TY  - JOUR
A1  - Koehler, Viktoria Florentine
A1  - Adam, Pia
A1  - Fuss, Carmina Teresa
A1  - Jiang, Linmiao
A1  - Berg, Elke
A1  - Frank-Raue, Karin
A1  - Raue, Friedhelm
A1  - Hoster, Eva
A1  - Knösel, Thomas
A1  - Schildhaus, Hans-Ulrich
A1  - Negele, Thomas
A1  - Siebolts, Udo
A1  - Lorenz, Kerstin
A1  - Allelein, Stephanie
A1  - Schott, Matthias
A1  - Spitzweg, Christine
A1  - Kroiss, Matthias
T1  - Treatment of RET-positive advanced medullary thyroid cancer with multi-tyrosine kinase inhibitors — a retrospective multi-center registry analysis
JF  - Cancers
N2  - Background: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. Methods: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. Results: In total, 44/48 (92%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66%) cases. In total, 2/32 (6%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3%) patient with a germline RET variant, additional variants were found. Only 1/48 (2%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95% CI (95% confidence interval), 32–NR (not reached); n = 36), and the median PFS was 21 months (12–39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13–79; n = 22), and the median PFS was 3.5 months (2–14; n = 22) in RET-positive cases. Conclusions: RET variants were highly prevalent in patients with advanced MTC. The treatment results in RET-positive cases were similar to those reported in unselected cohorts.
KW  - medullary thyroid cancer
KW  - rearranged during transfection
KW  - variant
KW  - multi-tyrosine kinase inhibitor
KW  - survival
KW  - treatment outcome
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281776
SN  - 2072-6694
VL  - 14
IS  - 14
ER  - 
TY  - JOUR
A1  - Graf, Christiana
A1  - Mondorf, Antonia
A1  - Knop, Viola
A1  - Peiffer, Kai-Henrik
A1  - Dietz, Julia
A1  - Friess, Julia
A1  - Wedemeyer, Heiner
A1  - Buggisch, Peter
A1  - Mauss, Stefan
A1  - Berg, Thomas
A1  - Rausch, Michael
A1  - Sprinzl, Martin
A1  - Klinker, Hartwig
A1  - Hinrichsen, Holger
A1  - Bronowicki, Jean-Pierre
A1  - Haag, Sebastian
A1  - Hüppe, Dietrich
A1  - Lutz, Thomas
A1  - Poynard, Thierry
A1  - Zeuzem, Stefan
A1  - Friedrich-Rust, Mireen
A1  - Sarrazin, Christoph
A1  - Vermehren, Johannes
T1  - Evaluation of point shear wave elastography using acoustic radiation force impulse imaging for longitudinal fibrosis assessment in patients with HBeAg-Negative HBV infection
JF  - Journal of Clinical Medicine
N2  - Background: Accurate assessment of hepatic fibrosis in patients with chronic HBeAg-negative Hepatitis B is of crucial importance not only to predict the long-term clinical course, but also to evaluate antiviral therapy indication. The aim of this study was to prospectively assess the utility of point shear wave elastography (pSWE) for longitudinal non-invasive fibrosis assessment in a large cohort of untreated patients with chronic HBeAg-negative hepatitis B virus (HBV) infection. Methods: 407 consecutive patients with HBeAg-negative HBV infection who underwent pSWE, transient elastography (TE) as well as laboratory fibrosis markers, including fibrosis index based on four factors (FIB-4), aspartate to platelet ratio index (APRI) and FibroTest, on the same day were prospectively followed up for six years. Patients were classified into one of the three groups: inactive carriers (IC; HBV-DNA <2000 IU/mL and ALT <40 U/L); grey zone group 1 (GZ-1; HBV DNA <2000 IU/mL and ALT >40 U/L); grey zone group 2 (GZ-2; HBV-DNA >2000 IU/mL and ALT <40 U/L). Results: pSWE results were significantly correlated with TE (r = 0.29, p < 0.001) and APRI (r = 0.17; p = 0.005). Median pSWE values did not differ between IC, GZ-1 and GZ-2 patients (p = 0.82, p = 0.17, p = 0.34). During six years of follow-up, median pSWE and TE values did not differ significantly over time (TE: p = 0.27; pSWE: p = 0.05). Conclusion: Our data indicate that pSWE could be useful for non-invasive fibrosis assessment and follow-up in patients with HBeAg-negative chronic HBV infection.
