Imatinib inhibits VEGF-independent angiogenesis by targeting neuropilin 1-dependent ABL1 activation in endothelial cells.

To enable new blood vessel growth, endothelial cells (ECs) express neuropilin 1 (NRP1), and NRP1 associates with the receptor tyrosine kinase VEGFR2 after binding the vascular endothelial growth factor A (VEGF) to enhance arteriogenesis. We report that NRP1 contributes to angiogenesis through a novel mechanism. In human and mouse ECs, the integrin ligand fibronectin (FN) stimulated actin remodeling and phosphorylation of the focal adhesion component paxillin (PXN) in a VEGF/VEGFR2-independent but NRP1-dependent manner. NRP1 formed a complex with ABL1 that was responsible for FN-dependent PXN activation and actin remodeling. This complex promoted EC motility in vitro and during angiogenesis on FN substrates in vivo. Accordingly, both physiological and pathological angiogenesis in the retina were inhibited by treatment with Imatinib, a small molecule inhibitor of ABL1 which is widely used to prevent the proliferation of tumor cells that express BCR-ABL fusion proteins. The finding that NRP1 regulates angiogenesis in a VEGF- and VEGFR2-independent fashion via ABL1 suggests that ABL1 inhibition provides a novel opportunity for anti-angiogenic therapy to complement VEGF or VEGFR2 blockade in eye disease or solid tumor growth

VEGF165-induced vascular permeability requires NRP1 for ABL-mediated SRC family kinase activation.

The vascular endothelial growth factor (VEGF) isoform VEGF165 stimulates vascular growth and hyperpermeability. Whereas blood vessel growth is essential to sustain organ health, chronic hyperpermeability causes damaging tissue edema. By combining in vivo and tissue culture models, we show here that VEGF165-induced vascular leakage requires both VEGFR2 and NRP1, including the VEGF164-binding site of NRP1 and the NRP1 cytoplasmic domain (NCD), but not the known NCD interactor GIPC1. In the VEGF165-bound receptor complex, the NCD promotes ABL kinase activation, which in turn is required to activate VEGFR2-recruited SRC family kinases (SFKs). These results elucidate the receptor complex and signaling hierarchy of downstream kinases that transduce the permeability response to VEGF165. In a mouse model with choroidal neovascularisation akin to age-related macular degeneration, NCD loss attenuated vessel leakage without affecting neovascularisation. These findings raise the possibility that targeting NRP1 or its NCD interactors may be a useful therapeutic strategy in neovascular disease to reduce VEGF165-induced edema without compromising vessel growth

NRP1 regulation of endothelial cell signalling

Neuropilin 1 (NRP1) is a transmembrane protein that is essential for blood vessel growth and the regulation of vascular barrier properties. Yet, at the time of starting my PhD research, it was poorly understood how NRP1 affects endothelial cell behaviour to enhance either blood vessel growth or modulate vascular permeability. In particular, it was controversial whether NRP1 mainly acts to promote VEGF signalling through the VEGF receptor tyrosine kinase VEGFR2, or if it has other roles that synergise with VEGFR2 pathways to promote effective tissue vascularisation or vascular permeability. The aims of this study were therefore to (a) investigate whether NRP1 modulates angiogenesis and vascular hyperpermeability together with or independently of VEGFR2, (b) determine whether NRP1 regulates gene transcription to modulate endothelial behaviour; (c) define the molecular mechanism by which NRP1 regulates angiogenesis and VEGF-induced vascular hyperpermeability. My experiments have revealed that NRP1 promotes blood vessel growth both independently of, and synergistically with, VEGFR2-driven pathways. In particular, I found that VEGFR2-independent signalling involves the intracellular signal transducers CDC42 and ABL1 kinase, which promote actin remodelling during cell migration. Instead, my experiments have revealed that NRP1 promotes VEGF-induced vascular permeability in a complex with VEGFR2. Specifically, I found that that both NRP1 and VEGFR2 are required for the VEGF induced activation of SRC family kinases (SFKs), which are known to be essential for VEGF-induced vascular permeability signalling. Moreover, I found that NRP1 is important, because it is required for ABL1 activation, which in turn is essential for SFK activation in this pathway. Finally, I observed that NRP1 regulates several transcription factors and the expression of their target genes in endothelial cells, particularly genes involved in actin remodelling and cell proliferation. Together, this knowledge increases our understanding of the mechanisms of blood vessel formation and function. By identifying molecular pathways in blood vessel growth and permeability, these findings may, in the long run, benefit translational research aimed at developing novel therapies for diseases with vascular dysfunction

Baseline Characteristics and mNAPSI Change from Baseline Scores Through Month 12 for Patients with Moderate-to-Severe Plaque Psoriasis and Concomitant Nail Psoriasis Treated with Biologics from PSoHO

