Towards improved understanding of cascading and interconnected risks from concurrent weather extremes: Analysis of historical heat and drought extreme events

Weather extremes can affect many different assets, sectors and systems of the human environment, including human security, health and well-being. Weather extremes that compound, such as heat and drought, and their interconnected risks are complex, difficult to understand and thus a challenge for risk analysis and management, because (in intertwined systems) impacts can propagate through multiple sectors. In a warming climate, extreme concurrent heat and drought events are expected to increase in frequency, intensity and duration, posing growing risks to societies. To gain a better understanding of compound extremes and associated risks, we analyze eight historical heat and drought extreme events in Europe, Africa and Australia. We investigated and visualized the direct and indirect impact paths through different sectors and systems together with the impacts of response and adaptation measures. We found the most important cascading processes and interlinkages centered around the health, energy and agriculture and food production sectors. The key cascades result in impacts on the economy, the state and public services and ultimately also on society and culture. Our analysis shows that cascading impacts can propagate through numerous sectors with far reaching consequences, potentially being able to destabilize entire socio-economic systems. We emphasize that the future challenge in research on and adaptation to concurrent extreme events lies in the integration of assets, sectors and systems with strong interlinkages to other sectors and with a large potential for cascading impacts, but for which we cannot resort to historical experiences. Integrating approaches to deal with concurrent extreme events should furthermore consider the effects of possible response and adaptation mechanisms to increase system resilience

Treatment of children with acute lymphoblastic leukemia in Cambodia

We report a retrospective analysis of 110 unselected pediatric patients with acute lymphoblastic leukemia (ALL) treated during 2015-2017 in a charity-funded public institution in Cambodia with a reduced intensity ALL-Moscow Berlin (MB)-91 protocol. No patient abandoned treatment. Sixty-three patients (57%) were high risk (HR). Seventy-two patients (65.5%) reached complete remission (CR) on day 36. The 3-year event-free survival (EFS) and overall survival (OS) was 34.9% (50.5% for standard risk [SR]). Most deaths resulted from infections (40 [53.3%]) and bleeding (15 [20%]). With further selective reduction of treatment intensity and access to platelet infusion, leukemia therapy is justified in this setting

Proteasomal degradation of the EWS-FLI1 fusion protein is regulated by a single lysine residue

E-26 transformation-specific (ETS) proteins are transcription factors directing gene expression through their conserved DNA binding domain. They are implicated as truncated forms or interchromosomal rearrangements in a variety of tumors including Ewing sarcoma, a pediatric tumor of the bone. Tumor cells express the chimeric oncoprotein EWS-FLI1 from a specific t(22;11)(q24;12) translocation. EWS-FLI1 harbors a strong transactivation domain from EWSR1 and the DNA-binding ETS domain of FLI1 in the C-terminal part of the protein. Although Ewing cells are crucially dependent on continuous expression of EWS-FLI1, its regulation of turnover has not been characterized in detail. Here, we identify the EWS-FLI1 protein as a substrate of the ubiquitin-proteasome system with a characteristic polyubiquitination pattern. Using a global protein stability approach, we determined the half-life of EWS-FLI1 to lie between 2 and 4 h, whereas full-length EWSR1 and FLI1 were more stable. By mass spectrometry, we identified two ubiquitin acceptor lysine residues of which only mutation of Lys-380 in the ETS domain of the FLI1 part abolished EWS-FLI1 ubiquitination and stabilized the protein posttranslationally. Expression of this highly stable mutant protein in Ewing cells while simultaneously depleting the endogenous wild type protein differentially modulates two subgroups of target genes to be either EWS-FLI1 protein-dependent or turnover-dependent. The majority of target genes are in an unaltered state and cannot be further activated. Our study provides novel insights into EWS-FLI1 turnover, a critical pathway in Ewing sarcoma pathogenesis, and lays new ground to develop novel therapeutic strategies in Ewing sarcoma

USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth

Abstract Ewing sarcoma is the second most common pediatric bone and soft tissue tumor presenting with an aggressive behavior and prevalence to metastasize. The diagnostic translocation t(22;11)(q24;12) leads to expression of the chimeric oncoprotein EWS-FLI1 which is uniquely expressed in all tumor cells and maintains their survival. Constant EWS-FLI1 protein turnover is regulated by the ubiquitin proteasome system. Here, we now identified ubiquitin specific protease 19 (USP19) as a regulator of EWS-FLI1 stability using an siRNA based screening approach. Depletion of USP19 resulted in diminished EWS-FLI1 protein levels and, vice versa, upregulation of active USP19 stabilized the fusion protein. Importantly, stabilization appears to be specific for the fusion protein as it could not be observed neither for EWSR1 nor for FLI1 wild type proteins even though USP19 binds to the N-terminal EWS region to regulate deubiquitination of both EWS-FLI1 and EWSR1. Further, stable shUSP19 depletion resulted in decreased cell growth and diminished colony forming capacity in vitro, and significantly delayed tumor growth in vivo. Our findings not only provide novel insights into the importance of the N-terminal EWSR1 domain for regulation of fusion protein stability, but also indicate that inhibition of deubiquitinating enzyme(s) might constitute a novel therapeutic strategy in treatment of Ewing sarcoma

