Regionalised spatiotemporal rainfall and temperature models for flood studies in the Basque Country, Spain

A spatiotemporal point process model of rainfall is fitted to data taken from three homogeneous regions in the Basque Country, Spain. The model is the superposition of two spatiotemporal Neyman–Scott processes, in which rain cells are modelled as discs with radii that follow exponential distributions. In addition, the model includes a parameter for the radius of storm discs, so that rain only occurs when both a cell and a storm disc overlap a point. The model is fitted to data for each month, taken from each of the three homogeneous regions, using a modified method of moments procedure that ensures a smooth seasonal variation in the parameter estimates. Daily temperature data from 23 sites are used to fit a stochastic temperature model. A principal component analysis of the maximum daily temperatures across the sites indicates that 92% of the variance is explained by the first component, implying that this component can be used to account for spatial variation. A harmonic equation with autoregressive error terms is fitted to the first principal component. The temperature model is obtained by regressing the maximum daily temperature on the first principal component, an indicator variable for the region, and altitude. This, together with scaling and a regression model of temperature range, enables hourly temperatures to be predicted. Rainfall is included as an explanatory variable but has only a marginal influence when predicting temperatures. A distributed model (TETIS; Francés et al., 2007) is calibrated for a selected catchment. Five hundred years of data are simulated using the rainfall and temperature models and used as input to the calibrated TETIS model to obtain simulated discharges to compare with observed discharges. Kolmogorov–Smirnov tests indicate that there is no significant difference in the distributions of observed and simulated maximum flows at the same sites, thus supporting the use of the spatiotemporal models for the intended application

Chronological reassessment of the Middle to Upper Paleolithic transition and Early Upper Paleolithic cultures in Cantabrian Spain

Abstract: Methodological advances in dating the Middle to Upper Paleolithic transition provide a better understanding of the replacement of local Neanderthal populations by Anatomically Modern Humans. Today we know that this replacement was not a single, pan-European event, but rather it took place at different times in different regions. Thus, local conditions could have played a role. Iberia represents a significant macro-region to study this process. Northern Atlantic Spain contains evidence of both Mousterian and Early Upper Paleolithic occupations, although most of them are not properly dated, thus hindering the chances of an adequate interpretation. Here we present 46 new radiocarbon dates conducted using ultrafiltration pre-treatment method of anthropogenically manipulated bones from 13 sites in the Cantabrian region containing Mousterian, Aurignacian and Gravettian levels, of which 30 are considered relevant. These dates, alongside previously reported ones, were integrated into a Bayesian age model to reconstruct an absolute timescale for the transitional period. According to it, the Mousterian disappeared in the region by 47.9?45.1ka cal BP, while the Châtelperronian lasted between 42.6k and 41.5ka cal BP. The Mousterian and Châtelperronian did not overlap, indicating that the latter might be either intrusive or an offshoot of the Mousterian. The new chronology also suggests that the Aurignacian appears between 43.3?40.5ka cal BP overlapping with the Châtelperronian, and ended around 34.6?33.1ka cal BP, after the Gravettian had already been established in the region. This evidence indicates that Neanderthals and AMH co-existed <1,000 years, with the caveat that no diagnostic human remains have been found with the latest Mousterian, Châtelperronian or earliest Aurignacian in Cantabrian Spain.This research has been supported by the European Commission through FP7-PEOPLE-2012-CIG (Ref: 322112), the Spanish Ministry of Economy and Competitiveness (HAR2012-33956 and RYC-2011-00695), Cantabria Campus International and University of Cantabria to ABMA. The Instituto Internacional de Investigaciones Prehistóricas de Cantabria is sponsored by the University of Cantabria, the Government of Cantabria and Banco Santander

POEMS Syndrome: Real World Experience in Diagnosis and Systemic Therapy - 108 Patients Multicenter Analysis