KW  - HBV
KW  - non-invasive fibrosis assessment
KW  - point shear wave elastography
KW  - acoustic radiation force impulse imaging
KW  - transient elastography
KW  - fibrotest
KW  - APRI
KW  - FIB-4
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193916
SN  - 2077-0383
VL  - 8
IS  - 12
ER  - 
TY  - JOUR
A1  - Grammatikos, Georgios
A1  - Lange, Christian
A1  - Susser, Simon
A1  - Schwendy, Susanne
A1  - Dikopoulos, Nektarios
A1  - Buggisch, Peter
A1  - Encke, Jens
A1  - Teuber, Gerlinde
A1  - Goeser, Tobias
A1  - Thimme, Robert
A1  - Klinker, Hartwig
A1  - Boecher, Wulf O.
A1  - Schulte-Frohlinde, Ewert
A1  - Penna-Martinez, Marissa
A1  - Badenhoop, Klaus
A1  - Zeuzem, Stefan
A1  - Berg, Thomas
A1  - Sarrazin, Christoph
T1  - Vitamin D Levels Vary during Antiviral Treatment but Are Unable to Predict Treatment Outcome in HCV Genotype 1 Infected Patients
JF  - PLOS ONE
N2  - Background: Different parameters have been determined for prediction of treatment outcome in hepatitis c virus genotype 1 infected patients undergoing pegylated interferon, ribavirin combination therapy. Results on the importance of vitamin D levels are conflicting. In the present study, a comprehensive analysis of vitamin D levels before and during therapy together with single nucleotide polymorphisms involved in vitamin D metabolism in the context of other known treatment predictors has been performed. 
Methods: In a well characterized prospective cohort of 398 genotype 1 infected patients treated with pegylated interferon-alpha and ribavirin for 24-72 weeks (INDIV-2 study) 25-OH-vitamin D levels and different single nucleotide polymorphisms were analyzed together with known biochemical parameters for a correlation with virologic treatment outcome. 
Results: Fluctuations of more than 5 (10) ng/ml in 25-OH-vitamin D-levels have been observed in 66 (39) % of patients during the course of antiviral therapy and neither pretreatment nor under treatment 25-OH-vitamin D-levels were associated with treatment outcome. The DHCR7-TT-polymorphism within the 7-dehydrocholesterol-reductase showed a significant association (P = 0.031) to sustained viral response in univariate analysis. Among numerous further parameters analyzed we found that age (OR = 1.028, CI = 1.002-1.056, P = 0.035), cholesterol (OR = 0.983, CI = 0.975-0.991, P<0.001), ferritin (OR = 1.002, CI = 1.000-1.004, P = 0.033), gGT (OR = 1.467, CI = 1.073-2.006, P = 0.016) and IL28B-genotype (OR = 2.442, CI = 1.271-4.695, P = 0.007) constituted the strongest predictors of treatment response. 
Conclusions: While 25-OH-vitamin D-levels levels show considerable variations during the long-lasting course of antiviral therapy they do not show any significant association to treatment outcome in genotype 1 infected patients.
KW  - chronic Hepatitis C
KW  - sustained virological response
KW  - common genetic determinants
KW  - D serum-levels
KW  - IL28B polymorphisms
KW  - interferon alpha
KW  - viral clearance
KW  - virus infection
KW  - severe fibrosis
KW  - D insufficiency
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117310
SN  - 1932-6203
VL  - 9
IS  - 2
ER  - 
TY  - JOUR
A1  - Hudson, Lawrence N.
A1  - Newbold, Tim
A1  - Contu, Sara
A1  - Hill, Samantha L. L.
A1  - Lysenko, Igor
A1  - De Palma, Adriana
A1  - Phillips, Helen R. P.
A1  - Senior, Rebecca A.
A1  - Bennett, Dominic J.
A1  - Booth, Hollie
A1  - Choimes, Argyrios
A1  - Correia, David L. P.
A1  - Day, Julie
A1  - Echeverria-Londono, Susy
A1  - Garon, Morgan
A1  - Harrison, Michelle L. K.
A1  - Ingram, Daniel J.
