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Background/Objectives: Microaneurysms (MAs) are important in the pathology of diabetic macular edema (DME) and its response to anti-vascular endothelial growth factor (VEGF) therapy. This study aimed to clarify the morphological characteristics of MAs in residual edema following consecutive faricimab injections, a bispecific antibody against angiopoietin-2 and VEGF. Methods: We selected patients with DME who exhibited residual edema after three monthly injections of faricimab. In both the residual and absorbed areas of edema, we counted the turnover of MAs, including those that were lost and those that were newly formed. The total number of MAs was determined based on the merged images from an optical coherence tomography (OCT) map and fluorescein angiography. Results: A total of 8 of the 42 patients who received three monthly injections of faricimab showed residual edema one month after the injections. In the residual edema, the density of MAs and the number of maintained MAs were significantly higher (p = 0.04), while the number of disappeared MAs (p = 0.04) and MA turnover (p = 0.01) were lower compared to the absorbed areas. Among the MAs that persisted after the initial injection, the proportion of large-sized MAs (p = 0.01) and their density were significantly greater than those in the absorbed area. In conclusion, the residual areas following three doses of faricimab displayed a higher MA density, less MA loss, and a high density of large-sized MAs compared to the absorbed areas. Our data suggest that large-size MAs located in the residual edema are characteristic of DME cases refractory to faricimab treatment. [ABSTRACT FROM AUTHOR]

Abstract Background BI 836880 is a humanized bispecific nanobody® that binds to and blocks vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2). A comprehensive biomarker and modeling approach is presented here that supported dose finding for BI 836880. Methods Two Phase I dose-escalation studies (1336.1 [NCT02674152], 1336.6 [NCT02689505]) assessed BI 836880 in adults with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy or for which standard therapy was not reliably effective. Two dosing schedules were investigated, 3 weeks (q3w) or once weekly (qw), starting at a dose of 40 mg. In a comprehensive biomarker approach, soluble pharmacodynamic markers (free and total plasma VEGF-A and Ang-2), as well as circulating angiogenic factors (soluble VEGF3, soluble Tie2 and placenta growth factor, amongst others) were analyzed to assess target engagement in peripheral blood for q3w doses. A Population based pharmacokinetics/pharmacodynamics (PopPK/PD) model was built using the limited Phase I dataset to support dose finding by simulations. In order to demonstrate drug activity in the tumor, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was applied. Results DCE-MRI scans supported target engagement in the tumor. Free VEGF-A was depleted at all doses, whereas free Ang-2 decreased dose-dependently, reaching depletion in most patients from 360 mg q3w onwards. While total VEGF-A levels increased in a dose-dependent manner, reaching saturation at 360 mg q3w, total Ang-2 levels increased, but did not plateau. Angiogenic biomarkers showed changes from doses ≥ 360 mg q3w. PopPK/PD modeling showed that doses ≥ 360 mg q3w led to > 90% inhibition of free Ang-2 at steady-state in most patients. By increasing the dose to ≥ 500 mg q3w, > 90% of patients are expected to achieve this level. Conclusions The comprehensive analyses of multiple target engagement markers support BI 836880 720 mg q3w as a biologically relevant monotherapy dose schedule. Trial registration: NCT02674152 and NCT02689505.

Background: BI 836880 is a humanized bispecific nanobody® that binds to and blocks vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2). A comprehensive biomarker and modeling approach is presented here that supported dose finding for BI 836880. Methods: Two Phase I dose-escalation studies (1336.1 [NCT02674152], 1336.6 [NCT02689505]) assessed BI 836880 in adults with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy or for which standard therapy was not reliably effective. Two dosing schedules were investigated, 3 weeks (q3w) or once weekly (qw), starting at a dose of 40 mg. In a comprehensive biomarker approach, soluble pharmacodynamic markers (free and total plasma VEGF-A and Ang-2), as well as circulating angiogenic factors (soluble VEGF3, soluble Tie2 and placenta growth factor, amongst others) were analyzed to assess target engagement in peripheral blood for q3w doses. A Population based pharmacokinetics/pharmacodynamics (PopPK/PD) model was built using the limited Phase I dataset to support dose finding by simulations. In order to demonstrate drug activity in the tumor, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was applied. Results: DCE-MRI scans supported target engagement in the tumor. Free VEGF-A was depleted at all doses, whereas free Ang-2 decreased dose-dependently, reaching depletion in most patients from 360 mg q3w onwards. While total VEGF-A levels increased in a dose-dependent manner, reaching saturation at 360 mg q3w, total Ang-2 levels increased, but did not plateau. Angiogenic biomarkers showed changes from doses ≥ 360 mg q3w. PopPK/PD modeling showed that doses ≥ 360 mg q3w led to > 90% inhibition of free Ang-2 at steady-state in most patients. By increasing the dose to ≥ 500 mg q3w, > 90% of patients are expected to achieve this level. Conclusions: The comprehensive analyses of multiple target engagement markers support BI 836880 720 mg q3w as a biologically relevant monotherapy dose schedule. Trial registration: NCT02674152 and NCT02689505. [ABSTRACT FROM AUTHOR]

