Trends in Annual Survival of Steller’s Eiders Molting at Izembek Lagoon on the Alaska Peninsula, 1993–2006

Izembek Lagoon, located on the Alaska Peninsula, is an important molting area for the Pacific population of Steller’s Eiders (Polysticta stelleri) and was the site of consistent banding effort during 1993–2006. We used Pradel mark-recapture models to estimate annual survival and population growth rates for adult Steller’s Eiders molting at Izembek Lagoon. We designed 32 models that included effects of sex and year on survival, recapture rate, and seniority, as well as potential trends in survival and seniority. The top model incorporated a two-phase trend (1993–98, 1999–2003) in survival and seniority for each sex and fully sex- and year-specific recapture rates. Average annual adult survival was estimated at 0.86 (SE = 0.030) for females and 0.87 (SE = 0.018) for males. Average annual population growth rates since 1998 were estimated to be approximately 1.0 for both sexes. A brief warming event in the Pacific Decadal Oscillation (1997–98) coincided with the lowest estimates of annual survival, while a subsequent return to cooler conditions in the Bering Sea coincided with the highest estimates and an increasing trend in annual survival.La lagune d’Izembek, située dans la péninsule de l’Alaska, constitue une aire de mue importante pour la population d’eiders de Steller (Polysticta stelleri) du Pacifique. Elle a fait l’objet de travaux de baguage soutenus entre 1993 et 2006. Nous nous sommes servis des modèles de marquage et de recapture de Pradel pour estimer les taux de survie et d’accroissement de la population d’eiders de Steller adultes en période de mue à la lagune d’Izembek. Nous avons conçu 32 modèles qui compre-naient les effets du sexe et de l’année sur le taux de survie, le taux de recapture et l’ancienneté. Le meilleur des modèles comprenait une tendance diphasique (de 1993 à 1998, et de 1999 à 2003) en ce qui a trait aux taux de survie et d’ancienneté de chacun des sexes ainsi qu’en ce qui a trait aux taux de recapture entièrement en fonction du sexe et de l’année. Chez les adultes, le taux de survie moyen était estimé à 0,86 (SE = 0,030) pour la femelle et à 0,87 (SE = 0,018) pour le mâle. Depuis 1998, les taux annuels d’accroissement de la population étaient estimés à environ 1,0 dans le cas des deux sexes. Un bref événement de réchauffement dans l’oscillation décadaire du Pacifique (1997-1998) a coïncidé avec les estimations de survie annuelles les plus faibles, tandis que le retour de conditions plus fraîches dans la mer de Béring a coïncidé avec les estimations les plus élevées ainsi qu’à une tendance à la hausse du taux de survie annuel

Enhanced Antibody Production in Clever-1/Stabilin-1-Deficient Mice

Clever-1, encoded by the Stab1 gene, is a scavenger and leukocyte trafficking receptor expressed by subsets of vascular and lymphatic endothelial cells and immunosuppressive macrophages. Monocyte Clever-1 also modulates T cell activation. However, nothing is known about the possible links between B cell function and Clever-1. Here, we found that Stab1 knockout mice (Stab1(-/-)) lacking the Clever-1 protein from all cells present with abnormally high antibody levels under resting conditions and show enhanced humoral immune responses after immunization with protein and carbohydrate antigens. Removal of the spleen does not abolish the augmented basal and post-immunization antibody levels in Clever-1-deficient mice. The increased IgG production is also present in mice in which Clever-1 is selectively ablated from macrophages. When compared to wildtype macrophages, Clever-1-deficient macrophages show increased TNF-alpha synthesis. In co-culture experiments, monocytes/macrophages deficient of Clever-1 support higher IgM production by B cells, which is blocked by TNF-alpha depletion. Collectively, our data show that the excessive inflammatory activity of monocytes/macrophages in the absence of Clever-1 results in augmented humoral immune responses in vivo

Compared to Intermittant Claudication Critical Limb Ischemia Is Associated with Elevated Levels of Cytokines

