Journal Articles

Identification of Ligand-Receptor Pairs Associated With Tumour Characteristics in Clear Cell Renal Cell Carcinoma

The tumour microenvironment (TME) of clear cell renal cell carcinoma (ccRCC) comprises multiple cell types, which promote tumour progression and modulate drug resistance and immune cell infiltrations via ligand-receptor (LR) interactions. However, the interactions, expression patterns, and clinical relevance of LR in the TME in ccRCC are insufficiently characterised. This study characterises the complex composition of the TME in ccRCC by analysing the single-cell sequencing (scRNA-seq) data of patients with ccRCC from the Gene expression omnibus database. On analysing the scRNA-seq data combined with the cancer genome atlas kidney renal clear cell carcinoma (TCGA-KIRC) dataset, 46 LR-pairs were identified that were significantly correlated and had prognostic values. Furthermore, a new molecular subtyping model was proposed based on these 46 LR-pairs. Molecular subtyping was performed in two ccRCC cohorts, revealing significant differences in prognosis between the subtypes of the two ccRCC cohorts. Different molecular subtypes exhibited different clinicopathological features, mutational, pathway, and immune signatures. Finally, the LR.score model that was constructed using ten essential LR-pairs that were identified based on LASSO Cox regression analysis revealed that the model could accurately predict the prognosis of patients with ccRCC. In addition, the differential expression of ten LR-pairs in tumour and normal cell lines was identified. Further functional experiments showed that CX3CL1 can exert anti-tumorigenic role in ccRCC cell line. Altogether, the effects of immunotherapy were connected to LR.scores, indicating that potential medications targeting these LR-pairs could contribute to the clinical benefit of immunotherapy. Therefore, this study identifies LR-pairs that could be effective biomarkers and predictors for molecular subtyping and immunotherapy effects in ccRCC. Targeting LR-pairs provides a new direction for immunotherapy regimens and prognostic evaluations in ccRCC.

Author Info: (1) Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden. (2) Department of Dermatology, Fujian Provincial Ge

Author Info: (1) Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden. (2) Department of Dermatology, Fujian Provincial Geriatric Hospital, Fuzhou, China. (3) Department of Internal Medicine, Chonnam National University Medical School, Gwangju, South Korea. (4) Guixi Key Laboratory for High Incidence Diseases, Youjiang Medical University for Nationalities, Baise, China. (5) Department of Nephrology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.

The role of IL-33/ST2 signaling in the tumor microenvironment and Treg immunotherapy

Interleukin (IL)-33 is a tissue-derived nuclear cytokine belonging to the IL-1 family. Stimulation-2 (ST2) is the only known IL-33 receptor. ST2 signals mostly on immune cells found within tissues, such as regulatory T cells (Treg cells), CD8+ T cells, and natural killer (NK) cells. Therefore, the IL-33/ST2 signaling pathway is important in the immune system. IL-33 deficiency impairs Treg cell function. ST2 signaling is also increased in active Treg cells, providing a new approach for Treg-related immunotherapy. The IL-33/ST2 signaling pathway regulates multiple immune-related cells by activating various intracellular kinases and factors in the tumor microenvironment (TME). Here, we review the latest studies on the role of the IL-33/ST2 signaling pathway in TME and Treg immunotherapy.

Author Info: (1) Department of Immunology, Guilin Medical University, Guilin 541199, Guangxi, China. Department of Pathophysiology, Guilin Medical University, Guilin 541199, Guangxi, China. Gua

Author Info: (1) Department of Immunology, Guilin Medical University, Guilin 541199, Guangxi, China. Department of Pathophysiology, Guilin Medical University, Guilin 541199, Guangxi, China. Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, Guangxi, China. (2) Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, Guangxi, China. (3) Department of Immunology, Guilin Medical University, Guilin 541199, Guangxi, China. (4) Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, Guangxi, China. (5) Department of Pathophysiology, Guilin Medical University, Guilin 541199, Guangxi, China. Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, Guangxi, China. (6) Department of Immunology, Guilin Medical University, Guilin 541199, Guangxi, China. Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, Guangxi, China.

