Behavior of 222Rn, 220Rn and their progenies along a daily cycle for different meteorological situations: Implications on atmospheric aerosol residence times and Rn daughters' equilibrium factors

The correct assessment of the radiological hazard from radon and daughters, external and internal doses, residence times and equilibrium factors, implies the need to properly determine 222Rn (radon), 220Rn (thoron) and their respective short-lived progenies (214Pb and 214Bi, and 212Pb and 212Bi, respectively), where the precise measurements of both progenies are quite complex due to their very short half-lives. In addition, it is important to study the temporal behavior of all these radionuclides along daily cycles. Therefore, the aim of this study was to analyze the temporal evolution of radon, thoron and their progenies, and of their activity ratios along daily cycles for two different meteorological situations (synoptic and mesoscale processes). Radon and thoron were measured using a radon monitoring system, while their respective progenies were collected onto atmospheric filters using an ASS-500 sampler, and then measured by gamma-ray spectrometry. Furthermore, the different relationships between the concentrations of radionuclides and the different meteorological variables of interest (temperature, ABL height, and speed and direction of the wind) were found. Finally, the atmospheric aerosol residence times and Rn daughters’ equilibrium factors were estimated for each sampling carried out along the two daily cycles, finding results consistent with previous studies.This research was partially funded by the University of Huelva and the Operative FEDER Program-Andalusia 2014–2020 (Refs.: UHU- 1255876, and UHU-202020), the European Regional Development Fund through the Research State Agency (Ref.: PID2020-116461RB-C21), the Andalusian Government (Ref.: PY20_00096), and the CSN (Nuclear Safety Council) projects with Refs.: SUBV-4/2022 (CLIMATOR) and SUBV-4/2021 (EXRADON).Departamento de Física Aplicad

From floodplain to aquatic sediments: Radiogeochronological fingerprints in a sediment core from the mining impacted Sancho Reservoir (SW Spain)

The Sancho Reservoir (SW Spain) was built in 1962, about the time of maximum 137Cs fallout, and it has been affected by acid mine drainage (AMD) particularly since the mining cease in 2001. This is a unique scenario for studying the radiogeochronological fingerprints in AMD-affected sediments deposited over the former flood plain. A sediment core sampled in 2011 was analysed for bulk density, 137Cs, 239Pu, 240Pu, 210Pb, 226Ra, 228Ra, 234Th (238U) and 40K, and studied with various radiometric dating models. Bulk density revealed unsteady compaction and likely depositional events. The activity concentrations of 226Ra, 228Ra, 234Th (238U) and 40K were uniform down-core, but declining overall in the upper 0–25 cm, revealing changes in provenance except for 238U, which increased in the top 10 cm likely due to its supply by AMD. The AMD fingerprint was also found in the 239+240Pu/137Cs activity ratio, which increased in the top sediment layers. The 137Cs and 239+240Pu profiles show well defined peaks at the same depth, with inventories being about four times higher than the expected integrated atmospheric deposition in the area. The unsupported 210Pb (210Pbexc) showed a complex non-monotonic profile interrupted at several sections, particularly around the 137Cs peak. The whole dataset cannot be interpreted in terms of continuous sedimentation processes. Based upon correlated features in the bulk density and 210Pbexc profiles, a series of depositional events (likely linked to peaks in the rainfall records) have been identified in the core. These events date back to the period comprised since the construction of the dam until its increase in height in 1972, which likely displaced upstream the main depositional area of riverine loads, as inferred from sediment trap data. The CRS (with a reference date) and (a piecewise) CIC models have been used for complementing and discussing the chronology.Ministerio de Economia y Competitividad CTM2015-68628-

Zalypsis has in vitro activity in acute myeloid blasts and leukemic progenitor cells through the induction of a DNA damage response

[EN]Although the majority of patients with acute myeloid leukemia initially respond to conventional chemotherapy, relapse is still the leading cause of death, probably because of the presence of leukemic stem cells that are insensitive to current therapies. We investigated the antileukemic activity and mechanism of action of zalypsis, a novel alkaloid of marine origin. The activity of zalypsis was studied in four acute myeloid leukemia cell lines and in freshly isolated blasts taken from patients with acute myeloid leukemia before they started therapy. Zalypsis-induced apoptosis of both malignant and normal cells was measured using flow cytometry techniques. Gene expression profiling and western blot studies were performed to assess the mechanism of action of the alkaloid. Zalypsis showed a very potent antileukemic activity in all the cell lines tested and potentiated the effect of conventional antileukemic drugs such as cytarabine, fludarabine and daunorubicin. Interestingly, zalypsis showed remarkable ex vivo potency, including activity against the most immature blast cells (CD34(+) CD38(-) Lin(-)) which include leukemic stem cells. Zalypsis-induced apoptosis was the result of an important deregulation of genes involved in the recognition of double-strand DNA breaks, such as Fanconi anemia genes and BRCA1, but also genes implicated in the repair of double-strand DNA breaks, such as RAD51 and RAD54. These gene findings were confirmed by an increase in several proteins involved in the pathway (pCHK1, pCHK2 and pH2AX). The potent and selective antileukemic effect of zalypsis on DNA damage response mechanisms observed in acute myeloid leukemia cell lines and in patients' samples provides the rationale for the investigation of this compound in clinical trials

Recent accumulation rates along the Guadalquivir Estuary margins

El estuario del río Guadalquivir se localiza en el centro del golfo de Cádiz. Se trata de un estuario drenado por uno de los ríos más largos de España. El canal estuarino del Guadalquivir se extiende desde la ciudad de Sevilla hasta su desembocadura, frente a Sanlúcar de Barrameda (Cádiz), limitando el Parque Nacional de Doñana por si margen oriental. El río Guadalquivir tiene un caudal medio de 185 m3 /s, con un acusado carácter estacional. La zona estuarina está caracterizada por un rango mesomareal con una amplitud media de 2 metros. Los márgenes del canal desarrollan principalmente facies fangosas con una laminación paralela muy visible. El agua tiene habitualmente altas concentraciones de materia en suspensión, siendo uno de los estuarios más turbios del mundo.os resultados (210 Pb y 14C) aportados en este trabajo sugieren una relación directa entre estas altas concentraciones de materia en suspensión y los altos valores de tasas de acumulación. Estas tasas oscilan entre 5 y 11 mm/año para los ambientes sub e intermareales no vegetadosThe Guadalquivir Estuary is located at center of the Cadiz Gulf. It is an estuary supplied by one of the longest rivers of Spain. The Guadalquivir estuarine channel extends from the town of Sevilla to its mouth in front of Sanlúcar de Barrameda (Cádiz), bordering Doñana National Park along its southeastern margin. Guadalquivir River has an average discharge of 185 m3 /s, with a strong seasonal character. This estuarine zone is characterized by its mesotidal range, with a mean tidal amplitude of two meters. The channel margins mainly develop muddy facies with a clearly visible parallel lamination. Water usually has a high concentration of suspended matter, being one of the most turbid estuaries in the world. The results (210Pb y 14C) supplied by this paper suggest a direct relation between the high concentrations of suspended matter and the high values of sedimentation rates. These rates oscillate between 5 and 11 mm/year for subtidal and intertidal unvegetated environment

A comparative study of alternative methods for 210Pb determination in environmental samples

The accurate determination of the levels of 210Pb in environmental samples (e.g. atmospheric aerosols, waters, soils, biota, etc.) is essential due to its multiple applications in geochronology, radiation protection, groundwaters flows, air masses movement, etc. For this purpose, it has been developed a novel and thorough study of three alternative radiometric measuring methods of 210Pb activity concentrations in several types of samples. The three selected methods were low-level gamma spectrometry (210Pb), alpha-particle spectrometry (via 210Po), and Cherenkov counting (via 210Bi). This study has been performed in terms of precision, linearity and proportionality as well as spent time, type of matrix, and showing the most appropriate method of measure in each case. Several kinds of samples were analyzed such as atmospheric filters, soils, sediments and phosphogypsum (PG) matrices. These samples contain different 210Pb activity concentrations and were measured by the three techniques carrying out radiochemical procedures when necessary. There were not significant differences in the results obtained for the samples analyzed by the three methods. The major precision was obtained by using alpha-particle spectrometry, but this method is more expensive and time consuming.This research was partially funded by a project of the Regional Government of Andalusia “Basic processes regulating the fractionations and enrichments of natural radionuclides under acid mine drainage conditions” (Ref.: UHU-1255876), and a project of the Projects for Novel Principal Investigators “Quantitative study of the variables involved in the radon exhalation rate for granular solids; application to rafts of granular solid phosphogypsum” (Ref.: UHUPJ-00005-632). A.B.L. ac- knowledges support from funds provided by the Spanish Ministry of Science, Innovation and Universities’ Research Agency and co-financing provided by the European Social Fund (ESF) and the Spanish National Youth Guarantee Implementation Plan under Contract No. PEJ2018- 002676-A. The authors acknowledge the funding for open access charge provided by Universidad de Huelva / CBU

Restoration of microRNA-214 expression reduces growth of myeloma cells through positive regulation of P53 and inhibition of DNA replication

This is an open-access paper.-- et al.MicroRNA have been demonstrated to be deregulated in multiple myeloma. We have previously reported that miR-214 is down-regulated in multiple myeloma compared to in normal plasma cells. The functional role of miR- 214 in myeloma pathogenesis was explored by transfecting myeloma cell lines with synthetic microRNA followed by gene expression profiling. Putative miR-214 targets were validated by luciferase reporter assay. Ectopic expression of miR-214 reduced cell growth and induced apoptosis of myeloma cells. In order to identify the potential direct target genes of miR-214 which could be involved in the biological pathways regulated by this microRNA, gene expression profiling of the H929 myeloma cell line transfected with precursor miR-214 was carried out. Functional analysis revealed significant enrichment for DNA replication, cell cycle phase and DNA binding. miR- 214 directly down-regulated the expression of PSMD10, which encodes the oncoprotein gankyrin, and ASF1B, a histone chaperone required for DNA replication, by binding to their 3'-untranslated regions. In addition, gankyrin inhibition induced an increase of P53mRNA levels and subsequent up-regulation of CDKN1A (p21Waf1/Cip1) and BAX transcripts, which are direct transcriptional targets of p53. In conclusion, MiR-214 functions as a tumor suppressor in myeloma by positive regulation of p53 and inhibition of DNA replication.This work was partially supported by the Spanish FIS (PI080568 and PS0901897), the >Gerencia Regional de Salud, Junta de Castilla y León> (GRS202/A08 and GRS 702/A/11), and the Spanish Myeloma Network Program (RD06/0020/0006). MES is supported by the Ministerio de Sanidad y Consumo (CA08/00212).Peer Reviewe

Phenotypic, genomic and functional characterization reveals no differences between CD138++ and CD138low subpopulations in multiple myeloma cell lines

This is an open-access article distributed under the terms of the Creative Commons Attribution License.Despite recent advances in the treatment of multiple myeloma (MM), it remains an incurable disease potentially due to the presence of resistant myeloma cancer stem cells (MM-CSC). Although the presence of clonogenic cells in MM was described three decades ago, the phenotype of MM-CSC is still controversial, especially with respect to the expression of syndecan-1 (CD138). Here, we demonstrate the presence of two subpopulations - CD138++ (95-99%) and CD138low (1-5%) - in eight MM cell lines. To find out possible stem-cell-like features, we have phenotypically, genomic and functionally characterized the two subpopulations. Our results show that the minor CD138low subpopulation is morphologically identical to the CD138++ fraction and does not represent a more immature B-cell compartment (with lack of CD19, CD20 and CD27 expression). Moreover, both subpopulations have similar gene expression and genomic profiles. Importantly, both CD138++ and CD138low subpopulations have similar sensitivity to bortezomib, melphalan and doxorubicin. Finally, serial engraftment in CB17-SCID mice shows that CD138++ as well as CD138low cells have self-renewal potential and they are phenotypically interconvertible. Overall, our results differ from previously published data in MM cell lines which attribute a B-cell phenotype to MM-CSC. Future characterization of clonal plasma cell subpopulations in MM patients' samples will guarantee the discovery of more reliable markers able to discriminate true clonogenic myeloma cells.This work was supported by the Cooperative Research Thematic Network (RTICs; RD06/0020/0006), the “Junta de Castilla y León. Consejería de Sanidad” (GRS 391/B/09), the “Ministerio de Ciencia e Innovación” (PS09/01897), the “Fundación Memoria D. Samuel Solórzano Barruso” (FS/2-2010) and Asociación Española Contra el Cáncer (AECC)(GCB120981SAN).Peer Reviewe

Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma

Background: Proviral Insertion site for Moloney murine leukemia virus (PIM) kinases are overexpressed in hematologic malignancies, including multiple myeloma. Previous preclinical data from our group demonstrated the anti-myeloma effect of the pan-PIM kinase inhibitor PIM447. Methods: Based on those data, we evaluate here, by in vitro and in vivo studies, the activity of the triple combination of PIM447 + pomalidomide + dexamethasone (PIM-Pd) in multiple myeloma. Results: Our results show that the PIM-Pd combination exerts a potent anti-myeloma effect in vitro and in vivo, where it markedly delays tumor growth and prolongs survival of treated mice. Mechanism of action studies performed in vitro and on mice tumor samples suggest that the combination PIM-Pd inhibits protein translation processes through the convergent inhibition of c-Myc and mTORC1, which subsequently disrupts the function of eIF4E. Interestingly the MM pro-survival factor IRF4 is also downregulated after PIM-Pd treatment. As a whole, all these molecular changes would promote cell cycle arrest and deregulation of metabolic pathways, including glycolysis and lipid biosynthesis, leading to inhibition of myeloma cell proliferation. Conclusions: Altogether, our data support the clinical evaluation of the triple combination PIM-Pd for the treatment of patients with multiple myeloma.This work was supported by funding from Spanish FIS (PI15/00067, PI15/02156 and PI18/01600) and FEDER, AECC (GCB120981SAN), Junta de Castilla y León, Consejería de Sanidad (GRS 862/A/13 and BIO/SA05/14), Fundación Memoria de D. Samuel Solórzano Barruso of the University of Salamanca (FS/22-2015), Fundación Ramón Areces (FRA16/003), Sociedad Española de Hematología y Hemoterapia and Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León. E.M.O. was supported by an Inplant grant from IDIVAL. T.P. is supported by a grant from AECC (INVES18043PAÍN)

A multiparameter flow cytometry immunophenotypic algorithm for the identification of newly diagnosed symptomatic myeloma with an MGUS-like signature and long-term disease control

GEM (Grupo Español de MM)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study group: et al.Achieving complete remission (CR) in multiple myeloma (MM) translates into extended survival, but two subgroups of patients fall outside this paradigm: cases with unsustained CR, and patients that do not achieve CR but return into a monoclonal gammopathy of undetermined significance (MGUS)-like status with long-term survival. Here, we describe a novel automated flow cytometric classification focused on the analysis of the plasma-cell compartment to identify among newly diagnosed symptomatic MM patients (N=698) cases with a baseline MGUS-like profile, by comparing them to MGUS (N=497) patients and validating the classification model in 114 smoldering MM patients. Overall, 59 symptomatic MM patients (8%) showed an MGUS-like profile. Despite achieving similar CR rates after high-dose therapy/autologous stem cell transplantation vs other MM patients, MGUS-like cases had unprecedented longer time-to-progression (TTP) and overall survival (OS; ∼60% at 10 years; P<0.001). Importantly, MGUS-like MM patients failing to achieve CR showed similar TTP (P=0.81) and OS (P=0.24) vs cases attaining CR. This automated classification also identified MGUS patients with shorter TTP (P=0.001, hazard ratio: 5.53) and ultra-high-risk smoldering MM (median TTP, 15 months). In summary, we have developed a biomarker that identifies a subset of symptomatic MM patients with an occult MGUS-like signature and an excellent outcome, independently of the depth of response.Peer Reviewe

Synergistic DNA-damaging effect in multiple myeloma with the combination of zalypsis, bor tezomib and dexamethasone

Despite new advances in multiple myeloma treatment and the consequent improvement in overall survival, most patients relapse or become refractory to treatment. This suggests that new molecules and combinations that may further inhibit important survival pathways for these tumor cells are needed. In this context, zalypsis is a novel compound, derived from marine organisms, with a powerful preclinical anti-myeloma effect based on the sensitivity of malignant plasma cells to DNA-damage induction; and it has already been tested in a phase I/II clinical trial in multiple myeloma. We hypothesized that the addition of this compound to the combination of bortezomib plus dexamethasone may improve efficacy with acceptable toxicity. The triple combination demonstrated strong synergy and higher efficacy compared with double combinations; not only in vitro, but also ex vivo and, especially, in in vivo experiments. The triple combination triggers cell death, mainly through a synergistic induction of DNA damage and a decrease in the nuclear localization of nuclear factor kappa B. Our findings support the clinical evaluation of this combination for relapsed and refractory myeloma patients.This work was in part funded by the Spanish ISCIII-FIS (PI 15/0067 and PI15/02156) and FEDER, the Spanish RTICC (RD12/0036/0058), "Asociación Española Contra el Cancer" (AECC, GCB120981SAN), the regional Council from “Castilla y León” (GRS 1175/A/15 and FIC335U14) and a research grant from Pharmamar SAU. MMS were also supported by the Network of Centers for Regenerative Medicine and Cellular Therapy from Castilla y León, Spain. A-A López-Iglesias was supported by a grant from the Spanish Society of Hematology and Hemotherapy.Peer Reviewe