Integration of car sharing (city car clubs) into urban planning and management

Integration of car sharing (city car clubs) into urban planning and managemen

Ibrutinib restores immune cell numbers and function in first-line and relapsed/refractory chronic lymphocytic leukemia

© 2020 The Authors Ibrutinib positively modulates many T-cell subsets in chronic lymphocytic leukemia (CLL). To understand ibrutinib\u27s effects on the broader landscape of immune cell populations, we comprehensively characterized changes in circulating counts of 21 immune blood cell subsets throughout the first year of treatment in patients with relapsed/refractory (R/R) CLL (n = 55, RESONATE) and previously untreated CLL (n = 50, RESONATE-2) compared with untreated age-matched healthy donors (n = 20). Ibrutinib normalized abnormal immune cell counts to levels similar to those of age-matched healthy donors. Ibrutinib significantly decreased pathologically high circulating B cells, regulatory T cells, effector/memory CD4+ and CD8+ T cells (including exhausted and chronically activated T cells), natural killer (NK) T cells, and myeloid-derived suppressor cells; preserved naive T cells and NK cells; and increased circulating classical monocytes. T-cell function was assessed in response to T-cell receptor stimulation in patients with R/R CLL (n = 21) compared with age-matched healthy donors (n = 18). Ibrutinib significantly restored T-cell proliferative ability, degranulation, and cytokine secretion. Over the same period, ofatumumab or chlorambucil did not confer the same spectrum of normalization as ibrutinib in multiple immune subsets. These results establish that ibrutinib has a significant and likely positive impact on circulating malignant and nonmalignant immune cells and restores healthy T-cell function

Targeting oncogenic Src homology 2 domain-containing phosphatase 2 (SHP2) by inhibiting its protein-protein interactions

We developed a new class of inhibitors of protein-protein interactions of the SHP2 phosphatase, which is pivotal in cell signaling and represents a central target in the therapy of cancer and rare diseases. Currently available SHP2 inhibitors target the catalytic site or an allosteric pocket but lack specificity or are ineffective for disease-associated SHP2 mutants. Considering that pathogenic lesions cause signaling hyperactivation due to increased levels of SHP2 association with cognate proteins, we developed peptide-based molecules with nanomolar affinity for the N-terminal Src homology domain of SHP2, good selectivity, stability to degradation, and an affinity for pathogenic variants of SHP2 that is 2-20 times higher than for the wild-type protein. The best peptide reverted the effects of a pathogenic variant (D61G) in zebrafish embryos. Our results provide a novel route for SHP2-targeted therapies and a tool for investigating the role of protein-protein interactions in the function of SHP2

The sixth international RASopathies symposium: Precision medicine—From promise to practice

The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS‐mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life‐limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion

Propranolol in the treatment of infantile haemangiomas:lessons from the European Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce survey

Oral propranolol is widely prescribed as first line treatment for infantile haemangiomas (IHs) and anecdotally prescribing practice differs widely between centres

Global exposure of population and land‐use to meteorological droughts under different warming levels and SSPs: a CORDEX‐based study

Global warming is likely to cause a progressive drought increase in some regions, but how population and natural resources will be affected is still underexplored. This study focuses on global population, forests, croplands and pastures exposure to meteorological drought hazard in the 21st century, expressed as frequency and severity of drought events. As input, we use a large ensemble of climate simulations from the Coordinated Regional Climate Downscaling Experiment (CORDEX), population projections from the NASA-SEDAC dataset and land-use projections from the Land-Use Harmonization 2 project for 1981–2100. The exposure to drought hazard is presented for five Shared Socioeconomic Pathways (SSP1-SSP5) at four Global Warming Levels (GWLs: 1.5°C to 4°C). Results show that considering only Standardized Precipitation Index (SPI; based on precipitation), the SSP3 at GWL4 projects the largest fraction of the global population (14%) to experience an increase in drought frequency and severity (versus 1981–2010), with this value increasing to 60% if temperature is considered (indirectly included in the Standardized Precipitation-Evapotranspiration Index, SPEI). With SPEI, considering the highest GWL for each SSP, 8 (for SSP2, SSP4, SSP5) and 11 (SSP3) billion people, that is, more than 90%, will be affected by at least one unprecedented drought. For SSP5 at GWL4, approximately 2 × 10$^{6}$ km$^{2}$ of forests and croplands (respectively, 6% and 11%) and 1.5 × 10$^{6}$ km$^{2}$ of pastures (19%) will be exposed to increased drought frequency and severity according to SPI, but for SPEI this extent will rise to 17 × 10$^{6}$ km$^{2}$ of forests (49%), 6 × 10$^{6}$ km$^{2}$ of pastures (78%) and 12 × 10$^{6}$ km$^{2}$ of croplands (67%), being mid-latitudes the most affected. The projected likely increase of drought frequency and severity significantly increases population and land-use exposure to drought, even at low GWLs, thus extensive mitigation and adaptation efforts are needed to avoid the most severe impacts of climate change

Cancer stem cell drugs target K-ras signaling in a stemness context

Cancer stem cells (CSCs) are considered to be responsible for treatment relapse and have therefore become a major target in cancer research. Salinomycin is the most established CSC inhibitor. However, its primary mechanistic target is still unclear, impeding the discovery of compounds with similar anti-CSC activity. Here, we show that salinomycin very specifically interferes with the activity of K-ras4B, but not H-ras, by disrupting its nanoscale membrane organization. We found that caveolae negatively regulate the sensitivity to this drug. On the basis of this novel mechanistic insight, we defined a K-ras-associated and stem cell-derived gene expression signature that predicts the drug response of cancer cells to salinomycin. Consistent with therapy resistance of CSC, 8% of tumor samples in the TCGA-database displayed our signature and were associated with a significantly higher mortality. Using our K-ras-specific screening platform, we identified several new candidate CSC drugs. Two of these, ophiobolin A and conglobatin A, possessed a similar or higher potency than salinomycin. Finally, we established that the most potent compound, ophiobolin A, exerts its K-ras4B-specific activity through inactivation of calmodulin. Our data suggest that specific interference with the K-ras4B/calmodulin interaction selectively inhibits CSC.Peer reviewe

Flood Disasters in the UK and India: A Critical Discourse Analysis of Media Reporting

Reports of flooding are becoming more frequent in the UK media, and evidence from the UK Environment Agency indicates that ‘living with flooding’ will become commonplace rather than exceptional. This study is the first to adopt a critical discourse analysis approach to compare UK newspaper reporting of floods in the developed and developing world. We present our analysis of major flood incidents in Northern England and Chennai, India, in 2015. Our findings identify that UK newspapers not only give greater prominence to flooding events that are local but also frame differently those affected. Reports of floods in Northern England reinforced similarities and shared values between victims and assumed readers by drawing upon personal stories, emotions and suffering. By contrast, reports about floods in Chennai portrayed victims as anonymous ‘distant Others’, emphasising the drama of the incident rather than the plight of individuals. We argue that the newspapers’ approach to covering flooding reveals how the Western-dominated global media continues to emphasise difference rather than similarity between people in the developed and developing world, presenting flooding in the UK as exceptional and flooding in India as normalised. We believe these findings have important implications in the context of globalisation and increasing migration