WorldWideScience

Sample records for targeting liver myofibroblasts

  1. Evolving insights on metabolism, autophagy and epigenetics in liver myofibroblasts

    Directory of Open Access Journals (Sweden)

    Zeribe Chike Nwosu

    2016-06-01

    Full Text Available Liver myofibroblasts (MFB are crucial mediators of extracellular matrix (ECM deposition in liver fibrosis. They arise mainly from hepatic stellate cells (HSCs upon a process termed activation. To a lesser extent, and depending on the cause of liver damage, portal fibroblasts, mesothelial cells and fibrocytes may also contribute to the MFB population. Targeting MFB to reduce liver fibrosis is currently an area of intense research. Unfortunately, a clog in the wheel of antifibrotic therapies is the fact that although MFB are known to mediate scar formation, and participate in liver inflammatory response, many of their molecular portraits are currently unknown. In this review, we discuss recent understanding of MFB in health and diseases, focusing specifically on three evolving research fields: metabolism, autophagy and epigenetics. We have emphasized on therapeutic prospects where applicable and mentioned techniques for use in MFB studies. Subsequently, we highlighted uncharted territories in MFB research to help direct future efforts aimed at bridging gaps in current knowledge.

  2. Inflammatory myofibroblastic tumour of the liver in a child: CT and MR findings

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Bo Yoon; Kim, Woo Sun; Cheon, Jung-Eun; Kim, In-One; Yeon, Kyung Mo [Department of Radiology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744 (Korea); Institute of Radiation Medicine, SNUMRC (Seoul National University Medical Research Center), Seoul (Korea); Clinical Research Institute, Seoul National University Hospital, Seoul (Korea); Kim, Chong Jai [Department of Pathology, Seoul National University College of Medicine, Seoul (Korea)

    2003-01-01

    Inflammatory myofibroblastic tumour of the liver is a rare disease in children and is characterized by an inflammatory mass of uncertain aetiology which simulates a true neoplasm, often resulting in a diagnostic dilemma. We report a pathologically proven case of inflammatory myofibroblastic tumour of the liver in a 14-month-old boy with jaundice. CT and MRI showed an ill-defined, homogeneously enhancing mass located in the hilar portion of the liver with biliary obstruction. He underwent percutaneous transhepatic biliary drainage to relieve obstructive jaundice, followed by lobectomy and, finally, liver transplantation. (orig.)

  3. Therapeutic Targeting of Redox Signaling in Myofibroblast Differentiation and Age-Related Fibrotic Disease

    Directory of Open Access Journals (Sweden)

    Natalie Sampson

    2012-01-01

    Full Text Available Myofibroblast activation plays a central role during normal wound healing. Whereas insufficient myofibroblast activation impairs wound healing, excessive myofibroblast activation promotes fibrosis in diverse tissues (including benign prostatic hyperplasia, BPH leading to organ dysfunction and also promotes a stromal response that supports tumor progression. The incidence of impaired wound healing, tissue fibrosis, BPH, and certain cancers strongly increases with age. This paper summarizes findings from in vitro fibroblast-to-myofibroblast differentiation systems that serve as cellular models to study fibrogenesis of diverse tissues. Supported by substantial in vivo data, a large body of evidence indicates that myofibroblast differentiation induced by the profibrotic cytokine transforming growth factor beta is driven by a prooxidant shift in redox homeostasis due to elevated production of NADPH oxidase 4 (NOX4-derived hydrogen peroxide and supported by concomitant decreases in nitric oxide/cGMP signaling and reactive oxygen species (ROS scavenging enzymes. Fibroblast-to-myofibroblast differentiation can be inhibited and reversed by restoring redox homeostasis using antioxidants or NOX4 inactivation as well as enhancing nitric oxide/cGMP signaling via activation of soluble guanylyl cyclases or inhibition of phosphodiesterases. Current evidence indicates the therapeutic potential of targeting the prooxidant shift in redox homeostasis for the treatment of age-related diseases associated with myofibroblast dysregulation.

  4. Hepatic stellate cell and myofibroblast-like cell gene expression in the explanted cirrhotic livers of patients undergoing liver transplantation.

    Science.gov (United States)

    Estep, J Michael; O'Reilly, Linda; Grant, Geraldine; Piper, James; Jonsson, Johann; Afendy, Arian; Chandhoke, Vikas; Younossi, Zobair M

    2010-02-01

    Hepatic stellate cells (HSC) are involved in hepatic fibrogenesis. Cell signaling associated with an insult to the liver affects an HSC transdifferentiation to fibrogenic myofibroblast-like cells. To investigate the transcriptional expression distinguishing HSC and myofibroblast-like cells between livers with and without cirrhosis. Tissue from ten cirrhotic livers (undergoing transplant) and four non-cirrhotic livers from the National Disease Research Interchange underwent cell separation to extract HSC and myofibroblast-like cell populations. Separated cell types as well as LI-90 cells were subjected to microarray analysis. Selected microarray results were verified by quantitative real-time PCR. Differential expression of some genes, such as IL-1beta, IL-1alpha, and IL-6, was associated with both transdifferentiation and disease. Other genes, such as fatty acid 2-hydroxylase only show differential expression in association with disease. Functional analysis supported these findings, indicating some signal transduction pathways (IL-6) are involved in disease and activation, whereas retinoid X receptor signaling in HSC from cirrhotic and non-cirrhotic livers varies in scope and quality. These findings indicate distinct phenotypes for HSC from cirrhotic and non-cirrhotic livers. Furthermore, coordinated differential expression between genes involved in the same signal transduction pathways provides some insight into the mechanisms that may control the balance between fibrogenesis and fibrolysis.

  5. Therapeutic targets in liver fibrosis.

    Science.gov (United States)

    Fallowfield, Jonathan A

    2011-05-01

    Detailed analysis of the cellular and molecular mechanisms that mediate liver fibrosis has provided a framework for therapeutic approaches to prevent, slow down, or even reverse fibrosis and cirrhosis. A pivotal event in the development of liver fibrosis is the activation of quiescent hepatic stellate cells (HSCs) to scar-forming myofibroblast-like cells. Consequently, HSCs and the factors that regulate HSC activation, proliferation, and function represent important antifibrotic targets. Drugs currently licensed in the US and Europe for other indications target HSC-related components of the fibrotic cascade. Their deployment in the near future looks likely. Ultimately, treatment strategies for liver fibrosis may vary on an individual basis according to etiology, risk of fibrosis progression, and the prevailing pathogenic milieu, meaning that a multiagent approach could be required. The field continues to develop rapidly and starts to identify exciting potential targets in proof-of-concept preclinical studies. Despite this, no antifibrotics are currently licensed for use in humans. With epidemiological predictions for the future prevalence of viral, obesity-related, and alcohol-related cirrhosis painting an increasingly gloomy picture, and a shortfall in donors for liver transplantation, the clinical urgency for new therapies is high. There is growing interest from stakeholders keen to exploit the market potential for antifibrotics. However, the design of future trials for agents in the developmental pipeline will depend on strategies that enable equal patient stratification, techniques to reliably monitor changes in fibrosis over time, and the definition of clinically meaningful end points.

  6. Agressive inflammatory myofibroblastic tumor of the liver with underlying schistosomiasis: a case report.

    Science.gov (United States)

    Pannain, Vera Lucia; Passos, Juliana Vial; Rocha Filho, Ariovaldo; Villela-Nogueira, Cristiane; Caroli-Bottino, Adriana

    2010-09-07

    Inflammatory myofibroblastic tumor (IMT) occurs infrequently in the liver. It is controversial whether it represents a low grade mesenchymal neoplasm or a reactive inflammatory lesion. Local recurrence and metastasis are rare and some tumors are associated with infectious agents. We report on a case of a large and partially resected IMT with local recurrence and diaphragm and kidney infiltration detected on routine surveillance two years later. Histologically, the tumor showed spindle cells without atypia, mitosis or necrotic areas in a myxoid and collagenized background with inflammatory cells. In the liver portal tracts, granulomatous lesions with viable eggs of Schistosoma mansoni were identified. Immunohistochemistry demonstrated spindle cells which were smooth-muscle actin and vimentin positive. In conclusion, this case points out that these histological patterns do not predict the aggressive biological behavior of the lesion. A reason for the recurrence and the infiltration may be incomplete tumor resection. Further investigation is necessary in order to better clarify an infectious cause in some IMTs.

  7. Peroxisome Proliferator-Activated Receptor Gamma Negatively Regulates the Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells Toward Myofibroblasts in Liver Fibrogenesis

    Directory of Open Access Journals (Sweden)

    Shuangshuang Jia

    2015-11-01

    Full Text Available Background/Aims: Bone marrow-derived mesenchymal stem cells (BMSCs have been confirmed to have capacity to differentiate toward hepatic myofibroblasts, which contribute to fibrogenesis in chronic liver diseases. Peroxisome proliferator-activated receptor gamma (PPARγ, a ligand-activated transcription factor, has gained a great deal of recent attention as it is involved in fibrosis and cell differentiation. However, whether it regulates the differentiation of BMSCs toward myofibroblasts remains to be defined. Methods: Carbon tetrachloride or bile duct ligation was used to induce mouse liver fibrosis. Expressions of PPARγ, α-smooth muscle actin, collagen α1 (I and collagen α1 (III were detected by real-time RT-PCR and Western blot or immunofluorescence assay. Results: PPARγ expression was decreased in mouse fibrotic liver. In addition, PPARγ was declined during the differentiation of BMSCs toward myofibroblasts induced by transforming growth factor β1. Activation of PPARγ stimulated by natural or synthetic ligands suppressed the differentiation of BMSCs. Additionally, knock down of PPARγ by siRNA contributed to BMSC differentiation toward myofibroblasts. Furthermore, PPARγ activation by natural ligand significantly inhibited the differentiation of BMSCs toward myofibroblasts in liver fibrogenesis and alleviated liver fibrosis. Conclusions: PPARγ negatively regulates the differentiation of BMSCs toward myofibroblasts, which highlights a further mechanism implicated in the BMSC differentiation.

  8. Cellular targeting of the apoptosis-inducing compound gliotoxin to fibrotic rat livers

    NARCIS (Netherlands)

    Hagens, W. I.; Beljaars, L.; Mann, D. A.; Wright, M. C.; Julien, B.; Lotersztajn, S.; Reker-Smit, C.; Poelstra, K.

    Liver fibrosis is associated with proliferation of hepatic stellate cells (HSCs) and their transformation into myofibroblastic cells that synthesize scar tissue. Several studies indicate that induction of apoptosis in myofibroblastic cells may prevent fibrogenesis. Gliotoxin (GTX) was found to

  9. Targeted Recombinant Fusion Proteins of IFNγ and Mimetic IFNγ with PDGFβR Bicyclic Peptide Inhibits Liver Fibrogenesis In Vivo

    NARCIS (Netherlands)

    Bansal, Ruchi; Prakash, Jai; de Ruiter, Marieke; Poelstra, Klaas

    2014-01-01

    Hepatic stellate cells (HSCs), following transdifferentiation to myofibroblasts plays a key role in liver fibrosis. Therefore, attempts to attenuate this myofibroblastic phenotype would be a promising therapeutic approach. Interferon gamma (IFNγ) is a potent anti-fibrotic cytokine, but its

  10. Origin and function of myofibroblasts in kidney fibrosis.

    Science.gov (United States)

    LeBleu, Valerie S; Taduri, Gangadhar; O'Connell, Joyce; Teng, Yingqi; Cooke, Vesselina G; Woda, Craig; Sugimoto, Hikaru; Kalluri, Raghu

    2013-08-01

    Myofibroblasts are associated with organ fibrosis, but their precise origin and functional role remain unknown. We used multiple genetically engineered mice to track, fate map and ablate cells to determine the source and function of myofibroblasts in kidney fibrosis. Through this comprehensive analysis, we identified that the total pool of myofibroblasts is split, with 50% arising from local resident fibroblasts through proliferation. The nonproliferating myofibroblasts derive through differentiation from bone marrow (35%), the endothelial-to-mesenchymal transition program (10%) and the epithelial-to-mesenchymal transition program (5%). Specific deletion of Tgfbr2 in α-smooth muscle actin (αSMA)(+) cells revealed the importance of this pathway in the recruitment of myofibroblasts through differentiation. Using genetic mouse models and a fate-mapping strategy, we determined that vascular pericytes probably do not contribute to the emergence of myofibroblasts or fibrosis. Our data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis.

  11. Fibroblasts and myofibroblasts in wound healing

    Directory of Open Access Journals (Sweden)

    Darby IA

    2014-11-01

    Full Text Available Ian A Darby,1 Betty Laverdet,2 Frédéric Bonté3, Alexis Desmoulière2 1School of Medical Sciences, RMIT University, Melbourne, VIC, Australia; 2Department of Physiology and EA 6309, FR 3503, Faculties of Medicine and Pharmacy, University of Limoges, Limoges, France; 3LVMH Recherche, Saint Jean de Braye, France Abstract: (Myofibroblasts are key players for maintaining skin homeostasis and for orchestrating physiological tissue repair. (Myofibroblasts are embedded in a sophisticated extracellular matrix (ECM that they secrete, and a complex and interactive dialogue exists between (myofibroblasts and their microenvironment. In addition to the secretion of the ECM, (myofibroblasts, by secreting matrix metalloproteinases and tissue inhibitors of metalloproteinases, are able to remodel this ECM. (Myofibroblasts and their microenvironment form an evolving network during tissue repair, with reciprocal actions leading to cell differentiation, proliferation, quiescence, or apoptosis, and actions on growth factor bioavailability by binding, sequestration, and activation. In addition, the (myofibroblast phenotype is regulated by mechanical stresses to which they are subjected and thus by mechanical signaling. In pathological situations (excessive scarring or fibrosis, or during aging, this dialogue between the (myofibroblasts and their microenvironment may be altered or disrupted, leading to repair defects or to injuries with damaged and/or cosmetic skin alterations such as wrinkle development. The intimate dialogue between the (myofibroblasts and their microenvironment therefore represents a fascinating domain that must be better understood in order not only to characterize new therapeutic targets and drugs able to prevent or treat pathological developments but also to interfere with skin alterations observed during normal aging or premature aging induced by a deleterious environment. Keywords: myofibroblast, fibroblast, α-smooth muscle actin

  12. Therapeutic Oligonucleotides Targeting Liver Disease: TTR Amyloidosis

    Directory of Open Access Journals (Sweden)

    Christoph Niemietz

    2015-09-01

    Full Text Available The liver has become an increasingly interesting target for oligonucleotide therapy. Mutations of the gene encoding transthyretin (TTR, expressed in vast amounts by the liver, result in a complex degenerative disease, termed familial amyloid polyneuropathy (FAP. Misfolded variants of TTR are linked to the establishment of extracellular protein deposition in various tissues, including the heart and the peripheral nervous system. Recent progress in the chemistry and formulation of antisense (ASO and small interfering RNA (siRNA designed for a knockdown of TTR mRNA in the liver has allowed to address the issue of gene-specific molecular therapy in a clinical setting of FAP. The two therapeutic oligonucleotides bind to RNA in a sequence specific manner but exploit different mechanisms. Here we describe major developments that have led to the advent of therapeutic oligonucleotides for treatment of TTR-related disease.

  13. Inflammatory myofibroblastic tumor

    Directory of Open Access Journals (Sweden)

    Sangeeta Palaskar

    2011-01-01

    Full Text Available Inflammatory myofibroblastic tumor is an uncommon lesion of unknown cause. It encompasses a spectrum of myofibroblastic proliferation along with varying amount of inflammatory infiltrate. A number of terms have been applied to the lesion, namely, inflammatory pseudotumor, fibrous xanthoma, plasma cell granuloma, pseudosarcoma, lymphoid hamartoma, myxoid hamartoma, inflammatory myofibrohistiocytic proliferation, benign myofibroblatoma, and most recently, inflammatory myofibroblastic tumor. The diverse nomenclature is mostly descriptive and reflects the uncertainty regarding true biologic nature of these lesions. Recently, the concept of this lesion being reactive has been challenged based on the clinical demonstration of recurrences and metastasis and cytogenetic evidence of acquired clonal chromosomal abnormalities. We hereby report a case of inflammatory pseudotumor and review its inflammatory versus neoplastic behavior.

  14. Renal inflammatory myofibroblastic tumor

    DEFF Research Database (Denmark)

    Heerwagen, S T; Jensen, C; Bagi, P

    2007-01-01

    Renal inflammatory myofibroblastic tumor (IMT) is a rare soft-tissue tumor of controversial etiology with a potential for local recurrence after incomplete surgical resection. The radiological findings in renal IMT are not well described. We report two cases in adults with a renal mass treated...

  15. Myofibroblasts in experimental hydronephrosis

    NARCIS (Netherlands)

    Diamond, J R; van Goor, H; Ding, G; Engelmyer, E

    Interstitial fibrosis is a common outcome of longterm ureteral obstruction. One pathological arm of the fibrotic reaction in diverse tissue loci and experimental models is the retraction of granulation tissue. The role of the myofibroblast in granulation tissue contraction and fibrocontractive

  16. Targeted Recombinant Fusion Proteins of IFN gamma and Mimetic IFN gamma with PDGF beta R Bicyclic Peptide Inhibits Liver Fibrogenesis In Vivo

    NARCIS (Netherlands)

    Bansal, Ruchi; Prakash, Jai; De Ruiter, Marieke; Poelstra, Klaas

    2014-01-01

    Hepatic stellate cells (HSCs), following transdifferentiation to myofibroblasts plays a key role in liver fibrosis. Therefore, attempts to attenuate this myofibroblastic phenotype would be a promising therapeutic approach. Interferon gamma (IFN gamma) is a potent anti-fibrotic cytokine, but its

  17. Targeted recombinant fusion proteins of IFNγ and mimetic IFNγ with PDGFβR bicyclic peptide inhibits liver fibrogenesis in vivo.

    Directory of Open Access Journals (Sweden)

    Ruchi Bansal

    Full Text Available Hepatic stellate cells (HSCs, following transdifferentiation to myofibroblasts plays a key role in liver fibrosis. Therefore, attempts to attenuate this myofibroblastic phenotype would be a promising therapeutic approach. Interferon gamma (IFNγ is a potent anti-fibrotic cytokine, but its pleiotropic receptor expression leading to severe adverse effects has limited its clinical application. Since, activated HSC express high-level of platelet derived growth factor beta receptor (PDGFβR, we investigated the potential of PDGFβR-specific targeting of IFNγ and its signaling peptide that lacks IFNγR binding site (mimetic IFNγ or mimIFNγ in liver fibrosis. We prepared DNA constructs expressing IFNγ, mimIFNγ or BiPPB (PDGFβR-specific bicyclic peptide-IFNγ, BiPPB-mimIFNγ fusion proteins. Both chimeric proteins alongwith IFNγ and mimIFNγ were produced in E.coli. The expressed proteins were purified and analyzed for PDGFβR-specific binding and in vitro effects. Subsequently, these recombinant proteins were investigated for the liver uptake (pSTAT1α signaling pathway, for anti-fibrotic effects and adverse effects (platelet counts in CCl4-induced liver fibrogenesis in mice. The purified HSC-targeted IFNγ and mimIFNγ fusion proteins showed PDGFβR-specific binding and significantly reduced TGFβ-induced collagen-I expression in human HSC (LX2 cells, while mouse IFNγ and mimIFNγ did not show any effect. Conversely, mouse IFNγ and BiPPB-IFNγ induced activation and dose-dependent nitric oxide release in mouse macrophages (express IFNγR while lack PDGFβR, which was not observed with mimIFNγ and BiPPB-mimIFNγ, due to the lack of IFNγR binding sites. In vivo, targeted BiPPB-IFNγ and BiPPB-mimIFNγ significantly activated intrahepatic IFNγ-signaling pathway compared to IFNγ and mimIFNγ suggesting increased liver accumulation. Furthermore, the targeted fusion proteins ameliorated liver fibrogenesis in mice by significantly reducing

  18. Pharmacologic inhibition of lactate production prevents myofibroblast differentiation.

    Science.gov (United States)

    Kottmann, Robert Matthew; Trawick, Emma; Judge, Jennifer L; Wahl, Lindsay A; Epa, Amali P; Owens, Kristina M; Thatcher, Thomas H; Phipps, Richard P; Sime, Patricia J

    2015-12-01

    Myofibroblasts are one of the primary cell types responsible for the accumulation of extracellular matrix in fibrosing diseases, and targeting myofibroblast differentiation is an important therapeutic strategy for the treatment of pulmonary fibrosis. Transforming growth factor-β (TGF-β) has been shown to be an important inducer of myofibroblast differentiation. We previously demonstrated that lactate dehydrogenase and its metabolic product lactic acid are important mediators of myofibroblast differentiation, via acid-induced activation of latent TGF-β. Here we explore whether pharmacologic inhibition of LDH activity can prevent TGF-β-induced myofibroblast differentiation. Primary human lung fibroblasts from healthy patients and those with pulmonary fibrosis were treated with TGF-β and or gossypol, an LDH inhibitor. Protein and RNA were analyzed for markers of myofibroblast differentiation and extracellular matrix generation. Gossypol inhibited TGF-β-induced expression of the myofibroblast marker α-smooth muscle actin (α-SMA) in a dose-dependent manner in both healthy and fibrotic human lung fibroblasts. Gossypol also inhibited expression of collagen 1, collagen 3, and fibronectin. Gossypol inhibited LDH activity, the generation of extracellular lactic acid, and the rate of extracellular acidification in a dose-dependent manner. Furthermore, gossypol inhibited TGF-β bioactivity in a dose-dependent manner. Concurrent treatment with an LDH siRNA increased the ability of gossypol to inhibit TGF-β-induced myofibroblast differentiation. Gossypol inhibits TGF-β-induced myofibroblast differentiation through inhibition of LDH, inhibition of extracellular accumulation of lactic acid, and inhibition of TGF-β bioactivity. These data support the hypothesis that pharmacologic inhibition of LDH may play an important role in the treatment of pulmonary fibrosis. Copyright © 2015 the American Physiological Society.

  19. An Unusual Case of Systemic Inflammatory Myofibroblastic Tumor with Successful Treatment with ALK-Inhibitor

    Directory of Open Access Journals (Sweden)

    Sanjivini V. Jacob

    2014-01-01

    Full Text Available Systemic inflammatory myofibroblastic tumor is an exceedingly rare entity. A 45-year-old Hispanic female presented with a 6-month history of left-sided thigh pain, low back pain, and generalized weakness. PET/CT scan revealed abnormal activity in the liver, adrenal gland, and pancreas. MRI of the abdomen demonstrated two 6-7 cm masses in the liver. MRI of the lumbar spine demonstrated lesions in the L2 to L4 spinous processes, paraspinal muscles, and subcutaneous tissues, as well as an 8 mm enhancing intradural lesion at T11, all thought to be metastatic disease. A biopsy of the liver showed portal tract expansion by a spindle cell proliferation rich in inflammation. Tumor cells showed immunoreactivity for smooth muscle actin and anaplastic lymphoma kinase 1 (ALK1. Tissue from the L5 vertebra showed a process histologically identical to that seen in the liver. FISH analysis of these lesions demonstrated an ALK (2p23 gene rearrangement. The patient was successfully treated with an ALK-inhibitor, Crizotinib, and is now in complete remission. We present the first reported case, to our knowledge, of inflammatory myofibroblastic tumor with systemic manifestations and ALK translocation. This case is a prime example of how personalized medicine has vastly improved patient care through the use of molecular-targeted therapy.

  20. Liver cell-targeted delivery of therapeutic molecules.

    Science.gov (United States)

    Kang, Jeong-Hun; Toita, Riki; Murata, Masaharu

    2016-01-01

    The liver is the largest internal organ in mammals and is involved in metabolism, detoxification, synthesis of proteins and lipids, secretion of cytokines and growth factors and immune/inflammatory responses. Hepatitis, alcoholic or non-alcoholic liver disease, hepatocellular carcinoma, hepatic veno-occlusive disease, and liver fibrosis and cirrhosis are the most common liver diseases. Safe and efficient delivery of therapeutic molecules (drugs, genes or proteins) into the liver is very important to increase the clinical efficacy of these molecules and to reduce their side effects in other organs. Several liver cell-targeted delivery systems have been developed and tested in vivo or ex vivo/in vitro. In this review, we discuss the literature concerning liver cell-targeted delivery systems, with a particular emphasis on the results of in vivo studies.

  1. Establishment and characterization of rat portal myofibroblast cell lines.

    Directory of Open Access Journals (Sweden)

    Michel Fausther

    Full Text Available The major sources of scar-forming myofibroblasts during liver fibrosis are activated hepatic stellate cells (HSC and portal fibroblasts (PF. In contrast to well-characterized HSC, PF remain understudied and poorly defined. This is largely due to the facts that isolation of rodent PF for functional studies is technically challenging and that PF cell lines had not been established. To address this, we have generated two polyclonal portal myofibroblast cell lines, RGF and RGF-N2. RGF and RGF-N2 were established from primary PF isolated from adult rat livers that underwent culture activation and subsequent SV40-mediated immortalization. Specifically, Ntpdase2/Cd39l1-sorted primary PF were used to generate the RGF-N2 cell line. Both cell lines were functionally characterized by RT-PCR, immunofluorescence, immunoblot and bromodeoxyuridine-based proliferation assay. First, immortalized RGF and RGF-N2 cells are positive for phenotypic myofibroblast markers alpha smooth muscle actin, type I collagen alpha-1, tissue inhibitor of metalloproteinases-1, PF-specific markers elastin, type XV collagen alpha-1 and Ntpdase2/Cd39l1, and mesenchymal cell marker ecto-5'-nucleotidase/Cd73, while negative for HSC-specific markers desmin and lecithin retinol acyltransferase. Second, both RGF and RGF-N2 cell lines are readily transfectable using standard methods. Finally, RGF and RGF-N2 cells attenuate the growth of Mz-ChA-1 cholangiocarcinoma cells in co-culture, as previously demonstrated for primary PF. Immortalized rat portal myofibroblast RGF and RGF-N2 cell lines express typical markers of activated PF-derived myofibroblasts, are suitable for DNA transfection, and can effectively inhibit cholangiocyte proliferation. Both RGF and RGF-N2 cell lines represent novel in vitro cellular models for the functional studies of portal (myofibroblasts and their contribution to the progression of liver fibrosis.

  2. Neonatal umbilical inflammatory myofibroblastic tumor

    African Journals Online (AJOL)

    antenatal scan. The preferred treatment option is resection of the tumor. Spontaneous regression has been described. Ann Pediatr Surg 13:160–162 c 2017 Annals of Pediatric. Surgery. ... Keywords: inflammatory myofibroblastic tumor, neonatal tumor, surgical resection ... Other anatomical regions were the brain, the.

  3. Oxidative Stress and Liver Cancer: Etiology and Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    Zhanpeng Wang

    2016-01-01

    Full Text Available Accumulating evidence has indicated that oxidative stress (OS is associated with the development of hepatocellular carcinoma (HCC. However, the mechanisms remain largely unknown. Normally, OS occurs when the body receives any danger signal—from either an internal or external source—and further induces DNA oxidative damage and abnormal protein expression, placing the body into a state of vulnerability to the development of various diseases such as cancer. There are many factors involved in liver carcinogenesis, including hepatitis B virus (HBV and hepatitis C virus (HCV infection, alcohol abuse, and nonalcoholic fatty liver disease (NAFLD. The relationship between OS and HCC has recently been attracting increasing attention. Therefore, elucidation of the impact of OS on the development of liver carcinogenesis is very important for the prevention and treatment of liver cancer. This review focuses mainly on the relationship between OS and the development of HCC from the perspective of cellular and molecular mechanisms and the etiology and therapeutic targets of HCC.

  4. Glypican-3 Targeting of Liver Cancer Cells Using Multifunctional Nanoparticles

    Directory of Open Access Journals (Sweden)

    James O. Park

    2011-01-01

    Full Text Available Imaging is essential in accurately detecting, staging, and treating primary liver cancer (hepatocellular carcinoma [HCC], one of the most prevalent and lethal malignancies. We developed a novel multifunctional nanoparticle (NP specifically targeting glypican-3 (GPC3, a proteoglycan implicated in promotion of cell growth that is overexpressed in most HCCs. Quantitative real-time polymerase chain reaction was performed to confirm the differential GPC3 expression in two human HCC cells, Hep G2 (high and HLF (negligible. These cells were treated with biotin-conjugated GPC3 monoclonal antibody (αGPC3 and subsequently targeted using superparamagnetic iron oxide NPs conjugated to streptavidin and Alexa Fluor 647. Flow cytometry demonstrated that only GPC3-expressing Hep G2 cells were specifically targeted using this αGPC3-NP conjugate (fourfold mean fluorescence over nontargeted NP, and magnetic resonance imaging (MRI experiments showed similar findings (threefold R2 relaxivity. Confocal fluorescence microscopy localized the αGPC3 NPs only to the cell surface of GPC3-expressing Hep G2 cells. Further characterization of this construct demonstrated a negatively charged, monodisperse, 50 nm NP, ideally suited for tumor targeting. This GPC3-specific NP system, with dual-modality imaging capability, may enhance pretreatment MRI, enable refined intraoperative HCC visualization by near-infrared fluorescence, and be potentially used as a carrier for delivery of tumor-targeted therapies, improving patient outcomes.

  5. Significance of myofibroblasts in oral squamous cell carcinoma

    DEFF Research Database (Denmark)

    Thode, Christenze; Jørgensen, Trine G.; Dabelsteen, Erik

    2011-01-01

    -smooth muscle actin-positive myofibroblast that often represent the majority of tumor stromal cells. Their production of growth factors chemokines and extracellular matrix facilitates tumor growth. Myofibroblast have been demonstrated in close to 50% of oral squamous cell carcinomas. In this review, we...... highlight the histological distribution of myofibroblast in oral squamous cell and the myofibroblast relation to tumor growth on prognosis....

  6. Possibility of sandwiched liver surgery with molecular targeting drugs, cetuximab and bevacizumab on colon cancer liver metastases: a case report

    Directory of Open Access Journals (Sweden)

    Toyama Yoichi

    2012-06-01

    Full Text Available Abstract A 31-year-old man with sigmoid colon cancer with concomitant simultaneous multiple liver metastases had received FOLFIRI (leucovorin, fluorouracil and irinotecan and FOLFOX6 (leucovorin, fluorouracil and oxaliplatin after an ordinary sigmoidectomy. However, his serum carcinoembryonic antigen (CEA level increased rapidly during the fifteen months after the operation while he was on FOLFOX6. Abdominal computed tomography revealed expanding multiple liver tumors. As the third line chemotherapy, a combination therapy of cetuximab with irinotecan was given, which markedly reduced his levels of serum CEA, and the size and number of liver tumors. He underwent lateral segmentectomy of the liver and microwave coagulation of the liver metastases in the remnant liver. Thereafter, a good quality of life with tumor dormancy was obtained for 6 months. However, his serum CEA started to rise again in the absence of liver tumors. Therefore, FOLFOX6 with bevacizumab was chosen as the fourth line chemotherapy, and the serum CEA was reduced with tumor dormancy. A good quality of life was obtained again at 3 years after the first surgery. This report indicates the effectiveness of sandwiched liver surgery with the molecular targeting drugs cetuximab and bevacizumab on multiple liver metastases of colon cancer, and suggests the possibility of a regimen consisting of bevacizumab following cetuximab.

  7. Cadmium stimulates myofibroblast differentiation and mouse lung fibrosis

    International Nuclear Information System (INIS)

    Hu, Xin; Fernandes, Jolyn; Jones, Dean P.; Go, Young-Mi

    2017-01-01

    Highlights: • Low-dose Cd stimulates differentiation of human lung fibroblast to myofibroblast. • Cd-stimulated fibrosis signaling involves activation of SMAD transcription factor. • Low-dose Cd intake in mice activates myofibroblast differentiation. - Abstract: Increasing evidence suggests that Cd at levels found in the human diet can cause oxidative stress and activate redox-sensitive transcription factors in inflammatory signaling. Following inflammation, tissue repair often involves activation of redox-sensitive transcription factors in fibroblasts. In lungs, epithelial barrier remodeling is required to restore gas exchange and barrier function, and aberrant myofibroblast differentiation leads to pulmonary fibrosis. Contributions of exogenous exposures, such as dietary Cd, to pulmonary fibrosis remain inCompletely defined. In the current study, we tested whether Cd activates fibrotic signaling in human fetal lung fibroblasts (HFLF) at micromolar and submicromolar Cd concentrations that do not cause cell death. Exposure of HFLF to low-dose Cd (≤1.0 μM) caused an increase in stress fibers and increased protein levels of myofibroblast differentiation markers, including α-smooth muscle actin (α-SMA) and extra-domain-A-containing fibronectin (ED-A-FN). Assay of transcription factor (TF) activity using a 45-TF array showed that Cd increased activity of 12 TF, including SMAD2/3/4 (mothers against decapentaplegic homolog) signaling differentiation and fibrosis. Results were confirmed by real-time PCR and supported by increased expression of target genes of SMAD2/3/4. Immunocytochemistry of lungs of mice exposed to low-dose Cd (0.3 and 1.0 mg/L in drinking water) showed increased α-SMA protein level with lung Cd accumulation similar to lung Cd in non-smoking humans. Together, the results show that relatively low Cd exposures stimulate pulmonary fibrotic signaling and myofibroblast differentiation by activating SMAD2/3/4-dependent signaling. The results

  8. Imaging of childhood inflammatory myofibroblastic tumor

    Energy Technology Data Exchange (ETDEWEB)

    Oguz, Berna; Ozcan, Hatice Nursun; Omay, Burak; Ozgen, Burce; Haliloglu, Mithat [Division of Pediatric Radiology, Hacettepe University Faculty of Medicine, Department of Radiology, Altindag / Sihhiye, Ankara (Turkey)

    2015-10-15

    Inflammatory myofibroblastic tumor is a rare benign neoplasm and most commonly involves the lung but occurs in extrapulmonary locations. To present imaging findings in inflammatory myofibroblastic tumors in children based on a single-centre experience. We retrospectively reviewed CT and MRI findings of children diagnosed with inflammatory myofibroblastic tumor in a single institution. We identified 15 children (range: 1-17 years) with inflammatory myofibroblastic tumor. The tumor was localized to the lung (n = 5), mediastinum (n = 3), trachea (n = 1), bronchus (n = 1), abdomen (n = 2) and orbit (n = 3). All the extraorbital tumors were solid masses with homogeneous or heterogeneous enhancement. Four lung tumors and one posterior mediastinal tumor contained calcification. Local recurrence following surgical removal occurred in two children with invasion of the esophagus and of the left atrium in one. Localized masses were seen in all children with orbital tumour. Two of these had episcleritis and perineuritis; one had episcleritis, tendonitis, perineuritis, myositis and dacryoadenitis. The locations and imaging features of inflammatory myofibroblastic tumors are variable. (orig.)

  9. Addressing liver fibrosis with Liposomes targeted to hepatic stellate cells

    NARCIS (Netherlands)

    Adrian, Joanna E.; Poelstra, Klaas; Kamps, Jan A. A. M.

    2007-01-01

    Liver fibrosis is a chronic disease that results from hepatitis B and C infections, alcohol abuse or metabolic and genetic disorders. Ultimately, progression of fibrosis leads to cirrhosis, a stage of the disease characterized by failure of the normal liver functions. Currently, the treatment of

  10. Dual-Functional Nanoparticles Targeting CXCR4 and Delivering Antiangiogenic siRNA Ameliorate Liver Fibrosis.

    Science.gov (United States)

    Liu, Chun-Hung; Chan, Kun-Ming; Chiang, Tsaiyu; Liu, Jia-Yu; Chern, Guann-Gen; Hsu, Fu-Fei; Wu, Yu-Hsuan; Liu, Ya-Chi; Chen, Yunching

    2016-07-05

    The progression of liver fibrosis, an intrinsic response to chronic liver injury, is associated with hepatic hypoxia, angiogenesis, abnormal inflammation, and significant matrix deposition, leading to the development of cirrhosis and hepatocellular carcinoma (HCC). Due to the complex pathogenesis of liver fibrosis, antifibrotic drug development has faced the challenge of efficiently and specifically targeting multiple pathogenic mechanisms. Therefore, CXCR4-targeted nanoparticles (NPs) were formulated to deliver siRNAs against vascular endothelial growth factor (VEGF) into fibrotic livers to block angiogenesis during the progression of liver fibrosis. AMD3100, a CXCR4 antagonist that was incorporated into the NPs, served dual functions: it acted as a targeting moiety and suppressed the progression of fibrosis by inhibiting the proliferation and activation of hepatic stellate cells (HSCs). We demonstrated that CXCR4-targeted NPs could deliver VEGF siRNAs to fibrotic livers, decrease VEGF expression, suppress angiogenesis and normalize the distorted vessels in the fibrotic livers in the carbon tetrachloride (CCl4) induced mouse model. Moreover, blocking SDF-1α/CXCR4 by CXCR4-targeted NPs in combination with VEGF siRNA significantly prevented the progression of liver fibrosis in CCl4-treated mice. In conclusion, the multifunctional CXCR4-targeted NPs delivering VEGF siRNAs provide an effective antifibrotic therapeutic strategy.

  11. The mechanical memory of lung myofibroblasts.

    Science.gov (United States)

    Balestrini, Jenna L; Chaudhry, Sidharth; Sarrazy, Vincent; Koehler, Anne; Hinz, Boris

    2012-04-01

    Fibroblasts differentiate into the highly synthetic and contractile myofibroblast phenotype when exposed to substrates with an elastic modulus corresponding to pathologically stiff fibrotic tissue. Cellular responses to changes in substrate stiffness are typically analyzed after hours or days, which does not enable the monitoring of myofibroblast persistence, a hallmark of fibrosis. To determine long-lasting effects on the fibrotic behavior of lung fibroblasts, we followed a novel approach of explanting and repeatedly passaging fibroblasts on silicone substrates with stiffness representing various states of lung health. Fibrotic activity was determined by assaying for myofibroblast proliferation, cell contractility, expression of α-smooth muscle actin, extracellular matrix and active TGFβ1. As predicted, myofibroblast activity was low on healthy soft substrates and increased with increasing substrate stiffness. However, explanting and mechanically priming lung fibroblasts for 3 weeks on pathologically stiff substrates resulted in sustained myofibroblast activity even after the cells were returned to healthy soft cultures for 2 weeks. Such primed cells retained higher fibrotic activity than cells that had been exclusively cultured on soft substrates, and were not statistically different from cells continuously passaged on stiff surfaces. Inversely, priming lung fibroblasts for 3 weeks on soft substrates partially protected from myofibroblast activation after the shift to stiff substrates. Hence, mechano-sensed information relating to physical conditions of the local cellular environment could permanently induce fibrotic behavior of lung fibroblasts. This priming effect has important implications for the progression and persistence of aggressive fibrotic diseases such as idiopathic pulmonary fibrosis. This journal is © The Royal Society of Chemistry 2012

  12. Integrin-linked kinase is required for TGF-β1 induction of dermal myofibroblast differentiation.

    Science.gov (United States)

    Vi, Linda; de Lasa, Cristina; DiGuglielmo, Gianni M; Dagnino, Lina

    2011-03-01

    Cutaneous repair after injury requires activation of resident dermal fibroblasts and their transition to myofibroblasts. The key stimuli for myofibroblast formation are activation of transforming growth factor-β (TGF-β) receptors and mechanotransduction mediated by integrins and associated proteins. We investigated the role of integrin-linked kinase (ILK) in TGF-β1 induction of dermal fibroblast transition to myofibroblasts. ILK-deficient fibroblasts treated with TGF-β1 exhibited attenuation of Smad 2 and 3 phosphorylation, accompanied by impaired transcriptional activation of Smad targets, such as α-smooth muscle actin. These alterations were not limited to Smad-associated TGF-β1 responses, as stimulation of noncanonical mitogen-activated protein kinase pathways by this growth factor was also diminished in the absence of ILK. ILK-deficient fibroblasts exhibited abnormalities in the actin cytoskeleton, and did not form supermature focal adhesions or contractile F-actin stress fibers, indicating a severe impairment in their capacity to differentiate into myofibroblasts. These defects extended to the inability of cells to contract extracellular matrices when embedded in collagen lattices. We conclude that ILK is necessary to transduce signals implicated in the transition of dermal fibroblasts to myofibroblasts originating from matrix substrates and TGF-β1.

  13. Inflammatory Myofibroblastic Tumor of the Bladder: Report of Two Cases

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Han Na; Oh, Soon Nam; Rha, Sung Eun; Jung, Seung Eun; Lee, Young Joon; Byun, Jae Young; Jung, Chan Kwon; Choi, Yeong Jin [Catholic University of Korea St. Mary' s Hospital, Seoul (Korea, Republic of)

    2010-06-15

    Inflammatory myofibroblastic tumor (IMT) is a rare condition of unknown origin. Pathologically, the lesion is composed of myofibroblastic spindle cells accompanied by an inflammatory infiltrate of plasma cells, lymphocytes, and eosinophils. We report two cases of inflammatory myofibroblastic tumor of the bladder which showed different imaging features and was falsely diagnosed as malignant tumors. We discuss the imaging findings along with a literature review

  14. Obstructive Sleep Apnea and Non-alcoholic Fatty Liver Disease: Is the Liver Another Target?

    Directory of Open Access Journals (Sweden)

    Aibek eMirrakhimov

    2012-10-01

    Full Text Available Obstructive sleep apnea (OSA is recurrent obstruction of the upper airway during sleep leading to intermittent hypoxia (IH. OSA has been associated with all components of the metabolic syndrome as well as with non-alcoholic fatty liver disease (NAFLD. NAFLD is a common condition ranging in severity from uncomplicated hepatic steatosis to steatohepatitis (NASH, liver fibrosis and cirrhosis. The gold standard for the diagnosis and staging of NAFLD is liver biopsy. Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known. Emerging evidence suggests that OSA may play a role in the progression of hepatic steatosis and the development of NASH. Several cross-sectional studies showed that the severity of IH in patients with OSA predicted the severity of NAFLD on liver biopsy. However, neither prospective nor interventional studies with continuous positive airway pressure (CPAP treatment have been performed. Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation. The mouse model provided insight in the pathogenesis of liver injury showing that (1 IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA flux into the liver; (2 IH up-regulates lipid biosynthetic pathways in the liver; (3 IH induces oxidative stress in the liver; (4 IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis. However, the role of FFA and different transcription factors in the pathogenesis of IH-induced NAFLD is yet to be established. Thus, multiple lines of evidence suggest that IH of OSA may contribute to the progression of NAFLD but definitive clinical studies and experiments in the mouse model have yet to be done.

  15. Unusual Behavior of a Lung Inflammatory Myofibroblastic Tumor: Case Report.

    Science.gov (United States)

    Rodrigues, Cristina; Cabral, Daniel; Almodovar, Teresa; Ribeiro, Analisa; Delgado, Diogo; Mota, Leonor; Mendes, Samuel; Alvoeiro, Magda; Torres, Carolina; Calado, Telma; Antunes, Mariana; Félix, Francisco

    2017-01-01

    55 years old, male patient. History of heavy smoking (65 UMA) and COPD. Admitted to hospital due to a left pneumonia. Thoracic CT and PET-Scan, showed left lower lobe mass measuring 92x89 mm (SUVmax 49). Several mediastinal node groups presented increased uptake of FDG. A fiberoptic bronchoscopy was performed. Citology of the bronchoalveolar lavage suggested a squamous carcinoma. EBUS of node stations 4R, 4L e 7 without evidence of malignancy. The case was taken to a multidisciplinary meeting staged as IIIA (T3N2M0). Neoadjuvant therapy (four cycles cysplatine and gemcitabine) was decided based on station 5, suspected disease. A left lower lobectomy was performed after a cervical mediastinoscopy excluded metastasis of node stations 4R and 4L. Histology of the specimen was compatible with inflammatory myofibroblastic tumor (IMT). No lymph node involvement was reported. It was restaged as IIB (ypT3N0M0). Three months after surgery one de novo nodule in the lingula with 12,7 of SUVmax was reported. The nodule was removed confirming a IMT metastasis. Four months after the nodule ressection a CT showed new lung and liver nodules. A total oclusion of the left main bronchus was documented and bronchoscopic debulking of the endobronchial mass again revealed IMT. Paliative radiotherapy was decided in the multidisciplinar group targeting the left main bronchus (five sessions of radiotherapy on a dose of 20Gy in 4Gy daily fractions). Ten months after surgery due to the onset of back pain, a CT revealed a sacrum lesion whose needle biopsy was suspicious for multiple myeloma. The patient was referred to another oncological center where previous non-surgical cases had been sent in the past. The patient is now proposed for histology reassessment and discussion by the hematology and pneumology medical teams. Inflammatory myofibrobastic tumors are considered benign or low-grade malignant tumors. The size of the tumour (cut-off of 3 cm) and secure surgical resection with free

  16. Novel Targets for Treating Ischemia-Reperfusion Injury in the Liver

    Directory of Open Access Journals (Sweden)

    Weili Yang

    2018-04-01

    Full Text Available Liver ischemia-reperfusion injury (IRI is a major complication of hemorrhagic shock, liver transplantation, and other liver surgeries. It is one of the leading causes for post-surgery hepatic dysfunction, always leading to morbidity and mortality. Several strategies, such as low-temperature reperfusion and ischemic preconditioning, are useful for ameliorating liver IRI in animal models. However, these methods are difficult to perform in clinical surgeries. It has been reported that the activation of peroxisome proliferator activated receptor gamma (PPARγ protects the liver against IRI, but with unidentified direct target gene(s and unclear mechanism(s. Recently, FAM3A, a direct target gene of PPARγ, had been shown to mediate PPARγ’s protective effects in liver IRI. Moreover, noncoding RNAs, including LncRNAs and miRNAs, had also been reported to play important roles in the process of hepatic IRI. This review briefly discussed the roles and mechanisms of several classes of important molecules, including PPARγ, FAM3A, miRNAs, and LncRNAs, in liver IRI. In particular, oral administration of PPARγ agonists before liver surgery or liver transplantation to activate hepatic FAM3A pathways holds great promise for attenuating human liver IRI.

  17. Reversible differentiation of myofibroblasts by MyoD

    International Nuclear Information System (INIS)

    Hecker, Louise; Jagirdar, Rajesh; Jin, Toni; Thannickal, Victor J.

    2011-01-01

    Myofibroblasts participate in tissue repair processes in diverse mammalian organ systems. The deactivation of myofibroblasts is critical for termination of the reparative response and restoration of tissue structure and function. The current paradigm on normal tissue repair is the apoptotic clearance of terminally differentiated myofibroblasts; while, the accumulation of activated myofibroblasts is associated with progressive human fibrotic disorders. The capacity of myofibroblasts to undergo de-differentiation as a potential mechanism for myofibroblast deactivation has not been examined. In this report, we have uncovered a role for MyoD in the induction of myofibroblast differentiation by transforming growth factor-β1 (TGF-β1). Myofibroblasts demonstrate the capacity for de-differentiation and proliferation by modulation of endogenous levels of MyoD. We propose a model of reciprocal signaling between TGF-β1/ALK5/MyoD and mitogen(s)/ERK-MAPK/CDKs that regulate myofibroblast differentiation and de-differentiation, respectively. Our studies provide the first evidence for MyoD in controlling myofibroblast activation and deactivation. Restricted capacity for de-differentiation of myofibroblasts may underlie the progressive nature of recalcitrant human fibrotic disorders.

  18. The Role of Butylidenephthalide in Targeting Microenvironment Contributes to the Ameliorate of Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Hong-Meng eChuang

    2016-04-01

    Full Text Available The treatment of liver fibrosis has clinical limitations because of its multiple etiologies, such as epithelial–mesenchymal transition (EMT promotion, cell regeneration and remodeling dysfunction, inflammatory cell activation, and scar tissue deposition. These factors might be considered as a new target for the fibrotic microenvironment, leading to increased fibrogenesis and liver fibrosis. Here, we investigate a small molecule named butylidenephthalide (BP and its multiple effects on liver fibrosis treatment. Thioacetamide was used in vivo to induce chronic liver fibrosis. BP was administered orally in rats for a period of 2 weeks and 4 weeks, which resulted in a significantly reduced fibrosis score (p<0.05 and (p<0.001, respectively. The inflammatory reaction of macrophage infiltration were reduced in the administration of BP, which led to the decrease in the transaminase levels. Moreover, we also found liver functions recovering (due to the increased serum albumin and reduced prothrombin time where liver cells regenerated, which can be seen in the increase of Ki-67 on Oval cell. In addition, the fibrotic scar was also reduced, along with the expression of matrix metalloprotease by hepatic stellate cell. Furthermore, regarding the mechanism/study of EMT reduced by BP, the knockdown of BMP-7, which could reduce α-SMA expression, was mediated by the regulation of TGF-β, which implies its major role on EMT. Finally, in the in vivo study, BP treatment of liver fibrosis was reduced by Bmp7 knockdown in zebrafish, suggesting that BP leads to the reduction of liver fibrosis, which also depends on BMP-7 induction. These results suggest that BP had multiple targets for treating liver fibrosis in the following ways: reduction of EMT, decreasing inflammatory reaction, and liver cell proliferation. This multiple targets approach provided a new mechanism to treat liver injury and fibrosis.

  19. Targeting the gut-liver axis in cirrhosis

    DEFF Research Database (Denmark)

    Madsen, Bjørn S; Havelund, Troels; Krag, Aleksander

    2013-01-01

    The gut-liver axis in cirrhosis and portal hypertension is gaining increasing attention as a key pathophysiological mechanism responsible for progression of liver failure and development of complications such as spontaneous infections and hepatocellular carcinoma. Antibiotics and non-selective β......-blockers (NSBB) intercept this axis and each drug has proven efficacy in clinical trials. A synergistic effect is a hitherto unproven possibility. There is an increasing body of evidence supporting improved outcome with expanded use of NSBB and antibiotic therapy beyond current indications. This review addresses...... the issue of pharmacological treatment of cirrhosis and portal hypertension with antibiotics and NSBB. We discuss their mechanism of action and suggest that combining the two treatment modalities could potentially reduce the risk of complications....

  20. Generation and Characterization of an Immortalized Human Esophageal Myofibroblast Line.

    Directory of Open Access Journals (Sweden)

    Chao Niu

    Full Text Available Stromal cells with a myofibroblast phenotype present in the normal human esophagus are increased in individuals with gastro-esophageal reflux disease (GERD. We have previously demonstrated that myofibroblasts stimulated with acid and TLR4 agonists increase IL-6 and IL-8 secretion using primary cultures of myofibroblasts established from normal human esophagus. While primary cultures have the advantage of reflecting the in vivo environment, a short life span and unavoidable heterogeneity limits the usefulness of this model in larger scale in vitro cellular signaling studies. The major aim of this paper therefore was to generate a human esophageal myofibroblast line with an extended lifespan. In the work presented here we have generated and characterized an immortalized human esophageal myofibroblast line by transfection with a commercially available GFP-hTERT lentivirus. Immortalized human esophageal myofibroblasts demonstrate phenotypic, genotypic and functional similarity to primary cultures of esophageal myofibroblasts we have previously described. We found that immortalized esophageal myofibroblasts retain myofibroblast spindle-shaped morphology at low and high confluence beyond passage 80, and express α-SMA, vimentin, and CD90 myofibroblast markers. Immortalized human esophageal myofibroblasts also express the putative acid receptor TRPV1 and TLR4 and retain the functional capacity to respond to stimuli encountered in GERD with secretion of IL-6. Finally, immortalized human esophageal myofibroblasts also support the stratified growth of squamous esophageal epithelial cells in 3D organotypic cultures. This newly characterized immortalized human esophageal myofibroblast cell line can be used in future cellular signaling and co-culture studies.

  1. Inflammatory Myofibroblastic Tumor of the Nasal Septum

    Directory of Open Access Journals (Sweden)

    Yuri Okumura

    2013-01-01

    Full Text Available We report an extremely rare case of inflammatory myofibroblastic tumor of the posterior edge of the nasal septum. An 11-year-old boy presented with frequent epistaxis and nasal obstruction persisting for one year. Based on the clinical presentation and imaging studies, juvenile angiofibroma was suspected, but angiography suggested the possibility of another type of tumor. Transnasal endoscopic surgery found that the tumor protruded into the nasopharynx from the posterior end of the nasal septum. Histological examination identified spindle cells with immunoreaction for vimentin, smooth muscle actin, and anaplastic lymphoma kinase (ALK, but not for desmin and cytokeratin. This is a report of inflammatory myofibroblastic tumor mimicking juvenile angiofibroma. This case suggests that angiography is helpful in the differential diagnosis of epipharyngeal tumor in adolescence.

  2. Pyruvate dehydrogenase complex and lactate dehydrogenase as targets for therapy of acute liver failure.

    Science.gov (United States)

    Ferriero, Rosa; Nusco, Edoardo; De Cegli, Rossella; Carissimo, Annamaria; Manco, Giuseppe; Brunetti-Pierri, Nicola

    2018-03-23

    Acute liver failure is a rapidly progressive deterioration of hepatic function resulting in high mortality and morbidity. Metabolic enzymes can translocate in the nucleus to regulate histone acetylation and gene expression. Levels and activities of pyruvate dehydrogenase complex (PDHC) and lactate dehydrogenase (LDH) were evaluated in nuclear fractions of livers of mice exposed to various hepatotoxins including CD95-Ab, α-amanitin, and acetaminophen. Whole-genome gene expression profiling by RNA-seq was performed in livers of mice with acute liver failure and analyzed by Gene Ontology Enrichment Analysis. Efficacy of histone acetyltransferase inhibitor garcinol and LDH inhibitor galloflavin at reducing liver damage was evaluated in mice with induced hepatotoxicity. Levels and activities of PDHC and LDH were increased in cytoplasmatic and nuclear fractions of livers of mice with acute liver failure. The increase of nuclear PDHC and LDH was associated with increased concentrations of acetyl-coA and lactate in nuclear fractions, and histone H3 hyper-acetylation. Gene expression in livers of mice with acute liver failure suggested that increased histone H3 acetylation induces the expression of genes related to response to damage. Reduced histone acetylation by the histone acetyltransferase inhibitor garcinol decreased liver damage and improved survival in mice with acute liver failure. Knock-down of PDHC or LDH improved viability in cells exposed to a pro-apoptotic stimulus. Treatment with the LDH inhibitor galloflavin that was also found to inhibit PDHC, reduced hepatic necrosis, apoptosis, and expression of pro-inflammatory cytokines in mice with acute liver failure. Mice treated with galloflavin also showed a dose-response increase in survival. PDHC and LDH translocate to the nucleus and are targets for therapy of acute liver failure. Acute liver failure is a rapidly progressive and life-threatening deterioration of liver function resulting in high mortality and

  3. Impact of target reproducibility on tumor dose in stereotactic radiotherapy of targets in the lung and liver

    International Nuclear Information System (INIS)

    Wulf, Joern; Haedinger, Ulrich; Oppitz, Ulrich; Thiele, Wibke; Flentje, Michael

    2003-01-01

    Background and purpose: Previous analyses of target reproducibility in extracranial stereotactic radiotherapy have revealed standard security margins for planning target volume (PTV) definition of 5 mm in axial and 5-10 mm in longitudinal direction. In this study the reproducibility of the clinical target volume (CTV) of lung and liver tumors within the PTV over the complete course of hypofractionated treatment is evaluated. The impact of target mobility on dose to the CTV is assessed by dose-volume histograms (DVH). Materials and methods: Twenty-two pulmonary and 21 hepatic targets were treated with three stereotactic fractions of 10 Gy to the PTV-enclosing 100%-isodose with normalization to 150% at the isocenter. A conformal dose distribution was related to the PTV, which was defined by margins of 5-10 mm added to the CTV. Prior to each fraction a computed tomography (CT)-simulation over the complete target volume was performed resulting in a total of 60 CT-simulations for lung and 58 CT-simulations for hepatic targets. The CTV from each CT-simulation was segmented and matched with the CT-study used for treatment planning. A DVH of the simulated CTV was calculated for each fraction. The target coverage (TC) of dose to the simulated CTV was defined as the proportion of the CTV receiving at least the reference dose (100%). Results: A decrease of TC to 3 . Conclusions: Target reproducibility was precise within the reference isodose in 91% of lung and 81% of liver tumors with a TC of the complete CTV ≥95% at each fraction of treatment. Pulmonary targets with increased breathing mobility and liver tumors >100 cm 3 are at risk for target deviation exceeding the standard security margins for PTV-definition at least for one fraction and require individual evaluation of sufficient margins

  4. Suppression of autophagy by extracellular vesicles promotes myofibroblast differentiation in COPD pathogenesis

    Directory of Open Access Journals (Sweden)

    Yu Fujita

    2015-11-01

    Full Text Available Extracellular vesicles (EVs, such as exosomes and microvesicles, encapsulate proteins and microRNAs (miRNAs as new modulators of both intercellular crosstalk and disease pathogenesis. The composition of EVs is modified by various triggers to maintain physiological homeostasis. In response to cigarette smoke exposure, the lungs develop emphysema, myofibroblast accumulation and airway remodelling, which contribute to chronic obstructive pulmonary disease (COPD. However, the lung disease pathogenesis through modified EVs in stress physiology is not understood. Here, we investigated an EV-mediated intercellular communication mechanism between primary human bronchial epithelial cells (HBECs and lung fibroblasts (LFs and discovered that cigarette smoke extract (CSE-induced HBEC-derived EVs promote myofibroblast differentiation in LFs. Thorough evaluations of the modified EVs and COPD lung samples showed that cigarette smoke induced relative upregulation of cellular and EV miR-210 expression of bronchial epithelial cells. Using co-culture assays, we showed that HBEC-derived EV miR-210 promotes myofibroblast differentiation in LFs. Surprisingly, we found that miR-210 directly regulates autophagy processes via targeting ATG7, and expression levels of miR-210 are inversely correlated with ATG7 expression in LFs. Importantly, autophagy induction was significantly decreased in LFs from COPD patients, and silencing ATG7 in LFs led to myofibroblast differentiation. These findings demonstrate that CSE triggers the modification of EV components and identify bronchial epithelial cell-derived miR-210 as a paracrine autophagy mediator of myofibroblast differentiation that has potential as a therapeutic target for COPD. Our findings show that stressor exposure changes EV compositions as emerging factors, potentially controlling pathological disorders such as airway remodelling in COPD.

  5. [Study on liver targeted drug delivery system of the effective anticancer component from Bolbstemma paniculatum].

    Science.gov (United States)

    Sun, Yi-Yi; Ll, Tong-Hui; Tang, Chen-Kang; Zhu, Zi-Ping; Chi, Qun; Hou, Shi-Xiang

    2005-06-01

    To study the liver targeted drug delivery system of TBMS--the effective anticancer component from Bolbstemma paniculatum, and to discuss the system's function of decreasing toxicity. BCA was used as carrier material. The preparation through overall feedback dynamic techniques. The properties of preparation and toxicology were also technology of nanoparticles was optimized studied. Thenanoparticles' targeting in mice vivo was observed with transmission electron microscopy. The function of decreasing toxicity was researched by the XXTX-2000 automatic quantitative analysis management system. D50 was 0.68 microm. Drug-loading rate and entrapment rate were 37.3% and 88.6% respectively. The release in vitro accorded with Weibull equation. The reaching release balance time and the t 1/2 extended 26 times and 19 times respectively comparing with injection. Nanoparticles mainly distributed in liver tissue. Their toxicity to lung and liver was evidently lower than injection. Nanoparticles' LD50 exceeded injection's by 13.5% and their stimulus was much lower than injection. The TBMS can be targeted to liver by liver targeted drug delivery system. At the same time, the problem about the toxicity hindering clinical application could be solved, which lays the foundation for the further studies on TBMS.

  6. Advances in ultrasound-targeted microbubble-mediated gene therapy for liver fibrosis.

    Science.gov (United States)

    Huang, Cuiyuan; Zhang, Hong; Bai, Ruidan

    2017-07-01

    Hepatic fibrosis develops as a wound-healing scar in response to acute and chronic liver inflammation and can lead to cirrhosis in patients with chronic hepatitis B and C. The condition arises due to increased synthesis and reduced degradation of extracellular matrix (ECM) and is a common pathological sequela of chronic liver disease. Excessive deposition of ECM in the liver causes liver dysfunction, ascites, and eventually upper gastrointestinal bleeding as well as a series of complications. However, fibrosis can be reversed before developing into cirrhosis and has thus been the subject of extensive researches particularly at the gene level. Currently, therapeutic genes are imported into the damaged liver to delay or prevent the development of liver fibrosis by regulating the expression of exogenous genes. One technique of gene delivery uses ultrasound targeting of microbubbles combined with therapeutic genes where the time and intensity of the ultrasound can control the release process. Ultrasound irradiation of microbubbles in the vicinity of cells changes the permeability of the cell membrane by its cavitation effect and enhances gene transfection. In this paper, recent progress in the field is reviewed with emphasis on the following aspects: the types of ultrasound microbubbles, the construction of an ultrasound-mediated gene delivery system, the mechanism of ultrasound microbubble-mediated gene transfer and the application of ultrasound microbubbles in the treatment of liver fibrosis.

  7. Advances in ultrasound-targeted microbubble-mediated gene therapy for liver fibrosis

    Directory of Open Access Journals (Sweden)

    Cuiyuan Huang

    2017-07-01

    Full Text Available Hepatic fibrosis develops as a wound-healing scar in response to acute and chronic liver inflammation and can lead to cirrhosis in patients with chronic hepatitis B and C. The condition arises due to increased synthesis and reduced degradation of extracellular matrix (ECM and is a common pathological sequela of chronic liver disease. Excessive deposition of ECM in the liver causes liver dysfunction, ascites, and eventually upper gastrointestinal bleeding as well as a series of complications. However, fibrosis can be reversed before developing into cirrhosis and has thus been the subject of extensive researches particularly at the gene level. Currently, therapeutic genes are imported into the damaged liver to delay or prevent the development of liver fibrosis by regulating the expression of exogenous genes. One technique of gene delivery uses ultrasound targeting of microbubbles combined with therapeutic genes where the time and intensity of the ultrasound can control the release process. Ultrasound irradiation of microbubbles in the vicinity of cells changes the permeability of the cell membrane by its cavitation effect and enhances gene transfection. In this paper, recent progress in the field is reviewed with emphasis on the following aspects: the types of ultrasound microbubbles, the construction of an ultrasound-mediated gene delivery system, the mechanism of ultrasound microbubble–mediated gene transfer and the application of ultrasound microbubbles in the treatment of liver fibrosis.

  8. Effects of joint immobilization on changes in myofibroblasts and collagen in the rat knee contracture model.

    Science.gov (United States)

    Sasabe, Ryo; Sakamoto, Junya; Goto, Kyo; Honda, Yuichiro; Kataoka, Hideki; Nakano, Jiro; Origuchi, Tomoki; Endo, Daisuke; Koji, Takehiko; Okita, Minoru

    2017-09-01

    The purpose of this study was to examine the time-dependent changes in the development of joint capsule fibrosis and in the number of myofibroblasts in the joint capsule after immobilization, using a rat knee contracture model. Both knee joints were fixed in full flexion for 1, 2, and 4 weeks (immobilization group). Untreated rats were bred for each immobilization period (control group). Histological analysis was performed to evaluate changes in the amount and density of collagen in the joint capsule. The changes in type I and III collagen mRNA were examined by in situ hybridization. The number of myofibroblasts in the joint capsule was assessed by immunohistochemical methods. In the immobilization group, the amount of collagen increased within 1 week and the density of collagen increased within 2 weeks, as compared with that in the control group. Type I collagen mRNA-positive cell numbers in the immobilization group increased at all time points. However, type III collagen mRNA-positive cell numbers did not increase. Myofibroblasts in the immobilization group significantly increased compared with those in the control group at all time points, and they increased significantly with the period of immobilization. These results suggest that joint capsule fibrosis with overexpression of type I collagen occurs and progresses within 1 week after immobilization, and an increase in myofibroblasts is related to the mechanism of joint capsule fibrosis. The findings suggest the need for a treatment targeting accumulation of type I collagen associated with an increase in myofibroblasts. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1998-2006, 2017. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  9. Impact of target reproducibility on tumor dose in stereotactic radiotherapy of targets in the lung and liver.

    Science.gov (United States)

    Wulf, Jörn; Hädinger, Ulrich; Oppitz, Ulrich; Thiele, Wibke; Flentje, Michael

    2003-02-01

    Previous analyses of target reproducibility in extracranial stereotactic radiotherapy have revealed standard security margins for planning target volume (PTV) definition of 5mm in axial and 5-10mm in longitudinal direction. In this study the reproducibility of the clinical target volume (CTV) of lung and liver tumors within the PTV over the complete course of hypofractionated treatment is evaluated. The impact of target mobility on dose to the CTV is assessed by dose-volume histograms (DVH). Twenty-two pulmonary and 21 hepatic targets were treated with three stereotactic fractions of 10 Gy to the PTV-enclosing 100%-isodose with normalization to 150% at the isocenter. A conformal dose distribution was related to the PTV, which was defined by margins of 5-10mm added to the CTV. Prior to each fraction a computed tomography (CT)-simulation over the complete target volume was performed resulting in a total of 60 CT-simulations for lung and 58 CT-simulations for hepatic targets. The CTV from each CT-simulation was segmented and matched with the CT-study used for treatment planning. A DVH of the simulated CTV was calculated for each fraction. The target coverage (TC) of dose to the simulated CTV was defined as the proportion of the CTV receiving at least the reference dose (100%). A decrease of TC to or=95% at each fraction of treatment. Pulmonary targets with increased breathing mobility and liver tumors >100 cm(3) are at risk for target deviation exceeding the standard security margins for PTV-definition at least for one fraction and require individual evaluation of sufficient margins.

  10. Immunohistochemical study of epithelial-myofibroblast interaction in Barrett metaplasia

    Directory of Open Access Journals (Sweden)

    Ochicha O

    2010-04-01

    Full Text Available Context: Sub-epithelial myofibroblasts are known to influence the biology (proliferation, differentiation and apoptosis of overlying epithelia. In the intestine, myofibroblasts have been demonstrated to be essential for epithelial differentiation. It is therefore hypothesized that myofibroblasts may also be involved in intestinal metaplasia that is characteristic of Barrett esophagus. Objective: This study endeavors to immunohistologically evaluate epithelial-myofibroblast interaction in Barrett′s metaplasia. Materials and Methods: Nineteen archival esophageal endoscopic biopsies of Barrett′s metaplasia were immune-phenotyped for the following epithelial and myofibroblast antigens - cytokeratins (CK 8, 13, 18, CDX2 (Caudal type homeobox 2, a-smooth muscle actin (SMA. Results: α-SMA immunostaining revealed close association between myofibroblasts and metaplastic Barrett′s epithelium but not with normal esophageal squamous epithelium. Myofibroblasts were more prominent in dysplastic than in non-dysplastic Barrett metaplasia. CDX2 and CK 8/18, indicators of intestinal differentiation were expressed in Barrett metaplasia but not normal esophageal squamous epithelium, while the reverse was the case for CK 13, which only stained normal esophageal squamous epithelium. Conclusion: Although their precise role is yet to be clearly defined, sub-epithelial myofibroblasts are very likely involved in the pathogenesis of Barrett′s metaplasia.

  11. Precision targeting of liver lesions using a novel electromagnetic navigation device in physiologic phantom and swine

    International Nuclear Information System (INIS)

    Banovac, Filip; Tang, Jonathan; Xu Sheng; Lindisch, David; Chung, Ho Young; Levy, Elliot B.; Chang, Thomas; McCullough, Michael F.; Yaniv, Ziv; Wood, Bradford J.; Cleary, Kevin

    2005-01-01

    Radiofrequency ablation of primary and metastatic liver tumors is becoming a potential alternative to surgical resection. We propose a novel system that uses real-time electromagnetic position sensing of the needle tip to help with precision guidance into a liver tumor. The purpose of this study was to evaluate this technology in phantom and animal models. Using an electromagnetic navigation device, instrumented 18 g needles were advanced into radioopaque tumor targets in a respiratory liver phantom. The phantom featured a moving liver target that simulated cranio-caudal liver motion due to respiration. Skin-to-target path planning and real-time needle guidance were provided by a custom-designed software interface based on pre-operative 1 mm CT data slices. Needle probes were advanced using only the electromagnetic navigation device and software display. No conventional real-time imaging was used to assist in advancing the needle to the target. Two experienced operators (interventional radiologists) and two inexperienced ones (residents) used the system. The same protocol was then also used in two anesthetized 45 kg Yorkshire swine where radioopaque agar nodules were injected into the liver to serve as targets. A total of 76 tumor targeting attempts were performed in the liver phantom, and 32 attempts were done in the swine. The average time for path planning was 30 s in the phantom, and 63 s in the swine. The median time for the actual needle puncture to reach the desired target was 33 s in the phantom, and 42 s in the swine. The average registration error between the CT coordinate system and electromagnetic coordinate system was 1.4 mm (SD 0.3 mm) in the phantom, and 1.9 mm (SD 0.4 mm) in the swine. The median distance from the final needle tip position to the center of the tumor was 6.4 mm (SD 3.3 mm, n=76) in the phantom, and 8.3 mm (SD 3.7 mm, n=32) in the swine. There was no statistical difference in the planning time, procedure time, or accuracy of needle

  12. Augmented liver targeting of exosomes by surface modification with cationized pullulan.

    Science.gov (United States)

    Tamura, Ryo; Uemoto, Shinji; Tabata, Yasuhiko

    2017-07-15

    Exosomes are membrane nanoparticles containing biological substances that are employed as therapeutics in experimental inflammatory models. Surface modification of exosomes for better tissue targetability and enhancement of their therapeutic ability was recently attempted mainly using gene transfection techniques. Here, we show for the first time that the surface modification of exosomes with cationized pullulan, which has the ability to target hepatocyte asialoglycoprotein receptors, can target injured liver and enhance the therapeutic effect of exosomes. Surface modification can be achieved by a simple mixing of original exosomes and cationized pullulan and through an electrostatic interaction of both substances. The exosomes modified with cationized pullulan were internalized into HepG2 cells in vitro to a significantly greater extent than unmodified ones and this internalization was induced through the asialoglycoprotein receptor that was specifically expressed on HepG2 cells and hepatocytes. When injected intravenously into mice with concanavalin A-induced liver injury, the modified exosomes accumulated in the liver tissue, resulting in an enhanced anti-inflammatory effect in vivo. It is concluded that the surface modification with cationized pullulan promoted accumulation of the exosomes in the liver and the subsequent biological function, resulting in a greater therapeutic effect on liver injury. Exosomes have shown potentials as therapeutics for various inflammatory disease models. This study is the first to show the specific accumulation of exosomes in the liver and enhanced anti-inflammatory effect via the surface modification of exosomes using pullulan, which is specifically recognized by the asialoglycoprotein receptor (AGPR) on HepG2 cells and hepatocytes. The pullulan was expressed on the surface of PKH-labeled exosomes, and it led increased accumulation of PKH into HepG2 cells, whereas the accumulation was canceled by AGPR inhibitor. In the mouse

  13. The mechanical environment modulates intracellular calcium oscillation activities of myofibroblasts.

    Directory of Open Access Journals (Sweden)

    Charles Godbout

    Full Text Available Myofibroblast contraction is fundamental in the excessive tissue remodeling that is characteristic of fibrotic tissue contractures. Tissue remodeling during development of fibrosis leads to gradually increasing stiffness of the extracellular matrix. We propose that this increased stiffness positively feeds back on the contractile activities of myofibroblasts. We have previously shown that cycles of contraction directly correlate with periodic intracellular calcium oscillations in cultured myofibroblasts. We analyze cytosolic calcium dynamics using fluorescent calcium indicators to evaluate the possible impact of mechanical stress on myofibroblast contractile activity. To modulate extracellular mechanics, we seeded primary rat subcutaneous myofibroblasts on silicone substrates and into collagen gels of different elastic modulus. We modulated cell stress by cell growth on differently adhesive culture substrates, by restricting cell spreading area on micro-printed adhesive islands, and depolymerizing actin with Cytochalasin D. In general, calcium oscillation frequencies in myofibroblasts increased with increasing mechanical challenge. These results provide new insight on how changing mechanical conditions for myofibroblasts are encoded in calcium oscillations and possibly explain how reparative cells adapt their contractile behavior to the stresses occurring in normal and pathological tissue repair.

  14. Targeted induction of interferon-λ in humanized chimeric mouse liver abrogates hepatotropic virus infection.

    Science.gov (United States)

    Nakagawa, Shin-ichiro; Hirata, Yuichi; Kameyama, Takeshi; Tokunaga, Yuko; Nishito, Yasumasa; Hirabayashi, Kazuko; Yano, Junichi; Ochiya, Takahiro; Tateno, Chise; Tanaka, Yasuhito; Mizokami, Masashi; Tsukiyama-Kohara, Kyoko; Inoue, Kazuaki; Yoshiba, Makoto; Takaoka, Akinori; Kohara, Michinori

    2013-01-01

    The interferon (IFN) system plays a critical role in innate antiviral response. We presume that targeted induction of IFN in human liver shows robust antiviral effects on hepatitis C virus (HCV) and hepatitis B virus (HBV). This study used chimeric mice harboring humanized livers and infected with HCV or HBV. This mouse model permitted simultaneous analysis of immune responses by human and mouse hepatocytes in the same liver and exploration of the mechanism of antiviral effect against these viruses. Targeted expression of IFN was induced by treating the animals with a complex comprising a hepatotropic cationic liposome and a synthetic double-stranded RNA analog, pIC (LIC-pIC). Viral replication, IFN gene expression, IFN protein production, and IFN antiviral activity were analyzed (for type I, II and III IFNs) in the livers and sera of these humanized chimeric mice. Following treatment with LIC-pIC, the humanized livers of chimeric mice exhibited increased expression (at the mRNA and protein level) of human IFN-λs, resulting in strong antiviral effect on HBV and HCV. Similar increases were not seen for human IFN-α or IFN-β in these animals. Strong induction of IFN-λs by LIC-pIC occurred only in human hepatocytes, and not in mouse hepatocytes nor in human cell lines derived from other (non-hepatic) tissues. LIC-pIC-induced IFN-λ production was mediated by the immune sensor adaptor molecules mitochondrial antiviral signaling protein (MAVS) and Toll/IL-1R domain-containing adaptor molecule-1 (TICAM-1), suggesting dual recognition of LIC-pIC by both sensor adaptor pathways. These findings demonstrate that the expression and function of various IFNs differ depending on the animal species and tissues under investigation. Chimeric mice harboring humanized livers demonstrate that IFN-λs play an important role in the defense against human hepatic virus infection.

  15. Targeted induction of interferon-λ in humanized chimeric mouse liver abrogates hepatotropic virus infection.

    Directory of Open Access Journals (Sweden)

    Shin-ichiro Nakagawa

    Full Text Available BACKGROUND & AIMS: The interferon (IFN system plays a critical role in innate antiviral response. We presume that targeted induction of IFN in human liver shows robust antiviral effects on hepatitis C virus (HCV and hepatitis B virus (HBV. METHODS: This study used chimeric mice harboring humanized livers and infected with HCV or HBV. This mouse model permitted simultaneous analysis of immune responses by human and mouse hepatocytes in the same liver and exploration of the mechanism of antiviral effect against these viruses. Targeted expression of IFN was induced by treating the animals with a complex comprising a hepatotropic cationic liposome and a synthetic double-stranded RNA analog, pIC (LIC-pIC. Viral replication, IFN gene expression, IFN protein production, and IFN antiviral activity were analyzed (for type I, II and III IFNs in the livers and sera of these humanized chimeric mice. RESULTS: Following treatment with LIC-pIC, the humanized livers of chimeric mice exhibited increased expression (at the mRNA and protein level of human IFN-λs, resulting in strong antiviral effect on HBV and HCV. Similar increases were not seen for human IFN-α or IFN-β in these animals. Strong induction of IFN-λs by LIC-pIC occurred only in human hepatocytes, and not in mouse hepatocytes nor in human cell lines derived from other (non-hepatic tissues. LIC-pIC-induced IFN-λ production was mediated by the immune sensor adaptor molecules mitochondrial antiviral signaling protein (MAVS and Toll/IL-1R domain-containing adaptor molecule-1 (TICAM-1, suggesting dual recognition of LIC-pIC by both sensor adaptor pathways. CONCLUSIONS: These findings demonstrate that the expression and function of various IFNs differ depending on the animal species and tissues under investigation. Chimeric mice harboring humanized livers demonstrate that IFN-λs play an important role in the defense against human hepatic virus infection.

  16. Identification of Pathways in Liver Repair Potentially Targeted by Secretory Proteins from Human Mesenchymal Stem Cells

    Directory of Open Access Journals (Sweden)

    Sandra Winkler

    2016-07-01

    Full Text Available Background: The beneficial impact of mesenchymal stem cells (MSC on both acute and chronic liver diseases has been confirmed, although the molecular mechanisms behind it remain elusive. We aim to identify factors secreted by undifferentiated and hepatocytic differentiated MSC in vitro in order to delineate liver repair pathways potentially targeted by MSC. Methods: Secreted factors were determined by protein arrays and related pathways identified by biomathematical analyses. Results: MSC from adipose tissue and bone marrow expressed a similar pattern of surface markers. After hepatocytic differentiation, CD54 (intercellular adhesion molecule 1, ICAM-1 increased and CD166 (activated leukocyte cell adhesion molecule, ALCAM decreased. MSC secreted different factors before and after differentiation. These comprised cytokines involved in innate immunity and growth factors regulating liver regeneration. Pathway analysis revealed cytokine-cytokine receptor interactions, chemokine signalling pathways, the complement and coagulation cascades as well as the Januskinase-signal transducers and activators of transcription (JAK-STAT and nucleotide-binding oligomerization domain-like receptor (NOD-like receptor signalling pathways as relevant networks. Relationships to transforming growth factor β (TGF-β and hypoxia-inducible factor 1-α (HIF1-α signalling seemed also relevant. Conclusion: MSC secreted proteins, which differed depending on cell source and degree of differentiation. The factors might address inflammatory and growth factor pathways as well as chemo-attraction and innate immunity. Since these are prone to dysregulation in most liver diseases, MSC release hepatotropic factors, potentially supporting liver regeneration.

  17. Management of rectal inflammatory myofibroblastic tumor recurrence

    Directory of Open Access Journals (Sweden)

    Lan Sun

    2014-01-01

    Full Text Available Inflammatory myofibroblastic tumor (IMT is an uncommon mesenchymal neoplasm of intermediate malignant potential. It may occur in various anatomic locations, but rarely in the rectum. This is a case discussion of a 36-year-old male patient with IMT of the rectum. After the patient underwent radical surgery, recurrence was seen after 18 months. Because the tumor was very close to the surrounding tissue, palliative tumor resection was performed followed by concurrent chemo-radiation and non-steroidal anti-inflammatory drugs (NSAID. After 2-year follow-up, the patient has no evidence of recurrence or metastasis. Surgical resection is very important for patient with rectal IMT, even in relapse cases. And adjuvant chemoradiotherapy and NSAID are in favor of the incompletely resected tumors as our case. But perhaps, the adjuvant treatments could be helpful after radical resection of rectal tumor.

  18. Synthesis of functionalized magnetite nanoparticles to use as liver targeting MRI contrast agent

    International Nuclear Information System (INIS)

    Yazdani, Farshad; Fattahi, Bahare; Azizi, Najmodin

    2016-01-01

    The aim of this research was the preparation of functionalized magnetite nanoparticles to use as a liver targeting contrast agent in magnetic resonance imaging (MRI). For this purpose, Fe_3O_4 nanoparticles were synthesized via the co-precipitation method. The synthesized nanoparticles were coated with silica via the Stober method and finally the coated nanoparticles were functionalized with mebrofenin. Formation of crystalline magnetite particles was confirmed by X-ray diffraction (XRD) analysis. The Fourier transform infrared spectroscopy (FTIR) and energy dispersive X-ray analyzer (EDX) of the final product showed that silica had been effectively bonded onto the surface of the magnetite nanoparticles and the coated nanoparticles functionalized with mebrofenin. The magnetic resonance imaging of the functional nanoparticles showed that the Fe_3O_4–SiO_2-mebrofenin composite is an effective MRI contrast agent for liver targeting. - Highlights: • Superparamagnetic magnetite nanoparticles have been synthesized by simple and economical method. • Preperation of functional MNPs as a MRI contrast agent for liver targeting. • Gaining a good r_2 relaxivity of the coated functional nanoparticles.