Lipid A analog CRX-527 conjugated to synthetic peptides enhances vaccination efficacy and tumor control

Adjuvants play a determinant role in cancer vaccination by optimally activating APCs and shaping the T cell response. Bacterial-derived lipid A is one of the most potent immune-stimulators known, and is recognized via Toll-like receptor 4 (TLR4). In this study, we explore the use of the synthetic, non-toxic, lipid A analog CRX-527 as an adjuvant for peptide cancer vaccines. This well-defined adjuvant was covalently conjugated to antigenic peptides as a strategy to improve vaccine efficacy. We show that coupling of this TLR4 agonist to peptide antigens improves vaccine uptake by dendritic cells (DCs), maturation of DCs and T cell activation in vitro, and stimulates DC migration and functional T cell priming in vivo. This translates into enhanced tumor protection upon prophylactic and therapeutic vaccination via intradermal injection against B16-OVA melanoma and HPV-related TC1 tumors. These results highlight the potential of CRX-527 as an adjuvant for molecularly defined cancer vaccines, and support the design of adjuvant-peptide conjugates as a strategy to optimize vaccine formulation.

Author Info: (1) Department of Immunology, Leiden University Medical Center, Leiden University, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (2) Bio-organic Synthesis, Leiden Institute of

Author Info: (1) Department of Immunology, Leiden University Medical Center, Leiden University, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (2) Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands. (3) Department of Immunology, Leiden University Medical Center, Leiden University, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (4) Department of Immunology, Leiden University Medical Center, Leiden University, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (5) Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands. (6) Department of Immunology, Leiden University Medical Center, Leiden University, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (7) Department of Immunology, Leiden University Medical Center, Leiden University, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (8) Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands. (9) Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands. (10) Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands. jcodee@chem.leidenuniv.nl. (11) Department of Immunology, Leiden University Medical Center, Leiden University, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. f.a.ossendorp@lumc.nl.

A degron system targeting endogenous PD-1 inhibits the growth of tumor cells in mice

Recently, targeted protein degradation systems have been developed using the ubiquitin-proteasome system. Here, we established Programmed cell death-1 (PD-1) knockdown mice as a model system for subjecting endogenous mouse proteins to the small molecule-assisted shutoff (SMASh) degron system. SMASh degron-tagged PD-1-mCherry in Jurkat cells and CD3(+) splenocytes were degraded by the NS3/4A protease inhibitors, asunaprevir (ASV) or grazoprevir (GRV). Growth of MC-38 colon adenocarcinoma cells injected in Pdcd1-mCherry-SMASh homozygous knock-in (KI) mice was repressed by ASV or GRV. Moreover, growth of MC-38 cells was suppressed in wild-type mice transplanted with KI bone marrow cells after GRV treatment. This is the first study to use a degron tag targeting an endogenous mouse protein in vivo. Our experimental system using the SMASh degron may be employed for treating diseases and characterizing the cellular functions of essential proteins.

Author Info: (1) Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. (2) Institute of Laboratory Animals, Graduat

Author Info: (1) Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. (2) Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. (3) Department of Pathology, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1104, Japan. (4) Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. (5) Laboratory Animal Resource Center, Transborder Medical Research Center, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. (6) Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.

Generation of immunocompetent syngeneic allograft mouse models for pediatric diffuse midline glioma

