TY  - JOUR
A1  - El-Helou, Sabine M.
A1  - Biegner, Anika-Kerstin
A1  - Bode, Sebastian
A1  - Ehl, Stephan R.
A1  - Heeg, Maximilian
A1  - Maccari, Maria E.
A1  - Ritterbusch, Henrike
A1  - Speckmann, Carsten
A1  - Rusch, Stephan
A1  - Scheible, Raphael
A1  - Warnatz, Klaus
A1  - Atschekzei, Faranaz
A1  - Beider, Renata
A1  - Ernst, Diana
A1  - Gerschmann, Stev
A1  - Jablonka, Alexandra
A1  - Mielke, Gudrun
A1  - Schmidt, Reinhold E.
A1  - Schürmann, Gesine
A1  - Sogkas, Georgios
A1  - Baumann, Ulrich H.
A1  - Klemann, Christian
A1  - Viemann, Dorothee
A1  - Bernuth, Horst von
A1  - Krüger, Renate
A1  - Hanitsch, Leif G.
A1  - Scheibenbogen, Carmen M.
A1  - Wittke, Kirsten
A1  - Albert, Michael H.
A1  - Eichinger, Anna
A1  - Hauck, Fabian
A1  - Klein, Christoph
A1  - Rack-Hoch, Anita
A1  - Sollinger, Franz M.
A1  - Avila, Anne
A1  - Borte, Michael
A1  - Borte, Stephan
A1  - Fasshauer, Maria
A1  - Hauenherm, Anja
A1  - Kellner, Nils
A1  - Müller, Anna H.
A1  - Ülzen, Anett
A1  - Bader, Peter
A1  - Bakhtiar, Shahrzad
A1  - Lee, Jae-Yun
A1  - Heß, Ursula
A1  - Schubert, Ralf
A1  - Wölke, Sandra
A1  - Zielen, Stefan
A1  - Ghosh, Sujal
A1  - Laws, Hans-Juergen
A1  - Neubert, Jennifer
A1  - Oommen, Prasad T.
A1  - Hönig, Manfred
A1  - Schulz, Ansgar
A1  - Steinmann, Sandra
A1  - Klaus, Schwarz
A1  - Dückers, Gregor
A1  - Lamers, Beate
A1  - Langemeyer, Vanessa
A1  - Niehues, Tim
A1  - Shai, Sonu
A1  - Graf, Dagmar
A1  - Müglich, Carmen
A1  - Schmalzing, Marc T.
A1  - Schwaneck, Eva C.
A1  - Tony, Hans-Peter
A1  - Dirks, Johannes
A1  - Haase, Gabriele
A1  - Liese, Johannes G.
A1  - Morbach, Henner
A1  - Foell, Dirk
A1  - Hellige, Antje
A1  - Wittkowski, Helmut
A1  - Masjosthusmann, Katja
A1  - Mohr, Michael
A1  - Geberzahn, Linda
A1  - Hedrich, Christian M.
A1  - Müller, Christiane
A1  - Rösen-Wolff, Angela
A1  - Roesler, Joachim
A1  - Zimmermann, Antje
A1  - Behrends, Uta
A1  - Rieber, Nikolaus
A1  - Schauer, Uwe
A1  - Handgretinger, Rupert
A1  - Holzer, Ursula
A1  - Henes, Jörg
A1  - Kanz, Lothar
A1  - Boesecke, Christoph
A1  - Rockstroh, Jürgen K.
A1  - Schwarze-Zander, Carolynne
A1  - Wasmuth, Jan-Christian
A1  - Dilloo, Dagmar
A1  - Hülsmann, Brigitte
A1  - Schönberger, Stefan
A1  - Schreiber, Stefan
A1  - Zeuner, Rainald
A1  - Ankermann, Tobias
A1  - Bismarck, Philipp von
A1  - Huppertz, Hans-Iko
A1  - Kaiser-Labusch, Petra
A1  - Greil, Johann
A1  - Jakoby, Donate
A1  - Kulozik, Andreas E.
A1  - Metzler, Markus
A1  - Naumann-Bartsch, Nora
A1  - Sobik, Bettina
A1  - Graf, Norbert
A1  - Heine, Sabine
A1  - Kobbe, Robin
A1  - Lehmberg, Kai
A1  - Müller, Ingo
A1  - Herrmann, Friedrich
A1  - Horneff, Gerd
A1  - Klein, Ariane
A1  - Peitz, Joachim
A1  - Schmidt, Nadine
A1  - Bielack, Stefan
A1  - Groß-Wieltsch, Ute
A1  - Classen, Carl F.
