TY - JOUR A1 - Kreß, Julia Katharina Charlotte A1 - Jessen, Christina A1 - Hufnagel, Anita A1 - Schmitz, Werner A1 - Da Xavier Silva, Thamara Nishida A1 - Ferreira Dos Santos, Ancély A1 - Mosteo, Laura A1 - Goding, Colin R. A1 - Friedmann Angeli, José Pedro A1 - Meierjohann, Svenja T1 - The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2 JF - Cell Reports N2 - Highlights • The integrated stress response leads to a general ATF4-dependent activation of NRF2 • ATF4 causes a CHAC1-dependent GSH depletion, resulting in NRF2 stabilization • An elevation of NRF2 transcript levels fosters this effect • NRF2 supports the ISR/ATF4 pathway by improving cystine and antioxidant supply Summary The redox regulator NRF2 becomes activated upon oxidative and electrophilic stress and orchestrates a response program associated with redox regulation, metabolism, tumor therapy resistance, and immune suppression. Here, we describe an unrecognized link between the integrated stress response (ISR) and NRF2 mediated by the ISR effector ATF4. The ISR is commonly activated after starvation or ER stress and plays a central role in tissue homeostasis and cancer plasticity. ATF4 increases NRF2 transcription and induces the glutathione-degrading enzyme CHAC1, which we now show to be critically important for maintaining NRF2 activation. In-depth analyses reveal that NRF2 supports ATF4-induced cells by increasing cystine uptake via the glutamate-cystine antiporter xCT. In addition, NRF2 upregulates genes mediating thioredoxin usage and regeneration, thus balancing the glutathione decrease. In conclusion, we demonstrate that the NRF2 response serves as second layer of the ISR, an observation highly relevant for the understanding of cellular resilience in health and disease. KW - NRF2 KW - ATF4 KW - integrated stress response KW - CHAC1 KW - melanoma KW - SLC7A11 KW - GSH Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350312 VL - 42 IS - 7 ER - TY - JOUR A1 - Bassler, Miriam C. A1 - Knoblich, Mona A1 - Gerhard-Hartmann, Elena A1 - Mukherjee, Ashutosh A1 - Youssef, Almoatazbellah A1 - Hagen, Rudolf A1 - Haug, Lukas A1 - Goncalves, Miguel A1 - Scherzad, Agmal A1 - Stöth, Manuel A1 - Ostertag, Edwin A1 - Steinke, Maria A1 - Brecht, Marc A1 - Hackenberg, Stephan A1 - Meyer, Till Jasper T1 - Differentiation of salivary gland and salivary gland tumor tissue via Raman imaging combined with multivariate data analysis JF - Diagnostics N2 - Salivary gland tumors (SGTs) are a relevant, highly diverse subgroup of head and neck tumors whose entity determination can be difficult. Confocal Raman imaging in combination with multivariate data analysis may possibly support their correct classification. For the analysis of the translational potential of Raman imaging in SGT determination, a multi-stage evaluation process is necessary. By measuring a sample set of Warthin tumor, pleomorphic adenoma and non-tumor salivary gland tissue, Raman data were obtained and a thorough Raman band analysis was performed. This evaluation revealed highly overlapping Raman patterns with only minor spectral differences. Consequently, a principal component analysis (PCA) was calculated and further combined with a discriminant analysis (DA) to enable the best possible distinction. The PCA-DA model was characterized by accuracy, sensitivity, selectivity and precision values above 90% and validated by predicting model-unknown Raman spectra, of which 93% were classified correctly. Thus, we state our PCA-DA to be suitable for parotid tumor and non-salivary salivary gland tissue discrimination and prediction. For evaluation of the translational potential, further validation steps are necessary. KW - salivary gland tumor KW - confocal Raman imaging KW - principal component analysis KW - discriminant analysis KW - multivariate data analysis KW - molecular diagnostics Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-355558 SN - 2075-4418 VL - 14 IS - 1 ER - TY - JOUR A1 - Wille, Michael A1 - Schümann, Antje A1 - Wree, Andreas A1 - Kreutzer, Michael A1 - Glocker, Michael O. A1 - Mutzbauer, Grit A1 - Schmitt, Oliver T1 - The Proteome Profiles of the Cerebellum of Juvenile, Adult and Aged Rats-An Ontogenetic Study JF - International Journal of Molecular Sciences N2 - In this study, we searched for proteins that change their expression in the cerebellum (Ce) of rats during ontogenesis. This study focuses on the question of whether specific proteins exist which are differentially expressed with regard to postnatal stages of development. A better characterization of the microenvironment and its development may result from these study findings. A