This study analyzes the dynamics of short-term treatment response to the first intravitreal faricimab injection in eyes with diabetic macular edema (DME). This retrospective, single-center, clinical trial was conducted at the Department of Ophthalmology, University Hospital Zurich. Patients with treatment-naïve and pretreated DME were included. Patient chart data and imaging were analyzed. Safety and efficacy (corrected visual acuity (CVA), central subfield thickness (CST), and signs of intraocular inflammation (IOI)) of the first faricimab intravitreal therapy (IVT) were evaluated weekly until 4 weeks after injection. Forty-three eyes (81% pretreated) of 31 patients were included. Four weeks after the first faricimab IVT, CVA remained stable and median CST (µm) decreased significantly (p < 0.001) from 325.0 (293.5–399.0) at baseline to 304.0 (286.5–358.0). CVA at week 4 was only associated with baseline CVA (p < 0.001). CST was the only predictive variable (p = 0.002) between baseline and week 4 CST. Weekly safety assessments did not show any sign of clinically significant IOI. This study suggests faricimab is an effective treatment for (pretreated) DME, showing structural benefit 1 month following the first injection without short-term safety signals. [ABSTRACT FROM AUTHOR]

Objective: To explore the relationship between serum tumor specific growth factor (TSGF), monocyte chemoattractant protein-1 (MCP-1), angiopoietin-2 (Ang-2) and recurrence after laparoscopic myomectomy (LM) and the construction of a nomograph prediction model. Methods: 213 uterine fibroids patients who were undergoing LM surgery admitted to our hospital from June 2018 to June 2020 were selected as study subjects. The serum levels of TSGF, MCP-1 and Ang-2 were detected in all patients. After 3 years of follow-up, patients were divided into recurrence group and non-recurrence group according to whether patients had recurred 3 years after operation, the serum levels of TSGF, MCP-1 and Ang-2 were compared between two groups. The risk factors of recurrence after LM in uterine fibroids patients were analyzed by univariate and multivariate Logistic regression analysis, and a nomograph prediction model for postoperative recurrence risk was constructed according to the risk factors. The predictive efficacy of serum MCP-1, TSGF and Ang-2 on the recurrence of LM in uterine fibroids patients were analyzed by receiver operating characteristic (ROC) curve. Results: 213 uterine fibroids patients were followed up for 3 years, and 8 patients were lost to follow-up, there were 37 cases of recurrence in 205 uterine fibroids patients 3 years after LM, and the recurrence rate was 18.05% (37/205). The serum levels of Ang-2, MCP-1 and TSGF in non-recurrence group were lower than those in recurrence group, and the differences were statistically significant(P<0.05). Multivariate Logistic regression analysis showed that, postoperative residual myoma, elevated serum TSGF, age≥35 years, elevated MCP-1, multiple fibroids and elevated Ang-2 were independent risk factors for recurrence after LM in uterine fibroids patients(P<0.05). ROC analysis showed that, the area under the curve (AUC) of serum TSGF, MCP-1, Ang-2 and nomograph prediction model was 0.873 (95%CI: 0.801~0.944), 0.721 (95%CI: 0.624~0.817), 0.803 (95%CI: 0.722~0.885), 0.986 (95%CI: 0.973~0.998). Internal validation (B=1000) showed that, the C-index was 0.972, suggesting that the nomograph prediction model had a good predictive ability. The decision analysis shows that, the threshold probability of the model was 0.01~0.95, and the net return rate was>0, which was higher than the two invalid lines. Conclusion: The increase of serum TSGF, MCP-1 and Ang-2 levels can lead to the recurrence of LM in uterine fibroids patients. Age≥35 years old, multiple fibroids, postoperative residual myoma, elevated serum TSGF, elevated MCP-1 and elevated Ang-2 are independent risk factors for recurrence after LM in uterine fibroids patients. The nomograph prediction model base on independent risk factors has a good predictive value for the recurrence of LM in uterine fibroids patients. [ABSTRACT FROM AUTHOR]

Purpose: To assess the short-term outcomes of intravitreal faricimab (IVF) for previously treated refractory neovascular age-related macular degeneration (nAMD) in a real-world setting. Methods: A retrospective monocentric study including 44 eyes treated with an upload of 4 × monthly intravitreal injections (IVI) of faricimab 6 mg/0.05 mL and followed for 4 weeks after last IVI (16 W). Patients were switched to IVF after treatment with at least three other anti-vascular endothelial growth factors (anti-VEGF). Main outcome measures included best-corrected visual acuity (BCVA), central macular thickness (CMT), subfoveal choroidal thickness (SFCT) and retinal fluid distribution. Results: 44 eyes of 44 patients with previously treated refractory nAMD (63% males) were included. Mean age was 79 ± 7 years. The total number of previous anti-VEGF before switching to IVF was 32 ± 15 IVIs/eye. BCVA (logMAR) improved significantly from 0.65 ± 0.26 to 0.50 ± 0.23 at 16 W (p <0.01). CMT (µm) decreased significantly from 422 ± 68 to 362 ± 47 at 16 W (p < 0.01). SFCT did not change significantly at 16 W (p = 0.06). The number of eyes with subretinal fluid (SRF) decreased significantly from 29 (65%) to 13 (29%) at 16 W (p =0.001). There were no significant changes regarding the distribution of intraretinal fluid or pigment epithelial detachment (p > 0.05). A complete fluid resolution was achieved in 8 eyes (18%). No adverse events were noticed. Conclusion: In the short term, IVF led to a significant decrease in CMT as well as a significant improvement of BCVA and thus appears to be an effective treatment option for previously treated refractory nAMD without relevant adverse effects. [ABSTRACT FROM AUTHOR]

