TY - JOUR A1 - Hausmann, Stefan A1 - Brandt, Evelyn A1 - Köchel, Carolin A1 - Einsele, Hermann A1 - Bargou, Ralf C. A1 - Seggewiss-Bernhardt, Ruth A1 - Stühmer, Thorsten T1 - Loss of serum and glucocorticoid-regulated kinase 3 (SGK3) does not affect proliferation and survival of multiple myeloma cell lines JF - PLoS ONE N2 - Multiple myeloma (MM) is a generally fatal plasma cell cancer that often shows activation of the phosphoinositide 3-kinase/Akt (PI3K/Akt) pathway. Targeted pharmacologic therapies, however, have not yet progressed beyond the clinical trial stage, and given the complexity of the PI3K/Akt signalling system (e.g. multiple protein isoforms, diverse feedback regulation mechanisms, strong variability between patients) it is mandatory to characterise its ramifications in order to better guide informed decisions about the best therapeutic approaches. Here we explore whether serum and glucocorticoid-regulated kinase 3 (SGK3), a potential downstream effector of PI3K, plays a role in oncogenic signalling in MM cells-either in concert with or independent of Akt. SGK3 was expressed in all MM cell lines and in all primary MM samples tested. Four MM cell lines representing a broad range of intrinsic Akt activation (very strong: MM. 1s, moderate: L 363 and JJN-3, absent: AMO-1) were chosen to test the effects of transient SGK3 knockdown alone and in combination with pharmacological inhibition of Akt, PI3K-p110\(\alpha\), or in the context of serum starvation. Although the electroporation protocol led to strong SGK3 depletion for at least 5 days its absence had no substantial effect on the activation status of potential downstream substrates, or on the survival, viability or proliferation of MM cells in all experimental contexts tested. We conclude that it is unlikely that SGK3 plays a significant role for oncogenic signalling in multiple myeloma. KW - Akt KW - phosphorylation KW - downstream KW - mechanism KW - pathway KW - isoforms KW - activation KW - cancer KW - inhibition KW - phosphatidylinositol 3-kinase/Akt Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148708 VL - 10 IS - 4 ER - TY - JOUR A1 - Becker, Philip P. A1 - Rau, Monika A1 - Schmitt, Johannes A1 - Malsch, Carolin A1 - Hammer, Christian A1 - Bantel, Heike A1 - Müllhaupt, Beat A1 - Geier, Andreas T1 - Performance of serum microRNAs -122, -192 and -21 as biomarkers in patients with non-alcoholic steatohepatitis JF - PLoS ONE N2 - Objectives Liver biopsies are the current gold standard in non-alcoholic steatohepatitis (NASH) diagnosis. Their invasive nature, however, still carries an increased risk for patients' health. The development of non-invasive diagnostic tools to differentiate between bland steatosis (NAFL) and NASH remains crucial. The aim of this study is the evaluation of investigated circulating microRNAs in combination with new targets in order to optimize the discrimination of NASH patients by non-invasive serum biomarkers. Methods Serum profiles of four microRNAs were evaluated in two cohorts consisting of 137 NAFLD patients and 61 healthy controls. In a binary logistic regression model microRNAs of relevance were detected. Correlation of microRNA appearance with known biomarkers like ALT and CK18-Asp396 was evaluated. A simplified scoring model was developed, combining the levels of microRNA in circulation and CK18-Asp396 fragments. Receiver operating characteristics were used to evaluate the potential of discriminating NASH. Results The new finding of our study is the different profile of circulating miR-21 in NASH patients (p<0.0001). Also, it validates recently published results of miR-122 and miR-192 to be differentially regulated in NAFL and NASH. Combined microRNA expression profiles with CK18-Asp396 fragment level scoring model had a higher potential of NASH prediction compared to other risk biomarkers (AUROC = 0.83, 95% CI = 0.754-0.908; p<0.001). Evaluation of score model for NAFL (Score = 0) and NASH (Score = 4) had shown high rates of sensitivity (91%) and specificity (83%). Conclusions Our study defines candidates for a combined model of miRNAs and CK18-Asp396 levels relevant as a promising expansion for diagnosis and in turn treatment of NASH. KW - fatty liver disease KW - independent marker KW - expression KW - injury KW - NAFLD KW - circulating micrornas KW - caspase activation KW - fibrosis KW - miR-122 KW - apoptosis Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145147 VL - 10 IS - 11 ER - TY - JOUR A1 - Barej, Michael F. A1 - Schmitz, Andreas A1 - Penner, Johannes A1 - Doumbia, Joseph A1 - Sandberger-Loua, Laura A1 - Hirschfeld, Mareike A1 - Brede, Christian A1 - Emmrich, Mike A1 - Kouamé, N'Goran Germain A1 - Hillers, Annika A1 - Gonwouo, Nono L. A1 - Nopper, Joachim A1 - Adeba, Patrick Joël A1 - Bangoura, Mohamed A. A1 - Gage, Ceri A1 - Anderson, Gail A1 - Rödel, Mark-Oliver T1 - Life in the spray zone - overlooked diversity in West African torrent-frogs (Anura, Odontobatrachidae, Odontobatrachus) JF - Zoosystematics and Evolution N2 - West African torrent-frogs of the genus Odontobatrachus currently belong to a single species: Odontobatrachus natator (Boulenger, 1905). Recently, molecular results and biogeographic separation led to the recognition of five Operational Taxonomic Units (OTUs) thus identifying a species-complex. Based on these insights, morphological analyses on more than 150 adult specimens, covering the entire distribution of the family and all OTUs, were carried out. Despite strong morphological congruence, combinations of morphological characters made the differentiation of OTUs successful and allowed the recognition of five distinct species: Odontobatrachus natator, and four species new to science: Odontobatrachus arndti sp. n., O. fouta sp. n., O. smithi sp. n. and O. ziama sp. n. All species occur in parapatry: Odontobatrachus natator is known from western Guinea to eastern Liberia, O. ziama sp. n. from eastern Guinea, O. smithi sp. n. and O. fouta sp. n. from western Guinea, O. arndti sp. n. from the border triangle Guinea-Liberia-Cote d'Ivoire. In addition, for the first time the advertisement call of a West African torrent-frog (O. arndti sp. n.) is described. KW - Guinean rain forest KW - molecular data KW - conservation KW - Upper Guinea KW - new species KW - Phrynobatrachus amphibia KW - Arthroleptis amphibia KW - ivory coast KW - genus KW - biodiversity KW - Ranidae KW - Petropedetidae KW - biodiversity hotspot KW - rainforest KW - taxonomy KW - Amphibia Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144254 VL - 91 IS - 2 ER - TY - JOUR A1 - Andersen, Jens Peter A1 - Bøgsted, Martin A1 - Dybkær, Karen A1 - Mellqvist, Ulf-Henrik A1 - Morgan, Gareth J. A1 - Goldschmidt, Hartmut A1 - Dimopoulos, Meletios A. A1 - Einsele, Hermann A1 - San Miguel, Jesús A1 - Palumbo, Antonio A1 - Sonneveld, Pieter A1 - Johnsen, Hans Erik T1 - Global myeloma research clusters, output, and citations: a bibliometric mapping and clustering analysis JF - PLoS ONE N2 - Background International collaborative research is a mechanism for improving the development of disease-specific therapies and for improving health at the population level. However, limited data are available to assess the trends in research output related to orphan diseases. Methods and Findings We used bibliometric mapping and clustering methods to illustrate the level of fragmentation in myeloma research and the development of collaborative efforts. Publication data from Thomson Reuters Web of Science were retrieved for 2005-2009 and followed until 2013. We created a database of multiple myeloma publications, and we analysed impact and co-authorship density to identify scientific collaborations, developments, and international key players over time. The global annual publication volume for studies on multiple myeloma increased from 1,144 in 2005 to 1,628 in 2009, which