Angiopoietin-2 Levels Research Articles

Prognostic Value of Angiopoietin-like 4 in Patients with Acute Respiratory Distress Syndrome.

Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that plays an important role in endothelial injury and the inflammatory response. Experimental models have implicated ANGPTL4 in acute respiratory distress syndrome (ARDS), but its impact on the progression of ARDS is unclear. Paired bronchoalveolar lavage fluid (BALF) and serum samples were obtained from patients with ARDS (n = 56) within 24 h of diagnosis and from control subjects (n = 32). ANGPTL4, angiopoietin-2, interleukin (IL)-6, and TNF-α levels were measured by magnetic Luminex assay. BALF albumin (BA) and serum albumin (SA) were evaluated by enzyme-linked immunosorbent assay. BALF and serum ANGPTL4 concentrations were higher in patients with ARDS than in controls and were even higher in non-survivors than in survivors. The serum ANGPTL4 level was higher in indirect (extrapulmonary) ARDS than in direct (pulmonary) ARDS. Furthermore, BALF and serum ANGPTL4 levels correlated well with angiopoietin-2, IL-6, and TNF-α levels in BALF and serum. BALF ANGPTL4 was positively correlated with the BA/SA ratio (an indicator of pulmonary vascular permeability), and serum ANGPTL4 was associated with the severity of multiple organ dysfunction syndrome based on SOFA and APACHE II scores. Moreover, serum ANGPTL4 was better able to predict 28-day ARDS-related mortality (AUC 0.746, P < 0.01) than the APACHE II score or PaO2/FiO2 ratio. Serum ANGPTL4 was identified as an independent risk factor for mortality in a univariate Cox regression model (P < 0.001). ANGPTL4 levels were elevated in patients with ARDS and significantly correlated with disease severity and mortality. ANGPTL4 may be a novel prognostic biomarker in ARDS.

Serum angiopoietin-2 level as a novel potential biomarker in oral lichen planus.

Lichen planus is a common chronic cutaneous inflammatory disease. Recent advances evidenced that angiogenesis is tightly connected to it. More recently, the endothelial specific growth factor angiopoietin-2 has been clarified to interact with vascular endothelial growth factor. Angiopoietin-2 level has not been investigated in lichen planus. To evaluate serum level of angiopoietin-2 in cutaneous and oral lichen planus. Ninety patients were investigated, 45 patients with lichen planus. In addition to forty-five healthy control, the activity of the disease was estimated at the time of examination. The serum level of angiopoietin-2 had been estimated by enzyme-linked immunosorbent assay. The relationships between angiopoietin-2 serum level and disease severity, type of lichen, and visual analogue scale score (VAS) were determined. The serum levels of angiopoietin-2 were substantially higher in patients with both cutaneous and oral lesions than patients with cutaneous lichen planus only (P<.001). Serum angiopoietin-2 is elevated in patients compared with normal subjects and is correlated with the presence of oral lesions and disease severity, that reflects its role in angiogenesis and inflammation, and angiopoietin-2 serum level could be a potential marker for monitoring the oral lichen to identify possible malignant transformation.

Serum levels and gene polymorphisms of angiopoietin 2 in systemic lupus erythematosus patients