  19. Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis.

    Science.gov (United States)

    Cao, Zhongwei; Ye, Tinghong; Sun, Yue; Ji, Gaili; Shido, Koji; Chen, Yutian; Luo, Lin; Na, Feifei; Li, Xiaoyan; Huang, Zhen; Ko, Jane L; Mittal, Vivek; Qiao, Lina; Chen, Chong; Martinez, Fernando J; Rafii, Shahin; Ding, Bi-Sen

    2017-08-30

    The regenerative capacity of lung and liver is sometimes impaired by chronic or overwhelming injury. Orthotopic transplantation of parenchymal stem cells to damaged organs might reinstate their self-repair ability. However, parenchymal cell engraftment is frequently hampered by the microenvironment in diseased recipient organs. We show that targeting both the vascular niche and perivascular fibroblasts establishes "hospitable soil" to foster the incorporation of "seed," in this case, the engraftment of parenchymal cells in injured organs. Specifically, ectopic induction of endothelial cell (EC)-expressed paracrine/angiocrine hepatocyte growth factor (HGF) and inhibition of perivascular NOX4 [NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase 4] synergistically enabled reconstitution of mouse and human parenchymal cells in damaged organs. Reciprocally, genetic knockout of Hgf in mouse ECs ( Hgf iΔEC/iΔEC ) aberrantly up-regulated perivascular NOX4 during liver and lung regeneration. Dysregulated HGF and NOX4 pathways subverted the function of vascular and perivascular cells from an epithelially inductive niche to a microenvironment that inhibited parenchymal reconstitution. Perivascular NOX4 induction in Hgf iΔEC/iΔEC mice recapitulated the phenotype of human and mouse liver and lung fibrosis. Consequently, EC-directed HGF and NOX4 inhibitor GKT137831 stimulated regenerative integration of mouse and human parenchymal cells in chronically injured lung and liver. Our data suggest that targeting dysfunctional perivascular and vascular cells in diseased organs can bypass fibrosis and enable reparative cell engraftment to reinstate lung and liver regeneration. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  20. Myofibroblastic tumor associated to superior vena cava syndrome

    International Nuclear Information System (INIS)

    Ortega Jaramillo, Hector; Durango Gutierrez, Luisa Fernanda; Perez Figueroa, Maria del Pilar

    2005-01-01

    Inflammatory myofibroblastic tumor (IMT) is an uncommon pathological entity of unknown cause, composed of differentiated myofibroblastic cells accompanied by plasma cells, lymphocytes and eosinophils, which involve extrapulmonary and pulmonary tissues. IMT has an unpredictable clinical course, rarely undergoes malignant transformation. Local invasion and involvement of the mediastinum and hiliar structures are unusual manifestations; however; we reports a case of superior vena cava syndrome and IMT

  1. Myofibroblast Numbers are Elevated in Human Elbow Capsules After Trauma

    OpenAIRE

    Hildebrand, Kevin A.; Zhang, Mei; van Snellenberg, Wistara; King, Graham J. W.; Hart, David A.

    2004-01-01

    Elbow contractures, a frequent problem after injury, can be treated by excision of the joint capsule. However, the underlying changes in the joint capsule are poorly understood. Based on skin healing work, we examined the hypotheses that myofibroblast numbers and expression of a myofibroblast marker α-smooth muscle actin, are elevated in patients with posttraumatic joint contractures. Anterior capsules were obtained from six patients who had operative release of posttraumatic contractures gre...

  2. Augmented environments for the targeting of hepatic lesions during image-guided robotic liver surgery.

    Science.gov (United States)

    Buchs, Nicolas C; Volonte, Francesco; Pugin, François; Toso, Christian; Fusaglia, Matteo; Gavaghan, Kate; Majno, Pietro E; Peterhans, Matthias; Weber, Stefan; Morel, Philippe

    2013-10-01

    Stereotactic navigation technology can enhance guidance during surgery and enable the precise reproduction of planned surgical strategies. Currently, specific systems (such as the CAS-One system) are available for instrument guidance in open liver surgery. This study aims to evaluate the implementation of such a system for the targeting of hepatic tumors during robotic liver surgery. Optical tracking references were attached to one of the robotic instruments and to the robotic endoscopic camera. After instrument and video calibration and patient-to-image registration, a virtual model of the tracked instrument and the available three-dimensional images of the liver were displayed directly within the robotic console, superimposed onto the endoscopic video image. An additional superimposed targeting viewer allowed for the visualization of the target tumor, relative to the tip of the instrument, for an assessment of the distance between the tumor and the tool for the realization of safe resection margins. Two cirrhotic patients underwent robotic navigated atypical hepatic resections for hepatocellular carcinoma. The augmented endoscopic view allowed for the definition of an accurate resection margin around the tumor. The overlay of reconstructed three-dimensional models was also used during parenchymal transection for the identification of vascular and biliary structures. Operative times were 240 min in the first case and 300 min in the second. There were no intraoperative complications. The da Vinci Surgical System provided an excellent platform for image-guided liver surgery with a stable optic and instrumentation. Robotic image guidance might improve the surgeon's orientation during the operation and increase accuracy in tumor resection. Further developments of this technological combination are needed to deal with organ deformation during surgery. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Gadolinium-conjugated PLA-PEG nanoparticles as liver targeted molecular MRI contrast agent.

    Science.gov (United States)

    Chen, Zhijin; Yu, Dexin; Liu, Chunxi; Yang, Xiaoyan; Zhang, Na; Ma, Chunhong; Song, Jibin; Lu, Zaijun

    2011-09-01

    A nanoparticle magnetic resonance imaging (MRI) contrast agent targeted to liver was developed by conjugation of gadolinium (Gd) chelate groups onto the biocompatible poly(l-lactide)-block-poly (ethylene glycol) (PLA-PEG) nanoparticles. PLA-PEG conjugated with diethylenetriaminopentaacetic acid (DTPA) was used to formulate PLA-PEG-DTPA nanoparticles by solvent diffusion method, and then Gd was loaded onto the nanoparticles by chelated with the unfolding DTPA on the surface of the PLA-PEG-DTPA nanoparticles. The mean size of the nanoparticles was 265.9 ± 6.7 nm. The relaxivity of the Gd-labeled nanoparticles was measured, and the distribution in vivo was evaluated in rats. Compared with conventional contrast agent (Magnevist), the Gd-labeled PLA-PEG nanoparticles showed significant enhancement both on liver targeting ability and imaging signal intensity. The T(1) and T(2) relaxivities per [Gd] of the Gd-labeled nanoparticles was 18.865 mM(-1) s(-1) and 24.863 mM(-1) s(-1) at 3 T, respectively. In addition, the signal intensity in vivo was stronger comparing with the Gd-DTPA and the T(1) weight time was lasting for 4.5 h. The liver targeting efficiency of the Gd-labeled PLA-PEG nanoparticles in rats was 14.57 comparing with Magnevist injection. Therefore, the Gd-labeled nanoparticles showed the potential as targeting molecular MRI contrast agent for further clinical utilization.

  4. Immunohistochemical evaluation of myofibroblast density in odontogenic cysts and tumors.

    Science.gov (United States)

    Kouhsoltani, Maryam; Halimi, Monireh; Jabbari, Golchin

    2016-01-01

    Background. The aim of this study was to investigate myofibroblast (MF) density in a broad spectrum of odontogenic cysts and tumors and the relation between the density of MFs and the clinical behavior of these lesions. Methods. A total of 105 cases of odontogenic lesions, including unicystic ameloblastoma (UAM), solid ameloblastoma (SA), odontogenic keratocyst (OKC), dentigerous cyst (DC), radicular cyst (RC) (15 for each category), and odontogenic myxoma (OM), adenomatoid odontogenic tumor (AOT), calcifying odontogenic cyst (COC) (10 for each category), were immunohistochemically stained with anti-α-smooth muscle actin antibody. The mean percentage of positive cells in 10 high-power fields was considered as MF density for each case. Results. A statistically significant difference was observed in the mean scores between the study groups (P 0.05). The number of MFs was significantly higher in OKC and lower in COC compared to other odontogenic cysts (P = 0.007 and P = 0.045, respectively). Conclusion. The results of the present study suggest a role for MFs in the aggressive behavior of odontogenic lesions. MFs may represent an important target of therapy, especially for aggressive odontogenic lesions. Our findings support the classification of OKC in the category of odontogenic tumors.

  5. Inflammatory Myofibroblastic Tumor of the Right Atrium

    Directory of Open Access Journals (Sweden)

    Neerod K. Jha

    2010-01-01

    Full Text Available Cardiac inflammatory myofibroblastic tumor (IMT is a rare entity and is associated with distinct clinical, pathological and molecular features. The clinical behavior, natural history, biological potential, management and prognosis of such tumors are unclear. We present herewith an adolescent girl who presented with similar entity involving the junction of the right atrium and the inferior vena cava (IVC in association with thrombocytosis and IVC thrombosis leading to obstruction of blood flow. Diagnostic tools included imaging and immuno-histopathology studies. Surgical management included resection of the tumor and thrombo-embolectomy of the IVC under cardiopulmonary bypass. This case is unique due to association of complete obstruction of IVC caused by the strategic location of the tumor, thrombosis of vena cava and association of thrombocytosis. These features have not been reported yet in relation to the cardiac IMT. This report will help in better understanding and management of similar cases in terms of planning cannulation of femoral veins or application of total hypothermic circulatory arrest during cardiopulmonary bypass and prompt us to look for recurrence or metastasis during follow up using echocardiography and laboratory investigations. The possibility of IMT should be kept in the differential diagnosis of cardiac tumors especially in children and adolescents.

  6. Inflammatory Myofibroblastic Tumour of the Skull Base

    Directory of Open Access Journals (Sweden)

    Jean-Philippe Maire

    2013-01-01

    Full Text Available Inflammatory myofibroblastic tumors (IMTs are rare benign clinical and pathological entities. IMTs have been described in the lungs, abdomen, retroperitoneum, and extremities but rarely in the head and neck region. A 38-year-old man presented with headache, right exophthalmia, and right 6th nerve palsy. A CT scan revealed enlargement of the right cavernous sinus and osteolytic lesions of the right sphenoid and clivus. MR imaging showed a large tumor of the skull base which was invading the sella turcica, right cavernous sinus, and sphenoidal sinus. A biopsy was performed and revealed an IMT. Corticosteroids were given for 3 months but were inefficient. In the framework of our pluridisciplinary consultation, fractionated conformal radiotherapy (FRT was indicated at a low dose; 20 Gy in 10 fractions of 2 Gy over 12 days were delivered. Clinical response was complete 3 months after FRT. Radiological response was subtotal 6 months after FRT. Two years later, the patient is well.

  7. Liver

    International Nuclear Information System (INIS)

    Bernardino, M.E.; Sones, P.J. Jr.; Barton Price, R.; Berkman, W.A.

    1984-01-01

    Evaluation of the liver for focal lesions is extremely important because the liver is one of the most common sites for metastatic disease. Most patients with metastatic deposits to the liver have a survival rate of about 6 months. Thus, metastatic disease to the liver has an extremely grave prognosis. In the past patients with hepatic lesions had no therapeutic recourse. However, with recent aggressive surgical advances (such as partial hepatectomies) and hepatic artery embolization, survival of patients with hepatic metastases has increased. Thus it is important for noninvasive imaging not only to detect lesions early in their course, but also to give their true hepatic involvement and the extent of the neoplastic process elsewhere in the body. Recent advances in imaging have been rapidly changing over the past 5 years. These changes have been more rapid in computed tomography (CT) and ultrasound than in radionuclide imaging. Thus, the question addressed in this chapter is: What is the relationship of hepatic ultrasound to the other current diagnostic modalities in detecting metastatic liver disease and other focal liver lesions? Also, what is its possible future relationship to nuclear magnetic resonance?

  8. Gene targeting and cloning in pigs using fetal liver derived cells.

    Science.gov (United States)

    Waghmare, Sanjeev K; Estrada, Jose; Reyes, Luz; Li, Ping; Ivary, Bess; Sidner, Richard A; Burlak, Chris; Tector, A Joseph

    2011-12-01

    Since there are no pig embryonic stem cells, pig genetic engineering is done in fetal fibroblasts that remain totipotent for only 3 to 5 wk. Nuclear donor cells that remain totipotent for longer periods of time would facilitate complicated genetic engineering in pigs. The goal of this study was to test the feasibility of using fetal liver-derived cells (FLDC) to perform gene targeting, and create a genetic knockout pig. FLDC were isolated and processed using a human liver stem cell protocol. Single copy α-1,3-galactosyl transferase knockout (GTKO) FLDCs were created using electroporation and neomycin resistant colonies were screened using PCR. Homozygous GTKO cells were created through loss of heterozygosity mutations in single GTKO FLDCs. Double GTKO FLDCs were used in somatic cell nuclear transfer (SCNT) to create GTKO pigs. FLDCs grew for more than 80 population doublings, maintaining normal karyotype. Gene targeting and loss of heterozygosity mutations produced homozygous GTKO FLDCs. FLDCs used in SCNT gave rise to homozygous GTKO pigs. FDLCs can be used in gene targeting and SCNT to produce genetically modified pigs. The increased life span in culture compared to fetal fibroblasts may facilitate genetic engineering in the pig. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. Hepatic stellate cell-targeted imatinib nanomedicine versus conventional imatinib: A novel strategy with potent efficacy in experimental liver fibrosis.

    Science.gov (United States)

    El-Mezayen, Nesrine S; El-Hadidy, Wessam F; El-Refaie, Wessam M; Shalaby, Th I; Khattab, Mahmoud M; El-Khatib, Aiman S

    2017-11-28

    Liver fibrosis is a global health problem without approved treatment. Imatinib inhibits two key profibrotic pathways; platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-β) and thus can be used to treat liver fibrosis. However, conventional imatinib therapy is hampered by low concentration at target tissue and increased toxicity to other tissues especially heart, lung and liver. Since hepatic stellate cells (HSCs) are the main contributors to liver fibrosis pathogenesis and sole hepatic vitamin A (V A ) storage cells, they can be actively targeted by coupling liposomes to V A . In this study, novel V A -coupled imatinib-loaded liposomes (ILC) were prepared and optimized regarding V A -coupling efficiency, imatinib entrapment efficiency, and particle size. Preferential accumulation of the selected formula in liver was proved by tracing intraperitoneally (i.p.)-injected V A -coupled liposomes loaded with Nile Red (LCNR) to rats with CCl 4 -induced liver fibrosis using live animal imaging. Co-localization of LCNR with immunofluorescently-labeled PDGFR-β in frozen liver tissue sections confirmed HSCs targeting. ILC bio-distribution, following single i.p. injection, revealed 13.5 folds higher hepatic accumulation than conventional imatinib in addition to limited bio-distribution to other organs including heart and lung reflecting diminished adverse effects. ILC therapy resulted in a potent inhibition of phosphorylated PDGFR-β expression when compared to conventional imatinib. Subsequently, there was a statistically significant improvement in liver function tests and reversal of hepatotoxicity along with liver fibrosis. Anti-fibrotic effect was evident from histopathologic Ishak score reduction as well as normalization of the level of profibrotic mediators (hydroxyproline, TGF-B and matrix metalloproteinase-2). Thus, HSC-targeted imatinib therapy shows outstanding anti-fibrotic effects with reduced cytotoxicity compared to conventional

  10. Liver-targeting of interferon-alpha with tissue-specific domain antibodies.

    Directory of Open Access Journals (Sweden)

    Edward Coulstock

    Full Text Available Interferon alpha (IFNα is used for the treatment of hepatitis C infection and whilst efficacious it is associated with multiple adverse events including reduced leukocyte, erythrocyte, and platelet counts, fatigue, and depression. These events are most likely caused by systemic exposure to interferon. We therefore hypothesise that targeting the therapeutic directly to the intended site of action in the liver would reduce exposure in blood and peripheral tissue and hence improve the safety and tolerability of IFNα therapy. We genetically fused IFN to a domain antibody (dAb specific to a hepatocyte restricted antigen, asialoglycoprotein receptor (ASGPR. Our results show that the murine IFNα2 homolog (mIFNα2 fused to an ASGPR specific dAb, termed DOM26h-196-61, could be expressed in mammalian tissue culture systems and retains the desirable biophysical properties and activity of both fusion partners when measured in vitro. Furthermore a clear increase in in vivo targeting of the liver by mIFNα2-ASGPR dAb fusion protein, compared to that observed with either unfused mIFNα2 or mIFNα2 fused to an isotype control dAb VHD2 (which does not bind ASGPR was demonstrated using microSPECT imaging. We suggest that these findings may be applicable in the development of a liver-targeted human IFN molecule with improved safety and patient compliance in comparison to the current standard of care, which could ultimately be used as a treatment for human hepatitis virus infections.

  11. Kit formulated asialoglycoprotein receptor targeting tracer based on copolymer for liver SPECT imaging

    International Nuclear Information System (INIS)

    Liu, Chang; Guo, Zhide; Zhang, Pu; Song, Manli; Zhao, Zuoquan; Wu, Xiaowei; Zhang, Xianzhong

    2014-01-01

    Introduction: Specific targeting of galactose-carrying molecule to ASGP-R in normal hepatocytes has been demonstrated before. In this study, galactosyl polystyrene was synthesized from controllable ratio of functional monomers and radio-labelled with 99m Tc by formulated kit for SPECT imaging of hepatic function. Methods: p(VLA-co-VNI)(46:54) was synthesized by free-radical copolymerization initiated by AIBN, purified by dialysis, lyophilized to kit with Tricine and TPPTS as co-ligands for 99m Tc labeling. Radiotracer 99m Tc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) was prepared and evaluated by in vitro stability, in vivo metabolism, ex vivo biodistribution and microSPECT/CT imaging in normal KM mice. MicroSPECT/CT and microMRI imaging were also performed in C57BL/b6 mice with xenograft hepatic carcinoma for hepatic function evaluation. Results: 99m Tc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) was obtained in high radio chemical purity (RCP) (> 99%) by using instant kit without further purification and excellent in vitro and in vivo stability. The result of biodistribution showed that liver had high uptake (90.49 ± 10.68 ID%/g) at 30 min after injection and was blocked significantly by cold copolymer. MicroSPECT imaging in normal KM mice at 1 h and 4 h after injection showed good liver retention and targeting properties. Significant defect of activity was observed in the tumor site which was confirmed by MRI imaging. Conclusion: 99m Tc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) with lower ratio of targeting moiety has no observable effect on the specific binding affinity and liver uptake. This makes it possible to introduce more imaging units for multi-modality imaging. Furthermore, the instant kit preparation of 99m Tc-labeling provides great potential for the evaluation of hepatocyte function in clinical application

  12. Multifunctional gadolinium-based dendritic macromolecules as liver targeting imaging probes.

    Science.gov (United States)

    Luo, Kui; Liu, Gang; He, Bin; Wu, Yao; Gong, Qingyong; Song, Bin; Ai, Hua; Gu, Zhongwei

    2011-04-01

    The quest for highly efficient and safe contrast agents has become the key factor for successful application of magnetic resonance imaging (MRI). The gadolinium (Gd) based dendritic macromolecules, with precise and tunable nanoscopic sizes, are excellent candidates as multivalent MRI probes. In this paper, a novel series of Gd-based multifunctional peptide dendritic probes (generation 2, 3, and 4) possessing highly controlled structures and single molecular weight were designed and prepared as liver MRI probes. These macromolecular Gd-ligand agents exhibited up to 3-fold increase in T(1) relaxivity comparing to Gd-DTPA complexes. No obvious in vitro cytotoxicity was observed from the measured concentrations. These dendritic probes were further functionalized with multiple galactosyl moieties and led to much higher cell uptake in vitro as demonstrated in T(1)-weighted scans. During in vivo animal studies, the probes provided better signal intensity (SI) enhancement in mouse liver, especially at 60 min post-injection, with the most efficient enhancement from the galactosyl moiety decorated third generation dendrimer. The imaging results were verified with analysis of Gd content in liver tissues. The design strategy of multifunctional Gd-ligand peptide dendritic macromolecules in this study may be used for developing other sensitive MRI probes with targeting capability. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. Targeting of superoxide dismutase to the liver results in anti-inflammatory effects in rats with fibrotic livers

    NARCIS (Netherlands)

    Swart, P J; Hirano, T; Kuipers, M E; Ito, Y; Smit, C; Hashida, M; Nishikawa, M; Beljaars, L; Meijer, D K; Poelstra, K

    1999-01-01

    Background/Aims: The rapid clearance from plasma and the limited uptake of superoxide dismutase (SOD) in the liver hampers the effectiveness of this enzyme in liver diseases. We therefore compared the pharmacokinetics and in vivo efficacy of SOD with two modified forms of this protein: SOD coupled

  14. Microinvasion of liver metastases from colorectal cancer: predictive factors and application for determining clinical target volume

    International Nuclear Information System (INIS)

    Qian, Yang; Zeng, Zhao-Chong; Ji, Yuan; Xiao, Yin-Ping

    2015-01-01

    This study evaluates the microscopic characteristics of liver metastases from colorectal cancer (LMCRC) invasion and provides a reference for expansion from gross tumor volume (GTV) to clinical targeting volume (CTV). Data from 129 LMCRC patients treated by surgical resection at our hospital between January 2008 and September 2009 were collected for study. Tissue sections used for pathology and clinical data were reviewed. Patient information used for the study included gender, age, original tumor site, number of tumors, tumor size, levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199), synchronous or metachronous liver metastases, and whether patients received chemotherapy. The distance of liver microinvasion from the tumor boundary was measured microscopically by two senior pathologists. Of 129 patients evaluated, 81 (62.8 %) presented microinvasion distances from the tumor boundary ranging between 1.0 − 7.0 mm. A GTV-to-CTV expansion of 5, 6.7, or 7.0 mm was required to provide a 95, 99, or 100 % probability, respectively, of obtaining clear resection margins by microscopic observation. The extent of invasion was not related to gender, age, synchronous or metachronous liver metastases, tumor size, CA199 level, or chemotherapy. The extent of invasion was related to original tumor site, CEA level, and number of tumors. A scoring system was established based on the latter three positive predictors. Using this system, an invasion distance less than 3 mm was measured in 93.4 % of patients with a score of ≤1 point, but in only 85.7 % of patients with a score of ≤2 points. The extent of tumor invasion in our LMCRC patient cohort correlated with original tumor site, CEA level, and number of tumors. These positive predictors may potentially be used as a scoring system for determining GTV-to-CTV expansion

  15. Target coverage in image-guided stereotactic body radiotherapy of liver tumors.

    Science.gov (United States)

    Wunderink, Wouter; Méndez Romero, Alejandra; Vásquez Osorio, Eliana M; de Boer, Hans C J; Brandwijk, René P; Levendag, Peter C; Heijmen, Ben J M

    2007-05-01

    To determine the effect of image-guided procedures (with computed tomography [CT] and electronic portal images before each treatment fraction) on target coverage in stereotactic body radiotherapy for liver patients using a stereotactic body frame (SBF) and abdominal compression. CT guidance was used to correct for day-to-day variations in the tumor's mean position in the SBF. By retrospectively evaluating 57 treatment sessions, tumor coverage, as obtained with the clinically applied CT-guided protocol, was compared with that of alternative procedures. The internal target volume-plus (ITV(+)) was introduced to explicitly include uncertainties in tumor delineations resulting from CT-imaging artifacts caused by residual respiratory motion. Tumor coverage was defined as the volume overlap of the ITV(+), derived from a tumor delineated in a treatment CT scan, and the planning target volume. Patient stability in the SBF, after acquisition of the treatment CT scan, was evaluated by measuring the displacement of the bony anatomy in the electronic portal images relative to CT. Application of our clinical protocol (with setup corrections following from manual measurements of the distances between the contours of the planning target volume and the daily clinical target volume in three orthogonal planes, multiple two-dimensional) increased the frequency of nearly full (> or = 99%) ITV(+) coverage to 77% compared with 63% without setup correction. An automated three-dimensional method further improved the frequency to 96%. Patient displacements in the SBF were generally small (design, patient stability in the SBF should be verified with portal imaging.

  16. Amelioration of liver injury by continuously targeted intervention against TNFRp55 in rats with acute-on-chronic liver failure.

    Directory of Open Access Journals (Sweden)

    Yumin Xu

    Full Text Available Acute-on-chronic liver failure (ACLF is an acute deterioration of established liver disease. Blocking the TNF (tumor necrosis factor/TNFR (tumor necrosis factor receptor 1 pathway may reduce hepatocyte apoptosis/necrosis, and subsequently decrease mortality during development of ACLF. We demonstrated that a long-acting TNF antagonist (soluble TNF receptor: IgG Fc [sTNFR:IgG-Fc] prevented/reduced development of acute liver failure by blocking the TNF/TNFR1 (TNFRp55 pathway. However, it is still unclear if sTNFR:IgG-Fc can inhibit hepatocyte damage during development of ACLF.Chronic liver disease (liver fibrosis/cirrhosis was induced in Wistar rats by repeatedly challenging with human serum albumin (HSA, and confirmed by histopathology. ACLF was induced with D-galactosamine (D-GalN/lipopolysaccharide (LPS i.p. in the rats with chronic liver disease. Serum and liver were collected for biochemical, pathological and molecular biological examinations.Reduced mortality was observed in sTNFR:IgG-Fc treated ACLF rats, consistent with reduced interleukin (IL-6 levels in serum and liver, as well as reduced hepatic caspase-3 activity, compared to that of mock treated group. Reduced hepatic damage was confirmed with histopathology in the sTNFR:IgG-Fc treated group, which is consistent with reduced Bcl-2 and Bax, at mRNA and protein levels, but increased hepatocyte proliferation (PCNA. This is also supported by the findings that caspase-3 production was up-regulated significantly in ACLF group compared to the mock treated group. Moreover, up-regulated caspase-3 was inhibited following sTNFR:IgG-Fc treatment. Finally, there was up-regulation of hepatic IL-22R in sTNFR:IgG-Fc treated ACLF rats.sTNFR:IgG-Fc improved survival rate during development of ACLF via ameliorating liver injury with a potential therapeutic value.

  17. Myofibroblast androgen receptor expression determines cell survival in co-cultures of myofibroblasts and prostate cancer cells in vitro.

    Science.gov (United States)

    Palethorpe, Helen M; Leach, Damien A; Need, Eleanor F; Drew, Paul A; Smith, Eric

    2018-04-10

    Fibroblasts express androgen receptor (AR) in the normal prostate and during prostate cancer development. We have reported that loss of AR expression in prostate cancer-associated fibroblasts is a poor prognostic indicator. Here we report outcomes of direct and indirect co-cultures of immortalised AR-positive (PShTert-AR) or AR-negative (PShTert) myofibroblasts with prostate cancer cells. In the initial co-cultures the AR-negative PC3 cell line was used so AR expression and signalling were restricted to the myofibroblasts. In both direct and indirect co-culture with PShTert-AR myofibroblasts, paracrine signalling to the PC3 cells slowed proliferation and induced apoptosis. In contrast, PC3 cells proliferated with PShTert myofibroblasts irrespective of the co-culture method. In direct co-culture PC3 cells induced apoptosis in and destroyed PShTerts by direct signalling. Similar results were seen in direct co-cultures with AR-negative DU145 and AR-positive LNCaP and C4-2B prostate cancer cell lines. The AR ligand 5α-dihydrotestosterone (DHT) inhibited the proliferation of the PShTert-AR myofibroblasts, thereby reducing the extent of their inhibitory effect on cancer cell growth. These results suggest loss of stromal AR would favour prostate cancer cell growth in vivo , providing an explanation for the clinical observation that reduced stromal AR is associated with a poorer outcome.

  18. [Myofibroblasts and afferent signalling in the urinary bladder. A concept].

    Science.gov (United States)

    Neuhaus, J; Scholler, U; Freick, K; Schwalenberg, T; Heinrich, M; Horn, L C; Stolzenburg, J U

    2008-09-01

    Afferent signal transduction in the urinary bladder is still not clearly understood. An increasing body of evidence supports the view of complex interactions between urothelium, suburothelial myofibroblasts, and sensory nerves. Bladder tissue from tumour patients was used in this study. Methods included confocal immunofluorescence, polymerase chain reaction, calcium imaging, and fluorescence recovery after photobleaching (FRAP).Myofibroblasts express muscarinic and purinergic receptors. They show constitutive spontaneous activity in calcium imaging, which completely depends on extracellular calcium. Stimulation with carbachol and ATP-evoked intracellular calcium transients also depend on extracellular calcium. The intensive coupling between the cells is significantly diminished by incubation with TGF-beta 1. Myofibroblasts form an important cellular element within the afferent signalling of the urinary bladder. They possess all features required to take part in the complex interactions with urothelial cells and sensory nerves. Modulation of their function by cytokines may provide a pathomechanism for bladder dysfunction.

  19. MiR-181b regulates steatosis in nonalcoholic fatty liver disease via targeting SIRT1.

    Science.gov (United States)

    Wang, Yunxia; Zhu, Kongxi; Yu, Weihua; Wang, Hongjuan; Liu, Lan; Wu, Qiong; Li, Shuai; Guo, Jianqiang

    2017-11-04

    Non-alcoholic fatty liver diseases (NAFLD) is one of the leading cause of chronic liver diseases in the world. However, the pathogenesis of NAFLD is still unclear. Emerging studies have demonstrated that microRNAs (miRs) are profoundly involved in NAFLD and related metabolic diseases. Here, we investigated the mechanisms by which miR-181b influences NAFLD via direct targeting SIRT1. The expression of miR181b was up-regulated while SIRT1 was down-regulated in both human NAFLD patients and high fat diet (HFD) induced NAFDL mice model. And palmitic acid (PA) treatment increased the miR-181b expression while decreased SIRT1 expression in HepG2 cells. Further, we identified that SIRT1 is a direct downstream target of miR-181b. Ectopic expression of miR-181b significantly repressed the 3'-UTR reporter activities of SIRT1 in a dose-dependent manner, while the effect of miR-181b was interrupted when the binding site of miR-181b within the SIRT1 3'-UTR was mutated. And overexpression of miR-181b reduced both the mRNA and protein levels of SIRT1 in HepG2 cells. We also found that inhibition of miR-181b expression alleviates hepatic steatosis both in vitro and in vivo. And the effect of miR-181b on steatosis was blocked by SIRT1 overexpression. Taken together, our data indicated that increased expression of miR-181b potentially contributes to altered lipid metabolism in NAFLD. Downregulation of miR-34a may be a therapeutic strategy against NAFLD by regulating its target SIRT1. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Kit formulated asialoglycoprotein receptor targeting tracer based on copolymer for liver SPECT imaging.

    Science.gov (United States)

    Liu, Chang; Guo, Zhide; Zhang, Pu; Song, Manli; Zhao, Zuoquan; Wu, Xiaowei; Zhang, Xianzhong

    2014-08-01

    Specific targeting of galactose-carrying molecule to ASGP-R in normal hepatocytes has been demonstrated before. In this study, galactosyl polystyrene was synthesized from controllable ratio of functional monomers and radio-labelled with (99m)Tc by formulated kit for SPECT imaging of hepatic function. p(VLA-co-VNI)(46:54) was synthesized by free-radical copolymerization initiated by AIBN, purified by dialysis, lyophilized to kit with Tricine and TPPTS as co-ligands for (99m)Tc labeling. Radiotracer (99m)Tc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) was prepared and evaluated by in vitro stability, in vivo metabolism, ex vivo biodistribution and microSPECT/CT imaging in normal KM mice. MicroSPECT/CT and microMRI imaging were also performed in C57BL/b6 mice with xenograft hepatic carcinoma for hepatic function evaluation. (99m)Tc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) was obtained in high radio chemical purity (RCP) (>99%) by using instant kit without further purification and excellent in vitro and in vivo stability. The result of biodistribution showed that liver had high uptake (90.49±10.68 ID%/g) at 30 min after injection and was blocked significantly by cold copolymer. MicroSPECT imaging in normal KM mice at 1h and 4h after injection showed good liver retention and targeting properties. Significant defect of activity was observed in the tumor site which was confirmed by MRI imaging. (99m)Tc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) with lower ratio of targeting moiety has no observable effect on the specific binding affinity and liver uptake. This makes it possible to introduce more imaging units for multi-modality imaging. Furthermore, the instant kit preparation of (99m)Tc-labeling provides great potential for the evaluation of hepatocyte function in clinical application. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. MicroRNAs and liver cancer associated with iron overload: Therapeutic targets unravelled

    Science.gov (United States)

    Greene, Catherine M; Varley, Robert B; Lawless, Matthew W

    2013-01-01

    Primary liver cancer is a global disease that is on the increase. Hepatocellular carcinoma (HCC) accounts for most primary liver cancers and has a notably low survival rate, largely attributable to late diagnosis, resistance to treatment, tumour recurrence and metastasis. MicroRNAs (miRNAs/miRs) are regulatory RNAs that modulate protein synthesis. miRNAs are involved in several biological and pathological processes including the development and progression of HCC. Given the poor outcomes with current HCC treatments, miRNAs represent an important new target for therapeutic intervention. Several studies have demonstrated their role in HCC development and progression. While many risk factors underlie the development of HCC, one process commonly altered is iron homeostasis. Iron overload occurs in several liver diseases associated with the development of HCC including Hepatitis C infection and the importance of miRNAs in iron homeostasis and hepatic iron overload is well characterised. Aberrant miRNA expression in hepatic fibrosis and injury response have been reported, as have dysregulated miRNA expression patterns affecting cell cycle progression, evasion of apoptosis, invasion and metastasis. In 2009, miR-26a delivery was shown to prevent HCC progression, highlighting its therapeutic potential. Several studies have since investigated the clinical potential of other miRNAs with one drug, Miravirsen, currently in phase II clinical trials. miRNAs also have potential as biomarkers for the diagnosis of HCC and to evaluate treatment efficacy. Ongoing studies and clinical trials suggest miRNA-based treatments and diagnostic methods will have novel clinical applications for HCC in the coming years, yielding improved HCC survival rates and patient outcomes. PMID:23983424

  2. Integrating respiratory-gated PET-based target volume delineation in liver SBRT planning, a pilot study

    International Nuclear Information System (INIS)

    Riou, Olivier; Thariat, Juliette; Serrano, Benjamin; Azria, David; Paulmier, Benoit; Villeneuve, Remy; Fenoglietto, Pascal; Artenie, Antonella; Ortholan, Cécile; Faraggi, Marc

    2014-01-01

    To assess the feasibility and benefit of integrating four-dimensional (4D) Positron Emission Tomography (PET) – computed tomography (CT) for liver stereotactic body radiation therapy (SBRT) planning. 8 patients with 14 metastases were accrued in the study. They all underwent a non-gated PET and a 4D PET centered on the liver. The same CT scan was used for attenuation correction, registration, and considered the planning CT for SBRT planning. Six PET phases were reconstructed for each 4D PET. By applying an individualized threshold to the 4D PET, a Biological Internal Target Volume (BITV) was generated for each lesion. A gated Planning Target Volume (PTVg) was created by adding 3 mm to account for set-up margins. This volume was compared to a manual Planning Target Volume (PTV) delineated with the help of a semi-automatic Biological Target Volume (BTV) obtained from the non-gated exam. A 5 mm radial and a 10 mm craniocaudal margins were applied to account for tumor motion and set-up margins to create the PTV. One undiagnosed liver metastasis was discovered thanks to the 4D PET. The semi-automatic BTV were significantly smaller than the BITV (p = 0.0031). However, after applying adapted margins, 4D PET allowed a statistically significant decrease in the PTVg as compared to the PTV (p = 0.0052). In comparison to non-gated PET, 4D PET may better define the respiratory movements of liver targets and improve SBRT planning for liver metastases. Furthermore, non respiratory-gated PET exams can both misdiagnose liver metastases and underestimate the real internal target volumes

  3. Target Coverage in Image-Guided Stereotactic Body Radiotherapy of Liver Tumors

    International Nuclear Information System (INIS)

    Wunderink, Wouter; Romero, Alejandra Mendez; Osorio, Eliana M. Vasquez; Boer, Hans C.J. de; Brandwijk, Rene P.; Levendag, Peter C.; Heijmen, Ben

    2007-01-01

    Purpose: To determine the effect of image-guided procedures (with computed tomography [CT] and electronic portal images before each treatment fraction) on target coverage in stereotactic body radiotherapy for liver patients using a stereotactic body frame (SBF) and abdominal compression. CT guidance was used to correct for day-to-day variations in the tumor's mean position in the SBF. Methods and Materials: By retrospectively evaluating 57 treatment sessions, tumor coverage, as obtained with the clinically applied CT-guided protocol, was compared with that of alternative procedures. The internal target volume-plus (ITV + ) was introduced to explicitly include uncertainties in tumor delineations resulting from CT-imaging artifacts caused by residual respiratory motion. Tumor coverage was defined as the volume overlap of the ITV + , derived from a tumor delineated in a treatment CT scan, and the planning target volume. Patient stability in the SBF, after acquisition of the treatment CT scan, was evaluated by measuring the displacement of the bony anatomy in the electronic portal images relative to CT. Results: Application of our clinical protocol (with setup corrections following from manual measurements of the distances between the contours of the planning target volume and the daily clinical target volume in three orthogonal planes, multiple two-dimensional) increased the frequency of nearly full (≥99%) ITV + coverage to 77% compared with 63% without setup correction. An automated three-dimensional method further improved the frequency to 96%. Patient displacements in the SBF were generally small (≤2 mm, 1 standard deviation), but large craniocaudal displacements (maximal 7.2 mm) were occasionally observed. Conclusion: Daily, CT-assisted patient setup may substantially improve tumor coverage, especially with the automated three-dimensional procedure. In the present treatment design, patient stability in the SBF should be verified with portal imaging

  4. Temporary presence of myofibroblasts in human elbow capsule after trauma

    NARCIS (Netherlands)

    Doornberg, Job N.; Bosse, Tjalling; Cohen, Mark S.; Jupiter, Jesse B.; Ring, David; Kloen, Peter

    2014-01-01

    Elbow stiffness is a common complication after elbow trauma. The elbow capsule is often thickened, fibrotic, and contracted at the time of surgical release. The limited studies available suggest that the capsule is contracted because of fibroblast-to-myofibroblast differentiation. We hypothesize

  5. Review article: the gut microbiome as a therapeutic target in the pathogenesis and treatment of chronic liver disease.

    Science.gov (United States)

    Woodhouse, C A; Patel, V C; Singanayagam, A; Shawcross, D L

    2018-01-01

    Mortality from chronic liver disease is rising exponentially. The liver is intimately linked to the gut via the portal vein, and exposure to gut microbiota and their metabolites translocating across the gut lumen may impact upon both the healthy and diseased liver. Modulation of gut microbiota could prove to be a potential therapeutic target. To characterise the changes in the gut microbiome that occur in chronic liver disease and to assess the impact of manipulation of the microbiome on the liver. We conducted a PubMed search using search terms including 'microbiome', 'liver' and 'cirrhosis' as well as 'non-alcoholic fatty liver disease', 'steatohepatitis', 'alcohol' and 'primary sclerosing cholangitis'. Relevant articles were also selected from references of articles and review of the ClinicalTrials.gov website. Reduced bacterial diversity, alcohol sensitivity and the development of gut dysbiosis are seen in several chronic liver diseases, including non-alcoholic fatty liver disease, alcohol-related liver disease and primary sclerosing cholangitis. Perturbations in gut commensals could lead to deficient priming of the immune system predisposing the development of immune-mediated diseases. Furthermore, transfer of stool from an animal with the metabolic syndrome may induce steatosis in a healthy counterpart. Patients with cirrhosis develop dysbiosis, small bowel bacterial overgrowth and increased gut wall permeability, allowing bacterial translocation and uptake of endotoxin inducing hepatic and systemic inflammation. Manipulation of the gut microbiota with diet, probiotics or faecal microbiota transplantation to promote the growth of "healthy" bacteria may ameliorate the dysbiosis and alter prognosis. © 2017 John Wiley & Sons Ltd.

  6. Stromal haze, myofibroblasts, and surface irregularity after PRK.

    Science.gov (United States)

    Netto, Marcelo V; Mohan, Rajiv R; Sinha, Sunilima; Sharma, Ajay; Dupps, William; Wilson, Steven E

    2006-05-01

    The aim of this study was to investigate the relationship between the level of stromal surface irregularity after photorefractive keratectomy (PRK) and myofibroblast generation along with the development of corneal haze. Variable levels of stromal surface irregularity were generated in rabbit corneas by positioning a fine mesh screen in the path of excimer laser during ablation for a variable percentage of the terminal pulses of the treatment for myopia that does not otherwise generate significant opacity. Ninety-six rabbits were divided into eight groups: [see table in text]. Slit lamp analysis and haze grading were performed in all groups. Rabbits were sacrificed at 4 hr or 4 weeks after surgery and histochemical analysis was performed on corneas for apoptosis (TUNEL assay), myofibroblast marker alpha-smooth muscle actin (SMA), and integrin alpha4 to delineate the epithelial basement membrane. Slit-lamp grading revealed severe haze formation in corneas in groups IV and VI, with significantly less haze in groups II, III, and VII and insignificant haze compared with the unwounded control in groups I and V. Analysis of SMA staining at 4 weeks after surgery, the approximate peak of haze formation in rabbits, revealed low myofibroblast formation in group I (1.2+/-0.2 cells/400x field) and group V (1.8+/-0.4), with significantly more in groups II (3.5+/-1.8), III (6.8+/-1.6), VII (7.9+/-3.8), IV (12.4+/-4.2) and VI (14.6+/-5.1). The screened groups were significantly different from each other (p PRK groups. The -9.0 diopter PRK group VI had significantly more myofibroblast generation than the -9.0 diopter PRK with PTK-smoothing group VII (p PRK and the level of stromal surface irregularity. PTK-smoothing with methylcellulose was an effective method to reduce stromal surface irregularity and decreased both haze and associated myofibroblast density. We hypothesize that stromal surface irregularity after PRK for high myopia results in defective basement membrane

  7. Liver-targeting Resibufogenin-loaded poly(lactic-co-glycolic acid-D-α-tocopheryl polyethylene glycol 1000 succinate nanoparticles for liver cancer therapy

    Directory of Open Access Journals (Sweden)

    Chu QC

    2016-01-01

    Full Text Available Qiuchen Chu,1,* Hong Xu,2,* Meng Gao,1 Xin Guan,1 Hongyan Liu,1 Sa Deng,1 Xiaokui Huo,1 Kexin Liu,1 Yan Tian,1 Xiaochi Ma1 1College of Pharmacy, 2College of Basic Medical Sciences, Dalian Medical University, Dalian, People’s Republic of China *These authors contributed equally to this work Abstract: Liver cancer remains a major problem around the world. Resibufogenin (RBG is a major bioactive compound that was isolated from Chansu (also called toad venom or toad poison, which is a popular traditional Chinese medicine that is obtained from the skin secretions of giant toads. RBG has strong antitumor effects, but its poor aqueous solubility and its cardiotoxicity have limited its clinical use. The aim of this study was to formulate RBG-loaded poly(lactic-co-glycolic acid (PLGA-D-α-tocopheryl polyethylene glycol 1000 succinate nanoparticle (RPTN to enhance the treatment of liver cancer. RPTN, RBG-loaded PLGA nanoparticle (RPN, and RBG/coumarin-6-loaded PLGA-D-α-tocopheryl polyethylene glycol 1000 succinate nanoparticle (RCPTN were prepared. The cellular uptake of RCPTN by HepG2 and HCa-F cells was analyzed using confocal laser scanning microscopy. Apoptosis was induced in HepG2 cells by RPTN, RBG solution (RS, and 5-fluorouracil solution (used as the negative controls, as assayed using flow cytometry. LD50 (median lethal dose values were determined for RS and RPTN, and the liver-targeting properties were determined for RCPTN in intravenously injected mice. A pharmacokinetic study was conducted in rats, and the in vivo therapeutic effects of RPTN, RPN, and RS were examined in a mouse tumor model. The results showed that RCPTN simultaneously delivered both coumarin-6 and RBG into HepG2 and HCa-F cells. The ratio of apoptotic cells was increased in the RPTN group. The LD50 for RPTN was 2.02-fold higher than the value for RS. Compared to RS, RPTN and RPN both showed a significant difference in vivo not only in the pharmacodynamic study but also in

  8. Liver fatty acid binding protein is the mitosis-associated polypeptide target of a carcinogen in rat hepatocytes

    International Nuclear Information System (INIS)

    Bassuk, J.A.; Tsichlis, P.N.; Sorof, S.

    1987-01-01

    Hepatocytes in normal rat liver were found previously to contain a cytoplasmic 14,000-dalton polypeptide (p14) that is associated with mitosis and is the principal early covalent target of activated metabolites of the carcinogen N-2-fluorenylacetamide (2-acetylaminofluorene). The level of immunohistochemically detected p14 was low when growth activity of hepatocytes was low, was markedly elevated during mitosis in normal and regenerating livers, but was very high throughout interphase during proliferation of hyperplastic and malignant hepatocytes induced in rat liver by a carcinogen (N-2-fluorenylacetamide or 3'-methyl-4-dimethylaminoazobenzene). The authors report here that p14 is the liver fatty acid binding protein. The nucleotide sequence of p14 cDNA clones, isolated by screening a rat liver cDNA library in bacteriophage λgt11 using p14 antiserum, was completely identical to part of the sequence reported for liver fatty acid binding protein. Furthermore, the two proteins shared the following properties: size of mRNA, amino acid composition, molecular size according to NaDodSO 4 gel electrophoresis, and electrophoretic mobilities in a Triton X-100/acetic acid/urea gel. The two polypeptides bound oleic acid similarly. Finally, identical elevations of cytoplasmic immunostain were detected specifically in mitotic hepatocytes with either antiserum. The collected findings are suggestive that liver fatty acid binding protein may carry ligands that promote hepatocyte division and may transport certain activated chemical carcinogens

  9. Targeting of liver tumour in rats by selective delivery of holmium-166 loaded microspheres: a biodistribution study

    Energy Technology Data Exchange (ETDEWEB)

    Nijsen, F.; Rook, D.; Zonnenberg, B.; Klerk, J. de; Rijk, P. van; Schip, F. van het [Dept. of Nuclear Medicine, University Medical Center, Utrecht (Netherlands); Brandt, C. [Animal Inst., Utrecht Univ. (Netherlands); Meijer, R. [Dept. of Radiology, Univ. Medical Center, Utrecht (Netherlands); Dullens, H. [Dept. of Pathology, Univ. Medical Center, Utrecht (Netherlands); Hennink, W. [Dept. of Pharmaceutics, Utrecht Univ. (Netherlands)

    2001-06-01

    Intra-arterial administration of beta-emitting particles that become trapped in the vascular bed of a tumour and remain there while delivering high doses, represents a unique approach in the treatment of both primary and metastatic liver tumours. Studies on selective internal radiation therapy of colorectal liver metastases using yttrium-90 glass microspheres have shown encouraging results. This study describes the biodistribution of 40-{mu}m poly lactic acid microspheres loaded with radioactive holmium-166, after intra-arterial administration into the hepatic artery of rats with implanted liver tumours. Radioactivity measurements showed >95% retention of injected activity in the liver and its resident tumour. The average activity detected in other tissues was {<=}0.1%ID/g, with incidental exceptions in the lungs and stomach. Very little {sup 166}Ho activity was detected in kidneys (<0.1%ID/g), thereby indicating the stability of the microspheres in vivo. Tumour targeting was very effective, with a mean tumour to liver ratio of 6.1{+-}2.9 for rats with tumour (n=15) versus 0.7{+-}0.5 for control rats (n=6; P<0.001). These ratios were not significantly affected by the use of adrenaline. Histological analysis showed that five times as many large (>10) and medium-sized (4-9) clusters of microspheres were present within tumour and peritumoural tissue, compared with normal liver. Single microspheres were equally dispersed throughout the tumour, as well as normal liver parenchyma. (orig.)

  10. Myofibroblasts and colonic anastomosis healing in Wistar rats

    Directory of Open Access Journals (Sweden)

    Vasiliadou Kalliopi

    2011-03-01

    Full Text Available Abstract Background The myofibroblasts play a central role in wound healing throughout the body. The process of wound healing in the colon was evaluated with emphasis on the role of myofibroblasts. Methods One hundred male Wistar rats weighing 274 ± 9.1 g (mean age: 3.5 months were used. A left colonic segment was transected and the colon was re-anastomosed. Animals were randomly divided into two groups. The first group experimental animals (n = 50 were sacrificed on postoperative day 3, while the second group rats (n = 50 were sacrificed on postoperative day 7. Healing of colonic anastomosis was studied in terms of anastomotic bursting pressure, as well as myofibroblastic reaction and expression of α-smooth muscle actin (α-SMA, adhesion formation, inflammatory reaction and neovascularization. Results The mean anastomotic bursting pressure increased from 20.6 ± 3.5 mmHg on the 3rd postoperative day to 148.8 ± 9.6 Hg on the 7th postoperative day. Adhesion formation was increased on the 7th day, as compared to the 3rd day. In addition, the myofibroblastic reaction was more profound on the 7th postoperative day in comparison with the 3rd postoperative day. The staining intensity for α-SMA was progressive from the 3rd to the 7th postoperative day. On the 7th day the α-SMA staining in the myofibroblats reached the level of muscular layer cells. Conclusions Our study emphasizes the pivotal role of myofibroblasts in the process of colonic anastomosis healing. The findings provide an explanation for the reduction in the incidence of wound dehiscence after the 7th postoperative day.

  11. CXC-type chemokines promote myofibroblast phenoconversion and prostatic fibrosis.

    Directory of Open Access Journals (Sweden)

    Mehrnaz Gharaee-Kermani

    Full Text Available Recent studies from our group suggest that extracellular matrix (ECM deposition and fibrosis characterize the peri-urethral prostate tissues of some men suffering from Lower Urinary Tract Symptoms (LUTS and that fibrosis may be a contributing factor to the etiology of LUTS. Fibrosis can generally be regarded as an errant wound-healing process in response to chronic inflammation, and several studies have shown that the aging prostate tissue microenvironment is rich with inflammatory cells and proteins. However, it is unclear whether these same inflammatory proteins, particularly CXC-type chemokines, can mediate myofibroblast phenoconversion and the ECM deposition necessary for the development of prostatic tissue fibrosis. To examine this, immortalized and primary prostate stromal fibroblasts treated with TGF-β1, CXCL5, CXCL8, or CXCL12 were evaluated morphologically by microscopy, by immunofluorescence and qRT-PCR for αSMA, collagen 1, vimentin, calponin, and tenascin protein and transcript expression, and by gel contraction assays for functional myofibroblast phenoconversion. The results of these studies showed that that immortalized and primary prostate stromal fibroblasts are induced to express collagen 1 and 3 and αSMA gene transcripts and proteins and to undergo complete and functional myofibroblast phenoconversion in response to CXC-type chemokines, even in the absence of exogenous TGF-β1. Moreover, CXCL12-mediated myofibroblast phenoconversion can be completely abrogated by inhibition of the CXCL12 receptor, CXCR4. These findings suggest that CXC-type chemokines, which comprise inflammatory proteins known to be highly expressed in the aging prostate, can efficiently and completely mediate myofibroblast phenoconversion and may thereby promote fibrotic changes in prostate tissue architecture associated with the development and progression of male lower urinary tract dysfunction.

  12. A simplified regimen of targeted antifungal prophylaxis in liver transplant recipients: A single-center experience.

    Science.gov (United States)

    Lavezzo, B; Patrono, D; Tandoi, F; Martini, S; Fop, F; Ballerini, V; Stratta, C; Skurzak, S; Lupo, F; Strignano, P; Donadio, P P; Salizzoni, M; Romagnoli, R; De Rosa, F G

    2018-04-01

    Invasive fungal infection (IFI) is a severe complication of liver transplantation burdened by high mortality. Guidelines recommend targeted rather than universal antifungal prophylaxis based on tiers of risk. We aimed to evaluate IFI incidence, risk factors, and outcome after implementation of a simplified two-tiered targeted prophylaxis regimen based on a single broad-spectrum antifungal drug (amphotericin B). Patients presenting 1 or more risk factors according to literature were administered prophylaxis. Prospectively collected data on all adult patients transplanted in Turin from January 2011 to December 2015 were reviewed. Patients re-transplanted before postoperative day 7 were considered once, yielding a study cohort of 581 cases. Prophylaxis was administered to 299 (51.4%) patients; adherence to protocol was 94.1%. Sixteen patients developed 18 IFIs for an overall rate of 2.8%. All IFI cases were in targeted prophylaxis group; none of the non-prophylaxis group developed IFI. Most cases (81.3%) presented within 30 days after transplantation during prophylaxis; predominant pathogens were molds (94.4%). Only 1 case of candidemia was observed. One-year mortality in IFI patients was 33.3% vs 6.4% in patients without IFI (P = .001); IFI attributable mortality was 6.3%. At multivariate analysis, significant risk factors for IFI were renal replacement therapy (OR = 8.1) and re-operation (OR = 5.2). The implementation of a simplified targeted prophylaxis regimen appeared to be safe and applicable and was associated with low IFI incidence and mortality. Association of IFI with re-operation and renal replacement therapy calls for further studies to identify optimal prophylaxis in this subset of patients. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Advances in ultrasound-targeted microbubble–mediated gene therapy for liver fibrosis

    OpenAIRE

    Huang, Cuiyuan; Zhang, Hong; Bai, Ruidan

    2017-01-01

    Hepatic fibrosis develops as a wound-healing scar in response to acute and chronic liver inflammation and can lead to cirrhosis in patients with chronic hepatitis B and C. The condition arises due to increased synthesis and reduced degradation of extracellular matrix (ECM) and is a common pathological sequela of chronic liver disease. Excessive deposition of ECM in the liver causes liver dysfunction, ascites, and eventually upper gastrointestinal bleeding as well as a series of complications....

  14. Silent information regulator 1 (SIRT1) ameliorates liver fibrosis via promoting activated stellate cell apoptosis and reversion

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Yuting, E-mail: wuyuting1302@sina.com; Liu, Xuejiao; Zhou, Qun; Huang, Cheng; Meng, Xiaoming; Xu, Fengyun; Li, Jun, E-mail: lj@ahmu.edu.cn

    2015-12-01

    SIRT1 (silent information regulator 1), a conserved NAD +-dependent histone deacetylase, is closely related with various biological processes. Moreover, the important role of SIRT1 in alcoholic liver disease, nonalcoholic fatty liver and HCC had been widely reported. Recently, a novel role of SIRT1 was uncovered in organ fibrosis diseases. Here, we investigated the inhibitory effect of SIRT1 in liver fibrogenesis. SIRT1 protein was dramatically decreased in CCl4-treated mice livers. Stimulation of LX-2 cells with TGF-β1 also resulted in a significant suppression of SIRT1 protein. Nevertheless, TGF-β1-induced LX-2 cell activation was inhibited by SIRT1 plasmid, and this was accompanied by up-regulation of cell apoptosis-related proteins. Overexpression of SIRT1 also attenuated TGF-β1-induced expression of myofibroblast markers α-SMA and COL1a. However, the important characteristic of the recovery of liver fibrosis is not only the apoptosis of activated stellate cells but also the reversal of the myofibroblast-like phenotype to a quiescent-like phenotype. Restoration of SIRT1 protein was observed in the in vivo spontaneously liver fibrosis reversion model and in vitro MDI (isobutylmethylxanthine, dexamethasone, and insulin)-induced reversed stellate cells, and forced expression of SIRT1 also promoted the reversal of activated stellate cells. Furthermore, lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) was increased in liver fibrosis. RNAi-mediated suppression of MALAT1 resulted in a decrease of myofibroblast markers and restoration of SIRT1 protein. These observations suggested that SIRT1 contributed to apoptosis and reversion of activated LX-2 cells and SIRT1 might be regulated by MALAT1 in liver fibrosis. Therefore, SIRT1 could be considered as a valuable therapeutic target for translational studies of liver fibrosis. - Highlights: • This is the first report of SIRT1 expression and function in liver fibrogenesis and reversion.

  15. Evaluation of potential internal target volume of liver tumors using cine-MRI.

    Science.gov (United States)

    Akino, Yuichi; Oh, Ryoong-Jin; Masai, Norihisa; Shiomi, Hiroya; Inoue, Toshihiko

    2014-11-01

    Four-dimensional computed tomography (4DCT) is widely used for evaluating moving tumors, including lung and liver cancers. For patients with unstable respiration, however, the 4DCT may not visualize tumor motion properly. High-speed magnetic resonance imaging (MRI) sequences (cine-MRI) permit direct visualization of respiratory motion of liver tumors without considering radiation dose exposure to patients. Here, the authors demonstrated a technique for evaluating internal target volume (ITV) with consideration of respiratory variation using cine-MRI. The authors retrospectively evaluated six patients who received stereotactic body radiotherapy (SBRT) to hepatocellular carcinoma. Before acquiring planning CT, sagittal and coronal cine-MRI images were acquired for 30 s with a frame rate of 2 frames/s. The patient immobilization was conducted under the same condition as SBRT. Planning CT images were then acquired within 15 min from cine-MRI image acquisitions, followed by a 4DCT scan. To calculate tumor motion, the motion vectors between two continuous frames of cine-MRI images were calculated for each frame using the pyramidal Lucas-Kanade method. The target contour was delineated on one frame, and each vertex of the contour was shifted and copied onto the following frame using neighboring motion vectors. 3D trajectory data were generated with the centroid of the contours on sagittal and coronal images. To evaluate the accuracy of the tracking method, the motion of clearly visible blood vessel was analyzed with the motion tracking and manual detection techniques. The target volume delineated on the 50% (end-exhale) phase of 4DCT was translated with the trajectory data, and the distribution of the occupancy probability of target volume was calculated as potential ITV (ITV Potential). The concordance between ITV Potential and ITV estimated with 4DCT (ITV 4DCT) was evaluated using the Dice's similarity coefficient (DSC). The distance between blood vessel positions

  16. Evaluation of potential internal target volume of liver tumors using cine-MRI

    Energy Technology Data Exchange (ETDEWEB)

    Akino, Yuichi, E-mail: akino@radonc.med.osaka-u.ac.jp [Department of Radiation Oncology, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan and Miyakojima IGRT Clinic, Miyakojima-ku, Osaka 5340021 (Japan); Oh, Ryoong-Jin; Masai, Norihisa; Shiomi, Hiroya; Inoue, Toshihiko [Miyakojima IGRT Clinic, Miyakojima-ku, Osaka 5340021 (Japan)

    2014-11-01

    Purpose: Four-dimensional computed tomography (4DCT) is widely used for evaluating moving tumors, including lung and liver cancers. For patients with unstable respiration, however, the 4DCT may not visualize tumor motion properly. High-speed magnetic resonance imaging (MRI) sequences (cine-MRI) permit direct visualization of respiratory motion of liver tumors without considering radiation dose exposure to patients. Here, the authors demonstrated a technique for evaluating internal target volume (ITV) with consideration of respiratory variation using cine-MRI. Methods: The authors retrospectively evaluated six patients who received stereotactic body radiotherapy (SBRT) to hepatocellular carcinoma. Before acquiring planning CT, sagittal and coronal cine-MRI images were acquired for 30 s with a frame rate of 2 frames/s. The patient immobilization was conducted under the same condition as SBRT. Planning CT images were then acquired within 15 min from cine-MRI image acquisitions, followed by a 4DCT scan. To calculate tumor motion, the motion vectors between two continuous frames of cine-MRI images were calculated for each frame using the pyramidal Lucas–Kanade method. The target contour was delineated on one frame, and each vertex of the contour was shifted and copied onto the following frame using neighboring motion vectors. 3D trajectory data were generated with the centroid of the contours on sagittal and coronal images. To evaluate the accuracy of the tracking method, the motion of clearly visible blood vessel was analyzed with the motion tracking and manual detection techniques. The target volume delineated on the 50% (end-exhale) phase of 4DCT was translated with the trajectory data, and the distribution of the occupancy probability of target volume was calculated as potential ITV (ITV {sub Potential}). The concordance between ITV {sub Potential} and ITV estimated with 4DCT (ITV {sub 4DCT}) was evaluated using the Dice’s similarity coefficient (DSC). Results

  17. Circulating MicroRNAs in Plasma of Hepatitis B e Antigen Positive Children Reveal Liver-Specific Target Genes

    DEFF Research Database (Denmark)

    Winther, Thilde Nordmann; Jacobsen, Kari Stougaard; Mirza, Aashiq Hussain

    2014-01-01

    Background and Aim. Hepatitis B e antigen positive (HBeAg-positive) children are at high risk of severe complications such as hepatocellular carcinoma and cirrhosis. Liver damage is caused by the host immune response to infected hepatocytes, and we hypothesise that specific microRNAs play a role...... in this complex interaction between virus and host. The study aimed to identify microRNAs with aberrant plasma expressions in HBeAg-positive children and with liver-specific target genes. Methods. By revisiting our previous screen of microRNA plasma levels in HBeAg-positive and HBeAg-negative children...... with chronic hepatitis B (CHB) and in healthy controls, candidate microRNAs with aberrant plasma expressions in HBeAg-positive children were identified. MicroRNAs targeting liver-specific genes were selected based on bioinformatics analysis and validated by qRT-PCR using plasma samples from 34 HBe...

  18. The hepatic stellate cell in sight : targeting antiproliferative drugs to the fibrotic liver

    NARCIS (Netherlands)

    Greupink, Albert Hendrikus

    2006-01-01

    Liver fibrosis is characterized by the accumulation of excessive amounts of scar tissue in response to chronic liver injury. Important causes of chronic liver injury are viral hepatitis, metabolic disorders such as Wilson’s disease, autoimmune diseases and chronic exposure to certain chemicals,

  19. A potential strategy to treat liver fibrosis : Drug targeting to hepatic stellate cells applying a novel linker technology

    NARCIS (Netherlands)

    Gonzalo Lázaro, Teresa

    2006-01-01

    Liver fibrosis is the 9th leading cause of death in the world. This chronic disease cannot be treated successfully with conventional antifibrotic and anti-inflammatory drugs currently on the market, because they either lack efficacy or cause too many side-effects. Targeting of antifibrotic agents to

  20. Interferon gamma peptidomimetic targeted to hepatic stellate cells ameliorates acute and chronic liver fibrosis in vivo.

    Science.gov (United States)

    Bansal, Ruchi; Prakash, Jai; De Ruiter, Marieke; Poelstra, Klaas

    2014-04-10

    Hepatic stellate cells play a crucial role in the pathogenesis of hepatic fibrosis. Thus, pharmacological inhibition of pro-fibrotic activities of these cells might lead to an effective therapy for this disease. Among the potent anti-fibrotics, interferon gamma (IFNγ), a proinflammatory cytokine, is highly efficacious but it failed in clinical trials due to the poor efficacy and multiple adverse effects attributed to the ubiquitous IFNγ receptor (IFNγR) expression. To resolve these drawbacks, we chemically synthesized a chimeric molecule containing (a) IFNγ signaling peptide (IFNγ peptidomimetic, mimγ) that retains the agonistic activities of IFNγ but lacks an extracellular receptor recognition sequence for IFNγR; coupled via heterobifunctional PEG linker to (b) bicyclic platelet derived growth factor beta receptor (PDGFβR)-binding peptide (BiPPB) to induce internalization into the stellate cells that express PDGFβR. The synthesized targeted IFNγ peptidomimetic (mimγ-BiPPB) was extensively investigated for its anti-fibrotic and adverse effects in acute and chronic CCl4-induced liver fibrosis models in mice. Treatment with mimγ-BiPPB, after the onset of disease, markedly inhibited both early and established hepatic fibrosis as reflected by a reduced intrahepatic α-SMA, desmin and collagen-I mRNA expression and protein levels. While untargeted mimγ and BiPPB had no effect, and native IFNγ only induced a moderate reduction. Additionally, no off-target effects, e.g. systemic inflammation, were found with mimγ-BiPPB, which were substantially observed in mice treated with native IFNγ. The present study highlights the beneficial effects of a novel BiPPB mediated cell-specific targeting of IFNγ peptidomimetic to the disease-inducing cells and therefore represents a highly potential therapeutic approach to treat fibrotic diseases. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Crosstalk Between Activated Myofibroblasts and β Cells in Injured Mouse Pancreas.

    Science.gov (United States)

    Bayan, Jennifer-Ann; Peng, Zhechu; Zeng, Ni; He, Lina; Chen, Jingyu; Stiles, Bangyan L

    2015-10-01

    In injury conditions, myofibroblasts are induced to lay down matrix proteins and support the repair process. In this study, we investigated the role of myofibroblasts, particularly stellate cells, in the growth and regeneration of pancreatic β cells. We used both in vitro and in vivo approaches to address whether stellate cells may promote the growth of β cells. Our experiments demonstrated that activated stellate cells support the proliferation of β cells in vitro. In vivo, mesenchymals surrounding the pancreatic islets are activated (induced to proliferate) in the islet regeneration model of Pten null mice. These mesenchymals display markers of pancreatic stellate cells, such as desmin and to a lesser extent, smooth muscle actin α. We have shown previously that targeted β-cell deletion of Pten lead to a significant increase in total islet mass. This phenotype was accompanied by an increase in peri-islet mitotic activity, particularly in islets injured by streptozotocin, a β cell-specific toxin. Together with the in vitro observations, our data, here, suggest that that these mesenchymal cells may support the regeneration of the islets. Identifying how the communication occurs may provide clinically relevant mechanism for inducing β-cell regeneration.

  2. Sialylation regulates myofibroblast differentiation of human skin fibroblasts.

    Science.gov (United States)

    Sasaki, Norihiko; Itakura, Yoko; Toyoda, Masashi

    2017-04-18

    Fibroblasts are key players in maintaining skin homeostasis and in orchestrating physiological tissue repair and skin regeneration. Dysfunctions in fibroblasts that occur with aging and the senescent process lead to the delayed healing observed in elderly people. The molecular mechanisms leading to fibroblast dysfunction during aging and the senescent process have not yet been clarified. Previously, changes in patterns of glycosylation were observed in fibroblasts in aging and the senescent process, but the effect of these changes on the function of fibroblasts has not been well documented. Here, we investigated whether changes in glycosylation during the process to senescence may have functional effects on fibroblasts. The changes in cell surface glycans on skin fibroblasts during the process to senescence were examined in early-passage (EP) and late-passage (LP) skin fibroblasts by fluorescence-activated cell sorting analysis using lectins. The contributors to the changes in cell surface glycans were examined by real-time polymerase chain reaction or Western blot analysis. The effects of changes in glycosylation on proliferation, migration, induction of cellular senescence, and myofibroblast differentiation induced by transforming growth factor (TGF)-β1 stimulation were examined in EP fibroblasts. The changes in glycosylation were performed by GalNAc-α-O-benzyl or sialidase treatment. A decrease in sialylation of glycoproteins and an increase in sialidase NEU1 were observed in LP fibroblasts. The reduction of sialylation did not have any effect on proliferation, migration, or induction of cellular senescence. On the other hand, myofibroblast differentiation was inhibited by the reduction of sialylation, indicating that sialylation is important for myofibroblast differentiation. The localization of CD44 in lipid rafts, which is required for myofibroblast differentiation, was inhibited by the reduction of sialylation. Furthermore, reduced myofibroblast

  3. Deletion of Gab2 in mice protects against hepatic steatosis and steatohepatitis: a novel therapeutic target for fatty liver disease.

    Science.gov (United States)

    Chen, Shuai; Kang, Yujia; Sun, Yan; Zhong, Yanhong; Li, Yanli; Deng, Lijuan; Tao, Jin; Li, Yang; Tian, Yingpu; Zhao, Yinan; Cheng, Jianghong; Liu, Wenjie; Feng, Gen-Sheng; Lu, Zhongxian

    2016-12-01

    Fatty liver disease is a serious health problem worldwide and is the most common cause for chronic liver disease and metabolic disorders. The major challenge in the prevention and intervention of this disease is the incomplete understanding of the underlying mechanism and thus lack of potent therapeutic targets due to multifaceted and interdependent disease factors. In this study, we investigated the role of a signaling adaptor protein, GRB2-associated-binding protein 2 (Gab2), in fatty liver using an animal disease model. Gab2 expression in hepatocytes responded to various disease factor stimulations, and Gab2 knockout mice exhibited resistance to fat-induced obesity, fat- or alcohol-stimulated hepatic steatosis, as well as methionine and choline deficiency-induced steatohepatitis. Concordantly, the forced expression or knockdown of Gab2 enhanced or diminished oleic acid (OA)- or ethanol-induced lipid production in hepatocytes in vitro, respectively. During lipid accumulation in hepatocytes, both fat and alcohol induced the recruitment of PI3K or Socs3 by Gab2 and the activation of their downstream signaling proteins AKT, ERK, and Stat3. Therefore, Gab2 may be a disease-associated protein that is induced by pathogenic factors to amplify and coordinate multifactor-induced signals to govern disease development in the liver. Our research provides a novel potential target for the prevention and intervention of fatty liver disease. © The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.

  4. Request of laboratory liver tests in primary care in Spain: potential savings if appropriateness indicator targets were achieved.

    Science.gov (United States)

    Salinas, Maria; López-Garrigós, Maite; Flores, Emilio; Uris, Joaquín; Leiva-Salinas, Carlos

    2015-10-01

    Liver laboratory tests are used to screen for liver disease, suggest the underlying cause, estimate the severity, assess prognosis, and monitor the efficacy of therapy. The aim of this study was to compare the liver laboratory tests requesting patterns by GPs in Spain, according to geographic and hospital characteristics, to investigate the degree of requesting appropriateness. One hundred and forty-one clinical laboratories were invited to participate from diverse regions across Spain. They filed out the number of laboratory liver tests requested by GPs for the year 2012. Two types of appropriateness indicators were calculated: every test request per 1000 inhabitants or ratios of related tests requests. The indicator results obtained were compared between the different hospitals, according to their setting, location, and management. The savings generated, if each area would have achieved indicator targets, were calculated. We recruited 76 laboratories covering a population of 17,679,195 inhabitants. GPs requested 20,916,780 laboratory liver tests in the year 2012. No differences were obtained according to their setting. Lactate dehydrogenase and direct bilirubin per 1000 inhabitants were significantly higher in institutions with private management. Largest differences were observed between communities. Nine, 31, 0, and 13 laboratories, respectively, achieved the aspartate aminotransferase, lactate dehydrogenase, γ-glutamyl transpeptidase, and total bilirubin-related alanine aminotransferase indicator targets. Reaching ratios would have resulted in savings of €1,028,468. There was a high variability in the request of liver tests. This emphasizes the need to implement interventions to improve appropriate use of liver tests.

  5. Inflammatory myofibroblastic tumor of inguinal lymph nodes, simulating lymphoma

    Directory of Open Access Journals (Sweden)

    Akansha Gandhi

    2015-01-01

    Full Text Available Multiple enlarged lymph nodes in an elderly female patient can have varied etiologies as well as histologic pictures. We are presenting the case of a 53-year-old female who presented with inguinal lymphadenopathy with fever, which was clinically misconstrued as lymphoma. Cytology could not exclude a lymphoma. Histology led to the unusual diagnosis of inflammatory myofibroblastic tumor of lymph node in this case. Inflammatory myofibroblastic tumor of the lymph node is a rare, distinctive reactive proliferative pattern in the lymph node which involves proliferation of the connective tissue elements of the lymph node, admixed with lymphocytes, plasma cells, eosinophils, and histiocytes. Multiple etiologic agents have been suggested in existing literature. Despite extensive search, no definite attributable cause could be sought. It is now widely accepted that inflammatory pseudotumor of the lymph node is a non-neoplastic proliferation which has a benign clinical course and excellent prognosis after surgical resection.

  6. The postnatal growth of ICRP target organs in reference humans: Spleen and liver

    International Nuclear Information System (INIS)

    Walker, J.T.

    1989-01-01

    Attempts to improve radiation dose estimates to infants and children are hampered because of the lack of mathematical models that describe the age variation in anatomical and physiological parameters. Specifically, for one anatomical parameter, organ size, there are no growth models available to the health physics community. In this paper, an empirical mathematical model is introduced for estimating age-specific masses of two ICRP target organs: the spleen and liver. That model, the Power Logistic Additive (PLA) growth model, is fitted to ICRP 23 organ growth data to determine five growth parameters. This model assumes that organs grow under the influence of two main processes: a primary (power function) and a sexual maturation (logistic function) process, which are additive from birth to adulthood. The results show that the model describes the ICRP growth data quite well. Growth parameters and tables listing the predicted masses and mass velocities as a function of age for each organ are provided for application in the ICRP modeling system

  7. Inflammation: A novel target of current therapies for hepatic encephalopathy in liver cirrhosis.

    Science.gov (United States)

    Luo, Ming; Guo, Jian-Yang; Cao, Wu-Kui

    2015-11-07

    Hepatic encephalopathy (HE) is a severe neuropsychiatric syndrome that most commonly occurs in decompensated liver cirrhosis and incorporates a spectrum of manifestations that ranges from mild cognitive impairment to coma. Although the etiology of HE is not completely understood, it is believed that multiple underlying mechanisms are involved in the pathogenesis of HE, and one of the main factors is thought to be ammonia; however, the ammonia hypothesis in the pathogenesis of HE is incomplete. Recently, it has been increasingly demonstrated that inflammation, including systemic inflammation, neuroinflammation and endotoxemia, acts in concert with ammonia in the pathogenesis of HE in cirrhotic patients. Meanwhile, a good number of studies have found that current therapies for HE, such as lactulose, rifaximin, probiotics and the molecular adsorbent recirculating system, could inhibit different types of inflammation, thereby improving the neuropsychiatric manifestations and preventing the progression of HE in cirrhotic patients. The anti-inflammatory effects of these current therapies provide a novel therapeutic approach for cirrhotic patients with HE. The purpose of this review is to describe the inflammatory mechanisms behind the etiology of HE in cirrhosis and discuss the current therapies that target the inflammatory pathogenesis of HE.

  8. Liver fat: a relevant target for dietary intervention? Summary of a Unilever workshop.

    Science.gov (United States)

    Peters, Harry P F; Schrauwen, Patrick; Verhoef, Petra; Byrne, Christopher D; Mela, David J; Pfeiffer, Andreas F H; Risérus, Ulf; Rosendaal, Frits R; Schrauwen-Hinderling, Vera

    2017-01-01

    Currently it is estimated that about 1 billion people globally have non-alcoholic fatty liver disease (NAFLD), a condition in which liver fat exceeds 5 % of liver weight in the absence of significant alcohol intake. Due to the central role of the liver in metabolism, the prevalence of NAFLD is increasing in parallel with the prevalence of obesity, insulin resistance and other risk factors of metabolic diseases. However, the contribution of liver fat to the risk of type 2 diabetes mellitus and CVD, relative to other ectopic fat depots and to other risk markers, is unclear. Various studies have suggested that the accumulation of liver fat can be reduced or prevented via dietary changes. However, the amount of liver fat reduction that would be physiologically relevant, and the timeframes and dose-effect relationships for achieving this through different diet-based approaches, are unclear. Also, it is still uncertain whether the changes in liver fat per se or the associated metabolic changes are relevant. Furthermore, the methods available to measure liver fat, or even individual fatty acids, differ in sensitivity and reliability. The present report summarises key messages of presentations from different experts and related discussions from a workshop intended to capture current views and research gaps relating to the points above.

  9. Podoplanin-positive myofibroblasts: a pathological hallmark of pleuroparenchymal fibroelastosis.

    Science.gov (United States)

    Enomoto, Yasunori; Matsushima, Sayomi; Meguro, Shiori; Kawasaki, Hideya; Kosugi, Isao; Fujisawa, Tomoyuki; Enomoto, Noriyuki; Inui, Naoki; Nakamura, Yutaro; Suda, Takafumi; Iwashita, Toshihide

    2018-02-22

    Pathological differential diagnoses of pleuroparenchymal fibroelastosis (PPFE) include usual interstitial pneumonia (UIP) and pulmonary apical cap (PAC); however, there are no specific immunostaining makers to distinguish between these diseases. We performed immunohistochemistry using several pleural mesothelial cell-related markers, including cytokeratin-5/6, CAM5.2, WT-1, calretinin, desmin and podoplanin, for PPFE (n = 4), UIP (n = 10) and PAC (n = 3) lung sections. Among the examined markers, in PPFE and PAC lungs podoplanin commonly showed positivity for spindle cells both in thickened pleura and subpleural fibroelastosis lesions; these cells were also stained with α-smooth muscle actin, a marker of myofibroblasts. However, even in elastic fibre-rich cases, UIP lungs did not show such podoplanin-positive myofibroblasts in pleura/subpleura and fibroblastic foci. These findings were also verified using immunofluorescence. By contrast, immunohistochemically as well as morphologically, the difference between PPFE and PAC was not apparent. The presence of podoplanin-positive myofibroblasts could be a pathological hallmark of PPFE, suggesting a pathogenic process distinct from UIP but common to PAC. © 2018 John Wiley & Sons Ltd.

  10. Targeting CCl4 -induced liver fibrosis by RNA interference-mediated inhibition of cyclin E1 in mice.

    Science.gov (United States)

    Bangen, Jörg-Martin; Hammerich, Linda; Sonntag, Roland; Baues, Maike; Haas, Ute; Lambertz, Daniela; Longerich, Thomas; Lammers, Twan; Tacke, Frank; Trautwein, Christian; Liedtke, Christian

    2017-10-01

    Initiation and progression of liver fibrosis requires proliferation and activation of resting hepatic stellate cells (HSCs). Cyclin E1 (CcnE1) is the regulatory subunit of the cyclin-dependent kinase 2 (Cdk2) and controls cell cycle re-entry. We have recently shown that genetic inactivation of CcnE1 prevents activation, proliferation, and survival of HSCs and protects from liver fibrogenesis. The aim of the present study was to translate these findings into preclinical applications using an RNA interference (RNAi)-based approach. CcnE1-siRNA (small interfering RNA) efficiently inhibited CcnE1 gene expression in murine and human HSC cell lines and in primary HSCs, resulting in diminished proliferation and increased cell death. In C57BL/6 wild-type (WT) mice, delivery of stabilized siRNA using a liposome-based carrier targeted approximately 95% of HSCs, 70% of hepatocytes, and 40% of CD45 + cells after single injection. Acute CCl 4 -mediated liver injury in WT mice induced endogenous CcnE1 expression and proliferation of surviving hepatocytes and nonparenchymal cells, including CD45 + leukocytes. Pretreatment with CcnE1-siRNA reverted CcnE1 induction to baseline levels of healthy mice, which was associated with reduced liver injury, diminished proliferation of hepatocytes and leukocytes, and attenuated overall inflammatory response. For induction of liver fibrosis, WT mice were challenged with CCl 4 for 4-6 weeks. Co-treatment with CcnE1-siRNA once a week was sufficient to continuously block CcnE1 expression and cell-cycle activity of hepatocytes and nonparenchymal cells, resulting in significantly ameliorated liver fibrosis and inflammation. Importantly, CcnE1-siRNA also prevented progression of liver fibrosis if applied after onset of chronic liver injury. Therapeutic targeting of CcnE1 in vivo using RNAi is feasible and has high antifibrotic activity. (Hepatology 2017;66:1242-1257). © 2017 by the American Association for the Study of Liver Diseases.

  11. Novel Antibody Targets Glypican-3 in Liver Cancer | Center for Cancer Research

    Science.gov (United States)

    New treatments for patients with liver cancer, the third most common cause of cancer-related death, are desperately needed. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and HCC tumors are particularly insensitive to chemotherapy. Surgery is the standard treatment for HCCs caught early, but only about a third of cases are identified at this stage. Antibody therapy offers a potential alternative for treating later-stage tumors.