represents a 43% increase. This increase is high compared to the 24% and 14% increases observed for lymphoma and leukaemia. The major proportion (> 90% of publications) was from the US and EU over the study period. The output and impact in terms of citations, identified several successful groups with a large number of intra-cluster collaborations in the US and EU. The US-based myeloma clusters clearly stand out as the most productive and highly cited, and the European Myeloma Network members exhibited a doubling of collaborative publications from 2005 to 2009, still increasing up to 2013. Conclusion and Perspective Multiple myeloma research output has increased substantially in the past decade. The fragmented European myeloma research activities based on national or regional groups are progressing, but they require a broad range of targeted research investments to improve multiple myeloma health care. KW - multiparametric flow cytometry KW - multiple myeloma KW - consensus statement KW - European experts KW - disorders KW - therapy KW - network Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144214 VL - 10 IS - 1 ER - TY - JOUR A1 - Spinner, Christoph D A1 - Wille, Florian A1 - Schwerdtfeger, Christiane A1 - Thies, Philipp A1 - Tanase, Ursula A1 - Von Figura, Guido A1 - Schmid, Roland M A1 - Heinz, Werner J A1 - Klinker, Hartwig Hf T1 - Pharmacokinetics of chewed vs. swallowed raltegravir in a patient with AIDS and MAI infection: some new conflicting data JF - AIDS Research and Therapy N2 - Background: While HIV, AIDS and atypical Mycobacterium infections are closely linked, the use of Integrase-Inhibitor based cART, notably raltegravir-based regimens is more widespread. RAL should be double-dosed to 800 mg semi-daily in situation of rifampicin co-medication, because RAL is more rapidly metabolized due to rifampicin-induced Uridine-5'-diphosph-gluronosyl-transferase (UGT1A1). Recently, it was speculated that chewed RAL might lead to increased absorption, which might compensate the inductive effect of rifampicin-rapid metabolized RAL, as part of cost-saving effects in countries with high-tuberculosis prevalence and less economic power. Methods: We report measurement of raltegravir pharmacokinetics in a 34-year AIDS-patient suffering from disseminated Mycobacterium avium infection with necessity of parenteral rifampicin treatment. RAL levels were measured with HPLC (internal standard: carbamazepine, LLQ 11 ng/ml, validation with Valistat 2.0 program (Arvecon, Germany)). For statistical analysis, a two-sided Wilcoxon signed rank test for paired samples was used. Results: High intra-personal variability in raltegravir serum levels was seen. Comparable C\(_{max}\) concentrations were found for 800 mg chewed and swallowed RAL, as well as for 400 mg chewed and swallowed RAL. While C\(_{max}\) seems to be more dependent from overall RAL dosing than from swallowed or chewed tablets, increased AUC(12) is clearly linked to higher RAL dosages per administration. Anyway, chewed raltegravir showed a rapid decrease in serum levels. Conclusions: We found no evidence that chewed 400 mg semi-daily raltegravir in rifampicin co-medication leads to optimized pharmacokinetics. There is need for more data from randomized trials for further recommendations. KW - pharmacology KW - drug KW - HIV KW - chewed KW - Mycobacterium avium KW - raltegravir KW - pharmacokinetic Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144058 VL - 12 IS - 1 ER - TY - JOUR A1 - Leonhardt, Ines A1 - Spielberg, Steffi A1 - Weber, Michael A1 - Albrecht-Eckardt, Daniela A1 - Bläss, Markus A1 - Claus, Ralf A1 - Barz, Dagmar A1 - Scherlach, Kirstin A1 - Hertweck, Christian A1 - Löffler, Jürgen A1 - Hünniger, Kerstin A1 - Kurzai, Oliver T1 - The fungal quorum-sensing molecule farnesol activates innate immune cells but suppresses cellular adaptive immunity JF - mBio N2 - Farnesol, produced by the polymorphic fungus Candida