differential two-dimensional polyacrylamide gel electrophoresis (2DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analysis of the samples revealed that the number of proteins of the functional classes differed depending on the developmental stages. Especially members of the functional classes of biosynthesis, regulatory proteins, chaperones and structural proteins show the highest differential expression within the analyzed stages of development. Therefore, members of these functional protein groups seem to be involved in the development and differentiation of the Ce within the analyzed development stages. In this study, changes in the expression of proteins in the Ce at different postnatal developmental stages (postnatal days (P) 7, 90, and 637) could be observed. At the same time, an identification of proteins which are involved in cell migration and differentiation was possible. Especially proteins involved in processes of the biosynthesis and regulation, the dynamic organization of the cytoskeleton as well as chaperones showed a high amount of differentially expressed proteins between the analyzed dates. KW - messenger RNA KW - brain KW - cerebellum KW - development KW - proteomics KW - rat KW - proteins KW - adenosine kinase KW - coated vesicles KW - phosphatase 2A KW - expression KW - neuronal differentiation KW - human brain KW - hnRNP K KW - postnatal development KW - binding Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151347 VL - 16 SP - 21454 EP - 21485 ER - TY - JOUR A1 - An, Ran A1 - Strissel, Pamela L. A1 - Al-Abboodi, Majida A1 - Robering, Jan W. A1 - Supachai, Reakasame A1 - Eckstein, Markus A1 - Peddi, Ajay A1 - Hauck, Theresa A1 - Bäuerle, Tobias A1 - Boccaccini, Aldo R. A1 - Youssef, Almoatazbellah A1 - Sun, Jiaming A1 - Strick, Reiner A1 - Horch, Raymund E. A1 - Boos, Anja M. A1 - Kengelbach-Weigand, Annika T1 - An innovative arteriovenous (AV) loop breast cancer model tailored for cancer research JF - Bioengineering N2 - Animal models are important tools to investigate the pathogenesis and develop treatment strategies for breast cancer in humans. In this study, we developed a new three-dimensional in vivo arteriovenous loop model of human breast cancer with the aid of biodegradable materials, including fibrin, alginate, and polycaprolactone. We examined the in vivo effects of various matrices on the growth of breast cancer cells by imaging and immunohistochemistry evaluation. Our findings clearly demonstrate that vascularized breast cancer microtissues could be engineered and recapitulate the in vivo situation and tumor-stromal interaction within an isolated environment in an in vivo organism. Alginate–fibrin hybrid matrices were considered as a highly powerful material for breast tumor engineering based on its stability and biocompatibility. We propose that the novel tumor model may not only serve as an invaluable platform for analyzing and understanding the molecular mechanisms and pattern of oncologic diseases, but also be tailored for individual therapy via transplantation of breast cancer patient-derived tumors. KW - arteriovenous loop KW - breast cancer KW - animal model Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-278919 SN - 2306-5354 VL - 9 IS - 7 ER - TY - JOUR A1 - Frings, Verena G. A1 - Roth, Sabine A1 - Rosenwald, Andreas A1 - Goebeler, Matthias A1 - Geissinger, Eva A1 - Wobser, Marion T1 - EBER in situ hybridization in subcutaneous aluminum granulomas/lymphoid hyperplasia: A diagnostic clue to differentiate injection-associated lymphoid hyperplasia from other forms of pseudolymphomas and cutaneous lymphomas JF - Journal of Cutaneous Pathology N2 - Background Subcutaneous vaccination or desensitization may induce persistent nodules at the injection sites. Without the knowledge of prior injection, histopathological work-up may be challenging. Objective Aim of this study was to contribute to the histopathological work-up of unclear subcutaneous nodules, especially their differentiation from cutaneous lymphoma. Methods We retrospectively reviewed clinical data and histopathological slides of four patients with subcutaneous nodules, which were suspected to suffer from cutaneous T- or B-cell lymphoma. Sections of these cases and 12 negative controls were stained with hematoxylin and eosin and a standardized immunohistochemical panel of B- and T-cell markers including EBER in situ hybridization as well as electron microscopy. Results In all cases, large histiocytes with granular cytoplasm compatible with intracellular aluminum hydroxide were present. EBER in situ hybridization revealed positive staining of these granular histiocytes