A1  - Jung, Martin
A1  - Kemp, Victoria
A1  - Kirkpatrick, Lucinda
A1  - Martin, Callum D.
A1  - Pan, Yuan
A1  - White, Hannah J.
A1  - Aben, Job
A1  - Abrahamczyk, Stefan
A1  - Adum, Gilbert B.
A1  - Aguilar-Barquero, Virginia
A1  - Aizen, Marcelo
A1  - Ancrenaz, Marc
A1  - Arbelaez-Cortes, Enrique
A1  - Armbrecht, Inge
A1  - Azhar, Badrul
A1  - Azpiroz, Adrian B.
A1  - Baeten, Lander
A1  - Báldi, András
A1  - Banks, John E.
A1  - Barlow, Jos
A1  - Batáry, Péter
A1  - Bates, Adam J.
A1  - Bayne, Erin M.
A1  - Beja, Pedro
A1  - Berg, Ake
A1  - Berry, Nicholas J.
A1  - Bicknell, Jake E.
A1  - Bihn, Jochen H.
A1  - Böhning-Gaese, Katrin
A1  - Boekhout, Teun
A1  - Boutin, Celine
A1  - Bouyer, Jeremy
A1  - Brearley, Francis Q.
A1  - Brito, Isabel
A1  - Brunet, Jörg
A1  - Buczkowski, Grzegorz
A1  - Buscardo, Erika
A1  - Cabra-Garcia, Jimmy
A1  - Calvino-Cancela, Maria
A1  - Cameron, Sydney A.
A1  - Cancello, Eliana M.
A1  - Carrijo, Tiago F.
A1  - Carvalho, Anelena L.
A1  - Castro, Helena
A1  - Castro-Luna, Alejandro A.
A1  - Cerda, Rolando
A1  - Cerezo, Alexis
A1  - Chauvat, Matthieu
A1  - Clarke, Frank M.
A1  - Cleary, Daniel F. R.
A1  - Connop, Stuart P.
A1  - D'Aniello, Biagio
A1  - da Silva, Pedro Giovani
A1  - Darvill, Ben
A1  - Dauber, Jens
A1  - Dejean, Alain
A1  - Diekötter, Tim
A1  - Dominguez-Haydar, Yamileth
A1  - Dormann, Carsten F.
A1  - Dumont, Bertrand
A1  - Dures, Simon G.
A1  - Dynesius, Mats
A1  - Edenius, Lars
A1  - Elek, Zoltán
A1  - Entling, Martin H.
A1  - Farwig, Nina
A1  - Fayle, Tom M.
A1  - Felicioli, Antonio
A1  - Felton, Annika M.
A1  - Ficetola, Gentile F.
A1  - Filgueiras, Bruno K. C.
A1  - Fonte, Steve J.
A1  - Fraser, Lauchlan H.
A1  - Fukuda, Daisuke
A1  - Furlani, Dario
A1  - Ganzhorn, Jörg U.
A1  - Garden, Jenni G.
A1  - Gheler-Costa, Carla
A1  - Giordani, Paolo
A1  - Giordano, Simonetta
A1  - Gottschalk, Marco S.
A1  - Goulson, Dave
A1  - Gove, Aaron D.
A1  - Grogan, James
A1  - Hanley, Mick E.
A1  - Hanson, Thor
A1  - Hashim, Nor R.
A1  - Hawes, Joseph E.
A1  - Hébert, Christian
A1  - Helden, Alvin J.
A1  - Henden, John-André
A1  - Hernández, Lionel
A1  - Herzog, Felix
A1  - Higuera-Diaz, Diego
A1  - Hilje, Branko
A1  - Horgan, Finbarr G.
A1  - Horváth, Roland
A1  - Hylander, Kristoffer
A1  - Horváth, Roland
A1  - Isaacs-Cubides, Paola
A1  - Ishitani, Mashiro
A1  - Jacobs, Carmen T.
A1  - Jaramillo, Victor J.
A1  - Jauker, Birgit
A1  - Jonsell, Matts
A1  - Jung, Thomas S.
A1  - Kapoor, Vena
A1  - Kati, Vassiliki
A1  - Katovai, Eric
A1  - Kessler, Michael
A1  - Knop, Eva
A1  - Kolb, Annette
A1  - Körösi, Àdám
A1  - Lachat, Thibault
A1  - Lantschner, Victoria
A1  - Le Féon, Violette
A1  - LeBuhn, Gretchen
A1  - Légaré, Jean-Philippe
A1  - Letcher, Susan G.
