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BACKGROUND AND OBJECTIVES: Haemovigilance (HV) systems aim to improve transfusion outcomes in patients and donor safety. An important question for blood regulators is how to ensure an effective HV system. MATERIALS AND METHODS: We retrospectively analysed the HV reports submitted to Paul-Ehrlich-Institut over the last two decades. RESULTS: Between 2011 and 2020, 50.86 million units of blood components were used, and 8931 suspected serious donor and recipient adverse reactions (SARs), 874 serious adverse events (SAEs) and 12,073 donor look-backs were reported. Following implementation of specific risk-minimization measures (RMMs) between 2000 and 2010, SAR reporting rates decreased for transfusion-transmitted viral infections (TTVIs), transfusion-related acute lung injury (TRALI) and transfusion-transmitted bacterial infections (TTBIs), while increasing for other serious adverse transfusion reactions. Within this decade, the overall blood component use decreased. CONCLUSION: Long-term data collection forms the basis to establish trends and changes in reporting and to evaluate the effect of RMM. Standardized criteria for reaction types, seriousness and imputability assessments and availability of a denominator are important elements. Central data collection and independent assessment allow for monitoring HV data in a nationwide context over time. Stakeholder involvement and transparent feedback on the benefit of RMM will help to achieve the objectives of HV.
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We present the long-term outcomes of 44 patients who developed cerebral venous sinus thrombosis after vaccination with the adenoviral vector ChAdOx1 nCoV-19 COVID-19 vaccine. Assessment of the Extended Glasgow Outcome Scale was performed within 3-6 months after the initial hospital admissions. Patient outcomes ranged from good recovery (13 patients, 29.6%) to moderate disability (11 patients, 25.0%) and severe disability or vegetative state (6 patients, 13.6%). Fatal outcomes were reported in 14 patients (31.8%).
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The induction of apoptosis is a direct way to eliminate tumor cells and improve cancer therapy. Apoptosis is tightly controlled by the balance of pro- and antiapoptotic Bcl-2 proteins. BH3 mimetics neutralize the antiapoptotic function of Bcl-2 proteins and are highly promising compounds inducing apoptosis in several cancer entities including pediatric malignancies. However, the clinical application of BH3 mimetics in solid tumors is impeded by the frequent resistance to single BH3 mimetics and the anticipated toxicity of high concentrations or combination treatments. One potential avenue to increase the potency of BH3 mimetics is the development of immune cell-based therapies to counteract the intrinsic apoptosis resistance of tumor cells and sensitize them to immune attack. Here, we describe spheroid cultures of pediatric cancer cells that can serve as models for drug testing. In these 3D models, we were able to demonstrate that activated allogeneic Natural Killer (NK) cells migrated into tumor spheroids and displayed cytotoxicity against a wide range of pediatric cancer spheroids, highlighting their potential as anti-tumor effector cells. Next, we investigated whether treatment of tumor spheroids with subtoxic concentrations of BH3 mimetics can increase the cytotoxicity of NK cells. Notably, the cytotoxic effects of NK cells were enhanced by the addition of BH3 mimetics. Treatment with either the Bcl-XL inhibitor A1331852 or the Mcl-1 inhibitor S63845 increased the cytotoxicity of NK cells and reduced spheroid size, while the Bcl-2 inhibitor ABT-199 had no effect on NK cell-mediated killing. Taken together, this is the first study to describe the combination of BH3 mimetics targeting Bcl-XL or Mcl-1 with NK cell-based immunotherapy, highlighting the potential of BH3 mimetics in immunotherapy.
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The removal of cells by apoptosis is an essential process regulating tissue homeostasis. Cancer cells acquire the ability to circumvent apoptosis and survive in an unphysiological tissue context. Thereby, the Bcl-2 protein family plays a key role in the initiation of apoptosis, and overexpression of the anti-apoptotic Bcl-2 proteins is one of the molecular mechanisms protecting cancer cells from apoptosis. Recently, small molecules targeting the anti-apoptotic Bcl-2 family proteins have been identified, and with venetoclax the first of these BH3 mimetics has been approved for the treatment of leukemia. In solid tumors the anti-apoptotic Bcl-2 family proteins Mcl-1 and Bcl-xL are frequently overexpressed or genetically amplified. In this review, we summarize the role of Mcl-1 and Bcl-xL in solid tumors and compare the different BH3 mimetics targeting Mcl-1 or Bcl-xL.
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Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Neoplasias/genética , Bibliotecas de Moléculas Pequeñas/farmacología , Proteína bcl-X/genética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Amplificación de Genes , Regulación Neoplásica de la Expresión Génica , Humanos , Imitación Molecular , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Dominios Proteicos , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Regulación hacia Arriba , Proteína bcl-X/antagonistas & inhibidoresRESUMEN
With the development of potent and selective inhibitors of MCL-1 (S63845) and BCL-XL (A-1331852) novel cancer treatment options have emerged. BCL-2 family proteins are important regulators of apoptosis in pediatric solid tumors. In the current study, we discover that rhabdomyosarcoma, Ewing sarcoma, osteosarcoma and neuroblastoma cell lines are co-dependent on BCL-XL and MCL-1 for survival. A-1331852/S63845 co-treatment, but not combinations of either inhibitor with ABT-199, synergistically induces rapid intrinsic apoptosis in vitro and demonstrates efficiency in an in vivo embryonic chicken model of rhabdomyosarcoma. Interestingly, A-1331852/S63845-induced apoptosis is BAX/BAK-dependent and mediated by displacement of BAK from BCL-XL and MCL-1, respectively. Moreover, BAK interacts with BAX to build a pore-forming complex in the outer mitochondrial membrane, leading to loss of mitochondrial outer membrane potential and caspase activation. Furthermore, in RD cells A-1331852/S63845 co-treatment disrupts BIM and NOXA in their interactions with BCL-XL and MCL-1, respectively, thereby contributing to apoptosis. Altogether, this study is the first to demonstrate the potency of A-1331852/S63845 in pediatric solid tumor cells and to describe the molecular mechanisms of A-1331852/S63845 co-treatment underlining the potential of BCL-XL and MCL-1 inhibition as treatment regime.
