The glycoprotein CD93 has recently been recognized to play an important role in the regulation of the angiogenic process. Moreover, CD93 is highly expressed in the endothelial cells of tumor blood ...vessel and faintly expressed in the non-proliferating endothelium. Much evidence suggests that CD93 mediates adhesion in the endothelium. Here we identify Multimerin 2 (MMRN2), a pan-endothelial extracellular matrix protein, as a specific ligand for CD93. We found that CD93 and MMRN2 are co-expressed in the blood vessels of various human tumors. Moreover, disruption of the CD93-MMRN2 interaction reduced endothelial cell adhesion and migration, making the interaction of CD93 with MMRN2 an ideal target to block pathological angiogenesis. Model structures and docking studies served to envisage the region of CD93 and MMRN2 involved in the interaction. Site-directed mutagenesis identified different residue hotspots either directly or indirectly involved in the binding. We propose a molecular model in which the coiled-coil domain of MMRN2 is engaged by F238 of CD93. Altogether, these studies identify the key interaction surfaces of the CD93-MMRN2 complex and provide a framework for exploring how to inhibit angiogenesis by hindering the CD93-MMRN2 interaction.
•CD93 and MMRN2 are molecular partners on the EC surface.•CD93 and MMRN2 are co-expressed in the blood vessels of various tumors.•The blockage of the CD93-MMRN2 interaction using a CD93 protein fragment inhibits in vitro angiogenesis.•A molecular model of the CD93-MMRN2 protein complex is described.•An amino acid residue of CD93 is essential for interaction with MMRN2 and for EC migration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Oxidative stress plays a key role in the pathophysiology of retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy, which are the major causes of irreversible ...blindness in developed countries. An excess of reactive oxygen species (ROS) can directly cause functional and morphological impairments in retinal pigment epithelium (RPE), endothelial cells, and retinal ganglion cells. Antioxidants may represent a preventive/therapeutic strategy and reduce the risk of progression of AMD. Among antioxidants, N-acetyl-L-cysteine (NAC) is widely studied and has been proposed to have therapeutic benefit in treating AMD by mitigating oxidative damage in RPE. Here, we demonstrate that N-acetyl-L-cysteine ethyl ester (NACET), a lipophilic cell-permeable cysteine derivative, increases the viability in oxidative stressed RPE cells more efficiently than NAC by reacting directly and more rapidly with oxidizing agents, and that NACET, but not NAC, pretreatment predisposes RPE cells to oxidative stress resistance and increases the intracellular reduced glutathione (GSH) pool available to act as natural antioxidant defense. Moreover, we demonstrate the ability of NACET to increase GSH levels in rats' eyes after oral administration. In conclusion, even if experiments in AMD animal models are still needed, our data suggest that NACET may play an important role in preventing and treating retinal diseases associated with oxidative stress, and may represent a valid and more efficient alternative to NAC in therapeutic protocols in which NAC has already shown promising results.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The purpose of this study was to evaluate the expression of high-temperature requirement A serine peptidase 1 (HTRA1), TGF-β1, bone morphogenetic protein 4 (BMP4), growth differentiation factor 6 ...(GDF6), and VEGFA proteins in the aqueous humor of patients with naïve choroidal neovascularization (nCNV) secondary to AMD.
We measured by ELISA the concentrations of HTRA1, TGF-β1, BMP4, GDF6, and VEGFA in the aqueous humor of 23 patients affected by nCNV who received three consecutive monthly intravitreal injections of 0.5 mg ranibizumab. Samples were collected at baseline (before the first injection), month 1 (before the second injection), and month 2 (before the third injection). Twenty-three age-matched cataract patients served as controls.