A1  - Klasen, Jessica
A1  - Deutz, Peter
A1  - Kamitz, Dirk
A1  - Lassy, Lisa
A1  - Tenbrock, Klaus
A1  - Wagner, Norbert
A1  - Bernbeck, Benedikt
A1  - Brummel, Bastian
A1  - Lara-Villacanas, Eusebia
A1  - Münstermann, Esther
A1  - Schneider, Dominik T.
A1  - Tietsch, Nadine
A1  - Westkemper, Marco
A1  - Weiß, Michael
A1  - Kramm, Christof
A1  - Kühnle, Ingrid
A1  - Kullmann, Silke
A1  - Girschick, Hermann
A1  - Specker, Christof
A1  - Vinnemeier-Laubenthal, Elisabeth
A1  - Haenicke, Henriette
A1  - Schulz, Claudia
A1  - Schweigerer, Lothar
A1  - Müller, Thomas G.
A1  - Stiefel, Martina
A1  - Belohradsky, Bernd H.
A1  - Soetedjo, Veronika
A1  - Kindle, Gerhard
A1  - Grimbacher, Bodo
T1  - The German national registry of primary immunodeficiencies (2012-2017)
JF  - Frontiers in Immunology
N2  - Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. 

Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. 

Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE-syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. 

Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
KW  - registry for primary immunodeficiency
KW  - primary immunodeficiency (PID)
KW  - German PID-NET registry
KW  - PID prevalence
KW  - European Society for Immunodeficiencies (ESID)
KW  - IgG substitution therapy
KW  - CVID
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226629
VL  - 10
ER  - 
TY  - JOUR
A1  - López, Cristina
A1  - Kleinheinz, Kortine
A1  - Aukema, Sietse M.
A1  - Rohde, Marius
A1  - Bernhart, Stephan H.
A1  - Hübschmann, Daniel
A1  - Wagener, Rabea
A1  - Toprak, Umut H.
A1  - Raimondi, Francesco
A1  - Kreuz, Markus
A1  - Waszak, Sebastian M.
A1  - Huang, Zhiqin
A1  - Sieverling, Lina
A1  - Paramasivam, Nagarajan
A1  - Seufert, Julian
A1  - Sungalee, Stephanie
A1  - Russell, Robert B.
A1  - Bausinger, Julia
A1  - Kretzmer, Helene
A1  - Ammerpohl, Ole
A1  - Bergmann, Anke K.
A1  - Binder, Hans
A1  - Borkhardt, Arndt
A1  - Brors, Benedikt
A1  - Claviez, Alexander
A1  - Doose, Gero
A1  - Feuerbach, Lars
A1  - Haake, Andrea
A1  - Hansmann, Martin-Leo
A1  - Hoell, Jessica
A1  - Hummel, Michael
A1  - Korbel, Jan O.
A1  - Lawerenz, Chris
A1  - Lenze, Dido
A1  - Radlwimmer, Bernhard
A1  - Richter, Julia
A1  - Rosenstiel, Philip
A1  - Rosenwald, Andreas
A1  - Schilhabel, Markus B.
A1  - Stein, Harald
A1  - Stilgenbauer, Stephan
A1  - Stadler, Peter F.
A1  - Szczepanowski, Monika
A1  - Weniger, Marc A.
A1  - Zapatka, Marc
A1  - Eils, Roland
A1  - Lichter, Peter
A1  - Loeffler, Markus
A1  - Möller, Peter
A1  - Trümper, Lorenz
A1  - Klapper, Wolfram
A1  - Hoffmann, Steve
A1  - Küppers, Ralf
A1  - Burkhardt, Birgit
A1  - Schlesner, Matthias
A1  - Siebert, Reiner
T1  - Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma
JF  - Nature Communications
N2  - Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.
KW  - cancer genomics
KW  - lymphocytes
KW  - lymphoid tissues
KW  - oncology
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237281
VL  - 10
ER  - 
TY  - JOUR
A1  - Dumont, Martine
A1  - Weber-Lassalle, Nana
A1  - Joly-Beauparlant, Charles
A1  - Ernst, Corinna
A1  - Droit, Arnaud
A1  - Feng, Bing-Jian
A1  - Dubois, Stéphane
A1  - Collin-Deschesnes, Annie-Claude
A1  - Soucy, Penny
A1  - Vallée, Maxime
A1  - Fournier, Frédéric
A1  - Lemaçon, Audrey
A1  - Adank, Muriel A.
A1  - Allen, Jamie
A1  - Altmüller, Janine
A1  - Arnold, Norbert
A1  - Ausems, Margreet G. E. M.
A1  - Berutti, Riccardo
A1  - Bolla, Manjeet K.