POEMS syndrome, a rare plasma cell disorder, is challenging both in the diagnostic and therapeutic management. We present real word retrospective analysis of 108 cases analyzing clinical features and therapeutic modes. We compare our results with the available literature. This is the first description with such wide use of proteasome inhibitors in first line treatment. POEMS (Polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) syndrome is a rare and challenging plasma cell disorder, both in the diagnostic and therapeutic management of the disease. Currently, the literature on POEMS is sparse with most evidence being case reports and small case studies. We present a retrospective real world experience of 108 patients with POEMS. We analyzed the clinical features and therapeutic interventions. Regarding clinical features, our findings demonstrated that skin lesions, thrombocythemia and polycythemia were present less frequently than reported previously. Regarding clinical interventions, this is one of the largest analyses of front line treatment in POEMS and the first one to include frequent utilization of proteasome inhibitors (37%). Bortezomib monotherapy was the most effective therapy achieving complete remission/very good partial remissions (CR/VGPR) in 69% of patients. Thirty percent of patients proceeded to planned autologous stem cell transplant (ASCT) as part of the front-line treatment resulting in statistically superior progression-free (PFS) and overall survival (OS) compared to non-ASCT treated patients (P= .003). In multivariate analysis, anemia, thrombocytopenia, and as age over 60 were associated with a negative impact on patient outcomes

Immunogenetic characterization of clonal plasma cells in systemic light-chain amyloidosis

This study was supported by the Centro de Investigación Biomédica en Red—Área de Oncología—del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369; and CB16/12/00489), Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS No. PI13/02196), Asociación Española Contra el Cáncer (GCB120981SAN and the Accelerator Award), CRIS against Cancer foundation grant 2014/0120, and the Black Swan Research Initiative of the International Myeloma Foundation.Peer reviewe

Tumor cells in light-chain amyloidosis and myeloma show distinct transcriptional rewiring of normal plasma cell development

Although light-chain amyloidosis (AL) and multiple myeloma (MM) are characterized by tumor plasma cell (PC) expansion in bone marrow (BM), their clinical presentation differs. Previous attempts to identify unique pathogenic mechanisms behind such differences were unsuccessful, and no studies have investigated the differentiation stage of tumor PCs in patients with AL and MM. We sought to define a transcriptional atlas of normal PC development in secondary lymphoid organs (SLOs), peripheral blood (PB), and BM for comparison with the transcriptional programs (TPs) of tumor PCs in AL, MM, and monoclonal gammopathy of undetermined significance (MGUS). Based on bulk and single-cell RNA sequencing, we observed 13 TPs during transition of normal PCs throughout SLOs, PB, and BM. We further noted the following: CD39 outperforms CD19 to discriminate newborn from long-lived BM-PCs; tumor PCs expressed the most advantageous TPs of normal PC differentiation; AL shares greater similarity to SLO-PCs whereas MM is transcriptionally closer to PB-PCs and newborn BM-PCs; patients with AL and MM enriched in immature TPs had inferior survival; and protein N-linked glycosylation–related TPs are upregulated in AL. Collectively, we provide a novel resource to understand normal PC development and the transcriptional reorganization of AL and other monoclonal gammopathies

Lenalidomide and dexamethasone with or without clarithromycin in patients with multiple myeloma ineligible for autologous transplant: a randomized trial

Although case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0-54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3-4 adverse events were neutropenia [12% vs 19%] and infections [30% vs 25%], similar between the two arms; however, the percentage of toxic deaths was higher in the C-Rd group (36/50 [72%] vs 22/40 [55%], p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the ?CR rate due to the higher number of toxic deaths in the C-Rd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEM-CLARIDEX: Ld vs BiRd and with the following identifier NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene

Generating flood data

The Climate Resilience Demonstrator, CReDo, is a climate change adaptation digital twin demonstrator project by the National Digital Twin programme to improve resilience across infrastructure networks. CReDo is a pioneering project to develop, for the first time in the UK, a digital twin across key services networks to provide a practical example of how connected-data and greater access to the right information can improve climate adaptation and resilience. CReDo looks specifically at the impact of extreme weather, in particular flooding, on energy, water and telecoms networks. It demonstrates how those who own and operate them can use secure, resilient, information sharing, across sector boundaries, to mitigate the effect of flooding on network performance and service delivery to customers. The CReDo digital twin uses an Information Management Framework approach to share data across sectors, integrating flood simulations for climate change scenarios with data from the utility networks. The digital twin models interdependence to illustrate the resilience of the networks as a combined system of systems

Aplidin, a marine organism-derived compound with potent antimyeloma activity in vitro and in vivo

Despite recent progress in its treatment, multiple myeloma (MM) remains incurable, thus necessitating identification of novel anti-MM agents. We report that the marine-derived cyclodepsipeptide Aplidin exhibits, at clinically achievable concentrations, potent in vitro activity against primary MM tumor cells and a broad spectrum of human MM cell lines, including cells resistant to conventional (e.g., dexamethasone, alkylating agents, and anthracyclines) or novel (e.g., thalidomide and bortezomib) anti-MM agents. Aplidin is active against MM cells in the presence of proliferative/antiapoptotic cytokines or bone marrow stromal cells and has additive or synergistic effects with some of the established anti-MM agents. Mechanistically, a short in vitro exposure to Aplidin induces MM cell death, which involves activation of p38 and c-jun NH2-terminal kinase signaling, Fas/CD95 translocation to lipid rafts, and caspase activation. The anti-MM effect of Aplidin is associated with suppression of a constellation of proliferative/antiapoptotic genes (e.g., MYC, MYBL2, BUB1, MCM2, MCM4, MCM5, and survivin) and up-regulation of several potential regulators of apoptosis (including c-JUN, TRAIL, CASP9, and Smac). Aplidin exhibited in vivo anti-MM activity in a mouse xenograft model. The profile of the anti-MM activity of Aplidin in our preclinical models provided the framework for its clinical testing in MM, which has already provided favorable preliminary results. ©2008 American Association for Cancer Research.The Multiple Myeloma Research Foundation (C.S. Mitsiades, N. Mitsiades, and J.F. San-Miguel), The Lauri Strauss Leukemia Foundation (C.S. Mitsiades and N. Mitsiades), The International Waldenstrom’s Macroglobulinemia Foundation (C.S. Mitsiades), The Fund to Cure Myeloma (K.C. Anderson), The Fulbright Commission (C.J. McMullan), Doris Duke Distinguished Clinical Research Scientist Award (K.C. Anderson), Fondo de Investigación Sanitaria and European Commission grants FIS-FEDER 04/0843 (F. Mollinedo) and 06/0813 (C. Gajate), Ministerio de Educación y Ciencia grant SAF2005-04293 (F. Mollinedo), Fundación de Investigación Médica Mutua Madrileña (F. Mollinedo), and Fundación ‘‘la Caixa’’ grant BM05-30-0 (F. Mollinedo). C. Gajate is supported by the Ramón y Cajal Program from the Ministerio de Educación y Ciencia of Spain; E.M. Ocio is supported by Carlos IIIFondo de Investigación Sanitaria-Ministerio de Ciencia y Tecnología grant CM04/0001; This work was supported by a grant from the Ministry of Education and Science of Spain (BFU2006-01813/BMC), and by an Institutional Cancer Center Network program from the ISCIII. The Cancer Research Institute receives support from the European Community through the regional development funding program (FEDER). P. Maiso was supported by the FIS-FEDER through projects to J.F. San-Miguel, and a Spanish Myeloma Network Program (G03/136). M. Garayoa is supported by ‘‘Instituto de Salud Carlos III-Fondo de Investigación Sanitaria-Ministerio de Ciencia y Tecnología’’ grant CP 05/0279.Peer Reviewe