TY - JOUR A1 - Mousset, Sabine A1 - Buchheidt, Dieter A1 - Heinz, Werner A1 - Ruhnke, Markus A1 - Cornely, Oliver A. A1 - Egerer, Gerlinde A1 - Krüger, William A1 - Link, Hartmut A1 - Neumann, Silke A1 - Ostermann, Helmut A1 - Panse, Jens A1 - Penack, Olaf A1 - Rieger, Christina A1 - Schmidt-Hieber, Martin A1 - Silling, Gerda A1 - Südhoff, Thomas A1 - Ullmann, Andrew J. A1 - Wolf, Hans-Heinrich A1 - Maschmeyer, Georg A1 - Böhme, Angelika T1 - Treatment of invasive fungal infections in cancer patients—updated recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) JF - Annals of Hematology N2 - Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. Early antifungal treatment is mandatory to improve survival. Today, a number of effective and better-tolerated but more expensive antifungal agents compared to the former gold standard amphotericin B deoxycholate are available. Clinical decision-making must consider results from numerous studies and published guidelines, as well as licensing status and cost pressure. New developments in antifungal prophylaxis improving survival rates result in a continuous need for actualization. The treatment options for invasive Candida infections include fluconazole, voriconazole, and amphotericin B and its lipid formulations, as well as echinocandins. Voriconazole, amphotericin B, amphotericin B lipid formulations, caspofungin, itraconazole, and posaconazole are available for the treatment of invasive aspergillosis. Additional procedures, such as surgical interventions, immunoregulatory therapy, and granulocyte transfusions, have to be considered. The Infectious Diseases Working Party of the German Society of Hematology and Oncology here presents its 2008 recommendations discussing the dos and do-nots, as well as the problems and possible solutions, of evidence criteria selection. KW - cancer KW - invasive fungal infections KW - antifungals KW - mycoses KW - hematologic malignancies KW - aspergillosis KW - antifungal agents KW - invasive candidiasis Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121340 VL - 96 ER - TY - JOUR A1 - Schartl, Manfred T1 - Beyond the zebrafish: diverse fish species for modeling human disease JF - Disease Models & Mechanisms N2 - In recent years, zebrafish, and to a lesser extent medaka, have become widely used small animal models for human diseases. These organisms have convincingly demonstrated the usefulness of fish for improving our understanding of the molecular and cellular mechanisms leading to pathological conditions, and for the development of new diagnostic and therapeutic tools. Despite the usefulness of zebrafish and medaka in the investigation of a wide spectrum of traits, there is evidence to suggest that other fish species could be better suited for more targeted questions. With the emergence of new, improved sequencing technologies that enable genomic resources to be generated with increasing efficiency and speed, the potential of non-mainstream fish species as disease models can now be explored. A key feature of these fish species is that the pathological condition that they model is often related to specific evolutionary adaptations. By exploring these adaptations, new disease-causing and disease-modifier genes might be identified; thus, diverse fish species could be exploited to better understand the complexity of disease processes. In addition, non-mainstream fish models could allow us to study the impact of environmental factors, as well as genetic variation, on complex disease phenotypes. This Review will discuss the opportunities that such fish models offer for current and future biomedical research. KW - evolutionary mutant model KW - natural variation KW - cancer KW - fish model Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119919 SN - 1754-8411 VL - 7 IS - 2 ER - TY - JOUR A1 - Gentschev, Ivaylo A1 - Patil, Sadeep S. A1 - Petrov, Ivan A1 - Cappello, Joseph A1 - Adelfinger, Marion A1 - Szalay, Aladar A. T1 - Oncolytic Virotherapy of Canine and Feline Cancer JF - Viruses N2 - Cancer is the leading cause of disease-related death in companion animals such as dogs and cats. Despite recent progress in the diagnosis and treatment of advanced canine and feline cancer, overall patient treatment outcome has not been substantially improved. Virotherapy using oncolytic viruses is one promising new strategy for cancer therapy. Oncolytic viruses (OVs) preferentially infect and lyse cancer cells, without causing excessive damage to surrounding healthy tissue, and initiate tumor-specific immunity. The current review describes the use of different oncolytic viruses for cancer therapy and their application to canine and feline cancer. KW - oncolytic virus KW - oncolysis KW - cancer KW - canine and feline cancer therapy Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119753 VL - 6 IS - 5 ER - TY - JOUR A1 - Peter, Stefanie A1 - Bultinck, Jennyfer A1 - Myant, Kevin A1 - Jaenicke, Laura A. A1 - Walz, Susanne A1 - Müller, Judith A1 - Gmachl, Michael A1 - Treu, Matthias A1 - Boehmelt, Guido A1 - Ade, Casten P. A1 - Schmitz, Werner A1 - Wiegering, Armin A1 - Otto, Christoph A1 - Popov, Nikita A1 - Sansom, Owen A1 - Kraut, Norbert A1 - Eilers, Martin T1 - H Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase JF - EMBO Molecular Medicine N2 - Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells. KW - colorectal cancer KW - HUWE1 KW - MIZ1 KW - MYC KW - ubiquitination KW - cancer KW - digestive system KW - pharmacology KW - drug discovery Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118132 SN - 1757-4684 VL - 6 IS - 12 ER - TY - JOUR A1 - Cardani, Diego A1 - Sardi, Claudia A1 - La Ferla, Barbara A1 - D'Orazio, Guiseppe A1 - Sommariva, Michele A1 - Marcucci, Fabrizio A1 - Olivero, Daniela A1 - Tagliabue, Elda A1 - Koepsell, Hermann A1 - Nicotra, Francesco A1 - Balsari, Andrea A1 - Rumio, Christiano T1 - Sodium glucose cotransporter 1 ligand BLF501 as a novel tool for management of gastrointestinal mucositis JF - Molecular Cancer N2 - Background: Recent studies demonstrated that engagement of sodium glucose transporter 1 (SGLT-1) by orally administered D-glucose protects the intestinal mucosa from lipopolysaccharide (LPS)-induced injury. We tested whether SGLT-1 engagement might protect the intestinal mucosa from doxorubicin (DXR)- and 5-fluorouracil (5-FU)-induced injury in animal models mimicking acute or chronic mucositis. Methods: Mice were treated intraperitoneally with DXR, alone or in combination with 5-FU, and orally with BLF501, a glucose-derived synthetic compound with high affinity for SGLT-1. Intestinal mucosal epithelium integrity was assessed by histological analysis, cellular proliferation assays, real-time PCR gene expression assays and Western blot assays. Student's t-test (paired two-tailed) and X-2 analyses were used for comparisons between groups. Differences were considered significant at p < 0.05. Results: BLF501 administration in mice treated with DXR and/or 5-FU decreased the injuries to the mucosa in terms of epithelial integrity and cellular proliferative ability. Co-treatment with BLF501 led to a normal expression and distribution of both zonula occludens-1 (ZO-1) and beta-catenin, which were underexpressed after treatment with either chemotherapeutic agent alone. BLF501 administration also restored normal expression of caspase-3 and ezrin/radixin/moesin (ERM), which were overexpressed after treatment with DXR and 5-FU. In SGLT1-/- mice, BLF501 had no detectable effects. BLF501 administration in wild-type mice with growing A431 tumors did not modify antitumor activity of DXR. Conclusions: BLF501-induced protection of the intestinal mucosa is a promising novel therapeutic approach to reducing the severity of chemotherapy-induced mucositis. KW - apoptosis KW - prevention KW - doxorubicin KW - cancer KW - gastrointestinal mucositis KW - SGLT-1 KW - synthetic D-glucose analogy KW - chemotherapy KW - inflammation KW - clinical practice guidelines KW - intestinal mucositis KW - epithelial cells KW - oral mucositis KW - gene-expression Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117352 SN - 1476-4598 VL - 13 IS - 23 ER - TY - JOUR A1 - Wilhelm, Martin A1 - Smetak, Manfred A1 - Schaefer-Eckart, Kerstin A1 - Kimmel, Brigitte A1 - Birkmann, Josef A1 - Einsele, Hermann A1 - Kunzmann, Volker T1 - Successful adoptive transfer and in vivo expansion of haploidentical γδ T cells JF - Journal of Translational Medicine N2 - Background: The primary aim of this pilot study was to determine the feasibility and safety of an adoptive transfer and in vivo expansion of human haploidentical gamma delta T lymphocytes. Methods: Patients with advanced haematological malignancies who are not eligible for allogeneic transplantation received peripheral blood mononuclear cells from half-matched family donors. For that, a single unstimulated leukapheresis product was incubated with both the anti-CD4 and anti-CD8 antibodies conjugated to paramagnetic particles. The depletion procedure was performed on a fully automated CliniMACS (R) device according to the manufacturer's instructions. On average, patients received 2.17 x 10(6)/kg (range 0.9-3.48) γδ T cells with <1% CD4-or CD8-positive cells remaining in the product. All patients received prior lymphopenia-inducing chemotherapy (fludarabine 20-25 mg/m(2) day -6 until day -2 and cyclophosphamide 30-60 mg/kg day -6 and -5) and were treated with 4 mg zoledronate on day 0 and 1.0x10(6) IU/m(2) IL-2 on day +1 until day +6 for the induction of gamma delta T cell proliferation in vivo. Results: This resulted in a marked in vivo expansion of donor γδ T cells and, to a lower extent, natural killer cells and double-negative αβ T cells (mean 68-fold, eight-fold, and eight-fold, respectively). Proliferation peaked by around day +8 and donor cells persisted up to 28 days. Although refractory to all prior therapies, three out of four patients achieved a complete remission, which lasted for 8 months in a patient with plasma cell leukaemia. One patient died from an infection 6 weeks after treatment. Conclusion: This pilot study shows that adoptive transfer and in vivo expansion of haploidentical γδ T lymphocytes is feasible and suggests a potential role of these cells in the treatment of haematological diseases. KW - NK cells KW - in vivo cell expansion KW - haploidentical γδ T lymphocytes KW - adoptive transfer KW - CD4(+) KW - innate immunity KW - stimulation KW - acute myeloid-leukemia KW - immunotherapy KW - cancer KW - infusion KW - Interleukin-2 KW - biophosphonate Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117290 VL - 12 IS - 45 ER -