Objective To investigate the predictive value of plasma signal peptide-CUB-epidermal growth factor-like domain-containing protein 1 (SCUBE-1), a disintegrin and metalloproteinase with thrombospondin motifs-9 (ADAMTS-9), and angiopoietin-2 (ANG-2) levels in assessing the severity and prognosis of acute pulmonary embolism (APE). Methods This study included 121 APE patients treated at our hospital. They were divided into mild (n= 34, PAOI＜30%), moderate (n= 45, 30%≤PAOI≤50%), and severe (n= 42, PAOI＞50%) groups based on the CT pulmonary artery obstruction index (PAOI). Based on prognosis, patients were divided into a good prognosis group (n= 86) and a poor prognosis group (n= 35). Plasma levels of SCUBE-1, ADAMTS-9, and ANG-2 were measured using enzyme-linked immunosorbent assay (ELISA). Multivariate logistic regression was used to analyze risk factors affecting poor prognosis in APE, and ROC curve analysis was performed to evaluate the predictive value of these plasma levels for poor prognosis. Pearson correlation analysis assessed the relationship between plasma levels and cardiac function indicators.Results The poor prognosis group had significantly higher plasma levels of SCUBE-1[ (24. 63±11. 70) ng/mLvs. (10. 17±5. 12) ng/mL], ADAMTS-9[ (47. 50±13. 25) ng/mLvs. (24. 28±7. 63) ng/mL], and ANG-2[ (15. 38±6. 27) ng/mL vs. (4. 15±1. 52) ng/mL]compared to the good prognosis group (P＜0. 001). Plasma levels of SCUBE-1, ADAMTS-9, and ANG-2 increased with APE severity, with levels in the severe group being the highest, followed by the moderate and mild groups (P＜0. 001). Multivariate logistic regression analysis showed that elevated levels of PAOI, CRP, cTnI, BNP, D-dimer, SCUBE-1, ADAMTS-9, and ANG-2 were risk factors for poor prognosis in APE (allP＜0. 05). ROC curve analysis indicated that the combined prediction of SCUBE-1, ADAMTS-9, and ANG-2 levels had the highest area under the curve (0. 931, 95%CI:0. 868 ～ 0. 996) with an accuracy of 88. 4%. Correlation analysis demonstrated that plasma SCUBE-1, ADAMTS-9, and ANG-2 levels were positively correlated with CRP, cTnI, BNP, D-dimer, and PAOI (P＜0. 05). Conclusion Elevated plasma levels of SCUBE-1, ADAMTS-9, and ANG-2 are associated with increased severity and poor prognosis of APE. These markers are risk factors for poor prognosis in APE, and their combined measurement provides significant predictive value. [ABSTRACT FROM AUTHOR]

High levels of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-2 and angiopoietin (ANG)-2 are found in tissues from oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs). As might be expected, VEGF, FGF-2, and ANG-2 overexpression parallels the development of new blood and lymphatic vessels that nourish the growing OPMDs or OSCCs and provide the latter with metastatic routes. Notably, VEGF, FGF-2, and ANG-2 are also linked to the epithelial-to-mesenchymal transition (EMT), a trans-differentiation process that respectively promotes or exasperates the invasiveness of normal and neoplastic oral epithelial cells. Here, we have summarized published work regarding the impact that the interplay among VEGF, FGF-2, ANG-2, vessel generation, and EMT has on oral carcinogenesis. Results from the reviewed studies indicate that VEGF, FGF-2, and ANG-2 spark either protein kinase B (AKT) or mitogen-activated protein kinases (MAPK), two signaling pathways that can promote both EMT and new vessels' formation in OPMDs and OSCCs. Since EMT and vessel generation are key to the onset and progression of OSCC, as well as to its radio- and chemo-resistance, these data encourage including AKT or MAPK inhibitors and/or antiangiogenic drugs in the treatment of this malignancy. [ABSTRACT FROM AUTHOR]

Pathological angiogenesis of liver sinusoidal endothelial cells (LSEC) plays a crucial role in the progression of metabolic dysfunction-associated steatohepatitis (MASH)-induced liver fibrosis. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have shown promising therapeutic potential against MASH. This study aimed to investigate the impact of MSC-sEV on LSEC angiogenesis and elucidate the underlying molecular mechanisms. The effects of MSC-sEV on LSEC angiogenesis were evaluated in Tumor Necrosis Factor- alpha (TNF-α)-treated LSECs in vitro and in Methionine and Choline Deficient Diet (MCD)-induced MASH mice in vivo. Herein, we found that MSC-sEV effectively suppressed LSEC angiogenesis by targeting the angiogenesis marker Angiogenin 2 (Ang-2) in both TNF-α-treated LSECs and MASH mice. Gene manipulation experiments revealed that the primary mechanism by which MSC-sEV inhibited LSEC angiogenesis was through the modulation of nuclear factor kappa B inhibitor alpha (IκBα) / nuclear factor kappa B (NF-κB) / Ang-2 pathway. Additionally, mass spectrometry and co-immunoprecipitation (Co-IP) data suggested that MSC-sEV delivered the ubiquitin specific peptidase 9 X-linked (USP9X) protein to LSECs, leading to enhanced IκBα deubiquitination and NF-κB in activation, ultimately resulting in the inhibition of Ang-2-mediated LSEC angiogenesis. Knockdown of USP9X attenuated the regulatory effects of MSC-sEV on Ang-2 expression, LSEC angiogenesis, and the progression of MASH. In conclusion, our findings indicate that USP9X delivered via MSC-sEV can suppress LSEC angiogenesis and alleviate MASH-induced liver fibrosis through the IκBα/NF-κB/Ang-2 signaling pathway.