  12. Targeted hepatic sonography during clinic visits for detection of fatty liver in overweight children: a pilot study.

    Science.gov (United States)

    Perito, Emily R; Tsai, Patrika M; Hawley, Sarah; Lustig, Robert H; Feldstein, Vickie A

    2013-04-01

    The purpose of this study was to assess the feasibility and utility of targeted hepatic sonography to evaluate for hepatic steatosis during a subspecialty clinic visit. In this pilot study, we performed targeted hepatic sonography on 25 overweight children aged 7 to 17 years consecutively seen in a pediatric obesity clinic. Long-axis images of the right lobe of the liver and a split-screen image of liver and spleen were taken. Images were interpreted in real time by the radiologist and shown to the family. Demographics, clinical measurements, and laboratory parameters were also collected from the specialty clinic visit on the same day. Sonography required a median of 4 minutes during the visit (interquartile range, 3-5 minutes). All consented patients completed the study. The median alanine aminotransferase (ALT) level was 23 U/L in those with no steatosis (n = 14), 26 U/L with mild steatosis (n = 6), and 41 U/L with moderate/marked steatosis (n = 5). Children with ALT levels of 25 to 50 U/L had very variable sonographic measures of hepatic steatosis. When the participants were categorized by the overall degree of fatty liver, hepatic steatosis was significantly associated with the aspartate aminotransferase level (P = .028), ALT level (P = .003), and diastolic blood pressure (P = .05) but did not correlate with age, sex, Latino race, or insulin resistance. Targeted hepatic sonography added information not apparent from routine ALT screening and provided immediate feedback to clinicians and families about the effect of obesity on end organs. This examination could be a feasible, informative addition to screening for children at high risk for nonalcoholic fatty liver disease who are seen in clinics that specialize in obesity.

  13. EGF-R is Expressed and AP-1 and NF-κ:B Are Activated in Stromal Myofibroblasts Surrounding Colon Adenocarcinomas Paralleling Expression of COX-2 and VEGF

    Directory of Open Access Journals (Sweden)

    Panagiotis A. Konstantinopoulos

    2007-01-01

    Full Text Available Background: COX-2 and VEGF are important triggers of colon cancer growth, metastasis and angiogenesis. Cox-2 promoter contains transcriptional regulatory elements for AP-1 and NF-κ:B transcription factors whilst vegf is a known AP-1 downstream target gene. We investigated whether stromal myofibroblasts surrounding colon adenocarcinomas express COX-2 and VEGF and whether activation of AP-1 and NF-κ:B, as well as expression of EGF-R parallel expression of COX-2 and VEGF in these cells. Methods: Immunohistochemical methodology was performed on archival sections from 40 patients with colon adenocarcinomas. We evaluated c-FOS, p-c-JUN (phosphorylated c-JUN, p-Iκ:B-α (phosphorylated Iκ:B-α, EGF-R, COX-2, NF-κ:B and VEGF expression in stromal myofibroblasts surrounding colon adenocarcinomas. Double immunostaining with a-smooth muscle actin and each antibody was done to verify the expression of these molecules in stromal myofibroblasts. Results: VEGF, p-Iκ:B-α, NF-κ:B, c-FOS, p-c-JUN, EGF-R and COX-2 were expressed in stromal myofibroblasts surrounding colon adenocarcinomas in the majority of cases. EGF-R, p-Iκ:B-α, NF-κ:B, c-FOS and p-c-JUN correlated positively with COX-2 and VEGF expression. Conclusion: Stromal myofibroblasts surrounding colon adenocarcinomas are an important source of VEGF and COX-2 production, while AP-1 and NF-κ:B transcription factors are activated and EGF-R is expressed in these cells and associated with COX-2 and VEGF production.

  14. SU-F-T-644: Reproducibility of Target Position Using Moderate Voluntary Breath- Hold During Liver Stereotactic Ablative Radiotherapy

    International Nuclear Information System (INIS)

    Cui, G; Trakul, N; Chang, E; Shiu, A

    2016-01-01

    Purpose: To evaluate the reproducibility of target position using moderate voluntary breath-hold during liver stereotactic ablative radiotherapy (SABR). Methods: Two patients who underwent liver SABR on a Varian TrueBeam STx linac were used for this study. Fiducial markers were placed in and around the target in the liver as surrogates for the target position and motion. GTVs were contoured by assessing tumor extent on contrast enhanced CT. The PTV was created from the GTV by adding 2 mm margins to account for the residual motion during breath-holds. A portable biofeedback system was used to facilitate the breath-hold to a reproducible position. The Varian RPM system was used for gating the linac. Proceeding each treatment, orthogonal kV pairs were taken, and alignment to nearby bony anatomy was performed. Then the breath-hold CBCT was acquired to align the fiducial markers. On-line fluoroscopy was used to fine-tune the breath-hold gating thresholds to correlate with the positions of the fiducial markers. The inter-fraction reproducibility of the target was evaluated by the offsets of the daily breath-hold CBCTs from the paired kV matches as a direct measure of the target position relative to the bony anatomy. The intra-fraction reproducibility of the target position was assessed by the gated window of the RPM marker block for each fraction. Results: The absolute mean offsets between the CBCT and paired kV matches in the vertical, longitudinal, and lateral directions were 0.06 cm, 0.10 cm, and 0.06 cm for patient 1, and 0.37 cm, 0.62 cm, and 0.09 cm for patient 2. The gated window of the RPM marker block for the breath-hold for each fraction was within 0.63 ± 0.16 cm and 0.59 ± 0.12 cm for patients 1 and 2, respectively. Conclusion: Moderate voluntary breath-hold showed good inter- and intra-fraction reproducibility of target position during liver SABR.

  15. SU-F-T-644: Reproducibility of Target Position Using Moderate Voluntary Breath- Hold During Liver Stereotactic Ablative Radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Cui, G; Trakul, N; Chang, E; Shiu, A [University Southern California, Los Angeles, CA (United States)

    2016-06-15

    Purpose: To evaluate the reproducibility of target position using moderate voluntary breath-hold during liver stereotactic ablative radiotherapy (SABR). Methods: Two patients who underwent liver SABR on a Varian TrueBeam STx linac were used for this study. Fiducial markers were placed in and around the target in the liver as surrogates for the target position and motion. GTVs were contoured by assessing tumor extent on contrast enhanced CT. The PTV was created from the GTV by adding 2 mm margins to account for the residual motion during breath-holds. A portable biofeedback system was used to facilitate the breath-hold to a reproducible position. The Varian RPM system was used for gating the linac. Proceeding each treatment, orthogonal kV pairs were taken, and alignment to nearby bony anatomy was performed. Then the breath-hold CBCT was acquired to align the fiducial markers. On-line fluoroscopy was used to fine-tune the breath-hold gating thresholds to correlate with the positions of the fiducial markers. The inter-fraction reproducibility of the target was evaluated by the offsets of the daily breath-hold CBCTs from the paired kV matches as a direct measure of the target position relative to the bony anatomy. The intra-fraction reproducibility of the target position was assessed by the gated window of the RPM marker block for each fraction. Results: The absolute mean offsets between the CBCT and paired kV matches in the vertical, longitudinal, and lateral directions were 0.06 cm, 0.10 cm, and 0.06 cm for patient 1, and 0.37 cm, 0.62 cm, and 0.09 cm for patient 2. The gated window of the RPM marker block for the breath-hold for each fraction was within 0.63 ± 0.16 cm and 0.59 ± 0.12 cm for patients 1 and 2, respectively. Conclusion: Moderate voluntary breath-hold showed good inter- and intra-fraction reproducibility of target position during liver SABR.

  16. Mitochondria As the Target for the Modulatory Effect of Curcumin in Oxaliplatin-induced Toxicity in Isolated Rat Liver Mitochondria.

    Science.gov (United States)

    Waseem, Mohammad; Parvez, Suhel; Tabassum, Heena

    2017-01-01

    To explore hepatoprotective action of curcumin (CMN, a bioflavonoid) on oxaliplatin (Oxa)-triggered mitochondrial oxidative stress and respiratory chain complexes in liver of rats. Oxa is a ubiquitously utilized platinum-based chemotherapeutic agent commonly used for the treatment of colorectal cancer. Mitochondria have recently emerged as targets for anticancer drugs in several kinds of toxicity including hepatotoxicity that can lead to neoplastic disease. There is a dearth of evidence involving the role of mitochondria in mediating Oxa-evoked hepatotoxicity and its underlying mechanism is still debatable. The study was performed in mitochondria isolated from liver of Wistar rats. Oxa (200 μg/mL) and CMN (5 μmol) were incubated under in vitro conditions. Oxa evoked a significant increase in the membrane lipid peroxidation (LPO) levels, protein carbonyl (PC) contents, decrease in reduced glutathione (GSH) and nonprotein thiol (NP-SH) levels. Oxa also caused a marked decline in the activities of enzymatic antioxidants and respiratory chain enzymes (I, II, III and V) in liver mitochondria. CMN pre-treatment significantly prevented the activities of enzymatic antioxidants and mitochondrial respiratory chain enzymes. CMN also restored the LPO and PC contents, GSH and NP-SH levels in liver mitochondria. CMN intake might be effective in regulation of Oxa-evoked mitotoxicity during chemotherapy. Moreover, it is included in the armamentarium for anticancer agent-induced oxidative stress. Copyright © 2017 IMSS. Published by Elsevier Inc. All rights reserved.

  17. Ischemic preconditioning protects against gap junctional uncoupling in cardiac myofibroblasts.

    Science.gov (United States)

    Sundset, Rune; Cooper, Marie; Mikalsen, Svein-Ole; Ytrehus, Kirsti

    2004-01-01

    Ischemic preconditioning increases the heart's tolerance to a subsequent longer ischemic period. The purpose of this study was to investigate the role of gap junction communication in simulated preconditioning in cultured neonatal rat cardiac myofibroblasts. Gap junctional intercellular communication was assessed by Lucifer yellow dye transfer. Preconditioning preserved intercellular coupling after prolonged ischemia. An initial reduction in coupling in response to the preconditioning stimulus was also observed. This may protect neighboring cells from damaging substances produced during subsequent regional ischemia in vivo, and may preserve gap junctional communication required for enhanced functional recovery during subsequent reperfusion.

  18. Magnetic targeting of iron-oxide-labeled fluorescent hepatoma cells to the liver

    Energy Technology Data Exchange (ETDEWEB)

    Luciani, Alain [Universite Rene Descartes, Hopital Europeen Georges Pompidou, Laboratoire de Recherche en Imagerie, EA 4062, Paris (France); Imagerie Medicale, Faculte de Medecine Paris XII, CHU Henri Mondor, Creteil cedex (France); Wilhelm, Claire; Gazeau, Florence [Universite Paris Diderot, Batiment Condorcet, Laboratoire Matiere et Systemes Complexes, CNRS-UMR 7057, Paris Cedex (France); Bruneval, Patrick [Anatomopathologie, Hopital Europeen Georges Pompidou, Paris (France); Cunin, Patrick [Unite de Recherche Clinique, Faculte de Medecine Paris XII, CHU Henri Mondor, Creteil cedex (France); Autret, Gwennhael; Clement, Olivier [Universite Rene Descartes, Hopital Europeen Georges Pompidou, Laboratoire de Recherche en Imagerie, EA 4062, Paris (France); Rahmouni, Alain [Imagerie Medicale, Faculte de Medecine Paris XII, CHU Henri Mondor, Creteil cedex (France)

    2009-05-15

    The purpose of this study was to determine whether an external magnet field can induce preferential trafficking of magnetically labeled Huh7 hepatoma cells to the liver following liver cell transplantation. Huh7 hepatoma cells were labeled with anionic magnetic nanoparticles (AMNP) and tagged with a fluorescent membrane marker (PKH67). Iron-uptake was measured by magnetophoresis. Twenty C57Bl6 mice received an intrasplenic injection of 2 x 10{sup 6} labeled cells. An external magnet (0.29 T; 25 T/m) was placed over the liver of 13 randomly selected animals (magnet group), while the remaining 7 animals served as controls. MRI (1.5 T) and confocal fluorescence microscopy (CFM) were performed 10 days post-transplantation. The presence and location of labeled cells within the livers were compared in the magnet group and controls, and confronted with histological analysis representing the standard of reference. Mean iron content per cell was 6 pg. Based on histology, labeled cells were more frequently present within recipient livers in the magnet group (p < 0.01) where their distribution was preferentially peri-vascular (p<0.05). MRI and CFM gave similar results for the overall detection of transplanted cells (kappa=0.828) and for the identification of peri-vascular cells (kappa=0.78). Application of an external magnet can modify the trafficking of transplanted cells, especially by promoting the formation of perivascular aggregates. (orig.)

  19. Magnetic targeting of iron-oxide-labeled fluorescent hepatoma cells to the liver

    International Nuclear Information System (INIS)

    Luciani, Alain; Wilhelm, Claire; Gazeau, Florence; Bruneval, Patrick; Cunin, Patrick; Autret, Gwennhael; Clement, Olivier; Rahmouni, Alain

    2009-01-01

    The purpose of this study was to determine whether an external magnet field can induce preferential trafficking of magnetically labeled Huh7 hepatoma cells to the liver following liver cell transplantation. Huh7 hepatoma cells were labeled with anionic magnetic nanoparticles (AMNP) and tagged with a fluorescent membrane marker (PKH67). Iron-uptake was measured by magnetophoresis. Twenty C57Bl6 mice received an intrasplenic injection of 2 x 10 6 labeled cells. An external magnet (0.29 T; 25 T/m) was placed over the liver of 13 randomly selected animals (magnet group), while the remaining 7 animals served as controls. MRI (1.5 T) and confocal fluorescence microscopy (CFM) were performed 10 days post-transplantation. The presence and location of labeled cells within the livers were compared in the magnet group and controls, and confronted with histological analysis representing the standard of reference. Mean iron content per cell was 6 pg. Based on histology, labeled cells were more frequently present within recipient livers in the magnet group (p < 0.01) where their distribution was preferentially peri-vascular (p<0.05). MRI and CFM gave similar results for the overall detection of transplanted cells (kappa=0.828) and for the identification of peri-vascular cells (kappa=0.78). Application of an external magnet can modify the trafficking of transplanted cells, especially by promoting the formation of perivascular aggregates. (orig.)

  20. Gene targeted therapeutics for liver disease in alpha-1 antitrypsin deficiency.

    LENUS (Irish Health Repository)

    McLean, Caitriona

    2009-01-01

    Alpha-1 antitrypsin (A1AT) is a 52 kDa serine protease inhibitor that is synthesized in and secreted from the liver. Although it is present in all tissues in the body the present consensus is that its main role is to inhibit neutrophil elastase in the lung. A1AT deficiency occurs due to mutations of the A1AT gene that reduce serum A1AT levels to <35% of normal. The most clinically significant form of A1AT deficiency is caused by the Z mutation (Glu342Lys). ZA1AT polymerizes in the endoplasmic reticulum of liver cells and the resulting accumulation of the mutant protein can lead to liver disease, while the reduction in circulating A1AT can result in lung disease including early onset emphysema. There is currently no available treatment for the liver disease other than transplantation and therapies for the lung manifestations of the disease remain limited. Gene therapy is an evolving field which may be of use as a treatment for A1AT deficiency. As the liver disease associated with A1AT deficiency may represent a gain of function possible gene therapies for this condition include the use of ribozymes, peptide nucleic acids (PNAs) and RNA interference (RNAi), which by decreasing the amount of aberrant protein in cells may impact on the pathogenesis of the condition.

  1. Comparative evaluation of the frequency of myofibroblasts between oral and cutaneous squamous cell carcinomas

    Directory of Open Access Journals (Sweden)

    Ali Dodani

    2016-09-01

    Full Text Available Introduction: Differentiation of fibroblasts to myofibroblasts is an initial and very important event in tumor genesis. Myofibroblasts produce proteinases that stimulate invasion in cancers. Due to the more malignant potential of oral squamous cell carcinoma (OSCC compared to cutaneous squamous cell carcinoma (CSCC , the aim of the present study was to compare myofibroblasts between OSCC and CSCC to understand whether myofibroblasts can help more malignant potential of OSCC compared to CSCC or not. Materials &Methods: This cross-sectional study included 40 cases of OSCC and CSCC and 20 cases of normal skin and normal oral mucosa. Then, 4-micron sections of paraffin-embedded tissue blocks of studied groups were stained immunohistochemically with α-SMA antibody. Mean percentage of myofibroblasts was calculated in invasive fronts of OSCCs with CSCCs and also in normal samples and staining intensity of cells for α-SMA marker and distribution pattern of myofibroblasts were determined. Results: The differences of average percentage of myofibroblasts in OSCC and CSCC compared to normal groups were significant (Pvalue=0.007and Pvalue=0.003 respectively, but when we compared OSCCs and CSCCs, the difference was not significant. Also, there were no significant differences between OSCC and CSCC with regard to staining intensity and pattern. Conclusion: Different biologic behavior of OSCC compared to CSCC doesn’t depend on myofibroblasts and other factors can be involved.

  2. Curcumin induces differential expression of cytoprotective enzymes but similar apoptotic responses in fibroblasts and myofibroblasts

    NARCIS (Netherlands)

    Lundvig, D.M.S.; Pennings, S.W.C.; Brouwer, K.M.; Mtaya-Mlangwa, M.; Mugonzibwa, E.A.; Kuijpers-Jagtman, A.M.; Hoff, J.W. Von den; Wagener, F.A.D.T.G.

    2015-01-01

    Excessive extracellular matrix (ECM) deposition and tissue contraction after injury can lead to esthetic and functional problems. Fibroblasts and myofibroblasts activated by transforming growth factor (TGF)-beta1 play a key role in these processes. The persistence of (myo)fibroblasts and their

  3. Inflammatory myofibroblastic tumor of the bladder in a child: a case report

    Energy Technology Data Exchange (ETDEWEB)

    Araujo Filho, Jose de Arimateia Batista, E-mail: ariaraujocg@hotmail.com [Radiology and Imaging Diagnosis, Instituto do Coracao (InCor) - Universidade de Sao Paulo (HC-FMUSP), Sao Paulo, SP (Brazil); Martines, Joao Augusto dos Santos; Martines, Brenda Margatho Ramos [Imaging Unit of Hospital Universitario - Universidade de Sao Paulo (HU-USP), Sao Paulo, SP (Brazil); Cavalcanti, Marcella Santos [Pathology, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HC-FMUSP), Sao Paulo, SP (Brazil); Cerri, Giovanni Guido; Castro, Claudio Campi de [Department of Radiology, Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), Sao Paulo, SP (Brazil)

    2012-07-15

    Inflammatory myofibroblastic tumors rarely affect the urinary tract or children, and frequently mimic malignancy on imaging studies. According to the recent literature, only 35 cases of such bladder tumors in children have been reported. The authors present the case of a child with a bladder myofibroblastic tumor with favorable progression following complete surgical resection. (author)

  4. Targeting human liver cancer cells with lactobionic acid-G(4)-PAMAM-FITC sorafenib loaded dendrimers.

    Science.gov (United States)

    Iacobazzi, Rosa Maria; Porcelli, Letizia; Lopedota, Angela Assunta; Laquintana, Valentino; Lopalco, Antonio; Cutrignelli, Annalisa; Altamura, Emiliano; Di Fonte, Roberta; Azzariti, Amalia; Franco, Massimo; Denora, Nunzio

    2017-08-07

    Reported here is the synthesis and biological evaluation of the asialoglycoprotein receptor (ASGP-R) targeted fourth generation poliamidoamine dendrimer (G(4)-PAMAM) loaded with sorafenib. The ASGP-R targeted dendrimer was obtained by conjugation of Lactobionic acid (La) to the G(4)-PAMAM dendrimer, followed by acetylation (Ac) of the free amino groups in order to reduce the non-specific interactions with the cell membrane. Moreover, by additionally grafting fluorescein (FITC), it was easy to characterize the internalization pathway and the intracellular fate of the targeted dendrimer Ac-La-G(4)-PAMAM-FITC. In vitro experiments performed on HepG-2 and HLE cell lines, allowed to study the ability of the dendrimers to affect the cell vitality. Confocal microscopy and cytofluorimetric analysis confirmed higher binding and uptake ability of the Ac-La-G(4)-PAMAM-FITC dendrimer in well differentiated and ASGP-R expressing human liver cancer cell line HepG-2 compared non-expressing HLE cells. Ac-La-G(4)-PAMAM-FITC dendrimer loaded with sorafenib was stable and showed sustained sorafenib release. As evidenced by the cytotoxicity studies, sorafenib included in the dendrimer maintained its effectiveness, and was able to produce a longer lasting effect over the time compared to molar equivalent doses of free sorafenib. This new targeted dendrimer appears to be a suitable carrier for the delivery of sorafenib to liver cancer cells expressing ASGP-R. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Customized nutrition intervention and personalized counseling helps achieve nutrition targets in perioperative liver transplant patients.

    Science.gov (United States)

    Daphnee, D K; John, Sheila; Rajalakshmi, P; Vaidya, Anil; Khakhar, Anand; Bhuvaneshwari, S; Ramamurthy, Anand

    2018-02-01

    Nutritional therapy is an integral part of care in all phases of liver transplantation (LTx). However, there are several factors that make it a challenge to manage malnutrition in these patients including, but not limited to, loss of appetite, dietary restrictions and dietary habits. Dietary habits are guided by personal choice, social, cultural and regional background with diversity ranging from veganism to vegetarianism with the latter predominant in Indian population. Therefore, it is difficult to improve nutritional intake of patients with standard dietary recommendations. We evaluated the effects of implementing personalized dietary counseling and a customized nutrition plan on its ability to enhance oral intake and, thereby improve nutritional status of patients with end stage liver disease (ESLD) being evaluated for LTx. We compared the outcomes with a matched group of patients who were prescribed standard dietary recommendations from a historic database. Primary outcome was measured by number of patients achieving ≥75% of recommended energy and protein requirements during hospitalization for LTx. Secondary outcomes included mean energy and protein intake, hours of ventilation, length of stay in Intensive Care Unit (ICU) and hospital, mortality and readmission rate in the acute phase (3months) after LTx. This was a prospective observational study, performed at a single LTx centre. All patients >18years who enrolled for LTx and consented for the study were included. The study was conducted after obtaining institutional ethics committee approval. A protocol based nutrition planning was implemented from April'14. According to this protocol, all patients being evaluated for LTx underwent a detailed nutritional assessment by a qualified Clinical Dietitian (CD) and regularly followed up with until LTx. Nutritional intervention, including a customized nutrition care plan and personalized dietary counseling, was provided based on the severity of malnutrition. To

  6. Liver carbohydrates metabolism: A new islet-neogenesis associated protein peptide (INGAP-PP) target.

    Science.gov (United States)

    Villagarcía, Hernán Gonzalo; Román, Carolina Lisi; Castro, María Cecilia; González, Luisa Arbeláez; Ronco, María Teresa; Francés, Daniel Eleazar; Massa, María Laura; Maiztegui, Bárbara; Flores, Luis Emilio; Gagliardino, Juan José; Francini, Flavio

    2018-03-01

    Islet-Neogenesis Associated Protein-Pentadecapeptide (INGAP-PP) increases β-cell mass and enhances glucose and amino acids-induced insulin secretion. Our aim was to demonstrate its effect on liver metabolism. For that purpose, adult male Wistar rats were injected twice-daily (10 days) with saline solution or INGAP-PP (250 μg). Thereafter, serum glucose, triglyceride and insulin levels were measured and homeostasis model assessment (HOMA-IR) and hepatic insulin sensitivity (HIS) were determined. Liver glucokinase and glucose-6-phosphatase (G-6-Pase) expression and activity, phosphoenolpyruvate carboxykinase (PEPCK) expression, phosphofructokinase-2 (PFK-2) protein content, P-Akt/Akt and glycogen synthase kinase-3β (P-GSK3/GSK3) protein ratios and glycogen deposit were also determined. Additionally, glucokinase activity and G-6-Pase and PEPCK gene expression were also determined in isolated hepatocytes from normal rats incubated with INGAP-PP (5 μg/ml). INGAP-PP administration did not modify any of the serum parameters tested but significantly increased activity of liver glucokinase and the protein level of its cytosolic activator, PFK-2. Conversely, INGAP-PP treated rats decreased gene expression and enzyme activity of gluconeogenic enzymes, G-6-Pase and PEPCK. They also showed a higher glycogen deposit and P-GSK3/GSK3 and P-Akt/Akt ratio. In isolated hepatocytes, INGAP-PP increased GK activity and decreased G-6-Pase and PEPCK expression. These results demonstrate a direct effect of INGAP-PP on the liver acting through P-Akt signaling pathway. INGAP-PP enhances liver glucose metabolism and deposit and reduces its production/output, thereby contributing to maintain normal glucose homeostasis. These results reinforce the concept that INGAP-PP might become a useful tool to treat people with impaired islet/liver glucose metabolism as it occurs in T2D. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Caffeine mediates sustained inactivation of breast cancer-associated myofibroblasts via up-regulation of tumor suppressor genes.

    Directory of Open Access Journals (Sweden)

    Mysoon M Al-Ansari

    Full Text Available BACKGROUND: Active cancer-associated fibroblasts (CAFs or myofibroblasts play important roles not only in the development and progression of breast carcinomas, but also in their prognosis and treatment. Therefore, targeting these cells through suppressing their supportive procarcinogenic paracrine effects is mandatory for improving the current therapies that are mainly targeting tumor cells. To this end, we investigated the effect of the natural and pharmacologically safe molecule, caffeine, on CAF cells and their various procarcinogenic effects. METHODOLOGY/PRINCIPAL FINDINGS: We have shown here that caffeine up-regulates the tumor suppressor proteins p16, p21, p53 and Cav-1, and reduces the expression/secretion of various cytokines (IL-6, TGF-β, SDF-1 and MMP-2, and down-regulates α-SMA. Furthermore, caffeine suppressed the migratory/invasiveness abilities of CAF cells through PTEN-dependent Akt/Erk1/2 inactivation. Moreover, caffeine reduced the paracrine pro-invasion/-migration effects of CAF cells on breast cancer cells. These results indicate that caffeine can inactivate breast stromal myofibroblasts. This has been confirmed by showing that caffeine also suppresses the paracrine pro-angiogenic effect of CAF cells through down-regulating HIF-1αand its downstream effector VEGF-A. Interestingly, these effects were sustained in absence of caffeine. CONCLUSION/SIGNIFICANCE: The present findings provide a proof of principle that breast cancer myofibroblasts can be inactivated, and thereby caffeine may provide a safe and effective prevention against breast tumor growth/recurrence through inhibition of the procarcinogenic effects of active stromal fibroblasts.

  8. Targeting Alpha-Fetoprotein (AFP)-MHC Complex with CAR T-Cell Therapy for Liver Cancer.

    Science.gov (United States)

    Liu, Hong; Xu, Yiyang; Xiang, Jingyi; Long, Li; Green, Shon; Yang, Zhiyuan; Zimdahl, Bryan; Lu, Jingwei; Cheng, Neal; Horan, Lucas H; Liu, Bin; Yan, Su; Wang, Pei; Diaz, Juan; Jin, Lu; Nakano, Yoko; Morales, Javier F; Zhang, Pengbo; Liu, Lian-Xing; Staley, Binnaz K; Priceman, Saul J; Brown, Christine E; Forman, Stephen J; Chan, Vivien W; Liu, Cheng

    2017-01-15

    The majority of tumor-specific antigens are intracellular and/or secreted and therefore inaccessible by conventional chimeric antigen receptor (CAR) T-cell therapy. Given that all intracellular/secreted proteins are processed into peptides and presented by class I MHC on the surface of tumor cells, we used alpha-fetoprotein (AFP), a specific liver cancer marker, as an example to determine whether peptide-MHC complexes can be targets for CAR T-cell therapy against solid tumors. We generated a fully human chimeric antigen receptor, ET1402L1-CAR (AFP-CAR), with exquisite selectivity and specificity for the AFP 158-166 peptide complexed with human leukocyte antigen (HLA)-A*02:01. We report that T cells expressing AFP-CAR selectively degranulated, released cytokines, and lysed liver cancer cells that were HLA-A*02:01 + /AFP + while sparing cells from multiple tissue types that were negative for either expressed proteins. In vivo, intratumoral injection of AFP-CAR T cells significantly regressed both Hep G2 and AFP 158 -expressing SK-HEP-1 tumors in SCID-Beige mice (n = 8 for each). Moreover, intravenous administration of AFP-CAR T cells in Hep G2 tumor-bearing NSG mice lead to rapid and profound tumor growth inhibition (n = 6). Finally, in an established intraperitoneal liver cancer xenograft model, AFP-CAR T cells showed robust antitumor activity (n = 6). This study demonstrates that CAR T-cell immunotherapy targeting intracellular/secreted solid tumor antigens can elicit a potent antitumor response. Our approach expands the spectrum of antigens available for redirected T-cell therapy against solid malignancies and offers a promising new avenue for liver cancer immunotherapy. Clin Cancer Res; 23(2); 478-88. ©2016 AACR. ©2016 American Association for Cancer Research.

  9. Screening for biomarkers of liver injury induced by Polygonum multiflorum: a targeted metabolomic study

    Directory of Open Access Journals (Sweden)

    Qin eDong

    2015-10-01

    Full Text Available Heshouwu (HSW, the dry roots of Polygonum multiflorum, a classical traditional Chinese medicine is used as a tonic for a wide range of conditions,particularly those associated with aging. However, it tends to be taken overdose or long term in these years, which has resulted in liver damage reported in many countries. In this study, the indicative roles of nine bile acids (BAs were evaluated to offer potential biomarkers for HSW induced liver injury. Nine BAs including cholic acid (CA and chenodeoxycholic acid (CDCA, taurocholic acid (TCA, glycocholic acid (GCA, glycochenodeoxycholic acid (GCDCA, deoxycholic acid (DCA, glycodeoxycholic acid (GDCA, ursodeoxycholic acid (UDCA and hyodeoxycholic acid (HDCA in rat bile and serum were detected by a developed LC-MS method after 42 days treatment. Partial least square-discriminate analysis (PLS-DA was applied to evaluate the indicative roles of the nine BAs, and metabolism of the nine BAs was summarized. Significant change was observed for the concentrations of nine BAs in treatment groups compared with normal control; In the PLS-DA plots of nine BAs in bile, normal control and raw HSW groups were separately clustered and could be clearly distinguished, GDCA was selected as the distinguished components for raw HSW overdose treatment group. In the PLS-DA plots of nine BAs in serum, the normal control and raw HSW overdose treatment group were separately clustered and could be clearly distinguished, and HDCA was selected as the distinguished components for raw HSW overdose treatment group. The results indicated the perturbation of nine BAs was associated with HSW induced liver injury; GDCA in bile, as well as HDCA in serum could be selected as potential biomarkers for HSW induced liver injury; it also laid the foundation for the further search on the mechanisms of liver injury induced by HSW .

  10. Gene targeted therapeutics for liver disease in alpha-1 antitrypsin deficiency

    Directory of Open Access Journals (Sweden)

    Caitriona McLean

    2009-01-01

    Full Text Available Caitriona McLean*, Catherine M Greene*, Noel G McElvaneyRespiratory Research Division, Dept. Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland; *Each of these authors contributed equally to this workAbstract: Alpha-1 antitrypsin (A1AT is a 52 kDa serine protease inhibitor that is synthesized in and secreted from the liver. Although it is present in all tissues in the body the present consensus is that its main role is to inhibit neutrophil elastase in the lung. A1AT deficiency occurs due to mutations of the A1AT gene that reduce serum A1AT levels to <35% of normal. The most clinically significant form of A1AT deficiency is caused by the Z mutation (Glu342Lys. ZA1AT polymerizes in the endoplasmic reticulum of liver cells and the resulting accumulation of the mutant protein can lead to liver disease, while the reduction in circulating A1AT can result in lung disease including early onset emphysema. There is currently no available treatment for the liver disease other than transplantation and therapies for the lung manifestations of the disease remain limited. Gene therapy is an evolving field which may be of use as a treatment for A1AT deficiency. As the liver disease associated with A1AT deficiency may represent a gain of function possible gene therapies for this condition include the use of ribozymes, peptide nucleic acids (PNAs and RNA interference (RNAi, which by decreasing the amount of aberrant protein in cells may impact on the pathogenesis of the condition.Keywords: alpha-1 antitrypsin deficiency, siRNA, peptide nucleic acid, ribozymes

  11. The anti-fibrotic effects of CCN1/CYR61 in primary portal myofibroblasts are mediated through induction of reactive oxygen species resulting in cellular senescence, apoptosis and attenuated TGF-β signaling.

    Science.gov (United States)

    Borkham-Kamphorst, Erawan; Schaffrath, Christian; Van de Leur, Eddy; Haas, Ute; Tihaa, Lidia; Meurer, Steffen K; Nevzorova, Yulia A; Liedtke, Christian; Weiskirchen, Ralf

    2014-05-01

    Cysteine-rich protein 61 (CCN1/CYR61) is a CCN (CYR61, CTGF (connective tissue growth factor), and NOV (Nephroblastoma overexpressed gene)) family matricellular protein comprising six secreted CCN proteins in mammals. CCN1/CYR61 expression is associated with inflammation and injury repair. Recent studies show that CCN1/CYR61 limits fibrosis in models of cutaneous wound healing by inducing cellular senescence in myofibroblasts of the granulation tissue which thereby transforms into an extracellular matrix-degrading phenotype. We here investigate CCN1/CYR61 expression in primary profibrogenic liver cells (i.e., hepatic stellate cells and periportal myofibroblasts) and found an increase of CCN1/CYR61 expression during early activation of hepatic stellate cells that declines in fully transdifferentiated myofibroblasts. By contrast, CCN1/CYR61 levels found in primary parenchymal liver cells (i.e., hepatocytes) were relatively low compared to the levels exhibited in hepatic stellate cells and portal myofibroblasts. In models of ongoing liver fibrogenesis, elevated levels of CCN1/CYR61 were particularly noticed during early periods of insult, while expression declined during prolonged phases of fibrogenesis. We generated an adenovirus type 5 encoding CCN1/CYR61 (i.e., Ad5-CMV-CCN1/CYR61) and overexpressed CCN1/CYR61 in primary portal myofibroblasts. Interestingly, overexpressed CCN1/CYR61 significantly inhibited production of collagen type I at both mRNA and protein levels as evidenced by quantitative real-time polymerase chain reaction, Western blot and immunocytochemistry. CCN1/CYR61 further induces production of reactive oxygen species (ROS) leading to dose-dependent cellular senescence and apoptosis. Additionally, we demonstrate that CCN1/CYR61 attenuates TGF-β signaling by scavenging TGF-β thereby mitigating in vivo liver fibrogenesis in a bile duct ligation model. In line with dermal fibrosis and scar formation, CCN1/CYR61 is involved in liver injury repair and

  12. Liver cancer cells: targeting and prolonged-release drug carriers consisting of mesoporous silica nanoparticles and alginate microspheres.

    Science.gov (United States)

    Liao, Yu-Te; Liu, Chia-Hung; Yu, Jiashing; Wu, Kevin C-W

    2014-01-01

    A new microsphere consisting of inorganic mesoporous silica nanoparticles (MSNs) and organic alginate (denoted as MSN@Alg) was successfully synthesized by air-dynamic atomization and applied to the intracellular drug delivery systems (DDS) of liver cancer cells with sustained release and specific targeting properties. MSN@Alg microspheres have the advantages of MSN and alginate, where MSN provides a large surface area for high drug loading and alginate provides excellent biocompatibility and COOH functionality for specific targeting. Rhodamine 6G was used as a model drug, and the sustained release behavior of the rhodamine 6G-loaded MSN@Alg microspheres can be prolonged up to 20 days. For targeting therapy, the anticancer drug doxorubicin was loaded into MSN@Alg microspheres, and the (lysine)4-tyrosine-arginine-glycine-aspartic acid (K4YRGD) peptide was functionalized onto the surface of MSN@Alg for targeting liver cancer cells, hepatocellular carcinoma (HepG2). The results of the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay and confocal laser scanning microscopy indicate that the MSN@Alg microspheres were successfully uptaken by HepG2 without apparent cytotoxicity. In addition, the intracellular drug delivery efficiency was greatly enhanced (ie, 3.5-fold) for the arginine-glycine-aspartic acid (RGD)-labeled, doxorubicin-loaded MSN@Alg drug delivery system compared with the non-RGD case. The synthesized MSN@Alg microspheres show great potential as drug vehicles with high biocompatibility, sustained release, and targeting features for future intracellular DDS.

  13. Nonspecific targeting of iron oxide nanoparticles to the liver, kidney and spleen: A novel approach to achieving specificity

    Science.gov (United States)

    Palihawadana Arachchige, Maheshika; Flack, Amanda; Chen, Xuequn; Li, Jing; Oupicky, David; Cheng, Y.-C. Norman; Shen, Yimin; Jena, Bhanu; Lawes, Gavin

    2013-03-01

    Recently, there has been significant interest in developing Fe3O4 nanoparticles for biomedical applications including targeted drug delivery and magnetic resonance imaging. One of the major problems in these applications is the undesirable filtration of these materials by the mononuclear phagocyte system. Preliminary magnetic resonance imaging and magnetization studies on hyaluronic acid coated nanoparticles injected intravenously into mice confirm that the nanoparticles accumulate in the liver, spleen, and kidneys. To identify whether certain specific proteins are responsible for nanoparticle accumulation in these organs, we exposed hyaluronic acid coated nanoparticles to proteins extracted from the liver, spleen, and kidneys, together with blood plasma proteins, then subsequently used gel electrophoresis and mass spectroscopy to identify the proteins binding to the nanoparticles. We find that the unwanted accumulation of nanoparticles in these organs can potentially be attributed to specific binding by a small number of proteins. By appropriately functionalizing the iron oxide nanoparticles, we expect that the nanoparticles uptake in the liver, spleen, and kidneys will be reduced.

  14. A Glycyrrhetinic Acid-Modified Curcumin Supramolecular Hydrogel for liver tumor targeting therapy

    Science.gov (United States)

    Chen, Guoqin; Li, Jinliang; Cai, Yanbin; Zhan, Jie; Gao, Jie; Song, Mingcai; Shi, Yang; Yang, Zhimou

    2017-03-01

    Curcumin (Cur), a phenolic anti-oxidant compound obtained from Curcuma longa plant, possesses a variety of therapeutic properties. However, it is suffered from its low water solubility and low bioavailability property, which seriously restricts its clinical application. In this study, we developed a glycyrrhetinic acid (GA) modified curcumin supramolecular pro-gelator (GA-Cur) and a control compound Nap-Cur by replacing GA with the naphthylacetic acid (Nap). Both compounds showed good water solubility and could form supramolecular gels by disulfide bond reduction triggered by glutathione (GSH) in vitro. Both formed gels could sustainedly release Cur in buffer solutions. We also investigated the cytotoxicity of pro-gelators to HepG2 cells by a MTT assay and determined the cellular uptake behaviours of them by fluorescence microscopy and LC-MS. Due to the over expression of GA receptor in liver cancer cells, our pro-gelator of GA-Cur showed an enhanced cellular uptake and better inhibition capacity to liver tumor cells than Nap-Cur. Therefore, the GA-Cur could significantly inhibit HepG2 cell growth. Our study provides a novel nanomaterial for liver tumor chemotherapy.

  15. Myofibroblastic sarcoma of the base of tongue. Case report and review of the literature

    International Nuclear Information System (INIS)

    Takacsi-Nagy, Zoltan; Fodor, Janos; Murakoezy, Gyoergyi; Pogany, Peter; Orosz, Zsolt

    2009-01-01

    Background: Mesenchymal malignancies with myofibroblastic differentiation exhibit a spectrum from low-grade myofibroblastic sarcoma mimicking fibromatosis to pleomorphic high-grade sarcoma. Low-grade myofibroblastic sarcoma shows a wide anatomic distribution with a predilection for the head-and-neck region; however, intermediate- and high-grade myofibroblastic sarcomas in this localization are exceptional. Case Report: A 56-year-old woman with intermediate-grade myofibroblastic sarcoma of the base of tongue is presented. She was treated with surgical excision, but computed tomography proved local residual tumor. Reexcision and chemotherapy were refused by the patient. Irradiation was given to a total dose of 66 Gy. Result: 50 months after completion of radiotherapy, the patient is in good health without any evidence of disease. According to the review of the literature, base of tongue as the primary site of myofibroblastic sarcoma has not been published so far. Conclusion: Similarly to the low-grade form, intermediate- and high-grade myofibroblastic sarcomas may also occur in the head-and-neck region. In case of incomplete excision, radiotherapy may be an effective treatment. (orig.)

  16. Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer.

    Science.gov (United States)

    Voutila, Jon; Reebye, Vikash; Roberts, Thomas C; Protopapa, Pantelitsa; Andrikakou, Pinelopi; Blakey, David C; Habib, Robert; Huber, Hans; Saetrom, Pal; Rossi, John J; Habib, Nagy A

    2017-12-06

    Small activating RNAs (saRNAs) are short double-stranded oligonucleotides that selectively increase gene transcription. Here, we describe the development of an saRNA that upregulates the transcription factor CCATT/enhancer binding protein alpha (CEBPA), investigate its mode of action, and describe its development into a clinical candidate. A bioinformatically directed nucleotide walk around the CEBPA gene identified an saRNA sequence that upregulates CEBPA mRNA 2.5-fold in human hepatocellular carcinoma cells. A nuclear run-on assay confirmed that this upregulation is a transcriptionally driven process. Mechanistic experiments demonstrate that Argonaute-2 (Ago2) is required for saRNA activity, with the guide strand of the saRNA shown to be associated with Ago2 and localized at the CEBPA genomic locus using RNA chromatin immunoprecipitation (ChIP) assays. The data support a sequence-specific on-target saRNA activity that leads to enhanced CEBPA mRNA transcription. Chemical modifications were introduced in the saRNA duplex to prevent activation of the innate immunity. This modified saRNA retains activation of CEBPA mRNA and downstream targets and inhibits growth of liver cancer cell lines in vitro. This novel drug has been encapsulated in a liposomal formulation for liver delivery, is currently in a phase I clinical trial for patients with liver cancer, and represents the first human study of an saRNA therapeutic. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  17. Cardiac inflammatory myofibroblastic tumor: does it recur after complete surgical resection in an adult?

    Directory of Open Access Journals (Sweden)

    Yang Xuedong

    2012-05-01

    Full Text Available Abstract Inflammatory myofibroblastic tumor is currently considered to be a low-grade neoplasm, and it rarely involves the heart. We reported a rare case of a 59-year-old female who received cardiac surgery for complete resection of inflammatory myofibroblastic tumor in the left atrium. Five months after surgery, the patient presented with acute cardiogenic pulmonary edema and subsequent sudden death due to a left atrial tumor which protruded into the left ventricle through mitral annulus during diastole. The recurrence of inflammatory myofibroblastic tumor in the left atrium was strongly suggested clinically.

  18. Targeted hyperthermia after selective embolization with ferromagnetic nanoparticles in a VX2 rabbit liver tumor model

    Directory of Open Access Journals (Sweden)

    Sun HL

    2013-10-01

    Full Text Available Hongliang Sun,1 Linfeng Xu,1 Tianyuan Fan,2 Hongzhi Zhan,3 Xiaodong Wang,3 Yanfei Zhou,2 Ren-jie Yang3 1Department of Interventional Therapy, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 2Pharmacy School of Beijing University, Beijing, 3Department of Interventional Therapy, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, People's Republic of China Background: The purpose of this study was to observe the effect and feasibility of hyperthermia and the influence of heat on surrounding organs in a VX2 rabbit liver model exposed to an alternating magnetic field after embolization with ferromagnetic nanoparticles. Methods: Forty rabbits containing implanted hepatic VX2 carcinomas were divided into four groups, each containing ten rabbits. Fourteen days after tumor transplantation, we opened the abdomen to observe the size and shape of the tumor. A transfemoral retrograde approach was then used for hepatic arterial catheterization in groups B, C, and D to perform angiography and embolization. The next day, three rabbits in group B and all rabbits in group D were exposed to an alternating magnetic field, and the temperature was recorded simultaneously in the center of the tumor, at the edge of the tumor, and in the normal liver parenchyma. On day 28, all animals was euthanized to observe changes in the implanted liver tumor and the condition of the abdomen. A pathologic examination was also done. Results: Before surgery, there was no significant difference in tumor volume between the four groups. Three different temperature points (center of the tumor, edge of the tumor, and in the normal liver parenchyma of group B under an alternating magnetic field were 37.2°C ± 1.1°C, 36.8°C ± 1.2°C, and 36.9°C ± 2.1°C, none of which were significantly different from pretreatment values. Three points basal temperature in group D showed no significant difference (F = 1.038, P = 0.413. Seven to 26

  19. Hepatic NAD(+) deficiency as a therapeutic target for non-alcoholic fatty liver disease in ageing.

    Science.gov (United States)

    Zhou, Can-Can; Yang, Xi; Hua, Xia; Liu, Jian; Fan, Mao-Bing; Li, Guo-Qiang; Song, Jie; Xu, Tian-Ying; Li, Zhi-Yong; Guan, Yun-Feng; Wang, Pei; Miao, Chao-Yu

    2016-08-01

    Ageing is an important risk factor of non-alcoholic fatty liver disease (NAFLD). Here, we investigated whether the deficiency of nicotinamide adenine dinucleotide (NAD(+) ), a ubiquitous coenzyme, links ageing with NAFLD. Hepatic concentrations of NAD(+) , protein levels of nicotinamide phosphoribosyltransferase (NAMPT) and several other critical enzymes regulating NAD(+) biosynthesis, were compared in middle-aged and aged mice or patients. The influences of NAD(+) decline on the steatosis and steatohepatitis were evaluated in wild-type and H247A dominant-negative, enzymically-inactive NAMPT transgenic mice (DN-NAMPT) given normal or high-fat diet (HFD). Hepatic NAD(+) level decreased in aged mice and humans. NAMPT-controlled NAD(+) salvage, but not de novo biosynthesis pathway, was compromised in liver of elderly mice and humans. Given normal chow, middle-age DN-NAMPT mice displayed systemic NAD(+) reduction and had moderate NAFLD phenotypes, including lipid accumulation, enhanced oxidative stress, triggered inflammation and impaired insulin sensitivity in liver. All these NAFLD phenotypes, especially release of pro-inflammatory factors, Kupffer cell accumulation, monocytes infiltration, NLRP3 inflammasome pathway and hepatic fibrosis (Masson's staining and α-SMA staining), deteriorated further under HFD challenge. Oral administration of nicotinamide riboside, a natural NAD(+) precursor, completely corrected these NAFLD phenotypes induced by NAD(+) deficiency alone or HFD, whereas adenovirus-mediated SIRT1 overexpression only partially rescued these phenotypes. These results provide the first evidence that ageing-associated NAD(+) deficiency is a critical risk factor for NAFLD, and suggest that supplementation with NAD(+) substrates may be a promising therapeutic strategy to prevent and treat NAFLD. © 2016 The British Pharmacological Society.

  20. Hepatic NAD+ deficiency as a therapeutic target for non‐alcoholic fatty liver disease in ageing

    Science.gov (United States)

    Zhou, Can‐Can; Yang, Xi; Hua, Xia; Liu, Jian; Fan, Mao‐Bing; Li, Guo‐Qiang; Song, Jie; Xu, Tian‐Ying; Li, Zhi‐Yong; Guan, Yun‐Feng

    2016-01-01

    Abstract Background and Purpose Ageing is an important risk factor of non‐alcoholic fatty liver disease (NAFLD). Here, we investigated whether the deficiency of nicotinamide adenine dinucleotide (NAD+), a ubiquitous coenzyme, links ageing with NAFLD. Experimental Approach Hepatic concentrations of NAD+, protein levels of nicotinamide phosphoribosyltransferase (NAMPT) and several other critical enzymes regulating NAD+ biosynthesis, were compared in middle‐aged and aged mice or patients. The influences of NAD+ decline on the steatosis and steatohepatitis were evaluated in wild‐type and H247A dominant‐negative, enzymically‐inactive NAMPT transgenic mice (DN‐NAMPT) given normal or high‐fat diet (HFD). Key Results Hepatic NAD+ level decreased in aged mice and humans. NAMPT‐controlled NAD+ salvage, but not de novo biosynthesis pathway, was compromised in liver of elderly mice and humans. Given normal chow, middle‐age DN‐NAMPT mice displayed systemic NAD+ reduction and had moderate NAFLD phenotypes, including lipid accumulation, enhanced oxidative stress, triggered inflammation and impaired insulin sensitivity in liver. All these NAFLD phenotypes, especially release of pro‐inflammatory factors, Kupffer cell accumulation, monocytes infiltration, NLRP3 inflammasome pathway and hepatic fibrosis (Masson's staining and α‐SMA staining), deteriorated further under HFD challenge. Oral administration of nicotinamide riboside, a natural NAD+ precursor, completely corrected these NAFLD phenotypes induced by NAD+ deficiency alone or HFD, whereas adenovirus‐mediated SIRT1 overexpression only partially rescued these phenotypes. Conclusions and Implications These results provide the first evidence that ageing‐associated NAD+ deficiency is a critical risk factor for NAFLD, and suggest that supplementation with NAD+ substrates may be a promising therapeutic strategy to prevent and treat NAFLD. PMID:27174364

  1. Liver/kidney microsomal antibody type 1 targets CYP2D6 on hepatocyte plasma membrane.

    Science.gov (United States)

    Muratori, L; Parola, M; Ripalti, A; Robino, G; Muratori, P; Bellomo, G; Carini, R; Lenzi, M; Landini, M P; Albano, E; Bianchi, F B

    2000-04-01

    Liver/kidney microsomal antibody type 1 (LKM1) is the marker of type 2 autoimmune hepatitis (AIH) and is detected in up to 6% of patients with hepatitis C virus (HCV) infection. It recognises linear and conformational epitopes of cytochrome P450IID6 (CYP2D6) and may have liver damaging activity, provided that CYP2D6 is accessible to effector mechanisms of autoimmune attack. The presence of LKM1 in the plasma membrane was investigated by indirect immunofluorescence and confocal laser microscopy of isolated rat hepatocytes probed with 10 LKM1 positive sera (five from patients with AIH and five from patients with chronic HCV infection) and a rabbit polyclonal anti-CYP2D6 serum. Serum from both types of patient stained the plasma membrane of non-permeabilised cells, where the fluorescent signal could be visualised as discrete clumps. Conversely, permeabilised hepatocytes showed diffuse submembranous/cytoplasmic staining. Adsorption with recombinant CYP2D6 substantially reduced plasma membrane staining and LKM1 immunoblot reactivity. Plasma membrane staining of LKM1 colocalised with that of anti-CYP2D6. Immunoprecipitation experiments showed that a single 50 kDa protein recognised by anti-CYP2D6 can be isolated from the plasma membrane of intact hepatocytes. AIH and HCV related LKM1 recognise CYP2D6 exposed on the plasma membrane of isolated hepatocytes. This observation supports the notion that anti-CYP2D6 autoreactivity may be involved in the pathogenesis of liver damage.

  2. Liver cancer cells: targeting and prolonged-release drug carriers consisting of mesoporous silica nanoparticles and alginate microspheres

    Directory of Open Access Journals (Sweden)

    Liao YT

    2014-06-01

    Full Text Available Yu-Te Liao,1 Chia-Hung Liu,2 Jiashing Yu,1 Kevin C-W Wu1,3 1Department of Chemical Engineering, National Taiwan University, Taipei, Taiwan; 2Department of Urology, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; 3Division of Medical Engineering Research, National Health Research Institutes, Zhunan Township, Miaoli County, Taiwan Abstract: A new microsphere consisting of inorganic mesoporous silica nanoparticles (MSNs and organic alginate (denoted as MSN@Alg was successfully synthesized by air-dynamic atomization and applied to the intracellular drug delivery systems (DDS of liver cancer cells with sustained release and specific targeting properties. MSN@Alg microspheres have the advantages of MSN and alginate, where MSN provides a large surface area for high drug loading and alginate provides excellent biocompatibility and COOH functionality for specific targeting. Rhodamine 6G was used as a model drug, and the sustained release behavior of the rhodamine 6G-loaded MSN@Alg microspheres can be prolonged up to 20 days. For targeting therapy, the anticancer drug doxorubicin was loaded into MSN@Alg microspheres, and the (lysine4-tyrosine-arginine-glycine-aspartic acid (K4YRGD peptide was functionalized onto the surface of MSN@Alg for targeting liver cancer cells, hepatocellular carcinoma (HepG2. The results of the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT assay and confocal laser scanning microscopy indicate that the MSN@Alg microspheres were successfully uptaken by HepG2 without apparent cytotoxicity. In addition, the intracellular drug delivery efficiency was greatly enhanced (ie, 3.5-fold for the arginine-glycine-aspartic acid (RGD-labeled, doxorubicin-loaded MSN@Alg drug delivery system compared with the non-RGD case. The synthesized MSN@Alg microspheres show great potential as drug vehicles with high biocompatibility, sustained release, and targeting features for future intracellular DDS. Keywords

  3. Use of Neoadjuvant Chemotherapy Plus Molecular Targeted Therapy in Colorectal Liver Metastases: A Systematic Review and Meta-analysis.

    Science.gov (United States)

    Sabanathan, Dhanusha; Eslick, Guy D; Shannon, Jenny

    2016-12-01

    Surgery remains the standard of care for patients with colorectal liver metastases (CLMs), with a 5-year survival rate approaching 35%. Perioperative chemotherapy confers a survival benefit in selected patients with CLMs. The use of molecular targeted therapy combined with neoadjuvant chemotherapy for CLMs, however, remains controversial. We reviewed the published data on combination neoadjuvant chemotherapy and molecular targeted therapy for resectable and initially unresectable CLMs. A literature search of the Medline and PubMed databases was conducted to identify studies of neoadjuvant chemotherapy plus molecular targeted therapy in the management of resectable or initially unresectable CLMs. We calculated the pooled proportion and 95% confidence intervals using a random effects model for the relationship of the combination neoadjuvant treatment on the overall response rate and performed a systematic review of all identified studies. The analysis was stratified according to the study design. The data from 11 studies of 908 patients who had undergone systemic chemotherapy plus targeted therapy for CLM were analyzed. The use of combination neoadjuvant therapy was associated with an overall response rate of 68% (95% confidence interval, 63%-73%), with significant heterogeneity observed in the studies (I 2  = 89.35; P chemotherapy plus molecular targeted agents for CLM confers high overall response rates. Combination treatment might also increase the resectability rates in initially unresectable CLM. Further studies are needed to examine the survival outcomes, with a focus on the differential role of molecular targeted therapy in the neoadjuvant versus adjuvant setting. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

  4. Adipose-derived stem cells inhibit the contractile myofibroblast in Dupuytren's disease.

    NARCIS (Netherlands)

    Verhoekx, J.S.; Mudera, V.; Walbeehm, E.T.; Hovius, S.E.

    2013-01-01

    BACKGROUND: In an attempt to provide minimally invasive treatment for Dupuytren's disease, percutaneous disruption of the affected tissue followed by lipografting is being tested. Contractile myofibroblasts drive this fibroproliferative disorder, whereas stem cells have recently been implicated in

  5. Shedding light on inflammatory pseudotumor in children: spotlight on inflammatory myofibroblastic tumor

    Energy Technology Data Exchange (ETDEWEB)

    Lai, Lillian M.; Kao, Simon C.S.; Moritani, Toshio; Clark, Eve; Ishigami, Kousei; Sato, Yutaka [University of Iowa Hospitals and Clinics, Department of Radiology, Carver College of Medicine, Iowa City, IA (United States); McCarville, M.B. [St. Jude Children' s Research Hospital, Department of Radiology, Memphis, TN (United States); Kirby, Patricia [University of Iowa Hospitals and Clinics, Department of Pathology, Carver College of Medicine, Iowa City, IA (United States); Bahrami, Armita [St. Jude Children' s Research Hospital, Department of Pathology, Memphis, TN (United States)

    2015-11-15

    Inflammatory pseudotumor is a generic term used to designate a heterogeneous group of inflammatory mass-forming lesions histologically characterized by myofibroblastic proliferation with chronic inflammatory infiltrate. Inflammatory pseudotumor is multifactorial in etiology and generally benign, but it is often mistaken for malignancy given its aggressive appearance. It can occur throughout the body and is seen in all age groups. Inflammatory pseudotumor has been described in the literature by many organ-specific names, resulting in confusion. Recently within this generic category of inflammatory pseudotumor, inflammatory myofibroblastic tumor has emerged as a distinct entity and is now recognized as a fibroblastic/myofibroblastic neoplasm with intermediate biological potential and occurring mostly in children. We present interesting pediatric cases of inflammatory myofibroblastic tumors given this entity's tendency to occur in children. Familiarity and knowledge of the imaging features of inflammatory pseudotumor can help in making an accurate diagnosis, thereby avoiding unnecessary radical surgery. (orig.)

  6. Effect of near-infrared lasers on myofibroblast differentiation and contraction

    Science.gov (United States)

    Vaughan, Melville B.; Spencer, Chelsea L.; Goddard, Jessica D.; Jose, Jessnie; Chen, Wei R.

    2012-03-01

    The ability to modulate the myofibroblast phenotype will have important implications in wound healing, aging and cancer development. Our objective was to determine whether irradiation using a 980-nm laser affects the presence of myofibroblasts and cellular contractility using an attached collagen lattice model. Fibroblasts in type I collagen lattices were allowed to generate tension for 5 days in the presence or absence of laser light stimulation on day 4. Immunostaining was used to determine the total number of cells in a representative image and percentage of myofibroblasts in the same image; tension generation was determined by releasing tension and measuring diameter change over time. One treatment demonstrated a slight lattice contraction increase over control, correlated with increased cell number. Myofibroblast percentage was low and was not correlated with lattice contraction. More experiments are necessary due to limited sample size and lack of large deviations from the control.

  7. Radio-induced superficial fibrosis: investigation of the activation mechanisms of the myo-fibroblast and characterization of the cicatricial epidermis

    International Nuclear Information System (INIS)

    Sivan, Virginie

    2001-01-01

    Whereas radio-induced cutaneous fibrosis is one of the frequent after-effects of accidental and therapeutic irradiations, this research thesis addresses the mechanisms which govern the activation of the myo-fibroblast. After some results obtained on cells from a radio-induced fibrosis on swine cells, the author proposes a signalling alteration as a mechanism. In a model a reconstructed skin, the author shows that myo-fibroblasts are a direct target of Superoxide Dismutase (SOD), and respond to this anti-fibrosis agent by a phenotype reversion. She reports the molecular characterization of epidermis of fibro-necrosis human lesions induced by an accidental or therapeutic irradiation. This leads to a better understanding of the role of the myo-fibroblast during the development and regression of fibrosis. Besides, the author shows that an alteration of the epidermis adjacent to dermis is developing in parallel with the fibrosis process. This suggests an active contribution of keratinocytes during the development of this radio-induced after-effect [fr

  8. Immunohistochemical evaluation of myofibroblasts in odontogenic cysts and tumors: A comparative study.

    Science.gov (United States)

    Syamala, Deepa; Suresh, Rakesh; Janardhanan, Mahija; Savithri, Vindhya; Anand, Prem P; Jose, Amrutha

    2016-01-01

    Myofibroblasts are fibroblasts with smooth muscle-like features characterized by the presence of a contractile apparatus and found in the connective tissue stroma of normal tissues such as blood vessels and lymph nodes. They are now thought to play a role in the synthesis and reorganization of extracellular matrix, which could contribute to the aggressive biologic behavior of the lesions. To compare the mean number of stromal myofibroblasts in dentigerous cysts (DCs), keratocystic odontogenic tumor (KCOT) and ameloblastoma; and to derive a correlation between the stromal myofibroblasts and the known biologic behavior of the lesions. A cross-sectional immunohistochemical analysis of cases of DC, KCOT and ameloblastoma. Twenty paraffin-embedded tissue blocks each of DC, KCOT and multicystic ameloblastoma were selected for the study and diagnosis confirmed through hematoxylin and eosin staining. Tissue sections were analyzed for the number of myofibroblasts using alpha smooth muscle actin (α-SMA) immunostaining. Differences in the mean number of α-SMA positive cells in each group were analyzed using one-way ANOVA test. Intergroup comparisons of mean values of α-SMA positive cells were performed using Mann-Whitney U-test. Ameloblastoma showed the highest number of myofibroblasts, whereas DC showed the lowest. Among the groups, there were significant differences between the myofibroblast counts among DC and KCOT and between DC and ameloblastoma, whereas the difference in counts was not statistically significant between KCOT and ameloblastoma. A positive correlation was observed between the myofibroblast count and the known biologic behavior of the lesions. Myofibroblasts may act in close association with the epithelial cells to bring about changes in stromal microenvironment, favorable to the growth and progression of the lesion. They may be of great value in predicting the biologic behavior and growth potential of such lesions.

  9. Evaluation of Role of Myofibroblasts in Oral Cancer: A Systematic Review.

    Science.gov (United States)

    Sekhon, Harjeet K; Sircar, Keya; Kaur, Gurbani; Marwah, Muneet

    2016-01-01

    To conduct a systematic review on the role of myofibroblasts in progression of oral cancer. The myofibroblast is essential for the integrity of the mammalian body by virtue of its role in wound healing, but it also plays a negative role due to their role in promoting tumor development. Systematic review. Bibliographic searches were conducted in several electronic databases using all publications in PubMed, PubMed central, EMBASE, CancerLit, Google scholar, and Cochrane CCTR between 1990 and June 2015. The search of all publications from various electronic databases revealed 1,371 citations. The total number of studies considered for systematic review was 43. The total number of patients included in the studies was 990. Myofibroblasts are a significant component in stroma of oral cancer cases, though not identified in all cases. This systematic review shows that clinical, pathological, and immunohistochemistry tests have correlated the presence of high myofibroblast count in oral cancer cell stroma. Myofibroblasts play a significant role in oral cancer invasion and progression. Various studies have demonstrated their association with oral cancer. This review tends to highlight their role in the pathogenesis of oral cancer over the decade. Sekhon HK, Sircar K, Kaur G, Marwah M. Evaluation of Role of Myofibroblasts in Oral Cancer: A Systematic Review. Int J Clin Pediatr Dent 2016;9(3):233-239.

  10. Myofibroblasts in interstitial lung diseases show diverse electron microscopic and invasive features.

    Science.gov (United States)

    Karvonen, Henna M; Lehtonen, Siri T; Sormunen, Raija T; Harju, Terttu H; Lappi-Blanco, Elisa; Bloigu, Risto S; Kaarteenaho, Riitta L

    2012-09-01

    The characteristic features of myofibroblasts in various lung disorders are poorly understood. We have evaluated the ultrastructure and invasive capacities of myofibroblasts cultured from small volumes of diagnostic bronchoalveolar lavage (BAL) fluid samples from patients with different types of lung diseases. Cells were cultured from samples of BAL fluid collected from 51 patients that had undergone bronchoscopy and BAL for diagnostic purposes. The cells were visualized by transmission electron microscopy and immunoelectron microscopy to achieve ultrastructural localization of alpha-smooth muscle actin (α-SMA) and fibronectin. The levels of α-SMA protein and mRNA and fibronectin mRNA were measured by western blot and quantitative real-time reverse transcriptase polymerase chain reaction. The invasive capacities of the cells were evaluated. The cultured cells were either fibroblasts or myofibroblasts. The structure of the fibronexus, and the amounts of intracellular actin, extracellular fibronectin and cell junctions of myofibroblasts varied in different diseases. In electron and immunoelectron microscopy, cells cultured from interstitial lung diseases (ILDs) expressed more actin filaments and α-SMA than normal lung. The invasive capacity of the cells obtained from patients with idiopathic pulmonary fibrosis was higher than that from patients with other type of ILDs. Cells expressing more actin filaments had a higher invasion capacity. It is concluded that electron and immunoelectron microscopic studies of myofibroblasts can reveal differential features in various diseases. An analysis of myofibroblasts cultured from diagnostic BAL fluid samples may represent a new kind of tool for diagnostics and research into lung diseases.

  11. Quantitative assessment of myofibroblast in severe dysplasia, microinvasion and oral squamous cell carcinoma: an immunohistochemical study.

    Science.gov (United States)

    Kapse, Sonam C; Rathod, Nanita; Baad, Rajendra; Mandlik, Jyoti; Sharma, Anupam S; Bommanavar, Sushma

    2013-01-01

    Myofibroblast are essential for the integrity of human body by virtue of its role in wound healing and pathological organ remodeling. Myofibroblast is a universal cellular component in mammalian lesions, but not a typical component of normal untraumatized tissues. Therefore its presence in abundance in case of cancer is a matter of concern. Tumor microenvironment plays a pivotal role in tumor progression. These so called cancer associated fibroblast or myofibroblast are the major components and occur in stromal tissue during carcinogenesis processes. This study is a quantitative assessment of presence and distribution of myofibroblast in severe dysplasia, microinvasion and oral squamous cell carcinoma (OSCC). Myofibroblast, Vimentin, α-SMA, OSCC, Severe dysplasia, Microinvasion. How to cite this article: Kapse SC, Rathod N, Baad R, Mandlik J, Sharma AS, Bommanavar S. Quantitative Assessment of Myofibroblast in Severe Dysplasia, Microinvasion and Oral Squamous Cell Carcinoma: An Immunohistochemical Study. J Contemp Dent Pract 2013;14(1):34-38. Source of support: Nil Conflict of interest: None declared.

  12. Phosphoproteomic profiling of in vivo signaling in liver by the mammalian target of rapamycin complex 1 (mTORC1.

    Directory of Open Access Journals (Sweden)

    Gokhan Demirkan

    Full Text Available Our understanding of signal transduction networks in the physiological context of an organism remains limited, partly due to the technical challenge of identifying serine/threonine phosphorylated peptides from complex tissue samples. In the present study, we focused on signaling through the mammalian target of rapamycin (mTOR complex 1 (mTORC1, which is at the center of a nutrient- and growth factor-responsive cell signaling network. Though studied extensively, the mechanisms involved in many mTORC1 biological functions remain poorly understood.We developed a phosphoproteomic strategy to purify, enrich and identify phosphopeptides from rat liver homogenates. Using the anticancer drug rapamycin, the only known target of which is mTORC1, we characterized signaling in liver from rats in which the complex was maximally activated by refeeding following 48 hr of starvation. Using protein and peptide fractionation methods, TiO(2 affinity purification of phosphopeptides and mass spectrometry, we reproducibly identified and quantified over four thousand phosphopeptides. Along with 5 known rapamycin-sensitive phosphorylation events, we identified 62 new rapamycin-responsive candidate phosphorylation sites. Among these were PRAS40, gephyrin, and AMP kinase 2. We observed similar proportions of increased and reduced phosphorylation in response to rapamycin. Gene ontology analysis revealed over-representation of mTOR pathway components among rapamycin-sensitive phosphopeptide candidates.In addition to identifying potential new mTORC1-mediated phosphorylation events, and providing information relevant to the biology of this signaling network, our experimental and analytical approaches indicate the feasibility of large-scale phosphoproteomic profiling of tissue samples to study physiological signaling events in vivo.

  13. A single blood test adjusted for different liver fibrosis targets improves fibrosis staging and especially cirrhosis diagnosis.

    Science.gov (United States)

    Calès, Paul; Boursier, Jérôme; Oberti, Frédéric; Moal, Valérie; Fouchard Hubert, Isabelle; Bertrais, Sandrine; Hunault, Gilles; Rousselet, Marie Christine

    2018-04-01

    Fibrosis blood tests are usually developed using significant fibrosis, which is a unique diagnostic target; however, these tests are employed for other diagnostic targets, such as cirrhosis. We aimed to improve fibrosis staging accuracy by simultaneously targeting biomarkers for several diagnostic targets. A total of 3,809 patients were included, comprising 1,012 individuals with chronic hepatitis C (CHC) into a derivation population and 2,797 individuals into validation populations of different etiologies (CHC, chronic hepatitis B, human immunodeficiency virus/CHC, nonalcoholic fatty liver disease, alcohol) using Metavir fibrosis stages as reference. FibroMeter biomarkers were targeted for different fibrosis-stage combinations into classical scores by logistic regression. Independent scores were combined into a single score reflecting Metavir stages by linear regression and called Multi-FibroMeter Version Second Generation (V2G). The primary objective was to combine the advantages of a test targeted for significant fibrosis (FibroMeter V2G ) with those of a test targeted for cirrhosis (CirrhoMeter V2G ). In the derivation CHC population, we first compared Multi-FibroMeter V2G to FibroMeter V2G and observed significant increases in the cirrhosis area under the receiver operating characteristic curve (AUROC), Obuchowski index (reflecting all fibrosis-stage AUROCs), and classification metric (six classes expressed as a correctly classified percentage) and a nonsignificant increase in significant fibrosis AUROC. Thereafter, we compared it to CirroMeter V2G and observed a nonsignificant increase in the cirrhosis AUROC. In all 3,809 patients, respective accuracies for Multi-FibroMeter V2G and FibroMeter V2G were the following: cirrhosis AUROC, 0.906 versus 0.878 ( P fibrosis AUROC, 0.833 versus 0.832 ( P = 0.366). Multi-FibroMeter V2G had the highest correlation with the area of portoseptal fibrosis and the highest reproducibility over time. Correct classification rates

  14. Lassa virus infection in experimentally infected marmosets: liver pathology and immunophenotypic alterations in target tissues.

    Science.gov (United States)

    Carrion, Ricardo; Brasky, Kathleen; Mansfield, Keith; Johnson, Curtis; Gonzales, Monica; Ticer, Anysha; Lukashevich, Igor; Tardif, Suzette; Patterson, Jean

    2007-06-01

    Lassa virus causes thousands of deaths annually in western Africa and is considered a potential biological weapon. In an attempt to develop a small nonhuman primate model of Lassa fever, common marmosets were subcutaneously inoculated with Lassa virus strain Josiah. This inoculation resulted in a systemic disease with clinical and morphological features mirroring those in fatal human Lassa infection: fever, weight loss, high viremia and viral RNA load in tissues, elevated liver enzymes, and severe morbidity between days 15 and 20. The most prominent histopathology findings included multifocal hepatic necrosis with mild inflammation and hepatocyte proliferation, lymphoid depletion, and interstitial nephritis. Cellular aggregates in regions of hepatocellular necrosis were largely composed of HAM56-positive macrophages, devoid of CD3-positive and CD20-positive cells, and characterized by marked reductions in the intensity of HLA-DP, DQ, DR staining. A marked reduction in the major histocompatibility complex class II expression was also observed in the lymph nodes. Immunophenotypic alterations in spleen included reductions in overall numbers of CD20-positive and CD3-positive cells and the disruption of lymphoid follicular architecture. These findings identify the common marmoset as an appropriate model of human Lassa fever and present the first experimental evidence that replication of Lassa virus in tissues is associated with alterations that would be expected to impair adaptive immunity.

  15. Quantitative Proteome Analysis of Mouse Liver Lysosomes Provides Evidence for Mannose 6-phosphate-independent Targeting Mechanisms of Acid Hydrolases in Mucolipidosis II.

    Science.gov (United States)

    Markmann, Sandra; Krambeck, Svenja; Hughes, Christopher J; Mirzaian, Mina; Aerts, Johannes M F G; Saftig, Paul; Schweizer, Michaela; Vissers, Johannes P C; Braulke, Thomas; Damme, Markus

    2017-03-01

    The efficient receptor-mediated targeting of soluble lysosomal proteins to lysosomes requires the modification with mannose 6-phosphate (M6P) residues. Although the absence of M6P results in misrouting and hypersecretion of lysosomal enzymes in many cells, normal levels of lysosomal enzymes have been reported in liver of patients lacking the M6P-generating phosphotransferase (PT). The identity of lysosomal proteins depending on M6P has not yet been comprehensively analyzed. In this study we purified lysosomes from liver of PT-defective mice and 67 known soluble lysosomal proteins were identified that illustrated quantitative changes using an ion mobility-assisted data-independent label-free LC-MS approach. After validation of various differentially expressed lysosomal components by Western blotting and enzyme activity assays, the data revealed a small number of lysosomal proteins depending on M6P, including neuraminidase 1, cathepsin F, Npc2, and cathepsin L, whereas the majority reach lysosomes by alternative pathways. These data were compared with findings on cultured hepatocytes and liver sinusoid endothelial cells isolated from the liver of wild-type and PT-defective mice. Our findings show that the relative expression, targeting efficiency and lysosomal localization of lysosomal proteins tested in cultured hepatic cells resemble their proportion in isolated liver lysosomes. Hypersecretion of newly synthesized nonphosphorylated lysosomal proteins suggest that secretion-recapture mechanisms contribute to maintain major lysosomal functions in liver. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Inflammatory myofibroblastic tumor of the larynx-a case report.

    Science.gov (United States)

    Do, Bao Anh; Varshney, Rickul; Zawawi, Faisal; Levental, Mark; Caglar, Derin; Young, Jonathan

    2014-03-01

    Inflammatory myofibroblastic tumor (IMT) is a borderline neoplasm with uncertain malignant potential. It is a rare disease also referred to as an inflammatory pseudotumor, a plasma cell granuloma, and an inflammatory fibrosarcoma. IMT rarely also involves the head and neck region with only 50 cases of laryngeal IMT reported in the literature, and this is the first case with reported magnetic resonance imaging (MRI) findings. A 37-year-old man with a 1-year history of hoarseness, dysphagia, and fatigue presented with a right vocal fold submucosal mass and was treated conservatively. The MRI of the neck revealed a mildly spontaneously hyperintense right true vocal fold on GRE images and relative hyperintensity on fat-saturation T2-weighted images. A biopsy of the right-sided submucosal laryngeal mass was performed and the pathologic examination revealed a lesion consistent with an IMT. IMT is a borderline neoplasm with uncertain malignant potential. There are many variants of IMT and its etiology is not truly understood. In general, IMT of the larynx has a benign clinical course with low rates of recurrence. Copyright © 2014 The Voice Foundation. Published by Mosby, Inc. All rights reserved.

  17. Vitamin A-coupled liposome system targeting free cholesterol accumulation in hepatic stellate cells offers a beneficial therapeutic strategy for liver fibrosis.

    Science.gov (United States)

    Furuhashi, Hirotaka; Tomita, Kengo; Teratani, Toshiaki; Shimizu, Motonori; Nishikawa, Makoto; Higashiyama, Masaaki; Takajo, Takeshi; Shirakabe, Kazuhiko; Maruta, Koji; Okada, Yoshikiyo; Kurihara, Chie; Watanabe, Chikako; Komoto, Shunsuke; Aosasa, Suefumi; Nagao, Shigeaki; Yamamoto, Junji; Miura, Soichiro; Hokari, Ryota

    2018-04-01

    Liver fibrosis is a life-threatening disorder for which no approved therapy is available. Recently, we reported that mouse hepatic stellate cell (HSC) activation increased free cholesterol (FC) accumulation, partly by enhancing signaling through sterol regulatory element-binding protein 2 (SREBP2) and microRNA-33a (miR-33a), which resulted in HSC sensitization to transforming growth factor-β (TGFβ)-induced activation in a "vicious cycle" of liver fibrosis. Human HSCs were isolated from surgical liver specimens from control patients and patients with liver fibrosis. C57BL/6 mice were treated with carbon tetrachloride for 4 weeks and concurrently given SREBP2-siRNA- or anti-miR-33a-bearing vitamin A-coupled liposomes. In human activated HSCs obtained from patients with liver fibrosis, FC accumulation was enhanced independently of serum cholesterol levels through increased signaling by both SREBP2 and miR-33a. This increased FC accumulation enhanced Toll-like receptor 4 (TLR4) protein levels and lowered the TGFβ-pseudoreceptor Bambi (bone morphogenetic protein and activin membrane-bound inhibitor) mRNA levels in HSCs. Notably, in a mouse liver fibrosis model, reduction of FC accumulation, specifically in activated HSCs by suppression of SREBP2 or miR-33a expression using SREBP2-siRNA- or anti-miR-33a-bearing vitamin A-coupled liposomes, downregulated TLR4 signaling, increased Bambi expression, and consequently ameliorated liver fibrosis. Our results suggest that FC accumulation in HSCs, as an intracellular mediator promoting HSC activation, contributes to a vicious cycle of HSC activation in human and mouse liver fibrosis independent of serum cholesterol levels. Targeting FC accumulation-related molecules in HSCs through a vitamin A-coupled liposomal system represents a favorable therapeutic strategy for liver fibrosis. © 2017 The Japan Society of Hepatology.

  18. Simvastatin induces apoptosis by a Rho-dependent mechanism in cultured cardiac fibroblasts and myofibroblasts

    International Nuclear Information System (INIS)

    Copaja, Miguel; Venegas, Daniel; Aranguiz, Pablo; Canales, Jimena; Vivar, Raul; Catalan, Mabel; Olmedo, Ivonne; Rodriguez, Andrea E.; Chiong, Mario; Leyton, Lisette; Lavandero, Sergio; Diaz-Araya, Guillermo

    2011-01-01

    Several clinical trials have shown the beneficial effects of statins in the prevention of coronary heart disease. Additionally, statins promote apoptosis in vascular smooth muscle cells, in renal tubular epithelial cells and also in a variety of cell lines; yet, the effects of statins on cardiac fibroblast and myofibroblast, primarily responsible for cardiac tissue healing are almost unknown. Here, we investigated the effects of simvastatin on cardiac fibroblast and myofibroblast viability and studied the molecular cell death mechanism triggered by simvastatin in both cell types. Methods: Rat neonatal cardiac fibroblasts and myofibroblasts were treated with simvastatin (0.1-10 μM) up to 72 h. Cell viability and apoptosis were evaluated by trypan blue exclusion method and by flow cytometry, respectively. Caspase-3 activation and Rho protein levels and activity were also determined by Western blot and pull-down assay, respectively. Results: Simvastatin induces caspase-dependent apoptosis of cardiac fibroblasts and myofibroblasts in a concentration- and time-dependent manner, with greater effects on fibroblasts than myofibroblasts. These effects were prevented by mevalonate, farnesylpyrophosphate and geranylgeranylpyrophosphate, but not squalene. These last results suggest that apoptosis was dependent on small GTPases of the Rho family rather than Ras. Conclusion: Simvastatin triggered apoptosis of cardiac fibroblasts and myofibroblasts by a mechanism independent of cholesterol synthesis, but dependent of isoprenilation of Rho protein. Additionally, cardiac fibroblasts were more susceptible to simvastatin-induced apoptosis than cardiac myofibroblasts. Thus simvastatin could avoid adverse cardiac remodeling leading to a less fibrotic repair of the damaged tissues. - Research Highlights: → Simvastatin decreases CF and CMF viability independent of cholesterol synthesis. → Simvastatin induces CF and CMF apoptosis in a caspase-dependent manner being CMF more resistant

  19. Liver tumor formation by a mutant retinoblastoma protein in the transgenic mice is caused by an upregulation of c-Myc target genes

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Bo; Hikosaka, Keisuke; Sultana, Nishat; Sharkar, Mohammad Tofael Kabir [Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Noritake, Hidenao [Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Kimura, Wataru; Wu, Yi-Xin [Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Kobayashi, Yoshimasa [Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Uezato, Tadayoshi [Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Miura, Naoyuki, E-mail: nmiura@hama-med.ac.jp [Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Fifty percent of the mutant Rb transgenic mice produced liver tumors. Black-Right-Pointing-Pointer In the tumor, Foxm1, Skp2, Bmi1 and AP-1 mRNAs were up-regulated. Black-Right-Pointing-Pointer No increase in expression of the Myc-target genes was observed in the non-tumorous liver. Black-Right-Pointing-Pointer Tumor formation depends on up-regulation of the Myc-target genes. -- Abstract: The retinoblastoma (Rb) tumor suppressor encodes a nuclear phosphoprotein that regulates cellular proliferation, apoptosis and differentiation. In order to adapt itself to these biological functions, Rb is subjected to modification cycle, phosphorylation and dephosphorylation. To directly determine the effect of phosphorylation-resistant Rb on liver development and function, we generated transgenic mice expressing phosphorylation-resistant human mutant Rb (mt-Rb) under the control of the rat hepatocyte nuclear factor-1 gene promoter/enhancer. Expression of mt-Rb in the liver resulted in macroscopic neoplastic nodules (adenomas) with {approx}50% incidence within 15 months old. Interestingly, quantitative reverse transcriptase-PCR analysis showed that c-Myc was up-regulated in the liver of mt-Rb transgenic mice irrespective of having tumor tissues or no tumor. In tumor tissues, several c-Myc target genes, Foxm1, c-Jun, c-Fos, Bmi1 and Skp2, were also up-regulated dramatically. We determined whether mt-Rb activated the Myc promoter in the HTP9 cells and demonstrated that mt-Rb acted as an inhibitor of wild-type Rb-induced repression on the Myc promoter. Our results suggest that continued upregulation of c-Myc target genes promotes the liver tumor formation after about 1 year of age.

  20. Low intensity 635 nm diode laser irradiation inhibits fibroblast-myofibroblast transition reducing TRPC1 channel expression/activity: New perspectives for tissue fibrosis treatment.

