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Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors.

Introducción: Los procedimientos vasculares invasivos ocasionan infecciones sanguíneas asociadas a cuidados de la salud, entre ellas endocarditis infecciosa. Este evento adverso conlleva mayor morbimortalidad que la endocarditis infecciosa adquirida en la comunidad. Objetivo: Evaluar la prevalencia de endocarditis infecciosa asociada al cuidado de la salud y describir las características demográficas de esta población, así como los agentes etiológicos. Método: Estudio de corte transversal, en el que se incluyó población mayor de 18 años con endocarditis infecciosa asociada al cuidado de la salud, documentada entre enero de 2013 y junio de 2018 en la Fundación Cardioinfantil. Se realizó un análisis estadístico con distribución de variables de edad, sexo, procedimientos invasivos asociados, mortalidad y microorganismo aislado. Resultados: Se incluyeron 41 pacientes con una edad promedio de 60,6 años. No hubo distinción entre hombres (22, 53.6%) y mujeres (19, 46.3%). Los pacientes se agruparon, según el procedimiento realizado, en implantación de dispositivos intravasculares de alto flujo (16, 39.02%), catéter venoso central (12, 29.26%) y dispositivos intracardiacos (11, 26.82%). La prevalencia general en los procedimientos evaluados fue del 0.21%, siendo del 1.42% en dispositivos intravasculares de alto flujo, del 0.72% en dispositivos intracardiacos y del 0.08% en catéteres centrales. La mortalidad registrada fue del 4.9% (2 pacientes). En el 78.05% de los pacientes se obtuvo aislamiento microbiológico. Conclusiones: Los pacientes sometidos a procedimientos invasivos pueden tener un riesgo elevado de endocarditis infecciosa, conferido por el procedimiento. La baja tasa de mortalidad intrahospitalaria puede estar relacionada con la notable tasa de aislamiento positivo en hemocultivos, lo cual facilitó la terapia antibiótica dirigida.

Aberrant expression of MYC family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYC induces massive lipid peroxidation upon depletion of cysteine, the rate-limiting amino acid for glutathione biosynthesis and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and irondependent type of cell death. In MYCN-amplified childhood neuroblastoma, MYCN mediates resistance to ferroptosis by activating transsulfuration of methionine to cysteine. MYCN may contribute to spontaneous tumor regression in low-risk neuroblastomas by promoting ferroptosis in cells with epigenetically silenced cystathionine-beta-synthase, the rate-limiting enzyme for transsulfuration. We identified enzymes and antiporter proteins crucial to ferroptotic escape, providing multiple previously unknown sites that may be acted on therapeutically.

Ferroptosis is a newly discovered form of cell death that is rapidly becoming associated to a variety of diseases and explaining their pathological mechanisms. This book addresses new emerging topics in the field of ferroptosis, with special attention to diseases more recently explained through ferroptotic mechanisms, including infectious diseases and neurodegeneration. In this chapter, we will provide the readers with an introduction to the concepts and pathways involved in ferroptosis to further move into a more detailed exposition of the topics advertised in this book. In special, we aim for this book to broaden the perspectives on how ferroptosis is regulated and connected to human diseases and motivate new studies in this emerging field.

Video and gene expression analyses coupled with the RNAi technique reveal microtubule-dependent, neuronal-like nucleokinetic migration in a noradrenergic type of neuroblastoma, providing a glimpse into the mechanism by which noradrenergic neuroblastoma cells may spread., The migrational propensity of neuroblastoma is affected by cell identity, but the mechanisms behind the divergence remain unknown. Using RNAi and time-lapse imaging, we show that ADRN-type NB cells exhibit RAC1- and kalirin-dependent nucleokinetic (NUC) migration that relies on several integral components of neuronal migration. Inhibition of NUC migration by RAC1 and kalirin-GEF1 inhibitors occurs without hampering cell proliferation and ADRN identity. Using three clinically relevant expression dichotomies, we reveal that most of up-regulated mRNAs in RAC1- and kalirin–GEF1–suppressed ADRN-type NB cells are associated with low-risk characteristics. The computational analysis shows that, in a context of overall gene set poverty, the upregulomes in RAC1- and kalirin–GEF1–suppressed ADRN-type cells are a batch of AU-rich element–containing mRNAs, which suggests a link between NUC migration and mRNA stability. Gene set enrichment analysis–based search for vulnerabilities reveals prospective weak points in RAC1- and kalirin–GEF1–suppressed ADRN-type NB cells, including activities of H3K27- and DNA methyltransferases. Altogether, these data support the introduction of NUC inhibitors into cancer treatment research.

