From a Biomarker to Targeting in a Proof-Of-Concept Trial

Background There is high medical need for safe long-term immunosuppression monotherapy in kidney transplantation. Selective targeting of post-transplant alloantigen-(re)activated effector-T cells by anti-TNF antibodies after global T cell depletion may allow safe drug minimization, however, it is unsolved what might be the best maintenance monotherapy. Methods In this open, prospective observational single-centre trial, 20 primary deceased donor kidney transplant recipients received 2x20 mg Alemtuzumab (d0/d1) followed by 5 mg/kg Infliximab (d2). For 14 days all patients received only tacrolimus, then they were allocated to either receive tacrolimus (TAC, n = 13) or sirolimus (SIR, n = 7) monotherapy, respectively. Protocol biopsies and extensive immune monitoring were performed and patients were followed-up for 60 months. Results TAC-monotherapy resulted in excellent graft survival (5yr 92%, 95%CI: 56.6–98.9) and function, normal histology, and no proteinuria. Immune monitoring revealed low intragraft inflammation (urinary IP-10) and hints for the development of operational tolerance signature in the TAC- but not SIR-group. Remarkably, the TAC-monotherapy was successful in all five presensitized (ELISPOT+) patients. However, recruitment into SIR-arm was stopped (after n = 7) because of high incidence of proteinuria and acute/chronic rejection in biopsies. No opportunistic infections occurred during follow-up. Conclusions In conclusion, our novel fast-track TAC- monotherapy protocol is likely to be safe and preliminary results indicated an excellent 5-year outcome, however, a full–scale study will be needed to confirm our findings. Trial Registration EudraCT Number: 2006-003110-1

Cooperative harassment strategy by the European Starling to usurp cavities and reproductive cost for the neotropical Green-barred Woodpecker

The European Starling (Sturnus vulgaris) is a cavity-nesting bird with great invasive potential. As a result of human intervention, this bird is now distributed across all continents (except Antarctica) and its distribution range is increasing at an alarming rate. The European Starling was introduced to Argentina in 1983 and is currently distributed across almost the entire country. It is considered one of the hundred most damaging invasive species in the world and constitutes a serious competitive threat to native cavity-nesting birds. Interactions between European Starlings and cavity-nesting birds generally have negative consequences on native bird populations, although there are still few reports in the literature that account for the degree of damage. In this study, we report for the first time details of the harassment strategy and subsequent cavity usurpation by European Starlings on a breeding pair of Green-barred Woodpeckers (Colaptes melanochloros) in an urban area of central-eastern Argentina. Over one breeding season, the woodpeckers excavated seven cavities, none of which were successful. In six of these reproductive attempts (86%) we recorded interactions with European Starlings and in five (71%) the cavity was usurped. On three occasions we recorded a cooperative harassment strategy by a group of European Starlings causing the woodpeckers to abandon the cavity. Our report is especially relevant if we consider the invasive potential of the European Starling worldwide and the frequently limited cavity supply in bird breeding habitats. Therefore, we encourage governmental authorities and environmental NGOs to take measures to control the populations of this aggressive invasive species.Instituto de Limnología "Dr. Raúl A. Ringuelet"Centro de Estudios Parasitológicos y de Vectore

Succès de reproduction élevé de l’Étourneau sansonnet par rapport aux espèces indigènes dans une forêt naturelle récemment envahie en Amérique du Sud