    Science.gov (United States)

    Sassoli, Chiara; Chellini, Flaminia; Squecco, Roberta; Tani, Alessia; Idrizaj, Eglantina; Nosi, Daniele; Giannelli, Marco; Zecchi-Orlandini, Sandra

    2016-03-01

    Low-level laser therapy (LLLT) or photobiomodulation therapy is emerging as a promising new therapeutic option for fibrosis in different damaged and/or diseased organs. However, the anti-fibrotic potential of this treatment needs to be elucidated and the cellular and molecular targets of the laser clarified. Here, we investigated the effects of a low intensity 635 ± 5 nm diode laser irradiation on fibroblast-myofibroblast transition, a key event in the onset of fibrosis, and elucidated some of the underlying molecular mechanisms. NIH/3T3 fibroblasts were cultured in a low serum medium in the presence of transforming growth factor (TGF)-β1 and irradiated with a 635 ± 5 nm diode laser (continuous wave, 89 mW, 0.3 J/cm(2) ). Fibroblast-myofibroblast differentiation was assayed by morphological, biochemical, and electrophysiological approaches. Expression of matrix metalloproteinase (MMP)-2 and MMP-9 and of Tissue inhibitor of MMPs, namely TIMP-1 and TIMP-2, after laser exposure was also evaluated by confocal immunofluorescence analyses. Moreover, the effect of the diode laser on transient receptor potential canonical channel (TRPC) 1/stretch-activated channel (SAC) expression and activity and on TGF-β1/Smad3 signaling was investigated. Diode laser treatment inhibited TGF-β1-induced fibroblast-myofibroblast transition as judged by reduction of stress fibers formation, α-smooth muscle actin (sma) and type-1 collagen expression and by changes in electrophysiological properties such as resting membrane potential, cell capacitance and inwardly rectifying K(+) currents. In addition, the irradiation up-regulated the expression of MMP-2 and MMP-9 and downregulated that of TIMP-1 and TIMP-2 in TGF-β1-treated cells. This laser effect was shown to involve TRPC1/SAC channel functionality. Finally, diode laser stimulation and TRPC1 functionality negatively affected fibroblast-myofibroblast transition by interfering with TGF-β1 signaling, namely reducing the

  1. Translation of Angiotensin-Converting Enzyme 2 upon Liver- and Lung-Targeted Delivery of Optimized Chemically Modified mRNA

    Directory of Open Access Journals (Sweden)

    Eva Schrom

    2017-06-01

    Full Text Available Changes in lifestyle and environmental conditions give rise to an increasing prevalence of liver and lung fibrosis, and both have a poor prognosis. Promising results have been reported for recombinant angiotensin-converting enzyme 2 (ACE2 protein administration in experimental liver and lung fibrosis. However, the full potential of ACE2 may be achieved by localized translation of a membrane-anchored form. For this purpose, we advanced the latest RNA technology for liver- and lung-targeted ACE2 translation. We demonstrated in vitro that transfection with ACE2 chemically modified messenger RNA (cmRNA leads to robust translation of fully matured, membrane-anchored ACE2 protein. In a second step, we designed eight modified ACE2 cmRNA sequences and identified a lead sequence for in vivo application. Finally, formulation of this ACE2 cmRNA in tailor-made lipidoid nanoparticles and in lipid nanoparticles led to liver- and lung-targeted translation of significant amounts of ACE2 protein, respectively. In summary, we provide evidence that RNA transcript therapy (RTT is a promising approach for ACE2-based treatment of liver and lung fibrosis to be tested in fibrotic disease models.

  2. The aryl hydrocarbon receptor ligand ITE inhibits TGFβ1-induced human myofibroblast differentiation.

    Science.gov (United States)

    Lehmann, Geniece M; Xi, Xia; Kulkarni, Ajit A; Olsen, Keith C; Pollock, Stephen J; Baglole, Carolyn J; Gupta, Shikha; Casey, Ann E; Huxlin, Krystel R; Sime, Patricia J; Feldon, Steven E; Phipps, Richard P

    2011-04-01

    Fibrosis can occur in any human tissue when the normal wound healing response is amplified. Such amplification results in fibroblast proliferation, myofibroblast differentiation, and excessive extracellular matrix deposition. Occurrence of these sequelae in organs such as the eye or lung can result in severe consequences to health. Unfortunately, medical treatment of fibrosis is limited by a lack of safe and effective therapies. These therapies may be developed by identifying agents that inhibit critical steps in fibrotic progression; one such step is myofibroblast differentiation triggered by transforming growth factor-β1 (TGFβ1). In this study, we demonstrate that TGFβ1-induced myofibroblast differentiation is blocked in human fibroblasts by a candidate endogenous aryl hydrocarbon receptor (AhR) ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Our data show that ITE disrupts TGFβ1 signaling by inhibiting the nuclear translocation of Smad2/3/4. Although ITE functions as an AhR agonist, and biologically persistent AhR agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, cause severe toxic effects, ITE exhibits no toxicity. Interestingly, ITE effectively inhibits TGFβ1-driven myofibroblast differentiation in AhR(-/-) fibroblasts: Its ability to inhibit TGFβ1 signaling is AhR independent. As supported by the results of this study, the small molecule ITE inhibits myofibroblast differentiation and may be useful clinically as an antiscarring agent. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  3. Low-grade myofibroblastic sarcoma arising in fibroadenoma of the breast-A case report.

    Science.gov (United States)

    Myong, Na-Hye; Min, Jun-Won

    2016-03-25

    Myofibroblastic sarcoma or myofibrosarcoma is a malignant tumor of myofibroblasts and known to develop rarely in the breast, but its underlying lesion and tumor cell origin have never been reported yet. A 61-year-old female presented with a gradually growing breast mass with well-demarcated ovoid nodular shape. The tumor was histologically characterized by fascicular-growing spindle cell proliferation with large areas of hyalinized fibrosis and focally ductal epithelial remnants embedded in myxoid stroma, mimicking a fibroadenomatous lesion. It had frequent mitoses of 5-16/10 high-power fields, hemorrhagic necrosis, and focally pericapsular invasion. The spindle cells were diffusely immunoreactive for fibronectin, smooth muscle actin, and calponin, which suggest a myofibroblastic origin. Multiple irregularly thickened vessels with medial or pericytic cell proliferation were found to be merged with the intrinsic tumor cells. The tumor could be diagnosed low-grade myofibroblastic sarcoma arising in an old fibroadenoma. We report a case of a low-grade mammary myofibrosarcoma that showed a background lesion of fibroadenoma first in the worldwide literature and suggest the pericytes or medial muscle cells of the intratumoral vessels as the cell origin of the myofibroblastic sarcoma.

  4. In Silico Identification of Proteins Associated with Drug-induced Liver Injury Based on the Prediction of Drug-target Interactions.

    Science.gov (United States)

    Ivanov, Sergey; Semin, Maxim; Lagunin, Alexey; Filimonov, Dmitry; Poroikov, Vladimir

    2017-07-01

    Drug-induced liver injury (DILI) is the leading cause of acute liver failure as well as one of the major reasons for drug withdrawal from clinical trials and the market. Elucidation of molecular interactions associated with DILI may help to detect potentially hazardous pharmacological agents at the early stages of drug development. The purpose of our study is to investigate which interactions with specific human protein targets may cause DILI. Prediction of interactions with 1534 human proteins was performed for the dataset with information about 699 drugs, which were divided into three categories of DILI: severe (178 drugs), moderate (310 drugs) and without DILI (211 drugs). Based on the comparison of drug-target interactions predicted for different drugs' categories and interpretation of those results using clustering, Gene Ontology, pathway and gene expression analysis, we identified 61 protein targets associated with DILI. Most of the revealed proteins were linked with hepatocytes' death caused by disruption of vital cellular processes, as well as the emergence of inflammation in the liver. It was found that interaction of a drug with the identified targets is the essential molecular mechanism of the severe DILI for the most of the considered pharmaceuticals. Thus, pharmaceutical agents interacting with many of the identified targets may be considered as candidates for filtering out at the early stages of drug research. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. TCDD dysregulation of 13 AHR-target genes in rat liver

    International Nuclear Information System (INIS)

    Watson, John D.; Prokopec, Stephenie D.; Smith, Ashley B.; Okey, Allan B.; Pohjanvirta, Raimo; Boutros, Paul C.

    2014-01-01

    Despite several decades of research, the complete mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other xenobiotic agonists of the aryl hydrocarbon receptor (AHR) cause toxicity remains unclear. While it has been shown that the AHR is required for all major manifestations of toxicity, the specific downstream changes involved in the development of toxic phenotypes remain unknown. Here we examine a panel of 13 genes that are AHR-regulated in many species and tissues. We profiled their hepatic mRNA abundances in two rat strains with very different sensitivities to TCDD: the TCDD-sensitive Long–Evans (Turku/AB; L–E) and the TCDD-resistant Han/Wistar (Kuopio; H/W). We evaluated doses ranging from 0 to 3000 μg/kg at 19 h after TCDD exposure and time points ranging from 1.5 to 384 h after exposure to 100 μg/kg TCDD. Twelve of 13 genes responded to TCDD in at least one strain, and seven of these showed statistically significant inter-strain differences in the time course analysis (Aldh3a1, Cyp1a2, Cyp1b1, Cyp2a1, Fmo1, Nfe2l2 and Nqo1). Cyp2s1 did not respond to TCDD in either rat strain. Five genes exhibited biphasic responses to TCDD insult (Ahrr, Aldh3a1, Cyp1b1, Nfe2l2 and Nqo1), suggesting a secondary event, such as association with additional transcriptional modulators. Of the 12 genes that responded to TCDD during the dose–response analysis, none had an ED 50 equivalent to that of Cyp1a1, the most sensitive gene in this study, while nine genes responded to doses at least 10–100 fold higher, in at least one strain (Ahrr (L–E), Aldh3a1 (both), Cyp1a2 (both), Cyp1b1 (both), Cyp2a1 (L–E), Inmt (both), Nfe2l2 (L–E), Nqo1 (L–E) and Tiparp (both)). These data shed new light on the association of the AHR target genes with TCDD toxicity, and in particular the seven genes exhibiting strain-specific differences represent strong candidate mediators of Type-II toxicities. - Highlights: • NanoString measured hepatic mRNA molecules following

  6. TCDD dysregulation of 13 AHR-target genes in rat liver

    Energy Technology Data Exchange (ETDEWEB)

    Watson, John D., E-mail: john.watson@oicr.on.ca [Ontario Institute for Cancer Research, Department of Informatics and Bio-computing Program, Toronto (Canada); Prokopec, Stephenie D., E-mail: stephenie.prokopec@oicr.on.ca [Ontario Institute for Cancer Research, Department of Informatics and Bio-computing Program, Toronto (Canada); Smith, Ashley B., E-mail: ashleyblaines@gmail.com [Ontario Institute for Cancer Research, Department of Informatics and Bio-computing Program, Toronto (Canada); Okey, Allan B., E-mail: allan.okey@utoronto.ca [Department of Pharmacology and Toxicology, University of Toronto, Toronto (Canada); Pohjanvirta, Raimo, E-mail: raimo.pohjanvirta@helsinki.fi [Laboratory of Toxicology, National Institute for Health and Welfare, Kuopio (Finland); Department of Food Hygiene and Environmental Health, University of Helsinki, Helsinki (Finland); Boutros, Paul C., E-mail: paul.boutros@oicr.on.ca [Ontario Institute for Cancer Research, Department of Informatics and Bio-computing Program, Toronto (Canada); Department of Pharmacology and Toxicology, University of Toronto, Toronto (Canada); Department of Medical Biophysics, University of Toronto, Toronto (Canada)

    2014-02-01

    Despite several decades of research, the complete mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other xenobiotic agonists of the aryl hydrocarbon receptor (AHR) cause toxicity remains unclear. While it has been shown that the AHR is required for all major manifestations of toxicity, the specific downstream changes involved in the development of toxic phenotypes remain unknown. Here we examine a panel of 13 genes that are AHR-regulated in many species and tissues. We profiled their hepatic mRNA abundances in two rat strains with very different sensitivities to TCDD: the TCDD-sensitive Long–Evans (Turku/AB; L–E) and the TCDD-resistant Han/Wistar (Kuopio; H/W). We evaluated doses ranging from 0 to 3000 μg/kg at 19 h after TCDD exposure and time points ranging from 1.5 to 384 h after exposure to 100 μg/kg TCDD. Twelve of 13 genes responded to TCDD in at least one strain, and seven of these showed statistically significant inter-strain differences in the time course analysis (Aldh3a1, Cyp1a2, Cyp1b1, Cyp2a1, Fmo1, Nfe2l2 and Nqo1). Cyp2s1 did not respond to TCDD in either rat strain. Five genes exhibited biphasic responses to TCDD insult (Ahrr, Aldh3a1, Cyp1b1, Nfe2l2 and Nqo1), suggesting a secondary event, such as association with additional transcriptional modulators. Of the 12 genes that responded to TCDD during the dose–response analysis, none had an ED{sub 50} equivalent to that of Cyp1a1, the most sensitive gene in this study, while nine genes responded to doses at least 10–100 fold higher, in at least one strain (Ahrr (L–E), Aldh3a1 (both), Cyp1a2 (both), Cyp1b1 (both), Cyp2a1 (L–E), Inmt (both), Nfe2l2 (L–E), Nqo1 (L–E) and Tiparp (both)). These data shed new light on the association of the AHR target genes with TCDD toxicity, and in particular the seven genes exhibiting strain-specific differences represent strong candidate mediators of Type-II toxicities. - Highlights: • NanoString measured hepatic mRNA molecules

  7. Adenovirus-Mediated Delivery of Decoy Hyper Binding Sites Targeting Oncogenic HMGA1 Reduces Pancreatic and Liver Cancer Cell Viability.

    Science.gov (United States)

    Hassan, Faizule; Ni, Shuisong; Arnett, Tyler C; McKell, Melanie C; Kennedy, Michael A

    2018-03-30

    High mobility group AT-hook 1 (HMGA1) protein is an oncogenic architectural transcription factor that plays an essential role in early development, but it is also implicated in many human cancers. Elevated levels of HMGA1 in cancer cells cause misregulation of gene expression and are associated with increased cancer cell proliferation and increased chemotherapy resistance. We have devised a strategy of using engineered viruses to deliver decoy hyper binding sites for HMGA1 to the nucleus of cancer cells with the goal of sequestering excess HMGA1 at the decoy hyper binding sites due to binding competition. Sequestration of excess HMGA1 at the decoy binding sites is intended to reduce HMGA1 binding at the naturally occurring genomic HMGA1 binding sites, which should result in normalized gene expression and restored sensitivity to chemotherapy. As proof of principle, we engineered the replication defective adenovirus serotype 5 genome to contain hyper binding sites for HMGA1 composed of six copies of an individual HMGA1 binding site, referred to as HMGA-6. A 70%-80% reduction in cell viability and increased sensitivity to gemcitabine was observed in five different pancreatic and liver cancer cell lines 72 hr after infection with replication defective engineered adenovirus serotype 5 virus containing the HMGA-6 decoy hyper binding sites. The decoy hyper binding site strategy should be general for targeting overexpression of any double-stranded DNA-binding oncogenic transcription factor responsible for cancer cell proliferation.

  8. How many sets of 4DCT images are sufficient to determine internal target volume for liver radiotherapy?

    International Nuclear Information System (INIS)

    Xi Mian; Liu Mengzhong; Zhang Li; Li Qiaoqiao; Huang Xiaoyan; Liu Hui; Hu Yonghong

    2009-01-01

    Background and purpose: To determine the feasibility of using limited four-dimensional computed tomography (4DCT) images for treatment planning. Materials and methods: The 4DCT scans of 16 patients with hepatocellular carcinoma (HCC) were analyzed. Gross tumor volumes (GTVs) were manually contoured on all 10 respiratory phases, and different internal clinical target volumes (ICTVs) were derived by encompassing volumes of the respective CTVs. Volume, position, and shape of ICTVs were calculated and compared. Results: The ICTV 2phases , ICTV 3phases , ICTV 4phases , and ICTV 6phases all showed excellent agreement with ICTV 10phases , and the ICTV 2phases encompassed ICTV 10phases by 94.1 ± 1.8% on average. The 3D shift between the centers of mass of the ICTVs was only 0.6 mm. The surface distance between ICTV 10phases and ICTV 2phases was 1.7 ± 0.8 mm in the left-right (LR) and anteroposterior (AP) directions. Conclusions: Contouring two extreme phases at end-inhalation and end-exhalation is a reasonably safe and labor-saving method of deriving ITV for liver radiotherapy with low and medium tumor motion amplitude (≤1.6 cm). Whether the larger tumor movement affects the results is the subject of ongoing research.

  9. Inflammatory myofibroblastic tumor appendix with concomitant mucosal dysplasia, simulating pseudomyxoma on preoperative aspiration cytology

    Directory of Open Access Journals (Sweden)

    Kaushik Majumdar

    2012-01-01

    Full Text Available Inflammatory myofibroblastic tumor (IMT has been described as a pseudosarcomatous proliferation of spindled myofibroblasts admixed with lymphoplasmacytic cells. The various terminologies like inflammatory pseudotumor, plasma cell granuloma, and inflammatory myofibrohistiocytic proliferation, used to describe this entity, highlight the controversial etiopathogenesis of this relatively indolent neoplasm. IMT has now been described in different anatomic locations. However, cases occurring in the gastrointestinal tract are rare with very few cases described in the appendix. We present a case of inflammatory myofibroblastic tumor appendix with mucosal dysplasia in a 41-year-old male, presenting with abdominal pain and lump in the right iliac fossa. Aspiration cytology yielded few atypical epithelial cells and spindle cells in a mucinous background, suggesting the possibility of pseudomyxoma peritonei. Awareness of IMT appendix with rare presence of mucosal dysplasia may help in preventing overzealous resection, especially in situations that on preoperative evaluation may suggest malignancy.

  10. [Structure and function of suburothelial myofibroblasts in the human urinary bladder under normal and pathological conditions].

    Science.gov (United States)

    Neuhaus, J; Heinrich, M; Schlichting, N; Oberbach, A; Fitzl, G; Schwalenberg, T; Horn, L-C; Stolzenburg, J-U

    2007-09-01

    Myofibroblasts play a pivotal role in numerous pathological alterations. Clarification of the structure and function and of the cellular plasticity of this cell type in the bladder may lead to new insights into the pathogenesis of lower urinary tract disorders. Bladder biopsies from patients with bladder carcinoma and interstitial cystitis were used to analyse the morphology and receptor expression using confocal immunofluorescence and electron microscopy. Cytokine effects and coupling behavior were tested in cultured myofibroblasts and detrusor smooth muscle cells. Myofibroblasts are in close contact with the suburothelial capillary network. They express Cx43 and form functional syncytia. The expression of muscarinic and purinergic receptors is highly variable. Dye coupling experiments showed differences to detrusor myocytes. Upregulation of smooth muscle cell alpha-actin and/or transdifferentiation into smooth muscle cells may contribute to the etiology of urge incontinence. A multi-step model is presented as a working hypothesis.

  11. Liver cell-derived microparticles activate hedgehog signaling and alter gene expression in hepatic endothelial cells.

    Science.gov (United States)

    Witek, Rafal P; Yang, Liu; Liu, Renshui; Jung, Youngmi; Omenetti, Alessia; Syn, Wing-Kin; Choi, Steve S; Cheong, Yeiwon; Fearing, Caitlin M; Agboola, Kolade M; Chen, Wei; Diehl, Anna Mae

    2009-01-01

    Angiogenesis contributes to vascular remodeling during cirrhosis. In cirrhotic livers, cholangiocytes, and myofibroblastic hepatic stellate cells (MF-HSC) produce Hedgehog (Hh) ligands. During embryogenesis Hh ligands are released from ligand-producing cells in microparticles and activate Hh signaling in endothelial cells. We studied whether adult liver cell-derived microparticles contain Hh ligands that alter hepatic sinusoidal endothelial cells (SEC). MF-HSC and cholangiocytes were exposed to platelet-derived growth factor to induce Hh ligands; microparticles were isolated from medium, analyzed by transmission electron microscopy and immunoblots, and applied to Hh-reporter-containing cells. Microparticles were obtained from serum and bile of rats after bile duct ligation (BDL) or sham surgery and applied to normal primary liver SEC with or without cyclopamine, an Hh signaling inhibitor. Effects on SEC gene expression were evaluated by quantitative reverse-transcription polymerase chain reaction and immunoblotting. Hh target gene expression and SEC activation markers were compared in primary SEC and in liver sections from healthy and BDL rats. Platelet-derived growth factor-treated MF-HSC and cholangiocytes released exosome-enriched microparticles containing biologically-active Hh ligands. BDL increased release of Hh-containing exosome-enriched microparticles into plasma and bile. Transmission electron microscopy and immunoblots revealed similarities among microparticles from all sources; all microparticles induced similar Hh-dependent changes in SEC gene expression. SEC from healthy livers did not express Hh target genes or activation markers, but both were up-regulated in SEC after BDL. Hh-containing exosome-enriched microparticles released from liver cells alter hepatic SEC gene expression, suggesting a novel mechanism for cirrhotic vasculopathy.

  12. The I kappa B kinase inhibitor ACHP strongly attenuates TGF beta 1-induced myofibroblast formation and collagen synthesis

    NARCIS (Netherlands)

    Mia, Masum M.; Bank, Ruud A.

    2015-01-01

    Excessive accumulation of a collagen-rich extracellular matrix (ECM) by myofibroblasts is a characteristic feature of fibrosis, a pathological state leading to serious organ dysfunction. Transforming growth factor beta1 (TGF beta 1) is a strong inducer of myofibroblast formation and subsequent

  13. Targeting of VX2 Rabbit Liver Tumor by Selective Delivery of 3-Bromopyruvate: A Biodistribution and Survival Study

    Science.gov (United States)

    Vali, Mustafa; Vossen, Josephina A.; Buijs, Manon; Engles, James M.; Liapi, Eleni; Ventura, Veronica Prieto; Khwaja, Afsheen; Acha-Ngwodo, Obele; Shanmugasundaram, Ganapathy; Syed, Labiq; Wahl, Richard L.; Geschwind, Jean-Francois H.

    2009-01-01

    The aim of this study was to determine the biodistribution and tumor targeting ability of 14C-labeled 3-bromopyruvate ([14C]3-BrPA) after i.a. and i.v. delivery in the VX2 rabbit model. In addition, we evaluated the effects of [14C]3-BrPA on tumor and healthy tissue glucose metabolism by determining 18F-deoxyglucose (FDG) uptake. Last, we determined the survival benefit of i.a. administered 3-BrPA. In total, 60 rabbits with VX2 liver tumor received either 1.75 mM [14C]3-BrPA i.a., 1.75 mM [14C]3-BrPA i.v., 20 mM [14C]3-BrPA i.v., or 25 ml of phosphate-buffered saline (PBS). All rabbits (with the exception of the 20 mM i.v. group) received FDG 1 h before sacrifice. Next, we compared survival of animals treated with i.a. administered 1.75 mM [14C]3-BrPA in 25 ml of PBS (n = 22) with controls (n = 10). After i.a. infusion, tumor uptake of [14C]3-BrPA was 1.8 ± 0.2% percentage of injected dose per gram of tissue (%ID/g), whereas other tissues showed minimal uptake. After i.v. infusion (1.75 mM), tumor uptake of [14C]3-BrPA was 0.03 ± 0.01% ID/g. After i.a. administration of [14C]3-BrPA, tumor uptake of FDG was 26 times lower than in controls. After i.v. administration of [14C]3-BrPA, there was no significant difference in tumor FDG uptake. Survival analysis showed that rabbits treated with 1.75 mM 3-BrPA survived longer (55 days) than controls (18.6 days). Intra-arterially delivered 3-BrPA has a favorable biodistribution profile, combining a high tumor uptake resulting in blockage of FDG uptake with no effects on healthy tissue. The local control of the liver tumor by 3-BrPA resulted in a significant survival benefit. PMID:18591216

  14. Nanosized As2O3/Fe2O3 complexes combined with magnetic fluid hyperthermia selectively target liver cancer cells.

    Science.gov (United States)

    Wang, Zi-Yu; Song, Jian; Zhang, Dong-Sheng

    2009-06-28

    To study the methods of preparing the magnetic nano-microspheres of Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) complexes and their therapeutic effects with magnetic fluid hyperthermia (MFH). Nanospheres were prepared by chemical co-precipitation and their shape and diameter were observed. Hemolysis, micronucleus, cell viability, and LD(50) along with other in vivo tests were performed to evaluate the Fe(2)O(3) microsphere biocompatibility. The inhibition ratio of tumors after Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) injections combined with induced hyperthermia in xenograft human hepatocarcinoma was calculated. Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) particles were round with an average diameter of 20 nm and 100 nm as observed under transmission electron microscope. Upon exposure to an alternating magnetic field (AMF), the temperature of the suspension of magnetic particles increased to 41-51 degrees C, depending on different particle concentrations, and remained stable thereafter. Nanosized Fe(2)O(3) microspheres are a new kind of biomaterial without cytotoxic effects. The LD(50) of both Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) in mice was higher than 5 g/kg. One to four weeks after Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) complex injections into healthy pig livers, no significant differences were found in serum AST, ALT, BUN and Cr levels among the pigs of all groups (P > 0.05), and no obvious pathological alterations were observed. After exposure to alternating magnetic fields, the inhibition ratio of the tumors was significantly different from controls in the Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) groups (68.74% and 82.79%, respectively; P < 0.01). Tumors of mice in treatment groups showed obvious necrosis, while normal tissues adjoining the tumor and internal organs did not. Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) complexes exerted radiofrequency-induced hyperthermia and drug toxicity on tumors without any liver or kidney damage. Therefore, nanospheres are ideal carriers for tumor-targeted therapy.

  15. Congenital peribronchial myofibroblastic tumor: prenatal imaging clues to differentiate from other fetal chest lesions

    Energy Technology Data Exchange (ETDEWEB)

    Calvo-Garcia, Maria A.; Bitters, Constance; Kline-Fath, Beth M. [Cincinnati Children' s Hospital Medical Center, Department of Radiology, MLC 5031, Cincinnati, OH (United States); Lim, Foong-Yen [Cincinnati Children' s Hospital Medical Center, Department of Pediatric Surgery and Fetal Care Center of Cincinnati, Cincinnati, OH (United States); Stanek, Jerzy [Cincinnati Children' s Hospital Medical Center, Department of Pathology, Cincinnati, OH (United States)

    2014-04-15

    We present a prenatal case of congenital peribronchial myofibroblastic tumor referred as a congenital pulmonary airway malformation (CPAM) with hydrops and polyhydramnios at 30 weeks' gestational age. US and fetal MRI findings did not fit with the referral diagnosis, raising the possibility of intrinsic lung tumor. Fetal hydrops worsened and the baby was successfully delivered by ex utero intrapartum treatment (EXIT) to resection at 31 weeks' gestational age. To the best of our knowledge, this is a unique case of congenital peribronchial myofibroblastic tumor that underwent comprehensive prenatal evaluation and EXIT procedure with good outcome. (orig.)

  16. Congenital peribronchial myofibroblastic tumor: prenatal imaging clues to differentiate from other fetal chest lesions

    International Nuclear Information System (INIS)

    Calvo-Garcia, Maria A.; Bitters, Constance; Kline-Fath, Beth M.; Lim, Foong-Yen; Stanek, Jerzy

    2014-01-01

    We present a prenatal case of congenital peribronchial myofibroblastic tumor referred as a congenital pulmonary airway malformation (CPAM) with hydrops and polyhydramnios at 30 weeks' gestational age. US and fetal MRI findings did not fit with the referral diagnosis, raising the possibility of intrinsic lung tumor. Fetal hydrops worsened and the baby was successfully delivered by ex utero intrapartum treatment (EXIT) to resection at 31 weeks' gestational age. To the best of our knowledge, this is a unique case of congenital peribronchial myofibroblastic tumor that underwent comprehensive prenatal evaluation and EXIT procedure with good outcome. (orig.)

  17. The Significance of the Stromal Response in Breast Cancer: An Immunohistochemical Study of Myofibroblasts in Primary and Metastatic Breast Cancer.

    Science.gov (United States)

    Roozdar, Alale; Hayes, Malcolm M; Pourseyedei, Bahram; Zeinalinejad, Hamid; Shamsi Meymandi, Manzumeh; Dabiri, Bahram; Dabiri, Shahriar

    2018-05-01

    Gene expression profiling of breast cancer has demonstrated the importance of stromal response in determining the prognosis of invasive breast cancer. The host response to breast cancer is of increasing interest to pathologists and may be a future focus for novel pharmacological treatments. This study describes the pattern of distribution of stromal myofibroblasts using immunostains for CD10 and smooth muscle actin (SMA) in 50 primary breast cancers and their matched nodal metastases (68.6% nodes positive and 31.4% nodes negative). The stroma within the tumor (intratumoral) and at the advancing tumor edge (peri-tumoral) was studied in both primary and nodal sites. A simple quantitative scoring system was employed for both immunostains. The correlation between expression of these markers by stromal cells and standard pathological prognostic factors of stage, grade, hormone receptor and Her-2 status was analysed. SMA-positive stromal cells were more abundant in peri-tumoral stroma compared with intratumoral stroma in both primary and metastatic lesions. SMA expression in the lymph node metastases showed a significant correlation with tumor stage. SMA expression in peri-tumoral stroma correlated with Her-2 status. The results of this study suggest that myofibroblasts, particularly those expressing SMA, might potentiate the progression of the carcinomatous process especially in nodal metastases. Thus these cells may be a potential therapeutic target. © 2018 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

  18. MRI findings of inflammatory myofibroblastic tumor of the soft tissue

    International Nuclear Information System (INIS)

    Deng Demao; Meng Quanfei; Chen Yinming; Zhou Chunxiang; Gao Zhenhua; Yang Zheng; Wang Liantang

    2008-01-01

    Objective: To describe MR findings in inflammatory myofibroblastic tumor (IMT) of the soft tissue. Methods: MR manifestations of 11 cases of IMT of the soft tissue were retrospectively analyzed, and the MR findings were correlated with surgical and histological results. Results: The pathological classification of the tumors was type I in 1 case, type II in 4 cases, mainly type II admixed with type I in 3 cases, and mainly type II admixed with type III in 3 eases. In 4 cases with primary tumor, the tumors were spheroid in shape, with well-defined margin and pseudocapsule. In 2 eases with primary axillary tumor and 5 cases with recurrent tumor, the tumors were irregular in shape, with ill-defined margin and invasion of adjacent structures. The tumors were mainly isointensive in T 1 -weighted images. Tumors of different pathological classifications had different signal intensities in T 2 -weighted images: 1 case of type I tumor was bright; 4 cases of type II tumor and 3 cases of type II tumor admixed with type I tumor were slightly bright; 3 cases of type II tumor admixed with type III were isointense or slightly hypointense in signal. All of the 11 cases in the study exhibited 'pitaya cross-section sign' in T 2 -weighted sequence, which referred to discrete punctuate foci of relatively hypointensity in the background of hyperintensity, slightly hypointensity or isointensity. All of the 11 cases exhibited inhomogeneously significant enhancement after gadolinium administration. In the follow-up of the 6 eases of primary tumor, 4 cases had recurrence, 1 case had no recurrence, and 1 case was lost in the follow-up process. In the follow-up of the 5 cases of recurrent tumor, 4 cases showed recurrence again, and 3 cases were lost in the follow-up process. Conclusions: The IMT of the soft tissue has characteristic MR features. The signal intensity of the tumor on T2-weighted sequence could reflect the pathological type of the tumor' to some extent. 'pitaya cross

  19. miR-21 regulates triglyceride and cholesterol metabolism in non-alcoholic fatty liver disease by targeting HMGCR.

    Science.gov (United States)

    Sun, Chuanzheng; Huang, Feizhou; Liu, Xunyang; Xiao, Xuefei; Yang, Mingshi; Hu, Gui; Liu, Huaizheng; Liao, Liangkan

    2015-03-01

    Non-alcoholic fatty liver disease (NAFLD) has emerged as a public health issue with a prevalence of 15-30% in Western populations and 6-25% in Asian populations. Certain studies have revealed the alteration of microRNA (miRNA or miR) profiles in NAFLD and it has been suggested that miR-21 is associated with NAFLD. In the present study, we measured the serum levels of miR-21 in patients with NAFLD and also performed in vitro experiments using a cellular model of NAFLD to further investigate the effects of miR-21 on triglyceride and cholesterol metabolism. Furthermore, a novel target through which miR-21 exerts its effects on NAFLD was identified. The results revealed that the serum levels of miR-21 were lower in patients with NAFLD compared with the healthy controls. In addition, 3-hydroxy-3-methylglutaryl-co-enzyme A reductase (HMGCR) expression was increased in the serum of patients with NAFLD both at the mRNA and protein level. To mimic the NAFLD condition in vitro, HepG2 cells were treated with palmitic acid (PA) and oleic acid (OA). Consistent with the results obtained in the in vivo experiments, the expression levels of miR-21 were decreased and those of HMGCR were increased in the in vitro model of NAFLD. Luciferase reporter assay revealed that HMGCR was a direct target of miR-21 and that miR-21 exerted an effect on both HMGCR transcript degradation and protein translation. Furthermore, the results from the in vitro experiments revealed that miR-21 decreased the levels of triglycerides (TG), free cholesterol (FC) and total cholesterol (TC) in the PA/OA-treated HepG2 cells and that this effect was attenuated by HMGCR overexpression. Taken together, to the best of our knowledge, the present study is the first to report that miR-21 regulates triglyceride and cholesterol metabolism in an in vitro model of NAFLD, and that this effect is achieved by the inhibition of HMGCR expression. We speculate that miR-21 may be a useful biomarker for the diagnosis and

  20. Antibody-Directed Glucocorticoid Targeting to CD163 in M2-type Macrophages Attenuates Fructose-Induced Liver Inflammatory Changes

    DEFF Research Database (Denmark)

    Svendsen, Pia; Graversen, Jonas Heilskov; Etzerodt, Anders

    2017-01-01

    Increased consumption of high-caloric carbohydrates contributes substantially to endemic non-alcoholic fatty liver disease in humans, covering a histological spectrum from fatty liver to steatohepatitis. Hypercaloric intake and lipogenetic effects of fructose and endotoxin-driven activation...... changes in rats on a high-fructose diet. The diet induced severe non-alcoholic steatohepatitis (NASH)-like changes within a few weeks but the antibody-drug conjugate strongly reduced inflammation, hepatocyte ballooning, fibrosis, and glycogen deposition. Non-conjugated dexamethasone or dexamethasone...... seems to be a promising approach for safe treatment of fructose-induced liver inflammation....

  1. Molecular magnetic resonance imaging of activated hepatic stellate cells with ultrasmall superparamagnetic iron oxide targeting integrin αvβ3 for staging liver fibrosis in rat model

    Directory of Open Access Journals (Sweden)

    Zhang C

    2016-03-01

    Full Text Available Caiyuan Zhang,1,* Huanhuan Liu,1,* Yanfen Cui,1,* Xiaoming Li,1 Zhongyang Zhang,1 Yong Zhang,2 Dengbin Wang1 1Department of Radiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 2MR Advanced Application and Research Center, GE Healthcare China, Shanghai, People’s Republic of China *These authors contributed equally to this work Purpose: To evaluate the expression level of integrin αvβ3 on activated hepatic stellate cells (HSCs at different stages of liver fibrosis induced by carbon tetrachloride (CCl4 in rat model and the feasibility to stage liver fibrosis by using molecular magnetic resonance imaging (MRI with arginine-glycine-aspartic acid (RGD peptide modified ultrasmall superparamagnetic iron oxide nanoparticle (USPIO specifically targeting integrin αvβ3.Materials and methods: All experiments received approval from our Institutional Animal Care and Use Committee. Thirty-six rats were randomly divided into three groups of 12 subjects each, and intraperitoneally injected with CCl4 for either 3, 6, or 9 weeks. Controls (n=10 received pure olive oil. The change in T2* relaxation rate (ΔR2* pre- and postintravenous administration of RGD-USPIO or naked USPIO was measured by 3.0T clinical MRI and compared by one-way analysis of variance or the Student’s t-test. The relationship between expression level of integrin αvβ3 and liver fibrotic degree was evaluated by Spearman’s ranked correlation.Results: Activated HSCs were confirmed to be the main cell types expressing integrin αvβ3 during liver fibrogenesis. The protein level of integrin αv and β3 subunit expressed on activated HSCs was upregulated and correlated well with the progression of liver fibrosis (r=0.954, P<0.001; r=0.931, P<0.001, respectively. After injection of RGD-USPIO, there is significant difference in ΔR2* among rats treated with 0, 3, 6, and 9 weeks of CCl4 (P<0.001. The accumulation of iron particles in fibrotic liver specimen is

  2. In situ targeting of dendritic cells sets tolerogenic environment and ameliorates CD4+ T-cell response in the postischemic liver.

    Science.gov (United States)

    Funken, Dominik; Ishikawa-Ankerhold, Hellen; Uhl, Bernd; Lerchenberger, Maximilian; Rentsch, Markus; Mayr, Doris; Massberg, Steffen; Werner, Jens; Khandoga, Andrej

    2017-11-01

    ., Khandoga, A. In situ targeting of dendritic cells sets tolerogenic environment and ameliorates CD4 + T-cell response in the postischemic liver. © FASEB.

  3. Liver transplant

    Science.gov (United States)

    Hepatic transplant; Transplant - liver; Orthotopic liver transplant; Liver failure - liver transplant; Cirrhosis - liver transplant ... The donated liver may be from: A donor who has recently died and has not had liver injury. This type of ...

  4. A reverse Warburg metabolism in oral squamous cell carcinoma is not dependent upon myofibroblasts

    DEFF Research Database (Denmark)

    Jensen, David Hebbelstrup; Therkildsen, Marianne Hamilton; Dabelsteen, Erik

    2015-01-01

    expression of MCT-4 have been shown to have prognostic importance, primarily in patients with breast cancer. However, this phenomenon has only scarcely been described in oral squamous cell carcinoma (OSCC). Given the prognostic importance of myofibroblasts in OSCC, we also examined a potential relationship...

  5. Myofibroblast Expression in Skin Wounds Is Enhanced by Collagen III Suppression

    Directory of Open Access Journals (Sweden)

    Mohammed M. Al-Qattan

    2015-01-01

    Full Text Available Generally speaking, the excessive expression of myofibroblasts is associated with excessive collagen production. One exception is seen in patients and animal models of Ehlers-Danlos syndrome type IV in which the COL3A1 gene mutation results in reduced collagen III but with concurrent increased myofibroblast expression. This paradox has not been examined with the use of external drugs/modalities to prevent hypertrophic scars. In this paper, we injected the rabbit ear wound model of hypertrophic scarring with two doses of a protein called nAG, which is known to reduce collagen expression and to suppress hypertrophic scarring in that animal model. The higher nAG dose was associated with significantly less collagen III expression and concurrent higher degree of myofibroblast expression. We concluded that collagen III content of the extracellular matrix may have a direct or an indirect effect on myofibroblast differentiation. However, further research is required to investigate the pathogenesis of this paradoxical phenomenon.

  6. Molecular analysis of the TGF-beta controlled gene expression program in chicken embryo dermal myofibroblasts

    Czech Academy of Sciences Publication Activity Database

    Kosla, Jan; Dvořák, Michal; Čermák, Vladimír

    2013-01-01

    Roč. 513, č. 1 (2013), s. 90-100 ISSN 0378-1119 R&D Projects: GA AV ČR KAN200520801 Institutional support: RVO:68378050 Keywords : microarray * myofibroblastic phenotype * inhibition of TGF-beta signaling Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.082, year: 2013

  7. Effective myofibroblast dedifferentiation by concomitant inhibition of TGF-beta signaling and perturbation of MAPK signaling

    Czech Academy of Sciences Publication Activity Database

    Kosla, Jan; Dvořáková, Marta; Dvořák, Michal; Čermák, Vladimír

    2013-01-01

    Roč. 92, č. 12 (2013), s. 363-373 ISSN 0171-9335 R&D Projects: GA AV ČR KAN200520801 Institutional support: RVO:68378050 Keywords : PDGFB * Ha-Ras(G12V) * EGR4 * TGF-beta * Myofibroblast * FOXG1 * Microarrays Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.699, year: 2013

  8. Identification of CARS-ALK fusion in primary and metastatic lesions of an inflammatory myofibroblastic tumor

    NARCIS (Netherlands)

    Debelenko, LV; Arthur, DC; Pack, SD; Helman, LJ; Schrump, DS; Tsokos, M

    Inflammatory myofibroblastic tumor (IMT) is a rare childhood neoplasm. The natural history of this disease is poorly understood. Recently chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene have been implicated in this tumor. We have studied a case of ALK-positive soft

  9. Aberrant SSEA-4 upregulation mediates myofibroblast activity to promote pre-cancerous oral submucous fibrosis

    Science.gov (United States)

    Yu, Cheng-Chia; Yu, Chuan-Hang; Chang, Yu-Chao

    2016-11-01

    Oral submucous fibrosis (OSF), regarded as a precancerous condition, is characterized by juxta-epithelial inflammatory reaction followed by fibro-elastic change in the lamina properia and epithelial atrophy. The pathologic mechanisms of OSF still need to be further clarified. In the study, we investigated the functional expression of SSEA-4, which is a well-known stemness marker, in myofibroblast activity and the clinical significance in OSF tissues. The expression of SSEA-4 in OSF was evaluated by immunohistochemical staining. Functional analysis of SSEA-4 on myofibroblast activity of OSF was achieved by lentiviral silencing ST3GAL2. Immunohisitochemistry demonstrated that SSEA-4 expression was significantly higher expression in areca quid chewing-associated OSF tissues than those of normal oral mucosa tissues. From flow cytometry analysis, arecoline dose-dependently activated SSEA-4 expression in primary human normal buccal mucosal fibroblasts (BMFs). Sorted SSEA-4-positive cells from fibrotic BMFs (fBMFs) have higher colony-forming unit, collagen gel contraction, and α-smooth muscle actin (α-SMA) expression than SSEA-4-negative subset. Knockdown of ST3GAL2 in fBMFs suppressed SSEA-4 expression, collagen contraction, migration, invasiveness, and wound healing capability. Consistently, silencing ST3GAL2 was found to repress arecoline-induced myofibroblast activity in BMFs. The study highlights SSEA-4 as a critical marker for therapeutic intervention to mediate myofibroblast transdifferentiation in areca quid chewing-associated OSF.

  10. Measuring the correlation between cell mechanics and myofibroblastic differentiation during maturation of 3D microtissues

    Science.gov (United States)

    Zhao, Ruogang; Wang, Weigang; Boudou, Thomas; Chen, Christopher; Reich, Daniel

    2013-03-01

    Tissue stiffness and cellular contractility are two of the most important biomechanical factors regulating pathological transitions of encapsulated cells, such as the differentiation of fibroblasts into myofibroblasts - a key event contributing to tissue fibrosis. However, a quantitative correlation between tissue stiffness and cellular contraction and myofibroblast differentiation has not yet been established in 3D environments, mainly due to the lack of suitable 3D tissue culture models that allow both tissue remodeling and simultaneous measurement of the cell/tissue mechanics. To address this, we have developed a magnetic microtissue tester system that allows the remodeling of arrays of cell-laden 3D collagen microtissues and the measurement of cell and tissue mechanics using magnetically actuated elastomeric microcantilevers. By measuring the development of cell/tissue mechanical properties and the expression level of α-smooth muscle actin (α-SMA, a marker for myofibroblast differentiation) during a 6 day culture period, we found microtissue stiffness increased by 45% and α-SMA expression increased by 38%, but tissue contraction forces only increased by 10%, indicating that tissue stiffness may be the predominant mechanical factor for regulation of myofibroblast differentiation. This study provides new quantitative insight into the regulatory effect of cell and tissue mechanics on cellular function. Supported in part by NIH grant HL090747

  11. Insulin alters the target size of the peripheral cyclic AMP phosphodiesterase but not the integral cyclic GMP-stimulated cyclic AMP phosphodiesterase in liver plasma membranes

    International Nuclear Information System (INIS)

    Wallace, A.V.; Martin, B.R.; Houslay, M.D.

    1990-01-01

    Radiation inactivation of the two high affinity cyclic AMP phosphodiesterases (PDE) found in liver plasma membranes afforded an estimation of their molecular target sizes in situ. The activity of the peripheral plasma membrane PDE decayed as a single exponential with a target size corresponding to a monomer of circa 54 kDa. The integral, cyclic GMP-stimulated PDE decayed as a dimer of circa 125 kDa. Preincubation of plasma membranes with insulin (10nM), prior to irradiation, caused the target size of only the peripheral plasma membrane PDE to increase. We suggest that insulin addition causes the peripheral plasma membrane PDE to alter its coupling to an integral plasma membrane protein with a target size of circa 90 kDa

  12. MO-FG-CAMPUS-JeP3-05: Evaluation of 4D CT-On-Rails Target Localization Methods for Free Breathing Liver Stereotactic Body Radiotherapy (SBRT)

    Energy Technology Data Exchange (ETDEWEB)

    Fan, J; Lin, T; Jin, L; Chen, L; Veltchev, I; Wang, L; Eldib, A; Chibani, O; Wang, B; Price, R; Ma, C [Fox Chase Cancer Center, Philadelphia, PA (United States); Xu, Q [MD Anderson Cancer Center at Cooper Mt Laurel, NJ (United States)

    2016-06-15

    Purpose: Liver SBRT patients unable to tolerate breath-hold for radiotherapy are treated free-breathing with image guidance. Target localization using 3D CBCT requires extra margins to accommodate the respiratory motion. The purpose of this study is to evaluate the accuracy and reproducibility of 4D CT-on-rails in target localization for free-breathing liver SBRT. Methods: A Siemens SOMATOM CT-on-Rails 4D with Anzai Pressure Belt system was used both as the simulation and the localization CT. Fiducial marker was placed close to the center of the target prior to the simulation. Amplitude based sorting was used in the scan. Eight or sixteen phases of reconstructed CT sets (depends on breathing pattern) can be sent to Velocity to create the maximum intensity projection (MIP) image set. Target ITV and fiducial ITV were drawn based on the MIP image. In patient localization, a 4D scan was taken with the same settings as the sim scan. Images were registered to match fiducial ITVs. Results: Ten liver cancer patients treated for 50Gy over 5 fractions, with amplitudes of breathing motion ranging from 4.3–14.5 mm, were analyzed in this study. Results show that the Intra & inter fraction variability in liver motion amplitude significantly less than the baseline inter-fraction shifts in liver position. 90% of amplitude change is less than 3 mm. The differences in the D99 and D95 GTV dose coverage between the 4D CT-on-Rails and the CBCT plan were small (within 5%) for all the selected cases. However, the average PTV volume by using the 4D CT-on-Rails is 37% less than the CBCT PTV volume. Conclusion: Simulation and Registration using 4D CT-on-Rails provides accurate target localization and is unaffected by larger breathing amplitudes as seen with 3D CBCT image registration. Localization with 4D CT-on-Rails can significantly reduce the PTV volume with sufficient tumor.

  13. MO-FG-CAMPUS-JeP3-05: Evaluation of 4D CT-On-Rails Target Localization Methods for Free Breathing Liver Stereotactic Body Radiotherapy (SBRT)

    International Nuclear Information System (INIS)

    Fan, J; Lin, T; Jin, L; Chen, L; Veltchev, I; Wang, L; Eldib, A; Chibani, O; Wang, B; Price, R; Ma, C; Xu, Q

    2016-01-01

    Purpose: Liver SBRT patients unable to tolerate breath-hold for radiotherapy are treated free-breathing with image guidance. Target localization using 3D CBCT requires extra margins to accommodate the respiratory motion. The purpose of this study is to evaluate the accuracy and reproducibility of 4D CT-on-rails in target localization for free-breathing liver SBRT. Methods: A Siemens SOMATOM CT-on-Rails 4D with Anzai Pressure Belt system was used both as the simulation and the localization CT. Fiducial marker was placed close to the center of the target prior to the simulation. Amplitude based sorting was used in the scan. Eight or sixteen phases of reconstructed CT sets (depends on breathing pattern) can be sent to Velocity to create the maximum intensity projection (MIP) image set. Target ITV and fiducial ITV were drawn based on the MIP image. In patient localization, a 4D scan was taken with the same settings as the sim scan. Images were registered to match fiducial ITVs. Results: Ten liver cancer patients treated for 50Gy over 5 fractions, with amplitudes of breathing motion ranging from 4.3–14.5 mm, were analyzed in this study. Results show that the Intra & inter fraction variability in liver motion amplitude significantly less than the baseline inter-fraction shifts in liver position. 90% of amplitude change is less than 3 mm. The differences in the D99 and D95 GTV dose coverage between the 4D CT-on-Rails and the CBCT plan were small (within 5%) for all the selected cases. However, the average PTV volume by using the 4D CT-on-Rails is 37% less than the CBCT PTV volume. Conclusion: Simulation and Registration using 4D CT-on-Rails provides accurate target localization and is unaffected by larger breathing amplitudes as seen with 3D CBCT image registration. Localization with 4D CT-on-Rails can significantly reduce the PTV volume with sufficient tumor

  14. Azithromycin attenuates myofibroblast differentiation and lung fibrosis development through proteasomal degradation of NOX4.

    Science.gov (United States)

    Tsubouchi, Kazuya; Araya, Jun; Minagawa, Shunsuke; Hara, Hiromichi; Ichikawa, Akihiro; Saito, Nayuta; Kadota, Tsukasa; Sato, Nahoko; Yoshida, Masahiro; Kurita, Yusuke; Kobayashi, Kenji; Ito, Saburo; Fujita, Yu; Utsumi, Hirofumi; Yanagisawa, Haruhiko; Hashimoto, Mitsuo; Wakui, Hiroshi; Yoshii, Yutaka; Ishikawa, Takeo; Numata, Takanori; Kaneko, Yumi; Asano, Hisatoshi; Yamashita, Makoto; Odaka, Makoto; Morikawa, Toshiaki; Nakayama, Katsutoshi; Nakanishi, Yoichi; Kuwano, Kazuyoshi

    2017-08-03

    Accumulation of profibrotic myofibroblasts is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF) pathogenesis. TGFB (transforming growth factor β) is one of the major profibrotic cytokines for myofibroblast differentiation and NOX4 (NADPH oxidase 4) has an essential role in TGFB-mediated cell signaling. Azithromycin (AZM), a second-generation antibacterial macrolide, has a pleiotropic effect on cellular processes including proteostasis. Hence, we hypothesized that AZM may regulate NOX4 levels by modulating proteostasis machineries, resulting in inhibition of TGFB-associated lung fibrosis development. Human lung fibroblasts (LF) were used to evaluate TGFB-induced myofibroblast differentiation. With respect to NOX4 regulation via proteostasis, assays for macroautophagy/autophagy, the unfolded protein response (UPR), and proteasome activity were performed. The potential anti-fibrotic property of AZM was examined by using bleomycin (BLM)-induced lung fibrosis mouse models. TGFB-induced NOX4 and myofibroblast differentiation were clearly inhibited by AZM treatment in LF. AZM-mediated NOX4 reduction was restored by treatment with MG132, a proteasome inhibitor. AZM inhibited autophagy and enhanced the UPR. Autophagy inhibition by AZM was linked to ubiquitination of NOX4 via increased protein levels of STUB1 (STIP1 homology and U-box containing protein 1), an E3 ubiquitin ligase. An increased UPR by AZM was associated with enhanced proteasome activity. AZM suppressed lung fibrosis development induced by BLM with concomitantly reduced NOX4 protein levels and enhanced proteasome activation. These results suggest that AZM suppresses NOX4 by promoting proteasomal degradation, resulting in inhibition of TGFB-induced myofibroblast differentiation and lung fibrosis development. AZM may be a candidate for the treatment of the fibrotic lung disease IPF.

  15. Xenosensor CAR mediates down-regulation of miR-122 and up-regulation of miR-122 targets in the liver

    Energy Technology Data Exchange (ETDEWEB)

    Kazantseva, Yuliya A.; Yarushkin, Andrei A.; Mostovich, Lyudmila A. [The Institute of Molecular Biology and Biophysics, Timakova str., 2/12, Novosibirsk 630117 (Russian Federation); Pustylnyak, Yuliya A. [Novosibirsk State University, Pirogova str., 2, Novosibirsk 630090 (Russian Federation); Pustylnyak, Vladimir O., E-mail: pustylnyak@ngs.ru [The Institute of Molecular Biology and Biophysics, Timakova str., 2/12, Novosibirsk 630117 (Russian Federation); Novosibirsk State University, Pirogova str., 2, Novosibirsk 630090 (Russian Federation); The Institute International Tomography Center of the Russian Academy of Sciences, Institutskaya str. 3-A, Novosibirsk 630090 (Russian Federation)

    2015-10-01

    MiR-122 is a major hepatic microRNA, accounting for more than 70% of the total liver miRNA population. It has been shown that miR-122 is associated with liver diseases, including hepatocellular carcinoma. Mir-122 is an intergenic miRNA with its own promoter. Pri-miR-122 expression is regulated by liver-enriched transcription factors, mainly by HNF4α, which mediates the expression via the interaction with a specific DR1 site. It has been shown that phenobarbital-mediated activation of constitutive androstane receptor (CAR), xenobiotic nuclear receptor, is associated with a decrease in miR-122 in the liver. In the present study, we investigated HNF4α–CAR cross-talk in the regulation of miR-122 levels and promitogenic signalling in mouse livers. The level of miR-122 was significantly repressed by treatment with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), which is an agonist of mouse CAR. ChIP assays demonstrated that TCPOBOP-activated CAR inhibited HNF4α transactivation by competing with HNF4α for binding to the DR1 site in the pri-miR-122 promoter. Such transcription factor replacement was strongly correlated with miR-122 down-regulation. Additionally, the decrease in miR-122 levels produced by CAR activation is accompanied by an increase in mRNA and cellular protein levels of E2f1 and its accumulation on the target cMyc gene promoter. The increase in accumulation of E2f1 on the target cMyc gene promoter is accompanied by an increase in cMyc levels and transcriptional activity. Thus, our results provide evidence to support the conclusion that CAR activation decreases miR-122 levels through suppression of HNF4α transcriptional activity and indirectly regulates the promitogenic protein cMyc. HNF4α–CAR cross-talk may provide new opportunities for understanding liver diseases and developing more effective therapeutic approaches to better drug treatments. - Highlights: • CAR activation decreased the level of miR-122 in mouse livers. • CAR decreases

  16. Xenosensor CAR mediates down-regulation of miR-122 and up-regulation of miR-122 targets in the liver

    International Nuclear Information System (INIS)

    Kazantseva, Yuliya A.; Yarushkin, Andrei A.; Mostovich, Lyudmila A.; Pustylnyak, Yuliya A.; Pustylnyak, Vladimir O.

    2015-01-01

    MiR-122 is a major hepatic microRNA, accounting for more than 70% of the total liver miRNA population. It has been shown that miR-122 is associated with liver diseases, including hepatocellular carcinoma. Mir-122 is an intergenic miRNA with its own promoter. Pri-miR-122 expression is regulated by liver-enriched transcription factors, mainly by HNF4α, which mediates the expression via the interaction with a specific DR1 site. It has been shown that phenobarbital-mediated activation of constitutive androstane receptor (CAR), xenobiotic nuclear receptor, is associated with a decrease in miR-122 in the liver. In the present study, we investigated HNF4α–CAR cross-talk in the regulation of miR-122 levels and promitogenic signalling in mouse livers. The level of miR-122 was significantly repressed by treatment with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), which is an agonist of mouse CAR. ChIP assays demonstrated that TCPOBOP-activated CAR inhibited HNF4α transactivation by competing with HNF4α for binding to the DR1 site in the pri-miR-122 promoter. Such transcription factor replacement was strongly correlated with miR-122 down-regulation. Additionally, the decrease in miR-122 levels produced by CAR activation is accompanied by an increase in mRNA and cellular protein levels of E2f1 and its accumulation on the target cMyc gene promoter. The increase in accumulation of E2f1 on the target cMyc gene promoter is accompanied by an increase in cMyc levels and transcriptional activity. Thus, our results provide evidence to support the conclusion that CAR activation decreases miR-122 levels through suppression of HNF4α transcriptional activity and indirectly regulates the promitogenic protein cMyc. HNF4α–CAR cross-talk may provide new opportunities for understanding liver diseases and developing more effective therapeutic approaches to better drug treatments. - Highlights: • CAR activation decreased the level of miR-122 in mouse livers. • CAR decreases

  17. Effects of Perfluorooctanoic Acid on Metabolic Profiles in Brain and Liver of Mouse Revealed by a High-throughput Targeted Metabolomics Approach

    Science.gov (United States)

    Yu, Nanyang; Wei, Si; Li, Meiying; Yang, Jingping; Li, Kan; Jin, Ling; Xie, Yuwei; Giesy, John P.; Zhang, Xiaowei; Yu, Hongxia

    2016-04-01

    Perfluorooctanoic acid (PFOA), a perfluoroalkyl acid, can result in hepatotoxicity and neurobehavioral effects in animals. The metabolome, which serves as a connection among transcriptome, proteome and toxic effects, provides pathway-based insights into effects of PFOA. Since understanding of changes in the metabolic profile during hepatotoxicity and neurotoxicity were still incomplete, a high-throughput targeted metabolomics approach (278 metabolites) was used to investigate effects of exposure to PFOA for 28 d on brain and liver of male Balb/c mice. Results of multivariate statistical analysis indicated that PFOA caused alterations in metabolic pathways in exposed individuals. Pathway analysis suggested that PFOA affected metabolism of amino acids, lipids, carbohydrates and energetics. Ten and 18 metabolites were identified as potential unique biomarkers of exposure to PFOA in brain and liver, respectively. In brain, PFOA affected concentrations of neurotransmitters, including serotonin, dopamine, norepinephrine, and glutamate in brain, which provides novel insights into mechanisms of PFOA-induced neurobehavioral effects. In liver, profiles of lipids revealed involvement of β-oxidation and biosynthesis of saturated and unsaturated fatty acids in PFOA-induced hepatotoxicity, while alterations in metabolism of arachidonic acid suggesting potential of PFOA to cause inflammation response in liver. These results provide insight into the mechanism and biomarkers for PFOA-induced effects.

  18. Expression and function of the atypical cadherin FAT1 in chronic liver disease

    International Nuclear Information System (INIS)

    Valletta, Daniela; Czech, Barbara; Thasler, Wolfgang E.; Müller, Martina; Bosserhoff, Anja-Katrin; Hellerbrand, Claus

    2012-01-01

    Highlights: ► The expression of the atypical cadherin FAT1 is increased in chronic liver disease. ► FAT1 expression goes up during the activation of hepatic stellate cells (HSCs). ► Activated HSCs are the cellular source of enhanced FAT1 expression in diseased livers. ► FAT1 enhanced NFkB activity and resistance to apoptosis in activated HSCs. ► FAT1 is a new therapeutic target for prevention and treatment of hepatic fibrosis. -- Abstract: Hepatic fibrosis can be considered as wound healing process in response to hepatocellular injury. Activation of hepatic stellate cells (HSCs) is a key event of hepatic fibrosis since activated HSCs are the cellular source of enhanced extracellular matrix deposition, and reversion of liver fibrosis is accompanied by clearance of activated HSCs by apoptosis. The atypical cadherin FAT1 has been shown to regulate diverse biological functions as cell proliferation and planar cell polarity, and also to affect wound healing. Here, we found increased FAT1 expression in different murine models of chronic liver injury and in cirrhotic livers of patients with different liver disease. Also in hepatic tissue of patients with non-alcoholic steatohepatitis FAT1 expression was significantly enhanced and correlated with collagen alpha I(1) expression. Immunohistochemistry revealed no significant differences in staining intensity between hepatocytes in normal and cirrhotic liver tissue but myofibroblast like cells in fibrotic septa of cirrhotic livers showed a prominent immunosignal. Furthermore, FAT1 mRNA and protein expression markedly increased during in vitro activation of primary human and murine HSCs. Together, these data indicated activated HSCs as cellular source of enhanced FAT1 expression in diseased livers. To gain insight into the functional role of FAT1 in activated HSCs we suppressed FAT1 in these cells by siRNA. We newly found that FAT1 suppression in activated HSCs caused a downregulation of NFκB activity. This

  19. Expression and function of the atypical cadherin FAT1 in chronic liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Valletta, Daniela; Czech, Barbara [Department of Internal Medicine I, University Hospital Regensburg, Regensburg (Germany); Thasler, Wolfgang E. [Grosshadern Tissue Bank and Center for Liver Cell Research, Department of Surgery, Ludwig-Maximilians-University Munich (Germany); Mueller, Martina [Department of Internal Medicine I, University Hospital Regensburg, Regensburg (Germany); Bosserhoff, Anja-Katrin [Institute of Pathology, University of Regensburg, Regensburg (Germany); Hellerbrand, Claus, E-mail: claus.hellerbrand@ukr.de [Department of Internal Medicine I, University Hospital Regensburg, Regensburg (Germany)

    2012-09-28

    Highlights: Black-Right-Pointing-Pointer The expression of the atypical cadherin FAT1 is increased in chronic liver disease. Black-Right-Pointing-Pointer FAT1 expression goes up during the activation of hepatic stellate cells (HSCs). Black-Right-Pointing-Pointer Activated HSCs are the cellular source of enhanced FAT1 expression in diseased livers. Black-Right-Pointing-Pointer FAT1 enhanced NFkB activity and resistance to apoptosis in activated HSCs. Black-Right-Pointing-Pointer FAT1 is a new therapeutic target for prevention and treatment of hepatic fibrosis. -- Abstract: Hepatic fibrosis can be considered as wound healing process in response to hepatocellular injury. Activation of hepatic stellate cells (HSCs) is a key event of hepatic fibrosis since activated HSCs are the cellular source of enhanced extracellular matrix deposition, and reversion of liver fibrosis is accompanied by clearance of activated HSCs by apoptosis. The atypical cadherin FAT1 has been shown to regulate diverse biological functions as cell proliferation and planar cell polarity, and also to affect wound healing. Here, we found increased FAT1 expression in different murine models of chronic liver injury and in cirrhotic livers of patients with different liver disease. Also in hepatic tissue of patients with non-alcoholic steatohepatitis FAT1 expression was significantly enhanced and correlated with collagen alpha I(1) expression. Immunohistochemistry revealed no significant differences in staining intensity between hepatocytes in normal and cirrhotic liver tissue but myofibroblast like cells in fibrotic septa of cirrhotic livers showed a prominent immunosignal. Furthermore, FAT1 mRNA and protein expression markedly increased during in vitro activation of primary human and murine HSCs. Together, these data indicated activated HSCs as cellular source of enhanced FAT1 expression in diseased livers. To gain insight into the functional role of FAT1 in activated HSCs we suppressed FAT1 in these

  20. Single photon emission computed tomographic studies (SPECT) of hepatic arterial perfusion scintigraphy (HAPS) in patients with colorectal liver metastases: improved tumour targetting by microspheres with angiotensin II.

    Science.gov (United States)

    Goldberg, J A; Bradnam, M S; Kerr, D J; McKillop, J H; Bessent, R G; McArdle, C S; Willmott, N; George, W D

    1987-12-01

    As intra-arterial chemotherapy for liver metastases of colorectal origin becomes accepted, methods of further improving drug delivery to the tumour have been devised. Degradable microspheres have been shown to reduce regional blood flow by transient arteriolar capillary block, thereby improving uptake of a co-administered drug, when injected into the hepatic artery. In our study of five patients, we combined hepatic arterial perfusion scintigraphy (HAPS) and SPECT to assess the localization of approximately 1 X 10(5) labelled microspheres of human serum albumin (99Tcm MSA) in tumour. In addition, in three patients, we assessed the effect of an intra-arterial infusion of the vasoactive agent angiotension II during HAPS. Results were interpreted by comparing transaxial slices with corresponding slices of a tin colloid liver-spleen scan. Two of five patients showed good localization of 99Tcm MSA in tumour without an angiotensin II infusion. Of the three patients receiving angiotensin II, all showed good tumour targetting with the vasoconstrictor compared with only one of these three before its use. Thus, hepatic arterial infusion of angiotensin II greatly improves microsphere localization in tumour in some patients with colorectal liver metastases. This technique may be useful in the assessment of tumour targetting before and during locoregional therapy.

  1. PET/CT-guided percutaneous liver mass biopsies and ablations: Targeting accuracy of a single 20 s breath-hold PET acquisition

    International Nuclear Information System (INIS)

    Shyn, P.B.; Tatli, S.; Sahni, V.A.; Sadow, C.A.; Forgione, K.; Mauri, G.; Morrison, P.R.; Catalano, P.J.; Silverman, S.G.

    2014-01-01

    Aim: To determine whether a single 20 s breath-hold positron-emission tomography (PET) acquisition obtained during combined PET/computed tomography (CT)-guided percutaneous liver biopsy or ablation procedures has the potential to target 2-[ 18 F]-fluoro-2-deoxy-D-glucose (FDG)-avid liver masses as accurately as up to 180 s breath-hold PET acquisitions. Materials and methods: This retrospective study included 10 adult patients with 13 liver masses who underwent FDG PET/CT-guided percutaneous biopsies (n = 5) or ablations (n = 5). PET was acquired as nine sequential 20 s, monitored, same-level breath-hold frames and CT was acquired in one monitored breath-hold. Twenty, 40, 60, and 180 s PET datasets were reconstructed. Two blinded readers marked tumour centres on randomized PET and CT datasets. Three-dimensional spatial localization differences between PET datasets and either 180 s PET or CT were analysed using multiple regression analyses. Statistical tests were two-sided and p < 0.05 was considered significant. Results: Targeting differences between 20 s PET and 180 s PET ranged from 0.7–20.3 mm (mean 5.3 ± 4.4 mm; median 4.3) and were not statistically different from 40 or 60 s PET (p = 0.74 and 0.91, respectively). Targeting differences between 20 s PET and CT ranged from 1.4–36 mm (mean 9.6 ± 7.1 mm; median 8.2 mm) and were not statistically different from 40, 60, or 180 s PET (p = 0.84, 0.77, and 0.35, respectively). Conclusion: Single 20 s breath-hold PET acquisitions from PET/CT-guided percutaneous liver procedures have the potential to target FDG-avid liver masses with equivalent accuracy to 180 s summed, breath-hold PET acquisitions and may facilitate strategies that improve image registration and shorten procedure times

  2. Liver/kidney microsomal antibody type 1 targets CYP2D6 on hepatocyte plasma membrane

    OpenAIRE

    Muratori, L; Parola, M; Ripalti, A; Robino, G; Muratori, P; Bellomo, G; Carini, R; Lenzi, M; Landini, M; Albano, E; Bianchi, F

    2000-01-01

    BACKGROUND—Liver/kidney microsomal antibody type 1 (LKM1) is the marker of type 2 autoimmune hepatitis (AIH) and is detected in up to 6% of patients with hepatitis C virus (HCV) infection. It recognises linear and conformational epitopes of cytochrome P450IID6 (CYP2D6) and may have liver damaging activity, provided that CYP2D6 is accessible to effector mechanisms of autoimmune attack.
METHODS—The presence of LKM1 in the plasma membrane was investigated by indirect immunofluorescence and confo...

  3. Epac is required for exogenous and endogenous stimulation of adenosine A2B receptor for inhibition of angiotensin II-induced collagen synthesis and myofibroblast differentiation.

    Science.gov (United States)

    Phosri, Sarawuth; Bunrukchai, Kwanchai; Parichatikanond, Warisara; Sato, Vilasinee H; Mangmool, Supachoke

    2018-01-10

    Angiotensin II (Ang II) plays an important role on the pathogenesis of cardiac fibrosis. Prolong and overstimulation of angiotensin II type 1 receptor with Ang II-induced collagen synthesis and myofibroblast differentiation in cardiac fibroblasts, leading to cardiac fibrosis. Although adenosine and its analogues are known to have cardioprotective effects, the mechanistic by which adenosine A 2 receptors (A 2 Rs) inhibit Ang II-induced cardiac fibrosis is not clearly understood. In the present study, we examined the effects of exogenous adenosine and endogenous adenosine on Ang II-induced collagen and myofibroblast differentiation determined by α-smooth muscle action (α-SMA) overexpression and their underlying signal transduction. Elevation of endogenous adenosine levels resulted in the inhibition of Ang II-induced collagen type I and III and α-SMA synthesis in cardiac fibroblasts. Moreover, treatment with exogenous adenosine which selectively stimulated A 2 Rs also suppressed Ang II-induced collagen synthesis and α-SMA production. These antifibrotic effects of both endogenous and exogenous adenosines are mediated through the A 2B receptor (A 2B R) subtype. Stimulation of A 2B R exhibited antifibrotic effects via the cAMP-dependent and Epac-dependent pathways. Our results provide new mechanistic insights regarding the role for cAMP and Epac on A 2B R-mediated antifibrotic effects. Thus, A 2B R is one of the potential therapeutic targets against cardiac fibrosis.

  4. Clinical Implications of 20-Hydroxyeicosatetraenoic Acid in the Kidney, Liver, Lung and Brain: An Emerging Therapeutic Target

    Directory of Open Access Journals (Sweden)

    Osama H. Elshenawy

    2017-02-01

    Full Text Available Cytochrome P450-mediated metabolism of arachidonic acid (AA is an important pathway for the formation of eicosanoids. The ω-hydroxylation of AA generates significant levels of 20-hydroxyeicosatetraenoic acid (20-HETE in various tissues. In the current review, we discussed the role of 20-HETE in the kidney, liver, lung, and brain during physiological and pathophysiological states. Moreover, we discussed the role of 20-HETE in tumor formation, metabolic syndrome and diabetes. In the kidney, 20-HETE is involved in modulation of preglomerular vascular tone and tubular ion transport. Furthermore, 20-HETE is involved in renal 19 ischemia/reperfusion (I/R injury and polycystic kidney diseases. The role of 20-HETE in the liver is not clearly understood although it represents 50%–75% of liver CYP-dependent AA metabolism, and it is associated with liver cirrhotic ascites. In the respiratory system, 20-HETE plays a role in pulmonary cell survival, pulmonary vascular tone and tone of the airways. As for the brain, 20-HETE is involved in cerebral I/R injury. Moreover, 20-HETE has angiogenic and mitogenic properties and thus helps in tumor promotion. Several inhibitors and inducers of the synthesis of 20-HETE as well as 20-HETE analogues and antagonists are recently available and could be promising therapeutic options for the treatment of many disease states in the future.

  5. Acyclic retinoid in chemoprevention of hepatocellular carcinoma: Targeting phosphorylated retinoid X receptor-α for prevention of liver carcinogenesis

    Directory of Open Access Journals (Sweden)

    Masahito Shimizu

    2012-01-01

    Full Text Available One of the key features of hepatocellular carcinoma (HCC is the high rate of intrahepatic recurrence that correlates with poor prognosis. Therefore, in order to improve the clinical outcome for patients with HCC, development of a chemopreventive agent that can decrease or delay the incidence of recurrence is a critical issue for urgent investigation. Acyclic retinoid (ACR, a synthetic retinoid, successfully improves HCC patient survival by preventing recurrence and the formation of secondary tumors. A malfunction of the retinoid X receptor-α (RXRα due to phosphorylation by the Ras-MAPK signaling pathway plays a critical role in liver carcinogenesis, and ACR exerts chemopreventive effects on HCC development by inhibiting RXRα phosphorylation. Here, we review the relationship between retinoid signaling abnormalities and liver disease, the mechanisms of how RXRα phosphorylation contributes to liver carcinogenesis, and the detailed effects of ACR on preventing HCC development, especially based on the results of our basic and clinical research. We also outline the concept of "clonal deletion and inhibition" therapy, which is defined as the removal and inhibition of latent malignant clones from the liver before they expand into clinically detectable HCC, because ACR prevents the development of HCC by implementing this concept. Looking toward the future, we discuss "combination chemoprevention" using ACR as a key drug since it can generate a synergistic effect, and may thus be an effective new strategy for the prevention of HCC.

  6. Somatostatin receptor gene therapy combined with targeted therapy with radiolabeled octreotide: a new treatment for liver metastases.

    NARCIS (Netherlands)

    A. Mearadji (Amir); W.A.P. Breeman (Wouter); L.J. Hofland (Leo); R.L. Marquet (Richard); J. Jeekel (Hans); E.P. Krenning (Eric); C.H.J. van Eijck (Casper); P.M. van Koetsveld (Peter)

    2002-01-01

    textabstractOBJECTIVE: To evaluate the effect of peptide receptor radionuclide therapy (PRRT) on somatostatin receptor (SSR)-transfected colon carcinoma cells in a rat liver metastases model.SUMMARY BACKGROUND DATA: Previously the authors have shown highly effective therapy with

  7. Docetaxel (DTX)-loaded polydopamine-modified TPGS-PLA nanoparticles as a targeted drug delivery system for the treatment of liver cancer.

    Science.gov (United States)

    Zhu, Dunwan; Tao, Wei; Zhang, Hongling; Liu, Gan; Wang, Teng; Zhang, Linhua; Zeng, Xiaowei; Mei, Lin

    2016-01-01

    Polydopamine-based surface modification is a simple way to functionalize polymeric nanoparticle (NP) surfaces with ligands and/or additional polymeric layers. In this work, we developed DTX-loaded formulations using polydopamine-modified NPs synthesized using D-α-tocopherol polyethylene glycol 1000 succinate-poly(lactide) (pD-TPGS-PLA/NPs). To target liver cancer cells, galactosamine was conjugated on the prepared NPs (Gal-pD-TPGS-PLA/NPs) to enhance the delivery of DTX via ligand-mediated endocytosis. The size and morphology of pD-TPGS-PLA/NPs and Gal-pD-TPGS-PLA/NPs changed obviously compared with TPGS-PLA/NPs. In vitro studies showed that TPGS-PLA/NPs, pD-TPGS-PLA/NPs and Gal-pD-TPGS-PLA/NPs had similar release profiles of DTX. Both confocal laser scanning microscopy and flow cytometric results showed that coumarin 6-loaded Gal-pD-TPGS-PLA/NPs had the highest cellular uptake efficiency in liver cancer cell line HepG2. Moreover, DTX-loaded Gal-pD-TPGS-PLA/NPs inhibited the growth of HepG2 cells more potently than TPGS-PLA/NPs, pD-TPGS-PLA/NPs, and a clinically available DTX formulation (Taxotere®). The in vivo biodistribution experiments show that the Gal-pD-TPGS-PLA/NPs are specifically targeted to the tumor. Furthermore, the in vivo anti-tumor effects study showed that injecting DTX-loaded Gal-pD-TPGS-PLA/NPs reduced the tumor size most significantly on hepatoma-bearing nude mice. These results suggest that Gal-pD-TPGS-PLA/NPs prepared in the study specifically interacted with the hepatocellular carcinoma cells through ligand-receptor recognition and they may be used as a potentially eligible drug delivery system targeting liver cancers. Polydopamine-based surface modification is a simple way to functionalize polymeric nanoparticle surfaces with ligands and/or additional polymeric layers. In this work, we developed docetaxel (DTX)-loaded formulations using polydopamine-modified NPs synthesized from D-α-tocopherol polyethylene glycol 1000 succinate

  8. Myofibroblast differentiation and its functional properties are inhibited by nicotine and e-cigarette via mitochondrial OXPHOS complex III

    OpenAIRE

    Lei, Wei; Lerner, Chad; Sundar, Isaac K.; Rahman, Irfan

    2017-01-01

    Nicotine is the major stimulant in tobacco products including e-cigarettes. Fibroblast to myofibroblast differentiation is a key process during wound healing and is dysregulated in lung diseases. The role of nicotine and e-cigarette derived nicotine on cellular functions including profibrotic response and other functional aspects is not known. We hypothesized that nicotine and e-cigarettes affect myofibroblast differentiation, gel contraction, and wound healing via mitochondria stress through...

  9. Inflammatory Myofibroblastic Tumor Presenting with Diabetes Insipidus in an Eight-Year-Old Boy: A Case Report.

    Science.gov (United States)

    Sarı, Erkan; Ataş, Erman; Bulut, Engin Burak; Sarı, Sebahattin; Akın, Onur; Saldır, Mehmet; Karslıoğlu, Yıldırım; Yeşilkaya, Ediz

    2015-12-01

    Inflammatory myofibroblastic tumors (IMT) develop as a non-neoplastic proliferation of myofibroblasts in a myxoid to collagenous stroma admixed with inflammatory cells. The symptoms depend on the specific location of the tumor, which can be anywhere, but is particularly in the respiratory system. Thus, patients with IMT can present with a variety of findings. A pediatric patient with IMT who presented with cough, breathlessness, polyuria-polydipsia, and convulsions is described in this report.

  10. Amelioration of cirrhotic portal hypertension by targeted cyclooxygenase-1 siRNA delivery to liver sinusoidal endothelium with polyethylenimine grafted hyaluronic acid.

    Science.gov (United States)

    Lin, Liteng; Cai, Mingyue; Deng, Shaohui; Huang, Wensou; Huang, Jingjun; Huang, Xinghua; Huang, Mingsheng; Wang, Yong; Shuai, Xintao; Zhu, Kangshun

    2017-10-01

    Portal hypertension (PH), a leading cause of mortality in cirrhosis, lacks effective clinical therapeutic strategies. The increased thromboxane A 2 (TXA 2 ), derived primarily from the upregulation of cyclooxygenase-1 (COX-1) in cirrhotic liver sinusoidal endothelial cells (LSECs), is responsible for hepatic endothelial dysfunction and PH. Thus, blocking the COX-1 pathway in cirrhotic LSECs may benefit the treatment of PH. In this study, hyaluronate-graft-polyethylenimine (HA-PEI) was synthesized for the targeted delivery of COX-1 siRNA to LSECs. Compared to non-targeted PEI, HA-PEI mediated much more efficient siRNA delivery, which resulted in potent targeted gene silencing in LSECs. In vivo, HA-PEI notably increased the accumulation of siRNA along the sinusoidal lining of the liver, inhibited over-activation of the COX-1/TXA 2 pathway in LSECs, and successfully reduced portal pressure in cirrhotic mice. These results highlight the potential of HA-PEI complexed siRNA to serve as a LSECs-specific nanomedical system for effective gene therapy in PH. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Inflammatory myofibroblastic tumor of the lung in pregnancy mimicking carcinoid tumor

    Directory of Open Access Journals (Sweden)

    Venkata Nagarjuna Maturu

    2016-01-01

    Full Text Available Inflammatory myofibroblastic tumors (IMT are uncommon neoplasms of the lung in adults. They constitute less than 1% of all lung neoplasms and usually present as parenchymal masses. Diagnosis requires a high index of suspicion. They are characterized by spindle-shaped tumor cells (fibroblasts/myofibroblasts in a background of lymphoplasmacytic infiltrate. About 50% of the tumors harbor an ALK gene rearrangement. They have to be differentiated from inflammatory pseudotumors (IPT, which show increased number of IgG4 plasma cells on immunostaining and are negative for anaplastic lymphoma kinase (ALK protein. Herein, we present a case of a 28-year old female who presented with hemoptysis and was diagnosed with an IMT of lung in the first trimester of pregnancy. We have not only reviewed the occurrence of IMT during pregnancy but also discuss the management options for IMT during pregnancy.

  12. A primary inflammatory myofibroblastic tumor of the scapula in a child: imaging findings

    Energy Technology Data Exchange (ETDEWEB)

    Inarejos Clemente, Emilio J.; Riaza Martin, Lucia [University of Barcelona, Hospital Sant Joan de Deu, Barcelona (Spain); Esplugues de Llobregat, Barcelona (Spain); Vilanova, Joan C. [University of Girona, Clinica Girona, Hospital Sta. Caterina, Girona (Spain); Guirao-Marin, Sara [CETIR Clinica Girona-ERESA, Girona (Spain)

    2015-05-01

    Inflammatory myofibroblastic tumor (IMT) is an uncommon tumor characterized by inflammatory cell infiltration and differentiated myofibroblastic spindle cells. IMT was first described in the lung and retroperitoneum. Occurrence in bone has been well described in the maxilla and occasionally in the long bones in the adult population. We present a unique case of IMT arising primarily from the scapula in an 8-year-old patient, not described previously in the pediatric or adult literature. Imaging demonstrated an ill-defined and aggressive osteolytic lesion with cortical bone destruction associated with an important soft tissue component that extended into the adjacent muscles. Histologically, the tumor was composed of spindle and polygonal cells distributed in an inflammatory background with different proportions of plasma cells, lymphocytes, eosinophils and neutrophils. The absence of cellular atypia helped to differentiate this entity from malignant spindle cell tumors, and imaging could differentiate the tumor from the nontumoral inflammatory reaction. (orig.)

