Characterization of the inhalable fraction (< 10 µm) of soil from highly urbanized and industrial environments: magnetic measurements, bioaccessibility, Pb isotopes and health risk assessment.

Soil in urban and industrial areas is one of the main sinks of pollutants. It is well known that there is a strong link between metal(loid)s bioaccessibility by inhalation pathway and human health. The critical size fraction is < 10 µm (inhalable fraction) since these particles can approach to the tracheobronchial region. Here, soil samples (< 10 µm) from a highly urbanized area and an industrialized city were characterized by combining magnetic measurements, bioaccessibility of metal(loids) and Pb isotope analyses. Thermomagnetic analysis indicated that the main magnetic mineral is impure magnetite. In vitro inhalation analysis showed that Cd, Mn, Pb and Zn were the elements with the highest bioaccessibility rates (%) for both settings. Anthropogenic sources that are responsible for Pb accumulation in < 10 µm fraction are traffic emissions for the highly urbanized environment, and Pb related to steel emissions and coal combustion in cement plant for the industrial setting. We did not establish differences in the Pb isotope composition between pseudo-total and bioaccessible Pb. The health risk assessment via the inhalation pathway showed limited non-carcinogenic risks for adults and children. The calculated risks based on pseudo-total and lung bioaccessible concentrations were identical for the two areas of contrasting anthropogenic pressures. Carcinogenic risks were under the threshold levels (CR < 10-4), with Ni being the dominant contributor to risk. This research contributes valuable insights into the lung bioaccessibility of metal(loids) in urban and industrial soils, incorporating advanced analytical techniques and health risk assessments for a comprehensive understanding.

Association of disease duration and PASI response rates at week 12 in patients with moderate-to-severe plaque psoriasis receiving biologics in the real-world psoriasis study of health outcomes (PSoHO).

PURPOSE: Currently, in the treatment of moderate-to-severe psoriasis (PsO) there is a lack of evidence demonstrating optimal biologic treatment response with respect to disease duration. The aim of this post-hoc analysis, using real world data from the Psoriasis Study of Health Outcomes (PSoHO), is to provide evidence if early intervention with biologics is associated with better treatment outcomes and if there is any difference among drug classes or individual biologics. MATERIALS AND METHODS: For this post-hoc analysis patients were categorised into two subgroups according to shorter (≤2 years) or longer (>2 years) disease duration. Analysis was performed on anti-interleukin (IL)-17A cohort vs other biologics cohort, anti-IL-17A vs other drug classes, and pairwise comparisons of ixekizumab vs individual biologics, provided that the statistical models converged. Analysis investigated the association of disease duration with the proportion of patients achieving 100% improvement in Psoriasis Area Severity Index score (PASI 100) at week 12. Adjusted comparative analyses, reported as odds ratio (OR), were performed using Frequentist Model Averaging (FMA) for each cohort or treatments within each subcategory of the subgroups. RESULTS: At week 12, anti-IL-17A and other biologics cohorts displayed minimal differences in numerical response rate for PASI 100 with respect to disease duration. The anti-IL-17A cohort showed a higher numerical PASI 100 response rate compared to the other biologic cohort irrespective of disease duration (≤2 years: 36.7% vs 21.8%; >2 years: 35.8% vs 21.9%). CONCLUSION: Overall, the results do not clearly indicate that treating patients early is critical in achieving optimal patient outcomes. Furthermore, patients treated with ixekizumab show numerically higher response rates relative to other individual biologics irrespective of disease duration.

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.

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.

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).

Treatment satisfaction of adult patients with moderate-to-severe atopic dermatitis treated with baricitinib in France, Germany, and the United Kingdom: results from a cross-sectional international patient survey.

INTRODUCTION: We explored patient satisfaction with baricitinib, an oral Janus kinase inhibitor, in patients with atopic dermatitis (AD) treated in routine clinical practice. METHODS: Adults with moderate-to-severe AD treated with baricitinib in clinical practice for ≥4 weeks in France, Germany, and the UK completed a one-time online survey under market research methodologies. Treatment satisfaction was assessed using a Likert scale and abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9). Patients reported demographic, disease, and treatment information. Data were analyzed descriptively. RESULTS: The survey was completed by 170 patients with a mean age of 39.3 years (SD = 13.5), 59% (n = 101) were female. At baricitinib initiation, 79% rated their AD as "Severe", yet 28% reported body surface area (BSA) involvement ≥10%. Most were "Satisfied" or "Very satisfied" (76%/18%) with baricitinib, with high rates reported for controlling itch (36%/56%). Itch improvements were noted by 97% of patients. Some tapered/stopped (50%/32%) topical corticosteroid use, aligned with reported improvements on the patient global assessment and BSA. Mean TSQM-9 convenience score was 78.0 (SD = 14.0). CONCLUSIONS: Satisfaction with itch control was particularly high, reflected in rates of improvement in itch since starting baricitinib. On the TSQM-9, the convenience score was the highest. Many patients tapered/stopped concomitant topicals, indicating baricitinib's effect in controlling AD symptoms.

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 Regulates CDC42 Activation to Promote Filopodia Formation in Endothelial Tip Cells.

Sprouting blood vessels are led by filopodia-studded endothelial tip cells that respond to angiogenic signals. Mosaic lineage tracing previously revealed that NRP1 is essential for tip cell function, although its mechanistic role in tip cells remains poorly defined. Here, we show that NRP1 is dispensable for genetic tip cell identity. Instead, we find that NRP1 is essential to form the filopodial bursts that distinguish tip cells morphologically from neighboring stalk cells, because it enables the extracellular matrix (ECM)-induced activation of CDC42, a key regulator of filopodia formation. Accordingly, NRP1 knockdown and pharmacological CDC42 inhibition similarly impaired filopodia formation in vitro and in developing zebrafish in vivo. During mouse retinal angiogenesis, CDC42 inhibition impaired tip cell and vascular network formation, causing defects that resembled those due to loss of ECM-induced, but not VEGF-induced, NRP1 signaling. We conclude that NRP1 enables ECM-induced filopodia formation for tip cell function during sprouting angiogenesis.

Neuropilin regulation of angiogenesis.

Blood vessel formation during vertebrate development relies on a process called angiogenesis and is essential for organ growth and tissue viability. In addition, angiogenesis leads to pathological blood vessel growth in diseases with tissue ischaemia, such as neovascular eye disease and cancer. Neuropilin 1 (NRP1) is a transmembrane protein that serves as a receptor for the VEGF165 isoform of the vascular endothelial growth factor (VEGF) to enhance cell migration during angiogenesis via VEGF receptor 2 (VEGFR2), and it is also essential for VEGF-induced vascular permeability and arteriogenesis. In addition, NRP1 activation affects angiogenesis independently of VEGF signalling by activating the intracellular kinase ABL1. NRP1 also acts as a receptor for the class 3 semaphorin (SEMA3A) to regulate vessel maturation during tumour angiogenesis and vascular permeability in eye disease. In the present paper, we review current knowledge of NRP1 regulation during angiogenesis and vascular pathology.

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.