A1  - Littlewood, Nick A.
A1  - López-Quintero, Carlos A.
A1  - Louhaichi, Mounir
A1  - Lövei, Gabor L.
A1  - Lucas-Borja, Manuel Esteban
A1  - Luja, Victor H.
A1  - Maeto, Kaoru
A1  - Magura, Tibor
A1  - Mallari, Neil Aldrin
A1  - Marin-Spiotta, Erika
A1  - Marhall, E. J. P.
A1  - Martínez, Eliana
A1  - Mayfield, Margaret M.
A1  - Mikusinski, Gregorz
A1  - Milder, Jeffery C.
A1  - Miller, James R.
A1  - Morales, Carolina L.
A1  - Muchane, Mary N.
A1  - Muchane, Muchai
A1  - Naidoo, Robin
A1  - Nakamura, Akihiro
A1  - Naoe, Shoji
A1  - Nates-Parra, Guiomar
A1  - Navarerete Gutierrez, Dario A.
A1  - Neuschulz, Eike L.
A1  - Noreika, Norbertas
A1  - Norfolk, Olivia
A1  - Noriega, Jorge Ari
A1  - Nöske, Nicole M.
A1  - O'Dea, Niall
A1  - Oduro, William
A1  - Ofori-Boateng, Caleb
A1  - Oke, Chris O.
A1  - Osgathorpe, Lynne M.
A1  - Paritsis, Juan
A1  - Parrah, Alejandro
A1  - Pelegrin, Nicolás
A1  - Peres, Carlos A.
A1  - Persson, Anna S.
A1  - Petanidou, Theodora
A1  - Phalan, Ben
A1  - Philips, T. Keith
A1  - Poveda, Katja
A1  - Power, Eileen F.
A1  - Presley, Steven J.
A1  - Proença, Vânia
A1  - Quaranta, Marino
A1  - Quintero, Carolina
A1  - Redpath-Downing, Nicola A.
A1  - Reid, J. Leighton
A1  - Reis, Yana T.
A1  - Ribeiro, Danilo B.
A1  - Richardson, Barbara A.
A1  - Richardson, Michael J.
A1  - Robles, Carolina A.
A1  - Römbke, Jörg
A1  - Romero-Duque, Luz Piedad
A1  - Rosselli, Loreta
A1  - Rossiter, Stephen J.
A1  - Roulston, T'ai H.
A1  - Rousseau, Laurent
A1  - Sadler, Jonathan P.
A1  - Sáfián, Szbolcs
A1  - Saldaña-Vásquez, Romeo A.
A1  - Samnegård, Ulrika
A1  - Schüepp, Christof
A1  - Schweiger, Oliver
A1  - Sedlock, Jodi L.
A1  - Shahabuddin, Ghazala
A1  - Sheil, Douglas
A1  - Silva, Fernando A. B.
A1  - Slade, Eleanor
A1  - Smith-Pardo, Allan H.
A1  - Sodhi, Navjot S.
A1  - Somarriba, Eduardo J.
A1  - Sosa, Ramón A.
A1  - Stout, Jane C.
A1  - Struebig, Matthew J.
A1  - Sung, Yik-Hei
A1  - Threlfall, Caragh G.
A1  - Tonietto, Rebecca
A1  - Tóthmérész, Béla
A1  - Tscharntke, Teja
A1  - Turner, Edgar C.
A1  - Tylianakis, Jason M.
A1  - Vanbergen, Adam J.
A1  - Vassilev, Kiril
A1  - Verboven, Hans A. F.
A1  - Vergara, Carlos H.
A1  - Vergara, Pablo M.
A1  - Verhulst, Jort
A1  - Walker, Tony R.
A1  - Wang, Yanping
A1  - Watling, James I.
A1  - Wells, Konstans
A1  - Williams, Christopher D.
A1  - Willig, Michael R.
A1  - Woinarski, John C. Z.
A1  - Wolf, Jan H. D.
A1  - Woodcock, Ben A.
A1  - Yu, Douglas W.
A1  - Zailsev, Andreys
A1  - Collen, Ben
A1  - Ewers, Rob M.
