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  1. Article: Hybrid Molecules of Benzylguanidine and the Alkylating Group of Melphalan: Synthesis and Effects on Neuroblastoma Cells.

    Bruchelt, Gernot / Klose, Chihab / Lischka, Matthias / Brandes, Marietta / Handgretinger, Rupert / Brueckner, Reinhard

    Journal of clinical medicine

    2023  Volume 12, Issue 13

    Abstract: The therapy of neuroblastoma relies, amongst other things, on administering chemotherapeutics and radioactive compounds, e.g., the ( ...

    Abstract The therapy of neuroblastoma relies, amongst other things, on administering chemotherapeutics and radioactive compounds, e.g., the (
    Language English
    Publishing date 2023-07-03
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662592-1
    ISSN 2077-0383
    ISSN 2077-0383
    DOI 10.3390/jcm12134469
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Hybrid Molecules of Benzylguanidine and the Alkylating Group of Melphalan

    Gernot Bruchelt / Chihab Klose / Matthias Lischka / Marietta Brandes / Rupert Handgretinger / Reinhard Brueckner

    Journal of Clinical Medicine, Vol 12, Iss 4469, p

    Synthesis and Effects on Neuroblastoma Cells

    2023  Volume 4469

    Abstract: The therapy of neuroblastoma relies, amongst other things, on administering chemotherapeutics and radioactive compounds, e.g., the ( meta -iodobenzyl)guanidine [ 131 I]mIBG. For special applications (conditioning before stem cell transplantation), ... ...

    Abstract The therapy of neuroblastoma relies, amongst other things, on administering chemotherapeutics and radioactive compounds, e.g., the ( meta -iodobenzyl)guanidine [ 131 I]mIBG. For special applications (conditioning before stem cell transplantation), busulfan and melphalan (M) proved to be effective. However, both drugs are not used for normal chemotherapy in neuroblastoma because of their side effects. The alkylating drug melphalan contains a (Cl-CH 2 -CH 2 -) 2 N- group in the para -position of the phenyl moiety of the essential amino acid phenylalanine (Phe) and can, therefore, be taken up by virtually all kinds of cells by amino acid transporters. In contrast, mIBG isotopologs are taken up more selectively by neuroblastoma cells via the noradrenaline transporter (NAT). The present study aimed at synthesising and studying hybrid molecules of benzylguanidine (BG) and the alkylating motif of M. Such hybrids should combine the preferential uptake of BGs into neuroblastoma cells with the cytotoxicity of M. Besides the hybrid of BG with the dialkylating group (Cl-CH 2 -CH 2 -) 2 N- bound in the para -position as in M (pMBG), we also synthesised mMBG, which is BG meta -substituted by a (Cl-CH 2 -CH 2 -) 2 N- group. Furthermore, two monoalkylating hybrid molecules were synthesised: the BG para -substituted by a (Cl-CH 2 -CH 2 -)NH- group (pM*BG) and the BG meta -substituted by a (Cl-CH 2 -CH 2 -)NH- group (mM*BG). The effects of the four new compounds were studied with human neuroblastoma cell lines (SK-N-SH, Kelly, and LS) with regard to uptake, viability, and proliferation by standard test systems. The dialkylating hybrid molecules pMBG and mMBG were at least as effective as M, whereas the monoalkylating hybrid molecules pM*BG and mM*BG were more effective than M. Considering the preferred uptake via the noradrenaline transporter by neuroblastoma cells, we conclude that they might be well suited for therapy.
    Keywords neuroblastoma ; melphalan (M) ; ( meta -iodobenzyl)guanidine (mIBG) ; melphalan benzylguanidine hybrids (MBGs) ; noradrenaline transporter (NAT) ; organic cation transporter (OCT) ; Medicine ; R
    Subject code 290
    Language English
    Publishing date 2023-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Book ; Online ; Thesis: Funktionelle Charakterisierung der Kationenkanäle TRPM3 und Melastatin (TRPM1)

    Klose, Chihab [Verfasser]

    2012  

    Author's details Chihab Klose
    Keywords Biowissenschaften, Biologie ; Life Science, Biology
    Subject code sg570
    Language German
    Publisher Freie Universität Berlin
    Publishing place Berlin
    Document type Book ; Online ; Thesis
    Database Digital theses on the web

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  4. Article ; Online: Influence of ATLG Serum Levels on CD3/CD19-depleted Hematopoietic Grafts and on Immune Recovery in Pediatric Haplo-HSCT.