A1  - Bull, Shelley
A1  - Carvalho, Sara
A1  - Cornelissen, Sten
A1  - Dufault, Michael R.
A1  - Dunning, Alison M.
A1  - Engel, Christoph
A1  - Gehrig, Andrea
A1  - Geurts-Giele, Willemina R. R.
A1  - Gieger, Christian
A1  - Green, Jessica
A1  - Hackmann, Karl
A1  - Helmy, Mohamed
A1  - Hentschel, Julia
A1  - Hogervorst, Frans B. L.
A1  - Hollestelle, Antoinette
A1  - Hooning, Maartje J.
A1  - Horváth, Judit
A1  - Ikram, M. Arfan
A1  - Kaulfuß, Silke
A1  - Keeman, Renske
A1  - Kuang, Da
A1  - Luccarini, Craig
A1  - Maier, Wolfgang
A1  - Martens, John W. M.
A1  - Niederacher, Dieter
A1  - Nürnberg, Peter
A1  - Ott, Claus-Eric
A1  - Peters, Annette
A1  - Pharoah, Paul D. P.
A1  - Ramirez, Alfredo
A1  - Ramser, Juliane
A1  - Riedel-Heller, Steffi
A1  - Schmidt, Gunnar
A1  - Shah, Mitul
A1  - Scherer, Martin
A1  - Stäbler, Antje
A1  - Strom, Tim M.
A1  - Sutter, Christian
A1  - Thiele, Holger
A1  - van Asperen, Christi J.
A1  - van der Kolk, Lizet
A1  - van der Luijt, Rob B.
A1  - Volk, Alexander E.
A1  - Wagner, Michael
A1  - Waisfisz, Quinten
A1  - Wang, Qin
A1  - Wang-Gohrke, Shan
A1  - Weber, Bernhard H. F.
A1  - Devilee, Peter
A1  - Tavtigian, Sean
A1  - Bader, Gary D.
A1  - Meindl, Alfons
A1  - Goldgar, David E.
A1  - Andrulis, Irene L.
A1  - Schmutzler, Rita K.
A1  - Easton, Douglas F.
A1  - Schmidt, Marjanka K.
A1  - Hahnen, Eric
A1  - Simard, Jacques
T1  - Uncovering the contribution of moderate-penetrance susceptibility genes to breast cancer by whole-exome sequencing and targeted enrichment sequencing of candidate genes in women of European ancestry
JF  - Cancers
N2  - Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.
KW  - breast cancer
KW  - genetic susceptibility
KW  - whole-exome sequencing
KW  - moderate-penetrance genes
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281768
SN  - 2072-6694
VL  - 14
IS  - 14
ER  - 
TY  - JOUR
A1  - Koch, Elias A. T.
A1  - Petzold, Anne
A1  - Wessely, Anja
A1  - Dippel, Edgar
A1  - Gesierich, Anja
A1  - Gutzmer, Ralf
A1  - Hassel, Jessica C.
A1  - Haferkamp, Sebastian
A1  - Hohberger, Bettina
A1  - Kähler, Katharina C.
A1  - Knorr, Harald
A1  - Kreuzberg, Nicole
A1  - Leiter, Ulrike
A1  - Loquai, Carmen
A1  - Meier, Friedegund
A1  - Meissner, Markus
A1  - Mohr, Peter
A1  - Pföhler, Claudia
A1  - Rahimi, Farnaz
A1  - Schadendorf, Dirk
A1  - Schell, Beatrice
A1  - Schlaak, Max
A1  - Terheyden, Patrick
A1  - Thoms, Kai-Martin
A1  - Schuler-Thurner, Beatrice
A1  - Ugurel, Selma
A1  - Ulrich, Jens
A1  - Utikal, Jochen
A1  - Weichenthal, Michael
A1  - Ziller, Fabian
A1  - Berking, Carola
A1  - Heppt, Markus
T1  - Immune checkpoint blockade for metastatic uveal melanoma: patterns of response and survival according to the presence of hepatic and extrahepatic metastasis
JF  - Cancers
N2  - Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan–Meier method. Log-rank tests, χ\(^2\) tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4–23.7) and the median PFS, 2.8 months (95% CI 2.5–3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.
KW  - uveal melanoma
KW  - immune checkpoint blockade
KW  - PD-1
KW  - CTLA-4
KW  - liver metastasis
KW  - treatment resistance
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242603
SN  - 2072-6694
VL  - 13
IS  - 13
ER  - 
TY  - JOUR
A1  - Lodde, Georg
A1  - Forschner, Andrea
A1  - Hassel, Jessica
A1  - Wulfken, Lena M.
