Spectral stability of monotone traveling fronts for reaction diffusion-degenerate Nagumo equations

This paper establishes the spectral stability of monotone traveling front solutions for reaction-diffusion equations where the reaction function is of Nagumo (or bistable) type and with diffusivities which are density dependent and degenerate at zero (one of the equilibrium points of the reaction). Spectral stability is understood as the property that the spectrum of the linearized operator around the wave, acting on an exponentially weighted space, is contained in the complex half plane with non-positive real part. Three different types of monotone waves are studied: (i) stationary diffusion-degenerate fronts, connecting the two stable equilibria of the reaction; (ii) traveling diffusion-degenerate fronts connecting zero with the unstable equilibrium; and, (iii) non-degenerate fronts. In the first two cases, the degeneracy is responsible of the loss of hyperbolicity of the asymptotic coefficient matrices of the spectral problem at one of the end points, precluding the application of standard techniques to locate the essential spectrum. This difficulty is overcome with a suitable partition of the spectrum, a generalized convergence of operators technique, the analysis of singular (or Weyl) sequences and the use of energy estimates. The monotonicity of the fronts, as well as detailed descriptions of the decay structure of eigenfunctions on a case by case basis, are key ingredients to show that all traveling fronts under consideration are spectrally stable in a suitably chosen exponentially weighted $L^2$ energy space.Comment: 53 pages, 8 figures, 1 tabl

The purinergic P2X7 receptor as a potential drug target to combat neuroinflammation in neurodegenerative diseases

Neurodegenerative diseases (NDDs) represent a huge social burden, particularly in Alzheimer's disease (AD) in which all proposed treatments investigated in murine models have failed during clinical trials (CTs). Thus, novel therapeutic strategies remain crucial. Neuroinflammation is a common pathogenic feature of NDDs. As purinergic P2X7 receptors (P2X7Rs) are gatekeepers of inflammation, they could be developed as drug targets for NDDs. Herein, we review this challenging hypothesis and comment on the numerous studies that have investigated P2X7Rs, emphasizing their molecular structure and functions, as well as their role in inflammation. Then, we elaborate on research undertaken in the field of medicinal chemistry to determine potential P2X7R antagonists. Subsequently, we review the state of neuroinflammation and P2X7R expression in the brain, in animal models and patients suffering from AD, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. Next, we summarize the in vivo studies testing the hypothesis that by mitigating neuroinflammation, P2X7R blockers afford neuroprotection, increasing neuroplasticity and neuronal repair in animal models of NDDs. Finally, we reviewed previous and ongoing CTs investigating compounds directed toward targets associated with NDDs; we propose that CTs with P2X7R antagonists should be initiated. Despite the high expectations for putative P2X7Rs antagonists in various central nervous system diseases, the field is moving forward at a relatively slow pace, presumably due to the complexity of P2X7Rs. A better pharmacological approach to combat NDDs would be a dual strategy, combining P2X7R antagonism with drugs targeting a selective pathway in a given NDD.The authors would like to acknowledge the support received from the EU Horizon 2020 Research and Innovation Program under Maria Sklodowska‐Curie (Grant Agreement No. 766124). The authors would also like to thank the support received from the Ministerio de Economía y Competitividad (MINECO, Spain; Grant No. SAF2016‐78892R to Luis Gandía and Antonio G. García) and Fundación Teófilo Hernando

FICARAM-15 Cruise Report 20th March – 22nd May 2013 on board BIO Hespérides by the Group FICARAM