Ferroptosis is a newly discovered form of cell death that is rapidly becoming associated to a variety of diseases and explaining their pathological mechanisms. This book addresses new emerging topics in the field of ferroptosis, with special attention to diseases more recently explained through ferroptotic mechanisms, including infectious diseases and neurodegeneration. In this chapter, we will provide the readers with an introduction to the concepts and pathways involved in ferroptosis to further move into a more detailed exposition of the topics advertised in this book. In special, we aim for this book to broaden the perspectives on how ferroptosis is regulated and connected to human diseases and motivate new studies in this emerging field.

Objective To identify and characterize high-order gene-to-gene interactions in antisocial personality disorder (ASPD).Methods Participants for case-control study were selected from the inmate male population in Bellavista prison from Medellin. The study included 310 individuals with ASPD and 200 with no ASPD. Diagnoses were made according to a best-estimate procedure based on a semistructured interview (diagnostic interview for genetic studies 3.0). We genotyped some single-nucleotide polymorphisms in candidate genes with main serotonin pathway effects. The gene-gene interaction was examined using the multifactor dimensionality reduction method version 2.0.alpha. We assessed model sizes of 2 and 3 loci and counted the number of replicates that contained the causal loci in the final best model that was identified using 10-fold cross validation.Results We find epistatic interaction with catechol-O-methyl transferase (COMT), tryptophan hydroxylase, and 5-HTR2A (serotonin receptor) with ASPD. This data supports an important role of polymorphism in serotonin receptors and low enzyme activity of COMT for susceptibility to ASPD.Conclusion This study suggests that gene interactions between genetic variants in COMT, 5-HTR2A and tryptophan hydroxylase gene would be associated with ASPD and influence the dopamine rewards pathways and modulate serotonin levels in ASPD. Psychiatr Genet 21: 115-124 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Aberrant expression of MYC family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. The purpose of the study was to analyze the interplay of oncogenic MYCN or c-MYC, referred to here as MYC(N), activity with cysteine metabolism and ferroptosis, an oxidative, non-apoptotic, and iron dependent form of regulated cell death caused by ROS-mediated massive lipid peroxidation (L-ROS), using MYC(N)-driven childhood neuroblastoma as a model.The intracellular amino acid levels at MYC(N)-high and MYC(N)-low cellular states were analyzed by HPLC. Effects on cell viability upon depletion of individual amino acids from the growth medium was tested in various cancer cell lines with regulable MYC(N). An unbiased high-throughput MYCN synthetic lethal siRNA screen was used to identify genes preferentially acting in the 'MYC(N)-high' state and protecting cells from ROS accumulation and ferroptosis. The capacity of cyst(e)ine uptake, intracellular cysteine synthesis via transsulfuration and glutathione biosynthesis was assessed in various neuroblastoma cell lines and tissues using metabolome, RNAseq, ChiP-seq and global proteome analyses. To investigate L-ROS formation at various conditions cells were stained with the lipid peroxidation sensor, C11-BODIPY, and flow cytometrically analyzed. Ferroptosis inducers (FINs) and inhibitors of transsulfuration were used to test their activity in various MYC(N)-dependent neuroblastoma cell lines and in vivo xenografts.We found that intracellular cysteine depletion in a 'MYC(N)-high' context induces cell death by ferroptosis and identified multiple points in glutathione synthesis and metabolism, particularly detoxification of L-ROS, that are vulnerable in the 'MYC(N)-high' state as compared to the 'MYC(N)-low' context. We could show that ferroptosis was dependent on MYC(N) expression and was enhanced by iron. We further demonstrated that both cystine import and intracellular cysteine synthesis via transulfuration achieved the intracellular state supportive of oncogenic MYC(N)-driven growth without endangering the cell to ferroptosis. We demonstrated the MYC(N) drives increased transsulfuration activity, rather than cysteine import, in tumor cells to maintain the cellular cysteine supply for glutathione synthesis. Our findings together with new descriptions of the ferroptotic process establish a novel functional link between oncogenic MYC(N) and ferroptosis, and imply regulation by cysteine-dependent glutathione availability. In MYCN-amplified childhood neuroblastoma, MYCN mediates resistance to ferroptosis by activating transsulfuration of methionine to cysteine. We identified enzymes and antiporter proteins crucial to ferroptotic escape, providing multiple previously unknown sites that may be acted on therapeutically. Citation Format: Frank Westermann, Hamed Alborzinia, Sina Gogolin, Andrés F. Flórez, Lena M. Brückner, Moritz Gartlgruber, Sabine Hartlieb, Daniel Dreidax, Michal Nadler-Holly, Matthias Ziehm, Chunxuan Shao, Matthias Selbach, Carlo Stresemann, Gernot Poschet, Barbara Nicke, Stefan Wölfl, Kai O. Henrich, Thomas Höfer. MYCN mediates cysteine addiction and sensitizes to ferroptosis in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4973.