This study aimed to discuss association between serum Angiopoietin2 (Ang2) levels, Ang2 gene polymorphisms and systemic lupus erythematosus (SLE) susceptibility. It was carried out by 235 SLE, 342 other inflammatory autoimmune diseases patients and 380 healthy individuals. Serum Ang2 levels was examinated by ELISA, and Ang2 rs12674822, rs1823375, rs1868554, rs2442598, rs3739390 and rs734701 polymorphisms were genotyped using KASP. Increased Ang2 concentrations in SLE patients were observed compared with healthy controls and patients with other inflammatory autoimmune diseases. For allelic contrast, except for rs1823375 (P = 0.058) and rs2442598 (P = 0.523), frequencies of alleles for other polymorphisms were significantly different between SLE patients and controls. Genotypes for rs12674822 (TT), rs1868554 (TT, TA and TT+TA), rs734701 (TT) were negatively correlated with SLE susceptibility (OR = 0.564 for rs12674822; OR = 0.572, OR = 0.625, OR = 0.607 for rs1868554; OR = 0.580 for rs734701). Patients carrying rs1868554 T allele and rs3739390 G allele were more likely to develop hematuria (P = 0.039; P = 0.003). The G allele frequencies of rs12674822 and rs2442598 were higher in SLE patients with proteinuria (P = 0.043; P = 0.043). GC genotype frequency of rs3739390 was higher in patients with ds-DNA (+) (P = 0.024). In summary, SLE had increased serum Ang2, which may be a potential biomarker, and the polymorphisms correlated with SLE.

Reduced Angiopoietin-2 as a Predictive Biomarker for Clomiphene Citrate Resistance in Polycystic Ovary Syndrome.

Background:Even though angiopoeitin-2 and interleukin (IL)-23 are known to be altered in polycystic ovary syndrome (PCOS), their association with clomiphene citrate (CC) resistance has not been studied.Aim:The objective of the study was to investigate whether angiopoietin-2 levels are associated with inflammation and CC resistance in PCOS.Settings and Design:This study was conducted in a tertiary care hospital.Materials and Methods:Eighty-one women diagnosed with PCOS and on treatment with CC were enrolled in the study. Angiopoeitin-2 and IL -23 were analyzed in all the subjects.Results:Angiopoietin-2 was significantly reduced (P = 0.018), and body mass index (BMI) (P = 0.049) and duration of infertility (0.006) were significantly increased in PCOS women with CC resistance compared to those who are sensitive to CC. In CC resistant PCOS, IL-23 predicts reduction in angiopoietin-2 levels (P = 0.010). Among angiopoietin-2, IL-23, BMI, and duration of infertility, we found that angiopoeitn-2 (P = 0.020) and duration of infertility (0.036) can predict resistance to CC therapy among PCOS subjects.Conclusion:We conclude that reduced angiopoietin-2 levels predict CC resistance in women with PCOS.

Effect of Vitamin E on Serum Levels of Vascular Endothelial Growth Factor and Angiopoietin-1 in Women with Polycystic Ovary Syndrome: A Pilot Randomized, Placebo-Controlled Trial.

BackgroundAngiogenesis disturbances are common in women with polycystic ovary syndrome (PCOS). Vitamin E has antiangiogenic properties. Data on the effects of vitamin E on angiogenesis in PCOS is limited, so the current study was conducted to evaluate its effects on angiogenic indices in PCOS patients.Materials and MethodsThis randomized, double-blind, placebo-controlled trial was performed on 43 women aged 20-40 years, diagnosed with PCOS (Rotterdam criteria). It was performed at the referral clinic affiliated to Tabriz University of Medical Sciences, Tabriz, Iran, from April 2017 to September 2017. Patients were randomly assigned into two groups to receive either 400 IU/day vitamin E -as alpha tocopheryl acetate- (n=22) or placebo (n=21), for 8 weeks. Anthropometric, and angiogenic parameters including body weight, fat mass and fat free mass, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiopoietin-1 (Ang- 1), and angiopoietin-2 (Ang-2) were measured by standard methods at the beginning and at the end of study. Statistical Package for Social Science version 25 was used for statistical analysis and P<0.05 were considered significant.ResultsAfter adjusting for potential confounders, we observed that vitamin E supplementation significantly reduced body weight, fat mass, Ang-1, Ang-1/Ang-2 ratio and VEGF (P<0.01). We did not observe any considerable effect for vitamin E on Ang-2 level or bFGF.ConclusionVitamin E supplementation for 8 weeks in the PCOS women had beneficial effects on body weight, Ang- 1, Ang-1/Ang-2 ratio, and VEGF level (Registration number: IRCT201610193140N18).