A1  - Mace, Georgina M.
A1  - Purves, Drew W.
A1  - Scharlemann, Jörn P. W.
A1  - Pervis, Andy
T1  - The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts
JF  - Ecology and Evolution
N2  - Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species' threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project - and avert - future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups - including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems - ). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.
KW  - urban-rural gradient
KW  - instensively managed farmland
KW  - Mexican coffee plantations
KW  - Bombus Spp. Hymenoptera
KW  - bumblebee nest density
KW  - data sharing
KW  - land use
KW  - habitat destruction
KW  - global change
KW  - land-use change
KW  - plant community composition
KW  - Northeastern Costa Rica
KW  - dung beetle coleoptera
KW  - bird species richness
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114425
VL  - 4
IS  - 24
ER  - 
TY  - JOUR
A1  - Wilde, Anne-Christin Beatrice
A1  - Lieb, Charlotte
A1  - Leicht, Elise
A1  - Greverath, Lena Maria
A1  - Steinhagen, Lara Marleen
A1  - Wald de Chamorro, Nina
A1  - Petersen, Jörg
A1  - Hofmann, Wolf Peter
A1  - Hinrichsen, Holger
A1  - Heyne, Renate
A1  - Berg, Thomas
A1  - Naumann, Uwe
A1  - Schwenzer, Jeannette
A1  - Vermehren, Johannes
A1  - Geier, Andreas
A1  - Tacke, Frank
A1  - Müller, Tobias
T1  - Real-world clinical management of patients with primary biliary cholangitis — a retrospective multicenter study from Germany
JF  - Journal of Clinical Medicine
N2  - Background: Clinical practice guidelines for patients with primary biliary cholangitis (PBC) have been recently revised and implemented for well-established response criteria to standard first-line ursodeoxycholic acid (UDCA) therapy at 12 months after treatment initiation for the early identification of high-risk patients with inadequate treatment responses who may require treatment modification. However, there are only very limited data concerning the real-world clinical management of patients with PBC in Germany. Objective: The aim of this retrospective multicenter study was to evaluate response rates to standard first-line UDCA therapy and subsequent Second-line treatment regimens in a large cohort of well-characterized patients with PBC from 10 independent hepatological referral centers in Germany prior to the introduction of obeticholic acid as a licensed second-line treatment option. Methods: Diagnostic confirmation of PBC, standard first-line UDCA treatment regimens and response rates at 12 months according to Paris-I, Paris-II, and Barcelona criteria, the follow-up cut-off alkaline phosphatase (ALP) ≤ 1.67 × upper limit of normal (ULN) and the normalization of bilirubin (bilirubin ≤ 1 × ULN) were retrospectively examined between June 1986 and March 2017. The management and hitherto applied second-line treatment regimens in patients with an inadequate response to UDCA and subsequent response rates at 12 months were also evaluated. Results: Overall, 480 PBC patients were included in this study. The median UDCA dosage was 13.2 mg UDCA/kg bodyweight (BW)/d. Adequate UDCA treatment response rates according to Paris-I, Paris-II, and Barcelona criteria were observed in 91, 71.3, and 61.3% of patients, respectively. In 83.8% of patients, ALP ≤ 1.67 × ULN were achieved. A total of 116 patients (24.2%) showed an inadequate response to UDCA according to at least one criterion. The diverse second-line treatment regimens applied led to significantly higher response rates according to Paris-II (35 vs. 60%, p = 0.005), Barcelona (13 vs. 34%, p = 0.0005), ALP ≤ 1.67 × ULN and bilirubin ≤ 1 × ULN (52.1 vs. 75%, p = 0.002). The addition of bezafibrates appeared to induce the strongest beneficial effect in this cohort (Paris II: 24 vs. 74%, p = 0.004; Barcelona: 50 vs. 84%, p = 0.046; ALP < 1.67 × ULN and bilirubin ≤ 1 × ULN: 33 vs. 86%, p = 0.001). Conclusion: Our large retrospective multicenter study confirms high response rates following UDCA first-line standard treatment in patients with PBC and highlights the need for close monitoring and early treatment modification in high-risk patients with an insufficient response to UDCA since early treatment modification significantly increases subsequent response rates of these patients.