while staining was absent in negative controls. Limitations Post hoc completion of medical history revealed that vaccination or specific immunotherapy had been applied before at the biopsy site in only three out of four patients; one patient was lost to follow-up. Conclusion EBER in situ hybridization is an adjunctive tool to differentiate aluminum-induced granuloma/lymphoid hyperplasia from other forms of pseudolymphoma and cutaneous B- or T-cell lymphomas. KW - RNA probe KW - aluminum granuloma KW - EBER in situ hybridization KW - lymphoid hyperplasia KW - pseudolymphoma Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258405 VL - 48 IS - 5 ER - TY - JOUR A1 - Sbiera, Iuliu A1 - Kircher, Stefan A1 - Altieri, Barbara A1 - Lenz, Kerstin A1 - Hantel, Constanze A1 - Fassnacht, Martin A1 - Sbiera, Silviu A1 - Kroiss, Matthias T1 - Role of FGF Receptors and Their Pathways in Adrenocortical Tumors and Possible Therapeutic Implications JF - Frontiers in Endocrinology N2 - Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and treatment of advanced disease is challenging. Clinical trials with multi-tyrosine kinase inhibitors in the past have yielded disappointing results. Here, we investigated fibroblast growth factor (FGF) receptors and their pathways in adrenocortical tumors as potential treatment targets. We performed real-time RT-PCR of 93 FGF pathway related genes in a cohort of 39 fresh frozen benign and malignant adrenocortical, 9 non-adrenal tissues and 4 cell lines. The expression of FGF receptors was validated in 166 formalin-fixed paraffin embedded (FFPE) tissues using RNA in situ hybridization (RNAscope) and correlated with clinical data. In malignant compared to benign adrenal tumors, we found significant differences in the expression of 16/94 FGF receptor pathway related genes. Genes involved in tissue differentiation and metastatic spread through epithelial to mesechymal transition were most strongly altered. The therapeutically targetable FGF receptors 1 and 4 were upregulated 4.6- and 6-fold, respectively, in malignant compared to benign adrenocortical tumors, which was confirmed by RNAscope in FFPE samples. High expression of FGFR1 and 4 was significantly associated with worse patient prognosis in univariate analysis. After multivariate adjustment for the known prognostic factors Ki-67 and ENSAT tumor stage, FGFR1 remained significantly associated with recurrence-free survival (HR=6.10, 95%CI: 1.78 – 20.86, p=0.004) and FGFR4 with overall survival (HR=3.23, 95%CI: 1.52 – 6.88, p=0.002). Collectively, our study supports a role of FGF pathways in malignant adrenocortical tumors. Quantification of FGF receptors may enable a stratification of ACC for the use of FGFR inhibitors in future clinical trials. KW - normal adrenal glands KW - adrenocortical tumors KW - FGF-pathway KW - FGFR KW - RNA Expression KW - RNAScope KW - unsupervised clustering KW - patient survival Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-251953 SN - 1664-2392 VL - 12 ER - TY - JOUR A1 - Zamò, Alberto A1 - Johnston, Peter A1 - Attygalle, Ayoma D A1 - Laurent, Camille A1 - Arber, Daniel A A1 - Fend, Falko T1 - Aggressive B‐cell lymphomas with a primary bone marrow presentation JF - Histopathology KW - aggressive B‐cell lymphoma KW - bone marrow biopsy KW - bone marrow–spleen–liver large B‐cell lymphoma KW - diffuse large B‐cell lymphoma KW - EAHP/SH bone marrow workshop KW - high‐grade B‐cell lymphoma KW - intravascular large B‐cell lymphoma KW - primary bone marrow presentation Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218327 VL - 77 IS - 3 SP - 369 EP - 379 ER - TY - JOUR A1 - Zhou, Xiang A1 - Steinhardt, Maximilian Johannes A1 - Düll, Johannes A1 - Krummenast, Franziska A1 - Danhof, Sophia A1 - Meckel, Katharina A1 - Nickel, Katharina A1 - Grathwohl, Denise A1 - Leicht, Hans‐Benno A1 - Rosenwald, Andreas A1 - Einsele, Hermann A1 - Rasche, Leo A1 - Kortüm, Martin T1 - Obinutuzumab and venetoclax induced complete remission in a patient with ibrutinib‐resistant non‐nodal leukemic mantle cell lymphoma JF - European Journal of Haematology N2 - We herein report the case of a 73‐year‐old male patient who was diagnosed with leukemic non‐nodal MCL. This patient had received six cycles of bendamustine, which resulted in a transient remission, and a second‐line therapy with ibrutinib, which unfortunately failed to induce remission. We started a treatment with single‐agent obinutuzumab at a dose of 20 mg on day 1, 50 mg on day 2‐4, 330 mg on day 5, and 1000 mg on day 6. The laboratory analysis showed a rapid decrease of leukocyte count. Four weeks later, we repeated the treatment