BACKGROUND: Diffuse midline gliomas (DMG) are highly malignant incurable pediatric brain tumors. A lack of effective treatment options highlights the need to investigate novel therapeutic strategies. This includes the use of immunotherapy, which has shown promise in other hard-to-treat tumors. To facilitate preclinical immunotherapeutic research, immunocompetent mouse models that accurately reflect the unique genetic, anatomical, and histological features of DMG patients are warranted. METHODS: We established cell cultures from primary DMG mouse models (C57BL/6) that were generated by brainstem targeted intra-uterine electroporation (IUE). We subsequently created allograft DMG mouse models by orthotopically implanting these tumor cells into syngeneic mice. Immunohistochemistry and -fluorescence, mass cytometry, and cell-viability assays were then used to verify that these murine tumors recapitulated human DMG. RESULTS: We generated three genetically distinct allograft models representing histone 3 wildtype (H3(WT)) and K27M-mutant DMG (H3.3(K27M) and H3.1(K27M)). These allograft models recapitulated the histopathologic phenotype of their human counterparts, including their diffuse infiltrative growth and expression of DMG-associated antigens. These murine pontine tumors also exhibited an immune microenvironment similar to human DMG, characterized by considerable myeloid cell infiltration and a paucity of T-lymphocytes and NK cells. Finally, we show that these murine DMG cells display similar sensitivity to histone deacetylase (HDAC) inhibition as patient-derived DMG cells. CONCLUSIONS: We created and validated an accessible method to generate immunocompetent allograft models reflecting different subtypes of DMG. These models adequately recapitulated the histopathology, immune microenvironment, and therapeutic response of human DMG, providing useful tools for future preclinical studies.

Author Info: (1) Princess M‡xima Center for Pediatric Oncology, Utrecht, the Netherlands. (2) Princess M‡xima Center for Pediatric Oncology, Utrecht, the Netherlands. (3) Princess M‡xima Center

Author Info: (1) Princess M‡xima Center for Pediatric Oncology, Utrecht, the Netherlands. (2) Princess M‡xima Center for Pediatric Oncology, Utrecht, the Netherlands. (3) Princess M‡xima Center for Pediatric Oncology, Utrecht, the Netherlands. (4) Princess M‡xima Center for Pediatric Oncology, Utrecht, the Netherlands. (5) Princess M‡xima Center for Pediatric Oncology, Utrecht, the Netherlands. (6) Department of Pathology, Amsterdam University Medical Centers, Amsterdam, the Netherlands. (7) Department of Pathology, Amsterdam University Medical Centers, Amsterdam, the Netherlands. (8) Departments of Neurology, Neurological Surgery, and Pediatrics, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA. (9) Departments of Neurology, Neurological Surgery, and Pediatrics, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA. (10) Departments of Neurology, Neurological Surgery, and Pediatrics, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA. (11) Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centers, Amsterdam, the Netherlands. (12) Princess M‡xima Center for Pediatric Oncology, Utrecht, the Netherlands. (13) Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati/Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. (14) Princess M‡xima Center for Pediatric Oncology, Utrecht, the Netherlands.

Preclinical Efficacy of BCMA-Directed CAR T Cells Incorporating a Novel D Domain Antigen Recognition Domain

Chimeric antigen receptor (CAR) T-cell therapies directed against B-cell maturation antigen (BCMA) have shown compelling clinical activity and manageable safety in subjects with relapsed and refractory multiple myeloma (RRMM). Prior reported CAR T cells have mostly used antibody fragments such as humanized or murine single-chain variable fragments or camelid heavy-chain antibody fragments as the antigen recognition motif. Herein, we describe the generation and preclinical evaluation of ddBCMA CAR, which uses a novel BCMA binding domain discovered from our D domain phage display libraries and incorporates a 4-1BB costimulatory motif and CD3-zeta T-cell activation domain. Preclinical in vitro studies of ddBCMA CAR T cells cocultured with BCMA-positive cell lines showed highly potent, dose-dependent measures of cytotoxicity, cytokine production, T-cell degranulation, and T-cell proliferation. In each assay, ddBCMA CAR performed as well as the BCMA-directed scFv-based C11D5.3 CAR. Furthermore, ddBCMA CAR T cells demonstrated in vivo tumor suppression in three disseminated BCMA-expressing tumor models in NSG-immunocompromised mice. On the basis of these promising preclinical data, CART-ddBCMA is being studied in a first-in-human phase I clinical study to assess the safety, pharmacokinetics, immunogenicity, efficacy, and duration of effect for patients with RRMM (NCT04155749).