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Benzotiazoles/farmacología , Isoquinolinas/farmacología , Neuroblastoma/metabolismo , Osteosarcoma/metabolismo , Pirimidinas/farmacología , Rabdomiosarcoma/metabolismo , Sarcoma de Ewing/metabolismo , Tiofenos/farmacología , Animales , Benzotiazoles/uso terapéutico , Caspasas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Embrión de Pollo , Niño , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Isoquinolinas/uso terapéutico , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Neuroblastoma/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Pirimidinas/uso terapéutico , Rabdomiosarcoma/tratamiento farmacológico , Sarcoma de Ewing/tratamiento farmacológico , Tiofenos/uso terapéutico , Proteína bcl-X/metabolismoRESUMEN
Lysine-specific demethylase 1 (LSD1), a histone lysine demethylase with the main specificity for H3K4me2, has been shown to be overexpressed in rhabdomyosarcoma (RMS) tumor samples. However, its role in RMS biology is not yet well understood. Here, we identified a new role of LSD1 in regulating adhesion of RMS cells. Genetic knockdown of LSD1 profoundly suppressed clonogenic growth in a panel of RMS cell lines, whereas LSD1 proved to be largely dispensable for regulating cell death and short-term survival. Combined RNA and ChIP-sequencing performed to analyze RNA expression and histone methylation at promoter regions revealed a gene set enrichment for adhesion-associated terms upon LSD1 knockdown. Consistently, LSD1 knockdown significantly reduced adhesion to untreated surfaces. Importantly, precoating of the plates with the adhesives collagen I or fibronectin rescued this reduced adhesion of LSD1 knockdown cells back to levels of control cells. Using KEGG pathway analysis, we identified 17 differentially expressed genes (DEGs) in LSD1 knockdown cells related to adhesion processes, which were validated by qRT-PCR. Combining RNA and ChIP-sequencing results revealed that, within this set of genes, SPP1, C3AR1, ITGA10 and SERPINE1 also exhibited increased H3K4me2 levels at their promoter regions in LSD1 knockdown compared to control cells. Indeed, LSD1 ChIP experiments confirmed enrichment of LSD1 at their promoter regions, suggesting a direct transcriptional regulation by LSD1. By identifying a new role of LSD1 in the modulation of cell adhesion and clonogenic growth of RMS cells, these findings highlight the importance of LSD1 in RMS.
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Adhesión Celular/genética , Histona Demetilasas/metabolismo , Rabdomiosarcoma/genética , Línea Celular Tumoral , Autorrenovación de las Células/genética , Desmetilación del ADN , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Secuenciación de Nucleótidos de Alto Rendimiento , Histona Demetilasas/genética , Histonas/genética , Humanos , Regiones Promotoras Genéticas/genética , Rabdomiosarcoma/patologíaRESUMEN
BH3 mimetics are emerging novel anticancer therapeutics that potently and specifically inhibit antiapoptotic BCL-2 proteins and thereby induce cell death in many cancer entities. Previously, we demonstrated that JNJ-26481585 (JNJ), a second-generation histone deacetylase inhibitor (HDACI), engages mitochondrial apoptosis via upregulation of several BH3-only proteins. In the present study, we describe synergistic interactions of JNJ with BH3 mimetics (i.e. ABT-737, ABT-199) in rhabdomyosarcoma (RMS) cells. Importantly, JNJ synergizes with ABT-199 to trigger apoptosis in primary-derived RMS cells isolated from tumor samples, underlining the translational importance of combining these compounds and their potential to improve cancer therapy. Importantly, JNJ/ABT-199 cotreatment also significantly inhibits long-term survival of RMS cells. Mechanistically, JNJ increases expression levels of the BH3-only protein BIM, while exposure to ABT-199 displaces BIM from BCL-2 and shuttles BIM to MCL-1, which also constitutively sequesters NOXA. Both BIM and NOXA contribute to JNJ/ABT-199-mediated cell death, as individual knockdown of NOXA or BIM significantly prevents cell death. Further, JNJ and ABT-199 act in concert to activate BAK and BAX, resulting in loss of the mitochondrial membrane potential (MMP) and caspase activation. These events are required for JNJ/ABT-199-mediated apoptosis, since BAK or BAX silencing or inhibition of caspases significantly protects from JNJ/ABT-199-induced cell death. Rescue experiments demonstrate that overexpression of MCL-1, but not overexpression of BCL-2, blocks JNJ/ABT-199-induced apoptosis. In conclusion, this study provides the first demonstration of ABT-199-induced priming, which sensitizes RMS cells to HDACI, such as JNJ, by engaging mitochondrial apoptosis, highlighting that BH3 mimetics show great promise for the treatment of RMS.