A1  - Meier, Friedegund
A1  - Mohr, Peter
A1  - Kähler, Katharina
A1  - Schilling, Bastian
A1  - Loquai, Carmen
A1  - Berking, Carola
A1  - Hüning, Svea
A1  - Schatton, Kerstin
A1  - Gebhardt, Christoffer
A1  - Eckardt, Julia
A1  - Gutzmer, Ralf
A1  - Reinhardt, Lydia
A1  - Glutsch, Valerie
A1  - Nikfarjam, Ulrike
A1  - Erdmann, Michael
A1  - Stang, Andreas
A1  - Kowall, Bernd
A1  - Roesch, Alexander
A1  - Ugurel, Selma
A1  - Zimmer, Lisa
A1  - Schadendorf, Dirk
A1  - Livingstone, Elisabeth
T1  - Factors influencing the adjuvant therapy decision: results of a real-world multicenter data analysis of 904 melanoma patients
JF  - Cancers
N2  - Adjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) and targeted therapy (TT) significantly improved recurrence-free survival. This study investigates the real-world situation of 904 patients from 13 German skin cancer centers with an indication for adjuvant treatment since the approval of adjuvant ICI and TT. From adjusted log-binomial regression models, we estimated relative risks for associations between various influence factors and treatment decisions (adjuvant therapy yes/no, TT vs. ICI in BRAF mutant patients). Of these patients, 76.9% (95% CI 74–80) opted for a systemic adjuvant treatment. The probability of starting an adjuvant treatment was 26% lower in patients >65 years (RR 0.74, 95% CI 68–80). The most common reasons against adjuvant treatment given by patients were age (29.4%, 95% CI 24–38), and fear of adverse events (21.1%, 95% CI 16–28) and impaired quality of life (11.9%, 95% CI 7–16). Of all BRAF-mutated patients who opted for adjuvant treatment, 52.9% (95% CI 47–59) decided for ICI. Treatment decision for TT or ICI was barely associated with age, gender and tumor stage, but with comorbidities and affiliated center. Shortly after their approval, adjuvant treatments have been well accepted by physicians and patients. Age plays a decisive role in the decision for adjuvant treatment, while pre-existing autoimmune disease and regional differences influence the choice between TT or ICI.
KW  - melanoma
KW  - adjuvant treatment
KW  - checkpoint blocker
KW  - targeted therapy
KW  - BRAF
KW  - PD-1
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239583
SN  - 2072-6694
VL  - 13
IS  - 10
ER  - 
TY  - JOUR
A1  - Löb, Sanja
A1  - Linsmeier, Eva
A1  - Herbert, Saskia-Laureen
A1  - Schlaiß, Tanja
A1  - Kiesel, Matthias
A1  - Wischhusen, Jörg
A1  - Salmen, Jessica
A1  - Kranke, Peter
A1  - Quenzer, Anne
A1  - Kurz, Florian
A1  - Weiss, Claire
A1  - Gerhard-Hartmann, Elena
A1  - Wöckel, Achim
A1  - Diessner, Joachim
T1  - Prognostic effect of HER2 evolution from primary breast cancer to breast cancer metastases
JF  - Journal of Cancer Research and Clinical Oncology
N2  - Purpose
Therapeutic options for breast cancer (BC) treatment are constantly evolving. The Human Epidermal Growth Factor 2 (HER2)-low BC entity is a new subgroup, representing about 55% of all BC patients. New antibody–drug conjugates demonstrated promising results for this BC subgroup. Currently, there is limited information about the conversion of HER2 subtypes between primary tumor and recurrent disease.

Methods
This retrospective study included women with BC at the University Medical Centre Wuerzburg from 1998 to 2021. Data were retrieved from patients' records. HER2 evolution from primary diagnosis to the first relapse and the development of secondary metastases was investigated.

Results
In the HR-positive subgroup without HER2 overexpression, HER2-low expression in primary BC was 56.7 vs. 14.6% in the triple-negative subgroup (p < 0.000). In the cohort of the first relapse, HER2-low represented 64.1% of HR-positive vs. 48.2% of the triple-negative cohort (p = 0.03). In patients with secondary metastases, HER2-low was 75.6% vs. 50% in the triple negative subgroup (p = 0.10). The subgroup of HER2-positive breast cancer patients numerically increased in the course of disease; the HER2-negative overall cohort decreased. A loss of HER2 expression from primary BC to the first relapse correlated with a better OS (p = 0.018). No clinicopathological or therapeutic features could be identified as potential risk factors for HER2 conversion.

Conclusion
HER2 expression is rising during the progression of BC disease. In view of upcoming therapeutical options, the re-analysis of newly developed metastasis will become increasingly important.