Critical limb ischemia (CLI) is the advanced stage of peripheral artery disease (PAD) and associated with an extremely poor clinical outcome. In order to understand the possible role of circulating cytokines and poor outcome associated with CLI we compared the circulating cytokine profile of patients with CLI against patients with intermittent claudication (IC). The levels of 48 circulating cytokines were examined in 226 consecutive patients with peripheral artery disease (PAD) admitted for elective, non-urgent, invasive treatment of IC or CLI. The PAD patient cohort was evenly distributed between subjects with IC (46.5%) and CLI (53.5%). As accustomed in PAD, CLI was associated with higher age, chronic kidney disease and diabetes when compared to IC (P < 0.01 for all). In multivariable linear regression modeling taking into account the baseline differences between IC and CLI groups CLI was independently associated with elevated levels of a large number of cytokines: IL-1 beta, IL-1ra, IL-2R alpha, IL-4, IL-6, IL-10, IFN-gamma, GM-CSF, G-CSF (P < 0.01 for all), and IL-2, IL-7, IL-12, IL-13, IL-17, bFGF, VEGF, SCGF-beta (P < 0.05 for all). The current findings indicate that CLI is associated with a circulating cytokine profile, which resembles serious medical conditions such as severe pancreatitis, sepsis, or even cancer. Compared to IC, CLI is a systemic inflammatory condition, which may explain the extremely poor outcome associated with it

Immunotherapeutic Blockade of Macrophage Clever-1 Reactivates the CD8(+) T-cell Response against Immunosuppressive Tumors

Purpose: As foremost regulators of cancer-related inflammation and immunotherapeutic resistance, tumor-associated macrophages have garnered major interest as immunotherapeutic drug targets. However, depletory strategies have yielded little benefit in clinical studies to date. An alternative approach is to exploit macrophage plasticity and "reeducate" tumorigenic macrophages toward an immunostimulatory phenotype to activate the host's antitumor immunity.Experimental Design: We investigated the role of the macrophage scavenger receptor common lymphatic endothelial and vascular endothelial receptor-1 (Clever-1) on tumor growth in multiple mouse cancer models with inflammatory and noninflammatory characteristics by using conditional knockouts, bone marrow chimeras, and cell depletion experiments. In addition, the efficacy of immunotherapeutic Clever-1 blockade as monotherapy or in combination with anti-PD-1 was tested.Results: Genetic deficiency of macrophage Clever-1 markedly impaired solid tumor growth. This effect was mediated by macrophages that became immunostimulatory in the absence of Clever-1, skewing the suppressive tumor microenvironment toward inflammation and activating endogenous antitumor CD8 thorn T cells. Comparable effects were achieved with immunotherapeutic blockade of Clever-1. Notably, these effects were similar to those achieved by PD-1 checkpoint inhibition. Moreover, combining anti-Clever-1 with anti-PD-1 provided synergistic benefit in aggressive, nonresponsive tumors.Conclusions: These findings demonstrate the importance of macrophages in mediating antitumor immune responses and support the clinical evaluation of immunotherapeutic Clever-1 blockade as a novel cancer treatment strategy.</div

Pim-1 Kinase Expression Predicts Radiation Response in Squamocellular Carcinoma of Head and Neck and Is under the Control of Epidermal Growth Factor Receptor

Pim-1 is an oncogenic serine/threonine kinase with poorly defined function in epithelial cancers. In this study, we determined 1) associations of Pim-1 expression with clinicopathological parameters including responsiveness to irradiation in squamocellular cancers of head and neck and 2) how Pim-1 expression is controlled subsequent to irradiation. Moderate to high expression of Pim-1 correlated to poor response to radiation therapy (P = .003). It is also associated to the expression of epidermal growth factor receptor (EGFR, P < .0001), which has been shown to be activated by irradiation. In radioresistant tumors, irradiation promoted nuclear translocation of Pim-1 (P < .005). When directly testing EGFR dependence of Pim-1 expression, up-regulation and nuclear translocation of Pim-1 could be induced through stimulation of EGFR with its ligands EGF or transforming growth factor a. Both ligand- and irradiation-induced changes in Pim-1 expression and localization could be inhibited by the monoclonal anti-EGFR antibody cetuximab and by the tyrosine kinase inhibitor gefitinib also targeting EGFR. These results suggest that irradiation-induced activation of EGFR upregulates Pim-1, and Pim-1 may be used as a novel predictive marker of radiation response in patients with squamocellular cancers of head and neck.</p