Endothelial dysfunction as an early marker for cardiovascular disease in patients with chronic kidney disease on maintenance hemodialysis

Background Cardiovascular disease is a major cause of mortality in dialysis patients. Magnesium (Mg) level has been found to correlate positively with endothelial function. Moreover, it is suggested that low Mg is associated with increased all-cause and cardiovascular mortality in hemodialysis (HD) patients. Objective Therefore, this study was conducted to define the relationship between Mg level and endothelial dysfunction as an early marker of cardiovascular disease in patients with end-stage renal disease (ESRD) on maintenance HD. Patients and methods In this cross-sectional study, 85 patients with ESRD on maintenance HD were included. Serum angiopoietin-2 (Ang-2) level, brachial flow-mediated dilation (BFMD), and carotid intima-media thickness (CIMT) were measured as indicators of endothelial dysfunction and atherosclerosis. Patients’ serum Mg levels were measured. All data are presented as mean and SD or percent frequency. Statistical tests, mainly t test, Mann–Whitney test, or χ 2 test, are used in comparison between groups for quantitative and qualitative data correspondingly. Results Our results indicate that Ang-2 and BFMD are associated and can predict atherosclerosis early in HD patients (P=0.036 and 0.006, respectively). When the patients were divided according to their serum Mg, there was no significant difference regarding Ang-2, BFMD, and CIMT between the two groups. Conclusion This study demonstrated that endothelial dysfunction markers such as Ang-2 and BFMD are associated and can predict atherosclerosis early in HD patients. On the contrary, Mg might not affect neither endothelial function (FMD and Ang-2) nor CIMT as a marker of atherosclerosis in ESRD on HD.

Evaluation of Angiopoietin 2 Serum Level in Lichen Planus and Psoriasis Patients

Background: Psoriasis and lichen planus (LP) are common chronic inflammatory skin diseases. The exact pathogenesis of these diseases until now is not fully determined. Angiogenesis is tightly regulated by a balance between pro- and anti-angiogenic mediators. Objective: To assess the relation of Ang-2 serum level with angiogenesis and inflammation that occurs in psoriasis and lichen planus. Patients and Methods: Thirty adult patients were included in this study. They were divided into 2 groups, 15 patients each, of psoriasis and lichen planus (8 patients with combined cutaneous and oral LP and 7 patients with cutaneous LP only). In addition to fifteen healthy subjects taken as control. The activity of the diseases was estimated at the time of examination using specific activity index for each disease. The serum level of angiopoietin 2 had been estimated by ELISA. Results: It was found that these diseases had significantly higher serum levels of angiopoietin 2 than the control group. The serum levels of angiopoietin 2 were higher in psoriasis compared to lichen planus, but the difference between psoriasis and lichen planus was not statistically significant. There was significant positive correlation between serum levels of angiopoietin 2 and the clinical severity of psoriasis. On the other hand, there was no correlation between serum level of angiopoietin 2 and the clinical severity of lichen planus. Conclusion: An important evidence on the importance of angiopoietin 2 serum level in pathogenesis of lichen planus as well as psoriasis. It elevated in serum of psoriasis and lichen planus patients that reflects its role in angiogenesis and inflammation that are important events in the development of these diseases.