KW  - breast cancer
KW  - HER2 conversion
KW  - HER2-low
KW  - trastuzumab deruxtecan
KW  - HER2 targeted therapy
KW  - trastuzumab
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324068
VL  - 149
IS  - 8
ER  - 
TY  - JOUR
A1  - Beyer, Felix
A1  - Jadasz, Janusz
A1  - Samper Agrelo, Iria
A1  - Schira‐Heinen, Jessica
A1  - Groh, Janos
A1  - Manousi, Anastasia
A1  - Bütermann, Christine
A1  - Estrada, Veronica
A1  - Reiche, Laura
A1  - Cantone, Martina
A1  - Vera, Julio
A1  - Viganò, Francesca
A1  - Dimou, Leda
A1  - Müller, Hans Werner
A1  - Hartung, Hans‐Peter
A1  - Küry, Patrick
T1  - Heterogeneous fate choice of genetically modulated adult neural stem cells in gray and white matter of the central nervous system
JF  - Glia
N2  - Apart from dedicated oligodendroglial progenitor cells, adult neural stem cells (aNSCs) can also give rise to new oligodendrocytes in the adult central nervous system (CNS). This process mainly confers myelinating glial cell replacement in pathological situations and can hence contribute to glial heterogeneity. Our previous studies demonstrated that the p57kip2 gene encodes an intrinsic regulator of glial fate acquisition and we here investigated to what degree its modulation can affect stem cell‐dependent oligodendrogenesis in different CNS environments. We therefore transplanted p57kip2 knockdown aNSCs into white and gray matter (WM and GM) regions of the mouse brain, into uninjured spinal cords as well as in the vicinity of spinal cord injuries and evaluated integration and differentiation in vivo. Our experiments revealed that under healthy conditions intrinsic suppression of p57kip2 as well as WM localization promote differentiation toward myelinating oligodendrocytes at the expense of astrocyte generation. Moreover, p57kip2 knockdown conferred a strong benefit on cell survival augmenting net oligodendrocyte generation. In the vicinity of hemisectioned spinal cords, the gene knockdown led to a similar induction of oligodendroglial features; however, newly generated oligodendrocytes appeared to suffer more from the hostile environment. This study contributes to our understanding of mechanisms of adult oligodendrogenesis and glial heterogeneity and further reveals critical factors when considering aNSC mediated cell replacement in injury and disease.
KW  - glial fate modulation
KW  - myelin
KW  - neural stem cell
KW  - p57kip2
KW  - regional heterogeneity
KW  - spinal cord injury
KW  - transplantation
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218566
VL  - 68
IS  - 2
SP  - 393
EP  - 406
ER  - 
TY  - JOUR
A1  - Rohmann, Jessica L.
A1  - Huo, Shufan
A1  - Sperber, Pia S.
A1  - Piper, Sophie K.
A1  - Rosendaal, Frits R.
A1  - Heuschmann, Peter U.
A1  - Endres, Matthias
A1  - Liman, Thomas G.
A1  - Siegerink, Bob
T1  - Coagulation factor XII, XI, and VIII activity levels and secondary events after first ischemic stroke
JF  - Journal of Thrombosis and Haemostasis
N2  - Background
Though risk for recurrent vascular events is high following ischemic stroke, little knowledge about risk factors for secondary events post‐stroke exists.

Objectives
Coagulation factors XII, XI, and VIII (FXII, FXI, and FVIII) have been implicated in first thrombotic events, and our aim was to estimate their effects on vascular outcomes within 3 years after first stroke.

Patients/Methods
In the Prospective Cohort with Incident Stroke Berlin (PROSCIS‐B) study, we followed participants aged 18 and older for 3 years after first mild to moderate ischemic stroke event or until occurrence of recurrent stroke, myocardial infarction, or all‐cause mortality. We compared high coagulation factor activity levels to normal and low levels and also analyzed activities as continuous variables. We used Cox proportional hazards models adjusted for age, sex, and cardiovascular risk factors to estimate hazard ratios (HRs) for the combined endpoint.

Results
In total, 94 events occurred in 576 included participants, resulting in an absolute rate of 6.6 events per 100 person‐years. After confounding adjustment, high FVIII activity showed the strongest relationship with the combined endpoint (HR = 2.05, 95% confidence interval [CI] 1.28–3.29). High FXI activity was also associated with a higher hazard (HR = 1.80, 95% CI 1.09–2.98), though high FXII activity was not (HR = 0.86, 95% CI 0.49–1.51). Continuous analyses yielded similar results.

Conclusions
In our study of mild to moderate ischemic stroke patients, high activity levels of FXI and FVIII but not FXII were associated with worse vascular outcomes in the 3‐year period after first ischemic stroke.
