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Age-related macular degeneration (AMD) constitutes a prevalent, chronic, and progressive retinal degenerative disease of the macula that affects elderly people and cause central vision impairment. Despite therapeutic advances in the management of neovascular AMD, none of the currently used treatments cures the disease or reverses its course. Medical treatment of neovascular AMD experienced a significant advance due to the introduction of vascular endothelial growth factor inhibitors (anti-VEGF), which dramatically changed the prognosis of the disease. However, although anti-VEGF therapy has become the standard treatment for neovascular AMD, many patients do not respond adequately to this therapy or experience a slow loss of efficacy of anti-VEGF agents after repeated administration. Additionally, current treatment with intravitreal anti-VEGF agents is associated with a significant treatment burden for patients, caregivers, and physicians. New approaches have been proposed for treating neovascular AMD. Among them, designed ankyrin repeat proteins (DARPins) seem to be as effective as monthly ranibizumab, but with greater durability, which may enhance patient compliance with needed injections.

ObjectiveLung injury activates multiple pro-inflammatory pathways, including neutrophils, epithelial, and endothelial injury, and coagulation factors leading to acute respiratory distress syndrome (ARDS). Low-dose methylprednisolone therapy (MPT) improved oxygenation and ventilation in early pediatric ARDS without altering duration of mechanical ventilation or mortality. We evaluated the effects of MPT on biomarkers of endothelial [Ang-2 and soluble intercellular adhesion molecule-1 (sICAM-1)] or epithelial [soluble receptor for activated glycation end products (sRAGE)] injury, neutrophil activation [matrix metalloproteinase-8 (MMP-8)], and coagulation (plasminogen activator inhibitor-1).DesignDouble-blind, placebo-controlled randomized trial.SettingTertiary-care pediatric intensive care unit (ICU).PatientsMechanically ventilated children (0-18 years) with early ARDS.InterventionsBlood samples were collected on days 0 (before MPT), 7, and 14 during low-dose MPT (n = 17) vs. placebo (n = 18) therapy. The MPT group received a 2-mg/kg loading dose followed by 1 mg/kg/day continuous infusions from days 1 to 7, tapered off over 7 days; placebo group received equivalent amounts of 0.9% saline. We analyzed plasma samples using a multiplex assay for five biomarkers of ARDS. Multiple regression models were constructed to predict associations between changes in biomarkers and the clinical outcomes reported earlier, including P/F ratio on days 8 and 9, plateau pressure on days 1 and 2, PaCO2 on days 2 and 3, racemic epinephrine following extubation, and supplemental oxygen at ICU discharge.ResultsNo differences occurred in biomarker concentrations between the groups on day 0. On day 7, reduction in MMP-8 levels (p = 0.0016) occurred in the MPT group, whereas increases in sICAM-1 levels (p = 0.0005) occurred in the placebo group (no increases in sICAM-1 in the MPT group). sRAGE levels decreased in both MPT and placebo groups (p < 0.0001) from day 0 to day 7. On day 7, sRAGE

Hereditary hemorrhagic telangiectasia (HHT) is a genetically heterogeneous disorder, involving mutations in two predominant genes known as Endoglin (ENG; HHT1) and activin receptor-like kinase 1 (ACVRL1/ALK1; HHT2), as well as in some less frequent genes, such as MADH4/SMAD4 (JP-HHT) or BMP9/GDF2 (HHT5). The diagnosis of HHT patients currently remains at the clinical level, according to the “Curaçao criteria,” whereas the molecular diagnosis is used to confirm or rule out suspected HHT cases, especially when a well characterized index case is present in the family or in an isolated population. Unfortunately, many suspected patients do not present a clear HHT diagnosis or do not show pathogenic mutations in HHT genes, prompting the need to investigate additional biomarkers of the disease. Here, several HHT biomarkers and novel methodological approaches developed during the last years will be reviewed. On one hand, products detected in plasma or serum samples: soluble proteins (vascular endothelial growth factor, transforming growth factor b1, soluble endoglin, angiopoietin-2)and microRNA variants (miR-27a, miR-205, miR-210). On the other hand, differential HHT gene expression fingerprinting, next generation sequencing of a panel of genes involved in HHT, and infrared spectroscopy combined with artificial neural network patterns will also be reviewed. All these biomarkers might help to improve and refine HHT diagnosis by distinguishing from the non-HHT population.