albicans, is the first quorum-sensing molecule discovered in eukaryotes. Its main function is control of C. albicans filamentation, a process closely linked to pathogenesis. In this study, we analyzed the effects of farnesol on innate immune cells known to be important for fungal clearance and protective immunity. Farnesol enhanced the expression of activation markers on monocytes (CD86 and HLA-DR) and neutrophils (CD66b and CD11b) and promoted oxidative burst and the release of proinflammatory cytokines (tumor necrosis factor alpha [TNF-\(\alpha\)] and macrophage inflammatory protein 1 alpha [MIP-1 \(\alpha\)]). However, this activation did not result in enhanced fungal uptake or killing. Furthermore, the differentiation of monocytes to immature dendritic cells (iDC) was significantly affected by farnesol. Several markers important for maturation and antigen presentation like CD1a, CD83, CD86, and CD80 were significantly reduced in the presence of farnesol. Furthermore, farnesol modulated migrational behavior and cytokine release and impaired the ability of DC to induce T cell proliferation. Of major importance was the absence of interleukin 12 (IL-12) induction in iDC generated in the presence of farnesol. Transcriptome analyses revealed a farnesol-induced shift in effector molecule expression and a down-regulation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor during monocytes to iDC differentiation. Taken together, our data unveil the ability of farnesol to act as a virulence factor of C. albicans by influencing innate immune cells to promote inflammation and mitigating the Th1 response, which is essential for fungal clearance. KW - human dendritic cells KW - Pseudomonas aeruginosa KW - induced apoptosis KW - cytokine production KW - biofilm formation KW - Candida albicans KW - mouse model KW - systemic candidiasis KW - oxidative stress KW - carcinoma cells Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143756 VL - 6 IS - 2 ER - TY - JOUR A1 - Kremer, Joel M A1 - Kivitz, Alan J A1 - Simon-Campos, Jesus A A1 - Nasonov, Evgeny L A1 - Tony, Hans-Peter A1 - Lee, Soo-Kon A1 - Vlahos, Bonnie A1 - Hammond, Constance A1 - Bukowski, Jack A1 - Li, Huihua A1 - Schulman, Seth L A1 - Raber, Susan A1 - Zuckerman, Andrea A1 - Isaacs, John D T1 - Evaluation of the effect of tofacitinib on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial JF - Arthritis Research & Therapy N2 - Introduction: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). During the clinical development programme, increases in mean serum creatinine (SCr) of approximately 0.07 mg/dL and 0.08 mg/dL were observed which plateaued early. This study assessed changes in measured glomerular filtration rate (mGFR) with tofacitinib relative to placebo in patients with active RA. Methods: This was a randomised, placebo-controlled, Phase 1 study (NCT01484561). Patients were aged \(\geq\)18 years with active RA. Patients were randomised 2: 1 to oral tofacitinib 10 mg twice daily (BID) in Period 1 then placebo BID in Period 2 (tofacitinib -> placebo); or oral placebo BID in both Periods (placebo. placebo). Change in mGFR was evaluated by iohexol serum clearance at four time points (run-in, pre-dose in Period 1, Period 1 end, and Period 2 end). The primary endpoint was the change in mGFR from baseline to Period 1 end. Secondary endpoints included: change in mGFR at other time points; change in estimated GFR (eGFR; Cockcroft-Gault equation) and SCr; efficacy; and safety. Results: 148 patients were randomised to tofacitinib -> placebo (N = 97) or placebo -> placebo (N = 51). Baseline characteristics were similar between groups. A reduction of 8% (90% confidence interval [CI]: 2%, 14%) from baseline in adjusted geometric mean mGFR was observed during tofacitinib treatment in Period 1 vs placebo. During Period 2, mean mGFR returned towards baseline during placebo treatment, and there was no difference between the two