KW  - coagulation
KW  - factor VIII
KW  - factor XI
KW  - factor XII
KW  - ischemic stroke
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-217877
VL  - 18
IS  - 12
SP  - 3316
EP  - 3324
ER  - 
TY  - JOUR
A1  - Schleicher, Ulrike
A1  - Paduch, Katrin
A1  - Debus, Andrea
A1  - Obermeyer, Stephanie
A1  - König, Till
A1  - Kling, Jessica C.
A1  - Ribechini, Eliana
A1  - Dudziak, Diana
A1  - Mougiakakos, Dimitrios
A1  - Murray, Peter J.
A1  - Ostuni, Renato
A1  - Körner, Heinrich
A1  - Bogdan, Christian
T1  - TNF-Mediated Restriction of Arginase 1 Expression in Myeloid Cells Triggers Type 2 NO Synthase Activity at the Site of Infection
JF  - Cell Reports
N2  - Neutralization or deletion of tumor necrosis factor (TNF) causes loss of control of intracellular pathogens in mice and humans, but the underlying mechanisms are incompletely understood. Here, we found that TNF antagonized alternative activation of macrophages and dendritic cells by IL-4. TNF inhibited IL-4-induced arginase 1 (Arg1) expression by decreasing histone acetylation, without affecting STAT6 phosphorylation and nuclear translocation. In Leishmania major-infected C57BL/6 wild-type mice, type 2 nitric oxide (NO) synthase (NOS2) was detected in inflammatory dendritic cells or macrophages, some of which co-expressed Arg1. In TNF-deficient mice, Arg1 was hyperexpressed, causing an impaired production of NO in situ. A similar phenotype was seen in L. major-infected BALB/c mice. Arg1 deletion in hematopoietic cells protected these mice from an otherwise lethal disease, although their disease-mediating T cell response (Th2, Treg) was maintained. Thus, deletion or TNF-mediated restriction of Arg1 unleashes the production of NO by NOS2, which is critical for pathogen control.
KW  - TNF
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164897
VL  - 15
IS  - 5
ER  - 
TY  - JOUR
A1  - Koch, Elias A. T.
A1  - Petzold, Anne
A1  - Wessely, Anja
A1  - Dippel, Edgar
A1  - Gesierich, Anja
A1  - Gutzmer, Ralf
A1  - Hassel, Jessica C.
A1  - Haferkamp, Sebastian
A1  - Kähler, Katharina C.
A1  - Knorr, Harald
A1  - Kreuzberg, Nicole
A1  - Leiter, Ulrike
A1  - Loquai, Carmen
A1  - Meier, Friedegund
A1  - Meissner, Markus
A1  - Mohr, Peter
A1  - Pföhler, Claudia
A1  - Rahimi, Farnaz
A1  - Schadendorf, Dirk
A1  - Schell, Beatrice
A1  - Schlaak, Max
A1  - Terheyden, Patrick
A1  - Thoms, Kai-Martin
A1  - Schuler-Thurner, Beatrice
A1  - Ugurel, Selma
A1  - Ulrich, Jens
A1  - Utikal, Jochen
A1  - Weichenthal, Michael
A1  - Ziller, Fabian
A1  - Berking, Carola
A1  - Heppt, Markus V.
T1  - Immune checkpoint blockade for metastatic uveal melanoma: re-induction following resistance or toxicity
JF  - Cancers
N2  - Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A, n = 52) versus those who received only one treatment line of ICB (cohort B, n = 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups (p = 0.1) with a median OS of 16.2 months (cohort A, 95% CI: 11.1–23.8) versus 9.4 months (cohort B, 95% CI: 6.1–14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities.
KW  - uveal melanoma
KW  - immune checkpoint blockade
KW  - PD-1
KW  - CTLA-4
KW  - re-induction
KW  - treatment resistance
KW  - toxicity
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254814
SN  - 2072-6694
VL  - 14
IS  - 3
ER  - 
TY  - JOUR
A1  - Vollmuth, Christoph
A1  - Muljukov, Olga
A1  - Abu-Mugheisib, Mazen
A1  - Angermeier, Anselm
A1  - Barlinn, Jessica
A1  - Busetto, Loraine
A1  - Grau, Armin J.
A1  - Günther, Albrecht
A1  - Gumbinger, Christoph
A1  - Hubert, Nikolai
A1  - Hüttemann, Katrin
A1  - Klingner, Carsten
A1  - Naumann, Markus
A1  - Palm, Frederick
A1  - Remi, Jan
A1  - Rücker, Viktoria
A1  - Schessl, Joachim
A1  - Schlachetzki, Felix
A1  - Schuppner, Ramona
A1  - Schwab, Stefan
A1  - Schwartz, Andreas
A1  - Trommer, Adrian
A1  - Urbanek, Christian
A1  - Volbers, Bastian
A1  - Weber, Joachim
A1  - Wojciechowski, Claudia
A1  - Worthmann, Hans
A1  - Zickler, Philipp
A1  - Heuschmann, Peter U.
