Usefulness of the Nonself-Self Algorithm of HLA Epitope Immunogenicity in the Specificity Analysis of Monospecific Antibodies Induced during Pregnancy

Background HLAMatchmaker is a program to analyze the epitope specificities of HLA antibodies. It considers each HLA allele as a string of eplets. Intralocus and interlocus comparisons between donor and recipient alleles offer a structural assessment of compatibility and an analysis of allele panel reactivity patterns can generate information about epitope specificities of HLA antibodies. However, HLAMatchmaker cannot always generate conclusive interpretations of reactivity patterns of all monospecific antibodies which by definition recognize single epitopes. Hypothesis We have therefore developed a new antibody analysis approach that utilizes the nonself-self algorithm of HLA epitope immunogenicity. It is based in the concept that HLA antibodies originate from B-cells with immunoglobulin receptors to self HLA epitopes on one given allele and which can be activated by epitopes defined by a few nonself residue differences whereas the remainder of the structural epitope of the immunizing allele consists of self residues. Methods Three human monoclonal class I antibodies from HLA typed women sensitized during pregnancy were tested in Ig-binding assays with single alleles on a Luminex platformFindings Three new HLA epitopes were identified; they are defined by combinations of nonself and self residues for one allele of the antibody producer. Conclusion The nonself-self paradigm of HLA epitope immunogenicity offers a second approach to analyze HLA antibody specificities

Analysis of microtubule movement on isolated Xenopus egg cortices provides evidence that the cortical rotation involves dynein as well as Kinesin Related Proteins and is regulated by local microtubule polymerisation

AbstractIn amphibians, the cortical rotation, a translocation of the egg cortex relative to the cytoplasm, specifies the dorsoventral axis. The cortical rotation involves an array of subcortical microtubules whose alignment is mediated by Kinesin–related proteins (KRPs), and stops as M-phase promoting factor (MPF) activation propagates across the egg. To dissect the role of different motor proteins in the cortical rotation and to analyse their regulation, we have developed an open cell assay system involving reactivation of microtubule movement on isolated cortices. Microtubule movements were dependent on ATP and consisted mainly of wriggling and flailing without net displacement, consistent with a tethering of microtubules to the cortex. Reactivated movements were inhibited by anti-KRP and anti-dynein antibodies perfused together but not separately, the KRP antibody alone becoming fixed to the cortex. Neither antibody could inhibit movement in the presence of MPF, indicating that arrest of the cortical rotation is not due to MPF-dependent inhibition of motor molecules. In contrast, D2O treatment of live eggs to protect microtubules from progressive depolymerisation prolonged the cortical rotation. We conclude that the cortical rotation probably involves cytoplasmic dynein as well as cortical KRPs and terminates as a result of local MPF-dependent microtubule depolymerisation

Climate Change Impacts on the Patagonian Shelf Break Front

We characterize long-term trends of sea surface temperature (SST), absolute dynamic topography, and chlorophyll-a (CHL) in the Patagonian shelf break front (SBF) using 27 years (1993–2019) of satellite data. Warming of the Argentinean shelf waters and the southwestward displacement of the Brazil-Malvinas Confluence (BMC) impact the northernmost extension of the SBF. Cooling of the Malvinas Current (MC) and the concurrent warming of the adjacent shelf waters lead to a significant increase of SST gradients along the outer shelf. The southwestward displacement of the BMC implies a similar shift of the SBF. An increase in CHL trend appears to be associated with southerly wind anomalies along the shelf break. We estimate a southward shift of the northernmost penetration of the MC of −0.11 ± 0.076°/decade.Fil: Franco, Barbara Cristie. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones del Mar y la Atmósfera. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones del Mar y la Atmósfera; ArgentinaFil: Ruiz Etcheverry, Laura Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones del Mar y la Atmósfera. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones del Mar y la Atmósfera; ArgentinaFil: Marrari, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Piola, Alberto Ricardo. Ministerio de Defensa. Armada Argentina. Servicio de Hidrografía Naval. Departamento Oceanografía; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones del Mar y la Atmósfera. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones del Mar y la Atmósfera; ArgentinaFil: Matano, R. P.. State University of Oregon; Estados Unido

Non-pegylated liposomal doxorubicin plus ifosfamide in metastatic soft tissue sarcoma: results from a phase-II trial

Non-pegylated liposomal doxorubicin (NPLD) has demonstrated antitumour activity equivalent to conventional doxorubicin and a significantly lower risk of cardiotoxicity. This phase II trial was performed to evaluate the activity and the safety of NPLD and ifosfamide combination in patients with metastatic soft tissue sarcoma