54 páginas, 19 figuras, 3 anexosThe FICARAM-15 is the fifteenth repetition of a section conducted in 1994. This section is part of the international program GOSHIP (http://www.go-ship.org/CruisePlans.html) to develop a globally coordinated network of sustained hydrographic sections as part of the global ocean/climate observing system. The objective of the FICARAM-15 cruise is to investigate the temporal evolution of the anthropogenic carbon and evaluate the CO2 absorption capacity of the South Atlantic region, the Equatorial zone, and the subtropical region of Azores-Gibraltar in the North Atlantic. This cruise is supported by the CATARINA project funded by the Ministry of Economy and Competitiveness (CTM2010-17141) and is part of the European Union FP7 project CARBOCHANGE (http://carbochange.b.uib.no/). The objective of FICARAM-15 cruise is framed in the CATARINA project conducted by the tasks I.2.1 (air-sea CO2 exchange) I.3 (ventilation of water masses), I.4.1 (zonal variability of N2O and CH4), I.4.2 (anthropogenic carbon storage), I.4.4 (saturation horizon of calcium carbonate along the section) and I.5.4 (evolution of the acidification rates). Another component of the FICARAM-15 cruise aims to examine the biological and biogeochemical mechanisms that hinder total dissolved organic carbon (DOC) remineralisation in marine systems, taking a multidisciplinary perspective and applying many different approaches. This is the global objective of the Spanish project DOREMI (CTM2012-34294) that joins this FICARAM-15 cruise.During the FICARAM cruise the physical oceanography group was responsible for collecting the following data sets: CTD and XBT data; vessel-mounted ADCP and lowered ADCP; continuous thermosalinograph. Physical oceanographers participated in the cruise financed through Project “Tipping Corners in the Meridional Overturning Circulation” (TIC-MOC), CTM2011-28867. The FICARAM-15 cruise was organized in two phases with a common sampling. LEG 1: From Punta Arenas (Chile) to Recife (Brazil): 62 stations. Chief Scientist: Aida F. Ríos, PI of CATARINA project LEG 2: From Recife (Brazil) to Cartagena (Spain): 46 stations Chief Scientist: Celia Marrasé, PI of DOREMI project This report contains the sampling of all the variables at each station along the FICARAM section, as well as the analysis of the biogeochemical variables and the preliminary results. The principal investigator of the DOREMI project produced another report with the common sampling section, showing the analysis and results of the experiments on dissolved organic matter carried out on board.This cruise is supported by the CATARINA project funded by the Ministry of Economy and Competitiveness (CTM2010-17141) and is part of the European Union FP7 project CARBOCHANGE (http://carbochange.b.uib.no/)Peer reviewe

A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

Introduction: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.<p></p> Methods: Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. Results: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis.<p></p> Conclusion: Our results suggest a role of PPARG gene in the development of SSc

Validation of the International Myeloma Working Group standard response criteria in the PETHEMA/GEM2012MENOS65 study: are these times of change?

Induction and consolidation based on proteasome inhibitors, immunomodulatory drugs, and corticoids integrated with high-dose therapy (HDT) and autologous stem cell transplantation (ASCT), are showing complete response (CR) rates >50% in multiple myeloma (MM).1-3 The addition of anti-CD38 monoclonal antibodies may increase these unprecedented CR rates.4-6 When more than half of transplant-eligible patients with MM achieve CR with frontline therapy, it is reasonable to ask, what other tests are clinically relevant after negative immunofixation. The achievement of deep responses with modern therapy led the International Myeloma Working Group (IMWG) to propose new guidelines that included definitions of negative minimal residual disease (MRD) for standard response criteria.7 Indeed, recent studies have reported nearly 50% MRD− rates,5,8,9 and, more importantly, the prognostic value of MRD criteria was validated in clinical trials8,10-12 and routine practice...

Circulating tumor cells for comprehensive and multiregional non-invasive genetic characterization of multiple myeloma

Multiple myeloma (MM) patients undergo repetitive bone marrow (BM) aspirates for genetic characterization. Circulating tumor cells (CTCs) are detectable in peripheral blood (PB) of virtually all MM cases and are prognostic, but their applicability for noninvasive screening has been poorly investigated. Here, we used next-generation flow (NGF) cytometry to isolate matched CTCs and BM tumor cells from 53 patients and compared their genetic profile. In eight cases, tumor cells from extramedullary (EM) plasmacytomas were also sorted and whole-exome sequencing was performed in the three spatially distributed tumor samples. CTCs were detectable by NGF in the PB of all patients with MM. Based on the cancer cell fraction of clonal and subclonal mutations, we found that ~22% of CTCs egressed from a BM (or EM) site distant from the matched BM aspirate. Concordance between BM tumor cells and CTCs was high for chromosome arm-level copy number alterations (≥95%) though not for translocations (39%). All high-risk genetic abnormalities except one t(4;14) were detected in CTCs whenever present in BM tumor cells. Noteworthy, ≥82% mutations present in BM and EM clones were detectable in CTCs. Altogether, these results support CTCs for noninvasive risk-stratification of MM patients based on their numbers and genetic profile.This study was supported by the Centro de Investigación Biomédica en Red—Área de Oncología—del Instituto de Salud Carlos III (CIBERONC; CB16/12/00236, CB16/12/00369, CB16/12/00489, and CB16/12/00400); by Cancer Research UK [C355/A26819] and FC AECC and AIRC under the Accelerator Award Program; by the Instituto de Salud Carlos III, FCAECC and co-financed by FEDER (ERANET-TRANSCAN-2 iMMunocell AC17/00101); the Spanish Ministry of Science and Innovation and co-financed by FSE (Torres Quevedo fellowship, PTQ-16-08623); the Black Swan Research Initiative of the International Myeloma Foundation; European Research Council (ERC) under the European Commission’s H2020 Framework Programme (MYELOMANEXT, 680200); the Qatar National Research Fund (QNRF) Award No. 7-916-3-237; the AACR-Millennium Fellowship in Multiple Myeloma Research (15-40-38-PAIV); the Leukemia Research Foundation; and the Multiple Myeloma Research Foundation (MMRF) under the 2019 Research Fellowship Award