A1  - Haeusler, Karl Georg
A1  - Hubert, Gordian Jan
T1  - Impact of the coronavirus disease 2019 pandemic on stroke teleconsultations in Germany in the first half of 2020
JF  - European Journal of Neurology
N2  - Background and purpose
The effects of the coronavirus disease 2019 (COVID-19) pandemic on telemedical care have not been described on a national level. Thus, we investigated the medical stroke treatment situation before, during, and after the first lockdown in Germany.

Methods
In this nationwide, multicenter study, data from 14 telemedical networks including 31 network centers and 155 spoke hospitals covering large parts of Germany were analyzed regarding patients' characteristics, stroke type/severity, and acute stroke treatment. A survey focusing on potential shortcomings of in-hospital and (telemedical) stroke care during the pandemic was conducted.

Results
Between January 2018 and June 2020, 67,033 telemedical consultations and 38,895 telemedical stroke consultations were conducted. A significant decline of telemedical (p < 0.001) and telemedical stroke consultations (p < 0.001) during the lockdown in March/April 2020 and a reciprocal increase after relaxation of COVID-19 measures in May/June 2020 were observed. Compared to 2018–2019, neither stroke patients' age (p = 0.38), gender (p = 0.44), nor severity of ischemic stroke (p = 0.32) differed in March/April 2020. Whereas the proportion of ischemic stroke patients for whom endovascular treatment (14.3% vs. 14.6%; p = 0.85) was recommended remained stable, there was a nonsignificant trend toward a lower proportion of recommendation of intravenous thrombolysis during the lockdown (19.0% vs. 22.1%; p = 0.052). Despite the majority of participating network centers treating patients with COVID-19, there were no relevant shortcomings reported regarding in-hospital stroke treatment or telemedical stroke care.

Conclusions
Telemedical stroke care in Germany was able to provide full service despite the COVID-19 pandemic, but telemedical consultations declined abruptly during the lockdown period and normalized after relaxation of COVID-19 measures in Germany.
KW  - COVID-19
KW  - SARS-CoV- 2
KW  - stroke
KW  - telemedicine
KW  - survey
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259396
VL  - 28
IS  - 10
ER  - 
TY  - JOUR
A1  - Zhou, Xiang
A1  - Ruckdeschel, Anna
A1  - Peter, Jessica
A1  - Böckle, David
A1  - Hornburger, Hannah
A1  - Danhof, Sophia
A1  - Steinhardt, Maximilian Johannes
A1  - Heimeshoff, Larissa
A1  - Einsele, Hermann
A1  - Kortüm, Klaus Martin
A1  - Rasche, Leo
T1  - Salvage therapy with "Dara-KDT-P(A)CE" in heavily pretreated, high-risk, proliferative, relapsed/refractory multiple myeloma
JF  - Hematological Oncology
N2  - The multi-agent therapy “VDT-PACE” represents an established regimen in relapsed/refractory multiple myeloma (RRMM). Here, we report on our experience with a “modified VDT-PACE” incorporating new generation anti-MM agents daratumumab and carfilzomib (“Dara-KDT-P(A)CE”). We retrospectively analyzed 38 patients with RRMM treated with “Dara-KDT-P(A)CE”. The median age was 62 (range 45–82) years, and the patients were heavily pretreated with a median of 5 (range 2–12) prior lines of therapy. Twenty-one (55%) patients suffered from penta-refractory MM. High-risk cytogenetics was present in 31 (81%) patients. The patients received a median of 2 (range 1–10) cycles of this therapy, and the overall response rate (ORR) was 70%. Patients with penta-refractory MM and high-risk cytogenetics showed similar ORR of 65% and 79%, respectively. The median progression-free survival (PFS) and overall survival were 4.1 (95% CI 2.7–5.4) and 8.4 (95% CI 6.7–10.0) months, respectively. Patients with lactate dehydrogenase >250 IU/L showed significantly shorter PFS in comparison with others patients (p = 0.006). We used this regimen as bridging therapy prior to chimeric antigen receptor T-cell infusion in four patients. In conclusion, “Dara-KDT-P(A)CE” is an effective salvage therapy for patients with heavily pretreated, multi-refractory, high-risk RRMM lacking alternative options.