Bone morphogenetic protein 4 and GDF6 were not detectable in any samples. Baseline HTRA1 was higher than controls (P < 0.0001) and higher than both the month 1 (P < 0.0001) and the month 2 (P < 0.0001) values. Baseline VEGFA was higher than controls (P < 0.0001), not different from month 1 value (P = 0.0821), but higher than month 2 value (P < 0.0001). Baseline TGF-β1 was higher than controls (P = 0.0015) and not different from month 1 (P = 0.129) and month 2 values (P = 0.5529). No correlation was found in naïve patients between concentrations of HTRA1 and TGF-β1, HTRA 1 and VEGFA, or TGF-β1 and VEGFA.
In nCNV patients, HTRA1 and TGF-β1 were significantly higher compared to controls. After treatment, TGF-β1 was persistently elevated, while HTRA1 returned to control levels, suggesting the involvement of TGF-β1 and HTRA1 in neovascular AMD and a VEGFA-independent role for TGF-β1.
Controversy still exists regarding the role of the TGF-β in neovascular age-related macular degeneration (nAMD), a major cause of severe visual loss in the elderly in developed countries. Here, we ...measured the concentrations of active TGF-β1, TGF-β2, and TGF-β3 by ELISA in the aqueous humor of 20 patients affected by nAMD, who received 3 consecutive monthly intravitreal injections of anti-VEGF-A antibody. Samples were collected at baseline (before the first injection), month 1 (before the second injection), and month 2 (before the third injection). The same samples were used in a luciferase-based reporter assay to test the TGF-β pathway activation. Active TGF-β1 concentrations in the aqueous humor were below the minimum detectable dose. Active TGF-β2 concentrations were significantly lower at baseline and at month 1, compared to controls. No significant differences in active TGF-β3 concentration were found among the sample groups. Moreover, TGF-β pathway activation was significantly lower at baseline compared to controls. Our data corroborate an anti-angiogenic role for TGF-β2 in nAMD. This should be considered from the perspective of a therapy using TGF-β inhibitors.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•COVID-19 pandemic has been associated with significant occupational stressors for healthcare workers (HCWs)•Supporting mental health of HCWs is a crucial part of the public health response to the ...COVID-19 pandemic•Many health organizations have already committed resources to the well-being of HCWs, but only a few published their protocols of intervention.•Further research is crucial to find out the best ways to support the resilience and mental well-being of HCWs.
The COVID-19 outbreak has been associated with significant occupational stressors and challenges for healthcare workers (HCWs) including the risk of exposure to SARS-CoV-2. Many reports from all over the world have already found that HCWs have significant levels of self-reported anxiety, depression and even symptoms of post-traumatic stress disorder. Therefore, supporting mental health of HCWs is a crucial part of the public health response to the COVID-19 pandemic. The aim of the present review is to ascertain the interventions put in place worldwide in reducing stress in HCWs during the COVID-19 outbreak. We evidenced how only few countries have published specific psychological support intervention protocols for HCWs. All programs were developed in university associated hospitals and highlighted the importance of multidisciplinary collaboration. All of them had as their purpose to manage the psychosocial challenges to HCW's during the pandemic in order to prevent mental health problems.Whether one program offers distinct benefit compared to the others cannot be known given the heterogeneity of the protocols and the lack of a rigorous protocol and clinical outcomes. Further research is crucial to find out the best ways to support the resilience and mental well-being of HCWs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Occupational stress represents a significant precipitating factor in different diseases but its role in Irritable Bowel Syndrome (IBS) needs to be clarified. The present cross-sectional study aimed ...at investigating the prevalence of IBS diagnosis in a sample of health workers and exploring the potential relationships between IBS, work-related stress levels and work ability.
653 health workers undergoing periodical occupational health surveillance at the Occupational and Preventive Medicine Unit of a major University Hospital in central Italy, were consecutively recruited and screened for IBS diagnosis, according to ROMA IV criteria. The rating scales IBS Severity Scoring System (IBS-SSS), Demand–Control–Support Questionnaire (DCSQ) and Work Ability Index (WAI) were used to assess respectively IBS severity, occupational stress and work ability levels.
