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Contribution of TLR signaling to the pathogenesis of colitisassociated cancer in inflammatory bowel disease

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World Journal of Gastroenterology 2014年第36期20卷 12713-12721页

作者： ferenc Sipos István Fri Miklós Constantinovits Zsolt Tulassay Gyrgyi Mzes 2nd Department of Internal Medicine Semmelweis University 1088 Budapest Hungary Molecular Medicine Research Unit Hungarian Academy of Sciences 1088 Budapest Hungary

In the intestine a balance between proinflammatory and repair signals of the immune system is essential for the maintenance of intestinal homeostasis. The innate immunity ensures a primary host response to microbial invasion, which induces an inflammatory process to localize the infection and prevent systemic dissemination of pathogens. The key elements of this process are the germline encoded pattern recognition receptors including Toll-like receptors (TLRs). If pathogens cannot be eliminated, they may elicit chronic inflammation, which may be partly mediated via TLRs. Additionally, chronic inflammation has long been suggested to trigger tissue tumorous transformation. Inflammation, the seventh hallmark of cancer, may affect all phases of tumor development, and evade the immune system. Inflammation acts as a cellular stressor and may trigger DNA damage or genetic instability. Furthermore, chronic inflammation can provoke genetic mutations and epigenetic mechanisms that promote malignant cell transformation. Colorectal cancers in inflammatory bowel disease patients are considered typical examples of inflammation-related cancers. Although data regarding the role of TLRs in the pathomechanism of cancer-associated colitis are rather conflicting, functionally these molecules can be classified as ”largely antitumorigenic” and ”largely pro-tumorigenic” with the caveat that the underlying signaling pathways are mainly context (i.e., organ-, tissue-, cell-) and ligand-dependent.

关键词： Inflammation Tissue repair Immunoregulation Colitis-associated cancer Toll-like receptor Inflammatory bowel disease Carcinogenesis

Efficacy of 6-mercaptopurine treatment after azathioprine hypersensitivity in inflammatory bowel disease

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World Journal of Gastroenterology 2008年第27期14卷 4342-4346页

作者： ferenc Nagy Tamás Molnár Zoltán Szepes Klaudia Farkas Tibor Nyári János Lonovics First Department of Medicine University of Szeged Faculty of Medicine Institute of Medical Informatics University of Szeged Faculty of Medicine

AIM:To investigate the efficacy of 6-mercaptopurine (6-MP) in cases of azathioprine (AZA) hypersensitivity in patients with inflammatory bowel disease. METHODS: Twenty nine previously confirmed Crohn’s disease (CD) (n = 14) and ulcerative colitis (UC) (n = 15) patients with a known previous (AZA) hypersensitivity reaction were studied prospectively. The 6-MP doses were gradually increased from 0.5 up to 1.0-1.5 mg/kg per day. Clinical activity indicies (CDAI/CAI), laboratory variables and daily doses of oral 5-ASA, corticosteroids, and 6-MP were assessed before and in the first, sixth and twelfth months of treatment. RESULTS: In 9 patients, 6-MP was withdrawn in the first 2 wk due to an early hypersensitivity reaction. Medication was ineffective within 6 mo in 6 CD patients, and myelotoxic reaction was observed in two. Data were evaluated at the end of the sixth month in 12 (8 UC, 4 CD) patients, and after the first year in 9 (6 UC, 3 CD) patients. CDAI decreased transiently at the end of the sixth month, but no significant changes were observed in the CDAI or the CAI values at the end of the year. Leukocyte counts (P = 0.01), CRP (P = 0.02), and serum iron (P = 0.05) values indicated decreased inflammatory reactions, especially in the UC patients at the end of the year, making the possibility to taper oral steroid doses. CONCLUSION: About one-third of the previously AZA- intolerant patients showed adverse effects on taking 6MP. In our series, 20 patients tolerated 6MP, but it was ineffective in 8 CD cases, and valuable mainly in ulcerative colitis patients.

关键词： Inflammatory bowel disease Azathioprine 6-mercaptopurine Side effects Efficacy

Restricted Summability of Fourier Transforms and Local Hardy Spaces

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Acta Mathematica Sinica,English Series 2010年第9期26卷 1627-1640页

作者： ferenc WEISZ Department of Numerical Analysis Etvs L. University

A general summability method, the so-called θ-summability is considered for multi-dimensional Fourier transforms. Under some conditions on θ, it is proved that the maximal operator of the θ-means defined in a cone is bounded from the amalgam Hardy space W（hp, e∞） to W（Lp,e∞）. This implies the almost everywhere convergence of the θ-means in a cone for all f ∈ W（L1, e∞） velong to L1.

关键词： Wiener amalgam spaces local Hardy spaces 0-summability of Fourier transforms atomic decomposition

Thermal Reversion of Plant Phytochromes

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Molecular Plant 2020年第3期13卷 386-397页

作者： Cornelia Klose ferenc Nagy Eberhard Schafer Institute of Biology II University of Freiburg79104 FreiburgGermany Institute of Plant Biology Biological Research CentreTemesvari krt.626726 SzegedHungary

Phytochromes are red/far-red reversible photoreceptors essential for plant growth and *** signaling is mediated by the physiologically active far-red-absorbing Pfr form that can be inactivated to the red-absorbing Pr ground state by light-dependent photoconversion or by light-independent thermal reversion,also termed dark *** the term“dark reversion”is justified by historical reasons and frequently used in the literature,“thermal reversion”more appropriately describes the process of light-independent but temperature-regulated Pfr relaxation that not only occurs in darkness but also in light and is used throughout the *** reversion is a critical parameter for the light sensitivity of phytochrome-mediated responses and has been studied for decades,often resulting in contradictory *** reversion is an intrinsic property of the phytochrome molecules but can be modulated by intra-and intermolecular interactions,as well as biochemical modifications,such as *** this review,we outline the research history of phytochrome thermal reversion,highlighting important predictions that have been made before knowing the molecular *** further summarize and discuss recent findings about the molecular mechanisms regulating phytochrome thermal reversion and its functional roles in light and temperature sensing in plants.

关键词： phytochrome phyA phyB thermal reversion dark reversion in vivo spectroscopy

Epithelial toll-like receptor 9 signaling in colorectal inflammation and cancer: Clinico-pathogenic aspects

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World Journal of Gastroenterology 2013年第26期19卷 4119-4126页

作者： István Fri ferenc Sipos Tiana M Germann Alexandra Kalmár Zsolt Tulassay Béla Molnár Gyrgyi Mzes 2nd Department of Internal Medicine Semmelweis University Faculty of Medicine Semmelweis University Molecular Medicine Research Unit Hungarian Academy of Sciences

Toll-like receptors (TLRs) recognize specific motifs which are frequently present in bacteria, fungi, prokaryotes and viruses. Amongst TLRs, TLR9 can be activated by such bacterial or viral DNA fragments, immunoglobulin-DNA complexes or synthetic oligonucleotides, which all contain unmethylated cytosineguanine nucleotide sequences (CpGs). Emerging data indicate that TLR9 signaling has a role in, and may influence, colorectal carcinogenesis and colonic inflammation. CpGs are classified into three groups according to their influence on both the antigen-specific humoraland cellular immunity, and the production of type 1 interferons and proinflammatory cytokines. TLR9 activation via CpGs may serve as a new therapeutic target for several cancerous and various inflammatory conditions. Due to its probable anti-cancer effects, the application possibilities of TLR9-signaling modulation may be extremely diverse even in colorectal tumors. In this review we aimed to summarize the current knowledge about TLR-signaling in the pathogenesis and therapy of inflammatory bowel diseases and colorectal cancer. Due to the species-specific differences in TLR9 expression, however, one must be careful in translating the animal model data into the human system, because of the differences between CpG-oligodeoxynucleotide-responsive cells. TLR9 agonist DNA-based immunomodulatory sequences could also represent a promising therapeutic alternative in systemic inflammatory conditions and chronic colonic inflammations as their side effects are not significant.

关键词： Toll-like receptor 9 Synthetic oligodeoxy-nucleotide sequences DNA-based immunomodulatory sequences Colorectal cancer Inflammatory bowel diseases

Epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions in the colon

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World Journal of Gastroenterology 2012年第7期18卷 601-608页

作者： ferenc Sipos Orsolya Galamb Cell Analysis Laboratory 2nd Department of Internal MedicineSemmelweis University1088 BudapestHungary Molecular Medicine Research Unit Hungarian Academy of Sciences1051 BudapestHungary

Epithelial-to-mesenchymal and mesenchymal-to-epi- thelial transitions are well established biological events which have an important role in not just normal tissue and organ development, but in the pathogenesis of diseases. Increasing evidence has established their presence in the human colon during colorectal carcinogenesis and cancer invasion, chronic inflammation-related fibrosis and in the course of mucosal healing. A large body of evidence supports the role for transforming growth factor-13 and its downstream Smad signaling, the phosphatidylinositol 3＇-kinase/Akt/mTOR axis, the Ras-mitogen-activated protein kinase/Snail/Slug and FOXC2 pathway, and Hedgehog signaling and microR- NAs in the development of colorectal cancers via epi- thelial-to-mesenchymal transition. C-met and Frizzled-7, among others, seem to be the principle effectors of mesenchymal-to-epithelial transition, hence have a role not just in mucosal regeneration but in the progression of colonic wall fibrosis. Here we discuss a role for these pathways in the initiation and development of the transition events. A better understanding of their induction and regulation may lead to the identification of pathways and factors that could be potent therapeu- tic targets. The inhibition of epithelial-to-mesenchymal transition using mTOR kinase inhibitors targeting theATP binding pocket and which inhibit both mTORC1 and mTORC2, RNA aptamers or peptide mimetics, such as a Wnt5A-mimetic, may all be useful in both cancer treatment and delaying fibrosis, while the induction of mesenchymal-to-epithelial transition in induced pluripotent stem cells may enhance epithelial healing in the case of severe mucosal damage. The preliminary results of the current studies are promising, but more clinical investigations are needed to develop new and safe therapeutic strategies for diseases of the colon.

关键词： Epithelial-to-mesenchymal transition Mesen-chymal-to-epithelial transition Colorectal cancer Fibrosis Mucosal healing

Effect of ageing on colonic mucosal regeneration

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World Journal of Gastroenterology 2011年第25期17卷 2981-2986页

作者： ferenc Sipos Katalin Leiszter Zsolt Tulassay 2nd Department of Internal Medicine Semmelweis University Molecular Medicine Research Unit Hungarian Academy of Sciences

The physiologic and pathologic cellular and molecular changes occurring with age in the human colon affect both the inflammatory process leading to mucosal injury and the regenerative capacity of the *** the one hand,age-related telomere shortening and inflamm-ageing may lead to the development of colonic inflammation,which results in epithelial *** the other hand,the altered migration and function of regenerative stem cells,the age-related methylation of mucosal healing-associated genes,together with the alterations of growth factor signaling with age,may be involved in delayed mucosal *** connections of these alterations to the process of ageing are not fully *** understanding and customtailored modification of these mechanisms are of great clinical importance with regard to disease prevention and modern therapeutic ***,we aim to summarize the age-related microscopic and molecular changes of the human colon,as well as their role in altered mucosal healing.

关键词： Colon Mucosal repair Ageing Colorectalcancer Telomere shortening DNA methylation

Isolated lymphoid follicles in colon: Switch points between inflammation and colorectal cancer?

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World Journal of Gastroenterology 2011年第13期17卷 1666-1673页

作者： ferenc Sipos Gyrgyi Müzes 2nd Department of Internal Medicine Semmelweis University

Gut-associated lymphoid tissue is supposed to play a central role in both the organization of colonic repair mechanisms and colorectal carcinogenesis. In inflammatory conditions, the number, diameter and density of isolated lymphoid follicles (ILFs) increases. They are not only involved in immune surveillance, but their presence is also indispensable in normal mucosal regeneration of the colon. In carcinogenesis, ILFs may play a dual role. On the one hand they may support tumor growth and the metastatic process by vascular endothelial growth factor receptor signaling and producing a specific cytokine and cellular milieu, but on the other hand their presence is sometimes associated with a better prognosis. The relation of ILFs to bone marrow derived stem cells, follicular dendritic cells, subepithelial myofibroblasts or crypt formation, which are all involved in mucosal repair and carcinogenesis, has not been directly studied. Data about the putative organizer role of ILFs is scattered in scientific literature.

关键词： Isolated lymphoid follicle Colon Mucosal repair Colorectal cancer Epithelial stem cell Myofibroblast Follicular dendritic cell Mesenchymal-epithelial transition Epithelial-mesenchymal transition

Wastewater Treatment and Sludge Utilisation in Hungary

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Journal of Environmental Science and Engineering(B) 2015年第3期4卷 141-147页

作者： ferenc Ligetvári ferenc Zsabokorszky Károly Kováics István Zsirai Department of Agricultural and Food Sciences the University of West Hungary Mosonmagyaróvár 9200 Hungary Departement of Research and Development of ENQUA Ltd Budapest 1073 Hungary Departement of Water & Process Technologies of General Electric Trevose RA 19053 USA Departement of Water Economic oVBDL Ltd Budanest 1118 Hungary

Hungary＇s accession to the European Union in 2004 marked the start of a new era. The completion of legal harmonization brought in new emission standards and thresholds, and this was followed by EU-assisted projects to build and reconstruct wastewater treatment plants. The utilization of sludge after it leaves the wastewater treatment plant is now a solely private-sector operation. There are new political priorities： increasing state involvement, buying out of major--formerly privatized--service providers, reintegration of isolated service providers, legally-imposed reduction of public utility charges. As a result, a demand has arisen for a greater central, i.e. government role in sludge utilization.

关键词： European Union legal harmonization utilization sludge political priorities public utility charges