    Maier, Claus-Philipp / Klose, Chihab / Seitz, Christian Martin / Heubach, Florian / Döring, Michaela / Meisel, Roland / Schuster, Friedhelm R / Gruhn, Bernd / Keller, Frieder / Rabsteyn, Armin / Arendt, Anne-Marie / Amorelli, Germano / Eichholz, Thomas / Feuchtinger, Tobias / Martinius, Holger / Nierkens, Stefan / Teltschik, Rouwen / Schulte, Johannes Hubertus / Lengerke, Claudia /
    Handgretinger, Rupert / Lang, Peter

    Blood advances

    2024  

    Abstract: Anti-T lymphocyte globulin (ATLG) significantly reduces the risk of engraftment failure in allogeneic hematopoietic stem cell transplantation (HSCT), but hampers post-transplant immune reconstitution. We hypothesized that in patients receiving ... ...

    Abstract Anti-T lymphocyte globulin (ATLG) significantly reduces the risk of engraftment failure in allogeneic hematopoietic stem cell transplantation (HSCT), but hampers post-transplant immune reconstitution. We hypothesized that in patients receiving haploidentical CD3/CD19-depleted grafts these double-edged effects could be better balanced by attaining high ATLG serum concentrations before transplant, but as low as possible on the day of transplant. Therefore, we moved the start of ATLG application to day -12 and determined serum concentrations of T cell specific ATLG in pediatric patients treated with three established dosing regimens (15, 30, or 60 mg/kg). Corresponding mean T cell specific ATLG serum concentrations at day 0 were 1.14, 2.99, or 12.10 µg/ml, respectively. Higher ATLG doses correlated with higher peak levels at days -8 and -7 and reduced graft rejection, while lower ATLG doses correlated with significantly faster post-transplant recovery of T and NK cells. The rate of graft-versus-host disease (GvHD) remained low independent from ATLG doses. Moreover, in vitro assays showed that ATLG concentrations of 2.0 µg/ml and lower only slightly reduced the activity of NK cells and, therefore, the function of such effector cells might be preserved in the grafts. Pharmacokinetic analysis, compatible with linear first order kinetics, revealed similar half-life values independent of ATLG doses. Hence, the day on which a desired ATLG serum level is reached can be calculated prior to HSCT. Our retrospective study demonstrates the relevance of dosing and time of administration of ATLG on engraftment and immune recovery in ex vivo CD3/CD19-depleted haploidentical HSCT.
    Language English
    Publishing date 2024-01-30
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2915908-8
    ISSN 2473-9537 ; 2473-9529
    ISSN (online) 2473-9537
    ISSN 2473-9529
    DOI 10.1182/bloodadvances.2023011016
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Biological treatment of pediatric sarcomas by combined virotherapy and NK cell therapy.

    Klose, Chihab / Berchtold, Susanne / Schmidt, Marina / Beil, Julia / Smirnow, Irina / Venturelli, Sascha / Burkard, Markus / Handgretinger, Rupert / Lauer, Ulrich M

    BMC cancer

    2019  Volume 19, Issue 1, Page(s) 1172

    Abstract: Background: In pediatric sarcomas, outcomes of established therapies still remain poor, especially due to high-grade resistances to chemotherapeutic compounds. Taking novel biological approaches into account, virotherapy was found to be efficient in ... ...