Background: To evaluate the outcomes of intravitreal faricimab (IVF) for refractory neovascular age-related macular degeneration (nAMD) and investigate the impact of baseline optical coherence tomography, biomarkers for total IVF injections are needed. Methods: A retrospective analysis of 33 eyes of patients who completed one year (52 W) of treatment with IVF. The eyes received four IVF injections (6 mg/0.05 mL) as the upload phase. Thereafter, the treatment interval was extended to 8 or 12 weeks if disease activity was not recorded. The outcome measures included best-corrected visual acuity (BCVA), central macular thickness (CMT), subfoveal choroidal thickness (SFCT), and retinal fluid distribution. Results: A total of 33 eyes were included. CMT decreased significantly at 52 W (p < 0.01). BCVA and SFCT did not change significantly at 52 W (p > 0.05). The number of eyes with subretinal fluid decreased significantly at 52 W (p < 0.01). Complete fluid resolution was achieved in 20 eyes (60%). The total number of injections was significantly negatively correlated with the presence of hyperreflective dots at baseline (HRDs, p < 0.01) and SFCT at baseline (p < 0.01). Conclusions: IVF led to a significant reduction in CMT with stabilization of BCVA. The total number of injections was lower in eyes with HRDs and increased SFCT at baseline. This might provide clues regarding response to IVF for future studies. [ABSTRACT FROM AUTHOR]

To explore the potential role of microRNA miR-221-5p on the angiopoietin-1 (Ang-1)/Ang-2/Tie-2 signaling axis after subarachnoid hemorrhage (SAH) in a rat model. Aspects of the rat's behavior were measured using the Kaoutzanis scoring system to test neurological responses. This included feeding behavior, body contraction, motor, and eye-opening responses. Brain sections were studied using transmission electron microscopy and Evans blue extravasation. Levels of Ang-1, Ang-2, and Tie-2 were determined by Western blot, while miR-221-5p was quantified using stem-loop real-time quantitative PCR (RT-qPCR). The SAH group responded worse to the neurological response test than the sham-operated group. The intercellular space was widened in the SAH group, but not in the sham-operated group. Evans blue dye leaked significantly more into brain tissue cells of the SAH group. Stem-loop qRT-PCR showed elevated miR-221-5p levels. Additionally, Ang-1 and Tie-2 were reduced but Ang-2 expression was increased after SAH. This led to a significant reduction of the Ang-1/Ang-2 ratio in the brain tissue, which was associated with the destruction of the blood-brain barrier. The data indicate that miR-221-5p might regulate blood-brain barrier dysfunction through the Ang-1/Ang-2/Tie-2 signaling axis, suggesting that it should be further investigated as a potential novel biomarker. [ABSTRACT FROM AUTHOR]

To investigate the effects of lenvatinib combined with transcatheter arterial chemoembolization (TACE) on tumor markers apoptotic molecules serum sialic acid transferase 1 (ST6Gal1) angiopoietin-2 (ANG-2) and hepatocyte growth factor(HGF) in patients with unresectable hepatocellular carcinoma. 114 patients with unresectable hepatocellular carcinoma who were admitted to Sichuan Mianyang 404 Hospital from March 2020 to December 2022 were divided into control group (n=57 TACE treatment) and study group (n=57 lenvatinib combine with TACE treatment) by random number table method. The efficacy tumor markers [alpha-fetoprotein (AFP) carbohydrate antigen 199 (CA199) carcinoembryonic antigen (CEA)] serum apoptotic molecules [B-celllymphoma-2-associated X protein (Bax) B-cell lymphoma-2 gene (Bcl-2) survivin (Survivin) cysteine aspartic protease-4 (Caspase-4)]and serum ST6Gal1 ANG-2 HGF levels were compared between two groups and the incidence of adverse reactions during treatment was observed. Compared with control group the total clinical effective rate in study group was higher (P<0. 05). Compared with control group the levels of AFP CA199 and CEA in study group were lower after treatment (P<0. 05). Compared with control group the levels of Bcl-2 and Survivin in study group were lower after treatment and the levels of Bax and Caspase-4 were higher (P<0. 05). Com-pared with control group the levels of ST6Gal1 ANG-2 and HGF in study group were lower after treatment (P<0. 05). There was no difference in the total incidence of adverse reactions between two groups (P>0. 05). Lenvatinib combined with TACE for patients with unresectable hepatocellular carcinoma which can improve the clinical treatment effect regulate the levels of tumor markers, apoptotic molecules and serum ST6Gal1 ANG-2 and HGF with good safety [ABSTRACT FROM AUTHOR]

Faricimab is a newly approved bispecific antibody for neovascular age-related macular degeneration (nAMD). Our study aims to evaluate clinical outcomes of faricimab switching in patients with treatment-refractory nAMD; determine parameters that predict these outcomes; and obtain patient subjective experience on this new injection. This is a retrospective case review with clinical and imaging data from a tertiary referral unit (Birmingham and Midland Eye Centre, UK), involving patients who were switched to faricimab between 1 January and 1 December 2023. In all, 63 eyes (54 patients) with a mean age of 79.2 ± 7.8 and mean of 41.5 ± 22.4 previous anti-VEGF injections were analysed. With a mean of 4.81 ± 1.16 faricimab injections over 6.98 ± 1.75 months, post-treatment visual acuity was logMAR 0.49 ± 0.36 and central macular thickness (CMT) was 320.3 ± 97.9 µm. After first dose, 39.1% achieved complete dryness and 89.1% had anatomical improvement. Presence of subretinal fluid was a predictor of better functional outcomes (p = 0.001, β = −0.182), while initial CMT predicted better anatomical outcomes (p = 0.001, β = 0.688). Compared to their experiences of previous anti-VEGF injections, 89% of patients reported no more discomfort and 87.0% experienced no more floaters, photopsia, or bubbles post-injection. Faricimab switching has anatomical efficacy but limited functional improvement in treatment-refractory AMD. Patient experiences of faricimab compared to previous injections were overall positive. [ABSTRACT FROM AUTHOR]