Maligna tumörer är något som drabbar såväl djur som människor över hela världen. Därför har stora ansträngningar lagts på att kartlägga mekanismerna bakom en av nyckelparametrarna för tumörtillväxt, tumörangiogenes. Studier har visat att tumörcellerna själva kan inducera neovaskulatur genom ökat uttryck av pro-angiogena faktorer, så som endotelial tillväxtfaktor och angiopoeitin-2. Anti-angiogenesterapi, i form av olika antikroppsderivat, riktar sig fram för allt mot de signalvägar som involverar pro-angiogena faktorer i ett försök att stävja tumörens tillväxtresurser. Idag används främst monoklonala antikroppar, var för sig, tillsammans eller i kombination med kemo- och/eller strålningsterapi. Tyvärr är anti-angiogenesresistens är ett växande problem, troligen relaterat till både adaptiva och inbyggda resistensmekanismer hos de tumörceller som behandlas. Ett effektivt sätt att motverka resistens skulle vara att simultant kunna slå mot flera mål hos tumörvaskulaturen med en antikropp. Studier visar att antikroppar med dubbel specificitet, så kallade bispecifika antikroppar, kan ha större effekt än kombinationen av monoklonala antikroppar med dessa specificiteter. Ännu finns dock inga godkända anti-angiogena bispecifika antikroppar på marknaden då dessa ofta har problem med produkthomogenicitet och dålig farmakokinetik men flera befinner sig i Fas I-II. För att till fullo kunna förstå de olika anti-angiogena terapiernas för och nackdelar krävs dock mer forskning kring såväl anti-angiogenesresistens och de olika antikropp-formateringarnas inneboende immunologiska egenskaper., Animals and humans, worldwide, suffer from malignant tumours. Large efforts have therefore been made to uncover the mechanisms of tumour angiogenesis, one of the key parameters behind tumour growth. Tumour cells can induce neovasculature by up regulating proangiogenic factors. In an attempt to inhibit tumour growth, anti-angioneeic agents have been developed to target the different signaling pathways of those factors. Presently antiangiogenic therapies foremost use monoclonal antibodies (mAb). Either using a single mAb species, a combination of multiple mAb species, or the two above in combination with chemo or radiation therapy. Unfortunally, resistance to the antiangiogenic agents is an emerging problem, most likely related to both evasive adaptation and intrinsic non-responsiveness of tumour cells. One effective method to countervail these hurdles is thought to involve hitting more than one target, within the tumour angiogenesis, with the same antibody. Studies show that the tumour growth inhibiting effects of antibodies with double specificities, bispecific antibodies, can be greater than that of combination therapy of monoclonal antibodies with the same specificities as the bispecific Ab. As of today, due to problems mostly related to poor pharmacokinetics and lack of product homogeneity, there are no approved bispecific antiangiogenic antibodies on the clinical market although several are in phase I-II clinical trials. To fully understand the pros and cons of different anti-angiogenic therapies, and the intrinsic immunological properties of different antibody formations, much more research is absolutely essential.

A murine modification of the Matrigel chamber assay originally developed for use on rats is presented. This modified assay permits improved quantification due to subcutaneous Matrigel implants of constant shape and volume. We have quantitatively assessed the angiogenic potential of the growth factors basic fibroblast growth factor (bFGF), VEGF, and Angiopoietin-2 (Ang-2) with special emphasis on their mutual interactions. A reproducible dose-response relationship for bFGF was established for doses between 150 and 1000 ng per chamber, whereas VEGF did not display angiogenic activity on its own in the tested dose of up to 200 ng per chamber. Conversely, we found a strong synergistic action of bFGF and VEGF when combined in a 3:1 ratio. Two other combinations (ratios) with greater VEGF doses were also tested, but the synergistic effect was only observed when 50 ng of VEGF was added to 150 ng per chamber of bFGF. This synergistic effect of bFGF and VEGF was significantly reduced by further addition of 100 ng Angiopoietin-2. Inhibition of the response to bFGF and VEGF was confirmed by in vitro EC migration experiments, which, together with our in vivo results, indicates that Ang-2 may target chemotactic responses to bFGF and VEGF in vivo.