Universidad y tecnologías: el conocimiento en la sociedad de la información y el aprendizaje colaborativo

Este trabajo continúa la línea de investigaciones propias anteriores que aborda la problemática relacionada con la formación académica de calidad. En comunicaciones previas, se ha destacado que las TIC (Tecnologías de Información y Comunicación) son ya herramientas de uso frecuente en todos los ámbitos de la educación, que modifican las formas de aprender y enseñar - y también el acceso a la información y al conocimiento. Aún más, las Tecnologías de la Información han optimizado el acercamiento al conocimiento hasta llegar a su gestión, dando origen a las Tecnologías del Aprendizaje y del Conocimiento (TAC). Este “aprendizaje aumentado”, que además incluye las denominadas TEP (Tecnologías de Empoderamiento y Participación), lleva al docente a una búsqueda incesante de la integración de la tecnología en la enseñanza con el contenido tratado, combinando permanentemente decisiones pedagógicas con los conocimientos construidos en el aula. Se busca, entonces, posibilitar la incorporación de nuevas tecnologías que favorezcan ambos, el aprendizaje autónomo del estudiante universitario y su participación en la generación del conocimiento en un mundo de cambios constantes. Así, el propósito de nuestro trabajo consiste en evaluar las herramientas tecnológicas disponibles con el objeto de implementar dispositivos didácticos que tiendan a la formación de calidad de un estudiante activo, participativo e independiente.Dirección de Educación a Distancia, Innovación en el aula y TIC (EAD

Trends and variability in local abundances of sailfish Istiophorus platypterus in Pacific waters of Costa Rica: Controls and effects on recreational fisheries

Fishing tourism represents a vital industry in Costa Rica, generating over US$520 million and attracting 150,000 tourists every year. The main objective of this study is to examine trends and variability in local abundances of sailfish Istiophorus platypterus, the main sportfish in Pacific waters of Costa Rica, and quantify the influence of environmental and anthropogenic factors. We compiled and analyzed sailfish information collected from sportfishing operations. Sailfish abundances were examined in relation to environmental conditions and commercial fishing. Timeseries analyses showed significant declining trends in local abundances of sailfish in the southern and central Pacific of Costa Rica over the last decade. Bycatch records from the commercial purse seine fleet operating in Costa Rican waters also show a declining trend in sailfish numbers. On the other hand, commercial landings from the national longline fleet show a significant increase of 108%, on average, over the past decade. Different numerical models indicated that fishing pressure from the national fleet and also sea surface temperature with different time lags affect local abundances of sailfish. While other countries in Central and North America protect sailfish and other species of tourist interest, Costa Rica still allows the landing and sales of billfishes as seafood. The results presented in this study highlight the need to allow for the recovery of local abundances of sailfish and promote the development of the coastal communities that depend on marine tourism as their main source of income

High-dose continuous-infusion ifosfamide in advanced well-differentiated/dedifferentiated liposarcoma

BACKGROUND: Liposarcomas represent the most common histological type of soft-tissue sarcomas (STS). Its main subgroups, WD/DD, is known to be poorly sensitive to chemotherapy, with few active agents, i.e., anthracyclines +/- ifosfamide and trabectedin. High-dose ifosfamide (HDIFX >12 g/m2) is active in STS pts pretreated with standard-dose IFX, though with greater toxicity. A prolonged continuous-infusion (ci) through a portable external pump may be an alternative way to administer HDIFX. METHODS: From March 2002 to August 2013, 28 pts (median age =60, range =37-73 yrs) with advanced disease (6 WD and 22 WD/DD) were given ciHDIFX, at the dose of 14 g/m2 as a 14-day continuous infusion every 4 weeks. Twenty-four pts (86%) were previously treated with chemotherapy (19 with anthracyclines and ifosfamide; 4 with anthracycline monotherapy; 1 with trabectedin). RESULTS: Seven PR (all in DDLPS), 2 minor response (MR) and 11 SD were observed. Of interest, 6 of 9 patients with PR or MR had had SD with the previous therapy with anthracycline plus ifosfamide. The median progression-free survival was 7 months. Most common side effects were mild myelosuppression (anemia G2-3 in 3 pts; G2-3 neutropenia in 3 pts and G4 in 1; G3 thrombocytopenia in 1 pt); nausea (G3 in 3 pts) and fatigue (G3 in 6 pts). One pts had transient G3 confusion. CONCLUSIONS: These data suggest that ciHDIFX is active in WD/DDLPS, even in patients already treated with a combination of anthracyclines plus ifosfamide. In this series, ciHDIFX regimen was better tolerated than HDIFX in published studies