KW  - primary biliary cholangitis
KW  - autoantibodies
KW  - ursodeoxycholic acid
KW  - treatment response
KW  - second line therapy
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234003
SN  - 2077-0383
VL  - 10
IS  - 5
ER  - 
TY  - JOUR
A1  - Müller, Stefanie H.
A1  - Girard, Simon L.
A1  - Hopfner, Franziska
A1  - Merner, Nancy D.
A1  - Bourassa, Cynthia V.
A1  - Lorenz, Delia
A1  - Clark, Lorraine N.
A1  - Tittmann, Lukas
A1  - Soto-Ortolaza, Alexandra I.
A1  - Klebe, Stephan
A1  - Hallett, Mark
A1  - Schneider, Susanne A.
A1  - Hodgkinson, Colin A.
A1  - Lieb, Wolfgang
A1  - Wszolek, Zbigniew K.
A1  - Pendziwiat, Manuela
A1  - Lorenzo-Betancor, Oswaldo
A1  - Poewe, Werner
A1  - Ortega-Cubero, Sara
A1  - Seppi, Klaus
A1  - Rajput, Alex
A1  - Hussl, Anna
A1  - Rajput, Ali H.
A1  - Berg, Daniela
A1  - Dion, Patrick A.
A1  - Wurster, Isabel
A1  - Shulman, Joshua M.
A1  - Srulijes, Karin
A1  - Haubenberger, Dietrich
A1  - Pastor, Pau
A1  - Vilariño-Güell, Carles
A1  - Postuma, Ronald B.
A1  - Bernard, Geneviève
A1  - Ladwig, Karl-Heinz
A1  - Dupré, Nicolas
A1  - Jankovic, Joseph
A1  - Strauch, Konstantin
A1  - Panisset, Michel
A1  - Winkelmann, Juliane
A1  - Testa, Claudia M.
A1  - Reischl, Eva
A1  - Zeuner, Kirsten E.
A1  - Ross, Owen A.
A1  - Arzberger, Thomas
A1  - Chouinard, Sylvain
A1  - Deuschl, Günther
A1  - Louis, Elan D.
A1  - Kuhlenbäumer, Gregor
A1  - Rouleau, Guy A.
T1  - Genome-wide association study in essential tremor identifies three new loci
JF  - Brain
N2  - We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.
KW  - quality-control
KW  - disease
KW  - tool
KW  - movement disorders
KW  - genome-wide association study
KW  - tremor
KW  - genetics
KW  - essential tremor
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186541
VL  - 139
ER  - 
TY  - JOUR
A1  - Adam, Pia
A1  - Kircher, Stefan
A1  - Sbiera, Iuliu
A1  - Koehler, Viktoria Florentine
A1  - Berg, Elke
A1  - Knösel, Thomas
A1  - Sandner, Benjamin
A1  - Fenske, Wiebke Kristin
A1  - Bläker, Hendrik
A1  - Smaxwil, Constantin
A1  - Zielke, Andreas
A1  - Sipos, Bence
A1  - Allelein, Stephanie
A1  - Schott, Matthias
A1  - Dierks, Christine
A1  - Spitzweg, Christine
A1  - Fassnacht, Martin
A1  - Kroiss, Matthias
T1  - FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical Rationale
JF  - Frontiers in Endocrinology
N2  - Background
Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising.


Materials and Methods
Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable.


Results
PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS.


Conclusion
High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.
KW  - tyrosine kinase inhibitor (TKI)
KW  - immune checkpoint inhibitor (ICI)
KW  - immunohistochemistry
KW  - immunotherapy
KW  - PD-L1
KW  - FGFR
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244653
SN  - 1664-2392
VL  - 12
ER  - 
TY  - JOUR
A1  - Rau, Monika
A1  - Schmitt, Johannes
A1  - Berg, Thomas
A1  - Kremer, Andreas E.
A1  - Stieger, Bruno
A1  - Spanaus, Katharina
A1  - Bengsch, Bertram
A1  - Romero, Marta R.
A1  - Marin, Jose J.