  13. MicroRNAs and their predicted target messenger RNAs are deregulated by exposure to a carcinogenic dose of comfrey in rat liver.

    Science.gov (United States)

    Li, Zhiguang; Fuscoe, James C; Chen, Tao

    2011-07-01

    MicroRNAs (MiRNAs) are small noncoding RNAs that function as regulators of gene expression to control cell growth and differentiation. In this study, we analyzed miRNA and mRNA expression in the livers of rats treated with a carcinogenic dose of comfrey (Symphytum officinale) for 12 weeks. Groups of six rats were fed a normal diet or a diet containing 8% comfrey root. The animals were sacrificed 1 day after the last treatment and the livers were isolated for miRNA expression analysis using LC Sciences miRNA microarrays and for mRNA expression analysis using Affymetrix rat genome microarrays. MiRNA expression levels were significantly changed by comfrey treatment. The treated samples were separated clearly from the control samples in both principal component analysis (PCA) and hierarchical clustering analysis (HCA). Quantitative measurements of seven miRNAs using TaqMan real-time PCR were consistent with the microarray results in terms of fold-change and the direction of the change in expression. Forty-five miRNAs (P comfrey treatment. Using a target prediction algorithm, 434 differentially expressed genes (DEGs) were predicted to be targeted by the differentially expressed miRNAs (DEMs). The DEM-targeted DEGs were more likely to be involved in carcinogenesis than the DEGs that were not targeted by the DEMs. The nontargeted DEGs were enriched in noncancer-related biological processes. Our data suggest that comfrey may exert its carcinogenic effects by disturbing miRNA expression resulting in altered mRNA levels of the DEM-targeted genes that are functionally associated with carcinogenesis. Copyright © 2011 Wiley-Liss, Inc.

  14. Epithelioid inflammatory myofibroblastic sarcoma responsive to surgery and an ALK inhibitor in a patient with panhypopituitarism.

    Science.gov (United States)

    Kurihara-Hosokawa, Kotomi; Kawasaki, Isao; Tamai, Anna; Yoshida, Yoko; Yakushiji, Yosuke; Ueno, Hiroki; Fukumoto, Mariko; Fukushima, Hiroko; Inoue, Takeshi; Hosoi, Masayuki

    2014-01-01

    We encountered a case of epithelioid inflammatory myofibroblastic sarcoma (EIMS) originating from an abdominal organ that rapidly regrew twice. The patient underwent two surgeries. Large tumors grew within three months after the second surgery. The patient subsequently received chemotherapy with an anaplastic lymphoma kinase (ALK) inhibitor. Although EIMS has a poor prognosis, the patient continues to be alive with disease 14 months after surgical treatment and the administration of the ALK inhibitor.

  15. Inflammatory Myofibroblastic Bladder Tumor in a Patient with Wolf-Hirschhorn Syndrome

    Directory of Open Access Journals (Sweden)

    Antonio Marte

    2013-01-01

    Full Text Available Inflammatory myofibroblastic tumor (IMT is a rare neoplasm described in several tissues and organs including genitourinary system, lung, head, and neck. The etiology of IMT is contentious, and whether it is a postinflammatory process or a true neoplasm remains controversial. To our knowledge, we report the first reported case of IMT of urinary bladder in a pediatric patient with Wolf-Hirschhorn (WHS. We also review the literature about patients with associated neoplasia.

  16. Differential expression of myofibroblasts on CO2 laser wounds and scalpel wounds: an experimental model

    Science.gov (United States)

    Machado, R. M.; Oliveira, C. R. B.; Vitória, L. A.; Xavier, F. C. A.; Pinheiro, A. L. B.; Freitas, A. C.; Ramalho, L. M. P.

    2018-04-01

    Wound contraction of both traumatic and surgical origin may reduce or limit the function of the tissue. Myofibroblasts are cells involved on the process of wound contraction, which is smaller on CO2 Laser wounds. The aims of this study were to quantitative and statistically assess the presence of myofibroblasts on both conventional and CO2 Laser wounds. Thirty-two animals (rattus norvegicus) were divided into four groups and operated using either the CO2 Laser (groups A1 and A2) or conventional scalpel (groups B1 and B2). The animals were sacrificed eight days post-operatively (groups: A1 and B1) and 14th days after surgery (groups: A2 and B2). The spec imens we re routinely processed to wax and stained with a-Smooth Muscle Actin (aSMA) and analyzed under light microscopy (40X). Two standard areas around the wound of each slide were selected and used to count the number of myofribroblasts present using a calibrated eyepiece and a graticule. The number of myofibroblasts at day eight was significantly higher than at day 14th. Comparison of the two techniques at day eight showed significant differences between the two groups (Laser, p=0.007 and scalpel, p=0.001). The number of cells present on group B1 was significantly higher than group A1 (p=0.001). However at the 14th day there was no such difference (p=0,072). It is concluded that the small number of myofibroblasts at day eight after wounding with the CO2 Lasermay be the reason why contraction on this wound is smaller than the one observed in conventional surgery.

  17. Myofibroblasts and their resistance to apoptosis: a possible mechanism of osteoradionecrosis

    Directory of Open Access Journals (Sweden)

    Tian L

    2012-07-01

    Full Text Available Lei Tian,1 Li-Sheng He,1 Bhavesh Soni,2 Hong-Tao Shang11Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, China; 2Maxillofacial Unit, Morriston Hospital, Swansea, Wales, UKAbstract: Osteoradionecrosis (ORN in the head and neck area is the most devastating long-term complication of radiotherapy, with slow progression and inability to heal spontaneously. ORN can lead to intolerable pain, fractures, and sequestration of devitalized bone and fistulae, making oral feeding impossible and causing facial deformation. In spite of its notorious reputation over at least 90 years, the precise pathogenesis of ORN has not been fully clarified, which has led to obstacles in the management of the disease. Several theories about its pathogenesis have been formulated, and radiation-induced fibrosis is the newest one. According to this theory, ORN is essentially a type of fibrosis induced by radiotherapy, and antifibrosis therapy has been shown to be effective in its treatment. We assumed that ORN, like fibrosis in other organs, is the result of a process of fibrogenesis in which myofibroblasts are the key effector cells. The uninterrupted accumulation of myofibroblasts and consequent persistent excess production of collagenous extracellular matrix and tensile force result in loss of normal function and ultimately radiation-induced fibrosis. During this process, myofibroblasts may be protected from apoptosis by acquiring an immune-privileged capacity, which allows continuous matrix synthesis. If this hypothesis proves to be correct, it would enable better understanding of the cellular and molecular mechanisms underlying the pathogenesis and progression of ORN, and would help improve our ability to prevent occurrence of ORN, give an earlier diagnosis, and treat it more effectively.Keywords: osteoradionecrosis, apoptosis, fibrosis, mandible, myofibroblast

  18. Pro-angiogenic capacities of microvesicles produced by skin wound myofibroblasts.

    Science.gov (United States)

    Merjaneh, Mays; Langlois, Amélie; Larochelle, Sébastien; Cloutier, Chanel Beaudoin; Ricard-Blum, Sylvie; Moulin, Véronique J

    2017-08-01

    Wound healing is a very highly organized process where numerous cell types are tightly regulated to restore injured tissue. Myofibroblasts are cells that produce new extracellular matrix and contract wound edges. We previously reported that the human myofibroblasts isolated from normal wound (WMyos) produced microvesicles (MVs) in the presence of the serum. In this study, MVs were further characterized using a proteomic strategy and potential functions of the MVs were determined. MV proteins isolated from six WMyo populations were separated using two-dimensional differential gel electrophoresis. Highly conserved spots were selected and analyzed using mass spectrometry resulting in the identification of 381 different human proteins. Using the DAVID database, clusters of proteins involved in cell motion, apoptosis and adhesion, but also in extracellular matrix production (21 proteins, enrichment score: 3.32) and in blood vessel development/angiogenesis (19 proteins, enrichment score: 2.66) were identified. Another analysis using the functional enrichment analysis tool FunRich was consistent with these results. While the action of the myofibroblasts on extracellular matrix formation is well known, their angiogenic potential is less studied. To further characterize the angiogenic activity of the MVs, they were added to cultured microvascular endothelial cells to evaluate their influence on cell growth and migration using scratch test and capillary-like structure formation in Matrigel ® . The addition of a MV-enriched preparation significantly increased endothelial cell growth, migration and capillary formation compared with controls. The release of microvesicles by the wound myofibroblasts brings new perspectives to the field of communication between cells during the normal healing process.

  19. In wound repair vimentin mediates the transition of mesenchymal leader cells to a myofibroblast phenotype.

    Science.gov (United States)

    Walker, J L; Bleaken, B M; Romisher, A R; Alnwibit, A A; Menko, A S

    2018-05-02

    Following injury, mesenchymal repair cells are activated to function as leader cells that modulate wound healing. These cells have the potential to differentiate to myofibroblasts, resulting in fibrosis and scarring. The signals underlying these differing pathways are complex and incompletely understood. The ex vivo mock cataract surgery cultures are an attractive model with which to address this question. With this model we study, concurrently, the mechanisms that control mesenchymal leader cell function in injury repair within their native microenvironment, and the signals that induce this same cell population to acquire a myofibroblast phenotype when these cells encounter the environment of the adjacent tissue culture platform. Here, we show that upon injury, the cytoskeletal protein vimentin is released into the extracellular space, binds to the cell surface of the mesenchymal leader cells located at the wound edge in the native matrix environment, and supports wound closure. In pro-fibrotic environments, the extracellular vimentin pool also links specifically to the mesenchymal leader cells, and has an essential role in signaling their fate change to a myofibroblast. These findings suggest a novel role for extracellular, cell-surface-associated vimentin in mediating repair-cell function in wound repair and in transitioning these cells to a myofibroblast phenotype. Movie S1 Movie S1 Collective movement of mesenchymal leader and epithelial follower cells across the tissue culture substrate (ECZ) in response to injury was followed by time-lapse imaging from D0-D3. The mesenchymal cells at the leading edge were easily distinguished morphologically from the lens epithelial follower cells.

  20. Differential representation of liver proteins in obese human subjects suggests novel biomarkers and promising targets for drug development in obesity.

    Science.gov (United States)

    Caira, Simonetta; Iannelli, Antonio; Sciarrillo, Rosaria; Picariello, Gianluca; Renzone, Giovanni; Scaloni, Andrea; Addeo, Pietro

    2017-12-01

    The proteome of liver biopsies from human obese (O) subjects has been compared to those of nonobese (NO) subjects using two-dimensional gel electrophoresis (2-DE). Differentially represented proteins were identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS)-based peptide mass fingerprinting (PMF) and nanoflow-liquid chromatography coupled to electrospray-tandem mass spectrometry (nLC-ESI-MS/MS). Overall, 61 gene products common to all of the liver biopsies were identified within 65 spots, among which 25 ones were differently represented between O and NO subjects. In particular, over-representation of short-chain acyl-CoA dehydrogenase, Δ(3,5)-Δ(2,4)dienoyl-CoA isomerase, acetyl-CoA acetyltransferase, glyoxylate reductase/hydroxypyruvate reductase, fructose-biphosphate aldolase B, peroxiredoxin I, protein DJ-1, catalase, α- and β-hemoglobin subunits, 3-mercaptopyruvate S-transferase, calreticulin, aminoacylase 1, phenazine biosynthesis-like domain-containing protein and a form of fatty acid-binding protein, together with downrepresentation of glutamate dehydrogenase, glutathione S-transferase A1, S-adenosylmethionine synthase 1A and a form of apolipoprotein A-I, was associated with the obesity condition. Some of these metabolic enzymes and antioxidant proteins have already been identified as putative diagnostic markers of liver dysfunction in animal models of steatosis or obesity, suggesting additional investigations on their role in these syndromes. Their differential representation in human liver was suggestive of their consideration as obesity human biomarkers and for the development of novel antiobesity drugs.

  1. Liver/kidney microsomal antibody type 1 targets CYP2D6 on hepatocyte plasma membrane

    Science.gov (United States)

    Muratori, L; Parola, M; Ripalti, A; Robino, G; Muratori, P; Bellomo, G; Carini, R; Lenzi, M; Landini, M; Albano, E; Bianchi, F

    2000-01-01

    BACKGROUND—Liver/kidney microsomal antibody type 1 (LKM1) is the marker of type 2 autoimmune hepatitis (AIH) and is detected in up to 6% of patients with hepatitis C virus (HCV) infection. It recognises linear and conformational epitopes of cytochrome P450IID6 (CYP2D6) and may have liver damaging activity, provided that CYP2D6 is accessible to effector mechanisms of autoimmune attack.
METHODS—The presence of LKM1 in the plasma membrane was investigated by indirect immunofluorescence and confocal laser microscopy of isolated rat hepatocytes probed with 10 LKM1 positive sera (five from patients with AIH and five from patients with chronic HCV infection) and a rabbit polyclonal anti-CYP2D6 serum.
RESULTS—Serum from both types of patient stained the plasma membrane of non-permeabilised cells, where the fluorescent signal could be visualised as discrete clumps. Conversely, permeabilised hepatocytes showed diffuse submembranous/cytoplasmic staining. Adsorption with recombinant CYP2D6 substantially reduced plasma membrane staining and LKM1 immunoblot reactivity. Plasma membrane staining of LKM1 colocalised with that of anti-CYP2D6. Immunoprecipitation experiments showed that a single 50 kDa protein recognised by anti-CYP2D6 can be isolated from the plasma membrane of intact hepatocytes.
CONCLUSIONS—AIH and HCV related LKM1 recognise CYP2D6 exposed on the plasma membrane of isolated hepatocytes. This observation supports the notion that anti-CYP2D6 autoreactivity may be involved in the pathogenesis of liver damage.


Keywords: liver/kidney microsomal antibody type 1; autoimmunity; autoimmune hepatitis; hepatitis C virus infection; confocal microscopy PMID:10716687

  2. Subepithelial myofibroblasts are novel nonprofessional APCs in the human colonic mucosa.

    Science.gov (United States)

    Saada, Jamal I; Pinchuk, Irina V; Barrera, Carlos A; Adegboyega, Patrick A; Suarez, Giovanni; Mifflin, Randy C; Di Mari, John F; Reyes, Victor E; Powell, Don W

    2006-11-01

    The human gastrointestinal mucosa is exposed to a diverse normal microflora and dietary Ags and is a common site of entry for pathogens. The mucosal immune system must respond to these diverse signals with either the initiation of immunity or tolerance. APCs are important accessory cells that modulate T cell responses which initiate and maintain adaptive immunity. The ability of APCs to communicate with CD4+ T cells is largely dependent on the expression of class II MHC molecules by the APCs. Using immunohistochemistry, confocal microscopy, and flow cytometry, we demonstrate that alpha-smooth muscle actin(+), CD90+ subepithelial myofibroblasts (stromal cells) constitutively express class II MHC molecules in normal colonic mucosa and that they are distinct from professional APCs such as macrophages and dendritic cells. Primary isolates of human colonic myofibroblasts (CMFs) cultured in vitro were able to stimulate allogeneic CD4+ T cell proliferation. This process was dependent on class II MHC and CD80/86 costimulatory molecule expression by the myofibroblasts. We also demonstrate that CMFs, engineered to express a specific DR4 allele, can process and present human serum albumin to a human serum albumin-specific and DR4 allele-restricted T cell hybridoma. These studies characterize a novel cell phenotype which, due to its strategic location and class II MHC expression, may be involved in capture of Ags that cross the epithelial barrier and present them to lamina propria CD4+ T cells. Thus, human CMFs may be important in regulating local immunity in the colon.

  3. A case of myofibroblastic sarcoma in the maxillary region suspected to be radiation-induced

    International Nuclear Information System (INIS)

    Sato, Hisashi; Kobayashi, Wataru; Kurita, Takayuki; Narita, Kenji; Fukui, Roh; Kimura, Hiroto

    2004-01-01

    Myofibroblastic sarcoma is an extremely rare malignant tumor in the oral and maxillofacial region. We report a case of myofibroblastic sarcoma probably induced by irradiation for maxillary sinus cancer. The patient was a 61-year-old man whose present history was as follows. In October 1989, he presented with pain in the left maxillary molar region. A squamous cell carcinoma of the left maxillary sinus was diagnosed, and he was treated with external irradiation of 50 Gy combined with chemotherapy. Left maxillectomy was done in February 1990. The postoperative course was satisfactory. However, in June 1998, he presented again with a tumor arising in the posterior region of the defect on the left side of the maxilla. Although histopathological examination of a biopsy specimen revealed granulation tissue with inflammatory changes, the tumor grew rapidly. The tumor was therefore suspected to be malignant and was resected under general anesthesia. Histopathological examination revealed atypical and spindle tumor cells with immunohistochemically positive staining for α-smooth muscle actin, desmin, vimentin, and muscle specific actin, but negative staining for h-caldesmon. On the basis of these histopathological and clinical findings, a final diagnosis of a myofibroblastic sarcoma of the maxillary region was made. The lesion was strongly suspected to be a radiation-induced tumor. The patient was followed up for 4 years 5 months after operation. The subsequent course was satisfactory, with no signs of recurrence or distant metastasis. (author)

  4. Unusual case of pancreatic inflammatory myofibroblastic tumor associated with spontaneous splenic rupture

    Directory of Open Access Journals (Sweden)

    Hassan Fadi K

    2010-11-01

    Full Text Available Abstract Background Spontaneous splenic rupture considered a relatively rare but life threatening. The three commonest causes of spontaneous splenic rupture are malignant hematological diseases, viral infections and local inflammatory and neoplastic disorders. We describe a unique and unusual case of inflammatory myofibroblastic tumor of the tail of pancreas presented with massively enlarged spleen and spontaneous splenic rupture. Case presentation A 19 years old male patient with no significant past medical history presented to emergency room with abdominal pain and fatigue. Massively enlarged spleen was detected. Hypotension and rapid reduction of hemoglobin level necessitated urgent laparatomy. About 1.75 liters of blood were found in abdominal cavity. A large tumor arising from the tail of pancreas and local rupture of an enlarged spleen adjacent to the tumor were detected. Distal pancreatectomy and splenectomy were performed. To our knowledge, we report the first case of massively enlarged spleen that was complicated with spontaneous splenic rupture as a result of splenic congestion due to mechanical obstruction caused by an inflammatory myofibroblastic tumor of the tail of pancreas. A review of the literature is also presented. Conclusion Inflammatory myofibroblastic tumor of the tail of pancreas should be included in the differential diagnosis of the etiological causes of massively enlarged spleen and spontaneous splenic rupture.

  5. Hepatitis C virus core protein targets 4E-BP1 expression and phosphorylation and potentiates Myc-induced liver carcinogenesis in transgenic mice.

    Science.gov (United States)

    Abdallah, Cosette; Lejamtel, Charlène; Benzoubir, Nassima; Battaglia, Serena; Sidahmed-Adrar, Nazha; Desterke, Christophe; Lemasson, Matthieu; Rosenberg, Arielle R; Samuel, Didier; Bréchot, Christian; Pflieger, Delphine; Le Naour, François; Bourgeade, Marie-Françoise

    2017-08-22

    Hepatitis C virus (HCV) is a leading cause of liver diseases including the development of hepatocellular carcinoma (HCC). Particularly, core protein has been involved in HCV-related liver pathologies. However, the impact of HCV core on signaling pathways supporting the genesis of HCC remains largely elusive. To decipher the host cell signaling pathways involved in the oncogenic potential of HCV core, a global quantitative phosphoproteomic approach was carried out. This study shed light on novel differentially phosphorylated proteins, in particular several components involved in translation. Among the eukaryotic initiation factors that govern the translational machinery, 4E-BP1 represents a master regulator of protein synthesis that is associated with the development and progression of cancers due to its ability to increase protein expression of oncogenic pathways. Enhanced levels of 4E-BP1 in non-modified and phosphorylated forms were validated in human hepatoma cells and in mouse primary hepatocytes expressing HCV core, in the livers of HCV core transgenic mice as well as in HCV-infected human primary hepatocytes. The contribution of HCV core in carcinogenesis and the status of 4E-BP1 expression and phosphorylation were studied in HCV core/Myc double transgenic mice. HCV core increased the levels of 4E-BP1 expression and phosphorylation and significantly accelerated the onset of Myc-induced tumorigenesis in these double transgenic mice. These results reveal a novel function of HCV core in liver carcinogenesis potentiation. They position 4E-BP1 as a tumor-specific target of HCV core and support the involvement of the 4E-BP1/eIF4E axis in hepatocarcinogenesis.

  6. Downregulation of IL6 Targeted MiR-376b May Contribute to a Positive IL6 Feedback Loop During Early Liver Regeneration in Mice

    Directory of Open Access Journals (Sweden)

    Shan Lu

    2015-08-01

    Full Text Available Background/Aims: MicroRNAs (miRNAs are a group of endogenous, small, noncoding RNAs implicated in a variety of biological processes, including cell proliferation, apoptosis, differentiation and metabolism. The present study aims to explore the potential role and molecular mechanism of miR-376b during the early phase of liver regeneration. Methods: MiRNA profiling microarrays were used to assess the changes in miRNA expression. For functional analysis, cell proliferation, apoptosis assays, real time quantitative PCR and westernblot analysis were performed. Results: The comprehensive miRNA expression profiling assays on regenerating liver tissues 4 h after partial hepatectomy (PH showed that three miRNAs (miR-127, miR-376b and miR-494 located in the Dlk1-Gtl2 miRNA cluster were significantly downregulated. In vitro functional studies demonstrated that high-level interleukin 6 (IL6 inhibited the expression of miR-376b, and miR-376b mimics treatment decreased cell proliferation and increased apoptosis. Further target analysis showed that miR-376b reduced the mRNA and protein expression levels of NF-kappa-B inhibitor zeta (NFKBIZ and signal transducers and transcription activators 3 (STAT3. Additionally, IL6-induced miR-376b downregulation would, in turn, increase the expression of IL-6 possibly via a feedback loop involving NFKBIZ or/and STAT3. Conclusion: During the early phase of liver regeneration, miR-376b expression was significantly decreased. Our findings reveal that a regulatory circuitry between miR-376b and IL-6 may exist, which trigger the initiation of liver regeneration.

  7. Lung Myofibroblasts Are Characterized by Down-Regulated Cyclooxygenase-2 and Its Main Metabolite, Prostaglandin E2

    Science.gov (United States)

    Gabasa, Marta; Royo, Dolores; Molina-Molina, Maria; Roca-Ferrer, Jordi; Pujols, Laura; Picado, Cesar

    2013-01-01

    Background Prostaglandin E2 (PGE2), the main metabolite of cyclooxygenase (COX), is a well-known anti-fibrotic agent. Moreover, myofibroblasts expressing α-smooth muscle actin (α-SMA), fibroblast expansion and epithelial-mesenchymal transition (EMT) are critical to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Our aim was to investigate the expression of COX-2 and PGE2 in human lung myofibroblasts and establish whether fibroblast-myofibroblast transition (FMT) and EMT are associated with COX-2 and PGE2 down-regulation. Methods Fibroblasts obtained from IPF patients (n = 6) and patients undergoing spontaneous pneumothorax (control, n = 6) and alveolar epithelial cell line A549 were incubated with TGF-β1 and FMT and EMT markers were evaluated. COX-2 and α-SMA expression, PGE2 secretion and cell proliferation were measured after IL-1β and PGE2 incubation. Results Myofibroblasts from both control and IPF fibroblast cultures stimulated with IL-1β showed no COX-2 expression. IPF fibroblasts showed increased myofibroblast population and reduced COX-2 expression in response to IL-1β. TGF-β1 increased the number of myofibroblasts in a time-dependent manner. In contrast, TGF-β1 induced slight COX-2 expression at 4 h (without increase in myofibroblasts) and 24 h, but not at 72 h. Both IPF and control cultures incubated with TGF-β1 for 72 h showed diminished COX-2 induction, PGE2 secretion and α-SMA expression after IL-1β addition. The latter decreased proliferation in fibroblasts but not in myofibroblasts. A549 cells incubated with TGF-β1 for 72 h showed down-regulated COX-2 expression and low basal PGE2 secretion in response to IL-1β. Immuno-histochemical analysis of IPF lung tissue showed no COX-2 immuno-reactivity in myofibroblast foci. Conclusions Myofibroblasts are associated with COX-2 down-regulation and reduced PGE2 production, which could be crucial in IPF development and progression. PMID:23755232

  8. Rhythmic expression of miR-27b-3p targets the clock gene Bmal1 at the posttranscriptional level in the mouse liver.

    Science.gov (United States)

    Zhang, Wenxiang; Wang, Peng; Chen, Siyu; Zhang, Zhao; Liang, Tingming; Liu, Chang

    2016-06-01

    Circadian clocks orchestrate daily oscillations in mammalian behaviors, physiology, and gene expression. MicroRNAs (miRNAs) play a crucial role in fine-tuning of the circadian system. However, little is known about the direct regulation of the clock genes by specific miRNAs. In this study, we found that miR-27b-3p exhibits rhythmic expression in the metabolic tissues of the mice subjected to constant darkness. MiR-27b-3p's expression is induced in livers of unfed and ob/ob mice. In addition, the oscillation phases of miR-27b-3p can be reversed by restricted feeding, suggesting a role of peripheral clock in regulating its rhythmicity. Bioinformatics analysis indicated that aryl hydrocarbon receptor nuclear translocator-like (also known as Bmal1) may be a direct target of miR-27b-3p. Luciferase reporter assay showed that miR-27b-3p suppressed Bmal1 3' UTR activity in a dose-dependent manner, and mutagenesis of their binding site abolished this suppression. Furthermore, overexpression of miR-27b-3p dose-dependently reduced the protein expression levels of BMAL1 and impaired the endogenous BMAL1 and gluconeogenic protein rhythmicity. Collectively, our results suggest that miR-27b-3p plays an important role in the posttranscriptional regulation of BMAL1 protein in the liver. MiR-27b-3p may serve as a novel node to integrate the circadian clock and energy metabolism.-Zhang, W., Wang, P., Chen, S., Zhang, Z., Liang, T., Liu, C. Rhythmic expression of miR-27b-3p targets the clock gene Bmal1 at the posttranscriptional level in the mouse liver. © FASEB.

  9. Phenobarbital mediates an epigenetic switch at the constitutive androstane receptor (CAR target gene Cyp2b10 in the liver of B6C3F1 mice.

    Directory of Open Access Journals (Sweden)

    Harri Lempiäinen

    2011-03-01

    Full Text Available Evidence suggests that epigenetic perturbations are involved in the adverse effects associated with some drugs and toxicants, including certain classes of non-genotoxic carcinogens. Such epigenetic changes (altered DNA methylation and covalent histone modifications may take place at the earliest stages of carcinogenesis and their identification holds great promise for biomedical research. Here, we evaluate the sensitivity and specificity of genome-wide epigenomic and transcriptomic profiling in phenobarbital (PB-treated B6C3F1 mice, a well-characterized rodent model of non-genotoxic liver carcinogenesis. Methylated DNA Immunoprecipitation (MeDIP-coupled microarray profiling of 17,967 promoter regions and 4,566 intergenic CpG islands was combined with genome-wide mRNA expression profiling to identify liver tissue-specific PB-mediated DNA methylation and transcriptional alterations. Only a limited number of significant anti-correlations were observed between PB-induced transcriptional and promoter-based DNA methylation perturbations. However, the constitutive androstane receptor (CAR target gene Cyp2b10 was found to be concomitantly hypomethylated and transcriptionally activated in a liver tissue-specific manner following PB treatment. Furthermore, analysis of active and repressive histone modifications using chromatin immunoprecipitation revealed a strong PB-mediated epigenetic switch at the Cyp2b10 promoter. Our data reveal that PB-induced transcriptional perturbations are not generally associated with broad changes in the DNA methylation status at proximal promoters and suggest that the drug-inducible CAR pathway regulates an epigenetic switch from repressive to active chromatin at the target gene Cyp2b10. This study demonstrates the utility of integrated epigenomic and transcriptomic profiling for elucidating early mechanisms and biomarkers of non-genotoxic carcinogenesis.

  10. Phenobarbital mediates an epigenetic switch at the constitutive androstane receptor (CAR) target gene Cyp2b10 in the liver of B6C3F1 mice.

    Science.gov (United States)

    Lempiäinen, Harri; Müller, Arne; Brasa, Sarah; Teo, Soon-Siong; Roloff, Tim-Christoph; Morawiec, Laurent; Zamurovic, Natasa; Vicart, Axel; Funhoff, Enrico; Couttet, Philippe; Schübeler, Dirk; Grenet, Olivier; Marlowe, Jennifer; Moggs, Jonathan; Terranova, Rémi

    2011-03-24

    Evidence suggests that epigenetic perturbations are involved in the adverse effects associated with some drugs and toxicants, including certain classes of non-genotoxic carcinogens. Such epigenetic changes (altered DNA methylation and covalent histone modifications) may take place at the earliest stages of carcinogenesis and their identification holds great promise for biomedical research. Here, we evaluate the sensitivity and specificity of genome-wide epigenomic and transcriptomic profiling in phenobarbital (PB)-treated B6C3F1 mice, a well-characterized rodent model of non-genotoxic liver carcinogenesis. Methylated DNA Immunoprecipitation (MeDIP)-coupled microarray profiling of 17,967 promoter regions and 4,566 intergenic CpG islands was combined with genome-wide mRNA expression profiling to identify liver tissue-specific PB-mediated DNA methylation and transcriptional alterations. Only a limited number of significant anti-correlations were observed between PB-induced transcriptional and promoter-based DNA methylation perturbations. However, the constitutive androstane receptor (CAR) target gene Cyp2b10 was found to be concomitantly hypomethylated and transcriptionally activated in a liver tissue-specific manner following PB treatment. Furthermore, analysis of active and repressive histone modifications using chromatin immunoprecipitation revealed a strong PB-mediated epigenetic switch at the Cyp2b10 promoter. Our data reveal that PB-induced transcriptional perturbations are not generally associated with broad changes in the DNA methylation status at proximal promoters and suggest that the drug-inducible CAR pathway regulates an epigenetic switch from repressive to active chromatin at the target gene Cyp2b10. This study demonstrates the utility of integrated epigenomic and transcriptomic profiling for elucidating early mechanisms and biomarkers of non-genotoxic carcinogenesis.

  11. Phenobarbital Mediates an Epigenetic Switch at the Constitutive Androstane Receptor (CAR) Target Gene Cyp2b10 in the Liver of B6C3F1 Mice

    Science.gov (United States)

    Brasa, Sarah; Teo, Soon-Siong; Roloff, Tim-Christoph; Morawiec, Laurent; Zamurovic, Natasa; Vicart, Axel; Funhoff, Enrico; Couttet, Philippe; Schübeler, Dirk; Grenet, Olivier; Marlowe, Jennifer; Moggs, Jonathan; Terranova, Rémi

    2011-01-01

    Evidence suggests that epigenetic perturbations are involved in the adverse effects associated with some drugs and toxicants, including certain classes of non-genotoxic carcinogens. Such epigenetic changes (altered DNA methylation and covalent histone modifications) may take place at the earliest stages of carcinogenesis and their identification holds great promise for biomedical research. Here, we evaluate the sensitivity and specificity of genome-wide epigenomic and transcriptomic profiling in phenobarbital (PB)-treated B6C3F1 mice, a well-characterized rodent model of non-genotoxic liver carcinogenesis. Methylated DNA Immunoprecipitation (MeDIP)-coupled microarray profiling of 17,967 promoter regions and 4,566 intergenic CpG islands was combined with genome-wide mRNA expression profiling to identify liver tissue-specific PB-mediated DNA methylation and transcriptional alterations. Only a limited number of significant anti-correlations were observed between PB-induced transcriptional and promoter-based DNA methylation perturbations. However, the constitutive androstane receptor (CAR) target gene Cyp2b10 was found to be concomitantly hypomethylated and transcriptionally activated in a liver tissue-specific manner following PB treatment. Furthermore, analysis of active and repressive histone modifications using chromatin immunoprecipitation revealed a strong PB-mediated epigenetic switch at the Cyp2b10 promoter. Our data reveal that PB-induced transcriptional perturbations are not generally associated with broad changes in the DNA methylation status at proximal promoters and suggest that the drug-inducible CAR pathway regulates an epigenetic switch from repressive to active chromatin at the target gene Cyp2b10. This study demonstrates the utility of integrated epigenomic and transcriptomic profiling for elucidating early mechanisms and biomarkers of non-genotoxic carcinogenesis. PMID:21455306

  12. Celecoxib induces proliferation and Amphiregulin production in colon subepithelial myofibroblasts, activating erk1-2 signaling in synergy with EGFR.

    Science.gov (United States)

    Benelli, Roberto; Venè, Roberta; Minghelli, Simona; Carlone, Sebastiano; Gatteschi, Beatrice; Ferrari, Nicoletta

    2013-01-01

    The COX-2 inhibitor Celecoxib, tested in phase III trials for the prevention of sporadic colon adenomas, reduced the appearance of new adenomas, but was unable to affect the incidence of colon cancer. Moreover the 5years follow-up showed that patients discontinuing Celecoxib treatment had an increased incidence of adenomas as compared to the placebo arm. In the APC(min/+) mouse model short term treatment with Celecoxib reduced gut adenomas, but a prolonged administration of the drug induced fibroblast activation and intestinal fibrosis with a final tumor burden. The way Celecoxib could directly activate human colon myofibroblasts (MF) has not yet been investigated. We found that MF are activated by non toxic doses of Celecoxib. Celecoxib induces erk1-2 and Akt phosphorylation within 5'. This short term activation is apparently insufficient to cause phenotypic changes, but the contemporary triggering of EGFR causes an impressive synergic effect inducing MF proliferation and the neo-expression and release of Amphiregulin (AREG), a well known EGFR agonist involved in colon cancer progression. As a confirm to these observations, the erk inhibitor U0126 and the EGFR inhibitors Tyrphostin and Cetuximab were able to contrast AREG induction. Our data provide evidence that Celecoxib directly activates MF empowering EGFR signaling. According to these results the association with EGFR (or erk1-2) inhibitors could abolish the off-target activity of Celecoxib, possibly extending the potential of this drug for colon cancer prevention. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  13. Covalent binding of benzo(a)pyrene-diol-epoxide to histone H2A in rat liver nuclei: target site specificity

    International Nuclear Information System (INIS)

    Kurokawa, M.; MacLeod, M.C.

    1986-01-01

    The authors have recently found that 7r,8t-dihydroxy-9t,10t-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDE-I), a strong carcinogen, binds selectively to histone H2A-2 variant in rat liver nuclei, using a high performance liquid chromatography (HPLC) system which can separate H4, H2B, 3 different fractions of H2A variants and 3 different H3 variants in an hour. Here the authors examined the binding site of BPDE-I to the H2A-2 variant. The H2A-2 variants were purified from the acid extracted core histones of rat liver nuclei treated with ( 3 H)-BPDE-I by the HPLC system with a semi-preparative Aquapore RP-300 column. HPLC analysis of cyanogen bromide treated-H2A-2, which has one methionine residue, showed that the binding site is located in C-terminal half of H2A-2. In addition, digestions with V8-protease, trypsin and different types of carboxypeptides suggested that there are some target amino acid residues for BPDE-I in the V8-proteolytic C-terminal octapeptide which contains 2 histadine and 3 lysine residues. Currently identification of the target amino acid is proceeding, using amino acid-BPDE adducts prepared in vitro

  14. Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) promotes lung fibroblast proliferation, survival and differentiation to myofibroblasts.

    Science.gov (United States)

    Hasaneen, Nadia A; Cao, Jian; Pulkoski-Gross, Ashleigh; Zucker, Stanley; Foda, Hussein D

    2016-02-17

    Idiopathic pulmonary fibrosis (IPF) is a chronic progressively fatal disease. Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) is a glycosylated transmembrane protein that induces the expression of some matrix metalloproteinase (MMP) in neighboring stromal cells through direct epithelial-stromal interactions. EMMPRIN is highly expressed in type II alveolar epithelial cells at the edges of the fibrotic areas in IPF lung sections. However, the exact role of EMMPRIN in IPF is unknown. To determine if EMMPRIN contributes to lung fibroblast proliferation, resistance to apoptosis, and differentiation to myofibroblasts, normal Human lung fibroblasts (NHLF) transiently transfected with either EMMPRIN/GFP or GFP were treated with TGF- β1 from 0 to 10 ng/ml for 48 h and examined for cell proliferation (thymidine incorporation), apoptosis (FACS analysis and Cell Death Detection ELISA assay), cell migration (Modified Boyden chamber) and differentiation to myofibroblasts using Western blot for α-smooth actin of cell lysates. The effect of EMMPRIN inhibition on NHLF proliferation, apoptosis, migration and differentiation to myofibroblasts after TGF- β1 treatment was examined using EMMPRIN blocking antibody. We examined the mechanism by which EMMPRIN induces its effects on fibroblasts by studying the β-catenin/canonical Wnt signaling pathway using Wnt luciferase reporter assays and Western blot for total and phosphorylated β-catenin. Human lung fibroblasts overexpressing EMMPRIN had a significant increase in cell proliferation and migration compared to control fibroblasts. Furthermore, EMMPRIN promoted lung fibroblasts resistance to apoptosis. Lung fibroblasts overexpressing EMMPRIN showed a significantly increased expression of α- smooth muscle actin, a marker of differentiation to myofibroblasts compared to control cells. TGF-β1 increased the expression of EMMPRIN in lung fibroblasts in a dose-dependent manner. Attenuation of EMMPRIN expression with the use of an

  15. Differential regulation of collagen secretion by kinin receptors in cardiac fibroblast and myofibroblast

    International Nuclear Information System (INIS)

    Catalán, Mabel; Smolic, Christian; Contreras, Ariel; Ayala, Pedro; Olmedo, Ivonne; Copaja, Miguel; Boza, Pía; Vivar, Raúl; Avalos, Yennifer; Lavandero, Sergio; Velarde, Victoria; Díaz-Araya, Guillermo

    2012-01-01

    Kinins mediate their cellular effects through B1 (B1R) and B2 (B2R) receptors, and the activation of B2R reduces collagen synthesis in cardiac fibroblasts (CF). However, the question of whether B1R and/or B2R have a role in cardiac myofibroblasts remains unanswered. Methods: CF were isolated from neonate rats and myofibroblasts were generated by an 84 h treatment with TGF-β1 (CMF). B1R was evaluated by western blot, immunocytochemistry and radioligand assay; B2R, inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and cyclooxygenases 1and 2 (COX-1, and COX-2) were evaluated by western blot; intracellular Ca +2 levels were evaluated with Fluo-4AM; collagen secretion was measured in the culture media using the picrosirius red assay kit. Results: B2R, iNOS, COX-1 and low levels of B1R but not eNOS, were detected by western blot in CF. Also, B1R, B2R, and COX-2 but not iNOS, eNOS or COX-1, were detected by western blot in CMF. By immunocytochemistry, our results showed lower intracellular B1R levels in CF and higher B1R levels in CMF, mainly localized on the cell membrane. Additionally, we found B1R only in CMF cellular membrane through radioligand displacement assay. Bradykinin (BK) B2R agonist increased intracellular Ca 2+ levels and reduced collagen secretion both in CF and CMF. These effects were blocked by HOE-140, and inhibited by L-NAME, 1400W and indomethacin. Des-Arg-kallidin (DAKD) B1R agonist did not increase intracellular Ca 2+ levels in CF; however, after preincubation for 1 h with DAKD and re-stimulation with the same agonist, we found a low increase in intracellular Ca 2+ levels. Finally, DAKD increased intracellular Ca 2+ levels and decreased collagen secretion in CMF, being this effect blocked by the B1R antagonist des-Arg9-Leu8-kallidin and indomethacin, but not by L-NAME or 1400 W. Conclusion: B1R, B2R, iNOS and COX-1 were expressed differently between CF and CMF, and collagen secretion was regulated differentially by

  16. Evolving role of molecular imaging for new understanding : targeting myofibroblasts to predict remodeling

    NARCIS (Netherlands)

    de Haas, Hans J; van den Borne, Susanne W; Boersma, Hendrikus H; Slart, Riemer H J A; Fuster, Valentin; Narula, Jagat

    Containment of the process of cardiac remodeling is a prerequisite for prevention of development of heart failure (HF) after myocardial infarction. For personalization of therapeutic intervention strategy, it may be of benefit to identify the subset of patients who are at higher risk for development

  17. Interferon gamma peptidomimetic targeted to interstitial myofibroblasts attenuates renal fibrosis after unilateral ureteral obstruction in mice

    NARCIS (Netherlands)

    Poosti, Fariba; Bansal, Ruchi; Yazdani, Saleh; Prakash, Jai; Beljaars, Leonie; van den Born, Jacob; de Borst, Martin H.; van Goor, Harry; Hillebrands, Jan-Luuk; Poelstra, Klaas

    2016-01-01

    Renal fibrosis cannot be adequately treated since anti-fibrotic treatment is lacking. Interferon-gamma is a pro-inflammatory cytokine with anti-fibrotic properties. Clinical use of interferon-gamma is hampered due to inflammation-mediated systemic side effects. We used an interferon-gamma

  18. Liver Transplant

    Science.gov (United States)

    ... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

  19. Bolstering cholesteryl ester hydrolysis in liver: A hepatocyte-targeting gene delivery strategy for potential alleviation of atherosclerosis.

    Science.gov (United States)

    He, Hongliang; Lancina, Michael G; Wang, Jing; Korzun, William J; Yang, Hu; Ghosh, Shobha

    2017-06-01

    Current atherosclerosis treatment strategies primarily focus on limiting further cholesteryl esters (CE) accumulation by reducing endogenous synthesis of cholesterol in the liver. No therapy is currently available to enhance the removal of CE, a crucial step to reduce the burden of the existing disease. Given the central role of hepatic cholesteryl ester hydrolase (CEH) in the intrahepatic hydrolysis of CE and subsequent removal of the resulting free cholesterol (FC), in this work, we applied galactose-functionalized polyamidoamine (PAMAM) dendrimer generation 5 (Gal-G5) for hepatocyte-specific delivery of CEH expression vector. The data presented herein show the increased specific uptake of Gal-G5/CEH expression vector complexes (simply Gal-G5/CEH) by hepatocytes in vitro and in vivo. Furthermore, the upregulated CEH expression in the hepatocytes significantly enhanced the intracellular hydrolysis of high density lipoprotein-associated CE (HDL-CE) and subsequent conversion/secretion of hydrolyzed FC as bile acids (BA). The increased CEH expression in the liver significantly increased the flux of HDL-CE to biliary as well as fecal FC and BA. Meanwhile, Gal-G5 did not induce hepatic or renal toxicity. It was also not immunotoxic. Because of these encouraging pre-clinical testing results, using this safe and highly efficient hepatocyte-specific gene delivery platform to enhance the hepatic processes involved in cholesterol elimination is a promising strategy for the alleviation of atherosclerosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Fibroblastic and myofibroblastic tumors of the head and neck: Comprehensive imaging-based review with pathologic correlation

    Energy Technology Data Exchange (ETDEWEB)

    Hourani, Roula, E-mail: rh64@aub.edu.lb [Department of Diagnostic Radiology, American University of Beirut Medical Center, Beirut (Lebanon); Taslakian, Bedros, E-mail: bt05@aub.edu.lb [Department of Diagnostic Radiology, American University of Beirut Medical Center, Beirut (Lebanon); Shabb, Nina S., E-mail: ns04@aub.edu.lb [Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut (Lebanon); Nassar, Lara, E-mail: ln07@aub.edu.lb [Department of Diagnostic Radiology, American University of Beirut Medical Center, Beirut (Lebanon); Hourani, Mukbil H., E-mail: mh17@aub.edu.lb [Department of Diagnostic Radiology, American University of Beirut Medical Center, Beirut (Lebanon); Moukarbel, Roger, E-mail: rm17@aub.edu.lb [Department of Otolaryngology – Head and Neck Surgery, American University of Beirut Medical Center, Beirut (Lebanon); Sabri, Alain, E-mail: as71@aub.edu.lb [Department of Otolaryngology – Head and Neck Surgery, American University of Beirut Medical Center, Beirut (Lebanon); Rizk, Toni, E-mail: tonirisk@hotmail.com [Department of Neurosurgery, Hôtel-Dieu de France, Saint-Joseph University, Beirut (Lebanon)

    2015-02-15

    Highlights: • Almost all fibroblastic tumors are evaluated with non-invasive imaging. • Radiologists should be familiar with the imaging appearance of fibroblastic tumors. • Most appropriate initial examination when fibromatosis coli suspected is ultrasound. • Most common location of ossifying fibromas is the tooth-bearing regions. - Abstract: Fibroblastic and myofibroblastic tumors of the head and neck are a heterogeneous group of disorders characterized by the proliferation of fibroblasts, myofibroblasts, or both. These tumors may be further subclassified on the basis of their behavior as benign, intermediate with malignant potential, or malignant. There are different types of fibroblastic and myofibroblastic tumors that can involve the head and neck including desmoid-type fibromatosis, solitary fibrous tumor, myofibroma/myofibromatosis, nodular fasciitis, nasopharyngeal angiofibroma, fibrosarcoma, dermatofibrosarcoma protuberans, fibromatosis coli, inflammatory myofibroblastic tumor, ossifying fibroma, fibrous histiocytoma, nodular fasciitis, fibromyxoma, hyaline fibromatosis and fibrous hamartoma. Although the imaging characteristics of fibroblastic and myofibroblastic tumors of the head and neck are nonspecific, imaging plays a pivotal role in the noninvasive diagnosis and characterization of these tumors, providing information about the constitution of tumors, their extension and invasion of adjacent structures. Correlation with the clinical history may help limit the differential diagnosis and radiologists should be familiar with the imaging appearance of these tumors to reach an accurate diagnosis.

  1. Immunohistochemical analysis of stromal fibrocytes and myofibroblasts to envision the invasion and lymph node metastasis in oral squamous cell carcinoma.

    Science.gov (United States)

    Rao, Sowmya J; Rao, Jyothi Bellur Madhava; Rao, Pp Jagadish

    2017-01-01

    Tumor cells work in close coordination with stromal elements from its stage of emergence to metastasis. The study was designed to assess the presence and distribution pattern of stromal fibrocytes and myofibroblasts in oral squamous cell carcinoma (OSCC). Possibility of using these stromal cells as a marker for invasion and lymphnode metastasis was evaluated. A total of 40 cases of OSCC consisting twenty cases of each lymph node positive (pN+) and lymph node negative (pN0) samples and ten normal oral mucosa (NOM) tissues were subjected to double immunostaining using CD34 and alpha-smooth muscle actin (α-SMA) antibodies. Stained sections were evaluated semiquantitatively. CD34 fibrocytes were seen in 70% of NOM and none of OSCC samples. α-SMA myofibroblasts were seen in 80% of OSCC and none of NOM samples. A statistically significant difference was found in fibrocyte values ( P < 0.001) and myofibroblast values ( P < 0.001) between NOM and OSCC study samples. No statistical significance in myofibroblast values between pN0 and pN+ study groups; however, their distribution pattern appreciably varied. This study suggested that fibrocytes could be used as one of the markers for early invasion. Abrupt loss of fibrocytes at the transition zone toward carcinoma and statistical significance in their values supported this inference. Heterogeneity in the distribution pattern of myofibroblasts in tumor stroma indicates that this variability may predict the tumor behavior toward nodal metastasis rather than their mere presence or absence.

  2. Fibroblastic and myofibroblastic tumors of the head and neck: Comprehensive imaging-based review with pathologic correlation

    International Nuclear Information System (INIS)

    Hourani, Roula; Taslakian, Bedros; Shabb, Nina S.; Nassar, Lara; Hourani, Mukbil H.; Moukarbel, Roger; Sabri, Alain; Rizk, Toni

    2015-01-01

    Highlights: • Almost all fibroblastic tumors are evaluated with non-invasive imaging. • Radiologists should be familiar with the imaging appearance of fibroblastic tumors. • Most appropriate initial examination when fibromatosis coli suspected is ultrasound. • Most common location of ossifying fibromas is the tooth-bearing regions. - Abstract: Fibroblastic and myofibroblastic tumors of the head and neck are a heterogeneous group of disorders characterized by the proliferation of fibroblasts, myofibroblasts, or both. These tumors may be further subclassified on the basis of their behavior as benign, intermediate with malignant potential, or malignant. There are different types of fibroblastic and myofibroblastic tumors that can involve the head and neck including desmoid-type fibromatosis, solitary fibrous tumor, myofibroma/myofibromatosis, nodular fasciitis, nasopharyngeal angiofibroma, fibrosarcoma, dermatofibrosarcoma protuberans, fibromatosis coli, inflammatory myofibroblastic tumor, ossifying fibroma, fibrous histiocytoma, nodular fasciitis, fibromyxoma, hyaline fibromatosis and fibrous hamartoma. Although the imaging characteristics of fibroblastic and myofibroblastic tumors of the head and neck are nonspecific, imaging plays a pivotal role in the noninvasive diagnosis and characterization of these tumors, providing information about the constitution of tumors, their extension and invasion of adjacent structures. Correlation with the clinical history may help limit the differential diagnosis and radiologists should be familiar with the imaging appearance of these tumors to reach an accurate diagnosis

  3. Non-Targeted Metabolomics Analysis of the Effects of Tyrosine Kinase Inhibitors Sunitinib and Erlotinib on Heart, Muscle, Liver and Serum Metabolism In Vivo

    Directory of Open Access Journals (Sweden)

    Brian C. Jensen

    2017-06-01

    Full Text Available Background: More than 90 tyrosine kinases have been implicated in the pathogenesis of malignant transformation and tumor angiogenesis. Tyrosine kinase inhibitors (TKIs have emerged as effective therapies in treating cancer by exploiting this kinase dependency. The TKI erlotinib targets the epidermal growth factor receptor (EGFR, whereas sunitinib targets primarily vascular endothelial growth factor receptor (VEGFR and platelet-derived growth factor receptor (PDGFR.TKIs that impact the function of non-malignant cells and have on- and off-target toxicities, including cardiotoxicities. Cardiotoxicity is very rare in patients treated with erlotinib, but considerably more common after sunitinib treatment. We hypothesized that the deleterious effects of TKIs on the heart were related to their impact on cardiac metabolism. Methods: Female FVB/N mice (10/group were treated with therapeutic doses of sunitinib (40 mg/kg, erlotinib (50 mg/kg, or vehicle daily for two weeks. Echocardiographic assessment of the heart in vivo was performed at baseline and on Day 14. Heart, skeletal muscle, liver and serum were flash frozen and prepped for non-targeted GC-MS metabolomics analysis. Results: Compared to vehicle-treated controls, sunitinib-treated mice had significant decreases in systolic function, whereas erlotinib-treated mice did not. Non-targeted metabolomics analysis of heart identified significant decreases in docosahexaenoic acid (DHA, arachidonic acid (AA/ eicosapentaenoic acid (EPA, O-phosphocolamine, and 6-hydroxynicotinic acid after sunitinib treatment. DHA was significantly decreased in skeletal muscle (quadriceps femoris, while elevated cholesterol was identified in liver and elevated ethanolamine identified in serum. In contrast, erlotinib affected only one metabolite (spermidine significantly increased. Conclusions: Mice treated with sunitinib exhibited systolic dysfunction within two weeks, with significantly lower heart and skeletal muscle

  4. Targeting the PDGF-B/PDGFR-β Interface with Destruxin A5 to Selectively Block PDGF-BB/PDGFR-ββ Signaling and Attenuate Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Xingqi Wang

    2016-05-01

    Full Text Available PDGF-BB/PDGFR-ββ signaling plays very crucial roles in the process of many diseases such as liver fibrosis. However, drug candidates with selective affinities for PDGF-B/PDGFR-β remain deficient. Here, we identified a natural cyclopeptide termed destruxin A5 that effectively inhibits PDGF-BB-induced PDGFR-β signaling. Interestingly and importantly, the inhibitory mechanism is distinct from the mechanism of tyrosine kinase inhibitors because destruxin A5 does not have the ability to bind to the ATP-binding pocket of PDGFR-β. Using Biacore T200 technology, thermal shift technology, microscale thermophoresis technology and computational analysis, we confirmed that destruxin A5 selectively targets the PDGF-B/PDGFR-β interaction interface to block this signaling. Additionally, the inhibitory effect of destruxin A5 on PDGF-BB/PDGFR-ββ signaling was verified using in vitro, ex vivo and in vivo models, in which the extent of liver fibrosis was effectively alleviated by destruxin A5. In summary, destruxin A5 may represent an efficacious and more selective inhibitor of PDGF-BB/PDGFR-ββ signaling.

  5. A novel assay for detecting antibodies to cytochrome P4502D6, the molecular target of liver kidney microsomal antibody type 1.

    Science.gov (United States)

    Kerkar, N; Ma, Y; Hussain, M; Muratori, L; Targett, C; Williams, R; Bianchi, F B; Mieli-Vergani, G; Vergani, D

    1999-03-04

    Liver Kidney Microsomal type 1 (LKM1) antibody, the diagnostic marker of autoimmune hepatitis type 2, is also found in a proportion of patients with hepatitis C virus infection (HCV). It is detected conventionally by the subjective immunofluorescence technique. Our aim was to establish a simple and objective enzyme-linked immunosorbent assay (ELISA) that measures antibodies to cytochrome P4502D6 (CYP2D6), the target of LKM1. An indirect ELISA using eukaryotically expressed CYP2D6 was designed. Absorbance values obtained against a reference microsomal preparation were subtracted from those obtained against a microsomal preparation over-expressing CYP2D6, thus removing the non-CYP2D6-specific reaction. Sera from 51 LKM1 positive patients (21 autoimmune hepatitis and 30 with HCV infection), 111 LKM1 negative patients with chronic liver disease (including 20 with HCV infection) and 43 healthy controls were tested. Of 51 patients positive by immunofluorescence, 48 were also positive by ELISA while all the 154 LKM1 negative subjects were also negative by ELISA. There was a high degree of association between IFL and ELISA as demonstrated by a kappa reliability value of 0.96. The absorbance values by ELISA correlated with immunofluorescence LKM1 titres both in autoimmune hepatitis (r = 0.74, p < 0.001) and HCV infection (r = 0.67, p < 0.001). The simple, objective ELISA described has the potential to replace the standard immunofluorescence technique.

  6. Vascular dysfunction by myofibroblast activation in patients with idiopathic pulmonary fibrosis and prognostic significance

    Directory of Open Access Journals (Sweden)

    E.R. Parra

    2012-07-01

    Full Text Available In this study, we demonstrated the importance of telomerase protein expression and determined the relationships among telomerase, endothelin-1 (ET-1 and myofibroblasts during early and late remodeling of parenchymal and vascular areas in usual interstitial pneumonia (UIP using 27 surgical lung biopsies from patients with idiopathic pulmonary fibrosis (IPF. Telomerase+, myofibroblasts α-SMA+, smooth muscle cells caldesmon+, endothelium ET-1+ cellularity, and fibrosis severity were evaluated in 30 fields covering normal lung parenchyma, minimal fibrosis (fibroblastic foci, severe (mural fibrosis, and vascular areas of UIP by the point-counting technique and a semiquantitative score. The impact of these markers was determined in pulmonary functional tests and follow-up until death from IPF. Telomerase and ET-1 expression was significantly increased in normal and vascular areas compared to areas of fibroblast foci. Telomerase and ET-1 expression was inversely correlated with minimal fibrosis in areas of fibroblast foci and directly associated with severe fibrosis in vascular areas. Telomerase activity in minimal fibrosis areas was directly associated with diffusing capacity of the lung for oxygen/alveolar volume and ET-1 expression and indirectly associated with diffusing capacity of the lungs for carbon monoxide and severe fibrosis in vascular areas. Cox proportional hazards regression revealed a low risk of death for females with minimal fibrosis displaying high telomerase and ET-1 expression in normal areas. Vascular dysfunction by telomerase/ET-1 expression was found earlier than vascular remodeling by myofibroblast activation in UIP with impact on IPF evolution, suggesting that strategies aimed at preventing the effect of these mediators may have a greater impact on patient outcome.

  7. Inflammatory Myofibroblastic Tumor of the Bladder: 2 Rare Cases Managed with Laparoscopic Partial Cystectomy

    Directory of Open Access Journals (Sweden)

    Sofia Santos Lopes

    2016-01-01

    Full Text Available Two cases of inflammatory myofibroblastic tumor (IMT of the bladder are reported here. Both patients were male and presented with macroscopic hematuria; in the first case terminal hematuria was associated with irritative voiding symptoms. The second case was a smoker with hematuria unresponsive to medical treatment and anemia. Clinical presentation, pathological features, treatment, and prognosis are discussed. Due to rarity of this pathological condition, there are no guidelines concerning treatment and follow-up. We present our follow-up scheme and highlight the use of laparoscopic partial cystectomy as a successful treatment approach.

  8. Fibrosis in connective tissue disease: the role of the myofibroblast and fibroblast-epithelial cell interactions

    Science.gov (United States)

    Krieg, Thomas; Abraham, David; Lafyatis, Robert

    2007-01-01

    Fibrosis, characterized by excessive extracellular matrix accumulation, is a common feature of many connective tissue diseases, notably scleroderma (systemic sclerosis). Experimental studies suggest that a complex network of intercellular interactions involving endothelial cells, epithelial cells, fibroblasts and immune cells, using an array of molecular mediators, drives the pathogenic events that lead to fibrosis. Transforming growth factor-β and endothelin-1, which are part of a cytokine hierarchy with connective tissue growth factor, are key mediators of fibrogenesis and are primarily responsible for the differentiation of fibroblasts toward a myofibroblast phenotype. The tight skin mouse (Tsk-1) model of cutaneous fibrosis suggests that numerous other genes may also be important. PMID:17767742

  9. Interface-Targeting Strategy Enables Two-Photon Fluorescent Lipid Droplet Probes for High-Fidelity Imaging of Turbid Tissues and Detecting Fatty Liver.

    Science.gov (United States)

    Guo, Lifang; Tian, Minggang; Feng, Ruiqing; Zhang, Ge; Zhang, Ruoyao; Li, Xuechen; Liu, Zhiqiang; He, Xiuquan; Sun, Jing Zhi; Yu, Xiaoqiang

    2018-04-04

    Lipid droplets (LDs) with unique interfacial architecture not only play crucial roles in protecting a cell from lipotoxicity and lipoapoptosis but also closely relate with many diseases such as fatty liver and diabetes. Thus, as one of the important applied biomaterials, fluorescent probes with ultrahigh selectivity for in situ and high-fidelity imaging of LDs in living cells and tissues are critical to elucidate relevant physiological and pathological events as well as detect related diseases. However, available probes only utilizing LDs' waterless neutral cores but ignoring the unique phospholipid monolayer interfaces exhibit low selectivity. They cannot differentiate neutral cores of LDs from intracellular other lipophilic microenvironments, which results in extensively cloud-like background noise and severely limited their bioapplications. Herein, to design LD probes with ultrahigh selectivity, the exceptional interfacial architecture of LDs is considered adequately and thus an interface-targeting strategy is proposed for the first time. According to the novel strategy, we have developed two amphipathic fluorescent probes (N-Cy and N-Py) by introducing different cations into a lipophilic fluorophore (nitrobenzoxadiazole (NBD)). Consequently, their cationic moiety precisely locates the interfaces through electrostatic interaction and simultaneously NBD entirely embeds into the waterless core via hydrophobic interaction. Thus, high-fidelity and background-free fluorescence imaging of LDs are expectably realized in living cells in situ. Moreover, LDs in turbid tissues like skeletal muscle slices have been clearly imaged (up to 82 μm depth) by a two-photon microscope. Importantly, using N-Cy, we not only intuitively monitored the variations of LDs in number, size, and morphology but also clearly revealed their abnormity in hepatic tissues resulting from fatty liver. Therefore, these unique probes provide excellent imaging tools for elucidating LD

  10. Bleomycin-Treated Chimeric Thy1-Deficient Mice with Thy1-Deficient Myofibroblasts and Thy-Positive Lymphocytes Resolve Inflammation without Affecting the Fibrotic Response

    Directory of Open Access Journals (Sweden)

    Pazit Y. Cohen

    2015-01-01

    Full Text Available Lung fibrosis is characterized by abnormal accumulation of fibroblasts in the interstitium of the alveolar space. Two populations of myofibroblasts, distinguished by Thy1 expression, are detected in human and murine lungs. Accumulation of Thy1-negative (Thy1− myofibroblasts was shown in the lungs of humans with idiopathic pulmonary fibrosis (IPF and of bleomycin-treated mice. We aimed to identify genetic changes in lung myofibroblasts following Thy1 crosslinking and assess the impact of specific lung myofibroblast Thy1-deficiency, in vivo, in bleomycin-injured mouse lungs. Thy1 increased in mouse lung lymphocytes following bleomycin injury but decreased in myofibroblasts when fibrosis was at the highest point (14 days, as assessed by immunohistochemistry. Using gene chip analysis, we detected that myofibroblast Thy1 crosslinking mediates downregulation of genes promoting cell proliferation, survival, and differentiation, and reduces production of extracellular matrix (ECM components, while concurrently mediating the upregulation of genes known to foster inflammation and immunological functions. Chimeric Thy1-deficient mice with Thy1+ lymphocytes and Thy1− myofibroblasts showed fibrosis similar to wild-type mice and an increased number of CD4/CD25 regulatory T cells, with a concomitant decrease in inflammation. Lung myofibroblasts downregulate Thy1 expression to increase their proliferation but to diminish the in vivo inflammatory milieu. Inflammation is not essential for evolution of fibrosis as was previously stated.

  11. The pro-fibrotic properties of transforming growth factor on human fibroblasts are counteracted by caffeic acid by inhibiting myofibroblast formation and collagen synthesis

    NARCIS (Netherlands)

    Mia, Masum M.; Bank, Ruud A.

    Fibrosis is a chronic disorder affecting many organs. A universal process in fibrosis is the formation of myofibroblasts and the subsequent collagen deposition by these cells. Transforming growth factor beta1 (TGF beta 1) plays a major role in the formation of myofibroblasts, e.g. by activating

  12. Paraneoplastic pemphigus associated with inflammatory myofibroblastic tumour of the mediastinum: A favourable response to treatment and review of the literature.

    Science.gov (United States)

    Ghandi, Narges; Ghanadan, Alireza; Azizian, Mohammad-Reza; Hejazi, Pardis; Aghazadeh, Nessa; Tavousi, Parvin; Daneshpazhooh, Maryam

    2015-05-01

    Paraneoplastic pemphigus (PNP) is an autoimmune blistering disorder that occurs in association with an underlying neoplasm. Inflammatory myofibroblastic tumour (IMT) is a rare low-grade sarcoma of fibroblasts and myofibroblasts associated with inflammatory cells, most commonly occurring in the lung. In this study, a case of PNP associated with IMT of the mediastinum is reported. The patient had a favourable outcome following surgical resection and treatment with a systemic steroid, azathioprine, and i.v. immunoglobulin. The occurrence of PNP with sarcomas, specifically IMT, is noteworthy although it is not well studied in the existing literature. © 2014 The Australasian College of Dermatologists.

  13. Swimming Exercise Prevents Fibrogenesis in Chronic Kidney Disease by Inhibiting the Myofibroblast Transdifferentiation

    Science.gov (United States)

    Peng, Chiung-Chi; Chen, Kuan-Chou; Hsieh, Chiu-Lan; Peng, Robert Y.

    2012-01-01

    Background The renal function of chronic kidney disease (CKD) patients may be improved by a number of rehabilitative mechanisms. Swimming exercise training was supposed to be beneficial to its recovery. Methodology/Principal Findings Doxorubicin-induced CKD (DRCKD) rat model was performed. Swimming training was programmed three days per week, 30 or 60 min per day for a total period of 11 weeks. Serum biochemical and pathological parameters were examined. In DRCKD, hyperlipidemia was observed. Active mesangial cell activation was evidenced by overexpression of PDGFR, P-PDGFR, MMP-2, MMP-9, α-SMA, and CD34 with a huge amount collagen deposition. Apparent myofibroblast transdifferentiation implicating fibrogenesis in the glomerular mesangium, glomerulonephritis and glomeruloscelorosis was observed with highly elevated proteinuria and urinary BUN excretion. The 60-min swimming exercise but not the 30 min equivalent rescued most of the symptoms. To quantify the effectiveness of exercise training, a physical parameter, i.e. “the strenuosity coefficient” or “the myokine releasing coefficient”, was estimated to be 7.154×10−3 pg/mL-J. Conclusions The 60-min swimming exercise may ameliorate DRCKD by inhibiting the transdifferentiation of myofibroblasts in the glomerular mesangium. Moreover, rehabilitative exercise training to rescue CKD is a personalized remedy. Benefits depend on the duration and strength of exercise, and more importantly, on the individual physiological condition. PMID:22761655

  14. Carinal resection and reconstruction following inflammatory myofibroblastic tumor resection: A case report

    Directory of Open Access Journals (Sweden)

    Julia G. Lyon

    2016-02-01

    Full Text Available Inflammatory myofibroblastic tumors (IMT are rare tumors of the respiratory tract that most commonly occur in the lung and are rarely seen in the trachea. They present most often in young patients. We report on a case of an IMT of the carina in a seven year old girl, requiring carinal resection and reconstruction with a novel technique in pediatric airway surgery. Attempts at endoscopic excision of the carinal IMT were unsuccessful. An open approach for resection of the involved carina, distal trachea, and proximal mainstem bronchi was performed via sternotomy and cardiopulmonary bypass. The resulting triangular defect in the trachea and bronchi was reconstructed with anastomosis of the proximal trachea and left mainstem bronchus using a rotational flap of the right lateral mainstem bronchial wall. The remaining right mainstem bronchus was anastomosed, end to side, to the intact trachea proximal to the primary anastomosis. Bronchoscopy and MRI 22 months post resection and reconstruction revealed a healthy neo-carina and patent distal airway with no evidence of recurrent IMT. Pediatric patients with carinal inflammatory myofibroblastic tumors can be successfully managed with open resection and reconstruction of the airway.

  15. Versican V1 Overexpression Induces a Myofibroblast-Like Phenotype in Cultured Fibroblasts.

    Directory of Open Access Journals (Sweden)

    Jon M Carthy

    Full Text Available Versican, a chondroitin sulphate proteoglycan, is one of the key components of the provisional extracellular matrix expressed after injury. The current study evaluated the hypothesis that a versican-rich matrix alters the phenotype of cultured fibroblasts.The full-length cDNA for the V1 isoform of human versican was cloned and the recombinant proteoglycan was expressed in murine fibroblasts. Versican expression induced a marked change in fibroblast phenotype. Functionally, the versican-expressing fibroblasts proliferated faster and displayed enhanced cell adhesion, but migrated slower than control cells. These changes in cell function were associated with greater N-cadherin and integrin β1 expression, along with increased FAK phosphorylation. The versican-expressing fibroblasts also displayed expression of smooth muscle α-actin, a marker of myofibroblast differentiation. Consistent with this observation, the versican fibroblasts displayed increased synthetic activity, as measured by collagen III mRNA expression, as well as a greater capacity to contract a collagen lattice. These changes appear to be mediated, at least in part, by an increase in active TGF-β signaling in the versican expressing fibroblasts, and this was measured by phosphorylation and nuclear accumulation of SMAD2.Collectively, these data indicate versican expression induces a myofibroblast-like phenotype in cultured fibroblasts.

  16. Pulmonary Inflammatory Myofibroblastic Tumor in Children: A Case Report and Brief Review of Literature

    Directory of Open Access Journals (Sweden)

    Federica Camela

    2018-02-01

    Full Text Available The inflammatory myofibroblastic tumor (IMT is a rare lesion of unclear etiology and variable clinical course, consisting of a proliferation of fibroblasts and myofibroblasts, mixed with inflammatory cells. Synonyms of IMT are inflammatory pseudotumor and plasma cell granuloma reflecting the alleged inflammatory nature attributed to this lesion, even though this heterogeneity in the disease denomination is probably involved in a dispersion of the literature data. Among primary pulmonary neoplasms, it represents the most frequent endobronchial tumor of childhood and beyond the lung it has been described mainly in the bladder, mediastinum and mesentery. Despite having a tendency for local recurrence, the risk of distant metastasis is low. Clinical presentation depends on localization therefore lung peripheral lesions are often asymptomatic resulting in a delayed diagnosis. Radiological findings can suggest the diagnosis that must be confirmed by histopathology assessment. The tumor has been characterized by the application of immunohistochemical techniques, molecular biology and cytogenetics, which are very precious for the diagnosis. The therapeutic approach consists in the complete surgical excision of the lesion that normally ensures excellent survival. Due to the potential risk of recurrence, close clinical trial is indicated. To date only 24 cases of pulmonary IMT have been described, although the prevalence is probably higher. We present a case report of a 3-year-old girl with pulmonary IMT and a brief review of known literature cases in order to highlight the most common clinical presentations, the most useful diagnostic tools and therapeutic approach.

  17. Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6 Is a Novel Nutritional Therapeutic Target for Hyperlipidemia, Non-Alcoholic Fatty Liver Disease, and Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Gwang-woong Go

    2015-06-01

    Full Text Available Low-density lipoprotein receptor-related protein 6 (LRP6 is a member of the low-density lipoprotein receptor family and has a unique structure, which facilitates its multiple functions as a co-receptor for Wnt/β-catenin signaling and as a ligand receptor for endocytosis. The role LRP6 plays in metabolic regulation, specifically in the nutrient-sensing pathway, has recently garnered considerable interest. Patients carrying an LRP6 mutation exhibit elevated levels of LDL cholesterol, triglycerides, and fasting glucose, which cooperatively constitute the risk factors of metabolic syndrome and atherosclerosis. Since the discovery of this mutation, the general role of LRP6 in lipid homeostasis, glucose metabolism, and atherosclerosis has been thoroughly researched. These studies have demonstrated that LRP6 plays a role in LDL receptor-mediated LDL uptake. In addition, when the LRP6 mutant impaired Wnt-LRP6 signaling, hyperlipidemia, non-alcoholic fatty liver disease, and atherosclerosis developed. LRP6 regulates lipid homeostasis and body fat mass via the nutrient-sensing mechanistic target of the rapamycin (mTOR pathway. Furthermore, the mutant LRP6 triggers atherosclerosis by activating platelet-derived growth factor (PDGF-dependent vascular smooth muscle cell differentiation. This review highlights the exceptional opportunities to study the pathophysiologic contributions of LRP6 to metabolic syndrome and cardiovascular diseases, which implicate LRP6 as a latent regulator of lipid metabolism and a novel therapeutic target for nutritional intervention.

  18. A Study of volumetric modulated arc therapy for stereotactic body radiation therapy in case of multi-target liver cancer using flattening filter free beam

    International Nuclear Information System (INIS)

    Yeom, Mi Sook; Yoon, In Ha; Hong, Dong Gi; Back, Geum Mun

    2015-01-01

    Stereotactic body radiation therapy (SBRT) has proved its efficacy in several patient populations with primary and metastatic limited tumors. Because SBRT prescription is high dose level than Conventional radiation therapy. SBRT plan is necessary for effective Organ at risk (OAR) protection and sufficient Planning target volume (PTV) dose coverage. In particular, multi-target cases may result excessive doses to OAR and hot spot due to dose overlap. This study evaluate usefulness of Volumetric modulated arc therapy (VMAT) in dosimetric and technical considerations using Flattening filter free (FFF) beam. The treatment plans for five patients, being treated on TrueBeam STx(Varian™, USA) with VMAT using 10MV FFF beam and Standard conformal radiotherapy (CRT) using 15MV Flattening filter (FF) beam. PTV, liver, duodenum, bowel, spinal cord, esophagus, stomach dose were evaluated using the dose volume histogram(DVH). Conformity index(CI), homogeneity index(HI), Paddick's index(PCI) for the PTV was assessed. Total Monitor unit (MU) and beam on time was assessed. Average value of CI, HI and PCI for PTV was 1.381±0.028, 1.096±0.016, 0.944±0.473 in VMAT and 1.381± 0.042, 1.136±0.042, 1.534±0.465 in CRT respectively. OAR dose in CRT plans evaluated 1.8 times higher than VMAT. Total MU in VMAT evaluated 1.3 times increase than CRT. Average beam on time was 6.8 minute in VMAT and 21.3 minute in CRT respectively. OAR dose in CRT plans evaluated 1.8 times higher than VMAT. Total MU in VMAT evaluated 1.3 times increase than CRT. Average beam on time was 6.8 minute in VMAT and 21.3 minute in CRT. VMAT for SBRT in multi-target liver cancer using FFF beam is effective treatment techniqe in dosimetric and technical considerations. VMAT decrease intra-fraction error due to treatment time shortening using high dose rate of FFF beam

  19. A Study of volumetric modulated arc therapy for stereotactic body radiation therapy in case of multi-target liver cancer using flattening filter free beam

    Energy Technology Data Exchange (ETDEWEB)

    Yeom, Mi Sook; Yoon, In Ha; Hong, Dong Gi; Back, Geum Mun [Dept. of Radiation Oncology, ASAN Medical Center, Seoul (Korea, Republic of)

    2015-06-15

    Stereotactic body radiation therapy (SBRT) has proved its efficacy in several patient populations with primary and metastatic limited tumors. Because SBRT prescription is high dose level than Conventional radiation therapy. SBRT plan is necessary for effective Organ at risk (OAR) protection and sufficient Planning target volume (PTV) dose coverage. In particular, multi-target cases may result excessive doses to OAR and hot spot due to dose overlap. This study evaluate usefulness of Volumetric modulated arc therapy (VMAT) in dosimetric and technical considerations using Flattening filter free (FFF) beam. The treatment plans for five patients, being treated on TrueBeam STx(Varian™, USA) with VMAT using 10MV FFF beam and Standard conformal radiotherapy (CRT) using 15MV Flattening filter (FF) beam. PTV, liver, duodenum, bowel, spinal cord, esophagus, stomach dose were evaluated using the dose volume histogram(DVH). Conformity index(CI), homogeneity index(HI), Paddick's index(PCI) for the PTV was assessed. Total Monitor unit (MU) and beam on time was assessed. Average value of CI, HI and PCI for PTV was 1.381±0.028, 1.096±0.016, 0.944±0.473 in VMAT and 1.381± 0.042, 1.136±0.042, 1.534±0.465 in CRT respectively. OAR dose in CRT plans evaluated 1.8 times higher than VMAT. Total MU in VMAT evaluated 1.3 times increase than CRT. Average beam on time was 6.8 minute in VMAT and 21.3 minute in CRT respectively. OAR dose in CRT plans evaluated 1.8 times higher than VMAT. Total MU in VMAT evaluated 1.3 times increase than CRT. Average beam on time was 6.8 minute in VMAT and 21.3 minute in CRT. VMAT for SBRT in multi-target liver cancer using FFF beam is effective treatment techniqe in dosimetric and technical considerations. VMAT decrease intra-fraction error due to treatment time shortening using high dose rate of FFF beam.

  20. Differential regulation of collagen secretion by kinin receptors in cardiac fibroblast and myofibroblast

    Energy Technology Data Exchange (ETDEWEB)

    Catalán, Mabel; Smolic, Christian [Centro de estudios moleculares de la célula, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile (Chile); Contreras, Ariel [Instituto Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile (Chile); Ayala, Pedro; Olmedo, Ivonne; Copaja, Miguel; Boza, Pía; Vivar, Raúl; Avalos, Yennifer [Centro de estudios moleculares de la célula, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile (Chile); Lavandero, Sergio [Centro de estudios moleculares de la célula, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile (Chile); Instituto Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile (Chile); Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, TX (United States); Velarde, Victoria [Departamento de Ciencias Fisiológicas, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago (Chile); Díaz-Araya, Guillermo, E-mail: gadiaz@ciq.uchile.cl [Centro de estudios moleculares de la célula, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile (Chile)

    2012-06-15

    Kinins mediate their cellular effects through B1 (B1R) and B2 (B2R) receptors, and the activation of B2R reduces collagen synthesis in cardiac fibroblasts (CF). However, the question of whether B1R and/or B2R have a role in cardiac myofibroblasts remains unanswered. Methods: CF were isolated from neonate rats and myofibroblasts were generated by an 84 h treatment with TGF-β1 (CMF). B1R was evaluated by western blot, immunocytochemistry and radioligand assay; B2R, inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and cyclooxygenases 1and 2 (COX-1, and COX-2) were evaluated by western blot; intracellular Ca{sup +2} levels were evaluated with Fluo-4AM; collagen secretion was measured in the culture media using the picrosirius red assay kit. Results: B2R, iNOS, COX-1 and low levels of B1R but not eNOS, were detected by western blot in CF. Also, B1R, B2R, and COX-2 but not iNOS, eNOS or COX-1, were detected by western blot in CMF. By immunocytochemistry, our results showed lower intracellular B1R levels in CF and higher B1R levels in CMF, mainly localized on the cell membrane. Additionally, we found B1R only in CMF cellular membrane through radioligand displacement assay. Bradykinin (BK) B2R agonist increased intracellular Ca{sup 2+} levels and reduced collagen secretion both in CF and CMF. These effects were blocked by HOE-140, and inhibited by L-NAME, 1400W and indomethacin. Des-Arg-kallidin (DAKD) B1R agonist did not increase intracellular Ca{sup 2+} levels in CF; however, after preincubation for 1 h with DAKD and re-stimulation with the same agonist, we found a low increase in intracellular Ca{sup 2+} levels. Finally, DAKD increased intracellular Ca{sup 2+} levels and decreased collagen secretion in CMF, being this effect blocked by the B1R antagonist des-Arg9-Leu8-kallidin and indomethacin, but not by L-NAME or 1400 W. Conclusion: B1R, B2R, iNOS and COX-1 were expressed differently between CF and CMF, and collagen secretion was

  1. ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-1α.

