D, Frieden IJ, Hess C, et al. Propranolol Use in PHACE Syndrome with Cervical and Intracranial Arterial Anomalies: Collective Experience in 32 Infants. Pediatric dermatology. Sep 20 2012.
Mitchell S, Siegel DH, Shieh JT, et al. Candidate locus analysis for PHACE syndrome. American journal of medical genetics. Part A. Jun 2012;158A(6):1363–1367.
Nieuwenhuis K, de Laat PC, Janmohamed SR, Madern GC, Oranje AP. Infantile Hemangioma: Treatment with Short Course Systemic Corticosteroid Therapy as an Alternative for Propranolol. Pediatric dermatology. Sep 7 2012.
Noel RJ, Duffy KJ, Kelly ME, Tondravi N, North PE, Drolet BA. Endoscopic management of gastrointestinal bleeding from multifocal lymphangioendotheliomatosis with thrombocytopenia: limited efficacy and complications. Journal of pediatric gastroenterology and nutrition. Jun 2012;54(6):822–824.
Odeyinde SO, Kangesu L, Badran M. Sclerotherapy for vascular malformations: Complications and a review of techniques to avoid them. Journal of plastic, reconstructive & aesthetic surgery: JPRAS. Oct 8 2012.
Pekkola J, Lappalainen K, Vuola P, Klockars T, Salminen P, Pitkaranta A. Head and Neck Arteriovenous Malformations: Results of Ethanol Sclerotherapy. AJNR. American journal of neuroradiology. Jul 5 2012.
Perman MJ, Castelo-Soccio L, Jen M. Differential diagnosis of infantile hemangiomas. Pediatr Ann. Aug 1 2012;41(8):1–7.
Phillips RJ, Penington AJ, Bekhor PS, Crock CM. Use of propranolol for treatment of infantile haemangiomas in an outpatient setting. Journal of paediatrics and child health. Oct 2012;48(10):902–906.
Renard D, Campello C, Taieb G, et al. Neurologic and Vascular Abnormalities in Klippel-Trenaunay-Weber Syndrome. Archives of neurology. Oct 22 2012:1–2.
Riou S, Morelon E, Guibaud L, Chotel F, Dijoud F, Marec-Berard P. Efficacy of rapamycin for refractory hemangioendotheliomas in Maffucci's syndrome. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Aug 10 2012;30(23):e213–215.
Ruggieri M, Milone P, Pavone P, et al. Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke-Davidoff-Masson type in two patients. American journal of medical genetics. Part A. Sep 18 2012.
Scribner DR, Jr., Lara-Torre E, Heineck RJ, Weiss PM. Klippel-Trenaunay Syndrome Complicated by Ascites and Vaginal Lymphatic Drainage in Adolescence: A Case Report. Journal of pediatric and adolescent gynecology. Oct 9 2012.
Shan G, Tang T, Zhang D. Expression of HLA-G in hemangioma and its clinical significance. Journal of Huazhong University of Science and Technology. Medical sciences=Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban=Huazhong keji daxue xuebao. Yixue Yingdewen ban. Oct 2012;32(5):713–718.
Shepherd D, Adams S, Wargon O, Jaffe A. Childhood wheeze while taking propranolol for treatment of infantile hemangiomas. Pediatric pulmonology. Jul 2012;47(7):713–715.
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Siegel DH, Tefft KA, Kelly T, et al. Stroke in children with posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities (PHACE) syndrome: a systematic review of the literature. Stroke; a journal of cerebral circulation. Jun 2012;43(6):1672–1674.
Smadja DM, Mulliken JB, Bischoff J. E-Selectin Mediates Stem Cell Adhesion and Formation of Blood Vessels in a Murine Model of Infantile Hemangioma. The American journal of pathology. Oct 4 2012.
Thayal PK, Bhandari PS, Sarin YK. Comparison of efficacy of intralesional bleomycin and oral propanolol in management of hemangiomas. Plastic and reconstructive surgery. Apr 2012;129(4):733e-735e.
Tu JB, Dong Q, Hu XY, et al. Proteomic analysis of mitochondria from infantile hemangioma endothelial cells treated with sodium morrhuate and its liposomal formulation. Journal of biochemical and molecular toxicology. Sep 2012;26(9):374–380.
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Vlastarakos PV, Papacharalampous GX, Chrysostomou M, et al. Propranolol is an effective treatment for airway haemangiomas: a critical analysis and meta-analysis of published interventional studies. Acta otorhinolaryngologica Italica : organo ufficiale della Societa italiana di otorinolaringologia e chirurgia cervico-facciale. Aug 2012;32(4):213–221.
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Wong A, Hardy KL, Kitajewski AM, Shawber CJ, Kitajewski JK, Wu JK. Propranolol accelerates adipogenesis in hemangioma stem cells and causes apoptosis of hemangioma endothelial cells. Plastic and reconstructive surgery. Nov 2012;130(5):1012–1021.
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Zhang Q, Kandic I, Faughnan ME, Kutryk MJ. Elevated circulating microRNA-210 levels in patients with hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations: a potential new biomarker. Biomarkers: biochemical indicators of exposure, response, and susceptibility to chemicals. Oct 10 2012.