A1  - Keitel, Verena
A1  - Klinker, Hartwig
A1  - Tony, Hans-Peter
A1  - Müllhaupt, Beat
A1  - Geier, Andreas
T1  - Serum IP-10 levels and increased DPPIV activity are linked to circulating CXCR3+ T cells in cholestatic HCV patients
JF  - PLoS ONE
N2  - Background & aims
Serum interferon-gamma-inducible protein-10 (IP-10) is elevated in cholestatic liver diseases and predicts response to antiviral therapy in patients with chronic hepatitis C virus (HCV) infection. Dipeptidylpeptidase 4 (DPPIV) cleaves active IP-10 into an inactive form, which inhibits recruitment of CXCR3+ T cells to the liver. In this study the link between IP-10 levels, DPPIV activity in serum and CXCR3+ T cells is analysed in cholestatic and non-cholestatic liver patients.

Methods
In serum DPPIV activity (by enzymatic assay), IP-10 (by ELISA) and bile acids (BA) (by enzymatic assay) were analysed in 229 naive HCV genotype (GT) 1 patients and in 16 patients with cholestatic liver disease. In a prospective follow-up (FU) cohort of 27 HCV GT 1 patients peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ cells were measured by FACS.

Results
In 229 HCV patients serum IP-10 levels correlated positively to DPPIV serum activity. Higher IP-10 levels and DPPIV activity were detected in cholestatic and in cirrhotic HCV patients. Increased IP-10 serum levels were associated with therapeutic non-response to antiviral treatment with pegylated-interferon and ribavirin. In the HCV FU cohort elevated IP-10 serum levels and increased BA were associated with higher frequencies of peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ T cells. Positive correlation between serum IP-10 levels and DPPIV activity was likewise validated in patients with cholestatic liver diseases.

Conclusions
A strong correlation between elevated serum levels of IP-10 and DPPIV activity was seen in different cholestatic patient groups. Furthermore, in cholestatic HCV patients a functional link to increased numbers of peripheral CXCR3+ immune cells could be observed. The source of DPPIV release in cholestatic patients remains open.
KW  - hepatitis C virus
KW  - T cells
KW  - liver diseases
KW  - chemokines
KW  - cytotoxic T cells
KW  - immune cells
KW  - cirrhosis
KW  - bile
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177674
VL  - 13
IS  - 12
ER  - 
TY  - JOUR
A1  - Moris, Victoria C.
A1  - Christmann, Katharina
A1  - Wirtgen, Aline
A1  - Belokobylskij, Sergey A.
A1  - Berg, Alexander
A1  - Liebig, Wolf-Harald
A1  - Soon, Villu
A1  - Baur, Hannes
A1  - Schmitt, Thomas
A1  - Niehuis, Oliver
T1  - Cuticular hydrocarbons on old museum specimens of the spiny mason wasp, Odynerus spinipes (Hymenoptera: Vespidae: Eumeninae), shed light on the distribution and on regional frequencies of distinct chemotypes
JF  - Chemoecology
N2  - The mason wasp Odynerus spinipes shows an exceptional case of intrasexual cuticular hydrocarbon (CHC) profile dimorphism. Females of this species display one of two CHC profiles (chemotypes) that differ qualitatively and quantitatively from each other. The ratio of the two chemotypes was previously shown to be close to 1:1 at three sites in Southern Germany, which might not be representative given the Palearctic distribution of the species. To infer the frequency of the two chemotypes across the entire distributional range of the species, we analyzed with GC–MS the CHC profile of 1042 dry-mounted specimens stored in private and museum collections. We complemented our sampling by including 324 samples collected and preserved specifically for studying their CHCs. We were capable of reliably identifying the chemotypes in 91% of dry-mounted samples, some of which collected almost 200 years ago. We found both chemotypes to occur in the Far East, the presumed glacial refuge of the species, and their frequency to differ considerably between sites and geographic regions. The geographic structure in the chemotype frequencies could be the result of differential selection regimes and/or different dispersal routes during the colonization of the Western Palearctic. The presented data pave the route for disentangling these factors by providing information where to geographically sample O. spinipes for population genetic analyses. They also form the much-needed basis for future studies aiming to understand the evolutionary and geographic origin as well as the genetics of the astounding CHC profile dimorphism that O. spinipes females exhibit.
KW  - cuticular hydrocarbons
KW  - chemotypes
KW  - dry-mounted samples
KW  - collections
KW  - distribution
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-306999
SN  - 0937-7409
SN  - 1423-0445
VL  - 31
IS  - 5
ER  -