Immunologic risk stratification of pediatric heart transplant patients by combining HLA-EMMA and PIRCHE-II

Human leukocyte antigen (HLA) molecular mismatch is a powerful biomarker of rejection. Few studies have explored its use in assessing rejection risk in heart transplant recipients. We tested the hypothesis that a combination of HLA Epitope Mismatch Algorithm (HLA-EMMA) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) algorithms can improve risk stratification of pediatric heart transplant recipients. Class I and II HLA genotyping were performed by next-generation sequencing on 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC). Using high-resolution genotypes, we performed HLA molecular mismatch analysis with HLA-EMMA and PIRCHE-II, and correlated these findings with clinical outcomes. Patients without pre-formed donor specific antibody (DSA) (n=100) were used for correlations with post-transplant DSA and antibody mediated rejection (ABMR). Risk cut-offs were determined for DSA and ABMR using both algorithms. HLA-EMMA cut-offs alone predict the risk of DSA and ABMR; however, if used in combination with PIRCHE-II, the population could be further stratified into low-, intermediate-, and high-risk groups. The combination of HLA-EMMA and PIRCHE-II enables more granular immunological risk stratification. Intermediate-risk cases, like low-risk cases, are at a lower risk of DSA and ABMR. This new way of risk evaluation may facilitate individualized immunosuppression and surveillance.</p

Phytoplankton and light limitation in the Southern Ocean: Learning from high-nutrient high-chlorophyll areas

Most of the Southern Ocean is a high-nutrient, low-chlorophyll (HNLC) area. There are exceptions to this situation downstream of some of the islands, where iron from the islands or surrounding shallow plateau fertilizes the mixed layer and causes a phytoplankton bloom in spring and summer. The main locations where this occurs are downstream of the South Georgia, Crozet, and Kerguelen islands. Data on mixed layer depths from Argo float profiles together with Sea-viewing Wide Field-of-view Sensor chlorophyll a (chl a) and photosynthetically available radiation from these high-nutrient, high-chlorophyll (HNHC) areas are combined to study the effects of mixed layer-averaged light availability on phytoplankton concentrations in areas where iron limitation has been lifted. The results of this analysis are then transferred to HNLC areas to assess the potential importance of light limitation through the year. We conclude that light limitation does not significantly constrain the annual integrated standing stock of chl a in the HNLC Southern Ocea

Response to sunitinib malate in advanced alveolar soft part sarcoma

Purpose: Alveolar soft part sarcoma (ASPS) is a rare, chemoresistant soft tissue sarcoma. ASPS harbors the t(17-X) (p11.2;q25) translocation, resulting in the ASPACR1-TFE3 fusion protein, causing MET autophosphorylation and activation of downstream signaling. The tumor vascular pattern prompted us to use sunitinib malate (SM), a tyrosine kinase inhibitor with antiangiogenic properties. Experimental Design: Since July 2007, five patients with progressive metastatic ASPS have been treated with continuous SM 37.5 mg/d on a named basis. Four patients are evaluable for response. In four cases, cryopreserved material was available. Upstream and downstream targets of receptor tyrosine kinase (RTK) pathways, as well as mechanisms of activation, were investigated by biochemical profiles, including human phospho-receptor RTK antibody arrays and immunoprecipitation/Western blotting, molecular analyses, immunohistochemistry, and fluorescence in situ hybridization analyses. Results: After 3 months, two patients had RECIST (response evaluation criteria in solid tumor) partial response, as well as positron emission tomography response and subjective improvement. One had a RECIST stable disease. One progressed and stopped treatment. One patient is still responding after 12 months. The upstream analysis showed activation of all the platelet-derived growth factor receptor (PDGFR) family members, as well as epidermal growth factor receptor, MET families, and RET. Vascular endothelial growth factor receptors (VEGFR1 and VEGFR2) were activated only in one case. The downstream target analysis showed strong activation of phosphatidylinositol 3-kinase/AKT, extracellular signal-regulated kinase 1/2, and mTOR and its targets (S6K and S6). The absence of any upstream mTOR effector deregulation and the presence of RTK cognate ligands support an autocrine-paracrine activation loop mechanism. Conclusion: SM may have antitumor activity in ASPS, possibly through a mechanism involving PDGFR and RET. The role of MET, epidermal growth factor receptor, and mTOR, as well as PDGFR inhibition, needs to be further explored