    Science.gov (United States)

    Lee, Joon Ho; Hur, Wonhee; Hong, Sung Woo; Kim, Jung-Hee; Kim, Sung Min; Lee, Eun Byul; Yoon, Seung Kew

    2017-02-01

    Hepatocellular carcinoma (HCC) is the fifth most common solid cancer and the third most common cause of cancer-related mortality. HCC develops via a multistep process associated with genetic aberrations that facilitate HCC invasion and migration and promote metastasis. A growing body of evidence indicates that cancer stem cells (CSCs) are responsible for tumorigenesis, cancer cell invasion and metastasis. Despite the extremely small proportion of cancer cells represented by this subpopulation of HCC cells, CSCs play a key role in cancer metastasis and poor prognosis. ELK3 (Net/SAP-2/Erp) is a transcription factor that is activated by the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. It plays several important roles in various physiological processes, including cell migration, invasion, wound healing, angiogenesis and tumorigenesis. In the present study, we investigated the role of ELK3 in cancer cell invasion and metastasis in CD133+/CD44+ liver cancer stem cells (LCSCs). We isolated LCSCs expressing CD133 and CD44 from Huh7 HCC cells and evaluated their metastatic potential using invasion and migration assays. We found that CD133+/CD44+ cells had increased metastatic potential compared with non-CD133+/CD44+ cells. We also demonstrated that ELK3 expression was upregulated in CD133+/CD44+ cells and that this aberration enhanced cell migration and invasion. In addition, we identified the molecular mechanism by which ELK3 promotes cancer cell migration and invasion. We found that silencing of ELK3 expression in CD133+/CD44+ LCSCs attenuated their metastatic potential by modulating the expression of heat shock-induced factor-1α (HIF-1α). Collectively, the results of the present study demonstrated that ELK3 overexpression promoted metastasis in CD133+/CD44+ cells by regulating HIF-1α expression and that silencing of ELK3 expression attenuated the metastatic potential of CD133+/CD44+ LCSCs. In conclusion, modulation of ELK3 expression may

  2. Arming drug carriers to disable the Hepatic Stellate Cell : the targeted delivery of apoptosis-inducing drugs to the fibrotic liver

    NARCIS (Netherlands)

    Hagens, Werner Ivo

    2006-01-01

    Chronic liver damage of various origins (e.g. viral hepatitis; chronic intoxication by alcohol, chemicals or drugs; Wilson’s disease) can eventually lead to liver cirrhosis, the end stage of liver fibrosis. This process is characterized by the accumulation of excessive amounts of scar tissue within

  3. The let-7/Lin28 axis regulates activation of hepatic stellate cells in alcoholic liver injury.

    Science.gov (United States)

    McDaniel, Kelly; Huang, Li; Sato, Keisaku; Wu, Nan; Annable, Tami; Zhou, Tianhao; Ramos-Lorenzo, Sugeily; Wan, Ying; Huang, Qiaobing; Francis, Heather; Glaser, Shannon; Tsukamoto, Hidekazu; Alpini, Gianfranco; Meng, Fanyin

    2017-07-07

    The let-7/Lin28 axis is associated with the regulation of key cellular regulatory genes known as microRNAs in various human disorders and cancer development. This study evaluated the role of the let-7/Lin28 axis in regulating a mesenchymal phenotype of hepatic stellate cells in alcoholic liver injury. We identified that ethanol feeding significantly down-regulated several members of the let-7 family in mouse liver, including let-7a and let-7b. Similarly, the treatment of human hepatic stellate cells (HSCs) with lipopolysaccharide (LPS) and transforming growth factor-β (TGF-β) significantly decreased the expressions of let-7a and let-7b. Conversely, overexpression of let-7a and let-7b suppressed the myofibroblastic activation of cultured human HSCs induced by LPS and TGF-β, as evidenced by repressed ACTA2 (α-actin 2), COL1A1 (collagen 1A1), TIMP1 (TIMP metallopeptidase inhibitor 1), and FN1 (fibronectin 1); this supports the notion that HSC activation is controlled by let-7. A combination of bioinformatics, dual-luciferase reporter assay, and Western blot analysis revealed that Lin28B and high-mobility group AT-hook (HMGA2) were the direct targets of let-7a and let-7b. Furthermore, Lin28B deficiency increased the expression of let-7a/let-7b as well as reduced HSC activation and liver fibrosis in mice with alcoholic liver injury. This feedback regulation of let-7 by Lin28B is verified in hepatic stellate cells isolated by laser capture microdissection from the model. The identification of the let-7/Lin28 axis as an important regulator of HSC activation as well as its upstream modulators and down-stream targets will provide insights into the involvement of altered microRNA expression in contributing to the pathogenesis of alcoholic liver fibrosis and novel therapeutic approaches for human alcoholic liver diseases. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. Natural Killer cells and liver fibrosis

    Directory of Open Access Journals (Sweden)

    Frank eFasbender

    2016-01-01

    Full Text Available In the 40 years since the discovery of Natural Killer (NK cells it has been well established that these innate lymphocytes are important for early and effective immune responses against transformed cells and infections with different pathogens. In addition to these classical functions of NK cells, we now know that they are part of a larger family of innate lymphoid cells and that they can even mediate memory-like responses. Additionally, tissue resident NK cells with distinct phenotypical and functional characteristics have been identified. Here we focus on the phenotype of different NK cell subpopulations that can be found in the liver and summarize the current knowledge about the functional role of these cells with a special emphasis on liver fibrosis. NK cell cytotoxicity can contribute to liver damage in different forms of liver disease. However, NK cells can limit liver fibrosis by killing hepatic stellate cell-derived myofibroblasts, which play a key role in this pathogenic process. Therefore, liver NK cells need to be tightly regulated in order to balance these beneficial and pathological effects.

  5. Ciclosporin Does Not Influence Bone Marrow-Derived Cell Differentiation to Myofibroblasts Early after Renal Ischemia/Reperfusion

    NARCIS (Netherlands)

    Broekema, Martine; Harmsen, Martin C.; Koerts, Jasper A.; van Kooten, Theo G.; Uges, Donald R. A.; Petersen, Arjen H.; van Luyn, Marja J. A.; Navis, Gerjan; Popa, Eliane R.

    2009-01-01

    Background: Ischemia/reperfusion injury (IRI) is a risk factor for the development of interstitial fibrosis. Previously we had shown that after renal IRI, bone marrow-derived cells (BMDC) can differentiate to interstitial myofibroblasts. Here we hypothesized that the immunosuppressant ciclosporin A

  6. Chronic Myelogenous Leukemia Cells Contribute to the Stromal Myofibroblasts in Leukemic NOD/SCID Mouse In Vivo

    Directory of Open Access Journals (Sweden)

    Ryosuke Shirasaki

    2012-01-01

    Full Text Available We recently reported that chronic myelogenous leukemia (CML cells converted into myofibroblasts to create a microenvironment for proliferation of CML cells in vitro. To analyze a biological contribution of CML-derived myofibroblasts in vivo, we observed the characters of leukemic nonobese diabetes/severe combined immunodeficiency (NOD/SCID mouse. Bone marrow nonadherent mononuclear cells as well as human CD45-positive cells obtained from CML patients were injected to the irradiated NOD/SCID mice. When the chimeric BCR-ABL transcript was demonstrated in blood, human CML cells were detected in NOD/SCID murine bone marrow. And CML-derived myofibroblasts composed with the bone marrow-stroma, which produced significant amounts of human vascular endothelial growth factor A. When the parental CML cells were cultured with myofibroblasts separated from CML cell-engrafted NOD/SCID murine bone marrow, CML cells proliferated significantly. These observations indicate that CML cells make an adequate microenvironment for their own proliferation in vivo.

  7. Increased expression of chemerin in squamous esophageal cancer myofibroblasts and role in recruitment of mesenchymal stromal cells.

    Directory of Open Access Journals (Sweden)

    J Dinesh Kumar

    Full Text Available Stromal cells such as myofibroblasts influence tumor progression. The mechanisms are unclear but may involve effects on both tumor cells and recruitment of bone marrow-derived mesenchymal stromal cells (MSCs which then colonize tumors. Using iTRAQ and LC-MS/MS we identified the adipokine, chemerin, as overexpressed in esophageal squamous cancer associated myofibroblasts (CAMs compared with adjacent tissue myofibroblasts (ATMs. The chemerin receptor, ChemR23, is expressed by MSCs. Conditioned media (CM from CAMs significantly increased MSC cell migration compared to ATM-CM; the action of CAM-CM was significantly reduced by chemerin-neutralising antibody, pretreatment of CAMs with chemerin siRNA, pretreatment of MSCs with ChemR23 siRNA, and by a ChemR23 receptor antagonist, CCX832. Stimulation of MSCs by chemerin increased phosphorylation of p42/44, p38 and JNK-II kinases and inhibitors of these kinases and PKC reversed chemerin-stimulated MSC migration. Chemerin stimulation of MSCs also induced expression and secretion of macrophage inhibitory factor (MIF that tended to restrict migratory responses to low concentrations of chemerin but not higher concentrations. In a xenograft model consisting of OE21 esophageal cancer cells and CAMs, homing of MSCs administered i.v. was inhibited by CCX832. Thus, chemerin secreted from esophageal cancer myofibroblasts is a potential chemoattractant for MSCs and its inhibition may delay tumor progression.

  8. αII-spectrin and βII-spectrin do not affect TGFβ1-induced myofibroblast differentiation.

    Science.gov (United States)

    Piersma, Bram; Wouters, Olaf Y; Bank, Ruud A

    2018-05-03

    Mechanosensing of fibroblasts plays a key role in the development of fibrosis. So far, no effective treatments are available to treat this devastating disorder. Spectrins regulate cell morphology and are potential mechanosensors in a variety of non-erythroid cells, but little is known about the role of spectrins in fibroblasts. We investigate whether αII- and βII-spectrin are required for the phenotypic properties of adult human dermal (myo)fibroblasts. Knockdown of αII- or βII-spectrin in fibroblasts did not affect cell adhesion, cell size and YAP nuclear/cytosolic localization. We further investigated whether αII- and βII-spectrin play a role in the phenotypical switch from fibroblasts to myofibroblasts under the influence of the pro-fibrotic cytokine TGFβ1. Knockdown of spectrins did not affect myofibroblast formation, nor did we observe changes in the organization of αSMA stress fibers. Focal adhesion assembly was unaffected by spectrin deficiency, as was collagen type I mRNA expression and protein deposition. Wound closure was unaffected as well, showing that important functional properties of myofibroblasts are unchanged without αII- or βII-spectrin. In fact, fibroblasts stimulated with TGFβ1 demonstrated significantly lower endogenous mRNA levels of αII- and βII-spectrin. Taken together, despite the diverse roles of spectrins in a variety of other cells, αII- and βII-spectrin do not regulate cell adhesion, cell size and YAP localization in human dermal fibroblasts and are not required for the dermal myofibroblast phenotypical switch.

  9. Liver Hemangioma

    Science.gov (United States)

    Liver hemangioma Overview A liver hemangioma (he-man-jee-O-muh) is a noncancerous (benign) mass in the liver. A liver hemangioma is made up of a tangle of blood vessels. Other terms for a liver hemangioma are hepatic hemangioma and cavernous hemangioma. Most ...

  10. Inflammatory myofibroblastic tumor of the mesentery associated with high fever and positive Widal test

    International Nuclear Information System (INIS)

    Chouairy, Camil J.; Bechara, Elie A.; Ghabril, Ramy H.; Gebran, Sleiman J.

    2008-01-01

    Inflammatory myofibroblastic tumor (IMT) is associated in 15-30% of cases with systemic symptomatology , such as prolonged fever, weight loss, elevated erythrocyte sedimentation rate (ESR) , anemia, thrombocytosis and leukocytosis. We report the case of a 4-year-old Lebanese boy who presented with high-grade fever of long duration and a single (unpaired) positive Widal agglutination test. Blood culture was negative. A diagnosis of typhoid fever was made. An abdominal (mesenteric) IMT was incidentally discovered, 30 days after the fever had appeared. After surgery, the fever disappeared immediately, and the ESR returned. We strongly favor the possibility of a false positive Widal test, due to polyclonal increase in serum immunoglobulins, which often occurs in IMT. We also think that IMT might be a mimicker of typhoid fever, both clinically and serologically. Physicians, especially pediatricians practicing in endemic areas, should probably be aware of this mimicry. (author)

  11. Inflammatory myofibroblastic tumor of the mesentery associated with high fever and positive Widal test

    Energy Technology Data Exchange (ETDEWEB)

    Chouairy, Camil J [Dept. of Pathology, Saint George Hospital, Beirut (Lebanon); Bechara, Elie A; Ghabril, Ramy H [Dept. of Pediatrics, Saint George Hospital, Beirut (Lebanon); Gebran, Sleiman J [Dept. of Pediatric Surgery, AlHada Armed Forces Hospital, Taif (Saudi Arabia)

    2008-07-01

    Inflammatory myofibroblastic tumor (IMT) is associated in 15-30% of cases with systemic symptomatology , such as prolonged fever, weight loss, elevated erythrocyte sedimentation rate (ESR) , anemia, thrombocytosis and leukocytosis. We report the case of a 4-year-old Lebanese boy who presented with high-grade fever of long duration and a single (unpaired) positive Widal agglutination test. Blood culture was negative. A diagnosis of typhoid fever was made. An abdominal (mesenteric) IMT was incidentally discovered, 30 days after the fever had appeared. After surgery, the fever disappeared immediately, and the ESR returned. We strongly favor the possibility of a false positive Widal test, due to polyclonal increase in serum immunoglobulins, which often occurs in IMT. We also think that IMT might be a mimicker of typhoid fever, both clinically and serologically. Physicians, especially pediatricians practicing in endemic areas, should probably be aware of this mimicry. (author)

  12. Bronchoscopic resection of endobronchial inflammatory myofibroblastic tumor: A case report and systematic review of the literature

    Directory of Open Access Journals (Sweden)

    Animesh Ray

    2014-01-01

    Full Text Available Inflammatory myofibroblastic tumour (IMT is a rare tumour affecting the tracheo-bronchial tree in the adult population. The clinical presentation of this tumour is diverse and diagnosis can be definitively clinched by histopathological examination. Treatment of this tumour usually requires surgical resection with bronchoscopic resection being described in few cases. We describe a 32 year old male presenting with hemoptysis who was diagnosed to have IMT. Resection of the tumour was done with the help of rigid bronchoscopy. Post-resection, hemoptysis stopped and no recurrence of tumour was noted on subsequent follow-up. We also present a systematic review of literature of all the cases of tracheo-bronchial IMT treated with bronchoscopic resection and conclude it to be a useful alternative to surgery in such cases.

  13. Inflammatory Myofibroblastic Tumor: A Rarely Seen Submucosal Lesion of the Stomach

    Directory of Open Access Journals (Sweden)

    Deniz Arslan

    2013-01-01

    Full Text Available Inflammatory myofibroblastic tumor (IMT is a rare mesenchymal benign tumor which is generally seen in children and in young adults. It is especially located in the lungs. In histopathological examination, neoplastic fusiform cells originating from a subtype of accessory immune system cells which are called fibroblastic reticulum cells are seen (Kouichi and Youichirou, 2008. Although IMT is histopathologically benign, imaging methods show its tendency for local recurrence and invasion. In most of the cases, it may not be possible to make a distinction whether it is malign or benign. Complete surgical resection is the most important treatment method. In this study, we have discussed the findings of our case having a gastric submucosal located IMT in light of the current literatures.

  14. Low-grade myofibroblastic sarcoma of the larynx: A rare entity with review of literature

    Directory of Open Access Journals (Sweden)

    Divya Khosla

    2013-01-01

    Full Text Available Mesenchymal neoplasms of the larynx are rare and make up approximately 0.3% to 1.0% of all malignancies at this location. Low grade myofibroblastic sarcoma (LGMS of larynx is a rare entity. We describe a rare case of LGMS of larynx who presented with complaint of hoarseness of voice. The patient was treated with total laryngectomy plus partial pharyngectomy followed by post-operative radiotherapy. Histopathologically, the lesion was composed of spindle cells that manifested variable cellular anaplasia and expressed smooth muscle actin (SMA and focally S-100.One of the resection limits was involved so patient was given post-operative radiotherapy. The patient is alive and disease free 14 months after surgery. The characteristic clinical, histopathological features and treatment of this case are described with a literature review.

  15. A rare tumor of trachea: Inflammatory myofibroblastic tumor diagnosis and endoscopic treatment

    Directory of Open Access Journals (Sweden)

    Mehmet Akif Özgül

    2014-01-01

    Full Text Available Inflammatory myofibroblastic tumors (IMTs are rare childhood neoplasms, with benign clinical course. Although etiology of IMTs are not clear, recent studies have reported that IMT is a true neoplasm rather than a reactive or inflammatory lesion. IMTs are rarely seen in adults and tracheal involvement is also rare both in adults and also in children. We describe a 16-year old female patient who was misdiagnosed and treated as asthma in another center for a few months and presented with acute respiratory distress due to upper airway obstruction. Computerized tomography (CT of the chest and rigid bronchoscopy revealed a mass lesion that was nearly totally obliterating tracheal lumen. Bronchoscopic resection was performed under general anesthesia and the final pathological diagnosis was tracheal IMT.

  16. Maillard reaction products enriched food extract reduce the expression of myofibroblast phenotype markers.

    Science.gov (United States)

    Ruhs, Stefanie; Nass, Norbert; Somoza, Veronika; Friess, Ulrich; Schinzel, Reinhard; Silber, Rolf-Edgar; Simm, Andreas

    2007-04-01

    Advanced glycation end products (AGE) are associated with a wide range of degenerative diseases. The present investigation aimed at analysing the influence of AGE containing nutritional extracts on cardiac fibroblasts (CFs) as the major cell type responsible for cardiac fibrosis. Mice CFs were treated with bread crust extract (BCE) which contained significant amounts of a variety of AGE modifications. BCE treatment with up to 30 mg/mL did not impair cell viability. Furthermore, BCE induced a moderate elevation of reactive oxygen species (ROS) production and activation of redox sensitive pathways like the p42/44(MAPK), p38(MAPK) and NF-kappaB but did not alter Akt kinase phosphorylation. Expression of smooth muscle alpha-actin and tropomyosin-1, which represent markers for myofibroblast differentiation, was reduced after bread crust treatment. These data suggest a putative antifibrotic effect of melanoidin-rich food.

  17. Identification of liver protein targets modified by tienilic acid metabolites using a two-dimensional Western blot-mass spectrometry approach

    Science.gov (United States)

    Methogo, Ruth Menque; Dansette, Patrick M.; Klarskov, Klaus

    2007-12-01

    A combined approach based on two-dimensional electrophoresis-immuno-blotting and nanoliquid chromatography coupled on-line with electrospray ionization mass spectrometry (nLC-MS/MS) was used to identify proteins modified by a reactive intermediate of tienilic acid (TA). Liver homogenates from rats exposed to TA were fractionated using ultra centrifugation; four fractions were obtained and subjected to 2D electrophoresis. Following transfer to PVDF membranes, modified proteins were visualized after India ink staining, using an anti-serum raised against TA and ECL detection. Immuno-reactive spots were localized on the PVDF membrane by superposition of the ECL image, protein spots of interest were excised, digested on the membrane with trypsin followed by nLC-MS/MS analysis and protein identification. A total of 15 proteins were identified as likely targets modified by a TA reactive metabolite. These include selenium binding protein 2, senescence marker protein SMP-30, adenosine kinase, Acy1 protein, adenosylhomocysteinase, capping protein (actin filament), protein disulfide isomerase, fumarylacetoacetase, arginase chain A, ketohexokinase, proteasome endopeptidase complex, triosephosphate isomerase, superoxide dismutase, dna-type molecular chaperone hsc73 and malate dehydrogenase.

  18. The Mammalian "Obesogen" Tributyltin Targets Hepatic Triglyceride Accumulation and the Transcriptional Regulation of Lipid Metabolism in the Liver and Brain of Zebrafish.

    Directory of Open Access Journals (Sweden)

    Angeliki Lyssimachou

    Full Text Available Recent findings indicate that different Endocrine Disrupting Chemicals (EDCs interfere with lipid metabolic pathways in mammals and promote fat accumulation, a previously unknown site of action for these compounds. The antifoulant and environmental pollutant tributyltin (TBT, which causes imposex in gastropod snails, induces an "obesogenic" phenotype in mammals, through the activation of the nuclear receptors retinoid X receptor (RXR and peroxisome proliferator-activated receptor gamma (PPARγ. In teleosts, the effects of TBT on the lipid metabolism are poorly understood, particularly following exposure to low, environmental concentrations. In this context, the present work shows that exposure of zebrafish to 10 and 50 ng/L of TBT (as Sn from pre-hatch to 9 months of age alters the body weight, condition factor, hepatosomatic index and hepatic triglycerides in a gender and dose related manner. Furthermore, TBT modulated the transcription of key lipid regulating factors and enzymes involved in adipogenesis, lipogenesis, glucocorticoid metabolism, growth and development in the brain and liver of exposed fish, revealing sexual dimorphic effects in the latter. Overall, the present study shows that the model mammalian obesogen TBT interferes with triglyceride accumulation and the transcriptional regulation of lipid metabolism in zebrafish and indentifies the brain lipogenic transcription profile of fish as a new target of this compound.

  19. The Mammalian “Obesogen” Tributyltin Targets Hepatic Triglyceride Accumulation and the Transcriptional Regulation of Lipid Metabolism in the Liver and Brain of Zebrafish

    Science.gov (United States)

    Lyssimachou, Angeliki; Santos, Joana G.; André, Ana; Soares, Joana; Lima, Daniela; Guimarães, Laura; Almeida, C. Marisa R.; Teixeira, Catarina; Castro, L. Filipe C.; Santos, Miguel M.

    2015-01-01

    Recent findings indicate that different Endocrine Disrupting Chemicals (EDCs) interfere with lipid metabolic pathways in mammals and promote fat accumulation, a previously unknown site of action for these compounds. The antifoulant and environmental pollutant tributyltin (TBT), which causes imposex in gastropod snails, induces an “obesogenic” phenotype in mammals, through the activation of the nuclear receptors retinoid X receptor (RXR) and peroxisome proliferator-activated receptor gamma (PPARγ). In teleosts, the effects of TBT on the lipid metabolism are poorly understood, particularly following exposure to low, environmental concentrations. In this context, the present work shows that exposure of zebrafish to 10 and 50 ng/L of TBT (as Sn) from pre-hatch to 9 months of age alters the body weight, condition factor, hepatosomatic index and hepatic triglycerides in a gender and dose related manner. Furthermore, TBT modulated the transcription of key lipid regulating factors and enzymes involved in adipogenesis, lipogenesis, glucocorticoid metabolism, growth and development in the brain and liver of exposed fish, revealing sexual dimorphic effects in the latter. Overall, the present study shows that the model mammalian obesogen TBT interferes with triglyceride accumulation and the transcriptional regulation of lipid metabolism in zebrafish and indentifies the brain lipogenic transcription profile of fish as a new target of this compound. PMID:26633012

  20. Dual role of the carboxyl-terminal region of pig liver L-kynurenine 3-monooxygenase: mitochondrial-targeting signal and enzymatic activity.

    Science.gov (United States)

    Hirai, Kumiko; Kuroyanagi, Hidehito; Tatebayashi, Yoshitaka; Hayashi, Yoshitaka; Hirabayashi-Takahashi, Kanako; Saito, Kuniaki; Haga, Seiich; Uemura, Tomihiko; Izumi, Susumu

    2010-12-01

    l-kynurenine 3-monooxygenase (KMO) is an NAD(P)H-dependent flavin monooxygenase that catalyses the hydroxylation of l-kynurenine to 3-hydroxykynurenine, and is localized as an oligomer in the mitochondrial outer membrane. In the human brain, KMO may play an important role in the formation of two neurotoxins, 3-hydroxykynurenine and quinolinic acid, both of which provoke severe neurodegenerative diseases. In mosquitos, it plays a role in the formation both of eye pigment and of an exflagellation-inducing factor (xanthurenic acid). Here, we present evidence that the C-terminal region of pig liver KMO plays a dual role. First, it is required for the enzymatic activity. Second, it functions as a mitochondrial targeting signal as seen in monoamine oxidase B (MAO B) or outer membrane cytochrome b(5). The first role was shown by the comparison of the enzymatic activity of two mutants (C-terminally FLAG-tagged KMO and carboxyl-terminal truncation form, KMOΔC50) with that of the wild-type enzyme expressed in COS-7 cells. The second role was demonstrated with fluorescence microscopy by the comparison of the intracellular localization of the wild-type, three carboxyl-terminal truncated forms (ΔC20, ΔC30 and ΔC50), C-terminally FLAG-tagged wild-type and a mutant KMO, where two arginine residues, Arg461-Arg462, were replaced with Ser residues.

  1. Immune Imbalances in Nonalcoholic Fatty Liver Disease: from General Biomarkers and Neutrophils, to Interleukin-17 Axis Activation, and New Therapeutics Targets

    Directory of Open Access Journals (Sweden)

    FELICIANO CHANANA PAQUISSI

    2016-11-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is an increasing problem worldwide and is associated with negative outcomes such as cirrhosis, hepatocellular carcinoma, insulin resistance, diabetes, and cardiovascular events. Current evidence shows that the immune response has an important participation driving the initiation, maintenance, and progression of the disease. So, various immune imbalances, from cellular to cytokines levels, have been studied, either for better compression of the disease pathophysiology or as biomarkers for severity assessment and outcome prediction. In this article, we performed a thorough review of studies that evaluated the role of inflammatory/immune imbalances in the NAFLD. At the cellular level, we gave special focus on the imbalance between neutrophils and lymphocytes counts (the neutrophil to lymphocyte ratio NLR, and that which occurs between T helper 17 (Th17 and regulatory T cells (Treg as emerging biomarkers. By extension, we reviewed the reflection of these imbalances at the molecular level through proinflammatory cytokines including those involved in Th17 differentiation (IL-6, IL-21, IL-23, and transforming growth factor-beta TGF-β, and those released by Th17 cells (IL-17A, IL-17F, IL-21, and IL-22. We gave particular attention to the role of IL-17, either produced by Th17 cells or neutrophils, in fibrogenesis and steatohepatitis. Finally, we reviewed the potential of this pathways as new therapeutics targets in NAFLD.

  2. MiR-218-targeting-Bmi-1 mediates the suppressive effect of 1,6,7-trihydroxyxanthone on liver cancer cells.

    Science.gov (United States)

    Fu, Wei-Ming; Tang, Li-Peng; Zhu, Xiao; Lu, Ying-Fei; Zhang, Yan-Ling; Lee, Wayne Yuk-Wai; Wang, Hua; Yu, Yang; Liang, Wei-Cheng; Ko, Chun-Hay; Xu, Hong-Xi; Kung, Hsiang-Fu; Zhang, Jin-Fang

    2015-01-01

    Traditional Chinese medicine is recently emerged as anti-cancer therapy or adjuvant with reduced side-effects and improved quality of life. In the present study, an active ingredient, 1,6,7-trihydroxyxanthone (THA), derived from Goodyera oblongifolia was found to strongly suppress cell growth and induce apoptosis in liver cancer cells. MicroRNAs are a group of small non-coding RNAs that regulate gene expression at post-transcriptional levels. Our results demonstrated that miR-218 was up-regulated and oncogene Bmi-1 was down-regulated by THA treatment. Further investigation showed that THA-induced-miR-218 up-regulation could lead to activation of tumor suppressor P16(Ink4a) and P14(ARF), the main down-stream targets of Bmi-1. In conclusion, THA might be a potential anti-cancer drug candidate, at least in part, through the activation of miR-218 and suppression of Bmi-1 expression.

  3. The Mammalian "Obesogen" Tributyltin Targets Hepatic Triglyceride Accumulation and the Transcriptional Regulation of Lipid Metabolism in the Liver and Brain of Zebrafish.

    Science.gov (United States)

    Lyssimachou, Angeliki; Santos, Joana G; André, Ana; Soares, Joana; Lima, Daniela; Guimarães, Laura; Almeida, C Marisa R; Teixeira, Catarina; Castro, L Filipe C; Santos, Miguel M

    2015-01-01

    Recent findings indicate that different Endocrine Disrupting Chemicals (EDCs) interfere with lipid metabolic pathways in mammals and promote fat accumulation, a previously unknown site of action for these compounds. The antifoulant and environmental pollutant tributyltin (TBT), which causes imposex in gastropod snails, induces an "obesogenic" phenotype in mammals, through the activation of the nuclear receptors retinoid X receptor (RXR) and peroxisome proliferator-activated receptor gamma (PPARγ). In teleosts, the effects of TBT on the lipid metabolism are poorly understood, particularly following exposure to low, environmental concentrations. In this context, the present work shows that exposure of zebrafish to 10 and 50 ng/L of TBT (as Sn) from pre-hatch to 9 months of age alters the body weight, condition factor, hepatosomatic index and hepatic triglycerides in a gender and dose related manner. Furthermore, TBT modulated the transcription of key lipid regulating factors and enzymes involved in adipogenesis, lipogenesis, glucocorticoid metabolism, growth and development in the brain and liver of exposed fish, revealing sexual dimorphic effects in the latter. Overall, the present study shows that the model mammalian obesogen TBT interferes with triglyceride accumulation and the transcriptional regulation of lipid metabolism in zebrafish and indentifies the brain lipogenic transcription profile of fish as a new target of this compound.

  4. Intestinal subepithelial myofibroblasts support in vitro and in vivo growth of human small intestinal epithelium.

    Directory of Open Access Journals (Sweden)

    Nicholas Lahar

    Full Text Available The intestinal crypt-niche interaction is thought to be essential to the function, maintenance, and proliferation of progenitor stem cells found at the bases of intestinal crypts. These stem cells are constantly renewing the intestinal epithelium by sending differentiated cells from the base of the crypts of Lieberkühn to the villus tips where they slough off into the intestinal lumen. The intestinal niche consists of various cell types, extracellular matrix, and growth factors and surrounds the intestinal progenitor cells. There have recently been advances in the understanding of the interactions that regulate the behavior of the intestinal epithelium and there is great interest in methods for isolating and expanding viable intestinal epithelium. However, there is no method to maintain primary human small intestinal epithelium in culture over a prolonged period of time. Similarly no method has been published that describes isolation and support of human intestinal epithelium in an in vivo model. We describe a technique to isolate and maintain human small intestinal epithelium in vitro from surgical specimens. We also describe a novel method to maintain human intestinal epithelium subcutaneously in a mouse model for a prolonged period of time. Our methods require various growth factors and the intimate interaction between intestinal sub-epithelial myofibroblasts (ISEMFs and the intestinal epithelial cells to support the epithelial in vitro and in vivo growth. Absence of these myofibroblasts precluded successful maintenance of epithelial cell formation and proliferation beyond just a few days, even in the presence of supportive growth factors. We believe that the methods described here can be used to explore the molecular basis of human intestinal stem cell support, maintenance, and growth.

  5. Loss of γ-cytoplasmic actin triggers myofibroblast transition of human epithelial cells.

    Science.gov (United States)

    Lechuga, Susana; Baranwal, Somesh; Li, Chao; Naydenov, Nayden G; Kuemmerle, John F; Dugina, Vera; Chaponnier, Christine; Ivanov, Andrei I

    2014-10-15

    Transdifferentiation of epithelial cells into mesenchymal cells and myofibroblasts plays an important role in tumor progression and tissue fibrosis. Such epithelial plasticity is accompanied by dramatic reorganizations of the actin cytoskeleton, although mechanisms underlying cytoskeletal effects on epithelial transdifferentiation remain poorly understood. In the present study, we observed that selective siRNA-mediated knockdown of γ-cytoplasmic actin (γ-CYA), but not β-cytoplasmic actin, induced epithelial-to-myofibroblast transition (EMyT) of different epithelial cells. The EMyT manifested by increased expression of α-smooth muscle actin and other contractile proteins, along with inhibition of genes responsible for cell proliferation. Induction of EMyT in γ-CYA-depleted cells depended on activation of serum response factor and its cofactors, myocardial-related transcriptional factors A and B. Loss of γ-CYA stimulated formin-mediated actin polymerization and activation of Rho GTPase, which appear to be essential for EMyT induction. Our findings demonstrate a previously unanticipated, unique role of γ-CYA in regulating epithelial phenotype and suppression of EMyT that may be essential for cell differentiation and tissue fibrosis. © 2014 Lechuga, Baranwal, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  6. Role of oxygen free radicals in the proliferation of myofibroblasts induced by AngII

    Directory of Open Access Journals (Sweden)

    Liying Wang

    2013-02-01

    Full Text Available Previous studies have demonstrated the important role of angiotension II (AngII in promoting proliferation of myofibroblasts (myoFbs and myocardial fibrosis. However, the underlying mechanisms and the role of oxygen free radicals in the proliferation of myofibroblasts induced by AngII are unclear. The present study was designed to shed light on this issue through exploration of AngII signaling pathways via in vitro experiments. Primary cultures of neonatal rat myoFbs were divided into five groups which were treated with AngII (10−8 to 10−6 M, AngII with the antioxidant N-acetyl-L-cysteine (NAC, or normal culture medium. We observed the proliferation of myoFbs as induced by AngII at different concentrations with MTT. Reactive oxygen species (ROS levels in myoFbs were detected by monitoring the fluorescence of 2′,7′-dichlorofluorescein. The contents and levels of oxygen free radicals (OH· in the three groups were detected by spectrophotometer, immunocytochemical staining, and confocal fluorescence. Western blot and image analysis were used to measure membrane translocation and expression of phospho-protein kinase Cα. MyoFbs incubated with AngII (10−8 to 10−6 M for 24 h increased their rate of proliferation, the content of OH·, and expression of ROS (P<0.01 vs. control group, whereas these parameters decreased in the presence of NAC. Immunocytochemistry, confocal fluorescence staining and image analysis showed that AngII could promote the translocation and expression of p-PKCα in membrane, and the antioxidant NAC blocked this increase (P<0.01. Western blot results also showed that NAC could inhibit the expression of p-PKCα.

  7. Human pericytes adopt myofibroblast properties in the microenvironment of the IPF lung.

    Science.gov (United States)

    Sava, Parid; Ramanathan, Anand; Dobronyi, Amelia; Peng, Xueyan; Sun, Huanxing; Ledesma-Mendoza, Adrian; Herzog, Erica L; Gonzalez, Anjelica L

    2017-12-21

    Idiopathic pulmonary fibrosis (IPF) is a fatal disease of unknown etiology characterized by a compositionally and mechanically altered extracellular matrix. Poor understanding of the origin of α-smooth muscle actin (α-SMA) expressing myofibroblasts has hindered curative therapies. Though proposed as a source of myofibroblasts in mammalian tissues, identification of microvascular pericytes (PC) as contributors to α-SMA-expressing populations in human IPF and the mechanisms driving this accumulation remain unexplored. Here, we demonstrate enhanced detection of α-SMA+ cells coexpressing the PC marker neural/glial antigen 2 in the human IPF lung. Isolated human PC cultured on decellularized IPF lung matrices adopt expression of α-SMA, demonstrating that these cells undergo phenotypic transition in response to direct contact with the extracellular matrix (ECM) of the fibrotic human lung. Using potentially novel human lung-conjugated hydrogels with tunable mechanical properties, we decoupled PC responses to matrix composition and stiffness to show that α-SMA+ PC accumulate in a mechanosensitive manner independent of matrix composition. PC activated with TGF-β1 remodel the normal lung matrix, increasing tissue stiffness to facilitate the emergence of α-SMA+ PC via MKL-1/MTRFA mechanotranduction. Nintedanib, a tyrosine-kinase inhibitor approved for IPF treatment, restores the elastic modulus of fibrotic lung matrices to reverse the α-SMA+ phenotype. This work furthers our understanding of the role that microvascular PC play in the evolution of IPF, describes the creation of an ex vivo platform that advances the study of fibrosis, and presents a potentially novel mode of action for a commonly used antifibrotic therapy that has great relevance for human disease.

  8. Cytochrome P4502D6(193-212): a new immunodominant epitope and target of virus/self cross-reactivity in liver kidney microsomal autoantibody type 1-positive liver disease.

    Science.gov (United States)

    Kerkar, Nanda; Choudhuri, Kaushik; Ma, Yun; Mahmoud, Ayman; Bogdanos, Dimitrios P; Muratori, Luigi; Bianchi, Francesco; Williams, Roger; Mieli-Vergani, Giorgina; Vergani, Diego

    2003-02-01

    Cytochrome P4502D6 (CYP2D6), target of liver kidney microsomal autoantibody type 1 (LKM1), characterizes autoimmune hepatitis type 2 (AIH2) but is also found in patients with chronic hepatitis C virus (HCV) infection. To provide a complete linear epitope B cell map of CYP2D6, we tested peptides spanning the entire sequence of CYP2D6. In addition to confirming previously described antigenic sites, we identified four new epitopes (193-212, 238-257, 268-287, and 478-497). CYP2D6(193-212) is immunodominant and was the target of 12 of 13 (93%) patients with AIH2 and 5 of 10 (50%) HCV/LKM1-positive patients. Because LKM1 is present in both AIH2 and a viral infection, we tested whether Abs to CYP2D6(193-212) arise through cross-reactive immunity between virus and self. We identified a hexameric sequence "RLLDLA" sharing 5 of 6 aa with "RLLDLS" of HCV(2985-2990) and all 6 aa with CMV(130-135). Of 17 CYP2D6(193-212)-reactive sera, 11 (7 AIH and 4 HCV) reacted by ELISA with the HCV homologue, 8 (5 AIH and 3 HCV) with the CMV homologue, and 8 (5 AIH and 3 HCV) showed double reactivity. Autoantibody binding to CYP2D6(193-212) was inhibited by preincubation with HCV(2977-2996) or CMV(121-140). Recombinant HCV-nonstructural protein 5 and CMV-UL98 proteins also inhibited Ab binding to CYP2D6(193-212). Affinity-purified CYP2D6(193-212)-specific Ab inhibited the metabolic activity of CYP2D6. The demonstrated similarity and cross-reactivity between CYP2D6(193-212) and two unrelated viruses suggests that multiple exposure to viruses mimicking self may represent an important pathway to the development of autoimmunity.

  9. Liver biopsy

    Science.gov (United States)

    Biopsy - liver; Percutaneous biopsy ... the biopsy needle to be inserted into the liver. This is often done by using ultrasound. The ... the chance of damage to the lung or liver. The needle is removed quickly. Pressure will be ...

  10. Resveratrol-loaded glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles: Preparation, characterization, and targeting effect on liver tumors.

    Science.gov (United States)

    Wu, Mingfang; Lian, Bolin; Deng, Yiping; Feng, Ziqi; Zhong, Chen; Wu, Weiwei; Huang, Yannian; Wang, Lingling; Zu, Chang; Zhao, Xiuhua

    2017-08-01

    for HepG2 cells was evaluated using fluorescence-modified albumin techniques. The uptake rate of glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles was higher than that of pure resveratrol and increased with increased nanoparticles concentration. The in vivo body distribution of glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles labeled with the near-infrared fluorophore Cy5 was monitored in H22 tumor-bearing mice through near-infrared fluorescence imaging systems. Glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles exhibited effective target orientation to liver tumor and sustained-release property.

  11. Design of planning target volume margin using an active breathing control and Varian image-guided radiotherapy (IGRT) system in unresectable liver tumor

    International Nuclear Information System (INIS)

    Yue Jinbo; Yu Jinming; Liu Jing; Liu Tonghai; Yin Yong; Shi Xuetao; Song Jinlong

    2007-01-01

    Objective: To define the planning target volume(PTV) margin with an active breathing control (ABC) and the Varian image-guided radiotherapy (IGRT) system. Methods: Thirteen patients with liver cancer were treated with radiotherapy from May 2006 to September 2006. Prior to radiotherapy, all patients had undergone transarterial chemoembolization (TACE) by infusing a mixture of iodized oil contrast medium and chemotherapeutic agents, kV fluoroscopy was used to measure the potential motion of lipiodol spot positions during ABC breath-holds. ABC was used for planning CT scan and radiation delivery, with the breath held at the same phase of the respiratory cycle (near end-exhalation). Cone beam CT (CBCT) was taken using Varian IGRT system, which was then compared online with planning CT using a 3 D-3 D matching tool. Analysis relied on lipiodol spots on planning CT and CBCT manually. The treatment table was moved to produce acceptable setup before treatment delivery. Repeated CBCT image and another analysis were obtained after irradiation. Results: No motion of the intrahepatic tumor was observed on fluoroscopy during ABC breath-holds. The estimated required PTV margins, calculated according to the Stroom formula, were 4.4 mm, 5.3 mm and 7.8 mm in the x, y and z axis directions before radiotherapy. The corresponding parameters were 2.5m, 2.6 mm and 3.9 mm after radiotherapy. Conclusions: We have adopted a PTV margin of 5 mm, 6 mm and 8 mm in the x, y and z axis directions with ABC, and 3,3 and 4 mm with ABC and on-line kilovoltage CBCT. (authors)

  12. MiR-150 deficiency ameliorated hepatosteatosis and insulin resistance in nonalcoholic fatty liver disease via targeting CASP8 and FADD-like apoptosis regulator.

    Science.gov (United States)

    Zhuge, Baozhong; Li, Guohong

    2017-12-16

    The prevalence of Non-alcoholic fatty liver diseases (NAFLD) increased rapidly in the world. However, the pathogenesis of is still unclear. Hepatic steatosis and insulin resistance are considered to be central to the pathophysiology of NAFLD. MicroRNAs are short non-coding RNAs and has been reported to be involved in pathogenesis of NAFLD and related metabolic diseases. Here, we investigated the mechanisms by which miR-150 regulate hepatic steatosis and insulin resistance in high fat diet (HFD) induced NAFLD model. The expression of miR-150 was up-regulated dramatically in both human NAFLD patients and HFD mice model, as well as in hepatocytes treated with oleic acid. miR-150 deficiency ameliorated the hepatic steatosis and insulin resistance significantly in NAFLD mice. miR-150 deficiency decreased the expression of genes related to fatty acid uptake, synthesis and gluconeogenesis, while increased the expression of genes related to fatty acid β-oxidation. Further, we identified that CFLAR is a direct downstream target of miR-150. Overexpression of miR-150 reduced both the mRNA and protein levels of CFLAR in vitro. And overexpression of miR-150 significantly inhibited the luciferase activity of CFLAR 3'-UTR, while the effect of miR-150 was blocked when the binding site of miR-150 within the CFLAR 3'-UTR was mutated. We also found that miR-150 deficiency decreased the expression of p-Jnk1 and p-Ask1, while the effect of miR-150 on steatosis and insulin signaling was blocked by CFLAR overexpression. In conclusion, our data indicated that miR-150 potentially contributes to the hepatic steatosis and insulin resistance in NAFLD. miR-150/CFLAR pathway may be a new therapeutic strategy against NAFLD. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Latrunculin B and substratum stiffness regulate corneal fibroblast to myofibroblast transformation.

    Science.gov (United States)

    Thomasy, Sara M; Raghunathan, Vijay Krishna; Miyagi, Hidetaka; Evashenk, Alexander T; Sermeno, Jasmyne C; Tripp, Geneva K; Morgan, Joshua T; Murphy, Christopher J

    2018-05-01

    The transformation of keratocytes and fibroblasts to myofibroblasts is important to corneal wound healing as well as formation of stromal haze. The purpose of this study was to determine the effect of latrunculin B, an actin cytoskeleton disruptor in conjunction with a fundamental biophysical cue, substrate stiffness, on myofibroblast transformation in vitro and in vivo. Rabbit corneal fibroblasts were cultured on substrates of differing compliance (1.5, 22, and 71 kPa) and tissue culture plastic (TCP; > 1 GPa) in media containing 0 or 10 ng/ml TGFβ1 for 72 h. Cells were treated with 0.4 μM Lat-B or DMSO for 30 min every 24 h for 72 h. RNA was collected from cells and expression of alpha-smooth muscle actin (α-SMA), keratocan, and ALDH1A1 determined using qPCR; immunocytochemistry was used to assess α-SMA protein expression. A rabbit phototherapeutic keratectomy (PTK) model was used to assess the impact of 0.1% Lat-B (n = 3) or 25% DMSO (vehicle control, n = 3) on corneal wound healing by assessment of epithelial wound size with fluorescein stain and semi-quantitative stromal haze scoring by an observer masked to treatment group as well as Fourier-domain optical coherence tomography (FD-OCT) at set time points. Statistical analysis was completed using one-way or two-way analysis of variance. Treatment with Lat-B versus DMSO resulted in significantly less αSMA mRNA (P ≤ 0.007) for RCF cells grown on 22 and 71 kPa substrates as well as TCP without or with TGFβ1, and significantly decreased α-SMA protein expression in RCFs cultured on the intermediate (22 kPa) stiffness in the absence (P = 0.028) or presence (P = 0.018) of TGFβ1. Treatment with Lat-B versus DMSO but did not significantly alter expression of keratocan or ALDH1A1 mRNA in RCFs (P > 0.05) in the absence or presence of TGFβ1, but RCFs grown on stiff hydrogels (71 kPa) had significantly more keratocan mRNA expression versus the 22 kPa hydrogel or

  14. Inflammatory myofibroblastic tumor of the orbit: A clinico-pathological study of 25 cases

    Directory of Open Access Journals (Sweden)

    Diego Strianese

    2018-01-01

    Full Text Available Background: Inflammatory myofibroblastic tumor (IMT is a rare entity characterized by the presence of myofibroblasts and inflammatory cells within a fibrous stroma, which typically occurs in children or young adults. The IMT is considered generally a benign lesion, although about 20% of cases may experience recurrence, and most rarely develop metastasis. Herein, we present the largest series of primary orbital IMT ever reported. Patients and methods: The clinical records of 25 patients, collected between the 1995 and 2015, with biopsy-proven diagnosis of orbital IMT were retrospectively reviewed to determine demographic, clinical, radiologic and pathological features, management, and outcome. Results: The study included 13 females and 12 male patients, age ranged from 5 to 76 years. Disease onset was in all cases unilateral (25/25, with posterior location (10/25 or extending anterior to posterior (7/25. The most common signs and symptoms were: proptosis (19/25, ptosis (18/25, diplopia (10/25, periocular swelling (9/25, pain (8/25, redness (7/25. All patients underwent to incisional biopsy which included total or subtotal tumor resection avoiding arming of the adjacent structure, followed by systemic steroid therapy (22/25 or radiotherapy (3/25. The disease recurred in 6 (24% patients who responded to the subsequent therapy. No one developed metastasis or died because of the disease. Conclusion: IMT is a distinct entity which may occur in the orbit primarily. It should be considered in differential diagnosis in all orbital masses, particularly with onset of acute or subcronic inflammation. Surgical biopsy associated to a partial debulcking of the tumor, avoiding to damage adjacent vital structure may contribute to improve the outcome. Steroid therapy, seems to be the suitable as first line medical therapy, although, as reported in literature, not all cases respond to this treatment regimen. Radiotherapy, may be considered as an alternative

  15. Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr-/- Mice

    DEFF Research Database (Denmark)

    Yu, Mikyung; Amengual, Jaume; Menon, Arjun

    2017-01-01

    The pharmacological manipulation of liver X receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. This study presents the development and efficacy of nanoparticles (NPs) incorporating the...

  16. Evidence for modulation of pericryptal sheath myofibroblasts in rat descending colon by Transforming Growth Factor β and Angiotensin II.

    Directory of Open Access Journals (Sweden)

    Pedley Kevin C

    2002-02-01

    Full Text Available Abstract Background Absorption of water and Na+ in descending colonic crypts is dependent on the barrier function of the surrounding myofibroblastic pericryptal sheath. Here the effects of high and low Na+ diets and exposure to whole body ionising radiation on the growth and activation of the descending colonic pericryptal myofibroblasts are evaluated. In addition the effect of a post-irradiation treatment with the angiotensin converting enzyme inhibitor Captopril was investigated. Methods The levels of Angiotensin II type 1 receptor (AT1, ACE, collagen type IV, transforming growth factor-β type 1 receptor (TGF-βR1, OB cadherin and α-smooth muscle actin in both descending colon and caecum were evaluated, using immunocytochemistry and confocal microscopy, in rats fed on high and low Na+ diets (LS. These parameters were also determined during 3 months post-irradiation with 8Gy from a 60Co source in the presence and absence of the angiotensin converting enzyme inhibitor, Captopril. Results Increases in AT1 receptor (135.6% ± 18.3, P Conclusions These results demonstrate an activation of descending colonic myofibroblasts to trophic stimuli, or irradiation, which can be attenuated by Captopril, indicative of local trophic control by angiotensin II and TGF-β release.

  17. Proteinase activated receptor 1 mediated fibrosis in a mouse model of liver injury: a role for bone marrow derived macrophages.

    Directory of Open Access Journals (Sweden)

    Yiannis N Kallis

    Full Text Available Liver fibrosis results from the co-ordinated actions of myofibroblasts and macrophages, a proportion of which are of bone marrow origin. The functional effect of such bone marrow-derived cells on liver fibrosis is unclear. We examine whether changing bone marrow genotype can down-regulate the liver's fibrotic response to injury and investigate mechanisms involved. Proteinase activated receptor 1 (PAR1 is up-regulated in fibrotic liver disease in humans, and deficiency of PAR1 is associated with reduced liver fibrosis in rodent models. In this study, recipient mice received bone marrow transplantation from PAR1-deficient or wild-type donors prior to carbon tetrachloride-induced liver fibrosis. Bone marrow transplantation alone from PAR1-deficient mice was able to confer significant reductions in hepatic collagen content and activated myofibroblast expansion on wild-type recipients. This effect was associated with a decrease in hepatic scar-associated macrophages and a reduction in macrophage recruitment from the bone marrow. In vitro, PAR1 signalling on bone marrow-derived macrophages directly induced their chemotaxis but did not stimulate proliferation. These data suggest that the bone marrow can modulate the fibrotic response of the liver to recurrent injury. PAR1 signalling can contribute to this response by mechanisms that include the regulation of macrophage recruitment.

  18. Inhibition of canonical WNT signaling pathway by β-catenin/CBP inhibitor ICG-001 ameliorates liver fibrosis in vivo through suppression of stromal CXCL12.

    Science.gov (United States)

    Akcora, Büsra Öztürk; Storm, Gert; Bansal, Ruchi

    2018-03-01

    Quiescent hepatic stellate cells (HSCs), in response to liver injury, undergo characteristic morphological transformation into proliferative, contractile and ECM-producing myofibroblasts. In this study, we investigated the implication of canonical Wnt signaling pathway in HSCs and liver fibrogenesis. Canonical Wnt signaling pathway activation and inhibition using β-catenin/CBP inhibitor ICG001 was examined in-vitro in TGFβ-activated 3T3, LX2, primary human HSCs, and in-vivo in CCl 4 -induced acute liver injury mouse model. Fibroblasts-conditioned medium studies were performed to assess the Wnt-regulated paracrine factors involved in crosstalk between HSCs-macrophages and HSCs-endothelial cells. Canonical Wnt signaling pathway components were significantly up-regulated in-vitro and in-vivo. In-vitro, ICG-001 significantly inhibited fibrotic parameters, 3D-collagen contractility and wound healing. Conditioned medium induced fibroblasts-mediated macrophage and endothelial cells activation was significantly inhibited by ICG-001. In-vivo, ICG-001 significantly attenuated collagen accumulation and HSC activation. Interestingly, ICG-001 drastically inhibited macrophage infiltration, intrahepatic inflammation and angiogenesis. We further analyzed the paracrine factors involved in Wnt-mediated effects and found CXCL12 was significantly suppressed both in-vitro and in-vivo following Wnt inhibition. Wnt-regulated CXCL12 secretion from activated HSCs potentiated macrophage infiltration and activation, and angiogenesis. Pharmacological inhibition of canonical Wnt signaling pathway via suppression of stromal CXCL12 suggests a potential therapeutic approach targeting activated HSCs in liver fibrosis. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  19. Adult Primary Liver Cancer Treatment (PDQ®)—Patient Version

    Science.gov (United States)

    Treatment of liver cancer in adults depends on the stage. Treatment options include hepatectomy, liver transplant, ablation, electroporation therapy (EPT), embolization therapy, targeted therapy, and/or radiation therapy. Learn more about treatment for the different stages of liver cancer.

  20. Polyphenolic extracts from cowpea (Vigna unguiculata) protect colonic myofibroblasts (CCD18Co cells) from lipopolysaccharide (LPS)-induced inflammation--modulation of microRNA 126.

    Science.gov (United States)

    Ojwang, Leonnard O; Banerjee, Nivedita; Noratto, Giuliana D; Angel-Morales, Gabriela; Hachibamba, Twambo; Awika, Joseph M; Mertens-Talcott, Susanne U

    2015-01-01

    Cowpea (Vigna unguiculata) is a drought tolerant crop with several agronomic advantages over other legumes. This study evaluated varieties from four major cowpea phenotypes (black, red, light brown and white) containing different phenolic profiles for their anti-inflammatory property on non-malignant colonic myofibroblasts (CCD18Co) cells challenged with an endotoxin (lipopolysaccharide, LPS). Intracellular reactive oxygen species (ROS) assay on the LPS-stimulated cells revealed antioxidative potential of black and red cowpea varieties. Real-time qRT-PCR analysis in LPS-stimulated cells revealed down-regulation of proinflammatory cytokines (IL-8, TNF-α, VCAM-1), transcription factor NF-κB and modulation of microRNA-126 (specific post-transcriptional regulator of VCAM-1) by cowpea polyphenolics. The ability of cowpea polyphenols to modulate miR-126 signaling and its target gene VCAM-1 were studied in LPS-stimulated endothelial cells transfected with a specific inhibitor of miR-126, and treated with 10 mg GAE/L black cowpea extract where the extract in part reversed the effect of the miR-126 inhibitor. This suggests that cowpea may exert their anti-inflammatory activities at least in part through induction of miR-126 that then down-regulate VCAM-1 mRNA and protein expressions. Overall, Cowpea therefore is promising as an anti-inflammatory dietary component.

  1. Microengineered in vitro model of cardiac fibrosis through modulating myofibroblast mechanotransduction

    International Nuclear Information System (INIS)

    Zhao, Hui; Li, Xiaokang; Zhao, Shan; Zeng, Yang; Ding, Haiyan; Du, Yanan; Zhao, Long; Sun, Wei

    2014-01-01

    Cardiac fibrosis greatly impairs normal heart function post infarction and there is no effective anti-fibrotic drug developed at present. The current therapies for cardiac infarction mainly take effect by eliminating occlusion in coronary artery by thrombolysis drugs, vascular stent grafting or heart bypass operation, which are capable to provide sufficient blood flow for intact myocardium yet showed subtle efficacy in ameliorating fibrosis condition. The advances of in vitro cell/tissue models open new avenues for drug assessment due to the low cost, good controllability and availability as well as the convenience for operation as compared to the animal models. To our knowledge, no proper biomimetic in vitro cardiac fibrosis model has been reported yet. Here we engineered an in vitro cardiac fibrosis model using heart-derived fibroblasts, and the fibrogenesis was recapitulated by patterning the substrate rigidity which mimicked the mechanical heterogeneity of myocardium post-infarction. Various biomarkers for cardiac fibrosis were assayed to validate the biomimicry of the engineered platform. Subsequent addition of Rho-associated protein kinase (ROCK) pathway inhibitor reduced the ratio of myofibroblasts, indicating the feasibility of applying this platform in screening anti-fibrosis drugs. (paper)

  2. Liver Immunology

    Science.gov (United States)

    Bogdanos, Dimitrios P.; Gao, Bin; Gershwin, M. Eric

    2014-01-01

    The liver is the largest organ in the body and is generally regarded by non-immunologists as not having lymphoid function. However, such is far from accurate. This review highlights the importance of the liver as a lymphoid organ. Firstly, we discuss experimental data surrounding the role of liver as a lymphoid organ. The liver facilitates a tolerance rather than immunoreactivity, which protects the host from antigenic overload of dietary components and drugs derived from the gut and is also instrumental to fetal immune tolerance. Loss of liver tolerance leads to autoaggressive phenomena which if are not controlled by regulatory lymphoid populations may lead to the induction of autoimmune liver diseases. Liver-related lymphoid subpopulations also act as critical antigen-presenting cells. The study of the immunological properties of liver and delineation of the microenvironment of the intrahepatic milieu in normal and diseased livers provides a platform to understand the hierarchy of a series of detrimental events which lead to immune-mediated destruction of the liver and the rejection of liver allografts. The majority of emphasis within this review will be on the normal mononuclear cell composition of the liver. However, within this context, we will discus select, but not all, immune mediated liver disease and attempt to place these data in the context of human autoimmunity. PMID:23720323

  3. Lactic Acid is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation Via pH-Dependent Activation of Transforming Growth Factor-β

    Energy Technology Data Exchange (ETDEWEB)

    Kottman, R. M.; Kulkarni, Ajit A.; Smolnycki, Katie A.; Lyda, Elizabeth; Dahanayake, Thinesh; Salibi, Rami; Honnons, Sylvie; Jones, Carolyn; Isern, Nancy G.; Hu, Jian Z.; Nathan, Steven D.; Grant, Geraldine; Phipps, Richard P.; Sime, Patricia J.

    2012-10-15

    Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex disease for which the pathogenesis is poorly understood. In this study, we identified lactic acid as a metabolite that is elevated in the lung tissue of patients with IPF. Objectives: This study examines the effect of lactic acid on myofibroblast differentiation and pulmonary fibrosis. Methods:We used metabolomic analysis to examine cellular metabolism in lung tissuefrom patients with IPFanddeterminedthe effects of lactic acid and lactate dehydrogenase-5 (LDH5) overexpression on myofibroblast differentiation and transforming growth factor (TGF)-b activation in vitro. Measurements and Main Results: Lactic acid concentrations from healthy and IPF lung tissue were determined by nuclear magnetic resonance spectroscopy; a-smooth muscle actin, calponin, and LDH5 expression were assessed by Western blot of cell culture lysates. Lactic acid and LDH5 were significantly elevated in IPF lung tissue compared with controls. Physiologic concentrations of lactic acid induced myofibroblast differentiation via activation of TGF-b. TGF-b induced expression of LDH5 via hypoxia-inducible factor 1a (HIF1a). Importantly, overexpression of both HIF1a and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low dose TGF-b to induce differentiation. Furthermore, inhibition of both HIF1a and LDH5 inhibited TGF-b–induced myofibroblast differentiation. Conclusions: We have identified the metabolite lactic acid as an important mediator of myofibroblast differentiation via a pHdependent activation of TGF-b. We propose that the metabolic milieu of the lung, and potentially other tissues, is an important driving force behind myofibroblast differentiation and potentially the initiation and progression of fibrotic disorders.

  4. Liver spots

    Science.gov (United States)

    ... skin changes - liver spots; Senile or solar lentigines; Skin spots - aging; Age spots ... Liver spots are changes in skin color that occur in older skin. The coloring may be due to aging, exposure to the sun ...

  5. Liver Diseases

    Science.gov (United States)

    Your liver is the largest organ inside your body. It helps your body digest food, store energy, and remove poisons. There are many kinds of liver diseases: Diseases caused by viruses, such as hepatitis ...

  6. Liver disease

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000205.htm Liver disease To use the sharing features on this page, please enable JavaScript. The term "liver disease" applies to many conditions that stop the ...

  7. Noninvasive theranostic imaging of HSV-TK/GCV suicide gene therapy in liver cancer by folate-targeted quantum dot-based liposomes

    NARCIS (Netherlands)

    Shao, D.; Li, J.; Pan, Y.; Zhang, X.; Zheng, X.; Wang, Z.; Zhang, M.; Zhang, H.; Chen, L.

    2015-01-01

    Theranostics is emerging as a popular strategy for cancer therapy; thanks to the development of nano-technology. In this work, we have combined an HSV-TK/GCV suicide gene system and near-infrared quantum dots, as the former is quite effective in liver cancer treatment and the latter facilitates

  8. The protective effect of ursodeoxycholic acid in an in vitro model of the human fetal heart occurs via targeting cardiac fibroblasts.

    Science.gov (United States)

    Schultz, Francisca; Hasan, Alveera; Alvarez-Laviada, Anita; Miragoli, Michele; Bhogal, Navneet; Wells, Sarah; Poulet, Claire; Chambers, Jenny; Williamson, Catherine; Gorelik, Julia

    2016-01-01

    Bile acids are elevated in the blood of women with intrahepatic cholestasis of pregnancy (ICP) and this may lead to fetal arrhythmia, fetal hypoxia and potentially fetal death in utero. The bile acid taurocholic acid (TC) causes abnormal calcium dynamics and contraction in neonatal rat cardiomyocytes. Ursodeoxycholic acid (UDCA), a drug clinically used to treat ICP, prevents adverse effects of TC. During development, the fetus is in a state of relative hypoxia. Although this is essential for the development of the heart and vasculature, resident fibroblasts can transiently differentiate into myofibroblasts and form gap junctions with cardiomyocytes in vitro, resulting in cardiomyocyte depolarization. We expanded on previously published work using an in vitro hypoxia model to investigate the differentiation of human fetal fibroblasts into myofibroblasts. Recent evidence shows that potassium channels are involved in maintaining the membrane potential of ventricular fibroblasts and that ATP-dependent potassium (KATP) channel subunits are expressed in cultured fibroblasts. KATP channels are a valuable target as they are thought to have a cardioprotective role during ischaemic and hypoxic conditions. We investigated whether UDCA could modulate fibroblast membrane potential. We established the isolation and culture of human fetal cardiomyocytes and fibroblasts to investigate the effect of hypoxia, TC and UDCA on human fetal cardiac cells. UDCA hyperpolarized myofibroblasts and prevented TC-induced depolarisation, possibly through the activation of KATP channels that are expressed in cultured fibroblasts. Also, similar to the rat model, UDCA can counteract TC-induced calcium abnormalities in human fetal cultures of cardiomyocytes and myofibroblasts. Under normoxic conditions, we found a higher number of myofibroblasts in cultures derived from human fetal hearts compared to cells isolated from neonatal rat hearts, indicating a possible increased number of myofibroblasts

  9. Soft-tissue inflammatory myofibroblastic tumors (IMTs) of the limbs: potential and limits of diagnostic imaging

    Energy Technology Data Exchange (ETDEWEB)

    Masciocchi, Carlo; Lanni, Giuseppe; Conti, Laura; Conchiglia, Armando; Fascetti, Eva; Barile, Antonio [University of L' Aquila, S. Salvatore Hospital, Department of Radiology, Coppito, L' Aquila (Italy); Flamini, Stefano [S. Salvatore Hospital, Department of Orthopaedic Surgery, Coppito, L' Aquila (Italy); Coletti, Gino [S. Salvatore Hospital, Department of Pathology, Coppito, L' Aquila (Italy)

    2012-06-15

    The objective of this work was to evaluate the potential of diagnostic imaging in the identification, localization, and characterization of soft-tissue inflammatory myofibroblastic tumors (IMTs) of limbs with correlation to differential diagnosis and therapy. From a retrospective analysis of 324 histologically verified soft-tissue lesions of limbs and extremities diagnosed in our institute from January 2002 to July 2010, we selected seven cases of histologically proven IMT. These included six males and one female, aged between 28 and 81 years (mean age, 57 years). Lesions were localized in three cases to the thigh, in two cases to the popliteal space, and in the remaining two cases, to the shoulder girdle. All patients were evaluated on the basis of US, CT, and MRI. Ultrasound detected the presence of a non-homogeneous solid formation in all cases and calcifications in three cases. CT showed the presence and type of calcification/ossification and bone reaction. On MRI, all cases had low signal intensity on SE T1-weighted sequences and an intermediate-low signal intensity on SE and FSE T2-weighted sequences in six of them; only one case had an intermediate-high signal intensity on SE and FSE T2-weighted sequences. Both contrast-enhanced CT and MRI showed precocious enhancement in association with multiple peripheral hypertrophic blood vessels. On the basis of integrated imaging data obtained by US, CT, and MRI, it is possible to evaluate the lesion extension to provide a loco-regional staging, to characterize IMTs, and to allow an optimal therapeutical planning. (orig.)

  10. [Inflammatory myofibroblastic tumor of the lymph node with paraneoplastic thrombosis and eosinophilia].

    Science.gov (United States)

    Behzad, Ali; Müller, Andrea; Rösler, Wolf; Amann, Kerstin; Linke, Rainer; Mackensen, Andreas

    2010-04-01

    A 52-year-old female patient was admitted to hospital because of progressive thrombosis despite therapeutic anticoagulation as well as leukocytosis with eosinophilia and thrombocytopenia. On examination, the patient presented with dyspnea and swelling oft her left leg and arm. The laboratory findings revealed leukocytosis (31,000/microl) with eosinophilia (54%), thrombocytopenia (58,000/microl), together with an increased C-reactive protein of 247 mg/dl (reference range < 5 mg/dl). Initial computed tomography scans showed pulmonary embolism and a slightly enlarged left inguinal lymph node. Histological examination of the lymph node biopsy revealed in part an epitheloid and spindle cell-like tumorous lesion with slightly increased tissue eosinophilia consistent with an inflammatory myofibroblastic tumor (IMT). Resection of the left inguinal lymph node resulted in an immediate regression of the paraneoplastic eosinophilia and thrombocytopenia. Anti-inflammatory medication with ibuprofen was subsequently initiated. Imaging and clinical examination at 3 months after discharge revealed no relapse and no signs of a paraneoplastic syndrome. The IMT is a rare soft-tissue tumor of intermediate dignity with a low tendency to metastasize. It is consistently accompanied by paraneoplastic syndromes. Therapy of choice is complete resection of the tumor. In nonresectable cases, corticosteroids and nonsteroidal antirheumatics have been shown to be effective. Because of the variable clinical course ranging from spontaneous regression to metastasis, IMTs might be separated into different entities (autoimmune, inflammatory, neoplastic subtype) which thus far cannot be classified on a histopathologic basis. A clinical assessment of the dignity is therefore important until further subclassifications of this rare disease become available.

  11. [Effects of hypoxia on the phenotype transformation of human dermal fibroblasts to myofibroblasts and the mechanism].

    Science.gov (United States)

    Zhao, B; Han, F; Zhang, W; Wang, X J; Zhang, J; Yang, F F; Shi, J H; Su, L L; Hu, D H

    2017-06-20

    Objective: To investigate the effects of hypoxia on the phenotype transformation of human dermal fibroblasts to myofibroblasts and the mechanism. Methods: The third passage of healthy adult human dermal fibroblasts in logarithmic phase were cultured in DMEM medium containing 10% fetal bovine serum for the following five experiments. (1) In experiments 1, 2, and 3, cells were divided into normoxia group and hypoxia group according to the random number table, with 10 dishes in each group. Cells of normoxia group were cultured in incubator containing 21% oxygen, while those of hypoxia group with 1% oxygen. At post culture hour (PCH) 0 and 48, 5 dishes of cells were collected from each group, respectively. mRNA expressions of markers of myofibroblasts including alpha smooth muscle actin (α-SMA), type Ⅰ collagen, and type Ⅲ collagen of cells were determined with real time fluorescent quantitative reverse transcription polymerase chain reaction in experiment 1. Protein expressions of α-SMA, type Ⅰ collagen, and type Ⅲ collagen of cells were determined with Western blotting in experiment 2. The protein expression of nuclear factor-kappa B (NF-κB) of cells was determined with Western blotting in experiment 3. (2) In experiment 4, cells were divided into normoxia group, hypoxia group, and hypoxia+ pyrrolidine dithiocarbamate (PDTC) group according to the random number table, with 5 dishes in each group. Cells in the former two groups were treated the same as those in experiment 1. Cells in hypoxia+ PDTC group were treated the same as those in hypoxia group plus adding 4 mL PDTC with a final molarity of 10 μmol/L in the culture medium. At PCH 48, the protein expression of NF-κB of cells was determined with Western blotting. (3) In experiment 5, cells were divided into normoxia group, hypoxia group, hypoxia+ PDTC group, and normoxia+ PDTC group according to the random number table, with 5 dishes in each group. Cells in the former three groups were treated the

  12. Breast Regression Protein-39/Chitinase 3-Like 1 Promotes Renal Fibrosis after Kidney Injury via Activation of Myofibroblasts.

    Science.gov (United States)

    Montgomery, Tinika A; Xu, Leyuan; Mason, Sherene; Chinnadurai, Amirtha; Lee, Chun Geun; Elias, Jack A; Cantley, Lloyd G

    2017-11-01

    The normal response to kidney injury includes a robust inflammatory infiltrate of PMNs and macrophages. We previously showed that the small secreted protein breast regression protein-39 (BRP-39), also known as chitinase 3-like 1 (CHI3L1) and encoded by the Chi3l1 gene, is expressed at high levels by macrophages during the early stages of kidney repair and promotes tubular cell survival via IL-13 receptor α 2 (IL13R α 2)-mediated signaling. Here, we investigated the role of BRP-39 in profibrotic responses after AKI. In wild-type mice, failure to resolve tubular injury after unilateral ischemia-reperfusion injury (U-IRI) led to sustained low-level Chi3l1 mRNA expression by renal cells and promoted macrophage persistence and severe interstitial fibrosis. Analysis of macrophages isolated from wild-type kidneys 14 days after U-IRI revealed high-level expression of the profibrotic BRP-39 receptor Ptgdr2 / Crth2 and expression of the profibrotic markers Lgals3 , Pdgfb , Egf , and Tgfb In comparison, injured kidneys from mice lacking BRP-39 had significantly fewer macrophages, reduced expression of profibrotic growth factors, and decreased accumulation of extracellular matrix. BRP-39 depletion did not affect myofibroblast accumulation but did attenuate myofibroblast expression of Col1a1 , Col3a1 , and Fn1 Together, these results identify BRP-39 as an important activator of macrophage-myofibroblast crosstalk and profibrotic signaling in the setting of maladaptive kidney repair. Copyright © 2017 by the American Society of Nephrology.

  13. Fatty Liver

    International Nuclear Information System (INIS)

    Filippone, A.; Digiovandomenico, V.; Digiovandomenico, E.; Genovesi, N.; Bonomo, L.

    1991-01-01

    The authors report their experience with the combined use of US and CT in the study of diffuse and subtotal fatty infiltration of the liver. An apparent disagreement was initially found between the two examinations in the study of fatty infiltration. Fifty-five patients were studied with US and CT of the upper abdomen, as suggested by clinics. US showed normal liver echogenicity in 30 patients and diffuse increased echogenicity (bright liver) in 25 cases. In 5 patients with bright liver, US demonstrated a solitary hypoechoic area, appearing as a 'skip area', in the quadrate lobe. In 2 patients with bright liver, the hypoechoic area was seen in the right lobe and exhibited no typical US features of 'Skip area'. Bright liver was quantified by measuring CT density of both liver and spleen. The relative attenuation values of spleen and liver were compared on plain and enhanced CT scans. In 5 cases with a hypoechoic area in the right lobe, CT findings were suggestive of hemangioma. A good correlation was found between broght liver and CT attenuation values, which decrease with increasing fat content of the liver. Moreover, CT attenuation values confirmed US findings in the study of typical 'skip area', by demonstrating normal density - which suggests that CT can characterize normal tissue in atypical 'skip area'

  14. Crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumours with and without anaplastic lymphoma kinase gene alterations (European Organisation for Research and Treatment of Cancer 90101 CREATE): a multicentre, single-drug, prospective, non-randomised phase 2 trial.

    Science.gov (United States)

    Schöffski, Patrick; Sufliarsky, Jozef; Gelderblom, Hans; Blay, Jean-Yves; Strauss, Sandra J; Stacchiotti, Silvia; Rutkowski, Piotr; Lindner, Lars H; Leahy, Michael G; Italiano, Antoine; Isambert, Nicolas; Debiec-Rychter, Maria; Sciot, Raf; Van Cann, Thomas; Marréaud, Sandrine; Nzokirantevye, Axelle; Collette, Sandra; Wozniak, Agnieszka

    2018-06-01

    An inflammatory myofibroblastic tumour (IMFT) is a rare mesenchymal neoplasm characterised by anaplastic lymphoma kinase (ALK) gene rearrangements. We assessed the activity and safety of crizotinib, a tyrosine kinase inhibitor, targeting ALK in patients with advanced IMFT either with or without ALK alterations. We did a multicentre, biomarker-driven, single-drug, non-randomised, open-label, two-stage phase 2 trial (European Organisation for Research and Treatment of Cancer 90101 CREATE) at 13 study sites (five university hospitals and eight specialty clinics) in eight European countries (Belgium, France, Germany, Italy, Netherlands, Poland, Slovakia, and the UK). Eligible participants were patients aged at least 15 years with a local diagnosis of advanced or metastatic IMFT deemed incurable with surgery, radiotherapy, or systemic therapy; measurable disease; an Eastern Cooperative Oncology Group performance status of 0-2; and adequate haematological, renal, and liver function. Central reference pathology was done for confirmation of the diagnosis, and ALK positivity or negativity was assessed centrally using immunohistochemistry and fluorescence in-situ hybridisation based on archival tumour tissue and defined as ALK immunopositivity or rearrangements in at least 15% of tumour cells. Eligible ALK-positive and ALK-negative patients received oral crizotinib 250 mg twice per day administered on a continuous daily dosing schedule (the duration of each treatment cycle was 21 days) until documented disease progression, unacceptable toxicity, or patient refusal. If at least two of the first 12 eligible and assessable ALK-positive patients achieved a confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, a maximum of 35 patients were to be enrolled. If at least six ALK-positive patients achieved a confirmed response, the trial would be deemed successful. The primary endpoint was the proportion of patients who achieved

  15. Matrix metalloproteinase inhibition delays wound healing and blocks the latent transforming growth factor-beta1-promoted myofibroblast formation and function

    DEFF Research Database (Denmark)

    Mirastschijski, Ursula; Schnabel, Reinhild; Claes, Juliane

    2010-01-01

    applied topically to full-thickness skin excisional wounds in rats and its ability to inhibit the promotion of myofibroblast formation and function by the latent transforming-growth factor-beta1 (TGF-beta1). BB-94 delayed wound contraction, as well as all other associated aspects of wound healing examined......, including myofibroblast formation, stromal cell proliferation, blood vessel formation, and epithelial wound coverage. Interestingly, BB-94 dramatically increased the level of latent and active MMP-9. The increased levels of active MMP-9 may eventually overcome the ability of BB-94 to inhibit this MMP...... and may explain why wound contraction and other associated events of wound healing were only delayed and not completely inhibited. BB-94 was also found to inhibit the ability of latent TGF-beta1 to promote the formation and function of myofibroblasts. These results suggest that BB-94 could delay wound...

  16. In vivo siRNA delivery system for targeting to the liver by poly-l-glutamic acid-coated lipoplex

    Directory of Open Access Journals (Sweden)

    Yoshiyuki Hattori

    2014-01-01

    Full Text Available In this study, we developed anionic polymer-coated liposome/siRNA complexes (lipoplexes with chondroitin sulfate C (CS, poly-l-glutamic acid (PGA and poly-aspartic acid (PAA for siRNA delivery by intravenous injection, and evaluated the biodistribution and gene silencing effect in mice. The sizes of CS-, PGA- and PAA-coated lipoplexes were about 200 nm and their ζ-potentials were negative. CS-, PGA- and PAA-coated lipoplexes did not induce agglutination after mixing with erythrocytes. In terms of biodistribution, siRNAs after intravenous administration of cationic lipoplexes were largely observed in the lungs, but those of CS-, PGA- and PAA-coated lipoplexes were in both the liver and the kidneys, indicating that siRNA might be partially released from the anionic polymer-coated lipoplexes in the blood circulation and accumulate in the kidney, although the lipoplexes can prevent the agglutination with blood components. To increase the association between siRNA and cationic liposome, we used cholesterol-modified siRNA (siRNA-Chol for preparation of the lipoplexes. When CS-, PGA- and PAA-coated lipoplexes of siRNA-Chol were injected into mice, siRNA-Chol was mainly observed in the liver, not in the kidneys. In terms of the suppression of gene expression in vivo, apolipoprotein B (ApoB mRNA in the liver was significantly reduced 48 h after single intravenous injection of PGA-coated lipoplex of ApoB siRNA-Chol (2.5 mg siRNA/kg, but not cationic, CS- and PAA-coated lipoplexes. In terms of toxicity after intravenous injection, CS-, PGA- and PAA-coated lipoplexes did not increase GOT and GPT concentrations in blood. From these findings, PGA coatings for cationic lipoplex of siRNA-Chol might produce a systemic vector of siRNA to the liver.

  17. ADP-ribosylation of actins in fibroblasts and myofibroblasts by botulinum C2 toxin: Influence on microfilament morphology and migratory behavior

    DEFF Research Database (Denmark)

    Rønnov-Jessen, Lone; Petersen, Ole William

    1996-01-01

    botulinum C2 toxin. The substrate for C2 toxin is globular actin, which upon ribosylation cannot incorporate into microfilaments. The pattern of actin ADP-ribosylation in (myo)fibroblasts in the presence of [32P]NAD was analyzed by isoelectric focusing, fluorography and immunoblotting. The influence of C2...... toxin on microfilaments in intact cells was further assessed by immunofluorescence, and motility was measured in a mass migration assay and by computerized video time-lapse microscopy. We show here that C2 toxin specifically ribosylates - and -actin in both fibroblasts and myofibroblasts. Whereas...

  18. Synergistic role of HSP90α and HSP90β to promote myofibroblast persistence in lung fibrosis.

    Science.gov (United States)

    Bellaye, Pierre-Simon; Shimbori, Chiko; Yanagihara, Toyoshi; Carlson, David A; Hughes, Philip; Upagupta, Chandak; Sato, Seidai; Wheildon, Nolan; Haystead, Timothy; Ask, Kjetil; Kolb, Martin

    2018-02-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lung parenchyma, causing significant morbidity through worsening dyspnoea and overall functional decline. IPF is characterised by apoptosis-resistant myofibroblasts, which are a major source for the excessive production of extracellular matrix (ECM) overtaking normal lung tissue. We sought to study the role of heat shock protein (HSP) isoforms HSP90α and HSP90β, whose distinct roles in lung fibrogenesis remain elusive.We determined the level of circulating HSP90α in IPF patients (n=31) and age-matched healthy controls (n=9) by ELISA. The release of HSP90α and HSP90β was evaluated in vitro in primary IPF and control lung fibroblasts and ex vivo after mechanical stretch on fibrotic lung slices from rats receiving adenovector-mediated transforming growth factor-β1.We demonstrate that circulating HSP90α is upregulated in IPF patients in correlation with disease severity. The release of HSP90α is enhanced by the increase in mechanical stress of the fibrotic ECM. This increase in extracellular HSP90α signals through low-density lipoprotein receptor-related protein 1 (LRP1) to promote myofibroblast differentiation and persistence. In parallel, we demonstrate that the intracellular form of HSP90β stabilises LRP1, thus amplifying HSP90α extracellular action.We believe that the specific inhibition of extracellular HSP90α is a promising therapeutic strategy to reduce pro-fibrotic signalling in IPF. Copyright ©ERS 2018.

  19. Protein and non-protein sulfhydryls and disulfides in gastric mucosa and liver after gastrotoxic chemicals and sucralfate: possible new targets of pharmacologic agents.

    Science.gov (United States)

    Nagy, Lajos; Nagata, Miki; Szabo, Sandor

    2007-04-14

    To investigate the role of major non-protein and protein sulfhydryls and disulfides in chemically induced gastric hemorrhagic mucosal lesions (HML) and the mechanism of gastroprotective effect of sucralfate. Rats were given 1 mL of 75% ethanol, 25% NaCl, 0.6 mol/L HCl, 0.2 mol/L NaOH or 1% ammonia solutions intragastrically (i.g.) and sacrificed 1, 3, 6 or 12 min later. Total (reduced and oxidized) glutathione (GSH + GSSG), glutathione disulfide (GSSG), protein free sulfhydryls (PSH), protein-glutathione mixed disulfides (PSSG) and protein cystine disulfides (PSSP) were measured in gastric mucosa and liver. Reduced glutathione (GSH) was depleted in the gastric mucosa after ethanol, HCl or NaCl exposure, while oxidized glutathione (GSSG) concentrations increased, except by HCl and NaOH exposure. Decreased levels of PSH after exposure to ethanol were observed, NaCl or NaOH while the total protein disulfides were increased. Ratios of reduced to oxidized glutathione or sulfhydrils to disulfides were decreased by all chemicals. No changes in thiol homeostasis were detected in the liver after i.g. abbreviation should be spelled out the first time here administration of ethanol. Sucralfate increased the concentrations of GSH and PSH and prevented the ethanol-induced changes in gastric mucosal thiol concentrations. Our modified methods are now suitable for direct measurements of major protein and non-protein thiols/disulfides in the gastric mucosa or liver. A common element in the pathogenesis of chemically induced HML and in the mechanism of gastroprotective drugs seems to be the decreased ratios of reduced and oxidized glutathione as well as protein sulfhydryls and disulfides.

  20. Protein and non-protein sulfhydryls and disulfides in gastric mucosa and liver after gastrotoxic chemicals and sucralfate: Possible new targets of pharmacologic agents

    Institute of Scientific and Technical Information of China (English)

    Lajos Nagy; Miki Nagata; Sandor Szabo

    2007-01-01

    AIM: To investigate the role of major non-protein and protein sulfhydryls and disulfides in chemically induced gastric hemorrhagic mucosal lesions (HML) and the mechanism of gastroprotective effect of sucralfate.METHODS: Rats were given 1 mL of 75% ethanol, 25%NaCl, 0.6 mol/L HCI, 0.2 mol/L NaOH or 1% ammonia solutions intragastrically (i.g.) and sacrificed 1, 3, 6 or 12 min later. Total (reduced and oxidized) glutathione (GSH + GSSG), glutathione disulfide (GSSG), protein free sulfhydryls (PSH), protein-glutathione mixed disulfides (PSSG) and protein cystine disulfides (PSSP) were measured in gastric mucosa and liver.RESULTS: Reduced glutathione (GSH) was depleted in the gastric mucosa after ethanol, HCI or NaCl exposure,while oxidized glutathione (GSSG) concentrations increased, except by HCI and NaOH exposure. Decreased levels of PSH after exposure to ethanol were observed,NaCl or NaOH while the total protein disulfides were increased. Ratios of reduced to oxidized glutathione or sulfhydrils to disulfides were decreased by all chemicals.No changes in thiol homeostasis were detected in the liver after i.g. abbreviation should be spelled out the first time here administration of ethanol. Sucralfate increased the concentrations of GSH and PSH and prevented the ethanol-induced changes in gastric mucosal thiol concentrations.CONCLUSION: Our modified methods are now suitable for direct measurements of major protein and nonprotein thiols/disulfides in the gastric mucosa or liver.A common element in the pathogenesis of chemically induced HML and in the mechanism of gastroprotective drugs seems to be the decreased ratios of reduced and oxidized glutathione as well as protein sulfhydryls and disulfides.