Early oxygen levels contribute to brain injury in extremely preterm infants

Background Extremely low gestational age newborns (ELGANs) are at risk of neurodevelopmental impairments that may originate in early NICU care. We hypothesized that early oxygen saturations (SpO(2)), arterial pO(2) levels, and supplemental oxygen (FiO(2)) would associate with later neuroanatomic changes. Methods SpO(2), arterial blood gases, and FiO(2) from 73 ELGANs (GA 26.4 +/- 1.2; BW 867 +/- 179 g) during the first 3 postnatal days were correlated with later white matter injury (WM, MRI, n = 69), secondary cortical somatosensory processing in magnetoencephalography (MEG-SII, n = 39), Hempel neurological examination (n = 66), and developmental quotients of Griffiths Mental Developmental Scales (GMDS, n = 58). Results The ELGANs with later WM abnormalities exhibited lower SpO(2) and pO(2) levels, and higher FiO(2) need during the first 3 days than those with normal WM. They also had higher pCO(2) values. The infants with abnormal MEG-SII showed opposite findings, i.e., displayed higher SpO(2) and pO(2) levels and lower FiO(2) need, than those with better outcomes. Severe WM changes and abnormal MEG-SII were correlated with adverse neurodevelopment. Conclusions Low oxygen levels and high FiO(2) need during the NICU care associate with WM abnormalities, whereas higher oxygen levels correlate with abnormal MEG-SII. The results may indicate certain brain structures being more vulnerable to hypoxia and others to hyperoxia, thus emphasizing the role of strict saturation targets. Impact This study indicates that both abnormally low and high oxygen levels during early NICU care are harmful for later neurodevelopmental outcomes in preterm neonates. Specific brain structures seem to be vulnerable to low and others to high oxygen levels. The findings may have clinical implications as oxygen is one of the most common therapies given in NICUs. The results emphasize the role of strict saturation targets during the early postnatal period in preterm infants.Peer reviewe

Systemic Blockade of Clever-1 Elicits Lymphocyte Activation Alongside Checkpoint Molecule Downregulation in Patients with Solid Tumors : Results from a Phase I/II Clinical Trial

Purpose: Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell-targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8 T-cell-mediated antitumor responses in mouse models of cancer, which supports the clinical development of Clever-1-targeting antibodies for cancer treatment. Patients and Methods: In this study, we analyzed the mode of action of a humanized IgG4 anti-Clever-1 antibody, FP-1305 (bexmarilimab), both in vitro and in patients with heavily pretreated metastatic cancer (n = 30) participating in part 1 (dose-finding) of a phase I/II open-label trial (NCT03733990). We studied the Clever-1 interactome in primary human macrophages in antibody pull-down assays and utilized mass cytometry, RNA sequencing, and cytokine profiling to evaluate FP-1305-induced systemic immune activation in patients with cancer. Results: Our pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPase-mediated endosomal acidification and improved the ability of macrophages to activate CD8(+)T-cells. In patients with cancer, FP-1305 administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. These effects were accompanied by a significant increase and activation of peripheral T-cells with indications of antitumor responses in some patients. Conclusions: Our results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral proinflammatory responses in patients with metastatic cancer.Peer reviewe

Proteolytic Processing of ErbB4 in Breast Cancer

Peer reviewe

Cell Death or Survival Promoted by Alternative Isoforms of ErbB4

The report demonstrates that two distinct isoforms of the ErbB4 receptor tyrosine kinase stimulate either proliferation or apoptosis by mechanisms involving differential transcriptional regulation of the PDGFRA gene. These data have implications for developing approaches to target ErbB4 signaling in cancer