This study analyzes the dynamics of short-term treatment response to the first intravitreal faricimab injection in eyes with diabetic macular edema (DME). This retrospective, single-center, clinical trial was conducted at the Department of Ophthalmology, University Hospital Zurich. Patients with treatment-naïve and pretreated DME were included. Patient chart data and imaging were analyzed. Safety and efficacy (corrected visual acuity (CVA), central subfield thickness (CST), and signs of intraocular inflammation (IOI)) of the first faricimab intravitreal therapy (IVT) were evaluated weekly until 4 weeks after injection. Forty-three eyes (81% pretreated) of 31 patients were included. Four weeks after the first faricimab IVT, CVA remained stable and median CST (µm) decreased significantly (p < 0.001) from 325.0 (293.5–399.0) at baseline to 304.0 (286.5–358.0). CVA at week 4 was only associated with baseline CVA (p < 0.001). CST was the only predictive variable (p = 0.002) between baseline and week 4 CST. Weekly safety assessments did not show any sign of clinically significant IOI. This study suggests faricimab is an effective treatment for (pretreated) DME, showing structural benefit 1 month following the first injection without short-term safety signals.

Purpose: In ovarian cancer, there are two main routes of metastasis, namely intraperitoneal and retroperitoneal. Their biologic background is poorly understood. Identifying molecular markers involved might enable the development of tailored therapy regimens. Moreover, no reliable markers for response to anti-angiogenic treatment with bevacizumab are yet established. Angiopoietin-2 (Ang-2) is an angiogenic growth factor, involved in lymphatic activation and is associated with tumor progression. Here, we assessed the potential of Ang-2 as a molecular marker in metastasis and treatment of ovarian cancer. Methods: In our study, quantitative and qualitative protein Ang-2 expression in tumor tissue of ovarian cancer patients was analyzed by Western blot (n = 138) and immunohistochemistry (n = 58). Further, Ang-2 levels in blood samples were quantified in enzyme-linked immunosorbent assay (n = 38). Expression levels of different tumor spread patterns were evaluated, and survival analyses were made. Results: We observed that Ang-2 expression is significantly higher in tumors with retroperitoneal dissemination (pT1a–pT3b, pN1) compared to those showing intraperitoneal tumor growth (pT3c, pN0). In addition, patients with high Ang-2 expression have significantly longer overall survival compared to patients with low Ang-2 expression. Patients with high Ang-2 expression benefit significantly from therapy with bevacizumab. Conclusion: All in all, Ang-2 may serve as a molecular marker for patients with tumors prone to spread to lymph nodes and for patients who might benefit from bevacizumab therapy. [ABSTRACT FROM AUTHOR]

Postembryonic angiogenesis is mainly induced by various proangiogenic factors derived from the original vascular network. Previous studies have shown that the role of Ang‐2 in angiogenesis is controversial. Tip cells play a vanguard role in angiogenesis and exhibit a transdifferentiated phenotype under the action of angiogenic factors. However, whether Ang‐2 promotes the transformation of endothelial cells to tip cells remains unknown. Our study found that miR‐221‐3p was highly expressed in HCMECs cultured for 4 h under hypoxic conditions (1% O2). Moreover, miR‐221‐3p overexpression inhibited HCMECs proliferation and tube formation, which may play an important role in hypoxia‐induced angiogenesis. By target gene prediction, we further demonstrated that Ang‐2 was a downstream target of miR‐221‐3p and miR‐221‐3p overexpression inhibited Ang‐2 expression in HCMECs under hypoxic conditions. Subsequently, qRT‐PCR and western blotting methods were performed to analyse the role of miR‐221‐3p and Ang‐2 on the regulation of tip cell marker genes. MiR‐221‐3p overexpression inhibited CD34, IGF1R, IGF‐2 and VEGFR2 proteins expression while Ang‐2 overexpression induced CD34, IGF1R, IGF‐2 and VEGFR2 expression in HCMECs under hypoxic conditions. In addition, we further confirmed that Ang‐2 played a dominant role in miR‐221‐3p inhibitors promoting the transformation of HCMECs to tip cells by using Ang‐2 shRNA to interfere with miR‐221‐3p inhibitor‐treated HCMECs under hypoxic conditions. Finally, we found that miR‐221‐3p expression was significantly elevated in both serum and myocardial tissue of AMI rats. Hence, our data showed that miR‐221‐3p may inhibit angiogenesis after acute myocardial infarction by targeting Ang‐2 to inhibit the transformation of HCMECs to tip cells. [ABSTRACT FROM AUTHOR]

High levels of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-2 and angiopoietin (ANG)-2 are found in tissues from oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs). As might be expected, VEGF, FGF-2, and ANG-2 overexpression parallels the development of new blood and lymphatic vessels that nourish the growing OPMDs or OSCCs and provide the latter with metastatic routes. Notably, VEGF, FGF-2, and ANG-2 are also linked to the epithelial-to-mesenchymal transition (EMT), a trans-differentiation process that respectively promotes or exasperates the invasiveness of normal and neoplastic oral epithelial cells. Here, we have summarized published work regarding the impact that the interplay among VEGF, FGF-2, ANG-2, vessel generation, and EMT has on oral carcinogenesis. Results from the reviewed studies indicate that VEGF, FGF-2, and ANG-2 spark either protein kinase B (AKT) or mitogen-activated protein kinases (MAPK), two signaling pathways that can promote both EMT and new vessels’ formation in OPMDs and OSCCs. Since EMT and vessel generation are key to the onset and progression of OSCC, as well as to its radio- and chemo-resistance, these data encourage including AKT or MAPK inhibitors and/or antiangiogenic drugs in the treatment of this malignancy.