  1. Liver Disease

    Science.gov (United States)

    ... and ridding your body of toxic substances. Liver disease can be inherited (genetic) or caused by a variety of factors that damage the ... that you can't stay still. Causes Liver disease has many ... or semen, contaminated food or water, or close contact with a person who is ...

  2. Liver scintigraphy

    International Nuclear Information System (INIS)

    Tateno, Yukio

    1996-01-01

    Liver scintigraphy can be classified into 3 major categories according to the properties of the radiopharmaceuticals used, i.e., methods using radiopharmaceuticals which are (1) incorporated by hepatocytes, (2) taken up by reticulo endothelial cells, and (3) distributed in the blood pool of the liver. Of these three categories, the liver scintigraphy of the present research falls into category 2. Radiopharmaceuticals which are taken up by endothelial cells include 198 Au colloids and 99m Tc-labelled colloids. Liver scintigraphy takes advantage of the property by which colloidal microparticles are phagocytosed by Kupffer cells, and reflect the distribution of endothelial cells and the intensity of their phagocytic capacity. This examination is indicated in the following situations: (i) when you suspect a localized intrahepatic lesion (tumour, abscess, cyst, etc.), (ii) when you want to follow the course of therapy of a localized lesion, (iii) when you suspect liver cirrhosis, (iv) when you want to know the severity of liver cirrhosis or hepatitis, (v) when there is hepatomegaly and you want to determine the morphology of the liver, (vi) differential diagnosis of upper abdominal masses, and (vii) when there are abnormalities of the right diaphragm and you want to know their relation to the liver

  3. Liver regeneration

    NARCIS (Netherlands)

    Chamuleau, R. A.; Bosman, D. K.

    1988-01-01

    Despite great advances in analysing hemodynamic, morphological and biochemical changes during the process of liver regeneration, the exact (patho)physiological mechanism is still unknown. A short survey of literature is given of the kinetics of liver regeneration and the significance of different

  4. Carcinoma-Associated Fibroblasts Are a Promising Therapeutic Target

    International Nuclear Information System (INIS)

    Togo, Shinsaku; Polanska, Urszula M.; Horimoto, Yoshiya; Orimo, Akira

    2013-01-01

    Human carcinomas frequently exhibit significant stromal reactions such as the so-called “desmoplastic stroma” or “reactive stroma”, which is characterised by the existence of large numbers of stromal cells and extracellular matrix proteins. Carcinoma-associated fibroblasts (CAFs), which are rich in activated fibroblast populations exemplified by myofibroblasts, are among the predominant cell types present within the tumour-associated stroma. Increased numbers of stromal myofibroblasts are often associated with high-grade malignancies with poor prognoses in humans. CAF myofibroblasts possess abilities to promote primary tumour development, growth and progression by stimulating the processes of neoangiogenesis as well as tumour cell proliferation, survival, migration and invasion. Moreover, it has been demonstrated that CAFs serve as a niche supporting the metastatic colonisation of disseminated carcinoma cells in distant organs. Their contribution to primary and secondary malignancies makes these fibroblasts a potential therapeutic target and they also appear to be relevant to the development of drug resistance and tumour recurrence. This review summarises our current knowledge of tumour-promoting CAFs and discusses the therapeutic feasibility of targeting these cells as well as disrupting heterotypic interactions with other cell types in tumours that may improve the efficacy of current anti-tumour therapies

  5. [Liver transplantation].

    Science.gov (United States)

    Pompili, Maurizio; Mirante, Vincenzo Giorgio; Rapaccini, Gian Ludovico; Gasbarrini, Giovanni

    2004-01-01

    Liver transplantation represents the first choice treatment for patients with fulminant acute hepatitis and for patients with chronic liver disease and advanced functional failure. Patients in the waiting list for liver transplantation are classified according to the severity of their clinical conditions (evaluated using staging systems mostly based on hematochemical parameters related to liver function). This classification, together with the blood group and the body size compatibility, remains the main criterion for organ allocation. The main indications for liver transplantation are cirrhosis (mainly HCV-, HBV- and alcohol-related) and hepatocellular carcinoma emerging in cirrhosis in adult patients, biliary atresia and some inborn errors of metabolism in pediatric patients. In adults the overall 5-year survival ranges between 60 and 70%, in both American and European series. Even better results have been reported for pediatric patients: in fact, the 5-year survival rate for children ranges between 70 and 80% in the main published series. In this study we evaluated the main medical problems correlated with liver transplantation such as immunosuppressive treatment, acute and chronic rejection, infectious complications, the recurrence of the liver disease leading to transplantation, and cardiovascular and metabolic complications.

  6. Inflammatory myofibroblastic tumor of the pancreatic head – a case report of a 6 months old child and review of the literature

    Directory of Open Access Journals (Sweden)

    Tomazic Ales

    2015-09-01

    Full Text Available Background. Inflammatory myofibroblastic tumors are rare in the pediatric population. Most common localizations were reported in the lungs. A localization in the pancreas needs differentiation from other tumors and chronic pancreatitis. Treatment is surgical resection, although there are reports of treatment with oral steroids and radiation therapy.

  7. Interleukin-1 beta Attenuates Myofibroblast Formation and Extracellular Matrix Production in Dermal and Lung Fibroblasts Exposed to Transforming Growth Factor-beta 1

    NARCIS (Netherlands)

    Mia, Masum M.; Boersema, Miriam; Bank, Ruud A.

    2014-01-01

    One of the most potent pro-fibrotic cytokines is transforming growth factor (TGF beta). TGF beta is involved in the activation of fibroblasts into myofibroblasts, resulting in the hallmark of fibrosis: the pathological accumulation of collagen. Interleukin-1 beta (IL1 beta) can influence the

  8. Effects of transforming growth factor-beta1 on cell motility, collagen gel contraction, myofibroblastic differentiation, and extracellular matrix expression of human adipose-derived stem cell.

    Science.gov (United States)

    Kakudo, Natsuko; Kushida, Satoshi; Suzuki, Kenji; Ogura, Tsunetaka; Notodihardjo, Priscilla Valentin; Hara, Tomoya; Kusumoto, Kenji

    2012-12-01

    Human adipose-derived stem cells (ASCs) are adult pluripotent stem cells, and their usefulness in plastic surgery has garnered attention in recent years. Although, there have been expectations that ASCs might function in wound repair and regeneration, no studies to date have examined the role of ASCs in the mechanism that promotes wound-healing. Transforming growth factor-beta1 (TGF-β1) is a strong candidate cytokine for the triggering of mesenchymal stem cell migration, construction of extracellular matrices, and differentiation of ASCs into myofibroblasts. Cell proliferation, motility, and differentiation, as well as extracellular matrix production, play an important role in wound-healing. We have evaluated the capacity of ASCs to proliferate and their potential to differentiate into phenotypic myofibroblasts, as well as their cell motility and collagen gel contraction ability, when cultured with TGF-β1. Cell motility was analyzed using a wound-healing assay. ASCs that differentiated into myofibroblasts expressed the gene for alpha-smooth muscle actin, and its protein expression was detected immunohistochemically. The extracellular matrix expression in ASCs was evaluated using real-time RT-PCR. Based on the results, we conclude that human ASCs have the potential for cell motility, extracellular matrix gene expression, gel contraction, and differentiation into myofibroblasts and, therefore, may play an important role in the wound-healing process.

  9. Benign Liver Tumors

    Science.gov (United States)

    ... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

  10. Liver Function Tests

    Science.gov (United States)

    ... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

  11. Progression of Liver Disease

    Science.gov (United States)

    ... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

  12. Liver (Hepatocellular) Cancer Screening

    Science.gov (United States)

    ... Treatment Liver Cancer Prevention Liver Cancer Screening Research Liver (Hepatocellular) Cancer Screening (PDQ®)–Patient Version What is ... These are called diagnostic tests . General Information About Liver (Hepatocellular) Cancer Key Points Liver cancer is a ...

  13. E. coli infection modulates the pharmacokinetics of oral enrofloxacin by targeting P-glycoprotein in small intestine and CYP450 3A in liver and kidney of broilers.

    Science.gov (United States)

    Guo, Mengjie; Sun, Yong; Zhang, Yu; Bughio, Shamsuddin; Dai, Xiaohua; Ren, Weilong; Wang, Liping

    2014-01-01

    P-glycoprotein (P-gp) expression determines the absorption, distribution, metabolism and excretion of many drugs in the body. Also, up-regulation of P-gp acts as a defense mechanism against acute inflammation. This study examined expression levels of abcb1 mRNA and localization of P-gp protein in the liver, kidney, duodenum, jejunum and ileum in healthy and E. coli infected broilers by real time RT-PCR and immunohistochemistry. Meanwhile, pharmacokinetics of orally administered enrofloxacin was also investigated in healthy and infected broilers by HPLC. The results indicated that E. coli infection up-regulated expression of abcb1 mRNA levels significantly in the kidney, jejunum and ileum (P0.05). However, the expression level of CYP 3A37 mRNA were observed significantly decreased only in liver and kidney of E. coli infected broilers (Penrofloxacin, significantly decreased Cmax (0.34 vs 0.98 µg mL(-1), P = 0.000) and AUC0-12h (4.37 vs 8.88 µg mL(-1) h, P = 0.042) of enrofloxacin, but increased Tmax (8.32 vs 3.28 h, P = 0.040), T1/2a(2.66 vs 1.64 h(-1), P = 0.050) and V/F (26.7 vs 5.2 L, P = 0.040). Treatment with verapamil, an inhibitor of P-gp, significantly improved the absorption of enrofloxacin in both healthy and infected broilers. The results suggest that the E. coli infection induces intestine P-gp expression, altering the absorption of orally administered enrofloxacin in broilers.

  14. 90Y microsphere (TheraSphere) treatment for unresectable colorectal cancer metastases of the liver: response to treatment at targeted doses of 135-150 Gy as measured by [18F]fluorodeoxyglucose positron emission tomography and computed tomographic imaging.

    Science.gov (United States)

    Lewandowski, Robert J; Thurston, Kenneth G; Goin, James E; Wong, Ching-Yee O; Gates, Vanessa L; Van Buskirk, Mark; Geschwind, Jean-Francois H; Salem, Riad

    2005-12-01

    The purpose of this phase II study was to determine the safety and efficacy of TheraSphere treatment (90Y microspheres) in patients with liver-dominant colorectal metastases in whom standard therapies had failed or were judged to be inappropriate. Twenty-seven patients with unresectable hepatic colorectal metastases were treated at a targeted absorbed dose of 135-150 Gy. Safety and toxicity were assessed according to the National Cancer Institute's Common Toxicity Criteria, version 3.0. Response was assessed with use of computed tomography (CT) and was correlated with response on [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Survival from first treatment was estimated with use of the Kaplan-Meier method. Tumor response measured by FDG PET imaging exceeded that measured by CT imaging for the first (88% vs 35%) and second (73% vs 36%) treated lobes. Tumor replacement of 25% or less (vs >25%) was associated with a statistically significant increase in median survival (339 days vs 162 days; P = .002). Treatment-related toxicities included mild fatigue (n = 13; 48%), nausea (n = 4; 15%), and vague abdominal pain (n = 5; 19%). There was one case of radiation-induced gastritis from inadvertent deposition of microspheres to the gastrointestinal tract (n = 1; 4%). Three patients (11%) experienced ascites/pleural effusion after treatment with TheraSphere as a consequence of liver failure in advanced-stage metastatic disease. With the exception of these three patients whose sequelae were not considered to be related to treatment, all observed toxicities were transient and resolved without medical intervention. TheraSphere administration appears to provide stabilization of liver disease with minimal toxicity in patients in whom standard systemic chemotherapy regimens have failed.

  15. in Human Liver Diseases

    Directory of Open Access Journals (Sweden)

    Minoru Fujimoto

    2010-01-01

    Full Text Available Toll-like receptor (TLR signaling pathways are strictly coordinated by several mechanisms to regulate adequate innate immune responses. Recent lines of evidence indicate that the suppressor of cytokine signaling (SOCS family proteins, originally identified as negative-feedback regulators in cytokine signaling, are involved in the regulation of TLR-mediated immune responses. SOCS1, a member of SOCS family, is strongly induced upon TLR stimulation. Cells lacking SOCS1 are hyperresponsive to TLR stimulation. Thus, SOCS1 is an important regulator for both cytokine and TLR-induced responses. As an immune organ, the liver contains various types of immune cells such as T cells, NK cells, NKT cells, and Kupffer cells and is continuously challenged with gut-derived bacterial and dietary antigens. SOCS1 may be implicated in pathophysiology of the liver. The studies using SOCS1-deficient mice revealed that endogenous SOCS1 is critical for the prevention of liver diseases such as hepatitis, cirrhosis, and cancers. Recent studies on humans suggest that SOCS1 is involved in the development of various liver disorders in humans. Thus, SOCS1 and other SOCS proteins are potential targets for the therapy of human liver diseases.

  16. Activation of Wnt/β-catenin signalling is required for TGF-β/Smad2/3 signalling during myofibroblast proliferation.

    Science.gov (United States)

    Xu, Liang; Cui, Wen-Hui; Zhou, Wen-Cheng; Li, De-Lin; Li, Liu-Cheng; Zhao, Ping; Mo, Xiao-Ting; Zhang, Zhihui; Gao, Jian

    2017-08-01

    Fibrosis in animal models and human diseases is associated with aberrant activation of the Wnt/β-catenin pathway. Despite extensive research efforts, effective therapies are still not available. Myofibroblasts are major effectors, responsible for extracellular matrix deposition. Inhibiting the proliferation of the myofibroblast is crucial for treatment of fibrosis. Proliferation of myofibroblasts can have many triggering effects that result in fibrosis. In recent years, the Wnt pathway has been studied as an underlying factor as a primary contributor to fibrotic diseases. These efforts notwithstanding, the specific mechanisms by which Wnt-mediated promotes fibrosis reaction remain obscure. The central role of the transforming growth factor-β (TGF-β) and myofibroblast activity in the pathogenesis of fibrosis has become generally accepted. The details of interaction between these two processes are not obvious. The present investigation was conducted to evaluate the level of sustained expression of fibrosis iconic proteins (vimentin, α-SMA and collagen I) and the TGF-β signalling pathway that include smad2/3 and its phosphorylated form p-smad2/3. Detailed analysis of the possible molecular mechanisms mediated by β-catenin revealed epithelial-mesenchymal transition and additionally demonstrated transitions of fibroblasts to myofibroblast cell forms, along with increased activity of β-catenin in regulation of the signalling network, which acts to counteract autocrine TGF-β/smad2/3 signalling. A major outcome of this study is improved insight into the mechanisms by which epithelial and mesenchymal cells activated by TGFβ1-smad2/3 signalling through Wnt/β-catenin contribute to lung fibrosis. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  17. Enlarged Liver

    Science.gov (United States)

    ... of liver damage. Medicinal herbs. Certain herbs, including comfrey, ma huang and mistletoe, can increase your risk ... herbs to avoid include germander, chaparral, senna, mistletoe, comfrey, ma huang, valerian root, kava, celandine and green ...

  18. Embryonal Rhabdomyosarcoma of the Adult Urinary Bladder: A Rare Case Report of Misclassification as Inflammatory Myofibroblastic Tumor

    Directory of Open Access Journals (Sweden)

    Kelven Weijing Chen

    2015-01-01

    Full Text Available Embryonal rhabdomyosarcoma (ERMS of the adult urinary bladder is a rare malignant tumour. Inflammatory myofibroblastic tumour (IMT of the bladder is a benign genitourinary tumour that may appear variable histologically but usually lacks unequivocal malignant traits. Techniques like flow cytometry and immunohistochemistry may be used to differentiate these two tumours. Our patient, a 46-year-old male, had rapidly recurring lower urinary tract symptoms after two transurethral resections of the prostate. He subsequently underwent a transvesical prostatectomy which showed IMT on histology. However, his symptoms did not resolve and an open resection done at our institution revealed a 6 cm tumour arising from the right bladder neck. This time, histology was ERMS with diffuse anaplasia of the bladder. Rapid recurrence of urinary symptoms with prostate regrowth after surgery is unusual. Differential diagnoses of uncommon bladder malignancies should be considered if there is an inconsistent clinical course as treatment approaches are different.

  19. Embryonal Rhabdomyosarcoma of the Adult Urinary Bladder: A Rare Case Report of Misclassification as Inflammatory Myofibroblastic Tumor

    Science.gov (United States)

    Chen, Kelven Weijing; Wu, Fiona Mei Wen; Lee, Victor Kwan Min; Esuvaranathan, Kesavan

    2015-01-01

    Embryonal rhabdomyosarcoma (ERMS) of the adult urinary bladder is a rare malignant tumour. Inflammatory myofibroblastic tumour (IMT) of the bladder is a benign genitourinary tumour that may appear variable histologically but usually lacks unequivocal malignant traits. Techniques like flow cytometry and immunohistochemistry may be used to differentiate these two tumours. Our patient, a 46-year-old male, had rapidly recurring lower urinary tract symptoms after two transurethral resections of the prostate. He subsequently underwent a transvesical prostatectomy which showed IMT on histology. However, his symptoms did not resolve and an open resection done at our institution revealed a 6 cm tumour arising from the right bladder neck. This time, histology was ERMS with diffuse anaplasia of the bladder. Rapid recurrence of urinary symptoms with prostate regrowth after surgery is unusual. Differential diagnoses of uncommon bladder malignancies should be considered if there is an inconsistent clinical course as treatment approaches are different. PMID:25737794

  20. In vivo targeting of surface-modified liposomes to metastatically growing colon carcinoma cells and sinusoidal endothelial cells in the rat liver.

    NARCIS (Netherlands)

    Scherphof, GL; Kamps, JAAM; Koning, GA

    1997-01-01

    We prepared immunoliposomes by covalent coupling of a randomly thiolated monoclonal antibody against the rat colon adenocarcinoma cell line CC531 to MPB-PE on the outer surface of conventional as well as PEGylated liposomes of about 100-nm diameter. We attempted to target these immunoliposomes in

  1. An improved method of sample preparation on AnchorChip targets for MALDI-MS and MS/MS and its application in the liver proteome project

    DEFF Research Database (Denmark)

    Zhang, Xumin; Shi, Liang; Shu, Shaokung

    2007-01-01

    An improved method for sample preparation for MALDI-MS and MS/MS using AnchorChip targets is presented. The method, termed the SMW method (sample, matrix wash), results in better sensitivity for peptide mass fingerprinting as well as for sequencing by MS/MS than previously published methods. The ...

  2. Protein Profiling of Isolated Leukocytes, Myofibroblasts, Epithelial, Basal, and Endothelial Cells from Normal, Hyperplastic, Cancerous, and Inflammatory Human Prostate Tissues

    Directory of Open Access Journals (Sweden)

    Zahraa I. Khamis, Kenneth A. Iczkowski, Ziad J. Sahab, Qing-Xiang Amy Sang

    2010-01-01

    Full Text Available In situ neoplastic prostate cells are not lethal unless they become invasive and metastatic. For cells to become invasive, the prostate gland must undergo degradation of the basement membrane and disruption of the basal cell layer underneath the luminal epithelia. Although the roles of proteinases in breaking down the basement membrane have been well-studied, little is known about the factors that induce basal cell layer disruption, degeneration, and its eventual disappearance in invasive cancer. It is hypothesized that microenvironmental factors may affect the degradation of the basal cell layer, which if protected may prevent tumor progression and invasion. In this study, we have revealed differential protein expression patterns between epithelial and stromal cells isolated from different prostate pathologies and identified several important epithelial and stromal proteins that may contribute to inflammation and malignant transformation of human benign prostate tissues to cancerous tissues using matrix-assisted laser desorption ionization time-of-flight mass spectrometry and proteomics methods. Cellular retinoic acid-binding protein 2 was downregulated in basal cells of benign prsotate. Caspase-1 and interleukin-18 receptor 1 were highly expressed in leukocytes of prostate cancer. Proto-oncogene Wnt-3 was downregulated in endothelial cells of prostatitis tissue and tyrosine phosphatase non receptor type 1 was only found in normal and benign endothelial cells. Poly ADP-ribose polymerase 14 was downregulated in myofibroblasts of prostatitis tissue. Interestingly, integrin alpha-6 was upregulated in epithelial cells but not detected in myofibroblasts of prostate cancer. Further validation of these proteins may generate new strategies for the prevention of basal cell layer disruption and subsequent cancer invasion.

  3. Recurrent targeted genes of hepatitis B virus in the liver cancer genomes identified by a next-generation sequencing-based approach.

    Directory of Open Access Journals (Sweden)

    Dong Ding

    Full Text Available Integration of the viral DNA into host chromosomes was found in most of the hepatitis B virus (HBV-related hepatocellular carcinomas (HCCs. Here we devised a massive anchored parallel sequencing (MAPS method using next-generation sequencing to isolate and sequence HBV integrants. Applying MAPS to 40 pairs of HBV-related HCC tissues (cancer and adjacent tissues, we identified 296 HBV integration events corresponding to 286 unique integration sites (UISs with precise HBV-Human DNA junctions. HBV integration favored chromosome 17 and preferentially integrated into human transcript units. HBV targeted genes were enriched in GO terms: cAMP metabolic processes, T cell differentiation and activation, TGF beta receptor pathway, ncRNA catabolic process, and dsRNA fragmentation and cellular response to dsRNA. The HBV targeted genes include 7 genes (PTPRJ, CNTN6, IL12B, MYOM1, FNDC3B, LRFN2, FN1 containing IPR003961 (Fibronectin, type III domain, 7 genes (NRG3, MASP2, NELL1, LRP1B, ADAM21, NRXN1, FN1 containing IPR013032 (EGF-like region, conserved site, and three genes (PDE7A, PDE4B, PDE11A containing IPR002073 (3', 5'-cyclic-nucleotide phosphodiesterase. Enriched pathways include hsa04512 (ECM-receptor interaction, hsa04510 (Focal adhesion, and hsa04012 (ErbB signaling pathway. Fewer integration events were found in cancers compared to cancer-adjacent tissues, suggesting a clonal expansion model in HCC development. Finally, we identified 8 genes that were recurrent target genes by HBV integration including fibronectin 1 (FN1 and telomerase reverse transcriptase (TERT1, two known recurrent target genes, and additional novel target genes such as SMAD family member 5 (SMAD5, phosphatase and actin regulator 4 (PHACTR4, and RNA binding protein fox-1 homolog (C. elegans 1 (RBFOX1. Integrating analysis with recently published whole-genome sequencing analysis, we identified 14 additional recurrent HBV target genes, greatly expanding the HBV recurrent target list

  4. Pharmacokinetics of IDX184, a liver-targeted oral prodrug of 2'-methylguanosine-5'-monophosphate, in the monkey and formulation optimization for human exposure.

    Science.gov (United States)

    Pan-Zhou, Xin-Ru; Mayes, Benjamin A; Rashidzadeh, Hassan; Gasparac, Rahela; Smith, Steven; Bhadresa, Sanjeev; Gupta, Kusum; Cohen, Marita Larsson; Bu, Charlie; Good, Steven S; Moussa, Adel; Rush, Roger

    2016-10-01

    IDX184 is a phosphoramidate prodrug of 2'-methylguanosine-5'-monophosphate, developed to treat patients infected with hepatitis C virus. A mass balance study of radiolabeled IDX184 and pharmacokinetic studies of IDX184 in portal vein-cannulated monkeys revealed relatively low IDX184 absorption but higher exposure of IDX184 in the portal vein than in the systemic circulation, indicating >90 % of the absorbed dose was subject to hepatic extraction. Systemic exposures to the main metabolite, 2'-methylguanosine (2'-MeG), were used as a surrogate for liver levels of the pharmacologically active entity 2'-MeG triphosphate, and accordingly, systemic levels of 2'-MeG in the monkey were used to optimize formulations for further clinical development of IDX184. Capsule formulations of IDX184 delivered acceptable levels of 2'-MeG in humans; however, the encapsulation process introduced low levels of the genotoxic impurity ethylene sulfide (ES), which necessitated formulation optimization. Animal pharmacokinetic data guided the development of a tablet with trace levels of ES and pharmacokinetic performance equal to that of the clinical capsule in the monkey. Under fed conditions in humans, the new tablet formulation showed similar exposure to the capsule used in prior clinical trials.

  5. Ventilatory strategy during liver transplantation

    DEFF Research Database (Denmark)

    Sørensen, Henrik; Grocott, Hilary P; Niemann, Mads

    2014-01-01

    BACKGROUND: As measured by near infrared spectroscopy (NIRS), cerebral oxygenation (ScO2) may be reduced by hyperventilation in the anhepatic phase of liver transplantation surgery (LTx). Conversely, the brain may be subjected to hyperperfusion during reperfusion of the grafted liver. We investig......, this retrospective analysis suggests that attention to maintain a targeted EtCO2 would result in a more stable ScO2 during the operation....

  6. Serum markers of liver fibrosis

    DEFF Research Database (Denmark)

    Veidal, Sanne Skovgård; Bay-Jensen, Anne-Christine; Tougas, Gervais

    2010-01-01

    -epitopes, may be targeted for novel biochemical marker development in fibrosis. We used the recently proposed BIPED system (Burden of disease, Investigative, Prognostic, Efficacy and Diagnostic) to characterise present serological markers. METHODS: Pubmed was search for keywords; Liver fibrosis, neo......, a systematic use of the neo-epitope approach, i.e. the quantification of peptide epitopes generated from enzymatic cleavage of proteins during extracellular remodeling, may prove productive in the quest to find new markers of liver fibrosis....

  7. Adult Primary Liver Cancer Treatment (PDQ®)—Health Professional Version

    Science.gov (United States)

    Adult primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma. Treatments include surveillance, surgery, liver transplant, ablation therapy, embolization therapy, targeted therapy, and radiation therapy. Get comprehensive information about liver cancer and treatment in this clinician summary.

  8. Simultaneous quantification of the abundance of several cytochrome P450 and uridine 5'-diphospho-glucuronosyltransferase enzymes in human liver microsomes using multiplexed targeted proteomics.

    Science.gov (United States)

    Achour, Brahim; Russell, Matthew R; Barber, Jill; Rostami-Hodjegan, Amin

    2014-04-01

    Cytochrome P450 (P450) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes mediate a major proportion of phase I and phase II metabolism of xenobiotics. In vitro-in vivo extrapolation (IVIVE) of hepatic clearance in conjunction with physiologically-based pharmacokinetics (PBPK) has become common practice in drug development. However, prediction of xenobiotic kinetics in virtual populations requires knowledge of both enzyme abundances and the extent to which these correlate. A multiplexed quantification concatemer (QconCAT) strategy was used in this study to quantify the expression of several P450 and UGT enzymes simultaneously and to establish correlations between various enzyme abundances in 24 individual liver samples (ages 27-66, 14 male). Abundances were comparable to previously reported values, including CYP2C9 (40.0 ± 26.0 pmol mg(-1)), CYP2D6 (11.9 ± 13.2 pmol mg(-1)), CYP3A4 (68.1 ± 52.3 pmol mg(-1)), UGT1A1 (33.6 ± 34.0 pmol mg(-1)), and UGT2B7 (82.9 ± 36.1 pmol mg(-1)), expressed as mean ± S.D. Previous reports of correlations in expression of various P450 (CYP3A4/CYP3A5*1/*3, CYP2C8/CYP2C9, and CYP3A4/CYP2B6) were confirmed. New correlations were demonstrated between UGTs [including UGT1A6/UGT1A9 (r(s) = 0.82, P enzymes were shown to be correlated [including CYP1A2/UGT2B4 (r(s) = 0.67, P = 0.0002)]. The expression of CYP3A5 in individuals with *1/*3 genotype (n = 11) was higher than those with *3/*3 genotype (n = 10) (P history of smoking or alcohol use on enzyme expression was observed; however, expression of several enzymes declined with age. The correlation matrix produced for the first time by this study can be used to generate more realistic virtual populations with respect to abundance of various enzymes.

  9. Amoebic liver

    African Journals Online (AJOL)

    lymphadenopathy were noted. The right-sided pleural effusion with relaxation atelectasis was also con- firmed (Fig. 4). The diagnosis of pos- sible amoebic liver abscess complicat- ed by rupture to the gallbladder was made at that stage. Ultrasound-guided abscess drainage was done and approximately 300 ml of pus was.

  10. Hepatic (Liver) Function Panel

    Science.gov (United States)

    ... Educators Search English Español Blood Test: Hepatic (Liver) Function Panel KidsHealth / For Parents / Blood Test: Hepatic (Liver) ... kidneys ) is working. What Is a Hepatic (Liver) Function Panel? A liver function panel is a blood ...

  11. American Liver Foundation

    Science.gov (United States)

    ... Cirrhosis Clinical Trials Galactosemia Gilbert Syndrome Hemochromatosis Hepatic Encephalopathy Hepatitis A Hepatitis B Hepatitis C Hepatocellular Carcinoma Lysosomal Acid Lipase Deficiency(LALD) Intrahepatic Cholestasis of Pregnancy (ICP) Liver Biopsy Liver Cancer Liver Cysts Liver Function Tests ...

  12. Elevated Liver Enzymes

    Science.gov (United States)

    Symptoms Elevated liver enzymes By Mayo Clinic Staff Elevated liver enzymes may indicate inflammation or damage to cells in the liver. Inflamed or ... than normal amounts of certain chemicals, including liver enzymes, into the bloodstream, which can result in elevated ...

  13. A54 peptide-mediated functionalized gold nanocages for targeted delivery of DOX as a combinational photothermal-chemotherapy for liver cancer

    Directory of Open Access Journals (Sweden)

    Huang S

    2017-07-01

    Full Text Available Shengnan Huang,1,* Chunming Li,2,* Weiping Wang,1 Huanjie Li,1 Zhi Sun,3 Chengzhi Song,4 Benyi Li,5 Shaofeng Duan,6,7 Yurong Hu1,8,9 1Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, People’s Republic of China; 2Department of Pharmacy, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing, People’s Republic of China; 3Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 4School of Physical Sciences, University of Science and Technology of China, Hefei, People’s Republic of China; 5Department of Urology and Cancer Center, the University of Kansas Medical Center, Kansas City, KS, USA; 6College of Pharmacy, Henan University, Kaifeng, People’s Republic of China; 7Department of Orthopedics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 8Key Laboratory of Key Technology of Drug Preparation, Ministry of Education, Institute of Drug Discovery & Development, Zhengzhou University, Zhengzhou, People’s Republic of China; 9Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, People’s Republic of China *These authors contributed equally to this work Abstract: The combination of photothermal therapy and chemotherapy (photothermal–­chemotherapy is a promising strategy for cancer therapy. Gold nanocages (AuNCs, with hollow and porous structures and unique optical properties, have become a rising star in the field of drug delivery. Here, we designed a novel targeted drug delivery system based on functionalized AuNCs and evaluated their therapeutic effects in vitro and in vivo. We then loaded doxorubicin into this promising system, designated as DHTPAuNCs consisting of hyaluronic acid-grafted and A54 peptide-targeted PEGylated AuNCs. Its formation was corroborated by ultraviolet

  14. Distribution of myofibroblast cells and microvessels around invasive ductal carcinoma of the breast and comparing with the adjacent range of their normal-to-DCIS zones.

    Science.gov (United States)

    Dabiri, Shahriar; Talebi, Amin; Shahryari, Jahanbanoo; Meymandi, Manzoumeh Shamsi; Safizadeh, Hossein

    2013-02-01

    This study seeks to determine the relationships between manifestation of myofibroblasts in the stroma tissue of hyperplastic pre-invasive breast lesions to invasive cancer by investigating clinicopathological data of patients, their effect on steroid receptor expression and HER2, and angiogenesis according to CD34 antigen expression. 100 cases of invasive ductal carcinoma were immunohistochemically investigated for the presence of smooth muscle actin (SMA), ER/PR, HER2, anti-CD34 antibody and microvessel count (MVC). Patients were scored in four different zones of invasive areas: invasive cancer, DCIS, fibrocystic disease ± ductal intraepithelial neoplasia (FCD ± DIN), and normal tissue.  There was a significant difference in stromal myofibroblasts between all areas except for the stroma of DCIS and FCD ± DIN (P normal areas (P = 0.054). There was a significant difference in MVC observed in all areas except for DCIS and FCD ± DIN (P < 0.001). We noted significant inverse correlations between MVC, HER2 expression, and the numbers of involved lymph nodes in invasive cancer and DCIS (P < 0.001). Most MVC were present in grade I, with the least frequent observed in grade III cases in the stroma of invasive cancer, DCIS and FCD ± DIN (P < 0.001).  Angiogenesis can be observed before any significant myofibroblastic changes in the pre-invasive breast lesions. The elevated content of myofibroblasts in stroma of tumor; probably may be a worse prognostic factor  and the steps from atypical epithelial hyperplasia to DCIS and then to the invasive carcinoma do not appear to be always part of a linear progression.

  15. Methylation of Septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Yuting, E-mail: wuyuting1302@sina.com; Bu, Fangtian; Yu, Haixia; Li, Wanxia; Huang, Cheng; Meng, Xiaoming; Zhang, Lei; Ma, Taotao; Li, Jun, E-mail: lj@ahmu.edu.cn

    2017-01-15

    Liver fibrosis, resulting from chronic and persistent injury to the liver, is a worldwide health problem. Advanced liver fibrosis results in cirrhosis, liver failure and even hepatocellular cancer (HCC), often eventually requiring liver transplantation, poses a huge health burden on the global community. However, the specific pathogenesis of liver fibrosis remains not fully understood. Numerous basic and clinical studies have provided evidence that epigenetic modifications, especially DNA methylation, might contribute to the activation of hepatic stellate cells (HSCs), the pivotal cell type responsible for the fibrous scar in liver. Here, reduced representation bisulfite sequencing (RRBS) and bisulfite pyrosequencing PCR (BSP) analysis identified hypermethylation status of Septin9 (Sept9) gene in liver fibrogenesis. Sept9 protein was dramatically decreased in livers of CCl4-treated mice and immortalized HSC-T6 cells exposed to TGF-β1. Nevertheless, the suppression of Sept9 could be blocked by DNMT3a-siRNA and DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (5-azadC). Overexpressed Sept9 attenuated TGF-β1-induced expression of myofibroblast markers α-SMA and Col1a1, accompanied by up-regulation of cell apoptosis-related proteins. Conversely, RNAi-mediated silencing of Sept9 enhanced accumulation of extracellular matrix. These observations suggested that Sept9 contributed to alleviate liver fibrosis might partially through promoting activated HSCs apoptosis and this anti-fibrogenesis effect might be blocked by DNMT-3a mediated methylation of Sept9. Therefore, pharmacological agents that inhibit Sept9 methylation and increase its expression could be considered as valuable treatments for liver fibrosis. - Highlights: • This is the first report of Sept9 methylation and function in liver fibrosis. • Ectopic expression of Sept9 could block the liver fibrogenesis. • DNMT3a might be responsible for the suppression of Sept9 in liver fibrosis.

  16. Methylation of Septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis

    International Nuclear Information System (INIS)

    Wu, Yuting; Bu, Fangtian; Yu, Haixia; Li, Wanxia; Huang, Cheng; Meng, Xiaoming; Zhang, Lei; Ma, Taotao; Li, Jun

    2017-01-01

    Liver fibrosis, resulting from chronic and persistent injury to the liver, is a worldwide health problem. Advanced liver fibrosis results in cirrhosis, liver failure and even hepatocellular cancer (HCC), often eventually requiring liver transplantation, poses a huge health burden on the global community. However, the specific pathogenesis of liver fibrosis remains not fully understood. Numerous basic and clinical studies have provided evidence that epigenetic modifications, especially DNA methylation, might contribute to the activation of hepatic stellate cells (HSCs), the pivotal cell type responsible for the fibrous scar in liver. Here, reduced representation bisulfite sequencing (RRBS) and bisulfite pyrosequencing PCR (BSP) analysis identified hypermethylation status of Septin9 (Sept9) gene in liver fibrogenesis. Sept9 protein was dramatically decreased in livers of CCl4-treated mice and immortalized HSC-T6 cells exposed to TGF-β1. Nevertheless, the suppression of Sept9 could be blocked by DNMT3a-siRNA and DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (5-azadC). Overexpressed Sept9 attenuated TGF-β1-induced expression of myofibroblast markers α-SMA and Col1a1, accompanied by up-regulation of cell apoptosis-related proteins. Conversely, RNAi-mediated silencing of Sept9 enhanced accumulation of extracellular matrix. These observations suggested that Sept9 contributed to alleviate liver fibrosis might partially through promoting activated HSCs apoptosis and this anti-fibrogenesis effect might be blocked by DNMT-3a mediated methylation of Sept9. Therefore, pharmacological agents that inhibit Sept9 methylation and increase its expression could be considered as valuable treatments for liver fibrosis. - Highlights: • This is the first report of Sept9 methylation and function in liver fibrosis. • Ectopic expression of Sept9 could block the liver fibrogenesis. • DNMT3a might be responsible for the suppression of Sept9 in liver fibrosis.

  17. Genetically engineered excitable cardiac myofibroblasts coupled to cardiomyocytes rescue normal propagation and reduce arrhythmia complexity in heterocellular monolayers.

    Directory of Open Access Journals (Sweden)

    Luqia Hou

    Full Text Available The use of genetic engineering of unexcitable cells to enable expression of gap junctions and inward rectifier potassium channels has suggested that cell therapies aimed at establishing electrical coupling of unexcitable donor cells to host cardiomyocytes may be arrhythmogenic. Whether similar considerations apply when the donor cells are electrically excitable has not been investigated. Here we tested the hypothesis that adenoviral transfer of genes coding Kir2.1 (I(K1, Na(V1.5 (I(Na and connexin-43 (Cx43 proteins into neonatal rat ventricular myofibroblasts (NRVF will convert them into fully excitable cells, rescue rapid conduction velocity (CV and reduce the incidence of complex reentry arrhythmias in an in vitro model.We used adenoviral (Ad- constructs encoding Kir2.1, Na(V1.5 and Cx43 in NRVF. In single NRVF, Ad-Kir2.1 or Ad-Na(V1.5 infection enabled us to regulate the densities of I(K1 and I(Na, respectively. At varying MOI ratios of 10/10, 5/10 and 5/20, NRVF co-infected with Ad-Kir2.1+ Na(V1.5 were hyperpolarized and generated action potentials (APs with upstroke velocities >100 V/s. However, when forming monolayers only the addition of Ad-Cx43 made the excitable NRVF capable of conducting electrical impulses (CV = 20.71±0.79 cm/s. When genetically engineered excitable NRVF overexpressing Kir2.1, Na(V1.5 and Cx43 were used to replace normal NRVF in heterocellular monolayers that included neonatal rat ventricular myocytes (NRVM, CV was significantly increased (27.59±0.76 cm/s vs. 21.18±0.65 cm/s, p<0.05, reaching values similar to those of pure myocytes monolayers (27.27±0.72 cm/s. Moreover, during reentry, propagation was faster and more organized, with a significantly lower number of wavebreaks in heterocellular monolayers formed by excitable compared with unexcitable NRVF.Viral transfer of genes coding Kir2.1, Na(V1.5 and Cx43 to cardiac myofibroblasts endows them with the ability to generate and propagate APs. The results

  18. Inflammatory myofibroblastic tumor of the pancreatic head – a case report of a 6 months old child and review of the literature

    International Nuclear Information System (INIS)

    Tomazic, Ales; Gvardijancic, Diana; Maucec, Joze; Homan, Matjaz

    2015-01-01

    Inflammatory myofibroblastic tumors are rare in the pediatric population. Most common localizations were reported in the lungs. A localization in the pancreas needs differentiation from other tumors and chronic pancreatitis. Treatment is surgical resection, although there are reports of treatment with oral steroids and radiation therapy. A 6-month-old child was treated due to a tumor in the head of the pancreas. On admission he was jaundiced with pruritus. US and MRI confirmed pancreatic tumor. Preoperative biopsy wasn’t conclusive regarding the nature of the tumor. Duodenopancreatectomy was performed. Postoperative course was uneventful. Histologic examination confirmed the diagnosis of inflammatory myofibroblastic tumor. On follow up, he remained with no evidence of recurrence. A literature review revealed 10 cases of pancreatic inflammatory myofibroblastic tumors in the pediatric age group. Our patient is the youngest reported. Despite major resection, there were no complications. However, management of this child might be possible with steroids, but conservative treatment might be insufficient, especially in aggressive forms of tumors

  19. A histological study on the effect of pressure therapy on the activities of myofibroblasts and keratinocytes in hypertrophic scar tissues after burn.

    Science.gov (United States)

    Li-Tsang, Cecilia W P; Feng, Beibei; Huang, Lin; Liu, Xusheng; Shu, Bin; Chan, Yvonne T Y; Cheung, Kwok-Kuen

    2015-08-01

    Although pressure therapy (PT) has been widely used as the first-line treatment for hypertrophic scars (HS), the histopathological changes involved have seldom been studied. This study aimed to examine the longitudinal effect of PT on the histopathological changes in HS. Ten scar samples were selected from six patients with HS after burn and they were given a standardized PT intervention for 3 months while 16 scar samples were obtained on those without PT. The scar biopsies were collected pre-treatment, 1 and 3 months post-intervention for both clinical and histopathological examinations. Clinical assessments demonstrated significant improvement in the thickness and redness of the scars after PT. Histological examination revealed that cell density in the dermal layer was markedly reduced in the 3-months post-pressurized scar tissues, while the arrangement of the collagen fiber was changed from nodular to wave-like pattern. The α-smooth muscle actin immunoreactivity was significantly decreased after 1-month pressure treatment. There was a significant reduction of myofibroblasts population and a concomitant increase in the apoptotic index in the dermal layer in the 3-months' post-pressurized scars. A significant negative correlation was found between the myofibroblasts population and the apoptotic index. The keratinocyte proliferation was found inhibited after PT. Results demonstrated that PT appeared to promote HS maturation by inhibiting the keratinocyte proliferation and suppressing myofibroblasts population, the latter possibly via apoptosis. Copyright © 2014 Elsevier Ltd and ISBI. All rights reserved.

  20. Lung fibrosis-associated soluble mediators and bronchoalveolar lavage from idiopathic pulmonary fibrosis patients promote the expression of fibrogenic factors in subepithelial lung myofibroblasts.

    Science.gov (United States)

    Bouros, Evangelos; Filidou, Eirini; Arvanitidis, Konstantinos; Mikroulis, Dimitrios; Steiropoulos, Paschalis; Bamias, George; Bouros, Demosthenes; Kolios, George

    2017-10-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by infiltration of inflammatory cells, excessive collagen production and accumulation of myofibroblasts. We explored the possible role of subepithelial lung myofibroblasts (SELMs) in the development of fibrosis in IPF. SELMs, isolated from surgical specimens of healthy lung tissue, were cultured with pro-inflammatory factors or bronchoalveolar lavage fluid (BALF) from patients with IPF or idiopathic non-specific interstitial pneumonia (iNSIP) and their fibrotic activity was assessed. Stimulation of SELMs with pro-inflammatory factors induced a significant increase of Tissue Factor (TF) and Tumor necrosis factor-Like cytokine 1 A (TL1A) expression and collagen production in culture supernatants. Stimulation with BALF from IPF patients with mild to moderate, but not severe disease, and from iNSIP patients induced a significant increase of TF expression. BALF from all IPF patients induced a significant increase of TL1A expression and collagen production, while BALF from iNSIP patients induced a significant increase of TL1A, but not of collagen production. Interestingly, TGF-β1 and BALF from all IPF, but not iNSIP patients, induced a significant increase in SELMs migration. In conclusion, BALF from IPF patients induces fibrotic activity in lung myofibroblasts, similar to mediators associated with lung fibrosis, indicating a key role of SELMs in IPF. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Liver Development, Regeneration, and Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Janet W. C. Kung

    2010-01-01

    Full Text Available The identification of putative liver stem cells has brought closer the previously separate fields of liver development, regeneration, and carcinogenesis. Significant overlaps in the regulation of these processes are now being described. For example, studies in embryonic liver development have already provided the basis for directed differentiation of human embryonic stem cells and induced pluripotent stem cells into hepatocyte-like cells. As a result, the understanding of the cell biology of proliferation and differentiation in the liver has been improved. This knowledge can be used to improve the function of hepatocyte-like cells for drug testing, bioartificial livers, and transplantation. In parallel, the mechanisms regulating cancer cell biology are now clearer, providing fertile soil for novel therapeutic approaches. Recognition of the relationships between development, regeneration, and carcinogenesis, and the increasing evidence for the role of stem cells in all of these areas, has sparked fresh enthusiasm in understanding the underlying molecular mechanisms and has led to new targeted therapies for liver cirrhosis and primary liver cancers.

  2. Aetiology and pathogenesis of alcoholic liver disease.

    Science.gov (United States)

    Lieber, C S

    1993-09-01

    carcinogens and even nutritional factors such as vitamin A. Ethanol causes not only vitamin A depletion but it also enhances its hepatotoxicity. Furthermore, induction of the microsomal pathway contributes to increased acetaldehyde generation, with formation of protein adducts, resulting in antibody production, enzyme inactivation and decreased DNA repair; it is also associated with a striking impairment of the capacity of the liver to utilize oxygen. Moreover, acetaldehyde promotes glutathione depletion, free-radical mediated toxicity and lipid peroxidation. In addition, acetaldehyde affects hepatic collagen synthesis: both in vivo and in vitro (in cultured myofibroblasts and lipocytes), ethanol and its metabolite acetaldehyde were found to increase collagen accumulation and mRNA levels for collagen. This new understanding of the pathogenesis of alcoholic liver disease may eventually improve therapy with drugs and nutrients.

  3. Interleukin-1β attenuates myofibroblast formation and extracellular matrix production in dermal and lung fibroblasts exposed to transforming growth factor-β1.

    Directory of Open Access Journals (Sweden)

    Masum M Mia

    Full Text Available One of the most potent pro-fibrotic cytokines is transforming growth factor (TGFβ. TGFβ is involved in the activation of fibroblasts into myofibroblasts, resulting in the hallmark of fibrosis: the pathological accumulation of collagen. Interleukin-1β (IL1β can influence the severity of fibrosis, however much less is known about the direct effects on fibroblasts. Using lung and dermal fibroblasts, we have investigated the effects of IL1β, TGFβ1, and IL1β in combination with TGFβ1 on myofibroblast formation, collagen synthesis and collagen modification (including prolyl hydroxylase, lysyl hydroxylase and lysyl oxidase, and matrix metalloproteinases (MMPs. We found that IL1β alone has no obvious pro-fibrotic effect on fibroblasts. However, IL1β is able to inhibit the TGFβ1-induced myofibroblast formation as well as collagen synthesis. Glioma-associated oncogene homolog 1 (GLI1, the Hedgehog transcription factor that is involved in the transformation of fibroblasts into myofibroblasts is upregulated by TGFβ1. The addition of IL1β reduced the expression of GLI1 and thereby also indirectly inhibits myofibroblast formation. Other potentially anti-fibrotic effects of IL1β that were observed are the increased levels of MMP1, -2, -9 and -14 produced by fibroblasts exposed to TGFβ1/IL1β in comparison with fibroblasts exposed to TGFβ1 alone. In addition, IL1β decreased the TGFβ1-induced upregulation of lysyl oxidase, an enzyme involved in collagen cross-linking. Furthermore, we found that lung and dermal fibroblasts do not always behave identically towards IL1β. Suppression of COL1A1 by IL1β in the presence of TGFβ1 is more pronounced in lung fibroblasts compared to dermal fibroblasts, whereas a higher upregulation of MMP1 is seen in dermal fibroblasts. The role of IL1β in fibrosis should be reconsidered, and the differences in phenotypical properties of fibroblasts derived from different organs should be taken into account in future

  4. Bone Marrow-derived Myofibroblasts Are the Providers of Pro-invasive Matrix Metalloproteinase 13 in Primary Tumor

    Directory of Open Access Journals (Sweden)

    Julie Lecomte

    2012-10-01

    Full Text Available Carcinoma-associated fibroblasts are key contributors of the tumor microenvironment that regulates carcinoma progression. They consist of a heterogeneous cell population with diverse origins, phenotypes, and functions. In the present report, we have explored the contribution of bone marrow (BM-derived cells to generate different fibroblast subsets that putatively produce the matrix metalloproteinase 13 (MMP13 and affect cancer cell invasion. A murine model of skin carcinoma was applied to mice, irradiated, and engrafted with BM isolated from green fluorescent protein (GFP transgenic mice. We provide evidence that one third of BM-derived GFP+ cells infiltrating the tumor expressed the chondroitin sulfate proteoglycan NG2 (pericytic marker or α-smooth muscle actin (α-SMA, myofibroblast marker, whereas almost 90% of Thy1+ fibroblasts were originating from resident GFP-negative cells. MMP13producing cells were exclusively α-SMA+ cells and derived from GFP+ BM cells. To investigate their impact on tumor invasion, we isolated mesenchymal stem cells (MSCs from the BM of wild-type and MMP13-deficient mice. Wild-type MSC promoted cancer cell invasion in a spheroid assay, whereas MSCs obtained from MMP13-deficient mice failed to. Our data support the concept of fibroblast subset specialization with BM-derived α-SMA+ cells being the main source of MMP13, a stromal mediator of cancer cell invasion.

  5. Stromal laminin chain distribution in normal, hyperplastic and malignant oral mucosa: relation to myofibroblast occurrence and vessel formation.

    Science.gov (United States)

    Franz, Marcus; Wolheim, Anke; Richter, Petra; Umbreit, Claudia; Dahse, Regine; Driemel, Oliver; Hyckel, Peter; Virtanen, Ismo; Kosmehl, Hartwig; Berndt, Alexander

    2010-04-01

    The contribution of stromal laminin chain expression to malignant potential, tumour stroma reorganization and vessel formation in oral squamous cell carcinoma (OSCC) is not fully understood. Therefore, the expression of the laminin chains alpha2, alpha3, alpha4, alpha5 and gamma2 in the stromal compartment/vascular structures in OSCC was analysed. Frozen tissue of OSCC (9x G1, 24x G2, 8x G3) and normal (2x)/hyperplastic (11x) oral mucosa was subjected to laminin chain and alpha-smooth muscle actin (ASMA) immunohistochemistry. Results were correlated to tumour grade. The relation of laminin chain positive vessels to total vessel number was assessed by immunofluorescence double labelling with CD31. Stromal laminin alpha2 chain significantly decreases and alpha3, alpha4, alpha5 and gamma2 chains and also ASMA significantly increase with rising grade. The amount of stromal alpha3, alpha4 and gamma2 chains significantly increased with rising ASMA positivity. There is a significant decrease in alpha3 chain positive vessels with neoplastic transformation. Mediated by myofibroblasts, OSCC development is associated with a stromal up-regulation of laminin isoforms possibly contributing to a migration promoting microenvironment. A vascular basement membrane reorganization concerning alpha3 and gamma2 chain laminins during tumour angioneogenesis is suggested.

  6. Quantification of Liver Fat with Magnetic Resonance Imaging

    Science.gov (United States)

    Reeder, Scott B.; Sirlin, Claude

    2010-01-01

    Intracellular fat accumulation is common feature of liver disease. Intracellular fat (steatosis) is the histological hallmark of non-alcoholic fatty liver disease (NAFLD) but also may occur with alcohol abuse, viral hepatitis, HIV and genetic lipodystrophies, and chemotherapy. This article reviews emerging magnetic resonance imaging techniques that attempt to quantify liver fat. The content provides an overview of fatty liver disease and diseases where fat is an important disease feature. Also discussed is the current use and limitation of non-targeted biopsy in diffuse liver disease, and why quantitative non-invasive biomarkers of liver fat would be beneficial. PMID:21094444

  7. Liver transplant for cholestatic liver diseases.

    Science.gov (United States)

    Carrion, Andres F; Bhamidimarri, Kalyan Ram

    2013-05-01

    Cholestatic liver diseases include a group of diverse disorders with different epidemiology, pathophysiology, clinical course, and prognosis. Despite significant advances in the clinical care of patients with cholestatic liver diseases, liver transplant (LT) remains the only definitive therapy for end-stage liver disease, regardless of the underlying cause. As per the United Network for Organ Sharing database, the rate of cadaveric LT for cholestatic liver disease was 18% in 1991, 10% in 2000, and 7.8% in 2008. This review summarizes the available evidence on various common and rare cholestatic liver diseases, disease-specific issues, and pertinent aspects of LT. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Development of Liver-Targeting Insulin

    Science.gov (United States)

    2017-08-01

    2017, we will file a patent application through the technology commercialization office at U of Utah. We will discuss with pharmaceutical companies for...other Internet sites. o NA • Technologies or techniques. o NA • Inventions, patent applications, and/or licenses. o A patent application will be filed by...supports the text. Examples include original copies of journal articles, reprints of manuscripts and abstracts, a curriculum vitae, patent applications

  9. Fatty Liver Disease

    Science.gov (United States)

    What is fatty liver disease? Your liver is the largest organ inside your body. It helps your body digest food, store energy, and remove poisons. Fatty liver disease is a condition in which fat builds ...

  10. Pyogenic liver abscess

    Science.gov (United States)

    Liver abscess; Bacterial liver abscess ... There are many possible causes of liver abscesses, including: Abdominal infection, such as appendicitis , diverticulitis , or a perforated bowel Infection in the blood Infection of the bile draining tubes ...

  11. SYNERGISTIC EFFECTS of CYCLIC TENSION and TRANSFORMING GROWTH FACTOR-β1 on the AORTIC VALVE MYOFIBROBLAST

    Science.gov (United States)

    Merryman, W. David; Lukoff, Howard D.; Long, Rebecca A.; Engelmayr, George C.; Hopkins, Richard A.; Sacks, Michael S.

    2007-01-01

    Background Phenotypically, the aortic valve interstitial cell (AVIC) is a dynamic myofibroblast, appearing contractile and activated in times of development, disease, and remodeling. The precise mechanism of phenotypic modulation is unclear, but it is speculated that both biomechanical and biochemical factors are influential. Therefore, we hypothesized that isolated and combined treatments of cyclic tension and TGF-β1 would alter the phenotype and subsequent collagen biosynthesis of AVICs in situ. Methods and Results Porcine aortic valve leaflets received 7 and 14 day treatments of 15% cyclic stretch (Tension), 0.5 ng/ml TGF-β1 (TGF), 15% cyclic stretch and 0.5 ng/ml TGF-β1 (Tension+TGF), or neither mechanical nor cytokine stimuli (Null). Tissues were homogenized and assayed for AVIC phenotype (smooth muscle α-actin (SMA)) and collagen biosynthesis (via heat shock protein 47 (Hsp47) which was further verified with type I collagen C-terminal propeptide (CICP)). At both 7 and 14 days, SMA, Hsp47, and CICP quantities were significantly greater (p<0.001) in the Tension+TGF group compared to all other groups. Additionally, Tension alone appeared to maintain SMA and Hsp47 levels that were measured at day 0, while TGF alone elicited an increase in SMA and Hsp47 compared to day 0 levels. Null treatment revealed diminished proteins at both time points. Conclusions Elevated TGF-β1 levels, in the presence of cyclic mechanical tension, resulted in synergistic increases in the contractile and biosynthetic proteins in AVICs. Since cyclic mechanical stimuli can never be relieved in vivo, the presence of TGF-β1 (possibly from infiltrating macrophages) may result in overly biosynthetic AVICs, leading to altered ECM architecture, compromised valve function, and ultimately degenerative valvular disease. PMID:17868877

  12. FDG-PET/CT at the end of immuno-chemotherapy in follicular lymphoma: the prognostic role of the ratio between target lesion and liver SUVmax (rPET).

    Science.gov (United States)

    Annunziata, Salvatore; Cuccaro, Annarosa; Tisi, Maria Chiara; Hohaus, Stefan; Rufini, Vittoria

    2018-06-01

    To retrospectively investigate the prognostic role of the ratio between target lesion and liver SUV max (rPET) in patients with follicular lymphoma (FL) submitted to FDG-PET/CT at the end of immuno-chemotherapy (PI-PET), and to compare rPET with International Harmonization Project criteria (IHP), Deauville Score (5p-DS) and FL International Prognostic Index at diagnosis (FLIPI). Eighty-nine patients with FL undergoing PI-PET were evaluated. The receiver operating characteristic (ROC) approach was applied to identify the optimal cut-point of rPET with respect to 5-years progression free survival (PFS). The prognostic significance of rPET was compared with IHP, DS and FLIPI. Positive predictive value (PPV) and negative predictive value (NPV) were calculated using the presence of adverse events as gold standard. The ROC analysis for rPET as predictor of progression showed an optimal rPET cut-point of 0.98. Patients with positive values of IHP, DS and rPET had a PFS of 50, 30 and 31%. PPV were of 56, 80 and 80%, NPV of 83, 86 and 88%, respectively. DS and rPET differed only in two patients. FLIPI was not predictive of progression and relapse. rPET is a prognostic factor in patients with FL submitted to PI-PET. Although it has a similar prognostic power as DS, it can have methodological advantages over visual analysis. PI-PET with different evaluation systems has a stronger prognostic power than FLIPI at diagnosis, so it could be useful to identify patients with FL at risk for early relapse after immuno-chemotherapy.

  13. Amebic liver abscess

    Science.gov (United States)

    Hepatic amebiasis; Extraintestinal amebiasis; Abscess - amebic liver ... Amebic liver abscess is caused by Entamoeba histolytica. This parasite causes amebiasis , an intestinal infection that is also called ...

  14. Hypoxia induces a phenotypic switch of fibroblasts to myofibroblasts through a MMP-2/TIMP mediated pathway: Implications for venous neointimal hyperplasia in hemodialysis access

    Science.gov (United States)

    Misra, Sanjay; Fu, Alex A.; Misra, Khamal D.; Shergill, Uday M.; Leof, Edward B; Mukhopadhyay, Debabrata

    2010-01-01

    Purpose Hemodialysis grafts fail because of venous neointimal hyperplasia formation caused by adventitial fibroblasts which have become myofibroblasts (α-smooth muscle actin positive cells) and migrate to the neointima. There is increased expression of hypoxia inducible factor-1 alpha (HIF-1α in venous neointimal hyperplasia formation in experimental animal model and clinical samples. We hypothesized that under hypoxic stimulus (HIF-1α fibroblasts will convert to myofibroblasts through a matrix metalloproteinase-2 (MMP-2) mediated pathway. Materials and methods Murine AKR-2B fibroblasts were made hypoxic or normoxic for 24, 48, and 72 hours. Protein expression for HIF-1α, α-smooth muscle actin, MMP-2, MMP-9, TIMP-1, and TIMP-2 was performed to determine the kinetic changes of these proteins. Immunostaining for α-smooth muscle actin, collagen, and fibronectin was performed. Results At all time points, there was significantly increased expression of HIF-1α in the hypoxic fibroblasts when compared to normoxic fibroblasts (P<0.05). There was significantly increased expression α-smooth muscle actin at all time points which peaked by 48 hours in hypoxic fibroblasts when compared to normoxic fibroblasts (P<0.05). There was a significant increase in the expression of active MMP-2 by 48-72 hours and a significant increase in tissue inhibitor of metalloproteinase-1 (TIMP-1) by 48-72 hours by hypoxic fibroblasts (P<0.05). By 72 hours, there was significant increase in TIMP-2 expression (P<0.05). Immunohistochemical analysis demonstrated increased expression for α-smooth muscle actin, collagen, and fibronectin as the length of hypoxia increased. Conclusions Under hypoxia, fibroblasts will convert to myofibroblasts through a MMP-2 mediated pathway which may provide insight into the mechanism of venous neointimal hyperplasia. PMID:20434368

  15. Enhancement of liver regeneration and liver surgery

    NARCIS (Netherlands)

    Olthof, P.B.

    2017-01-01

    Liver regeneration allows surgical resection of up to 75% of the liver and enables curative treatment potential for patients with primary or secondary hepatic malignancies. Liver surgery is associated with substantial risks, reflected by considerable morbidity and mortality rates. Optimization of

  16. Liver Transplantation in the Mouse: Insights Into Liver Immunobiology, Tissue Injury and Allograft Tolerance

    Science.gov (United States)

    Yokota, Shinichiro; Yoshida, Osamu; Ono, Yoshihiro; Geller, David A.; Thomson, Angus W.

    2016-01-01

    The surgically-demanding mouse orthotopic liver transplant model was first described in 1991. It has proved a powerful research tool for investigation of liver biology, tissue injury, the regulation of alloimmunity and tolerance induction and the pathogenesis of specific liver diseases. Liver transplantation in mice has unique advantages over transplantation of the liver in larger species, such as the rat or pig, since the mouse genome is well-characterized and there is much greater availability of both genetically-modified animals and research reagents. Liver transplant experiments using various transgenic or gene knockout mice has provided valuable mechanistic insights into the immuno- and pathobiology of the liver and the regulation of graft rejection and tolerance over the past 25 years. The molecular pathways identified in regulation of tissue injury and promotion of liver transplant tolerance provide new potential targets for therapeutic intervention to control adverse inflammatory responses/ immune-mediated events in the hepatic environment and systemically. Conclusion: Orthotopic liver transplantation in the mouse is a valuable model for gaining improved insights into liver biology, immunopathology and allograft tolerance that may result in therapeutic innovation in liver and other diseases. PMID:26709949

  17. CT manifestations of liver abscess

    International Nuclear Information System (INIS)

    Yan Jianfeng; Peng Yongjun

    2006-01-01

    Objective: To study CT findings of hepatic abscess. Methods: CT findings and clinical materials of 38 patients with liver abscess verified by aspiration were retrospectively viewed. All patients were examined by non-enhanced and contrast enhanced CT. Results: In 25 cases, inhomogeneous hypodense lesions with unclear demarcation were found on non-enhanced CT. On contrast enhanced CT scan, target or cluster enhancement was found Additionally, air was found within some lesions. In the rest 13 cases with early stage liver abscess, no typical sign was found on non-enhanced CT, while rosette sign and continued enhancement sign were demonstrated after the contrast agent was given. Conclusion: Various CT findings are found in different stages of liver abscess. The diagnosis and differential diagnosis should be based on CT manifestations and clinical history as well. (authors)

  18. Therapeutic effects of the traditional medicinal plant Ipomoea stolonifera for the treatment of liver diseases

    NARCIS (Netherlands)

    Bai, Xueting

    2016-01-01

    Liver diseases are categorized into acute liver failure (ALF) and chronic liver failure (CLF). Massive cell death is a hallmark of ALF and leads to a dramatic loss of liver function. Therefore, specific interventions targeted to prevent or attenuate this massive cell death may be very effective in

  19. Flavanones from Sedum sarmentosum Bunge Alleviate CCl4-Induced Liver Fibrosis in Rats by Targeting TGF-β1/TβR/Smad Pathway In Turn Inhibiting Epithelial Mesenchymal Transition

    Directory of Open Access Journals (Sweden)

    Yuancan Lin

    2018-01-01

    Full Text Available Objective. The aim of the study is to evaluate the therapeutic effects of flavanones from Sedum sarmentosum Bunge (FSSB on CCl4-induced liver fibrosis in rats and the underlying mechanisms of action. Methods. An experimental model of liver fibrosis was established by subcutaneous injection of rats with CCl4 (40% v/v, 3 ml/kg twice per week for six weeks. FSSB (100, 200, and 400 mg/kg was intragastrically administered once per day consecutively for five weeks. Results. Our results showed that FSSB significantly attenuated CCl4-induced liver fibrosis as evidenced by reducing the elevated levels of serum biochemical indexes and improving the histological changes, including decreasing the elevation in serum alanine transaminase (ALT, aspartate transaminase (AST, hyaluronic acid (HA, and laminin (LN level, reducing infiltration of inflammatory cells and collagen fibers in liver tissue. In addition, compared to the model group, FSSB markedly downregulated the protein and mRNA expression of TGF-β1, TGF-β1 receptors I and II (TβRI and TβRII, Smad2, Smad3, and Vimentin in liver tissue, at the mean time upregulating the expression of Smad7 and E-cadherin. Conclusions. The results suggest that FSSB alleviated CCl4-induced liver fibrosis probably through inhibition of TGF-β/TβR/Smad pathway in turn inhibiting epithelial mesenchymal transition.

  20. Role of liver progenitors in liver regeneration.

    Science.gov (United States)

    Best, Jan; Manka, Paul; Syn, Wing-Kin; Dollé, Laurent; van Grunsven, Leo A; Canbay, Ali

    2015-02-01

    During massive liver injury and hepatocyte loss, the intrinsic regenerative capacity of the liver by replication of resident hepatocytes is overwhelmed. Treatment of this condition depends on the cause of liver injury, though in many cases liver transplantation (LT) remains the only curative option. LT for end stage chronic and acute liver diseases is hampered by shortage of donor organs and requires immunosuppression. Hepatocyte transplantation is limited by yet unresolved technical difficulties. Since currently no treatment is available to facilitate liver regeneration directly, therapies involving the use of resident liver stem or progenitor cells (LPCs) or non-liver stem cells are coming to fore. LPCs are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. Non-liver stem cells include embryonic stem cells (ES cells) and mesenchymal stem cells (MSCs). In the first section, we aim to provide an overview of the role of putative cytokines, growth factors, mitogens and hormones in regulating LPC response and briefly discuss the prognostic value of the LPC response in clinical practice. In the latter section, we will highlight the role of other (non-liver) stem cells in transplantation and discuss advantages and disadvantages of ES cells, induced pluripotent stem cells (iPS), as well as MSCs.

  1. Cod Liver Oil

    Science.gov (United States)

    Cod liver oil can be obtained from eating fresh cod liver or by taking supplements. Cod liver oil is used as a source of vitamin A ... called macular degeneration. Some people put cod liver oil on their skin to speed healing of wounds, ...

  2. Liver Cell Culture Devices

    NARCIS (Netherlands)

    Andria, B.; Bracco, A.; Cirino, G.; Chamuleau, R. A. F. M.

    2010-01-01

    In the last 15 years many different liver cell culture devices, consisting of functional liver cells and artificial materials, have been developed. They have been devised for numerous different applications, such as temporary organ replacement (a bridge to liver transplantation or native liver

  3. Aberrant Hedgehog ligands induce progressive pancreatic fibrosis by paracrine activation of myofibroblasts and ductular cells in transgenic zebrafish.

    Directory of Open Access Journals (Sweden)

    In Hye Jung

    Full Text Available Hedgehog (Hh signaling is frequently up-regulated in fibrogenic pancreatic diseases including chronic pancreatitis and pancreatic cancer. Although recent series suggest exclusive paracrine activation of stromal cells by Hh ligands from epithelial components, debates still exist on how Hh signaling works in pathologic conditions. To explore how Hh signaling affects the pancreas, we investigated transgenic phenotypes in zebrafish that over-express either Indian Hh or Sonic Hh along with green fluorescence protein (GFP to enable real-time observation, or GFP alone as control, at the ptf1a domain. Transgenic embryos and zebrafish were serially followed for transgenic phenotypes, and investigated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR, in situ hybridization, and immunohistochemistry. Over-expression of Ihh or Shh reveals virtually identical phenotypes. Hh induces morphologic changes in a developing pancreas without derangement in acinar differentiation. In older zebrafish, Hh induces progressive pancreatic fibrosis intermingled with proliferating ductular structures, which is accompanied by the destruction of the acinar structures. Both myofibroblasts and ductular are activated and proliferated by paracrine Hh signaling, showing restricted expression of Hh downstream components including Patched1 (Ptc1, Smoothened (Smo, and Gli1/2 in those Hh-responsive cells. Hh ligands induce matrix metalloproteinases (MMPs, especially MMP9 in all Hh-responsive cells, and transform growth factor-ß1 (TGFß1 only in ductular cells. Aberrant Hh over-expression, however, does not induce pancreatic tumors. On treatment with inhibitors, embryonic phenotypes are reversed by either cyclopamine or Hedgehog Primary Inhibitor-4 (HPI-4. Pancreatic fibrosis is only prevented by HPI-4. Our study provides strong evidence of Hh signaling which induces pancreatic fibrosis through paracrine activation of Hh-responsive cells in vivo. Induction of

  4. TNF-α-induced NF-κB activation promotes myofibroblast differentiation of LR-MSCs and exacerbates bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Hou, Jiwei; Ma, Tan; Cao, Honghui; Chen, Yabing; Wang, Cong; Chen, Xiang; Xiang, Zou; Han, Xiaodong

    2018-03-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible lung disease of unknown cause. It has been reported that both lung resident mesenchymal stem cells (LR-MSCs) and tumor necrosis factor-α (TNF-α) play important roles in the development of pulmonary fibrosis. However, the underlying connections between LR-MSCs and TNF-α in the pathogenesis of pulmonary fibrosis are still elusive. In this study, we found that the pro-inflammatory cytokine TNF-α and the transcription factor nuclear factor kappa B (NF-κB) p65 subunit were both upregulated in bleomycin-induced fibrotic lung tissue. In addition, we discovered that TNF-α promotes myofibroblast differentiation of LR-MSCs through activating NF-κB signaling. Interestingly, we also found that TNF-α promotes the expression of β-catenin. Moreover, we demonstrated that suppression of the NF-κB signaling could attenuate myofibroblast differentiation of LR-MSCs and bleomycin-induced pulmonary fibrosis which were accompanied with decreased expression of β-catenin. Our data implicates that inhibition of the NF-κB signaling pathway may provide a therapeutic strategy for pulmonary fibrosis, a disease that warrants more effective treatment approaches. © 2017 Wiley Periodicals, Inc.

  5. Immune mediated liver failure

    OpenAIRE

    Wang, Xiaojing; Ning, Qin

    2014-01-01

    Liver failure is a clinical syndrome of various etiologies, manifesting as jaundice, encephalopathy, coagulopathy and circulatory dysfunction, which result in subsequent multiorgan failure. Clinically, liver failure is classified into four categories: acute, subacute, acute-on-chronic and chronic liver failure. Massive hepatocyte death is considered to be the core event in the development of liver failure, which occurs when the extent of hepatocyte death is beyond the liver regenerative capac...

  6. Uridine prevents fenofibrate-induced fatty liver.

    Directory of Open Access Journals (Sweden)

    Thuc T Le

    Full Text Available Uridine, a pyrimidine nucleoside, can modulate liver lipid metabolism although its specific acting targets have not been identified. Using mice with fenofibrate-induced fatty liver as a model system, the effects of uridine on liver lipid metabolism are examined. At a daily dosage of 400 mg/kg, fenofibrate treatment causes reduction of liver NAD(+/NADH ratio, induces hyper-acetylation of peroxisomal bifunctional enzyme (ECHD and acyl-CoA oxidase 1 (ACOX1, and induces excessive accumulation of long chain fatty acids (LCFA and very long chain fatty acids (VLCFA. Uridine co-administration at a daily dosage of 400 mg/kg raises NAD(+/NADH ratio, inhibits fenofibrate-induced hyper-acetylation of ECHD, ACOX1, and reduces accumulation of LCFA and VLCFA. Our data indicates a therapeutic potential for uridine co-administration to prevent fenofibrate-induced fatty liver.

  7. Liver scanning in diffuse liver disease

    International Nuclear Information System (INIS)

    Aiginger, P.; Atefie, K.; Scherak, O.; Wolf, A.; Hoefer, R.; Seyfried, H.

    1975-01-01

    The results of liver scans performed with sup(99m)Tc-sulphur colloid in 169 patients suffering from diffuse liver diseases and in 48 normal controls were evaluated. The patients with reactive hepatitis, acute hepatitis, chronic persistent hepatitis, fatty liver and fibrosis of the liver show only minimal deviations from the scintigraphic pattern. On the contrary, highly increased colloid uptake in the spleen is found in cases of chronic aggressive hepatitis, whilst the intrahepatic distribution of the colloid is approximately normal. In cases of liver cirrhosis, increased colloid uptake is found in the left lobe of the liver as well as in the spleen and in the bone marrow. Either normal findings or cirrhosis-like changes of the colloid distribution are observed in patients with alcoholic hepatitis. (orig.) [de

  8. Intestinal inflammatory myofibroblastic tumour

    African Journals Online (AJOL)

    abdominal X-ray of patients 1, 3 and 4 demonstrated dilated small bowel loops with fluid levels in keeping with intestinal ... myxoid/vascular pattern characterised by a variable admixture of capillary-calibre blood vessels, .... in the present study had a past history of abdominal trauma or surgery. Ancillary histopathological ...

  9. Deficiency of NOX1 or NOX4 Prevents Liver Inflammation and Fibrosis in Mice through Inhibition of Hepatic Stellate Cell Activation.

    Directory of Open Access Journals (Sweden)

    Tian Lan

    Full Text Available Reactive oxygen species (ROS produced by nicotinamide adenine dinucleotide phosphate oxidase (NOX play a key role in liver injury and fibrosis. Previous studies demonstrated that GKT137831, a dual NOX1/4 inhibitor, attenuated liver fibrosis in mice as well as pro-fibrotic genes in hepatic stellate cells (HSCs as well as hepatocyte apoptosis. The effect of NOX1 and NOX4 deficiency in liver fibrosis is unclear, and has never been directly compared. HSCs are the primary myofibroblasts in the pathogenesis of liver fibrosis. Therefore, we aimed to determine the role of NOX1 and NOX4 in liver fibrosis, and investigated whether NOX1 and NOX4 signaling mediates liver fibrosis by regulating HSC activation. Mice were treated with carbon tetrachloride (CCl4 to induce liver fibrosis. Deficiency of either NOX1 or NOX4 attenuates liver injury, inflammation, and fibrosis after CCl4 compared to wild-type mice. NOX1 or NOX4 deficiency reduced lipid peroxidation and ROS production in mice with liver fibrosis. NOX1 and NOX4 deficiency are approximately equally effective in preventing liver injury in the mice. The NOX1/4 dual inhibitor GKT137831 suppressed ROS production as well as inflammatory and proliferative genes induced by lipopolysaccharide (LPS, platelet-derived growth factor (PDGF, or sonic hedgehog (Shh in primary mouse HSCs. Furthermore, the mRNAs of proliferative and pro-fibrotic genes were downregulated in NOX1 and NOX4 knock-out activated HSCs (cultured on plastic for 5 days. Finally, NOX1 and NOX4 protein levels were increased in human livers with cirrhosis compared with normal controls. Thus, NOX1 and NOX4 signaling mediates the pathogenesis of liver fibrosis, including the direct activation of HSC.

  10. Multi-institutional Quantitative Evaluation and Clinical Validation of Smart Probabilistic Image Contouring Engine (SPICE) Autosegmentation of Target Structures and Normal Tissues on Computer Tomography Images in the Head and Neck, Thorax, Liver, and Male Pelvis Areas

    NARCIS (Netherlands)

    Zhu, Mingyao; Bzdusek, Karl; Brink, Carsten; Eriksen, Jesper Grau; Hansen, Olfred; Jensen, Helle Anita; Gay, Hiram A.; Thorstad, Wade; Widder, Joachim; Brouwer, Charlotte L.; Steenbakkers, Roel J. H. M.; Vanhauten, Hubertus A. M.; Cao, Jeffrey Q.; McBrayne, Gail; Patel, Salil H.; Cannon, Donald M.; Hardcastle, Nicholas; Tome, Wolfgang A.; Guckenberg, Matthias; Parikh, Parag J.

    2013-01-01

    Purpose: Clinical validation and quantitative evaluation of computed tomography (CT) image autosegmentation using Smart Probabilistic Image Contouring Engine (SPICE). Methods and Materials: CT images of 125 treated patients (32 head and neck [HN], 40 thorax, 23 liver, and 30 prostate) in 7

  11. Liver disease in pregnancy

    Institute of Scientific and Technical Information of China (English)

    Noel M Lee; Carla W Brady

    2009-01-01

    Liver diseases in pregnancy may be categorized into liver disorders that occur only in the setting of pregnancy and liver diseases that occur coincidentally with pregnancy. Hyperemesis gravidarum, preeclampsia/eclampsia, syndrome of hemolysis, elevated liver tests and low platelets (HELLP), acute fatty liver of pregnancy, and intrahepatic cholestasis of pregnancy are pregnancy-specific disorders that may cause elevations in liver tests and hepatic dysfunction. Chronic liver diseases, including cholestatic liver disease, autoimmune hepatitis, Wilson disease, and viral hepatitis may also be seen in pregnancy. Management of liver disease in pregnancy requires collaboration between obstetricians and gastroenterologists/hepatologists. Treatment of pregnancy-specific liver disorders usually involves delivery of the fetus and supportive care, whereas management of chronic liver disease in pregnancy is directed toward optimizing control of the liver disorder. Cirrhosis in the setting of pregnancy is less commonly observed but offers unique challenges for patients and practitioners. This article reviews the epidemiology, pathophysiology, diagnosis, and management of liver diseases seen in pregnancy.

  12. Immunoexpression of intermediate filaments and morphological changes in the liver and bile duct of rats infected with Fasciola hepatica.

    Science.gov (United States)

    Kolodziejczyk, L; Laszczyńska, M; Masiuk, M; Grabowska, M; Skrzydlewska, E

    2015-01-01

    We investigated the immunoexpression of the intermediate filament proteins, cytokeratin and desmin, and the morphological changes in the liver of rats during experimental fasciolosis at 4, 7 and 10 weeks post-infection. Rats were infected with 30 Fasciola hepatica metacercariae. Paraffin sections of the liver were stained using H & E, PAS and azan stains. Immunohistochemical reactions were performed using antibodies against cytokeratin and desmin. The experimental F. hepatica infection led to fibrosis and cirrhosis of the liver, and to inflammation of the common bile ducts. The expression of cytokeratin was increased in the epithelial cells of both the liver bile ductules at 4, 7 and 10 weeks post-infection and in the common bile ducts at 7 and 10 weeks post-infection compared to uninfected rats; expression in the common bile ducts was more intense. The myofibroblasts of the liver and smooth myocytes of the interlobular bile ducts and common bile ducts, showed a slight increase in desmin expression compared to the uninfected rats. The increased expression of cytokeratins in the hyperplastic rat common bile duct epithelium during the biliary phase of fasciolosis at 7 and 10 weeks post-infection may be explained by mechanical irritation by the parasite and an inflammatory reaction in the bile duct epithelium and in periductal fibrous tissue.

  13. Treatment of colorectal liver metastases

    Directory of Open Access Journals (Sweden)

    Ismaili Nabil

    2011-11-01

    Full Text Available Abstract Colorectal cancer (CRC is the third most common cancer in the word. Liver metastasis is the most common site of colorectal metastases. The prognosis of resectable colorectal liver metastases (CRLM was improved in the recent years with the consideration of chemotherapy and surgical resection as part of the multidisciplinary management of the disease; the current 5-year survival rates after resection of liver metastases are 25% to 40%. Resectable synchronous or metachronous liver metastases should be treated with perioperative chemotherapy based on three months of FOLFOX4 (5-fluorouracil [5FU], folinic acid [LV], and oxaliplatin chemotherapy before surgery and three months after surgery. In the case of primary surgery, pseudo-adjuvant chemotherapy for 6 months, based on 5FU/LV, FOLFOX4, XELOX (capecitabine and oxaliplatin or FOLFIRI (5FU/LV and irinotecan, should be indicated. In potentially resectable disease, primary chemotherapy based on more intensive regimens such as FOLFIRINOX (5FU/LV, irinotecan and oxaliplatin should be considered to enhance the chance of cure. The palliative chemotherapy based on FOLFIRI, or FOLFOX4/XELOX with or without targeted therapies, is the mainstay treatment of unresectable disease. This review would provide additional insight into the problem of optimal integration of chemotherapy and surgery in the management of CRLM.

  14. Transplantation in autoimmune liver diseases

    Institute of Scientific and Technical Information of China (English)

    Marcus Mottershead; James Neuberger

    2008-01-01

    Liver transplantation remains an effective treatment for those with end-stage disease and with intractable liver-related symptoms.The shortage of organs for transplantation has resulted in the need for rationing.A variety of approaches to selection and allocation have been developed and vary from country to country.The shortage of donors has meant that new approaches have to be adopted to make maximal use of the available organs;these include splitting grafts,use of extended criteria livers,livers from nonheart-beating donors and from living donors.Post transplantation, most patients will need life-long immunosuppression,although a small proportion can have immunosuppression successfully withdrawn.Newer immunosuppressive drugs and different strategies may allow a more targeted approach with a reduction in sideeffects and so improve the patient and graft survival.For autoimmune diseases, transplantation is associated with significant improvement in the quality and length of life.Disease may recur after transplantation and may affect patient and graft survival.