Evaluation of Angiopoietin 2 Serum Level in Lichen Planus and Psoriasis Patients

Background: Psoriasis and lichen planus (LP) are common chronic inflammatory skin diseases. The exact pathogenesis of these diseases until now is not fully determined. Angiogenesis is tightly regulated by a balance between pro- and anti-angiogenic mediators. Objective: To assess the relation of Ang-2 serum level with angiogenesis and inflammation that occurs in psoriasis and lichen planus. Patients and Methods: Thirty adult patients were included in this study. They were divided into 2 groups, 15 patients each, of psoriasis and lichen planus (8 patients with combined cutaneous and oral LP and 7 patients with cutaneous LP only). In addition to fifteen healthy subjects taken as control. The activity of the diseases was estimated at the time of examination using specific activity index for each disease. The serum level of angiopoietin 2 had been estimated by ELISA. Results: It was found that these diseases had significantly higher serum levels of angiopoietin 2 than the control group. The serum levels of angiopoietin 2 were higher in psoriasis compared to lichen planus, but the difference between psoriasis and lichen planus was not statistically significant. There was significant positive correlation between serum levels of angiopoietin 2 and the clinical severity of psoriasis. On the other hand, there was no correlation between serum level of angiopoietin 2 and the clinical severity of lichen planus. Conclusion: An important evidence on the importance of angiopoietin 2 serum level in pathogenesis of lichen planus as well as psoriasis. It elevated in serum of psoriasis and lichen planus patients that reflects its role in angiogenesis and inflammation that are important events in the development of these diseases.

Serum Levels of Markers of Endothelial Activation Are Not Associated with a Positive Blood Culture in Surinamese Children with Suspected Severe Infection.

Systemic serum levels of markers of endothelial activation are associated with infection. We hypothesize that levels of markers of endothelial activation are associated with the presence of a positive blood culture as a manifestation of a systemic infection in children with a suspected severe infection in Suriname. In this prospective observational cohort study, children between 1 month and 18 years of age suspected of severe infection as assessed by the threating physician, and in whom laboratory testing and blood culturing was performed before start of intravenous antibiotic treatment, were recruited at the emergency department of the Academic Hospital Paramaribo, Suriname. Serum was collected at blood culturing and after 48-72 h of admission. Serum was stored for measurement of levels of Angiopoietin (Ang)-1, Ang-2, soluble (s)P-selectin, sE-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and platelet and endothelial cell adhesion molecule-1. Fifty-one children were included of whom 10 had a positive blood culture. Baseline characteristics were similar between children with and without a positive blood culture. No significant differences in serum levels of the Angiopoietins or soluble cellular adhesion molecules between groups were observed at start of antibiotic treatment nor after 48-72 h. The data from this study indicate that in children with severe infection, serum levels of markers of endothelial cell activation are not associated with a positive blood culture. Thus, having a positive bacterial blood culture may not be the only factor driving endothelial activation in this patient population.

Regulation of Angiopoietin-2 Before and After Mechanical Circulatory Support Therapy.

Gastrointestinal bleeding (GIB) during mechanical circulatory support (MCS) is a major unsolved comorbidity. Inadequate activation of angiopoietin-2-related systems is considered as a major cause of GIB. However, the regulation of angiopoietin-2 remains unknown. Consecutive 20 patients who received continuous-flow MCS therapy (MCS group) and 12 with advanced heart failure (HF; HF group) were prospectively enrolled and their angiopoetin-2 levels were compared. Angiopoietin-2 level had a moderate correlation with log10 B-type natriuretic peptide (BNP; r = 0.39, p < 0.001). The MCS group had significantly higher angiopoietin-2 level divided by log10 BNP compared with the HF group (2.80 ± 0.20 vs. 1.88 ± 0.17, p < 0.001). Angiopoetin-2 had a moderate correlation with central venous pressure and C-reactive protein during the MCS support (r = 0.51 and r = 0.45, respectively). Higher angiopoietin-2 level divided by log10 BNP (> 4.3) was significantly associated with the occurrence of GIB with a hazard ratio of 296 (95% confidence interval 2.24-38620, p = 0.0224). Angiopoietin-2 was already elevated in the HF cohort and more elevated following MCS initiation. Among the MCS cohort, angiopoietin-2 was particularly elevated in patients with systemic congestion and inflammation and was associated with higher incidence of GIB.

Circulating angiopoietin-2 and angiogenic microRNAs associate with cerebral small vessel disease and cognitive decline in older patients reaching end-stage renal disease.