    Abstract Background: In pediatric sarcomas, outcomes of established therapies still remain poor, especially due to high-grade resistances to chemotherapeutic compounds. Taking novel biological approaches into account, virotherapy was found to be efficient in many pediatric sarcoma types. Also NK cell therapy was denoted to represent a promising upcoming strategy for pediatric sarcoma patients. We here investigated a combinatorial approach employing oncolytic measles vaccine virotherapeutics (MeV) together with activated human NK cells (or PBMCs).
    Methods: The human sarcoma cell lines A673 and HT1080 were used to evaluate the efficacy of this combinatorial treatment modality. Oncolysis was determined by measuring real-time cell proliferation using the xCELLigence RTCA SP system. Furthermore, expression of receptors on NK cells and the respective ligands on A673 cells was analyzed by flow cytometry. To measure the protein release of activated NK cells a LEGENDplex™ assay was performed.
    Results: Monotherapy with MeV led to a time- and dose-dependent oncolytic reduction of A673 and HT1080 sarcoma tumor cell masses. Concurrently, such MeV infections did not change the expression of NK cell ligands MICA/B, ULBP1, 2, and 3, CD112, and CD155. As shown by real-time proliferation assays, infections of A673 and HT1080 sarcoma cells with MeV followed by co-culture with activated NK cells or PBMCs led to enhanced sarcoma cell destruction when compared to the respective monotherapies. In parallel, this dual therapy resulted in an increased release of granzymes, perforin, and granulysin from NK cells. In contrast, expression of activation and ontogenesis receptors on NK cells was not found to be altered after co-culture with MeV-infected A673 sarcoma cells.
    Conclusions: Taken together, the combined treatment strategy comprising oncolytic MeV and activated NK cells resulted in enhanced oncolysis of A673 and HT1080 cells when compared to the respective monotherapies. In parallel, we observed an increased release of NK cell activation markers upon co-culture with MeV-infected A673 human sarcoma cells. These results support the onset of clinical trials combining oncolytic virotherapy with NK cell based immunotherapies.
    MeSH term(s) Animals ; Cell Line, Tumor ; Cell Proliferation/physiology ; Cell- and Tissue-Based Therapy/methods ; Child ; Chlorocebus aethiops ; Coculture Techniques ; Combined Modality Therapy ; Humans ; Immunotherapy, Adoptive/methods ; Killer Cells, Natural/immunology ; Killer Cells, Natural/transplantation ; Measles virus/physiology ; Oncolytic Virotherapy/methods ; Programmed Cell Death 1 Receptor/biosynthesis ; Programmed Cell Death 1 Receptor/immunology ; Sarcoma/immunology ; Sarcoma/therapy ; Sarcoma/virology ; Vero Cells
    Chemical Substances PDCD1 protein, human ; Programmed Cell Death 1 Receptor
    Language English
    Publishing date 2019-12-03
    Publishing country England
    Document type Journal Article
    ISSN 1471-2407
    ISSN (online) 1471-2407
    DOI 10.1186/s12885-019-6387-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Synthetic modulators of TRP channel activity.

    Harteneck, Christian / Klose, Chihab / Krautwurst, Dietmar

    Advances in experimental medicine and biology

    2011  Volume 704, Page(s) 87–106

    Abstract: In humans, 27 TRP channels from 6 related families contribute to a broad spectrum of cellular functions, such as thermo-, pressure-, volume-, pain- and chemosensation. Pain and inflammation-inducing compounds represent potent plant and animal defense ... ...

    Abstract In humans, 27 TRP channels from 6 related families contribute to a broad spectrum of cellular functions, such as thermo-, pressure-, volume-, pain- and chemosensation. Pain and inflammation-inducing compounds represent potent plant and animal defense mechanisms explaining the great variety of the naturally occurring, TRPV1-, TRPM8-, and TRPA1-activating ligands. The discovery of the first vanilloid receptor (TRPV1) and its involvement in nociception triggered the euphoria and the hope in novel therapeutic strategies treating pain, and this clear-cut indication inspired the development of TRPV1-selective ligands. On the other hand the nescience in the physiological role and putative clinical indication hampered the development of a selective drug in the case of the other TRP channels. Therefore, currently only a handful of mostly un-selective blocker is available to target TRP channels. Nevertheless, there is an ongoing quest for new, natural or synthetic ligands and modulators. In this chapter, we will give an overview on available broad-range blocker, as well as first TRP channel-selective compounds.
    MeSH term(s) Animals ; Humans ; Molecular Structure ; Transient Receptor Potential Channels/drug effects
    Chemical Substances Transient Receptor Potential Channels
    Language English
    Publishing date 2011
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ISSN 2214-8019 ; 0065-2598
    ISSN (online) 2214-8019
    ISSN 0065-2598
    DOI 10.1007/978-94-007-0265-3_4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Fenamates as TRP channel blockers: mefenamic acid selectively blocks TRPM3.