Prognostic Value of Serum Paraprotein Response Kinetics in Patients With Newly Diagnosed Multiple Myeloma

Response kinetics is not well-established as a prognostic marker in multiple myeloma (MM). We developed a mathematical model to assess the prognostic value of serum monoclonal component (MC) response kinetics during 6 induction cycles in 373 newly diagnosed MM patients. The model calculated a resistance parameter that reflects the stagnation in the response after an initial descent, dividing the patients into two kinetics categories with significantly different progression-free survival (PFS). Introduction: Response kinetics is a well-established prognostic marker in acute lymphoblastic leukemia. The situation is not clear in multiple myeloma (MM) despite having a biomarker for response monitoring (monoclonal component [MC]). Materials and Methods: We developed a mathematical model to assess the prognostic value of serum MC response kinetics during 6 induction cycles, in 373 NDMM transplanted patients treated in the GEM2012Menos65 clinical trial. The model calculated a resistance parameter that reflects the stagnation in the response after an initial descent. Results: Two patient subgroups were defined based on low and high resistance, that respectively captured sensitive and refractory kinetics, with progression-free survival (PFS) at 5 years of 72% and 59% (HR 0.64, 95% CI 0.44-0.93; P =.02). Resistance significantly correlated with depth of response measured after consolidation (80.9% CR and 68.4% minimal residual disease negativity in patients with sensitive vs. 31% and 20% in those with refractory kinetics). Furthermore, it modulated the impact of reaching CR after consolidation; thus, within CR patients those with refractory kinetics had significantly shorter PFS than those with sensitive kinetics (median 54 months vs. NR; P =.02). Minimal residual disease negativity abrogated this effect. Our study also questions the benefit of rapid responders compared to late responders (5-year PFS 59.7% vs. 76.5%, respectively [P <.002]). Of note, 85% of patients considered as late responders were classified as having sensitive kinetics. Conclusion: This semi-mechanistic modeling of M-component kinetics could be of great value to identify patients at risk of early treatment failure, who may benefit from early rescue intervention strategies. (C) 2022 The Authors. Published by Elsevier Inc

Sixty-four new records for the flora of Peru from rapid biological inventories in the Peruvian Amazon

Durante el período 2000 – 2016, se llevaron a cabo 15 inventarios biológicos en áreas remotas en el pie de monte andino y el llano amazónico del Perú. En estos inventarios, 27 botánicos colectaron un total de 9397 especímenes de plantas vasculares fértiles. Hasta finales del 2017, más de la mitad de estos especímenes se han identificado a nivel de especie, de los cuales 64 especies y 2 géneros (Dicorynia y Monopteryx) representan nuevos registros para la flora del Perú. Si esta tasa de novedades se mantiene, el número de registros nuevos en el material de los inventarios podría aumentar, lo cual nos indica que aún queda mucho por descubrir en la flora andino-amazónica del Perú.Between 2000 and 2016 we carried out 15 rapid biological inventories in remote areas of the Andean foothills and Amazon basin in Peru. During these inventories, 27 botanists collected 9397 fertile vascular plant specimens. By the end of 2017, more than half of these specimens had been identified to species. Of the 2303 species identified to date, 64 species and 2 genera (Dicorynia and Monopteryx) are new records for the flora of Peru. If this rate of discovery proves typical, the number of new records for Peru in the rapid inventory material could increase, which indicates that there is still much to discover in the Peruvian flora

Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non–Small Cell Lung Carcinoma: the ROSING Study

Introduction: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data. Methods: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific). Results: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2+ or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively). Conclusions: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm