Flow cytometry for fast screening and automated risk assessment in systemic light-chain amyloidosis

Early diagnosis and risk stratification are key to improve outcomes in light-chain (AL) amyloidosis. Here we used multidimensional-flow-cytometry (MFC) to characterize bone marrow (BM) plasma cells (PCs) from a series of 166 patients including newly-diagnosed AL amyloidosis (N = 94), MGUS (N = 20) and multiple myeloma (MM, N = 52) vs. healthy adults (N = 30). MFC detected clonality in virtually all AL amyloidosis (99%) patients. Furthermore, we developed an automated risk-stratification system based on BMPCs features, with independent prognostic impact on progression-free and overall survival of AL amyloidosis patients (hazard ratio: ≥ 2.9;P ≤ .03). Simultaneous assessment of the clonal PCs immunophenotypic protein expression profile and the BM cellular composition, mapped AL amyloidosis in the crossroad between MGUS and MM; however, lack of homogenously-positive CD56 expression, reduction of B-cell precursors and a predominantly-clonal PC compartment in the absence of an MM-like tumor PC expansion, emerged as hallmarks of AL amyloidosis (ROC-AUC = 0.74;P < .001), and might potentially be used as biomarkers for the identification of MGUS and MM patients, who are candidates for monitoring pre-symptomatic organ damage related to AL amyloidosis. Altogether, this study addressed the need for consensus on how to use flow cytometry in AL amyloidosis, and proposes a standardized MFC-based automated risk classification ready for implementation in clinical practice

Prognostic value of antigen expression in multiple myeloma: a PETHEMA/GEM study on 1,265 patients enrolled in four consecutive clinical trials

Persistence of minimal residual disease (MRD) after treatment for myeloma predicts inferior outcomes, but within MRD-positive patients there is great heterogeneity with both early and very late relapses. Among different MRD techniques, flow cytometry provides additional information about antigen expression on tumor cells, which could potentially contribute to stratify MRD-positive patients. We investigated the prognostic value of those antigens required to monitor MRD in 1265 newly diagnosed patients enrolled in the GEM2000, GEM2005MENOS65, GEM2005MAS65 and GEM2010MAS65 protocols. Overall, CD19pos, CD27neg, CD38lo, CD45pos, CD81pos, CD117neg and CD138lo expression predicted inferior outcomes. Through principal component analysis, we found that simultaneous CD38lowCD81posCD117neg expression emerged as the most powerful combination with independent prognostic value for progression-free survival (HR:1.69; P=0.002). This unique phenotypic profile retained prognostic value among MRD-positive patients. We then used next-generation flow to determine antigen stability throughout the course of the disease, and found that the expression of antigens required to monitor MRD is mostly stable from diagnosis to MRD stages, except for CD81 whose expression progressively increased from baseline to chemoresistant tumor cells (14 vs 28%). Altogether, we showed that the phenotypic profile of tumor cells provides additional prognostic information, and could be used to further predict risk of relapse among MRD-positive patients

Improving Scientific Knowledge of Mallorca Channel Seamounts (Western Mediterranean) within the Framework of Natura 2000 Network

The scientific exploration of Mallorca Channel seamounts (western Mediterranean) is improving the knowledge of the Ses Olives (SO), Ausias March (AM), and Emile Baudot (EB) seamounts for their inclusion in the Natura 2000 network. The aims are to map and characterize benthic species and habitats by means of a geological and biological multidisciplinary approach: high-resolution acoustics, sediment and rock dredges, beam trawl, bottom trawl, and underwater imagery. Among the seamounts, 15 different morphological features were differentiated, highlighting the presence of 4000 pockmarks, which are seafloor rounded depressions indicators of focused fluid flow escapes, usually gas and/or water, from beneath the seabed sediments. So far, a total of 547 species or taxa have been inventoried, with sponges, fishes, mollusks, and crustaceans the most diverse groups including new taxa and new geographical records. Up to 29 categories of benthic habitats have been found, highlighting those included in the Habitats Directive: maërl beds on the summits of AM and EB, pockmarks around the seamounts and coral reefs in their rocky escarpments as well as fields of Isidella elongata on sedimentary bathyal bottoms. Trawling is the main demersal fishery developed around SO and AM, which are targeted to deep water crustaceans: Parapenaeus longirostris, Nephrops norvegicus, and Aristeus antennatus. This study provides scientific information for the proposal of the Mallorca Channel seamounts as a Site of Community Importance and for its final declaration as a Special Area of Conservation

Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials

Purpose To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM). Patients and Methods Data were analyzed from 609 patients who were enrolled in the GEM (Grupo Español de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months. Results Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P , .001) and OS (median not reached; P , .001) overall and in subgroups defined by prior transplantation, disease stage, and cytogenetics, with prognostic superiority of MRD negativity versus CR particularly evident in patients with high-risk cytogenetics. Accordingly, Harrell C statistics showed higher discrimination for both PFS and OS in Cox models that included MRD (as opposed to CR) for response assessment. Superior MRD-negative rates after different induction regimens anticipated prolonged PFS. Among 34 MRD-negative patients withMMand a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of “operational cure” was high; median PFS was 12 years, and the 10-year OS rate was 94%. Conclusion Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM

Minimal residual disease monitoring and immune profiling using second generation flow cytometry in elderly multiple myeloma

The value of minimal residual disease (MRD) in multiple myeloma (MM) has been more frequently investigated in transplant-eligible than elderly patients. Since an optimal balance between treatment efficacy and toxicity is of utmost importance in elderly MM, sensitive MRD monitoring might be particularly valuable in this patient population. Here, we used 2nd generation 8-color multiparameter-flow-cytometry (MFC) to monitor MRD in 162 transplant-ineligible MM patients enrolled in the PETHEMA/GEM2010MAS65 study, The transition from 1st to 2nd generation MFC resulted in increased sensitivity, and allowed to identify three patient groups according to MRD levels: MRD-negative (75-years (HR:4.8; P<.001), and those with high-risk cytogenetics (HR:12.6; P=.01). Using 2nd generation MFC, immune profiling concomitant to MRD monitoring also contributed to identify patients with poor, intermediate and favorable outcome (25%, 61% and 100% OS at 3-years; P=.01); the later patients being characterized by an increased compartment of mature B-cells. Our results show that similarly to transplant-candidates, MRD monitoring is one of the most relevant prognostic factors in elderly MM, irrespectively of patients’ age and cytogenetic risk

Predicting long-term disease control in transplant-ineligible patients with multiple myeloma: impact of an MGUS-like signature

Disease control at 5 years would be a desirable endpoint for elderly multiple myeloma (MM) patients, but biomarkers predicting this are not defined. Therefore, to gain further insights in this endpoint, a population of 498 newly diagnosed transplant-ineligible patients enrolled in two Spanish trials (GEM2005MAS65 and GEM2010MAS65), has been analyzed. Among the 435 patients included in this post-hoc study, 18.6% remained alive and progression free after 5 years of treatment initiation. In these patients, overall survival (OS) rate at 10 years was 60.8% as compared with 11.8% for those progressing within the first 5 years. Hemoglobin (Hb) >= 12 g/dl (OR 2.74, p = 0.001) and MGUS-like profile (OR 4.18, p = 0.005) were the two baseline variables associated with long-term disease-free survival. Upon including depth of response (and MRD), Hb >= 12 g/dl (OR 2.27) and MGUS-like signature (OR 7.48) retained their predictive value along with MRD negativity (OR 5.18). This study shows that despite the use of novel agents, the probability of disease control at 5 years is still restricted to a small fraction (18.6%) of elderly MM patients. Since this endpoint is associated with higher rates of OS, this study provides important information about diagnostic and post-treatment biomarkers helpful in predicting the likelihood of disease control at 5 years

Revisión y Control del Plan de Vigilancia Ambiental de las obras de dragado del Puerto de Maó