    Klose, Chihab / Straub, Isabelle / Riehle, Marc / Ranta, Felicia / Krautwurst, Dietmar / Ullrich, Susanne / Meyerhof, Wolfgang / Harteneck, Christian

    British journal of pharmacology

    2011  Volume 162, Issue 8, Page(s) 1757–1769

    Abstract: Background and purpose: Fenamates are N-phenyl-substituted anthranilic acid derivatives clinically used as non-steroid anti-inflammatory drugs in pain treatment. Reports describing fenamates as tools to interfere with cellular volume regulation ... ...

    Abstract Background and purpose: Fenamates are N-phenyl-substituted anthranilic acid derivatives clinically used as non-steroid anti-inflammatory drugs in pain treatment. Reports describing fenamates as tools to interfere with cellular volume regulation attracted our attention based on our interest in the role of the volume-modulated transient receptor potential (TRP) channels TRPM3 and TRPV4.
    Experimental approach: Firstly, we measured the blocking potencies and selectivities of fenamates on TRPM3 and TRPV4 as well as TRPC6 and TRPM2 by Ca(2+) imaging in the heterologous HEK293 cell system. Secondly, we further investigated the effects of mefenamic acid on cytosolic Ca(2+) and on the membrane voltage in single HEK293 cells that exogenously express TRPM3. Thirdly, in insulin-secreting INS-1E cells, which endogenously express TRPM3, we validated the effect of mefenamic acid on cytosolic Ca(2+) and insulin secretion.
    Key results: We identified and characterized mefenamic acid as a selective and potent TRPM3 blocker, whereas other fenamate structures non-selectively blocked TRPM3, TRPV4, TRPC6 and TRPM2.
    Conclusions and implications: This study reveals that mefenamic acid selectively inhibits TRPM3-mediated calcium entry. This selectivity was further confirmed using insulin-secreting cells. K(ATP) channel-dependent increases in cytosolic Ca(2+) and insulin secretion were not blocked by mefenamic acid, but the selective stimulation of TRPM3-dependent Ca(2+) entry and insulin secretion induced by pregnenolone sulphate were inhibited. However, the physiological regulator of TRPM3 in insulin-secreting cells remains to be elucidated, as well as the conditions under which the inhibition of TRPM3 can impair pancreatic β-cell function. Our results strongly suggest mefenamic acid is the most selective fenamate to interfere with TRPM3 function.
    MeSH term(s) Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Calcium/metabolism ; Fenamates/pharmacology ; HEK293 Cells ; Humans ; Insulin/metabolism ; Insulin-Secreting Cells/metabolism ; Mefenamic Acid/pharmacology ; Mice ; TRPC Cation Channels/antagonists & inhibitors ; TRPM Cation Channels/antagonists & inhibitors ; TRPV Cation Channels/antagonists & inhibitors
    Chemical Substances Anti-Inflammatory Agents, Non-Steroidal ; Fenamates ; Insulin ; TRPC Cation Channels ; TRPM Cation Channels ; TRPM3 protein, human ; TRPV Cation Channels ; TRPV4 protein, human ; Mefenamic Acid (367589PJ2C) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2011-01-03
    Publishing country England
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80081-8
    ISSN 1476-5381 ; 0007-1188
    ISSN (online) 1476-5381
    ISSN 0007-1188
    DOI 10.1111/j.1476-5381.2010.01186.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uf I Zs.146: Show issues Location:
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