The prevalence of end-stage renal disease (ESRD) is increasing worldwide, with the majority of new ESRD cases diagnosed in patients >60 years of age. These older patients are at increased risk for impaired cognitive functioning, potentially through cerebral small vessel disease (SVD). Novel markers of vascular integrity may be of clinical value for identifying patients at high risk for cognitive impairment. We aimed to associate the levels of angiopoietin-2 (Ang-2), asymmetric dimethylarginine and a selection of eight circulating angiogenic microRNAs (miRNAs) with SVD and cognitive impairment in older patients reaching ESRD that did not yet initiate renal replacement therapy (n = 129; mean age 75.3 years, mean eGFR 16.4 mL/min). We assessed brain magnetic resonance imaging changes of SVD (white matter hyperintensity volume, microbleeds and the presence of lacunes) and measures of cognition in domains of memory, psychomotor speed and executive function in a neuropsychological test battery. Older patients reaching ESRD showed an unfavourable angiogenic profile, as indicated by aberrant levels of Ang-2 and five angiogenic miRNAs (miR-27a, miR-126, miR-132, miR-223 and miR-326), compared with healthy persons and patients with diabetic nephropathy. Moreover, Ang-2 was associated with SVD and with the domains of psychomotor speed and executive function, while miR-223 and miR-29a were associated with memory function. Taken together, these novel angiogenic markers might serve to identify older patients with ESRD at risk of cognitive decline, as well as provide insights into the underlying (vascular) pathophysiology.

Complement promotes endothelial von Willebrand factor and angiopoietin-2 release in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is highly prevalent and triples vascular thromboembolic risk. Intermittent hypoxia (IH) during transient cessation of breathing in OSA impairs endothelial protection against complement. Complement activation stimulates the endothelial release of a pro-thrombotic von Willebrand factor (vWF). We investigated whether increased complement activity in OSA promotes the endothelial release of vWF and pro-inflammatory angiopoietin-2. We further investigated whether improving complement protection with statins reverses these changes. Using endothelial cells (ECs) and blood collected from OSA patients (n = 109) and controls (n = 67), we assessed whether altered cellular localization of complement inhibitor CD59 in OSA modulates exocytosis of Weibel-Palade bodies (WPB), secretory granules that store vWF and angiopoietin-2. These interactions were also assessed in vitro in ECs exposed to normoxia or IH with or without recombinant complement C9 and with or without atorvastatin. Circulating levels of angiopoietin-2 were greater in OSA than controls and levels of vWF cleavage products correlated with OSA severity. In cultured ECs, IH enhanced complement-stimulated angiopoietin-2 and vWF release by reducing EC surface and increasing intracellular expression of complement inhibitor CD59. Intracellular CD59 co-localized with WPB in OSA. IH increased binding of intracellular CD59 to syntaxin-3, which dissociated syntaxin-3 from voltage-sensitive calcium channel Cav1.2, and activated WPB exocytosis in a calcium-dependent manner. Atorvastatin reversed IH-enhanced endothelial release of vWF and angiopoietin-2. IH promotes the complement-mediated release of vWF and angiopoietin-2, which may contribute to pro-thrombotic and pro-inflammatory conditions in OSA. Statin reversed these effects, suggesting a potential approach to reduce cardiovascular risk in OSA.

Prognostic Biomarkers for Thrombotic Microangiopathy after Acute Graft-versus-Host Disease: A Nested Case-Control Study