IBS prevalence in the sample was 16.8%. Participants suffering from IBS were characterized by a higher prevalence of psychiatric diagnosis and sleep disturbances, higher levels of job strain and isostrain as well as by lower levels of work ability compared to non affected subjects. Moreover, the severity of IBS correlated positively with occupational stress and both were negatively associated with work ability.
The present results suggest the need for preventive, organizational and management strategies at workplace aimed at protecting the health and well-being but also productivity of the worker with IBS.
•IBS was found in 16.8% of 653 healthcare workers (worldwide prevalence of 5%).•IBS healthcare workers show higher levels of job stress and lower of work ability.•Work ability is negatively associated with age, IBS severity and job stress.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Work-related stress is an emerging risk for psychiatric occupational disorders including Adjustment Disorders (AD). The aim of this study was to investigate in workers exposed to occupational stress ...suffering from AD about putative indices of stress and mental health resilience such as serum cortisol (seC) levels, Heart Rate Variability (HRV) and affective temperaments. We consecutively recruited 15 male and 15 female AD patients between workers evaluated for occupational stress at an Italian Occupational Medicine Unit. SeC levels were measured by specific immunoassay. HRV indices were recorded using Task Force® Monitor system (CNSystems, Graz, Austria). Specific questionnaires were used to measure perceived and occupational stress, psychopathological symptoms and temperament. Women presented higher levels of occupational stress, higher High-Frequency HRV (HF-HRV) and lower Low-Frequency HRV (LF-HRV) than men. SeC levels were positively correlated with LF-HRV values and negatively with HF-HRV values. The LF/HF ratio resulted to be inversely correlated with the score of Harm Avoidance temperament dimension and directly with the score of Reward Dependence temperament dimension. In conclusion, in AD patients exposed to occupational stress high seC levels and reward dependence appear to be associated with a pattern of HRV reflecting less mental health resilience.
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FSPLJ, IJS, NUK, OILJ, SIK, UL, UM, UPUK, VSZLJ
To evaluate if the assessment of coagulation abnormalities at ED admission could improve prognostic assessment of septic patients. This report utilizes a portion of the data collected in a ...prospective study, with the aim to identify reliable biomarkers for an early sepsis diagnosis. In the period November 2011–December 2016, we enrolled 268 patients, admitted to our High-Dependency Unit with a diagnosis severe sepsis/septic shock. Study-related blood samplings were performed at ED-HDU admission (T0), after 6 h (T6) and 24 h (T24): D-dimer, thrombin–antithrombin complex (TAT) and prothrombin fragment F1 + 2 levels were analyzed. The primary end-points were day-7 and in-hospital mortality. Day-7 mortality rate was 16%. D-dimer (T0: 4661 ± 4562 µg/ml vs 3190 ± 7188 µg/ml; T6: 4498 ± 4931 µg/ml vs 2822 ± 5623 µg/ml; T24 2905 ± 2823 µg/ml vs 2465 ± 4988 µg/ml, all
p
< 0.05) and TAT levels (T0 29 ± 45 vs 22 ± 83; T6 21 ± 22 vs 15 ± 35; T24 16 ± 19 vs 13 ± 30, all
p
< 0.05) were higher among non-survivors compared to survivors. We defined an abnormal coagulation activation (COAG+) as D-dimer > 500 µg/ml and TAT > 8 ng/ml (for both, twice the upper normal value). Compared to COAG−, COAG+ patients showed higher lactate levels at the earliest evaluations (T0: 3.3 ± 2.7 vs 2.5 ± 2.3, p = 0.041; T6: 2.8 ± 3.4 vs 1.8 ± 1.6,
p
= 0.015); SOFA score was higher after 24 h (T24: 6.7 ± 3.1 vs 5.4 ± 2.9,
p
= 0.008). At T0, COAG+ patients showed a higher day-7 mortality rate (HR 2.64; 95% CI 1.14–6.11,
p
= 0.023), after adjustment for SOFA score and lactate level. Presence of abnormal coagulation at ED admission shows an independent association with an increased short-term mortality rate.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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