PurposeTo describe the early experiences of patients with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) whose treatment was switched to faricimab from other anti-vascular endothelial growth factor (VEGF) agents.MethodsThis is a prospective cohort of eyes with nAMD and PCV that were previously treated with anti-VEGF agents other than faricimab. We evaluated visual acuity (VA), central subfield thickness (CST), macular volume (MV), pigment epithelial detachment (PED) height, and choroidal thickness (CT) after one administration of faricimab. Where present, fluid was further evaluated according to intraretinal fluid (IRF), subretinal fluid (SRF), or within PED.ResultsSeventy-one eyes from 71 patients were included (45.07% PCV and 54.93% typical nAMD). The mean [standard deviation (± SD)] VA, CST, and MV improved from 0.50 logMAR (± 0.27 logMAR) to 0.46 logMAR (± 0.27 logMAR) (p = 0.20), 383.35 µm (± 111.24 µm) to 322.46 µm (± 103.89 µm (p < 0.01), and 9.40 mm3 (± 1.52 mm3) to 8.75 mm3 (± 1.17 mm3) (p < 0.01) from switch to post switch visit, respectively. The CT reduced from 167 µm (± 151 µm) to 149 µm (± 113 µm) (p < 0.01). There was also a significant reduction in the maximum PED height between visits [302.66 µm (± 217.97 µm)] and the post switch visit [236.66 µm (± 189.05 µm); p < 0.01]. This difference was greater in PEDs that were predominantly serous in nature. In the eyes with typical nAMD (n = 39), improvements were significant for CST, MV, CT, and PED. In the eyes with PCV (n = 32), only reductions in CT were statistically significant, while VA, CST, MV, and PED only showed numerically smaller improvements. One patient developed mild vitritis without vasculitis, which resolved with topical steroids with no sequelae.ConclusionsIn our case series of Asian nAMD patients, switching to faricimab was associated with a stable VA and meaningful anatomical improvements, particularly with typical nAMD subtypes.

Simple Summary: In modern, highly industrialized countries, endometrial cancer is the most common gynecological cancer. Endometrial cancer risk has been found to be influenced by a number of variables. The pathogenesis of endometrial cancer is heavily influenced by fatty food consumption in excess, a lack of physical activity and the subsequent development of obesity or diabetes. The first symptoms of endometrial cancer may be unusual vaginal bleeding or pelvic discomfort, but they are also typical of many other diseases. It is important to search for new biomarkers that could help detect endometrial cancer, even if it shows symptoms in its early stages. PDGF-AB, PDGF-BB, TGF-α, EGF and ANG-2 are growth factor proteins. We investigated whether growth factor proteins can be clinically useful diagnostic markers in endometrial cancer. The study's objective was to identify the clinical relevance of the proteins under investigation. We made a comparison between the serum protein concentrations of people with endometrial cancer and those with non-cancerous endometrial lesions. (1) Background: It is relevant to find new diagnostic biomarkers for endometrial cancer. This study aimed to investigate whether PDGF-AB, PDGF-BB, TGF-α, EGF and ANG-2 could be considered new useful markers for diagnosis and survival of endometrial cancer. (2) Methods: A total of 93 women diagnosed with endometrial cancer (EC) and 66 patients with non-cancerous endometrial lesions (NCEL) were included in this study. (3) Results: Median serum levels of PDGF-AB, PDGF-BB, TGF-α, EGF and ANG-2 were significantly higher in the EC group compared to the NCEL group (for PDGF-AB, PDGF-BB, TGF-α and ANG-2, p = 0.0000; for EGF, p = 0.0186). The cut-off level of PDGF-AB was set at 127.69 pg/mL with a sensitivity of 87.1% and a specificity of 66.67% (AUC = 0.78, p < 0.000001). The cut-off level of PDGF-BB was set at 207.86 ng/L with a sensitivity of 82.8% and a specificity of 75.76% (AUC = 0.85, p < 0.000001). The cut-off level of TGF-α was set at 33.85 ng/L with a sensitivity of 82.8% and a specificity of 75.76% (AUC = 0.82, p < 0.000001). The cut-off level of EGF was set at 934.76 pg/mL with a sensitivity of 83.87% and a specificity of 28.79% (AUC = 0.61, p = 0.018472). The cut-off level of ANG-2 was set at 3120.68 pg/mL with a sensitivity of 72.04% and a specificity of 93.94% (AUC = 0.87, p < 0.000001). (4) Conlusion: It was concluded that all the proteins studied could be potential diagnostic markers in endometrial cancer. [ABSTRACT FROM AUTHOR]

Background: To evaluate the outcomes of intravitreal faricimab (IVF) for refractory neovascular age-related macular degeneration (nAMD) and investigate the impact of baseline optical coherence tomography, biomarkers for total IVF injections are needed. Methods: A retrospective analysis of 33 eyes of patients who completed one year (52 W) of treatment with IVF. The eyes received four IVF injections (6 mg/0.05 mL) as the upload phase. Thereafter, the treatment interval was extended to 8 or 12 weeks if disease activity was not recorded. The outcome measures included best-corrected visual acuity (BCVA), central macular thickness (CMT), subfoveal choroidal thickness (SFCT), and retinal fluid distribution. Results: A total of 33 eyes were included. CMT decreased significantly at 52 W (p < 0.01). BCVA and SFCT did not change significantly at 52 W (p > 0.05). The number of eyes with subretinal fluid decreased significantly at 52 W (p < 0.01). Complete fluid resolution was achieved in 20 eyes (60%). The total number of injections was significantly negatively correlated with the presence of hyperreflective dots at baseline (HRDs, p < 0.01) and SFCT at baseline (p < 0.01). Conclusions: IVF led to a significant reduction in CMT with stabilization of BCVA. The total number of injections was lower in eyes with HRDs and increased SFCT at baseline. This might provide clues regarding response to IVF for future studies.