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9)

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9)

Activation of cytotoxic T lymphocytes by self-differentiated myeloid-derived dendritic cells for killing breast cancer cells expressing folate receptor alpha protein

Adoptive cell transfer (ACT) is a promising approach for cancer treatment. Activation of T lymphocytes by self-differentiated myeloid-derived antigen-presenting-cells reactive against tumor (SmartDC) resulted in specific anti-cancer function. Folate receptor alpha (FR_) is highly expressed in breast cancer (BC) cells and thus potential to be a target antigen for ACT. To explore the SmartDC technology for treatment of BC, we create SmartDC expressing FR_ antigen (SmartDC-FR_) for activation of FR_-specific T lymphocytes. Human primary monocytes were transduced with lentiviruses containing tri-cistronic complementary DNA sequences encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-4 (IL-4), and FR_ to generate SmartDC-FR_. Autologous T lymphocytes were activated by SmartDC-FR_ by coculture. The activated T lymphocytes exhibited enhanced cytotoxicity against FR_-expressing BC cell cultures. Up to 84.9 ± 6.2% of MDA-MB-231 and 89.7 ± 1.9% of MCF-7 BC cell lines were specifically lysed at an effector-to-target ratio of 20:1. The cytotoxicity of T lymphocytes activated by SmartDC-FR_ was also demonstrated in three-dimensional (3D) spheroid culture of FR_-expressing BC cells marked by size reduction and spheroid disruption. This study thus portray the potential development of T lymphocytes activated by SmartDC-FR_ as ACT in FR_-expressing BC treatment.

Author Info: (1) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Division of Molecular

Author Info: (1) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol, University, Bangkok, Thailand. (2) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol, University, Bangkok, Thailand. (3) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. (4) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol, University, Bangkok, Thailand. (5) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol, University, Bangkok, Thailand.

Generation of CAR-T Cells with Sleeping Beauty Transposon Gene Transfer

Human T lymphocytes that transgenically express a chimeric antigen receptor (CAR) have proven efficacy and safety in gene- and cell-based immunotherapy of certain hematological cancers. Appropriate gene vectors and methods of genetic engineering are required for therapeutic cell products to be biologically potent and their manufacturing to be economically viable. Transposon-based gene transfer satisfies these needs, and is currently being evaluated in clinical trials. In this protocol we describe the basic Sleeping Beauty (SB) transposon vector components required for stable gene integration in human cells, with special emphasis on minicircle DNA vectors and the use of synthetic mRNA. We provide a protocol for functional validation of the vector components in cultured human cell lines on the basis of fluorescent reporter gene expression. Finally, we provide a protocol for CAR-T cell engineering and describe assays that address transgene expression, biological potency and genomic vector copy numbers in polyclonal cell populations. Because transposons allow virus-free gene transfer with naked nucleic acids, the protocol can be adopted by any laboratory equipped with biological safety level S1 facilities.

Author Info: (1) Department of Internal Medicine II, University Hospital of WŸrzburg, WŸrzburg, Germany. (2) Department of Internal Medicine II, University Hospital of WŸrzburg, WŸrzburg, Germa

Author Info: (1) Department of Internal Medicine II, University Hospital of WŸrzburg, WŸrzburg, Germany. (2) Department of Internal Medicine II, University Hospital of WŸrzburg, WŸrzburg, Germany. (3) Division of Medical Biotechnology, Paul Ehrlich Institute, Langen, Germany. (4) Division of Medical Biotechnology, Paul Ehrlich Institute, Langen, Germany. (5) Division of Medical Biotechnology, Paul Ehrlich Institute, Langen, Germany. (6) Department of Internal Medicine II, University Hospital of WŸrzburg, WŸrzburg, Germany. (7) Department of Internal Medicine II, University Hospital of WŸrzburg, WŸrzburg, Germany. (8) Division of Medical Biotechnology, Paul Ehrlich Institute, Langen, Germany. zoltan.ivics@pei.de.