treatment groups at the end of the study - ratio (tofacitinib -> placebo/placebo -> placebo) of adjusted geometric mean fold change of mGFR was 1.04 (90% CI: 0.97, 1.11). Post-hoc analyses, focussed on mGFR variability in placebo -> placebo patients, were consistent with this conclusion. At study end, similar results were observed for eGFR and SCr. Clinical efficacy and safety were consistent with prior studies. Conclusion: Increases in mean SCr and decreases in eGFR in tofacitinib-treated patients with RA may occur in parallel with decreases in mean mGFR; mGFR returned towards baseline after tofacitinib discontinuation, with no significant difference vs placebo, even after post-hoc analyses. Safety monitoring will continue in ongoing and future clinical studies and routine pharmacovigilance. KW - janus kinase inhibitor KW - renal function KW - CP-690,550 KW - iohexol KW - disease comorbidities KW - plasma clearance KW - serum creatinine KW - kidney function KW - methotrexate Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143409 VL - 17 IS - 95 ER - TY - JOUR A1 - Lee, Marcel A1 - Eyer, Florian A1 - Felgenhauer, Norbert A1 - Klinker, Hartwig H. F. A1 - Spinner, Christoph D. T1 - Overdose of dolutegravir in combination with tenofovir disaproxil fumarate/emtricitabine in suicide attempt in a 21-year old patient JF - AIDS Research and Therapy N2 - A 21 year old MSM patient with newly diagnosed HIV infection was hospitalized in our department after ingestion of an overdose of his antiretroviral therapy (ART) comprising dolutegravir (DTG - Tivicay\(^{®}\)) and tenofovir disaproxil fumarate/emtricitabine (Truvada\(^{®}\)) in suicidal intention. On admission, the patient did not show any clinical signs of intoxication and laboratory findings were unremarkable. After 6 hours of intensive care monitoring, the patient was referred to a psychiatric clinic. 5 days after the day of intoxication, serum creatinine levels increased to high normal values (1.2 mg/dl). However, levels never exceeded the upper threshold. 8 and 12 weeks later, serum creatinine normalized to levels measured prior to the intoxication. No other adverse events occurred, and the patient does not suffer from permanent impairments. KW - integrase inhibitor KW - HIV KW - AIDS KW - suicide attempt KW - dolutegravir KW - tenofovir disaproxil fumarate KW - emtricitabine KW - overdose Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151994 VL - 12 IS - 18 ER - TY - JOUR A1 - Heidrich, Benjamin A1 - Cordes, Hans-Jörg A1 - Klinker, Hartwig A1 - Möller, Bernd A1 - Naumann, Uwe A1 - Rössle, Martin A1 - Kraus, Michael R. A1 - Böker, Klaus H. A1 - Roggel, Christoph A1 - Schuchmann, Marcus A1 - Stoehr, Albrecht A1 - Trein, Andreas A1 - Hardtke, Svenja A1 - Gonnermann, Andrea A1 - Koch, Armin A1 - Wedemeyer, Heiner A1 - Manns, Michael P. A1 - Cornberg, Markus T1 - Treatment Extension of Pegylated Interferon Alpha and Ribavirin Does Not Improve SVR in Patients with Genotypes 2/3 without Rapid Virological Response (OPTEX Trial): A Prospective, Randomized, Two-Arm, Multicentre Phase IV Clinical Trial JF - PLoS ONE N2 - Although sofosbuvir has been approved for patients with genotypes 2/3 (G2/3), many parts of the world still consider pegylated Interferon alpha (P) and ribavirin (R) as standard of care for G2/3. Patients with rapid virological response (RVR) show response rates >80%. However, SVR (sustained virological response) in non-RVR patients is not satisfactory. Longer treatment duration may be required but evidence from prospective trials are lacking. A total of 1006 chronic HCV genotype 2/3 patients treated with P/R were recruited into a German HepNet multicenter screening registry. Of those, only 226 patients were still HCV RNA positive at week 4 (non-RVR). Non-RVR patients with ongoing response after 24 weeks P-2b/R qualified for OPTEX, a randomized trial investigating treatment extension of additional 24 weeks (total 48 