Invasive species present numerous threats to ecosystems as they compete with other species for resources and displace them from their habitats. One of the most invasive birds is the European Starling (Sturnus vulgaris), which recently invaded and started to expand throughout South America. Despite its negative impacts on the South American native fauna, there is no information on its breeding success, the factors affecting it, and its population recruitment rate. We monitored 100 European Starling nests in a native forest of central-eastern Argentina during the 2020-2021 and 2021-2022 breeding seasons. We estimated breeding parameters for the population (clutch size, number of fledglings, nest survival, among others) and measured nest-site features at different spatial scales to assess if they influenced nest survival and productivity. Starlings started breeding earlier than native species, used three cavity types (natural, woodpecker, and Rufous Hornero, Furnarius rufus), produced ~3 fledglings per successful nest, and had a 38% estimated nest success probability. Daily survival rates were negatively related to nest-tree diameter at breast height (DBH) but not related to landscape features. Nest survival and productivity were higher than those of native cavity-nesting birds. Moreover, starling successful occupancy of cavities earlier in the season may delay native cavity-nesting birds nest initiation dates, which negatively affects their breeding success. The inverse relationship between DBH and nest survival could indicate preservation of mature trees may help to reduce nest success rate but such a relationship deserves further study. The high reproductive rates in our study and effective nest usurpation by starlings shown elsewhere suggests that the effect of starlings on endangered native species needs further study and starlings may need to be controlled.Les espèces envahissantes représentent de nombreuses menaces pour les écosystèmes, car elles entrent en compétition avec les autres espèces pour s’approprier les ressources et les déplacent de leur habitat. L’Étourneau sansonnet (Sturnus vulgaris), un des oiseaux les plus envahissants, a récemment envahi l’Amérique du Sud et a commencé à s’y étendre. Malgré son effet négatif sur la faune indigène d’Amérique du Sud, il n’existe aucune information sur son succès de reproduction, les facteurs qui l’affectent et le taux de recrutement de sa population. Nous avons suivi 100 nids d’étourneaux dans une forêt indigène du centre-est de l’Argentine pendant les saisons de reproduction 2020-2021 et 2021-2022. Nous avons calculé les paramètres de reproduction de la population (taille de la ponte, nombre d’oisillons, survie du nid, entre autres) et mesuré les caractéristiques du site de nidification à différentes échelles spatiales afin d’évaluer si elles influençaient la survie du nid et la productivité. Les étourneaux ont commencé à nicher plus tôt que les espèces indigènes, ont utilisé trois types de cavités (naturelle, pic et Fournier roux, Furnarius rufus), ont produit ~3 oisillons par nid réussi et ont eu une probabilité de succès de nidification estimée à 38 %. Les taux de survie quotidiens ont été négativement liés au diamètre à hauteur de poitrine (DHP) de l’arbre de nidification, mais n’ont pas été liés aux caractéristiques du paysage. La survie du nid et la productivité étaient plus élevées que celles des oiseaux indigènes nichant dans des cavités. De plus, l’occupation réussie des cavités par les étourneaux plus tôt dans la saison retarde sans doute les dates d’initiation des nids des oiseaux indigènes nichant dans des cavités, ce qui affecte négativement leur succès de reproduction. La relation inverse entre le DHP et la survie des nids pourrait indiquer que la préservation des arbres matures contribuerait peut-être à réduire le taux de succès des nids, mais une relation de ce type mérite d’être étudiée plus amplement. Les taux de reproduction élevés de notre étude et l’usurpation effective des nids par les étourneaux, démontrée ailleurs, donnent à penser que l’effet des étourneaux sur les espèces indigènes menacées doit être étudié plus à fond et qu’il pourrait être nécessaire de contrôler les étourneaux.Fil: Jauregui, Adrian. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. División Zoología de Vertebrados; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Limnología "Dr. Raúl A. Ringuelet". Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Limnología; ArgentinaFil: Gerstmayer, Paula Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Limnología "Dr. Raúl A. Ringuelet". Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Limnología; ArgentinaFil: Colombo, Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Limnología "Dr. Raúl A. Ringuelet". Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Limnología; ArgentinaFil: Segura, Luciano Noel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Limnología "Dr. Raúl A. Ringuelet". Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Limnología; Argentin

Cooperative harassment strategy by the European Starling to usurp cavities and reproductive cost for the neotropical Green-barred Woodpecker

The European Starling (Sturnus vulgaris) is a cavity-nesting bird with great invasive potential. As a result of human intervention, this bird is now distributed across all continents (except Antarctica) and its distribution range is increasing at an alarming rate. The European Starling was introduced to Argentina in 1983 and is currently distributed across almost the entire country. It is considered one of the hundred most damaging invasive species in the world and constitutes a serious competitive threat to native cavity-nesting birds. Interactions between European Starlings and cavity-nesting birds generally have negative consequences on native bird populations, although there are still few reports in the literature that account for the degree of damage. In this study, we report for the first time details of the harassment strategy and subsequent cavity usurpation by European Starlings on a breeding pair of Green-barred Woodpeckers (Colaptes melanochloros) in an urban area of central-eastern Argentina. Over one breeding season, the woodpeckers excavated seven cavities, none of which were successful. In six of these reproductive attempts (86%) we recorded interactions with European Starlings and in five (71%) the cavity was usurped. On three occasions we recorded a cooperative harassment strategy by a group of European Starlings causing the woodpeckers to abandon the cavity. Our report is especially relevant if we consider the invasive potential of the European Starling worldwide and the frequently limited cavity supply in bird breeding habitats. Therefore, we encourage governmental authorities and environmental NGOs to take measures to control the populations of this aggressive invasive species.Instituto de Limnología "Dr. Raúl A. Ringuelet"Centro de Estudios Parasitológicos y de Vectore

Resistin-Like Molecule-β Inhibits SGLT-1 Activity and Enhances GLUT2-Dependent Jejunal Glucose Transport