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a complication of allogeneic hematopoietic cell transplantation (HCT) that often occurs following the development of acute graft-versus-host disease (aGVHD). In this study, we aimed to identify early TMA biomarkers among patients with aGVHD. We performed a nested-case-control study from a prospective cohort of allogeneic HCT recipients, matching on the timing and severity of antecedent aGVHD. We identified 13 TMA cases and 25 non-TMA controls from 208 patients in the cohort. Using multivariable conditional logistic regression, the odds ratio for TMA compared with non-TMA was 2.65 (95% confidence interval [CI], 1.00 to 7.04) for every 100 ng/mL increase in terminal complement complex sC5b9 and 2.62 (95% CI, 1.56 to 4.38) for every 1000 pg/mL increase in angiopoietin-2 (ANG2) at the onset of aGVHD. ADAMTS13 and von Willebrand factor (VWF) antigens were not appreciably associated with TMA. Using a Cox regression model incorporating sC5b9 >300 ng/mL and ANG2 >3000 pg/mL at the onset of aGVHD, the adjusted hazard ratio for mortality was 5.33 (95% CI, 1.57 to 18.03) for the high-risk group (both elevated) and 4.40 (95% CI, 1.60 to 12.07) for the intermediate-risk group (one elevated) compared with the low-risk group (neither elevated). In conclusion, we found that elevated sC5b9 and ANG2 levels at the onset of aGVHD were associated with the development of TMA and possibly mortality after accounting for the timing and severity of aGVHD. The results suggest important roles of complement activation and endothelial dysfunction in the pathogenesis of TMA. Measurement of these biomarkers at the onset of aGVHD may inform prognostic enrichment for preventive trials and improve clinical care.

Determining the Value of Angiopoietin-2 Biomarker in Predicting Complications of Leptospirosis

Background: Leptospirosis is a common zoonosis disease that is potentially life-threatening all around the world. Angiopoietin-2 can be used as an indicator to determine the severity of the disease in critically ill patients. Objectives: This study aimed to determine the value of angiopoietin-2 biomarker in predicting leptospirosis complications. Methods: In this prospective observational study, 90 participants, including 45 patients with leptospirosis and 45 participants in the control group, are studied. Three to five days after the onset of symptoms before starting treatment with antibiotics, 5 mL venous blood was taken to measuring the angiopoietin-2 level by enzyme-linked immunosorbent assay (ELISA). Results: In this study, 75 men (83.3%) and 15 women (16.7%) with an age distribution of 23 to 75 years participated. A total of 74 (82.3%) patients were employed in the agriculture sector, while 59 (65.6%) lived in rural areas. There was a significant relationship between patients with severe forms of leptospirosis and levels of angiopoietin-2 (P-value &lt; 0.01). Also, there was a significant relationship between angiopoietin-2 biomarker level and markers of disease severity such as anemia (P-value &lt; 0.01), oliguria (P-value &lt; 0.01), severe thrombocytopenia (P-value &lt; 0.01), length of stay (P-value &lt; 0.01), and CRP more than 2+ (P-value &lt; 0.001). Conclusions: This study demonstrated that angiopoietin-2 biomarker can be used in screening disease severity and predicting complications of leptospirosis.

Dexmedetomidine protects against endothelial injury in septic rats induced by cecal ligation and puncture by decreasing angiopoietin 2 and increasing vascular endothelial cadherin levels.

The aim of the present study was to investigate the protective effect of dexmedetomidine (Dex) on endothelial injury in a cecal ligation and puncture (CLP)-induced rat model of sepsis. A total of 36 male Sprague-Dawley rats were divided into three groups: Sham, CLP and CLP + Dex. The wet/dry (W/D) ratio of lung weight, hematoxylin and eosin (H&E) staining of lung tissue, plasma levels of angiopoietin (Ang)1 and 2, ratio of Ang2/1 and vascular endothelial (VE)-cadherin protein expression levels in lung tissue were determined. The W/D ratio of lung tissue in the CLP + Dex group was significantly lower than that in the CLP group (P<0.01). The H&E staining results indicated that Dex treatment reduced the levels of CLP-induced alveolar septum widening, infiltrating white blood cells and congestion, when compared with CLP alone. In addition, the expression levels of plasma Ang2 and the Ang2/1 ratio in the CLP + Dex group were significantly lower than those of the CLP rats (P<0.01). Furthermore, the level of VE-cadherin protein in lung tissue of the CLP + Dex group was higher than that of the CLP group (P<0.05). The results indicated that Dex had a protective effect against CLP-induced endothelial injury, through the ability to reduce expression of the endothelial injury factor Ang2 and increase the expression of the endothelial adhesion junction factor VE-cadherin in a septic rat model. These data suggest a potential application of Dex in the clinical treatment of sepsis.