Pathological angiogenesis of liver sinusoidal endothelial cells (LSEC) plays a crucial role in the progression of metabolic dysfunction-associated steatohepatitis (MASH)-induced liver fibrosis. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have shown promising therapeutic potential against MASH. This study aimed to investigate the impact of MSC-sEV on LSEC angiogenesis and elucidate the underlying molecular mechanisms. The effects of MSC-sEV on LSEC angiogenesis were evaluated in Tumor Necrosis Factor- alpha (TNF-α)-treated LSECs in vitro and in Methionine and Choline Deficient Diet (MCD)-induced MASH mice in vivo. Herein, we found that MSC-sEV effectively suppressed LSEC angiogenesis by targeting the angiogenesis marker Angiogenin 2 (Ang-2) in both TNF-α-treated LSECs and MASH mice. Gene manipulation experiments revealed that the primary mechanism by which MSC-sEV inhibited LSEC angiogenesis was through the modulation of nuclear factor kappa B inhibitor alpha (IκBα) / nuclear factor kappa B (NF-κB) / Ang-2 pathway. Additionally, mass spectrometry and co-immunoprecipitation (Co-IP) data suggested that MSC-sEV delivered the ubiquitin specific peptidase 9 X-linked (USP9X) protein to LSECs, leading to enhanced IκBα deubiquitination and NF-κB in activation, ultimately resulting in the inhibition of Ang-2-mediated LSEC angiogenesis. Knockdown of USP9X attenuated the regulatory effects of MSC-sEV on Ang-2 expression, LSEC angiogenesis, and the progression of MASH. In conclusion, our findings indicate that USP9X delivered via MSC-sEV can suppress LSEC angiogenesis and alleviate MASH-induced liver fibrosis through the IκBα/NF-κB/Ang-2 signaling pathway. [Display omitted] • MSC-sEV suppresses LSEC angiogenesis and alleviates MASH in mice. • MSC-sEV-transferred USP9X is responsible for reducing LSEC angiogenesis. • USP9X inhibits LSEC angiogenesis via IκBα/NF-κB/Ang-2 pathway. [ABSTRACT FROM AUTHOR]

Faricimab is a newly approved bispecific antibody for neovascular age-related macular degeneration (nAMD). Our study aims to evaluate clinical outcomes of faricimab switching in patients with treatment-refractory nAMD; determine parameters that predict these outcomes; and obtain patient subjective experience on this new injection. This is a retrospective case review with clinical and imaging data from a tertiary referral unit (Birmingham and Midland Eye Centre, UK), involving patients who were switched to faricimab between 1 January and 1 December 2023. In all, 63 eyes (54 patients) with a mean age of 79.2 ± 7.8 and mean of 41.5 ± 22.4 previous anti-VEGF injections were analysed. With a mean of 4.81 ± 1.16 faricimab injections over 6.98 ± 1.75 months, post-treatment visual acuity was logMAR 0.49 ± 0.36 and central macular thickness (CMT) was 320.3 ± 97.9 µm. After first dose, 39.1% achieved complete dryness and 89.1% had anatomical improvement. Presence of subretinal fluid was a predictor of better functional outcomes (p = 0.001, β = −0.182), while initial CMT predicted better anatomical outcomes (p = 0.001, β = 0.688). Compared to their experiences of previous anti-VEGF injections, 89% of patients reported no more discomfort and 87.0% experienced no more floaters, photopsia, or bubbles post-injection. Faricimab switching has anatomical efficacy but limited functional improvement in treatment-refractory AMD. Patient experiences of faricimab compared to previous injections were overall positive.

Moyamoya arteriopathy (MMA) is a rare cerebrovascular disorder that causes recurrent ischemic and hemorrhagic strokes, leading young patients to severe neurological deficits. The pathogenesis of MMA is still unknown. The disease onset in a wide number of pediatric cases raises the question of the role of genetic factors in the disease's pathogenesis. In these patients, MMA's clinical course, or progression, is largely unclear. By performing a comprehensive molecular and cellular profile in the plasma and CSF, respectively, of MMA pediatric patients, our study is aimed at assessing the levels of circulating endothelial progenitor cells (cEPC) and the release of selected proteins at an early disease stage to clarify MMA pathogenesis and progression. We employed cytofluorimetric methods and immunoassays in pediatric MMA patients and matched control subjects by age and sex. We detected increased levels of cEPC in peripheral blood and an upregulation of angiogenic markers in CSF (i.e., angiopoietin-2 and VEGF-A). This finding is probably associated with deregulated angiogenesis, as stated by the moderate severity of collateral vessel network development (Suzuki III-IV). The absence of significant modulation of neurofilament light in CSF led us to rule out the presence of substantial neuronal injury in MMA children. Despite the limited cohort of pediatric patients, we found some peculiar cellular and molecular characteristics in their blood and CSF samples. Our findings may be confirmed by wider and perspective studies to identify predictive or prognostic circulating biomarkers and potential therapeutic targets for personalized care of MMA pediatric patients. [ABSTRACT FROM AUTHOR]