Vaccines for immunoprevention of DNA mismatch repair deficient cancers

The development of cancer vaccines to induce tumor-antigen specific immune responses was sparked by the identification of antigens specific to or overexpressed in cancer cells. However, weak immunogenicity and the mutational heterogeneity in many cancers have dampened cancer vaccine successes. With increasing information about mutational landscapes of cancers, mutational neoantigens can be predicted computationally to elicit strong immune responses by CD8 +cytotoxic_T cells as major mediators of anticancer immune response. Neoantigens are potentially more robust immunogens and have revived interest in cancer vaccines. Cancers with deficiency in DNA mismatch repair have an exceptionally high mutational burden, including predictable neoantigens. Lynch syndrome is the most common inherited cancer syndrome and is caused by DNA mismatch repair gene mutations. Insertion and deletion mutations in coding microsatellites that occur during DNA replication include tumorigenesis drivers. The induced shift of protein reading frame generates neoantigens that are foreign to the immune system. Mismatch repair-deficient cancers and Lynch syndrome represent a paradigm population for the development of a preventive cancer vaccine, as the mutations induced by mismatch repair deficiency are predictable, resulting in a defined set of frameshift peptide neoantigens. Furthermore, Lynch syndrome mutation carriers constitute an identifiable high-risk population. We discuss the pathogenesis of DNA mismatch repair deficient cancers, in both Lynch syndrome and sporadic microsatellite-unstable cancers. We review evidence for pre-existing immune surveillance, the three mechanisms of immune evasion that occur in cancers and assess the implications of a preventive frameshift peptide neoantigen-based vaccine. We consider both preclinical and clinical experience to date. We discuss the feasibility of a cancer preventive vaccine for Lynch syndrome carriers and review current antigen selection and delivery strategies. Finally, we propose RNA vaccines as having robust potential for immunoprevention of Lynch syndrome cancers.

Author Info: (1) Department of Applied Tumor Biology, University Hospital Heidelberg Institute of Pathology, Heidelberg, Germany. (2) Department of Medicine, Weill Cornell Medicine, New York, N

Author Info: (1) Department of Applied Tumor Biology, University Hospital Heidelberg Institute of Pathology, Heidelberg, Germany. (2) Department of Medicine, Weill Cornell Medicine, New York, New York, USA. (3) Department of Medicine, Weill Cornell Medicine, New York, New York, USA. (4) Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, USA. (5) Department of Medicine, Weill Cornell Medicine, New York, New York, USA stl2012@med.cornell.edu. (6) University Hospital Heidelberg, Institute of Pathology, Department of Applied Tumor Biology, Heidelberg, Germany.

Gene Gun Her2/neu DNA Vaccination: Evaluation of Vaccine Efficacy in a Syngeneic Her2/neu Mouse Tumor Model

Genetic vaccination using naked plasmid DNA is an immunization strategy both against infectious diseases and cancer.In order to improve efficacy of DNA vaccines, particularly in large animals and humans, different strategies have been pursued. These vaccination strategies are based on different application routes, schedules and coexpression of immunomodulatory molecules as adjuvants. Our mouse tumor model offers the possibility to investigate Her2/neu DNA vaccines in different settings, that is, intramuscular or intradermal application with or without coexpression of adjuvants. The immunogenicity of predicted peptides for Her2/neu specific memory T cells were screened and confirmed after intramuscular and intradermal application. Protection from tumor growth in tumor challenge experiments and both T cell and humoral immune responses against Her2/neu peptides are used as surrogate parameters for vaccine efficacy.

Author Info: (1) Experimental and Clinical Research Center, CharitŽ - UniversitŠtsmedizin Berlin, Berlin, Germany. hoai-tam.nguyen@charite.de. (2) Robert Koch Institute, Berlin, Germany. (3) Ch

Author Info: (1) Experimental and Clinical Research Center, CharitŽ - UniversitŠtsmedizin Berlin, Berlin, Germany. hoai-tam.nguyen@charite.de. (2) Robert Koch Institute, Berlin, Germany. (3) CharitŽ - UniversitŠtsmedizin Berlin and Max-DelbrŸck-Center for Molecular Medicine, Berlin, Germany. (4) Department Hematology, Oncology and Immunology, CharitŽ - UniversitŠtsmedizin Berlin, Berlin, Germany.

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