weeks, Group A) or additional 12 weeks (total 36 weeks, group B) of 1.5 \(\mu\)g/kg P-2b and 800-1400 mg R. Due to the low number of patients without RVR, the number of 150 anticipated study patients was not met and only 99 non-RVR patients (n=50 Group A, n=49 Group B) could be enrolled into the OPTEX trial. Baseline factors did not differ between groups. Sixteen patients had G2 and 83 patients G3. Based on the ITT (intention-to-treat) analysis, 68% [55%; 81%] in Group A and 57% [43%; 71%] in Group B achieved SVR (p=0.31). The primary endpoint of better SVR rates in Group A compared to a historical control group (SVR 70%) was not met. In conclusion, approximately 23% of G2/3 patients did not achieve RVR in a real world setting. However, subsequent recruitment in a treatment-extension study was difficult. Prolonged therapy beyond 24 weeks did not result in higher SVR compared to a historical control group. KW - chronic hepatitis C KW - peginterferon alpha-2b KW - infection KW - sofosbuvir KW - therapy KW - HCV genotype 2 Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151811 VL - 10 IS - 6 ER - TY - JOUR A1 - Hecht, Markus A1 - Erber, Sonja A1 - Harrer, Thomas A1 - Klinker, Hartwig A1 - Roth, Thomas A1 - Parsch, Hans A1 - Fiebig, Nora A1 - Fietkau, Rainer A1 - Distel, Luitpold V. T1 - Efavirenz Has the Highest Anti-Proliferative Effect of Non-Nucleoside Reverse Transcriptase Inhibitors against Pancreatic Cancer Cells JF - PLoS ONE N2 - Background Cancer prevention and therapy in HIV-1-infected patients will play an important role in future. The non-nucleoside reverse transcriptase inhibitors (NNRTI) Efavirenz and Nevirapine are cytotoxic against cancer cells in vitro. As other NNRTIs have not been studied so far, all clinically used NNRTIs were tested and the in vitro toxic concentrations were compared to drug levels in patients to predict possible anti-cancer effects in vivo. Methods Cytotoxicity was studied by Annexin-V-APC/7AAD staining and flow cytometry in the pancreatic cancer cell lines BxPC-3 and Panc-1 and confirmed by colony formation assays. The 50% effective cytotoxic concentrations (EC50) were calculated and compared to the blood levels in our patients and published data. Results The in vitro EC50 of the different drugs in the BxPC-3 pancreatic cancer cells were: Efavirenz 31.5\(\mu\)mol/l (= 9944ng/ml), Nevirapine 239\(\mu\)mol/l (= 63786ng/ml), Etravirine 89.0\(\mu\)mol/l (= 38740ng/ml), Lersivirine 543\(\mu\)mol/l (= 168523ng/ml), Delavirdine 171\(\mu\)mol/l (= 78072ng/ml), Rilpivirine 24.4\(\mu\)mol/l (= 8941ng/ml). As Efavirenz and Rilpivirine had the highest cytotoxic potential and Nevirapine is frequently used in HIV-1 positive patients, the results of these three drugs were further studied in Panc-1 pancreatic cancer cells and confirmed with colony formation assays. 205 patient blood levels of Efavirenz, 127 of Rilpivirine and 31 of Nevirapine were analyzed. The mean blood level of Efavirenz was 3587ng/ml (range 162-15363ng/ml), of Rilpivirine 144ng/ml (range 0-572ng/ml) and of Nevirapine 4955ng/ml (range 1856-8697ng/ml). Blood levels from our patients and from published data had comparable Efavirenz levels to the in vitro toxic EC50 in about 1 to 5% of all patients. Conclusion All studied NNRTIs were toxic against cancer cells. A low percentage of patients taking Efavirenz reached in vitro cytotoxic blood levels. It can be speculated that in HIV-1 positive patients having high Efavirenz blood levels pancreatic cancer incidence might be reduced. Efavirenz might be a new option in the treatment of cancer. KW - human hepatic cells KW - active antiretroviral therapy KW - differentiated thyroid tumor KW - HIV-infected patients KW - pharmacokinetic interaction KW - LINE-1 retrotransposition KW - HIV-1-infected subjects KW - healthy volunteers KW - prostate cancer KW - i-131 uptake Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151694 VL - 10 IS - 6 ER -