PI3K/AKT signaling modulates transcriptional expression of EWS/FLI1 through specificity protein 1

Ewing sarcoma (ES) is the second most frequent bone cancer in childhood and is characterized by the presence of the balanced translocation t(11;22)(q24;q12) in more than 85% of cases, generating a dysregulated transcription factor EWS/FLI1. This fusion protein is an essential oncogenic component of ES development which is necessary for tumor cell maintenance and represents an attractive therapeutic target. To search for modulators of EWS/FLI1 activity we screened a library of 153 targeted compounds and identified inhibitors of the PI3K pathway to directly modulate EWS/FLI1 transcription. Surprisingly, treatment of four different ES cell lines with BEZ235 resulted in down regulation of EWS/FLI1 mRNA and protein by ~50% with subsequent modulation of target gene expression. Analysis of the EWS/FLI1 promoter region (-2239/+67) using various deletion constructs identified two 14bp minimal elements as being important for EWS/FLI1 transcription. We identified SP1 as modulator of EWS/FLI1 gene expression and demonstrated direct binding to one of these regions in the EWS/FLI1 promoter by EMSA and ChIP experiments. These results provide the first insights on the transcriptional regulation of EWS/FLI1, an area that has not been investigated so far, and offer an additional molecular explanation for the known sensitivity of ES cell lines to PI3K inhibition

Candidature au poste de Premier Ministre.

Document collected by the University of Texas Libraries from the web-site of the Reseau Documentaire International Sur La Region Des Grands Lacs Africains (International Documentation Network on the Great African Lakes Region). The Reseau distributes "gray literature", non-published or limited distribution government or NGO documents regarding the Great Lakes area of central Africa including Rwanda, Burundi, and the Democratic Republic of Congo.UT Librarie

Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance

In vivo resistance to first-line chemotherapy, including to glucocorticoids, is a strong predictor of poor outcome in children with acute lymphoblastic leukemia (ALL). Modulation of cell death regulators represents an attractive strategy for subverting such drug resistance. Here we report complete resensitization of multidrug-resistant childhood ALL cells to glucocorticoids and other cytotoxic agents with subcytotoxic concentrations of obatoclax, a putative antagonist of BCL-2 family members. The reversal of glucocorticoid resistance occurred through rapid activation of autophagy-dependent necroptosis, which bypassed the block in mitochondrial apoptosis. This effect was associated with dissociation of the autophagy inducer beclin-1 from the antiapoptotic BCL-2 family member myeloid cell leukemia sequence 1 (MCL-1) and with a marked decrease in mammalian target of rapamycin (mTOR) activity. Consistent with a protective role for mTOR in glucocorticoid resistance in childhood ALL, combination of rapamycin with the glucocorticoid dexamethasone triggered autophagy-dependent cell death, with characteristic features of necroptosis. Execution of cell death, but not induction of autophagy, was strictly dependent on expression of receptor-interacting protein (RIP-1) kinase and cylindromatosis (turban tumor syndrome) (CYLD), two key regulators of necroptosis. Accordingly, both inhibition of RIP-1 and interference with CYLD restored glucocorticoid resistance completely. Together with evidence for a chemosensitizing activity of obatoclax in vivo, our data provide a compelling rationale for clinical translation of this pharmacological approach into treatments for patients with refractory ALL

Hearing loss and quality of life in survivors of paediatric CNS tumours and other cancers

PurposeHearing loss, a complication of cancer treatment, may reduce health-related quality of life (HRQoL), especially in childhood cancer survivors of central nervous system (CNS) tumours who often have multiple late effects. We examined the effect of hearing loss on HRQoL in young survivors of CNS and other childhood cancers.MethodsWithin the Swiss Childhood Cancer Survivor Study, we sent questionnaires about hearing loss and HRQoL (KIDSCREEN-27) to parents of survivors aged 8-15years. We stratified the effect of hearing loss on HRQoL by cancer diagnosis, using multivariable logistic regression and adjusting for sociodemographic and clinical factors.ResultsHearing loss was associated with impaired physical well-being [unadjusted estimated differences -4.6 (CI -9.2, -0.1); adjusted -4.0 (CI -7.6, -0.3)] and peers and social support [unadjusted -6.7 (CI -13.0, -0.3); adjusted -5.0 (CI -10.5, 0.9)] scores in survivors of CNS tumours (n=123), but not in children diagnosed with other cancers (all p-values>0.20, n=577).ConclusionClinicians should be alert to signs of reduced physical well-being and impaired relationships with peers. Especially survivors of CNS tumours may benefit most from strict audiological monitoring and timely intervention to mitigate secondary consequences of hearing loss on HRQoL