Stromal SNAI2 Is Required for ERBB2 Breast Cancer Progression.

SNAI2 overexpression appears to be associated with poor prognosis in breast cancer, yet it remains unclear in which breast cancer subtypes this occurs. Here we show that excess SNAI2 is associated with a poor prognosis of luminal B HER2+/ERBB2+ breast cancers in which SNAI2 expression in the stroma but not the epithelium correlates with tumor proliferation. To determine how stromal SNAI2 might influence HER2+ tumor behavior, Snai2-deficient mice were crossed with a mouse line carrying the ErbB2/Neu protooncogene to generate HER2+/ERBB2+ breast cancer. Tumors generated in this model expressed SNAI2 in the stroma but not the epithelium, allowing for the role of stromal SNAI2 to be studied without interference from the epithelial compartment. The absence of SNAI2 in the stroma of HER2+/ERBB2+ tumors is associated with: (i) lower levels of cyclin D1 (CCND1) and reduced tumor epithelium proliferation; (ii) higher levels of AKT and a lower incidence of metastasis; (iii) lower levels of angiopoietin-2 (ANGPT2), and more necrosis. Together, these results indicate that the loss of SNAI2 in cancer-associated fibroblasts limits the production of some cytokines, which influences AKT/ERK tumor signaling and subsequent proliferative and metastatic capacity of ERBB2+ breast cancer cells. Accordingly, SNAI2 expression in the stroma enhanced the tumorigenicity of luminal B HER2+/ERBB2+ breast cancers. This work emphasizes the importance of stromal SNAI2 in breast cancer progression and patients' prognosis. SIGNIFICANCE: Stromal SNAI2 expression enhances the tumorigenicity of luminal B HER2+ breast cancers and can identify a subset of patients with poor prognosis, making SNAI2 a potential therapeutic target for this disease. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/23/5216/F1.large.jpg.

New Horizons: Does Mineralocorticoid Receptor Activation by Cortisol Cause ATP Release and COVID-19 Complications?

This paper attempts to explain how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes the complications that make coronavirus disease 2019 (COVID-19) a serious disease in specific patient subgroups. It suggests that cortisol-associated activation of the mineralocorticoid receptor (MR) in epithelial and endothelial cells infected with the virus stimulates the release of adenosine 5′-triphosphate (ATP), which then acts back on purinergic receptors. In the lung this could produce the nonproductive cough via purinergic P2X3 receptors on vagal afferent nerves. In endothelial cells it could stimulate exocytosis of Weibel-Palade bodies (WPBs) that contain angiopoietin-2, which is important in the pathogenesis of acute respiratory distress syndrome (ARDS) by increasing capillary permeability and von Willebrand factor (VWF), which mediates platelet adhesion to the endothelium and hence clotting. Angiopoietin-2 and VWF levels both are markedly elevated in COVID-19–associated ARDS. This paper offers an explanation for the sex differences in SARS-CoV-2 complications and also for why these are strongly associated with age, race, diabetes, and body mass index. It also explains why individuals with blood group A have a higher risk of severe infection than those with blood group O. Dexamethasone has been shown to be of benefit in coronavirus ARDS patients and has been thought to act as an anti-inflammatory drug. This paper suggests that a major part of its effect may be due to suppression of cortisol secretion. There is an urgent need to trial the combination of dexamethasone and an MR antagonist such as spironolactone to more effectively block the MR and hence the exocytosis of WPBs.