KW  - Dara-KDT-P(A)CE
KW  - multiple myeloma
KW  - refractory
KW  - salvage
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-257495
VL  - 40
IS  - 2
ER  - 
TY  - JOUR
A1  - Samper Agrelo, Iria
A1  - Schira-Heinen, Jessica
A1  - Beyer, Felix
A1  - Groh, Janos
A1  - Bütermann, Christine
A1  - Estrada, Veronica
A1  - Poschmann, Gereon
A1  - Bribian, Ana
A1  - Jadasz, Janusz J.
A1  - Lopez-Mascaraque, Laura
A1  - Kremer, David
A1  - Martini, Rudolf
A1  - Müller, Hans Werner
A1  - Hartung, Hans Peter
A1  - Adjaye, James
A1  - Stühler, Kai
A1  - Küry, Patrick
T1  - Secretome analysis of mesenchymal stem cell factors fostering oligodendroglial differentiation of neural stem cells in vivo
JF  - International Journal of Molecular Sciences
N2  - Mesenchymal stem cell (MSC)-secreted factors have been shown to significantly promote oligodendrogenesis from cultured primary adult neural stem cells (aNSCs) and oligodendroglial precursor cells (OPCs). Revealing underlying mechanisms of how aNSCs can be fostered to differentiate into a specific cell lineage could provide important insights for the establishment of novel neuroregenerative treatment approaches aiming at myelin repair. However, the nature of MSC-derived differentiation and maturation factors acting on the oligodendroglial lineage has not been identified thus far. In addition to missing information on active ingredients, the degree to which MSC-dependent lineage instruction is functional in vivo also remains to be established. We here demonstrate that MSC-derived factors can indeed stimulate oligodendrogenesis and myelin sheath generation of aNSCs transplanted into different rodent central nervous system (CNS) regions, and furthermore, we provide insights into the underlying mechanism on the basis of a comparative mass spectrometry secretome analysis. We identified a number of secreted proteins known to act on oligodendroglia lineage differentiation. Among them, the tissue inhibitor of metalloproteinase type 1 (TIMP-1) was revealed to be an active component of the MSC-conditioned medium, thus validating our chosen secretome approach.
KW  - neural stem cells
KW  - mesenchymal stem cells
KW  - transplantation
KW  - oligodendroglia
KW  - glial fate modulation
KW  - myelin
KW  - spinal cord
KW  - secretome
KW  - TIMP-1
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285465
SN  - 1422-0067
VL  - 21
IS  - 12
ER  - 
TY  - JOUR
A1  - Baluapuri, Apoorva
A1  - Hofstetter, Julia
A1  - Dudvarski Stankovic, Nevenka
A1  - Endres, Theresa
A1  - Bhandare, Pranjali
A1  - Vos, Seychelle Monique
A1  - Adhikari, Bikash
A1  - Schwarz, Jessica Denise
A1  - Narain, Ashwin
A1  - Vogt, Markus
A1  - Wang, Shuang-Yan
A1  - Düster, Robert
A1  - Jung, Lisa Anna
A1  - Vanselow, Jens Thorsten
A1  - Wiegering, Armin
A1  - Geyer, Matthias
A1  - Maric, Hans Michael
A1  - Gallant, Peter
A1  - Walz, Susanne
A1  - Schlosser, Andreas
A1  - Cramer, Patrick
A1  - Eilers, Martin
A1  - Wolf, Elmar
T1  - MYC Recruits SPT5 to RNA Polymerase II to Promote Processive Transcription Elongation
JF  - Molecular Cell
N2  - The MYC oncoprotein binds to promoter-proximal regions of virtually all transcribed genes and enhances RNA polymerase II (Pol II) function, but its precise mode of action is poorly understood. Using mass spectrometry of both MYC and Pol II complexes, we show here that MYC controls the assembly of Pol II with a small set of transcription elongation factors that includes SPT5, a subunit of the elongation factor DSIF. MYC directly binds SPT5, recruits SPT5 to promoters, and enables the CDK7-dependent transfer of SPT5 onto Pol II. Consistent with known functions of SPT5, MYC is required for fast and processive transcription elongation. Intriguingly, the high levels of MYC that are expressed in tumors sequester SPT5 into non-functional complexes, thereby decreasing the expression of growth-suppressive genes. Altogether, these results argue that MYC controls the productive assembly of processive Pol II elongation complexes and provide insight into how oncogenic levels of MYC permit uncontrolled cellular growth.
KW  - MYC
KW  - SPT5
KW  - SUPT5H
KW  - SPT6
KW  - RNA polymerase II
KW  - transcription
KW  - elongation rate
KW  - processivity
KW  - directionality
KW  - tumorigenesis
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221438
VL  - 74
ER  -