Abstract Introduction Nail psoriasis is highly prevalent among patients with psoriasis yet remains one of the most challenging areas to treat. To better understand the treatment landscape for psoriatic nail disease, more studies are needed that compare the effectiveness of different biologics for patients with nail psoriasis. This study contributes to this objective by directly comparing the effectiveness of approved biologics in improving nail psoriasis for patients up to month 12 in a real-world setting. Methods Psoriasis Study of Health Outcomes (PSoHO) is an ongoing 3-year, prospective, non-interventional cohort study of adults with chronic moderate-to-severe plaque psoriasis initiating or switching to a new biologic. This study assessed the change in modified Nail Psoriasis Severity Index (mNAPSI) score from baseline to months 3, 6 and 12 for 763 patients and compared the effectiveness of anti-interleukin (IL)-17A biologics versus other approved biologics, as well as ixekizumab versus secukinumab, guselkumab, risankizumab and adalimumab. Comparative adjusted analyses used frequentist model averaging (FMA). Least square mean difference (LSMD) in mNAPSI scores are presented as observed. Results Irrespective of the severity of nail psoriasis at baseline, the anti-IL-17A cohort had greater mean mNAPSI reductions from baseline compared to the other biologics cohort through month 12, reaching significance at months 3 and 6 in the adjusted analysis. For patients with moderate-to-severe nail psoriasis, ixekizumab showed numerically higher mean reductions in mNAPSI scores compared to all other studied biologics, reaching significance versus guselkumab at all timepoints and risankizumab at month 6. Conclusion This real-world study showed that patients with moderate-to-severe psoriasis and any severity of concomitant nail involvement had significantly faster and more substantial improvements in nail psoriasis up to month 6 in the anti-IL-17A cohort compared to the other biologics cohort. Of the individual biologics studied, ixekizumab showed the highest numerical improvements in nail psoriasis at month 12. Trial registration EUPAS24207

Comparing Achievement of National Psoriasis Foundation Treatment Targets among Patients with Plaque Psoriasis Treated with Ixekizumab versus Other Biologics in Clinical and Real-World Studies

Abstract Introduction The National Psoriasis Foundation (NPF) recommends evaluating patient response to treatment at week 12, with a target response of ≤ 1% body surface area (BSA) affected by plaque psoriasis and an acceptable response of BSA ≤ 3% or ≥ 75% improvement. This post hoc analysis compared the achievement of NPF target and acceptable responses for ixekizumab (IXE) versus other biologics. Methods Outcomes were evaluated at week 12 for patients with moderate-to-severe plaque psoriasis from four head-to-head randomized clinical trials (RCTs; UNCOVER-2, UNCOVER-3, IXORA-R, and IXORA-S) and one real-world prospective observational study (Psoriasis Study of Health Outcomes; PSoHO). RCT patients were treated with IXE or etanercept (ETN; UNCOVER-2/3), guselkumab (GUS; IXORA-R), or ustekinumab (UST; IXORA-S). PSoHO patients were treated with anti-interleukin (IL)-17A biologics (IXE, secukinumab, SEC) and other approved biologics for the treatment of plaque psoriasis. Patients with missing outcomes were imputed as non-responder imputation. For RCT data, statistical comparisons between treatment groups were performed using Fisher’s exact test with no multiplicity adjustments. For real-world data, adjusted comparative analyses were performed using frequentist model averaging (FMA) and reported as odds ratio (OR). Results Across the four head-to-head clinical trials analyzed, significantly higher proportions of patients achieved target and acceptable responses at week 12 with IXE versus ETN, GUS, or UST. Likewise, the proportion of PSoHO patients achieving target and acceptable response at week 12 was higher with IXE compared with other individual biologics. Adjusted comparative analyses showed that IXE had significantly greater odds of target and acceptable response at week 12 versus SEC, GUS, risankizumab (RIS), adalimumab (ADA), UST, and tildrakizumab (TILD) and numerically greater odds of target and acceptable response at week 12 versus brodalumab (BROD). Conclusion Across both clinical studies and real-world settings, more patients treated with IXE achieved NPF target and acceptable responses at week 12 compared with those treated with other biologics. Trial Registration UNCOVER-2 (NCT01597245); UNCOVER-3 (NCT01646177); IXORA-R (NCT03573323); IXORA-S (NCT02561806); PSoHO (EUPAS24207)

Disabled students' narratives about their schooling experiences

An ongoing interest in disabled learners' voices has been reflected in a number of studies that explore students' experiences of schooling, as part of the quest to understand how inclusive education can be achieved. These studies, however, have been conducted mainly in industrially developed countries, while very few studies exist from industrially developing countries such as Greece in which disabled people's voices are under-represented not only in political processes but in research as well. The aim of this study was to investigate disabled students' educational experience, their social interactions with peers and teachers, the choice of school and the support they received for responding to curricular demands and complexities. The results of the study confirmed that disabled students can provide invaluable information on matters involving their education, and showed how personal experiences of disability are influenced by the socio-cultural experiences lived in different social arenas, such as that of education