The Role of Angiopoietin-2 Gene Mutation on Clinical Severity of Dengue Disease in Children

BACKGROUND: In general, angiopoietin-2 levels are increased concomitantly with dengue clinical severity. &#x0D; AIM: This research aims to determine the role of mutation on angiopoietin-2 on dengue clinical severity.&#x0D; METHODS: A cross-sectional study of 108 children with dengue disease grouped by severity. Angiopoietin-2 level was examined by enzyme-linked immunosorbent assay. Polymerase chain reaction and double nucleic acid sequencing are using 2 Exon 4-F primers.&#x0D; RESULTS: Angiopoietin-2 levels on rs7834131 mutant are higher in dengue fever (p &lt; 0.05) and dengue hemorrhage fever group than non-mutant, while on dengue shock syndrome, it is lower than non-mutant.&#x0D; CONCLUSION: Angiopoietin-2 mutation on rs7834131 might have a protective effect on dengue disease severity.

Vascular density with optical coherence tomography angiography and systemic biomarkers in low and high cardiovascular risk patients

We aimed to compare retinal vascular density in Optical Coherence Tomography Angiography (OCT-A) between patients hospitalized for acute coronary syndrome (ACS) and control patients and to investigate correlation with angiogenesis biomarkers. Patients hospitalized for an acute coronary syndrome (ACS) in the Intensive Care Unit were included in the “high cardiovascular risk” group while patients without cardiovascular risk presenting in the Ophthalmology department were included as “control”. Both groups had blood sampling and OCT-A imaging. Retina microvascularization density in the superficial capillary plexus was measured on 3 × 3 mm angiograms centered on the macula. Angiopoietin-2, TGF-β1, osteoprotegerin, GDF-15 and ST-2 were explored with ELISA or multiplex method. Overall, 62 eyes of ACS patients and 42 eyes of controls were included. ACS patients had significantly lower inner vessel length density than control patients (p = 0.004). A ROC curve found that an inner vessel length density threshold below 20.05 mm−1 was moderately associated with ACS. Significant correlation was found between serum levels of angiopoietin-2 and osteoprotegerin, and retinal microvascularization in OCT-A (R = − 0.293, p = 0.003; R = − 0.310, p = 0.001). Lower inner vessel length density measured with OCT-A was associated with ACS event and was also correlated with higher concentrations of angiopoietin-2 and osteoprotegerin.

Serum IL-8 level as a candidate prognostic marker of response to anti-angiogenic therapy for metastatic colorectal cancer.

Liver metastasis (LM) is associated with poor prognosis in patients with metastatic colorectal cancer (mCRC). Here, we investigated the prognostic utility of several serum factors in mCRC patients with or without LM who were treated with anti-angiogenic agents in first-line (FL) or salvage-line (SL) settings. A combined cohort of 125 patients was analyzed in this single institute pooled analysis: FL cohort receiving bevacizumab (n = 71) and SL cohort receiving regorafenib (n = 54). Blood samples were obtained at baseline (BL) and during treatment, and serum factors were measured by ELISA. Overall survival (OS) was analyzed using Kaplan-Meier curves, the log-rank test, and Cox proportional hazard regression methods. In univariate analysis of the combined cohort, right-sided CRC, primary unresected tumor, wild-type KRAS, LM, ≥ 2 metastatic sites, and SL were associated with shorter OS; in multivariable analysis, LM and SL remained significant. Serum angiopoietin-2 (Ang-2) levels ≥ 2190.3 pg/ml and interleukin (IL)-8 levels ≥ 15.1 pg/ml at BL were significantly associated with LM. Using these cut-off values, patients with higher Ang-2 or IL-8 levels at BL had shorter OS than those with lower BL levels (Ang-2: hazard ratio [HR] 2.57, 95% confidence interval [CI] 1.47-4.51, P = 0.001; IL-8: HR 4.31, 95%CI 2.11-8.79, P < 0.001). High serum IL-8 level remained a significant predictor of shorter OS in multivariable analysis (HR 3.24, 95%CI 1.47-7.16, P = 0.004). Circulating IL-8 and Ang-2 levels are associated with LM in mCRC patients. IL-8 may be a prognostic marker of response to anti-angiogenic therapy, regardless of the treatment timing.