Se integra información hidrográfica, geomorfológica, sedimentológica y biológica, para la caracterización de los ecosistemas marinos en el punto de vertido y área adyacente previa al inicio de las obras de dragado del Puerto de Maó.RESUMEN: En este documento se presentan los trabajos científicos realizados por el Instituto Español de Oceanografía, dentro del Plan de Vigilancia Ambiental del dragado del Puerto de Maó (Menorca, Islas Baleares), para la caracterización de los ecosistema marino en el punto de vertido y área adyacente, previa al inicio de las obras. Se incluyen los resultados y las conclusiones de los estudios realizados por diversos grupos de investigación, principalmente en Enero-Marzo 2014, en relación al fondo marino, la hidrodinámica, las praderas de Posidonia oceanica y el molusco bivalvo Pinna nobilis, el macro-bentos de los fondos circalitorales blandos y los contaminantes en agua, sedimentos y biota, así como en especies de interés comercial para el consumo humano. Este informe se contempla en el contrato entre la Autoridad Portuaria de Baleares y el Instituto Español de Oceanografía, suscrito el 5 Febrero 2014, para los trabajos de asistencia técnica para la revisión y control del Plan de Vigilancia Ambiental del dragado del Puerto de Maó.RESUM: En aquest document es presenten els treballs científics realitzats per l’Instituto Español de Oceanografía, dins del Pla de Vigilància Ambiental del dragat del Port de Maó (Menorca, Illes Balears), per a la caracterització dels ecosistemes marins en el punt de vessament i àrea adjacent, prèvia a l’inici de les obres. S’inclouen els resultats i les conclusions del estudis realitzats per diversos grups de recerca, principalment durant Gener-Març 2014, en relació al fons marí, la hidrodinàmica, les praderies de Posidonia oceanica i el mol•lusc bivalve Pinna nobilis, el macro-bentos dels fons circalitorals tous i els contaminants en aigua, sediments i biota, així com en espècies d’interès comercial pel consum humà. Aquest informe es contempla en el contracte entre l’Autoritat Portuària de Balears i el Instituto Español de Oceanografía, subscrit el 5 Febrer 2014, pels treballs d’assistència tècnica per a la revisió i control del Pla de Vigilància Ambiental del dragat de Port de Maó.ABSTRACT: This document presents the scientific actions developed by the Instituto Español de Oceanografía within the Environmental Monitoring Plan of the works of dredging the Port of Maó (Minorca, Balearic Islands), for the characterization of the marine ecosystems in the point of discharge of dredged material and adjacent area, before the beginning of the dredging. The results and conclusions of the studies developed by several research groups, mainly in January-March 2014, in relation to the bottom, hydrodynamics, Posidonia oceanica meadows, and the bivalve mollusc Pinna nobilis, the macro-benthos of the circalittoral soft bottoms and the contaminants in water, sediments and biota, as well as in commercial species for human consumption, are included. This report is contemplated within the contract between the Autoridad Portuaria de Baleares and the Instituto Español de Oceanografía, signed on 5 February 2014, for the technical assistance activities to review and control the Environmental Monitoring Plan of the works of dredging the Port of Maó.Autoridad Portuaria de Baleare

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Preparation and characterization of carbon-enriched coal fly ash

9 pages, 8 figures, 5 tables.-- PMID: 17826888 [PubMed].-- Available online Sep 10, 2007.Carbon-enriched fractions have been obtained from two coal fly ash (FA) samples. The FA came from two pulverized-coal fired power stations (Lada and Escucha, Spain) and were collected from baghouse filters. Sieving was used to obtain carbon-enriched fractions, which were further subjected to two beneficiation processes: acid demineralization using HCl and HF, and oil agglomeration using soya oil–water. Yield in weight after sieving, unburned carbon content, and several physicochemical characteristics of the obtained fractions were used to compare the performance of the beneficiation methods. Low carbon concentration was obtained by sieving, particularly in the case of Escucha FA. However, after acid demineralization or oil agglomeration, fractions containing unburned carbon in a range of 63% to 68% were obtained. These fractions showed differences in mineral phase composition and distribution depending on the FA and on the beneficiation method used. The textural properties of the obtained fractions varied as a function of their carbon content and the beneficiation method used. However, no significant differences in morphology of the carbonaceous particles were found.The Ministry of Education and Science of Spain and European Community (FEDER) provided financial support for this work, Project No. CTM2004-04252-C02. The authors acknowledge Electric Power Stations in Lada and Escucha for supplying the FA used in this work.Peer reviewe

Method of heavy reformate conversion into btx over metal-impregnated ZSM-5+nanocrystalline beta zeolite composite catalyst; said composite catalyst

Method of making BTX compounds including benzene, toluene, and xylene, including feeding heavy reformate to a reactor containing a composite zeolite catalyst. The composite zeolite catalyst includes a mixture of nanocrystalline Beta zeolite (Nano-Beta) comprising crystal size in the range of 10 to 40 nm and ZSM-5. The Nano-Beta, the ZSM-5, or both include one or more impregnated metals. The method further includes producing the BTX compounds by simultaneously performing transalkylation and dealkylation of the heavy reformate in the reactor. The composite zeolite catalyst is able to simultaneously catalyze both the transalkylation and dealkylation reactionsPeer reviewedSaudi Arabian Oil Company, Instituto de Tecnologia Quimica (UPV-CSIC), Universitat Politècnica de València, Consejo Superior de Investigaciones Científicas (España)A1 Solicitud de patente con informe sobre el estado de la técnic