While many tumors initially respond to chemotherapy, regrowth of surviving cells compromises treatment efficacy in the long term. The cell-biological basis of this regrowth is not understood. Here, we characterize the response of individual, patient-derived neuroblastoma cells driven by the prominent oncogene MYC to the first-line chemotherapy, doxorubicin. Combining live-cell imaging, cell-cycle-resolved transcriptomics, and mathematical modeling, we demonstrate that a cell's treatment response is dictated by its expression level of MYC and its cell-cycle position prior to treatment. All low-MYC cells enter therapy-induced senescence. High-MYC cells, by contrast, disable their cell-cycle checkpoints, forcing renewed proliferation despite treatment-induced DNA damage. After treatment, the viability of high-MYC cells depends on their cell-cycle position during treatment: newborn cells promptly halt in G1 phase, repair DNA damage, and form re-growing clones; all other cells show protracted DNA repair and ultimately die. These findings demonstrate that fast-proliferating tumor cells may resist cytotoxic treatment non-genetically, by arresting within a favorable window of the cell cycle.

Andres F. Florez1,2, Stanley Watowich3 and Carlos Muskus2 1German Cancer Research Center (DKFZ)/ Division Theoretical Systems Biology, Heidelberg 2Universidad de Antioquia/Programa de Estudio y Control de Enfermedades Tropicales – PECET, Medellin 3University of Texas Medical Branch/Department of Biochemistry and Molecular Biology and the Sealy Center for Structural Biology and Molecular Biophysics, Galveston 1Germany 2Colombia 3USA

Background Leishmaniasis is a virulent parasitic infection that causes a worldwide disease burden. Most treatments have toxic side-effects and efficacy has decreased due to the emergence of resistant strains. The outlook is worsened by the absence of promising drug targets for this disease. We have taken a computational approach to the detection of new drug targets, which may become an effective strategy for the discovery of new drugs for this tropical disease. Results We have predicted the protein interaction network of Leishmania major by using three validated methods: PSIMAP, PEIMAP, and iPfam. Combining the results from these methods, we calculated a high confidence network (confidence score > 0.70) with 1,366 nodes and 33,861 interactions. We were able to predict the biological process for 263 interacting proteins by doing enrichment analysis of the clusters detected. Analyzing the topology of the network with metrics such as connectivity and betweenness centrality, we detected 142 potential drug targets after homology filtering with the human proteome. Further experiments can be done to validate these targets. Conclusion We have constructed the first protein interaction network of the Leishmania major parasite by using a computational approach. The topological analysis of the protein network enabled us to identify a set of candidate proteins that may be both (1) essential for parasite survival and (2) without human orthologs. These potential targets are promising for further experimental validation. This strategy, if validated, may augment established drug discovery methodologies, for this and possibly other tropical diseases, with a relatively low additional investment of time and resources.