International audienceOBJECTIVE: An increased expression of RELM-beta (resistin-like molecule-beta), a gut-derived hormone, is observed in animal models of insulin resistance/obesity and intestinal inflammation. Intestinal sugar absorption is modulated by dietary environment and hormones/cytokines. The aim of this study was to investigate the effect of RELM-beta on intestinal glucose absorption. RESEARCH DESIGN AND METHODS: Oral glucose tolerance test was performed in mice and rats in the presence and the absence of RELM-beta. The RELM-beta action on glucose transport in rat jejunal sacs, everted rings, and mucosal strips was explored as well as downstream kinases modulating SGLT-1 and GLUT2 glucose transporters. RESULTS: Oral glucose tolerance test carried out in rodents showed that oral administration of RELM-beta increased glycemia. Studies in rat jejunal tissue indicated that mucosal RELM-beta promoted absorption of glucose from the gut lumen. RELM-beta had no effect on paracellular mannitol transport, suggesting a transporter-mediated transcellular mechanism. In studies with jejunal mucosa mounted in Ussing chamber, luminal RELM-beta inhibited SGLT-1 activity in line with a diminished SGLT-1 abundance in brush border membranes (BBMs). Further, the potentiating effect of RELM-beta on jejunal glucose uptake was associated with an increased abundance of GLUT2 at BBMs. The effects of RELM-beta were associated with an increased amount of protein kinase C betaII in BBMs and an increased phosphorylation of AMP-activated protein kinase (AMPK). CONCLUSIONS: The regulation of SGLT-1 and GLUT2 by RELM-beta expands the role of gut hormones in short-term AMPK/protein kinase C mediated control of energy balance

Human Resistin Is a Systemic Immune-Derived Proinflammatory Cytokine Targeting both Leukocytes and Adipocytes

The characteristics of human resistin (RETN) are unclear and controversial despite intensive adipose-focused research. Its transcriptional and functional similarity with the murine myeloid-specific and CCAAT/enhancer binding protein epsilon (Cebpe)-dependent gene, resistin-like gamma (Retnlg), is unexplored. We examined the human CEBPE-regulatory pathway by unbiased reference and custom gene expression assays. Real-time RT-PCR analysis demonstrated lack of both the transcriptional factor CEBPE and RETN expression in adipose and muscle cells. In contrast, primary myelocytic samples revealed a concerted CEBPE-RETN transcription that was significantly elevated in inflammatory synoviocytes relative to intact peripheral blood mononuclear cells (PBMC). Mouse Cebpe and Retnlg were predictably expressed in macrophages, whereas Retn was abundant in adipocytes. Quite the opposite, a low and inconsistent RETN transcription was seen in some human white adipose tissue (WAT) biopsies without any relationship to body mass index, insulin sensitivity, or fat depot. However, in these cases, RETN was co-detected with CEBPE and the leukocyte-specific marker, EMR1, indicating the presence of inflammatory cells and their possible resistin-mediated effect on adipocytes. Indeed, addition of human resistin to WAT in culture induced, like in PBMC, the inflammatory cytokines IL6, IL8 and TNF. Importantly, the expression of the adipose-specific markers CEBPA, FABP4 and SLC2A4 was unchanged, while the expected inhibitory effect was seen with TNF. Both cytokines increased the mRNA level of CCL2 and MMP3, which may further promote inflammation in WAT. Thus, the myeloid-restricted nature of CEBPE precludes the expression of RETN in human adipocytes which, however, are targeted by this innate immune-derived proinflammatory cytokine

Phase I clinical study of the recombinant antibody toxin scFv(FRP5)-ETA specific for the ErbB2/HER2 receptor in patients with advanced solid malignomas

INTRODUCTION: ScFv(FRP5)-ETA is a recombinant antibody toxin with binding specificity for ErbB2 (HER2). It consists of an N-terminal single-chain antibody fragment (scFv), genetically linked to truncated Pseudomonas exotoxin A (ETA). Potent antitumoral activity of scFv(FRP5)-ETA against ErbB2-overexpressing tumor cells was previously demonstrated in vitro and in animal models. Here we report the first systemic application of scFv(FRP5)-ETA in human cancer patients. METHODS: We have performed a phase I dose-finding study, with the objective to assess the maximum tolerated dose and the dose-limiting toxicity of intravenously injected scFv(FRP5)-ETA. Eighteen patients suffering from ErbB2-expressing metastatic breast cancers, prostate cancers, head and neck cancer, non small cell lung cancer, or transitional cell carcinoma were treated. Dose levels of 2, 4, 10, 12.5, and 20 μg/kg scFv(FRP5)-ETA were administered as five daily infusions each for two consecutive weeks. RESULTS: No hematologic, renal, and/or cardiovascular toxicities were noted in any of the patients treated. However, transient elevation of liver enzymes was observed, and considered dose limiting, in one of six patients at the maximum tolerated dose of 12.5 μg/kg, and in two of three patients at 20 μg/kg. Fifteen minutes after injection, peak concentrations of more than 100 ng/ml scFv(FRP5)-ETA were obtained at a dose of 10 μg/kg, indicating that predicted therapeutic levels of the recombinant protein can be applied without inducing toxic side effects. Induction of antibodies against scFv(FRP5)-ETA was observed 8 days after initiation of therapy in 13 patients investigated, but only in five of these patients could neutralizing activity be detected. Two patients showed stable disease and in three patients clinical signs of activity in terms of signs and symptoms were observed (all treated at doses ≥ 10 μg/kg). Disease progression occurred in 11 of the patients. CONCLUSION: Our results demonstrate that systemic therapy with scFv(FRP5)-ETA can be safely administered up to a maximum tolerated dose of 12.5 μg/kg in patients with ErbB2-expressing tumors, justifying further clinical development