with obinutuzumab at a dose of 1000 mg q4w and started a therapy with venetoclax at a dose of 400 mg qd, which could be increased to 800 mg qd from the third cycle. This combination therapy was well tolerated. The patient achieved a complete remission (CR) after three cycles of obinutuzumab and venetoclax. To date, the patient has a progression‐free survival of 17 months under ongoing obinutuzumab maintenance q4w. This is the first report about obinutuzumab and venetoclax induced CR in rituximab‐intolerant patient with an ibrutinib‐resistant MCL. This case suggests that obinutuzumab‐ and venetoclax‐based combination therapy might be salvage therapy in patients with ibrutinib‐resistant MCL. KW - mantle cell lymphoma KW - obinutuzumab KW - venetoclax Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215513 VL - 104 IS - 4 SP - 352 EP - 355 ER - TY - JOUR A1 - Barahona de Brito, Carlotta A1 - Patra, Amiya Kumar T1 - NFAT factors are dispensable for the development but are critical for the maintenance of Foxp3\(^+\) regulatory T cells JF - Cells N2 - The transcription factors of the nuclear factor of activated T cell (NFAT) family play a crucial role in multiple aspects of T cell function. It has recently been reported that NFATs play an important role in the suppressive function of CD4\(^+\)CD25\(^+\)Foxp3\(^+\) regulatory T (T\(_{reg}\)) cells. In this study, we have investigated the role of NFATs in the thymic development of T\(_{reg}\) cells in mice. We show that NFAT factors are dispensable for the development of Foxp3\(^+\) T\(_{reg}\) cells in the thymus but are critical for the maintenance of both the phenotype and survival of T\(_{reg}\) cells in the thymus as well as in peripheral lymphoid organs. Specifically, the homeostasis of CD4\(^+\)CD25\(^+\)Foxp3\(^+\) but not the CD4\(^+\)CD25\(^-\)Foxp3\(^+\) fraction is severely perturbed when NFAT signaling is blocked, leading to a strongly reduced T\(_{reg}\) population. We underscored this intriguing effect of NFAT on CD4\(^+\)CD25\(^+\)Foxp3\(^+\) T\(_{reg}\) cells to the disruption of survival signals provided by interleukin 2 (IL-2). Accordingly, blocking T\(_{reg}\) cell death by abolishing the activity of pro-apoptotic Bcl-2 family member Bim, compensated for the survival defects induced due to a lack of NFAT-IL-2-IL-2R signaling. Inhibition of NFAT activity led to a strong reduction in the number of Foxp3\(^+\) T\(_{reg}\) cells; however, it did not influence the level of Foxp3 expression on an individual cell basis. In addition, we show a differential effect of IL-2 and IL-7 signaling on Foxp3\(^+\) T\(_{reg}\) versus CD4\(^+\)CD25\(^-\) T cell development, again underlining the dispensability of NFAT signaling in the development, but not in the maintenance of Foxp3\(^+\) T\(_{reg}\) cells. KW - thymocytes KW - NFAT KW - cyclosporine A KW - T\(_{reg}\) and Foxp3 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270668 SN - 2073-4409 VL - 11 IS - 9 ER - TY - JOUR A1 - Bohnert, Simone A1 - Georgiades, Kosmas A1 - Monoranu, Camelia-Maria A1 - Bohnert, Michael A1 - Büttner, Andreas A1 - Ondruschka, Benjamin T1 - Quantitative evidence of suppressed TMEM119 microglial immunohistochemistry in fatal morphine intoxications JF - International Journal of Legal Medicine N2 - The aim of this pilot study was to investigate the diagnostic potential of TMEM119 as a useful microglia-specific marker in combination with immunostainings for phagocytic function and infiltrating capacity of monocytes in cases of lethal monosubstance intoxications by morphine (MOR), methamphetamine (METH), and of ethanol-associated death (ETH) respectively. Human brain tissue samples were obtained from forensic autopsies of cases with single substance abuse (MOR, n = 8; ETH, n = 10; METH, n = 9) and then compared to a cohort of cardiovascular fatalities as controls (n = 9). Brain tissue samples of cortex, white matter, and hippocampus were collected and stained immunohistochemically with antibodies against TMEM119, CD68KiM1P, and CCR2. We could document the lowest density of TMEM119-positive cells in MOR deaths with highly significant differences to the control densities in all three regions investigated. In ETH and METH deaths, the expression of TMEM119 was comparable to cell densities in controls. The results indicate that the immunoreaction in brain tissue is different in these groups depending on the drug type used for abuse. KW - immunohistochemistry KW - drug abuse KW - forensic neuropathology KW - neuroinflammation KW - neurotoxicity KW - microglia Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266934 SN - 1437-1596 VL - 135 IS - 6 ER -