  15. Liver Function Tests

    Science.gov (United States)

    ... Legacy Society Make Gifts of Stock Donate Your Car Personal Fundraising Partnership & Support Share Your Story Spread the Word Give While You Shop Contact Us Donate Now Diagnosing Liver Disease – Liver ...

  16. Diet - liver disease

    Science.gov (United States)

    Proteins normally help the body repair tissue. They also prevent fatty buildup and damage to the liver cells. In people with badly damaged livers, proteins are not properly processed. Waste products may build up and affect the brain. Dietary ...

  17. Liver Function Tests

    Science.gov (United States)

    ... digest food, store energy, and remove poisons. Liver function tests are blood tests that check to see ... as hepatitis and cirrhosis. You may have liver function tests as part of a regular checkup. Or ...

  18. Alcoholic Liver Disease

    Science.gov (United States)

    ... may be increased in women because their digestive system may be less able to process alcohol, thus increasing the amount of alcohol reaching the liver. Genetic makeup Genetic makeup is thought to be involved because alcoholic liver disease often ...

  19. Liver cancer - hepatocellular carcinoma

    Science.gov (United States)

    ... Autoimmune diseases of the liver Hepatitis B or hepatitis C virus infection Inflammation of the liver that is long-term (chronic) Iron overload in the body ( hemochromatosis ) People with hepatitis B or C are at high risk of ...

  20. Autoimmune liver disease panel

    Science.gov (United States)

    Liver disease test panel - autoimmune ... Autoimmune disorders are a possible cause of liver disease. The most common of these diseases are autoimmune hepatitis and primary biliary cholangitis (formerly called primary biliary cirrhosis). This group of tests ...

  1. Standardisation of liver MDCT by tracking liver parenchyma enhancement to trigger imaging

    International Nuclear Information System (INIS)

    Brodoefel, H.; Tognolini, A.; Zamboni, G.A.; Gourtsoyianni, S.; Raptopoulos, V.; Claussen, C.D.

    2012-01-01

    To assess parenchymal bolus-triggering in terms of liver enhancement, lesion-to-liver conspicuity and inter-image variability across serial follow-up MDCTs. We reviewed MDCTs of 50 patients with hepatic metastases who had a baseline CT and two follow-up examinations. In 25 consecutive patients CT data acquisition was initiated by liver parenchyma triggering at a 50-HU enhancement threshold. In a matched control group, imaging was performed with an empirical delay of 65 s. CT attenuation values were assessed in vessels, liver parenchyma and metastasis. Target lesions were classified according to five enhancement patterns. Compared with the control group, liver enhancement was significantly higher with parenchyma triggering (59.8 ± 7.6 HU vs. 48.8 ± 11.2 HU, P = 0.0002). The same was true for conspicuity (liver parenchyma - lesion attenuation) of hypo-enhancing lesions (72.2 ± 15.9 HU vs. 52.7 ± 19.4 HU, P = 0.0006). Liver triggering was associated with reduced variability for liver enhancement among different patients (P = 0.035) and across serial follow-up examinations in individual patients (P < 0.0001). The number of patients presenting with uniform lesion enhancement pattern across serial examinations was significantly higher in the triggered group (20 vs. 11; P = 0.018). Liver parenchyma triggering provides superior lesion conspicuity and improves standardisation of image quality across follow-up examinations with greater uniformity of enhancement patterns. (orig.)

  2. Liver transplantation in polycystic liver disease

    DEFF Research Database (Denmark)

    Krohn, Paul S; Hillingsø, Jens; Kirkegaard, Preben

    2008-01-01

    OBJECTIVE: Polycystic liver disease (PLD) is a rare, hereditary, benign disorder. Hepatic failure is uncommon and symptoms are caused by mass effects leading to abdominal distension and pain. Liver transplantation (LTX) offers fully curative treatment, but there is still some controversy about...... whether it is a relevant modality considering the absence of liver failure, relative organ shortage, perioperative risks and lifelong immunosuppression. The purpose of this study was to review our experience of LTX for PLD and to compare the survival with the overall survival of patients who underwent LTX...... from 1992 to 2005. MATERIAL AND METHODS: A retrospective study of the journals of 440 patients, who underwent 506 LTXs between 1992 and 2005, showed that 14 patients underwent LTX for PLD. All patients had normal liver function. Three were receiving haemodialysis and thus underwent combined liver...

  3. Immune mediated liver failure.

    Science.gov (United States)

    Wang, Xiaojing; Ning, Qin

    2014-01-01

    Liver failure is a clinical syndrome of various etiologies, manifesting as jaundice, encephalopathy, coagulopathy and circulatory dysfunction, which result in subsequent multiorgan failure. Clinically, liver failure is classified into four categories: acute, subacute, acute-on-chronic and chronic liver failure. Massive hepatocyte death is considered to be the core event in the development of liver failure, which occurs when the extent of hepatocyte death is beyond the liver regenerative capacity. Direct damage and immune-mediated liver injury are two major factors involved in this process. Increasing evidence has suggested the essential role of immune-mediated liver injury in the pathogenesis of liver failure. Here, we review the evolved concepts concerning the mechanisms of immune-mediated liver injury in liver failure from human and animal studies. Both innate and adaptive immunity, especially the interaction of various immune cells and molecules as well as death receptor signaling system are discussed. In addition, we highlight the concept of "immune coagulation", which has been shown to be related to the disease progression and liver injury exacerbation in HBV related acute-on-chronic liver failure.

  4. Liver Tumors (For Parents)

    Science.gov (United States)

    ... Staying Safe Videos for Educators Search English Español Liver Tumors KidsHealth / For Parents / Liver Tumors What's in this article? Types of Tumors ... Cancerous) Tumors Symptoms Diagnosis Treatment Coping Print The liver is the body's largest solid organ. Lying next ...

  5. Inflammatory myofibroblastic tumor of maxilla showing sarcomatous change in an edentulous site with a history of tooth extraction following periodontitis: A case report with discussion.

    Science.gov (United States)

    Biniraj, K R; Janardhanan, Mahija

    2014-05-01

    Inflammatory myofibroblastic tumor (IMT) is a rare tumor of uncertain origin with variable biological behavior ranging from reactive lesions to highly aggressive malignancy. Oral IMTs are extremely rare and only 25 cases had been reported so far. A case of IMT with sarcomatous transformation in an extraction site with a history of tooth extraction following tooth mobility of an upper left molar tooth is presented here. The tooth was extracted following a complaint of gingival swelling and mobility of tooth. Though malignant transformation in IMTs had been documented in the extra oral sites, wide search of associated literature suggests, this is the first case of oral IMT showing malignant change associated with gingiva. The case report attempts to highlight the variant possibilities of tooth mobility other than periodontitis and the importance of assessing the primary cause of such conditions.

  6. The telocytes/myofibroblasts 3-D network forms a stretch receptor in the human bladder mucosa. Is this structure involved in the detrusor overactive diseases?

    Science.gov (United States)

    Vannucchi, Maria-Giuliana; Traini, Chiara

    2018-04-11

    Several connective tissue cells are present in the human bladder wall; among them, the myofibroblasts (MyF) and the so-called interstitial cells (IC) are a matter of investigation either by basic researchers or clinicians. The interest derives from the possibility that these two cell types could regulate the organ function forming a special sensory system in the bladder mucosa. Whereas attention for the myofibroblasts was mainly focused on understanding their role, the so-called IC are debatable starting from their nomenclature. Indeed, the IC should correspond to the previously called fibroblasts-like cells/interstitial Cajal-like cells (ICLC)/interstitial cells of Cajal (ICC) or PDGFRα positive cells, or CD34 positive cells. Recently a proper name was proposed to give them an identity, i.e. telocyte (TC). To date, this nomenclature is a better term than IC that is quite vague and can be used for all the cells that reside in the connective tissue. Noteworthy, in the bladder mucosa, TC and MyF form a hetero-cellular 3-D network. The detrusor overactivity/overactive bladder (DO/OAB) are pathological conditions characterized by hypersensitivity to filling. It has been hypothesized that erroneous afferent inputs generated in the mucosa affect the efferent pathways and, consequently, the detrusor response. Presently, we review the literature regarding the presence and the potential role of TC and MyF in control conditions and in DO/OAB. On the possibility that the 3D-network made up by these two cell types might play a major role in the genesis of anomalous afferent stimuli will be given attention. Copyright © 2018 Elsevier GmbH. All rights reserved.

  7. Keratocyte apoptosis and not myofibroblast differentiation mark the graft/host interface at early time-points post-DSAEK in a cat model.

    Directory of Open Access Journals (Sweden)

    Adam J Weis

    Full Text Available To evaluate myofibroblast differentiation as an etiology of haze at the graft-host interface in a cat model of Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK.DSAEK was performed on 10 eyes of 5 adult domestic short-hair cats. In vivo corneal imaging with slit lamp, confocal, and optical coherence tomography (OCT were performed twice weekly. Cats were sacrificed and corneas harvested 4 hours, and 2, 4, 6, and 9 days post-DSAEK. Corneal sections were stained with the TUNEL method and immunohistochemistry was performed for α-smooth muscle actin (α-SMA and fibronectin with DAPI counterstain.At all in vivo imaging time-points, corneal OCT revealed an increase in backscatter of light and confocal imaging revealed an acellular zone at the graft-host interface. At all post-mortem time-points, immunohistochemistry revealed a complete absence of α-SMA staining at the graft-host interface. At 4 hours, extracellular fibronectin staining was identified along the graft-host interface and both fibronectin and TUNEL assay were positive within adjacent cells extending into the host stroma. By day 2, fibronectin and TUNEL staining diminished and a distinct acellular zone was present in the region of previously TUNEL-positive cells.OCT imaging consistently showed increased reflectivity at the graft-host interface in cat corneas in the days post-DSAEK. This was not associated with myofibroblast differentiation at the graft-host interface, but rather with apoptosis and the development of a subsequent acellular zone. The roles of extracellular matrix changes and keratocyte cell death and repopulation should be investigated further as potential contributors to the interface optical changes.

  8. Myo/Nog cells: targets for preventing the accumulation of skeletal muscle-like cells in the human lens.

    Directory of Open Access Journals (Sweden)

    Jacquelyn Gerhart

    Full Text Available Posterior capsule opacification (PCO is a vision impairing condition that arises in some patients following cataract surgery. The fibrotic form of PCO is caused by myofibroblasts that may emerge in the lens years after surgery. In the chick embryo lens, myofibroblasts are derived from Myo/Nog cells that are identified by their expression of the skeletal muscle specific transcription factor MyoD, the bone morphogenetic protein inhibitor Noggin, and the epitope recognized by the G8 monoclonal antibody. The goal of this study was to test the hypothesis that depletion of Myo/Nog cells will prevent the accumulation of myofibroblasts in human lens tissue. Myo/Nog cells were present in anterior, equatorial and bow regions of the human lens, cornea and ciliary processes. In anterior lens tissue removed by capsulorhexis, Myo/Nog cells had synthesized myofibroblast and skeletal muscle proteins, including vimentin, MyoD and sarcomeric myosin. Alpha smooth muscle actin (α-SMA was detected in a subpopulation of Myo/Nog cells. Areas of the capsule denuded of epithelial cells were surrounded by Myo/Nog cells. Some of these cell free areas contained a wrinkle in the capsule. Depletion of Myo/Nog cells eliminated cells expressing skeletal muscle proteins in 5-day cultures but did not affect cells immunoreactive for beaded filament proteins that accumulate in differentiating lens epithelial cells. Transforming growth factor-betas 1 and 2 that mediate an epithelial-mesenchymal transition, did not induce the expression of skeletal muscle proteins in lens cells following Myo/Nog cell depletion. This study demonstrates that Myo/Nog cells in anterior lens tissue removed from cataract patients have undergone a partial differentiation to skeletal muscle. Myo/Nog cells appear to be the source of skeletal muscle-like cells in explants of human lens tissue. Targeting Myo/Nog cells with the G8 antibody during cataract surgery may reduce the incidence of PCO.

  9. Hypervascular liver lesions in radiologically normal liver

    Energy Technology Data Exchange (ETDEWEB)

    Amico, Enio Campos; Alves, Jose Roberto; Souza, Dyego Leandro Bezerra de; Salviano, Fellipe Alexandre Macena; Joao, Samir Assi; Liguori, Adriano de Araujo Lima, E-mail: ecamic@uol.com.br [Hospital Universitario Onofre Lopes (HUOL/UFRN), Natal, RN (Brazil). Clinica Gastrocentro e Ambulatorios de Cirurgia do Aparelho Digestivo e de Cirurgia Hepatobiliopancreatica

    2017-09-01

    Background: The hypervascular liver lesions represent a diagnostic challenge. Aim: To identify risk factors for cancer in patients with non-hemangiomatous hypervascular hepatic lesions in radiologically normal liver. Method: This prospective study included patients with hypervascular liver lesions in radiologically normal liver. The diagnosis was made by biopsy or was presumed on the basis of radiologic stability in follow-up period of one year. Cirrhosis or patients with typical imaging characteristics of haemangioma were excluded. Results: Eighty eight patients were included. The average age was 42.4. The lesions were unique and were between 2-5 cm in size in most cases. Liver biopsy was performed in approximately 1/3 of cases. The lesions were benign or most likely benign in 81.8%, while cancer was diagnosed in 12.5% of cases. Univariate analysis showed that age >45 years (p< 0.001), personal history of cancer (p=0.020), presence of >3 nodules (p=0.003) and elevated alkaline phosphatase (p=0.013) were significant risk factors for cancer. Conclusion: It is safe to observe hypervascular liver lesions in normal liver in patients up to 45 years, normal alanine amino transaminase, up to three nodules and no personal history of cancer. Lesion biopsies are safe in patients with atypical lesions and define the treatment to be established for most of these patients. (author)

  10. Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver

    DEFF Research Database (Denmark)

    Elmen, Joachim; Lindow, Morten; Silahtaroglu, Asli

    2008-01-01

    ’end of miR-122 leads to specific, dose-dependent silencing of miR-122 and shows no hepatotoxicity in mice. Antagonism of miR-122 is due to formation of stable heteroduplexes between the LNA-antimiR and miR-122 as detected by northern analysis. Fluorescence in situ hybridization demonstrated uptake...... of the LNA-antimiR in mouse liver cells, which was accompanied by markedly reduced hybridization signals for mature miR-122 in treated mice. Functional antagonism of miR-122 was inferred from a low cholesterol phenotype and derepression within 24 h of 199 liver mRNAs showing significant enrichment for mi...

  11. Increased Whole-Body and Sustained Liver Cortisol Regeneration by 11β-Hydroxysteroid Dehydrogenase Type 1 in Obese Men With Type 2 Diabetes Provides a Target for Enzyme Inhibition

    Science.gov (United States)

    Stimson, Roland H.; Andrew, Ruth; McAvoy, Norma C.; Tripathi, Dhiraj; Hayes, Peter C.; Walker, Brian R.

    2011-01-01

    OBJECTIVE The cortisol-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies glucocorticoid levels in liver and adipose tissue. 11β-HSD1 inhibitors are being developed to treat type 2 diabetes. In obesity, 11β-HSD1 is increased in adipose tissue but decreased in liver. The benefits of pharmacological inhibition may be reduced if hepatic 11β-HSD1 is similarly decreased in obese patients with type 2 diabetes. To examine this, we quantified in vivo whole-body, splanchnic, and hepatic 11β-HSD1 activity in obese type 2 diabetic subjects. RESEARCH DESIGN AND METHODS Ten obese men with type 2 diabetes and seven normal-weight control subjects were infused with 9,11,12,12-[2H]4cortisol (40%) and cortisol (60%) at 1.74 mg/h. Adrenal cortisol secretion was suppressed with dexamethasone. Samples were obtained from the hepatic vein and an arterialized hand vein at steady state and after oral administration of cortisone (5 mg) to estimate whole-body and liver 11β-HSD1 activity using tracer dilution. RESULTS In obese type 2 diabetic subjects, the appearance rate of 9,12,12-[2H]3cortisol in arterialized blood was increased (35 ± 2 vs. 29 ± 1 nmol/min, P cortisol production was not reduced (29 ± 6 vs. 29 ± 6 nmol/min), and cortisol appearance in the hepatic vein after oral cortisone was unchanged. CONCLUSIONS Whole-body 11β-HSD1 activity is increased in obese men with type 2 diabetes, whereas liver 11β-HSD1 activity is sustained, unlike in euglycemic obesity. This supports the concept that inhibitors of 11β-HSD1 are likely to be most effective in obese type 2 diabetic subjects. PMID:21266326

  12. Increased whole-body and sustained liver cortisol regeneration by 11beta-hydroxysteroid dehydrogenase type 1 in obese men with type 2 diabetes provides a target for enzyme inhibition.

    Science.gov (United States)

    Stimson, Roland H; Andrew, Ruth; McAvoy, Norma C; Tripathi, Dhiraj; Hayes, Peter C; Walker, Brian R

    2011-03-01

    The cortisol-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies glucocorticoid levels in liver and adipose tissue. 11β-HSD1 inhibitors are being developed to treat type 2 diabetes. In obesity, 11β-HSD1 is increased in adipose tissue but decreased in liver. The benefits of pharmacological inhibition may be reduced if hepatic 11β-HSD1 is similarly decreased in obese patients with type 2 diabetes. To examine this, we quantified in vivo whole-body, splanchnic, and hepatic 11β-HSD1 activity in obese type 2 diabetic subjects. Ten obese men with type 2 diabetes and seven normal-weight control subjects were infused with 9,11,12,12-[(2)H](4)cortisol (40%) and cortisol (60%) at 1.74 mg/h. Adrenal cortisol secretion was suppressed with dexamethasone. Samples were obtained from the hepatic vein and an arterialized hand vein at steady state and after oral administration of cortisone (5 mg) to estimate whole-body and liver 11β-HSD1 activity using tracer dilution. In obese type 2 diabetic subjects, the appearance rate of 9,12,12-[(2)H](3)cortisol in arterialized blood was increased (35 ± 2 vs. 29 ± 1 nmol/min, P cortisol production was not reduced (29 ± 6 vs. 29 ± 6 nmol/min), and cortisol appearance in the hepatic vein after oral cortisone was unchanged. Whole-body 11β-HSD1 activity is increased in obese men with type 2 diabetes, whereas liver 11β-HSD1 activity is sustained, unlike in euglycemic obesity. This supports the concept that inhibitors of 11β-HSD1 are likely to be most effective in obese type 2 diabetic subjects.

  13. Multi-institutional Quantitative Evaluation and Clinical Validation of Smart Probabilistic Image Contouring Engine (SPICE) Autosegmentation of Target Structures and Normal Tissues on Computer Tomography Images in the Head and Neck, Thorax, Liver, and Male Pelvis Areas

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Mingyao [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Bzdusek, Karl [Philips Healthcare, Fitchburg, Wisconsin (United States); Brink, Carsten [Institute of Clinical Research, University of Southern Denmark, Odense (Denmark); Laboratory of Radiation Physics, Odense University Hospital, Odense (Denmark); Eriksen, Jesper Grau [Department of Oncology, Odense University Hospital, Odense (Denmark); Hansen, Olfred [Institute of Clinical Research, University of Southern Denmark, Odense (Denmark); Department of Oncology, Odense University Hospital, Odense (Denmark); Jensen, Helle Anita [Department of Oncology, Odense University Hospital, Odense (Denmark); Gay, Hiram A.; Thorstad, Wade [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Widder, Joachim; Brouwer, Charlotte L.; Steenbakkers, Roel J.H.M.; Vanhauten, Hubertus A.M. [Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen (Netherlands); Cao, Jeffrey Q.; McBrayne, Gail [London Regional Cancer Centre, Ontario (Canada); Patel, Salil H. [Department of Radiation Oncology, Rhode Island Hospital, Providence, Rhode Island (United States); Cannon, Donald M. [Department of Human Oncology, University of Wisconsin—Madison (United States); Hardcastle, Nicholas [Department of Physical Science, Peter MacCallum Cancer Centre, Melbourne (Australia); Tomé, Wolfgang A. [Montefiore Medical Center and Institute of Onco-Physics, Albert Einstein College of Medicine, Bronx, New York (United States); Guckenberg, Matthias [University of Würzburg, Department of Radiation Oncology, Würzburg (Germany); Parikh, Parag J., E-mail: pparikh@radonc.wustl.edu [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States)

    2013-11-15

    Purpose: Clinical validation and quantitative evaluation of computed tomography (CT) image autosegmentation using Smart Probabilistic Image Contouring Engine (SPICE). Methods and Materials: CT images of 125 treated patients (32 head and neck [HN], 40 thorax, 23 liver, and 30 prostate) in 7 independent institutions were autosegmented using SPICE and computational times were recorded. The number of structures autocontoured were 25 for the HN, 7 for the thorax, 3 for the liver, and 6 for the male pelvis regions. Using the clinical contours as reference, autocontours of 22 selected structures were quantitatively evaluated using Dice Similarity Coefficient (DSC) and Mean Slice-wise Hausdorff Distance (MSHD). All 40 autocontours were evaluated by a radiation oncologist from the institution that treated the patients. Results: The mean computational times to autosegment all the structures using SPICE were 3.1 to 11.1 minutes per patient. For the HN region, the mean DSC was >0.70 for all evaluated structures, and the MSHD ranged from 3.2 to 10.0 mm. For the thorax region, the mean DSC was 0.95 for the lungs and 0.90 for the heart, and the MSHD ranged from 2.8 to 12.8 mm. For the liver region, the mean DSC was >0.92 for all structures, and the MSHD ranged from 5.2 to 15.9 mm. For the male pelvis region, the mean DSC was >0.76 for all structures, and the MSHD ranged from 4.8 to 10.5 mm. Out of the 40 autocontoured structures reviews by experts, 25 were scored useful as autocontoured or with minor edits for at least 90% of the patients and 33 were scored useful autocontoured or with minor edits for at least 80% of the patients. Conclusions: Compared with manual contouring, autosegmentation using SPICE for the HN, thorax, liver, and male pelvis regions is efficient and shows significant promise for clinical utility.

  14. Multi-institutional Quantitative Evaluation and Clinical Validation of Smart Probabilistic Image Contouring Engine (SPICE) Autosegmentation of Target Structures and Normal Tissues on Computer Tomography Images in the Head and Neck, Thorax, Liver, and Male Pelvis Areas

    International Nuclear Information System (INIS)

    Zhu, Mingyao; Bzdusek, Karl; Brink, Carsten; Eriksen, Jesper Grau; Hansen, Olfred; Jensen, Helle Anita; Gay, Hiram A.; Thorstad, Wade; Widder, Joachim; Brouwer, Charlotte L.; Steenbakkers, Roel J.H.M.; Vanhauten, Hubertus A.M.; Cao, Jeffrey Q.; McBrayne, Gail; Patel, Salil H.; Cannon, Donald M.; Hardcastle, Nicholas; Tomé, Wolfgang A.; Guckenberg, Matthias; Parikh, Parag J.

    2013-01-01

    Purpose: Clinical validation and quantitative evaluation of computed tomography (CT) image autosegmentation using Smart Probabilistic Image Contouring Engine (SPICE). Methods and Materials: CT images of 125 treated patients (32 head and neck [HN], 40 thorax, 23 liver, and 30 prostate) in 7 independent institutions were autosegmented using SPICE and computational times were recorded. The number of structures autocontoured were 25 for the HN, 7 for the thorax, 3 for the liver, and 6 for the male pelvis regions. Using the clinical contours as reference, autocontours of 22 selected structures were quantitatively evaluated using Dice Similarity Coefficient (DSC) and Mean Slice-wise Hausdorff Distance (MSHD). All 40 autocontours were evaluated by a radiation oncologist from the institution that treated the patients. Results: The mean computational times to autosegment all the structures using SPICE were 3.1 to 11.1 minutes per patient. For the HN region, the mean DSC was >0.70 for all evaluated structures, and the MSHD ranged from 3.2 to 10.0 mm. For the thorax region, the mean DSC was 0.95 for the lungs and 0.90 for the heart, and the MSHD ranged from 2.8 to 12.8 mm. For the liver region, the mean DSC was >0.92 for all structures, and the MSHD ranged from 5.2 to 15.9 mm. For the male pelvis region, the mean DSC was >0.76 for all structures, and the MSHD ranged from 4.8 to 10.5 mm. Out of the 40 autocontoured structures reviews by experts, 25 were scored useful as autocontoured or with minor edits for at least 90% of the patients and 33 were scored useful autocontoured or with minor edits for at least 80% of the patients. Conclusions: Compared with manual contouring, autosegmentation using SPICE for the HN, thorax, liver, and male pelvis regions is efficient and shows significant promise for clinical utility

  15. Liver and gastrointestinal tract

    International Nuclear Information System (INIS)

    Shahid, M.A.

    1992-01-01

    Liver is often a site of a variety of diseases. A palpable liver during a routine clinical examination is an important finding and requires further investigations. The availability of non-invasive liver imaging procedures using nuclear, ultrasound, CT (and now MRI) techniques have immensely enhanced diagnostic accuracy in liver diseases. In this Chapter, a detailed description of routinely practised nuclear medicine procedures related to liver is given. Brief reference is also made to other imaging techniques, particularly ultrasonography, only for the purposes of comparison. Most of the information is based on our own clinical experience of past 30 years

  16. Liver and gastrointestinal tract

    Energy Technology Data Exchange (ETDEWEB)

    Shahid, M A

    1993-12-31

    Liver is often a site of a variety of diseases. A palpable liver during a routine clinical examination is an important finding and requires further investigations. The availability of non-invasive liver imaging procedures using nuclear, ultrasound, CT (and now MRI) techniques have immensely enhanced diagnostic accuracy in liver diseases. In this Chapter, a detailed description of routinely practised nuclear medicine procedures related to liver is given. Brief reference is also made to other imaging techniques, particularly ultrasonography, only for the purposes of comparison. Most of the information is based on our own clinical experience of past 30 years 12 figs, 4 tabs

  17. Inflammatory angiomyolipoma of the liver: a rare hepatic tumor

    Directory of Open Access Journals (Sweden)

    Liu Yang

    2012-09-01

    Full Text Available Abstract Angiomyolipoma (AML is a rare mesenchymal neoplasm of the tumor, composed of a varying heterogeneous mixture of three tissue components: blood vessels, smooth muscle and adipose cells. Hepatic AML may demonstrate a marked histological diversity. We herein present one case of hepatic AML exhibiting prominent inflammatory cells in the background, which happened in a 61-year-old Chinese female patient, without signs of tuberous sclerosis. Histologically, the striking feature was the infiltration of numerous inflammatory cells in the background, including small lymphocytes, plasma cells, and eosnophils. The tumor cells were spindled and histiocytoid in shape, with slightly eosinophilic cytoplasm, and arranged along the vessels or scattered among the inflammatory background. Sinusoid structure was obviously seen in the tumor. Mature adipocytes and thick-walled blood vessels were focally observed at the boundaries between the tumor and surrounding liver tissues. The tumor cells were positive immunostaining for HMB-45, Melan-A, and smooth muscle actin. The inflammatory AML should be distinguished from other tumors with inflammatory background such as inflammatory myofibroblastic tumor and follicular dendritic cell tumor and deserves wider recognition for its occurrence as a primary hepatic tumor. Virtual slides The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1828633072762370

  18. Coffee and Liver Disease.

    Science.gov (United States)

    Wadhawan, Manav; Anand, Anil C

    2016-03-01

    Coffee is the most popular beverage in the world. Consumption of coffee has been shown to benefit health in general, and liver health in particular. This article reviews the effects of coffee intake on development and progression of liver disease due to various causes. We also describe the putative mechanisms by which coffee exerts the protective effect. The clinical evidence of benefit of coffee consumption in Hepatitis B and C, as well as nonalcoholic fatty liver disease and alcoholic liver disease, has also been presented. Coffee consumption is associated with improvement in liver enzymes (ALT, AST, and GGTP), especially in individuals with risk for liver disease. Coffee intake more than 2 cups per day in patients with preexisting liver disease has been shown to be associated with lower incidence of fibrosis and cirrhosis, lower hepatocellular carcinoma rates, as well as decreased mortality.

  19. Immunohistochemical and radiological characterization of wound healing in porcine liver after radiofrequency ablation.

    Science.gov (United States)

    Stadlbauer, Vanessa; Lang-Olip, Ingrid; Leber, Bettina; Mayrhauser, Ursula; Koestenbauer, Sonja; Tawdrous, Monika; Moche, Michael; Sereinigg, Michael; Seider, Daniel; Iberer, Florian; Wiederstein-Grasser, Iris; Portugaller, Rupert Horst; Stiegler, Philipp

    2016-01-01

    Radiofrequency ablation (RFA) is a minimal invasive therapeutic option for patients with hepatocellular carcinoma or liver metastases. We investigated RFA-induced cellular changes in the liver of pigs. Healthy pigs (n=18) were sacrificed between day 0 and 3 months after RFA. The wound healing process was evaluated by computed tomography (CT), chromotrope anilinblue (CAB) staining of large-scale and standard tissue sections. Immunohistochemistry (IHC) for heat shock protein 70, Caspase-3, Ki67, Reelin, Vinculin, Vimentin and α-SMA was perfomed. One day after RFA, CAB staining showed cell damage and massive hyperaemia. All IHC markers were predominantly expressed at the outer borders of the lesion, except Reelin, which was mainly detected in untreated liver regions. By staining for Hsp70, the heat stress during RFA was monitored, which was most distinct 1-2 days after RFA. CT revealed decreased lesion size after one week. Development of a Vimentin and α-SMA positive fibrotic capsule was observed. In the early phase signs of cell damage, apoptosis and proliferation are dominant. Reduced expression of Reelin suggests a minor role of hepatic stellate cells in the RFA zone. After one week myofibroblasts become prominent and contribute to the development of the fibrotic capsule. This elucidates the pathophysiology of RFA and could contribute to the future optimization of RFA procedures.

  20. Digital liver biopsy: Bio-imaging of fatty liver for translational and clinical research.

    Science.gov (United States)

    Mancini, Marcello; Summers, Paul; Faita, Francesco; Brunetto, Maurizia R; Callea, Francesco; De Nicola, Andrea; Di Lascio, Nicole; Farinati, Fabio; Gastaldelli, Amalia; Gridelli, Bruno; Mirabelli, Peppino; Neri, Emanuele; Salvadori, Piero A; Rebelos, Eleni; Tiribelli, Claudio; Valenti, Luca; Salvatore, Marco; Bonino, Ferruccio

    2018-02-27

    The rapidly growing field of functional, molecular and structural bio-imaging is providing an extraordinary new opportunity to overcome the limits of invasive liver biopsy and introduce a "digital biopsy" for in vivo study of liver pathophysiology. To foster the application of bio-imaging in clinical and translational research, there is a need to standardize the methods of both acquisition and the storage of the bio-images of the liver. It can be hoped that the combination of digital, liquid and histologic liver biopsies will provide an innovative synergistic tri-dimensional approach to identifying new aetiologies, diagnostic and prognostic biomarkers and therapeutic targets for the optimization of personalized therapy of liver diseases and liver cancer. A group of experts of different disciplines (Special Interest Group for Personalized Hepatology of the Italian Association for the Study of the Liver, Institute for Biostructures and Bio-imaging of the National Research Council and Bio-banking and Biomolecular Resources Research Infrastructure) discussed criteria, methods and guidelines for facilitating the requisite application of data collection. This manuscript provides a multi-Author review of the issue with special focus on fatty liver.

  1. Extracellular Matrix Molecular Remodeling in Human Liver Fibrosis Evolution.

    Directory of Open Access Journals (Sweden)

    Andrea Baiocchini

    Full Text Available Chronic liver damage leads to pathological accumulation of ECM proteins (liver fibrosis. Comprehensive characterization of the human ECM molecular composition is essential for gaining insights into the mechanisms of liver disease. To date, studies of ECM remodeling in human liver diseases have been hampered by the unavailability of purified ECM. Here, we developed a decellularization method to purify ECM scaffolds from human liver tissues. Histological and electron microscopy analyses demonstrated that the ECM scaffolds, devoid of plasma and cellular components, preserved the three-dimensional ECM structure and zonal distribution of ECM components. This method has been then applied on 57 liver biopsies of HCV-infected patients at different stages of liver fibrosis according to METAVIR classification. Label-free nLC-MS/MS proteomics and computation biology were performed to analyze the ECM molecular composition in liver fibrosis progression, thus unveiling protein expression signatures specific for the HCV-related liver fibrotic stages. In particular, the ECM molecular composition of liver fibrosis was found to involve dynamic changes in matrix stiffness, flexibility and density related to the dysregulation of predominant collagen, elastic fibers and minor components with both structural and signaling properties. This study contributes to the understanding of the molecular bases underlying ECM remodeling in liver fibrosis and suggests new molecular targets for fibrolytic strategies.

  2. Nanoparticles for the treatment of liver fibrosis

    Directory of Open Access Journals (Sweden)

    Poilil Surendran S

    2017-09-01

    Full Text Available Suchithra Poilil Surendran, Reju George Thomas, Myeong Ju Moon, Yong Yeon Jeong Department of Radiology, BioMolecular Theranostics (BiT Lab, Chonnam National University Medical School, Chonnam National University Hwasun Hospital (CNUHH, South Korea Abstract: Chronic liver diseases represent a global health problem due to their high prevalence worldwide and the limited available curative treatment options. They can result from various causes, both infectious and noninfectious diseases. The application of nanoparticle (NP systems has emerged as a rapidly evolving area of interest for the safe delivery of various drugs and nucleic acids for chronic liver diseases. This review presents the pathogenesis, diagnosis and the emerging nanoparticulate systems used in the treatment of chronic liver diseases caused by liver fibrosis. Activated hepatic stellate cell (HSC is considered to be the main mechanism for liver fibrosis. Ultrasonography and magnetic resonance imaging techniques are widely used noninvasive diagnostic methods for hepatic fibrosis. A variety of nanoparticulate systems are mainly focused on targeting HSC in the treatment of hepatic fibrosis. As early liver fibrosis is reversible by current NP therapy, it is being studied in preclinical as well as clinical trials. Among various nanoparticulate systems, inorganic NPs, liposomes and nanomicelles have been widely studied due to their distinct properties to deliver drugs as well as other therapeutic moieties. Liposomal NPs in clinical trials is considered to be a milestone in the treatment of hepatic fibrosis. Currently, NP therapy for liver fibrosis is updating fast, and hopefully, it can be the future remedy for liver fibrosis. Keywords: liver fibrosis, inorganic nanoparticles, liposomes, micelles

  3. Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD

    Directory of Open Access Journals (Sweden)

    Ali Saeed

    2017-12-01

    Full Text Available Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs and retinoid X receptors (RXRs.The liver plays a central role in vitamin A metabolism: (1 it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2 it produces retinol binding protein 4 (RBP4 that distributes vitamin A, as retinol, to peripheral tissues; and (3 it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs. In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH; it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M is the most prominent

  4. Pathomorphology of liver fibrosis in trepanobioptates of patients with steatohepatitis: main types, sources of development, features of progression

    Directory of Open Access Journals (Sweden)

    V. A. Tumanskiy

    2017-12-01

    Full Text Available Until recently, among the pathologists, hepatologists and gastroenterologists, a discussion continues on the morphogenesis and gradation of liver fibrosis in non-alcoholic patients (NASH and alcoholic steatohepatitis (ASH. Purpose of the study. Studying the main types and sources of liver fibrosis in patients with nonalcoholic and alcoholic steatohepatitis, justifying the gradation of its severity, taking into account the quantitative dynamics of fibrogenic producer cells, the relative area of fibrosis and the deposition of type I, III and IV collagen in the liver. Material and methods. Histological and histochemical examination of liver fibrosis was performed in 198 patients with NASH of 18-79 years and in 79 patients with ASH of 47-63 years. Immunohistochemical study with measurement of the area of expression of activated αSMA + perisinusoidal stellate cells and αSMA + portal myofibroblasts with F1 (mild, F2 (moderate, F3 (severe fibrosis and F4 fibrosis / cirrhosis was performed in 80 trepanobioptates of patients with NASH (20 cases in each group, electron microscopic examination of the liver – in 10 deceased patients suffering from NASH. Results. In patients with NASH and ASH, there are two major types of liver fibrosis progress: the perisinusoidal pericellular and portal-Z3 perisinusoidal fibrosis, the development of which is the new generation of αSMA + star cells and αSMA + portal myofibroblasts of the fibrogenic immunophenotype, with co-expression of fascin and vimentin and absence of desmine expression. As the perisinusoidal pericellular fibrosis progresses from the mild F1 degree, to the severe F3 fibrosis and to the extremely severe F4 fibrosis / cirrhosis of the pericellular type, the area of the Masson-positive extracellular molecular-fibrous matrix (H = 88,70 р = 0,05 and the area of αSMA + collagen-producing stellate cells of perisinusoidal-pericellular localization (H = 45,12, p = 0,05. According to the data of

  5. Contrast-enhanced Ultrasound for Non-tumor Liver Diseases

    Directory of Open Access Journals (Sweden)

    H Maruyama

    2012-03-01

    Full Text Available Contrast-enhanced ultrasound (CEUS is a simple, safe and reliable technique for the clinical management of patients with various liver diseases. Although the major target of the technique may be focal hepatic lesions, it is also effective for the diagnosis of non-tumor liver diseases, such as grading hepatic fibrosis, characterization of chronic liver diseases and diagnosis of portal vein thrombosis. This review article aimed to overview the recent application of CEUS in the assessment of non-tumor liver diseases. Keywords: Cirrhosis, contrast agent, fibrosis, idiopathic portal hypertension, microbubble, portal vein thrombosis, ultrasound.

  6. Diagnosis of fatty liver

    International Nuclear Information System (INIS)

    Saitoh, Shuichi; Nagamine, Takeaki; Takagi, Hitoshi

    1988-01-01

    Diagnostic values of various ultrasonographic findings were evaluated from fatty infiltration ratio calculated by liver specimens in 42 patients. The ratio of the CT number of liver to those of spleen were also compared with fatty infiltration ratio in 11 patients. Fatty bandless sign one plus (perirenal bright echo between the liver and the right kidney is masked partially) or more and the fatty score 3 (it is calculated by several ultrasonographic findings) and the less than 0.90 of the ratio of CT number of liver to those of spleen were useful for diagnosis of fatty liver, the sensitivity was 100%, 87.5%, 85.7% and the accuracy was 78.1%, 81.8%, 81.8% respectively. It was considered that these criteria were suitable in screening study of fatty liver. (author)

  7. [Liver and sport].

    Science.gov (United States)

    Watelet, J

    2008-11-01

    The liver is a vital organ and plays a central role in energy exchange, protein synthesis as well as the elimination of waste products from the body. Acute and chronic injury may disturb a variety of liver functions to different degrees. Over the last three decades, the effects of physical activity and competitive sport on the liver have been described by various investigators. These include viral hepatitis and drug-induced liver disorders. Herein, we review acute and chronic liver diseases potentially caused by sport. Team physicians, trainers and others, responsible for the health of athletes, should be familiar with the risk factors, clinical features, and consequences of liver diseases that occur in sports.

  8. Robotic liver surgery

    Science.gov (United States)

    Leung, Universe

    2014-01-01

    Robotic surgery is an evolving technology that has been successfully applied to a number of surgical specialties, but its use in liver surgery has so far been limited. In this review article we discuss the challenges of minimally invasive liver surgery, the pros and cons of robotics, the evolution of medical robots, and the potentials in applying this technology to liver surgery. The current data in the literature are also presented. PMID:25392840

  9. Features of liver tissue remodeling in intestinal failure during and after weaning off parenteral nutrition.

    Science.gov (United States)

    Mutanen, Annika; Lohi, Jouko; Sorsa, Timo; Jalanko, Hannu; Pakarinen, Mikko P

    2016-09-01

    Intestinal failure is associated frequently with liver injury, which persists after weaning off parenteral nutrition. We compared features of liver remodeling in intestinal failure during and after weaning off parenteral nutrition. Liver biopsies and serum samples were obtained from 25 intestinal failure patients at a median age of 9.7 years (interquartile range: 4.6-18) and from age-matched control patients. Seven patients had been receiving parenteral nutrition for 53 months (22-160), and 18 patients had been weaned off parenteral nutrition 6.3 years (2.4-17) earlier, after having received parenteral nutrition for 10 months (3.3-34). Expression of alpha-smooth muscle actin, collagen 1, proinflammatory cytokines, growth factors, and matrix metalloproteinases (MMPs) was measured. Significant increases in immunohistochemical expression of alpha-smooth muscle actin and collagen 1 were observed predominantly in portal areas and were similar to increases seen in patients currently receiving parenteral nutrition and in patients weaned off parenteral nutrition. Gene and protein expressions of alpha-smooth muscle actin and collagen were interrelated. Gene expression of ACTA2, encoding alpha-smooth muscle actin, was increased only in patients who were receiving parenteral nutrition currently. Comparable upregulation of interleukin-1 (α and ß), epidermal growth factor, integrin-ß6, and MMP9 gene expression was observed in both patient groups, irrespective of whether they were receiving parenteral nutrition currently. Liver expression and serum levels of TIMP1 and MMP7 were increased only in the patients on parenteral nutrition currently but were not increased after weaning off parenteral nutrition. Intestinal failure is characterized by abnormal activation of hepatic myofibroblast and accumulation of collagen both during and after weaning off parenteral nutrition. Persistent transcriptional upregulation of proinflammatory and fibrogenic cytokines after weaning off

  10. Adipokines in Liver Cirrhosis.

    Science.gov (United States)

    Buechler, Christa; Haberl, Elisabeth M; Rein-Fischboeck, Lisa; Aslanidis, Charalampos

    2017-06-29

    Liver fibrosis can progress to cirrhosis, which is considered a serious disease. The Child-Pugh score and the model of end-stage liver disease score have been established to assess residual liver function in patients with liver cirrhosis. The development of portal hypertension contributes to ascites, variceal bleeding and further complications in these patients. A transjugular intrahepatic portosystemic shunt (TIPS) is used to lower portal pressure, which represents a major improvement in the treatment of patients. Adipokines are proteins released from adipose tissue and modulate hepatic fibrogenesis. These proteins affect various biological processes that are involved in liver function, including angiogenesis, vasodilation, inflammation and deposition of extracellular matrix proteins. The best studied adipokines are adiponectin and leptin. Adiponectin protects against hepatic inflammation and fibrogenesis, and leptin functions as a profibrogenic factor. These and other adipokines are supposed to modulate disease severity in patients with liver cirrhosis. Consequently, circulating levels of these proteins have been analyzed to identify associations with parameters of hepatic function, portal hypertension and its associated complications in patients with liver cirrhosis. This review article briefly addresses the role of adipokines in hepatitis and liver fibrosis. Here, studies having analyzed these proteins in systemic blood in cirrhotic patients are listed to identify adipokines that are comparably changed in the different cohorts of patients with liver cirrhosis. Some studies measured these proteins in systemic, hepatic and portal vein blood or after TIPS to specify the tissues contributing to circulating levels of these proteins and the effect of portal hypertension, respectively.

  11. Nonalcoholic fatty liver disease

    DEFF Research Database (Denmark)

    Patrick-Melin, A J; Kalinski, M I; Kelly, K R

    2009-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a rapidly emerging chronic liver disease and is reported to affect up to 70-80% of overweight and obese individuals. NAFLD represents a spectrum of liver diseases that range from simple hepatic steatosis, to a more severe and treatment resistant stage...... that features steatosis plus inflammation, termed nonalcoholic steatohepatitis (NASH), which may in turn progress to hepatic fibrosis, cirrhosis, and sub-acute liver failure. Thus, NAFLD and its subsequent complications create a significant health burden, and currently there is no effective treatment strategy...

  12. Non-Alcoholic Fatty Liver Disease in HIV Infection.

    Science.gov (United States)

    Macías, Juan; Pineda, Juan A; Real, Luis M

    2017-01-01

    Non-alcoholic fatty liver disease is one of the most frequent chronic hepatic conditions worldwide. The spectrum of non-alcoholic fatty liver disease goes from hepatic steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Risk factors for non-alcoholic fatty liver disease are metabolic, mainly obesity and the accompanying consequences. Treatment and prevention of non-alcoholic fatty liver disease should target those metabolic abnormalities. The frequency of and the factors associated with hepatic steatosis in HIV infection seem to be similar to those reported in the general population, though direct comparisons are lacking. Hepatic steatosis in HIV infection may also be secondary to antiretroviral drugs or HCV-related factors in HCV-coinfected subjects. However, more recent data suggest that hepatic steatosis in HIV infection represents true non-alcoholic fatty liver disease. As such, management of non-alcoholic fatty liver disease in HIV infection should follow the same principles as in the general population.

  13. Abdominal MR: liver and pancreas

    International Nuclear Information System (INIS)

    Bartolozzi, C.; Lencioni, R.; Donati, F.; Cioni, D.

    1999-01-01

    Following the introduction of rapid, high-quality scan techniques and the development of new, tissue-specific contrast agents, the applications of MRI for abdominal imaging are experiencing unprecedented growth. This article examines the current status of liver and pancreatic MRI, highlighting technical and methodological approach, use of contrast agents, and main clinical applications. The MRI technique appears to be the ideal diagnostic tool for detection and characterization of benign and malignant liver neoplasms, and for evaluating tumor response after nonsurgical treatments. Dynamic imaging after bolus injection of a gadolinium chelate is currently a fundamental component of an MRI examination of the liver in many instances. Optimal dynamic scanning depends on the use of a multisection spoiled gradient-echo technique that allows one to image the entire region of interest during a single suspended respiration. Images are obtained during four phases relative to the injection of the contrast agent: precontrast, arterial (pre-sinusoidal), portal (sinusoidal), and delayed (extracellular) phase. Liver-specific contrast agents, including hepatobiliary agents and reticuloendothelial system-targeted iron oxide particles, however, may offer advantages over gadolinium chelates in some clinical settings. Computed tomography is still preferred to MRI for imaging the pancreas. However, state-of-the-art MRI may currently be at least as accurate as spiral CT for depiction of inflammatory and neoplastic pancreatic diseases. Moreover, MRI has the advantage of allowing simultaneous investigation of the biliary tree, owing to cholangiopancreatography techniques. Hence, a comprehensive assessment of most pancreatic diseases can be achieved with a single examination. (orig.)

  14. Liver immunology and its role in inflammation and homeostasis.

    Science.gov (United States)

    Robinson, Mark W; Harmon, Cathal; O'Farrelly, Cliona

    2016-05-01

    The human liver is usually perceived as a non-immunological organ engaged primarily in metabolic, nutrient storage and detoxification activities. However, we now know that the healthy liver is also a site of complex immunological activity mediated by a diverse immune cell repertoire as well as non-hematopoietic cell populations. In the non-diseased liver, metabolic and tissue remodeling functions require elements of inflammation. This inflammation, in combination with regular exposure to dietary and microbial products, creates the potential for excessive immune activation. In this complex microenvironment, the hepatic immune system tolerates harmless molecules while at the same time remaining alert to possible infectious agents, malignant cells or tissue damage. Upon appropriate immune activation to challenge by pathogens or tissue damage, mechanisms to resolve inflammation are essential to maintain liver homeostasis. Failure to clear 'dangerous' stimuli or regulate appropriately activated immune mechanisms leads to pathological inflammation and disrupted tissue homeostasis characterized by the progressive development of fibrosis, cirrhosis and eventual liver failure. Hepatic inflammatory mechanisms therefore have a spectrum of roles in the healthy adult liver; they are essential to maintain tissue and organ homeostasis and, when dysregulated, are key drivers of the liver pathology associated with chronic infection, autoimmunity and malignancy. In this review, we explore the changing perception of inflammation and inflammatory mediators in normal liver homeostasis and propose targeting of liver-specific immune regulation pathways as a therapeutic approach to treat liver disease.

  15. Liver regeneration and restoration of liver function after partial hepatectomy in patients with liver tumors

    NARCIS (Netherlands)

    Jansen, P. L.; Chamuleau, R. A.; van Leeuwen, D. J.; Schipper, H. G.; Busemann-Sokole, E.; van der Heyde, M. N.

    1990-01-01

    Liver regeneration and restoration of liver function were studied in six patients who underwent partial hepatectomy with removal of 30-70% of the liver. Liver volume and liver regeneration were studied by single-photon computed tomography (SPECT), using 99mTc-colloid as tracer. The method was

  16. Auxiliary partial liver transplantation

    NARCIS (Netherlands)

    C.B. Reuvers (Cornelis Bastiaan)

    1986-01-01

    textabstractIn this thesis studies on auxiliary partial liver transplantation in the dog and the pig are reported. The motive to perform this study was the fact that patients with acute hepatic failure or end-stage chronic liver disease are often considered to form too great a risk for successful

  17. Liver Disease and IBD

    Science.gov (United States)

    ... The gallbladder is a sac attached below the liver to the common bile duct. Gallstones form when bile (the liquid stored in ... a stone may have passed down the common bile duct to the area where it joins the ... of the liver. Chronic (long term) hepatitis can be from inflammation ...

  18. Polyploidization of liver cells.

    Science.gov (United States)

    Celton-Morizur, Séverine; Desdouets, Chantal

    2010-01-01

    Eukaryotic organisms usually contain a diploid complement of chromosomes. However, there are a number of exceptions. Organisms containing an increase in DNA content by whole number multiples of the entire set of chromosomes are defined as polyploid. Cells that contain more than two sets of chromosomes were first observed in plants about a century ago and it is now recognized that polyploidy cells form in many eukaryotes under a wide variety of circumstance. Although it is less common in mammals, some tissues, including the liver, show a high percentage of polyploid cells. Thus, during postnatal growth, the liver parenchyma undergoes dramatic changes characterized by gradual polyploidization during which hepatocytes of several ploidy classes emerge as a result of modified cell-division cycles. This process generates the successive appearance of tetraploid and octoploid cell classes with one or two nuclei (mononucleated or binucleated). Liver cells polyploidy is generally considered to indicate terminal differentiation and senescence and to lead both to the progressive loss of cell pluripotency and a markedly decreased replication capacity. In adults, liver polyploidization is differentially regulated upon loss of liver mass and liver damage. Interestingly, partial hepatectomy induces marked cell proliferation followed by an increase in liver ploidy. In contrast, during hepatocarcinoma (HCC), growth shifts to a nonpolyploidizing pattern and expansion of the diploid hepatocytes population is observed in neoplastic nodules. Here we review the current state of understanding about how polyploidization is regulated during normal and pathological liver growth and detail by which mechanisms hepatocytes become polyploid.

  19. Prolactin and liver disease

    NARCIS (Netherlands)

    A.G.C. Bauer (Alexander)

    1982-01-01

    textabstractCirrhosis of the liver is associated with profound endocrinological disturbances. Until recently it was thought that these disturbances were caused mainly by ineffective elimination of hormones by the diseased liver. It is now known that the pathogenesis of disturbed hormonal function in

  20. Acute liver failure

    DEFF Research Database (Denmark)

    Bernal, William; Lee, William M; Wendon, Julia

    2015-01-01

    Over the last three decades acute liver failure (ALF) has been transformed from a rare and poorly understood condition with a near universally fatal outcome, to one with a well characterized phenotype and disease course. Complex critical care protocols are now applied and emergency liver...

  1. Liver Disease and Adult Vaccination

    Science.gov (United States)

    ... The Basics Adult Vaccination Resources for Healthcare Professionals Liver Disease and Adult Vaccination Recommend on Facebook Tweet ... critical for people with health conditions such as liver disease. If you have chronic liver disease, talk ...

  2. Percutaneous laser ablation of hepatocellular carcinoma in patients with liver cirrhosis awaiting liver transplantation

    International Nuclear Information System (INIS)

    Pompili, Maurizio; Pacella, Claudio Maurizio; Francica, Giampiero; Angelico, Mario; Tisone, Giuseppe; Craboledda, Paolo; Nicolardi, Erica; Rapaccini, Gian Ludovico; Gasbarrini, Giovanni

    2010-01-01

    Objective: The aim of this study was to determine the effectiveness and safety of percutaneous laser ablation for the treatment of cirrhotic patients with hepatocellular carcinoma awaiting liver transplantation. Materials and methods: The data of 9 male cirrhotic patients (mean age 50 years, range 45-60 years) with 12 biopsy proven nodules of hepatocellular carcinoma (mean diameter 2.0 cm, range 1.0-3.0 cm) treated by laser ablation before liver transplantation between June 2000 and January 2006 were retrospectively reviewed. Laser ablation was carried out by inserting 300 nm optical fibers through 21-Gauge needles (from two to four) positioned under ultrasound guidance into the target lesions. A continuous wave Neodymium:Yttrium Aluminium Garnet laser was used. Transarterial chemoembolization prior to liver transplantation was performed in two incompletely ablated tumors. Results: No procedure-related major complications were recorded. During the waiting time to liver transplantation local tumor progression after ablation occurred in 3 nodules (25%). At histological examination of the explanted livers complete necrosis was found in 8 nodules (66.7%, all treated exclusively with laser ablation), partial necrosis >50% in 3 nodules (25%), and partial necrosis <50% in 1 nodule. Conclusion: In patients with cirrhotic livers awaiting liver transplantation, percutaneous laser ablation is safe and effective for the management of small hepatocellular carcinoma.

  3. Fraction from human and rat liver which is inhibitory for proliferation of liver cells.

    Science.gov (United States)

    Chen, T S; Ottenweller, J; Luke, A; Santos, S; Keeting, P; Cuy, R; Lea, M A

    1989-01-01

    A comparative study was undertaken with human and rat liver of a fraction reported to have growth inhibitory activity when prepared from rat liver. Fractions which were soluble in 70% ethanol and insoluble in 87% ethanol were prepared from liver cytosols. Electrophoretic analysis under denaturing conditions indicated that there were several quantitative or qualitative differences in the fractions from the two species. Fractions from both human and rat liver were found to be inhibitory for the incorporation of 3H-thymidine into DNA of foetal chick hepatocytes. Under conditions in which the rat fraction inhibited precursor incorporation into DNA of rat liver epithelial cells there was not a significant inhibitory effect with the fraction from human liver. DNA synthesis in a rat hepatoma cell line was not significantly inhibited by preparations from either species. The data suggested that corresponding fractions from both rat and human liver could have inhibitory effects on precursor incorporation into DNA but the magnitude of the effects and target cell specificity may differ.

  4. Evaluation of stromal myofibroblasts in oral leukoplakia, oral submucous fibrosis, and oral squamous cell carcinoma - an immunohistochemical study

    Directory of Open Access Journals (Sweden)

    Kanupriya Gupta

    2015-01-01

    Conclusion: These findings are suggestive of role of MFs with the creation of a permissive environment for tumor invasion in OSCC. Hence the presence of MF is a prognostic marker and evaluation of the frequency in the stroma can be used as therapeutic targets.

  5. Liver cancer oncogenomics

    DEFF Research Database (Denmark)

    Marquardt, Jens U; Andersen, Jesper B

    2015-01-01

    Primary liver cancers are among the most rapidly evolving malignant tumors worldwide. An underlying chronic inflammatory liver disease, which precedes liver cancer development for several decades and frequently creates a pro-oncogenic microenvironment, impairs progress in therapeutic approaches....... Molecular heterogeneity of liver cancer is potentiated by a crosstalk between epithelial tumor and stromal cells that complicate translational efforts to unravel molecular mechanisms of hepatocarcinogenesis with a drugable intend. Next-generation sequencing has greatly advanced our understanding of cancer...... development. With regards to liver cancer, the unprecedented coverage of next-generation sequencing has created a detailed map of genetic alterations and identified key somatic changes such as CTNNB1 and TP53 as well as several previously unrecognized recurrent disease-causing alterations that could...

  6. Inflammatory myofibroblastic tumor in the head of the pancreas with anorexia and vomiting in a 69-year-old man: A case report.

    Science.gov (United States)

    Ding, Ding; Bu, Xianmin; Tian, Feng

    2016-08-01

    Inflammatory myofibroblastic tumor (IMT) is a rare condition of unclear etiology that is commonly observed in the lung but rarely in the pancreas. WHO classified IMT as a potentially malignant or aggressive tumor. In the present report, the case of a 69-year-old male patient with an IMT in the head of the pancreas, who experienced anorexia, nausea and vomiting, is presented. The patient's clinical symptoms were nonspecific, and the imaging findings revealed a hypovascularized pancreatic mass with stenosis of the descending duodenum. The electronic endoscopy findings revealed protruding lesions in the duodenal bulb and the descending duodenum. Biopsies of the mass were conducted with an electronic endoscope, but were not diagnostic. Subsequent duodenopancreatectomy aided in determining a pathological diagnosis of IMT, based on the histology and immunohistochemistry results. The patient experienced a recovery without further incident, as observed during a regular follow-up 3 years later. IMT in the head of the pancreas is rare, particularly in adults. In the present study, an extremely rare case of IMT involving the head of the pancreas in an adult patient is presented, and the therapeutic options for this condition are discussed.

  7. Cytokines and Liver Diseases

    Directory of Open Access Journals (Sweden)

    Herbert Tilg

    2001-01-01

    Full Text Available Cytokines are pleiotropic peptides produced by virtually every nucleated cell in the body. In most tissues, including the liver, constitutive production of cytokines is absent or minimal. There is increasing evidence that several cytokines mediate hepatic inflammation, apoptosis and necrosis of liver cells, cholestasis and fibrosis. Interestingly, the same mediators also mediate the regeneration of liver tissue after injury. Among the various cytokines, the proinflammatory cytokine tumour necrosis factor-alpha (TNF-a has emerged as a key factor in various aspects of liver disease, such as cachexia and/or cholestasis. Thus, antagonism of TNF-a and other injury-related cytokines in liver diseases merits evaluation as a treatment of these diseases. However, because the same cytokines are also necessary for the regeneration of the tissue after the liver has been injured, inhibition of these mediators might impair hepatic recovery. The near future will bring the exiting clinical challenge of testing new anticytokine strategies in various liver diseases.

  8. Moro orange juice prevents fatty liver in mice.

    Science.gov (United States)

    Salamone, Federico; Li Volti, Giovanni; Titta, Lucilla; Puzzo, Lidia; Barbagallo, Ignazio; La Delia, Francesco; Zelber-Sagi, Shira; Malaguarnera, Michele; Pelicci, Pier Giuseppe; Giorgio, Marco; Galvano, Fabio

    2012-08-07

    To establish if the juice of Moro, an anthocyanin-rich orange, may improve liver damage in mice with diet-induced obesity. Eight-week-old mice were fed a high-fat diet (HFD) and were administrated water or Moro juice for 12 wk. Liver morphology, gene expression of lipid transcription factors, and metabolic enzymes were assessed. Mice fed HFD displayed increased body weight, insulin resistance and dyslipidemia. Moro juice administration limited body weight gain, enhanced insulin sensitivity, and decreased serum triglycerides and total cholesterol. Mice fed HFD showed liver steatosis associated with ballooning. Dietary Moro juice markedly improved liver steatosis by inducing the expression of peroxisome proliferator-activated receptor-α and its target gene acylCoA-oxidase, a key enzyme of lipid oxidation. Consistently, Moro juice consumption suppressed the expression of liver X receptor-α and its target gene fatty acid synthase, and restored liver glycerol-3-phosphate acyltransferase 1 activity. Moro juice counteracts liver steatogenesis in mice with diet-induced obesity and thus may represent a promising dietary option for the prevention of fatty liver.

  9. Elastin in the Liver

    Directory of Open Access Journals (Sweden)

    Jiri Kanta

    2016-10-01

    Full Text Available A characteristic feature of liver cirrhosis is the accumulation of large amounts of connective tissue with the prevailing content of type I collagen. Elastin is a minor connective tissue component in normal liver but it is actively synthesized by hepatic stellate cells and portal fibroblasts in diseased liver. The accumulation of elastic fibers in later stages of liver fibrosis may contribute to the decreasing reversibility of the disease with advancing time. Elastin is formed by polymerization of tropoelastin monomers. It is an amorphous protein highly resistant to the action of proteases that forms the core of elastic fibers. Microfibrils surrounding the core are composed of fibrillins that bind a number of proteins involved in fiber formation. They include microfibril-associated glycoproteins (MAGPs, microfibrillar-associated proteins (MFAPs and fibulins. Lysyl oxidase (LOX and lysyl oxidase-like proteins (LOXLs are responsible for tropoelastin cross-linking and polymerization. TGF-β complexes attached to microfibrils release this cytokine and influence the behavior of the cells in the neighborhood. The role of TGF-β as the main profibrotic cytokine in the liver is well-known and the release of the cytokines of TGF-β superfamily from their storage in elastic fibers may affect the course of fibrosis. Elastic fibres are often studied in the tissues where they provide elasticity and resilience but their role is no longer viewed as purely mechanical. Tropoelastin, elastin polymer and elastin peptides resulting from partial elastin degradation influence fibroblastic and inflammatory cells as well as angiogenesis. A similar role may be performed by elastin in the liver. This article reviews the results of the research of liver elastic fibers on the backgound of the present knowledge of elastin biochemistry and physiology. The regulation of liver elastin synthesis and degradation may be important for the outcome of liver fibrosis.

  10. A wandering liver

    International Nuclear Information System (INIS)

    Nichols, Brandon W.; Figarola, Maria S.; Standley, Todd B.

    2010-01-01

    A wandering liver has been described throughout modern medical literature as a rare entity. During the last few years, an increasing number of cases have been reported associated with colonic volvulus. We report a 17-year-old with a hypermobile liver seen on multiple radiographs and CT. The intraoperative findings demonstrated the liver in its normal anatomic position. We suggest that this entity is more common than thought, and the rise in incidence is likely secondary to increased utilization of pre-operative imaging of patients with colonic obstruction. Increased suspicion might result in further increased incidence of this exceedingly rare entity. (orig.)

  11. A wandering liver

    Energy Technology Data Exchange (ETDEWEB)

    Nichols, Brandon W.; Figarola, Maria S.; Standley, Todd B. [University of South Alabama, Department of Radiology, Mobile, AL (United States)

    2010-08-15

    A wandering liver has been described throughout modern medical literature as a rare entity. During the last few years, an increasing number of cases have been reported associated with colonic volvulus. We report a 17-year-old with a hypermobile liver seen on multiple radiographs and CT. The intraoperative findings demonstrated the liver in its normal anatomic position. We suggest that this entity is more common than thought, and the rise in incidence is likely secondary to increased utilization of pre-operative imaging of patients with colonic obstruction. Increased suspicion might result in further increased incidence of this exceedingly rare entity. (orig.)

  12. 25 Ways to Love Your Liver

    Science.gov (United States)

    ... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

  13. [Management of synchronous colorectal liver metastases].

    Science.gov (United States)

    Dupré, Aurélien; Gagnière, Johan; Chen, Yao; Rivoire, Michel

    2013-04-01

    At time of diagnosis, 10 to 25% of patients with colorectal cancer present synchronous liver metastases. The treatment of such patients remains controversial without any evidence based organization. Therapeutic sequences are discussed including chemotherapy, colorectal surgery, liver resection and even radio-chemotherapy for some rectal cancers. In case of resectable liver metastases, preoperative chemotherapy offers the advantage of earlier treatment of micro-metastases as well as evaluation of tumor responsiveness, which can help shape future therapy. In this setting, different surgical strategies can be chosen (classical staged procedures with colorectal surgery followed by liver surgery, simultaneous resections or liver first approach) depending on the importance of the primary and metastatic tumors. The literature remains limited, but the results of these strategies seem identical in term of postoperative morbidity and long-term survival. Staged procedures are preferred in case of major liver resection. Location of the primary tumor on the low or mid rectum will necessitate preoperative long course chemoradiotherapy and a more complex multidisciplinary organization. For patients with extensive liver metastases, non-resectability must be assessed by experienced surgeon and radiologist before treatment and during chemotherapy. In this group of patients, improved chemotherapy regimen associated with targeted therapies and new surgical strategies (portal vein embolization, ablation, staged hepatectomies…) have improved resection rate (15 to 30-40%) and long-term survival. Treatment organization for the primary tumor remains controversial. Resection of the primary to manage symptoms such as obstruction, perforation or bleeding is advocated. For patients with asymptomatic primary a non-surgical approach permits to begin rapidly chemotherapy and obtain a better control of the disease. On the other hand, initial resection of the primary may avoid complications and

  14. Contribution of Gut Bacteria to Liver Pathobiology

    Directory of Open Access Journals (Sweden)

    Gakuhei Son

    2010-01-01

    Full Text Available Emerging evidence suggests a strong interaction between the gut microbiota and health and disease. The interactions of the gut microbiota and the liver have only recently been investigated in detail. Receiving approximately 70% of its blood supply from the intestinal venous outflow, the liver represents the first line of defense against gut-derived antigens and is equipped with a broad array of immune cells (i.e., macrophages, lymphocytes, natural killer cells, and dendritic cells to accomplish this function. In the setting of tissue injury, whereby the liver is otherwise damaged (e.g., viral infection, toxin exposure, ischemic tissue damage, etc., these same immune cell populations and their interactions with the infiltrating gut bacteria likely contribute to and promote these pathologies. The following paper will highlight recent studies investigating the relationship between the gut microbiota, liver biology, and pathobiology. Defining these connections will likely provide new targets for therapy or prevention of a wide variety of acute and chronic liver pathologies.

  15. Bile Acid Metabolism in Liver Pathobiology

    Science.gov (United States)

    Chiang, John Y. L.; Ferrell, Jessica M.

    2018-01-01

    Bile acids facilitate intestinal nutrient absorption and biliary cholesterol secretion to maintain bile acid homeostasis, which is essential for protecting liver and other tissues and cells from cholesterol and bile acid toxicity. Bile acid metabolism is tightly regulated by bile acid synthesis in the liver and bile acid biotransformation in the intestine. Bile acids are endogenous ligands that activate a complex network of nuclear receptor farnesoid X receptor and membrane G protein-coupled bile acid receptor-1 to regulate hepatic lipid and glucose metabolic homeostasis and energy metabolism. The gut-to-liver axis plays a critical role in the regulation of enterohepatic circulation of bile acids, bile acid pool size, and bile acid composition. Bile acids control gut bacteria overgrowth, and gut bacteria metabolize bile acids to regulate host metabolism. Alteration of bile acid metabolism by high-fat diets, sleep disruption, alcohol, and drugs reshapes gut microbiome and causes dysbiosis, obesity, and metabolic disorders. Gender differences in bile acid metabolism, FXR signaling, and gut microbiota have been linked to higher prevalence of fatty liver disease and hepatocellular carcinoma in males. Alteration of bile acid homeostasis contributes to cholestatic liver diseases, inflammatory diseases in the digestive system, obesity, and diabetes. Bile acid-activated receptors are potential therapeutic targets for developing drugs to treat metabolic disorders. PMID:29325602

  16. Progression of Liver Disease

    Science.gov (United States)

    ... Legacy Society Make Gifts of Stock Donate Your Car Personal Fundraising Partnership & Support Share Your Story Spread the Word Give While You Shop Contact Us Donate Now The Progression of Liver ...

  17. Benign Liver Tumors

    Science.gov (United States)

    ... Legacy Society Make Gifts of Stock Donate Your Car Personal Fundraising Partnership & Support Share Your Story Spread the Word Give While You Shop Contact Us Donate Now Benign Liver Tumors Back ...

  18. Acute Liver Failure

    Science.gov (United States)

    ... can cause acute liver failure. It is an industrial chemical found in refrigerants and solvents for waxes, varnishes ... measures when spraying insecticides, fungicides, paint and other toxic chemicals. Follow product instructions carefully. Watch what gets on ...

  19. Liver Aspiration Cytology

    African Journals Online (AJOL)

    1974-11-02

    Nov 2, 1974 ... S.A. MEDICAL. JOURNAL .... be the result of either an anatomical obstruction in the biliary system or of ... contour of these droplets indicates their canalicular origin. ..... terminology for cytological changes in the liver has not.

  20. [Diabetes in liver cirrhosis].

    Science.gov (United States)

    García-Compeán, Diego; Jáquez-Quintana, Joel O; González-González, José A; Lavalle-González, Fernando J; Villarreal-Pérez, Jesús Z; Maldonado-Garza, Hector J

    2013-01-01

    The prevalence of overt diabetes mellitus (DM) in liver cirrhosis is about 30%. However, DM or impaired glucose tolerance can be observed in 90% after an oral glucose tolerance test in patients with normal fasting plasma glucose. Type 2 DM may produce cirrhosis, whereas DM may be a complication of cirrhosis. The latter is known as «hepatogenous diabetes». Overt and subclinical DM is associated with liver complications and death in cirrhotic patients. Treating diabetes is difficult in cirrhotic patients because of the metabolic impairments due to liver disease and because the most appropriate pharmacologic treatment has not been defined. It is also unknown if glycemic control with hypoglycemic agents has any impact on the course of the liver disease. Copyright © 2013 Elsevier España, S.L. y AEEH y AEG. All rights reserved.

  1. Progression of Liver Disease

    Science.gov (United States)

    ... If cirrhosis is not treated, the liver will fail and will not be able to work well ... Gifts of Stock Donate Your Car Personal Fundraising Partnership & Support Share Your Story Spread the Word Give ...

  2. Liver Transplant: Nutrition

    Science.gov (United States)

    ... Liver Transplant: Nutrition Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For Veterans and the Public Veterans and the Public Home Hepatitis A Hepatitis B Hepatitis C Hepatitis C Home Getting ...

  3. Alcoholic liver disease

    Science.gov (United States)

    ... FF, ed. Ferri's Clinical Advisor 2018 . Philadelphia, PA: Elsevier; 2018:59-60. Carithers RL, McClain C. Alcoholic ... Gastrointestinal and Liver Disease . 10th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 86. Haines EJ, Oyama LC. ...

  4. Periodontal disease and liver cirrhosis

    DEFF Research Database (Denmark)

    Grønkjær, Lea Ladegaard

    2015-01-01

    and liver cirrhosis and to identify opportunities and directions for future research in this area. METHODS: A systematic review of English articles in the PubMed, EMBASE, and Scopus databases was conducted using search terms including 'liver cirrhosis', 'end-stage liver disease', 'liver diseases', 'oral...

  5. Antioxidant supplements for liver diseases

    DEFF Research Database (Denmark)

    Bjelakovic, Goran; Gluud, Lise Lotte; Nikolova, Dimitrinka

    2011-01-01

    Several liver diseases have been associated with oxidative stress. Accordingly, antioxidants have been suggested as potential therapeutics for various liver diseases. The evidence supporting these suggestions is equivocal.......Several liver diseases have been associated with oxidative stress. Accordingly, antioxidants have been suggested as potential therapeutics for various liver diseases. The evidence supporting these suggestions is equivocal....

  6. Mice with humanized liver endothelium

    NARCIS (Netherlands)

    el Filali, E.

    2014-01-01

    The only curative treatment option for a large proportion of patients suffering from a liver disorder is liver transplantation. The use of ex vivo genetically modified autologous liver cells instead of whole liver transplantation could overcome the problem of donor scarcity. Even though clinical

  7. Liver Effects of Clinical Drugs Differentiated in Human Liver Slices

    Directory of Open Access Journals (Sweden)

    Alison E. M. Vickers

    2017-03-01

    Full Text Available Drugs with clinical adverse effects are compared in an ex vivo 3-dimensional multi-cellular human liver slice model. Functional markers of oxidative stress and mitochondrial function, glutathione GSH and ATP levels, were affected by acetaminophen (APAP, 1 mM, diclofenac (DCF, 1 mM and etomoxir (ETM, 100 μM. Drugs targeting mitochondria more than GSH were dantrolene (DTL, 10 μM and cyclosporin A (CSA, 10 μM, while GSH was affected more than ATP by methimazole (MMI, 500 μM, terbinafine (TBF, 100 μM, and carbamazepine (CBZ 100 μM. Oxidative stress genes were affected by TBF (18%, CBZ, APAP, and ETM (12%–11%, and mitochondrial genes were altered by CBZ, APAP, MMI, and ETM (8%–6%. Apoptosis genes were affected by DCF (14%, while apoptosis plus necrosis were altered by APAP and ETM (15%. Activation of oxidative stress, mitochondrial energy, heat shock, ER stress, apoptosis, necrosis, DNA damage, immune and inflammation genes ranked CSA (75%, ETM (66%, DCF, TBF, MMI (61%–60%, APAP, CBZ (57%–56%, and DTL (48%. Gene changes in fatty acid metabolism, cholestasis, immune and inflammation were affected by DTL (51%, CBZ and ETM (44%–43%, APAP and DCF (40%–38%, MMI, TBF and CSA (37%–35%. This model advances multiple dosing in a human ex vivo model, plus functional markers and gene profile markers of drug induced human liver side-effects.

  8. Pitfalls in liver imaging

    Energy Technology Data Exchange (ETDEWEB)

    Itai, Yuji; Saida, Yukihisa [Department of Radiology, Institute of Clinical Medicine, University of Tsukuba (Japan)

    2002-05-01

    Localized, abnormal attenuation/intensity areas on unenhanced and/or enhanced study of CT/MR imaging do not necessarily correspond to tumors themselves or real tumor size. Pitfalls in the diagnosis of liver tumor are described dividing into enhanced study (vascular variants, vascular abnormalities, hyperplastic nodules, around the tumor, and miscellaneous) and unenhanced study (fatty change, focal spared area of diffuse fatty liver, and miscellaneous). (orig.)

  9. Pitfalls in liver imaging

    International Nuclear Information System (INIS)

    Itai, Yuji; Saida, Yukihisa

    2002-01-01

    Localized, abnormal attenuation/intensity areas on unenhanced and/or enhanced study of CT/MR imaging do not necessarily correspond to tumors themselves or real tumor size. Pitfalls in the diagnosis of liver tumor are described dividing into enhanced study (vascular variants, vascular abnormalities, hyperplastic nodules, around the tumor, and miscellaneous) and unenhanced study (fatty change, focal spared area of diffuse fatty liver, and miscellaneous). (orig.)

  10. Acute liver failure

    DEFF Research Database (Denmark)

    Larsen, Fin Stolze; Bjerring, Peter Nissen

    2011-01-01

    Acute liver failure (ALF) results in a multitude of serious complications that often lead to multi-organ failure. This brief review focuses on the pathophysiological processes in ALF and how to manage these.......Acute liver failure (ALF) results in a multitude of serious complications that often lead to multi-organ failure. This brief review focuses on the pathophysiological processes in ALF and how to manage these....

  11. Autoimmune liver disease 2007.

    Science.gov (United States)

    Muratori, Paolo; Granito, Alessandro; Pappas, Georgios; Muratori, Luigi; Lenzi, Marco; Bianchi, Francesco B

    2008-01-01

    Autoimmune liver disease (ALD) includes a spectrum of diseases which comprises both cholestatic and hepatitic forms: autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and the so called "overlap" syndromes where hepatitic and cholestatic damage coexists. All these diseases are characterized by an extremely high heterogeneity of presentation, varying from asymptomatic, acute (as in a subset of AIH) or chronic (with aspecific symptoms such as fatigue and myalgia in AIH or fatigue and pruritus in PBC and PSC). The detection and characterization of non organ specific autoantibodies plays a major role in the diagnostic approach of autoimmune liver disease; anti nuclear reactivities (ANA) and anti smooth muscle antibodies (SMA) mark type 1 AIH, liver kidney microsomal antibody type 1 (LKM1) and liver cytosol type 1 (LC1) are the serological markers of type 2 AIH; antimitochondrial antibodies (AMA) are associated with PBC, while no specific marker is found in PSC, since anticytoplasmic neutrophil antibodies with perinuclear pattern (atypical p-ANCA or p-ANNA) are also detected in a substantial proportion of type 1 AIH cases. Treatment options rely on immunosoppressive therapy (steroids and azathioprine) in AIH and on ursodeoxycholic acid in cholestatic conditions; in all these diseases liver transplantation remains the only therapeutical approach for the end stage of liver disease.

  12. Gaming the Liver Transplant Market

    OpenAIRE

    Jason Snyder

    2010-01-01

    The liver transplant waiting list is designed to allocate livers to the sickest patients first. Before March 1, 2002, livers were allocated to patients based on objective clinical indicators and subjective factors. In particular, a center placing a prospective transplant recipient in the intensive care unit (ICU) leads to a higher position on the liver transplant waiting list. After March 1, 2002, a policy reform mandated that priority on the liver transplant waiting list no longer be influen...

  13. Targeting cancer stem cells in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    He AR

    2014-12-01

    Full Text Available Aiwu Ruth He,1 Daniel C Smith,1 Lopa Mishra2 1Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 2Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Abstract: The poor outcome of patients with hepatocellular carcinoma (HCC is attributed to recurrence of the disease after curative treatment and the resistance of HCC cells to conventional chemotherapy, which may be explained partly by the function of liver cancer stem cells (CSCs. Liver CSCs have emerged as an important therapeutic target against HCC. Numerous surface markers for liver CSCs have been identified, and include CD133, CD90, CD44, CD13, and epithelial cell adhesion molecules. These surface markers serve not only as tools for identifying and isolating liver CSCs but also as therapeutic targets for eradicating these cells. In studies of animal models and large-scale genomic analyses of human HCC samples, many signaling pathways observed in normal stem cells have been found to be altered in liver CSCs, which accounts for the stemness and aggressive behavior of these cells. Antibodies and small molecule inhibitors targeting the signaling pathways have been evaluated at different levels of preclinical and clinical development. Another strategy is to promote the differentiation of liver CSCs to less aggressive HCC that is sensitive to conventional chemotherapy. Disruption of the tumor niche essential for liver CSC homeostasis has become a novel strategy in cancer treatment. To overcome the challenges in developing treatment for liver CSCs, more research into the genetic makeup of patient tumors that respond to treatment may lead to more effective therapy. Standardization of HCC CSC tumor markers would be helpful for measuring the CSC response to these agents. Herein, we review the current strategies for developing treatment to eradicate liver CSCs and to improve the outcome for patients with

  14. Structural changes in the liver in metabolic syndrome

    Directory of Open Access Journals (Sweden)

    D. V. Vasendin

    2015-01-01

    Full Text Available Scientifically proven close relationship of nonalcoholic fatty liver disease with development of metabolic syndrome and its individual components involves the conclusion that the target organ in metabolic symptom, even regardless of the severity of obesity, the liver occupies a dominant position, as the body undergoes the first characteristic of non-alcoholic fatty liver disease changes, involving violation of metabolism in the body. Dislipoproteinemia plays an important role in the formation of metabolic syndrome in obesity and other obesity-associated diseases. Altered liver function are the root cause of violations of processes of lipid metabolism and, consequently, abnormal functioning of the liver may be a separate, additional and independent risk factor for development of dyslipidemia and obesity as the main component of the metabolic syndrome.

  15. Bioartificial liver and liver transplantation: new modalities for the treatment of liver failure

    Directory of Open Access Journals (Sweden)

    DING Yitao

    2017-09-01

    Full Text Available The main features of liver failure are extensive necrosis of hepatocytes, rapid disease progression, and poor prognosis, and at present, there are no effective drugs and methods for the treatment of liver failure. This article summarizes four treatment methods for liver failure, i.e., medical treatment, cell transplantation, liver transplantation, and artificial liver support therapy, and elaborates on the existing treatment methods. The current medical treatment regimen should be optimized; cell transplantation has not been used in clinical practice; liver transplantation is the most effective method, but it is limited by donor liver shortage and high costs; artificial liver can effectively remove toxic substances in human body. Therefore, this article puts forward artificial liver as a transition for liver transplantation; artificial liver can buy time for liver regeneration or liver transplantation and prolong patients′ survival time and thus has a promising future. The new treatment modality of bioartificial liver combined with liver transplantation may bring good news to patients with liver failure.

  16. Perioperative management of liver surgery-review on pathophysiology of liver disease and liver failure.

    Science.gov (United States)

    Gasteiger, Lukas; Eschertzhuber, Stephan; Tiefenthaler, Werner

    2018-01-01

    An increasing number of patients present for liver surgery. Given the complex pathophysiological changes in chronic liver disease (CLD), it is pivotal to understand the fundamentals of chronic and acute liver failure. This review will give an overview on related organ dysfunction as well as recommendations for perioperative management and treatment of liver failure-related symptoms.

  17. Excellent survival after liver transplantation for isolated polycystic liver disease : an European Liver Transplant Registry study

    NARCIS (Netherlands)

    van Keimpema, Loes; Nevens, Frederik; Adam, Rene; Porte, Robert J.; Fikatas, Panagiotis; Becker, Thomas; Kirkegaard, Preben; Metselaar, Herold J.; Drenth, Joost P. H.

    2011-01-01

    Patients with end