Angiopoietin-2 (Ang-2) has been implicated in the development of several types of cancer, including lung malignancy. In the present study, we examined the impact of Ang-2 serum concentration on the development, dissemination, and 5-year overall survival of NSCLC and SCLC. A total of 99 patients with lung cancer were tested. The OS of NSCLC and SCLC patients was estimated using Kaplan–Meier curves and compared through log-rank test. The median serum level of Ang-2 at baseline in both NSCLC and SCLC patients was significantly higher than that of controls (p < 0.0001). The Ang-2 serum concentration was not related to metastasis, neither in NSCLC nor in SCLC cases. The OS was found to be significantly shorter for stage IIIβ NSCLC patients with a high baseline Ang-2 serum concentration (p = 0.012), while Cox regression analysis showed that Ang-2 is a significant independent factor for poor prognosis for stage IIIβ NSCLC (hazard ratio = 2.97, 95% CI: 1.05–8.40, p = 0.04). The concentration of Ang-2 has no impact on the prognosis of SCLC. Ang-2 could be considered as a significant molecular marker that enables the prediction of NSCLC and SCLC development, and is involved in the poor prognosis of stage IIIβ NSCLC. [ABSTRACT FROM AUTHOR]

Growth factors play a significant role in the immunopathogenesis of liver diseases, especially in liver fibrosis and cirrhosis. They can also play a role in liver regeneration and tissue repair. The regenerative capacity of the liver has been well established. Molecular mechanisms leading to regeneration involve a complex network of diverse molecules. Chronic liver injury leads to the dysregulation of regenerative mechanisms in the liver that, in addition to molecular oncogenesis, lead to uncontrolled cell proliferation and development of hepatocellular carcinoma (HCC). Stem cell factor (SCF), epidermal growth factor (EGF) and Angiopietin-2 (Ang-2) have been shown to be extremely important in the pathogenesis of liver diseases, and given their role in hepatitis B (HBV) or C virus (HCV), HCC and nonalcoholic fatty liver disease (NAFLD), they seem to be potential targets for future research into antifibrotic drugs. The role of SCF receptor c-kit in the liver is debatable, as it has impact on both liver regeneration and liver disease. EGF is a potential indicator of the survival of patients with HCC and can be a biomarker and therapeutic target structure in HCC. Further research is needed to investigate the potential role of Ang-2 for NAFLD associated with liver damage as a non-invasive circulating biomarker. [ABSTRACT FROM AUTHOR]

Abstract Background Forkhead box C2 (FOXC2) is a crucial factor involving in various cancers. However, its functions in hepatocellular carcinoma (HCC) is unknown. Here, we explored the role of FOXC2 in the progression of HCC and its potential mechanisms. Methods FOXC2 expression in HCC tissue and cells were detected by immunohistochemistry or western blot and real-time PCR. CCK8, wound healing and transwell assay were used to measure cell growth and invasion. Tumor formation experiment was carried out to assess the tumorigenicity of HCC cells. Regulation of FOXC2 on Ang-2 was validated by luciferase assay and complementary experiments. Results Increased FOXC2 expression was found to be associated positively with more aggressive clinicopathologic features. HCC patients with higher FOXC2 expression had significantly shorter overall survival. FOXC2 expression was indentified as an independent risk factor for resectable HCC. Increased FOXC2 expression accelerated the migration and invasion of HCC cells, accompanied by enhanced Ang-2 expression. Likewise, FOXC2 knockdown yielded opposite results. Moreover, FOXC2 stimulated the activation of the Ang-2 promoter. Suppression of Ang-2 expression hindered the FOXC2-mediated EMT processs, cell migration and invasion of HCC. Conclusions FOXC2 is a novel prognostic predictor for HCC and may facilitate the growth and invasion through Ang-2.

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

Angiogenesis is a biological process that involves the formation of new blood vessels from the existing vasculature, and it plays a fundamental role in the development and progression of several types of cancer, including lung cancer. The angiopoietin/Tie2 ligand/receptor system orchestrates vascular integrity. In particular, Angiopoietin-1 activates the endothelial cell (EC)-specific receptor tyrosine kinase, Tie2, which is essential for preserving endothelial quiescence. On the other hand, Angiopoietin-2 acts as an inhibitor of the Angiopoietin-1/Tie2 signaling pathways, thus facilitating the destabilization of quiescent endothelium in cases of inflammation and cancer. Clinical studies have proven that high levels of Angiopoietin-2 indicate the development of non-small-cell lung carcinomas (NSCLC), while high levels of Angiopoietin-2 are strongly related to tumor angiogenesis, lymphangiogenesis, metastasis, and poor prognosis. Interestingly, the association of Angiopoietin-2 levels with the type of surgical approach makes Angiopoietin-2 a valuable factor in selecting the most suitable therapeutic strategy for lung cancer patients. The role of the Angiopoietin-1 and Angiopoietin-4 levels in NSCLC development requires further investigation. The present review focuses on the clinical impact of the Angiopoietin-1, Angiopoietin-2, and Angiopoietin-4 levels in patients diagnosed with NSCLC, emphasizing the interaction between them, and how they affect the development, progression, and metastasis of lung disease. Finally, it estimates the role of angiopoietins levels in the effective therapy of lung cancer patients. [ABSTRACT FROM AUTHOR]

Growth factors play a significant role in the immunopathogenesis of liver diseases, especially in liver fibrosis and cirrhosis. They can also play a role in liver regeneration and tissue repair. The regenerative capacity of the liver has been well established. Molecular mechanisms leading to regeneration involve a complex network of diverse molecules. Chronic liver injury leads to the dysregulation of regenerative mechanisms in the liver that, in addition to molecular oncogenesis, lead to uncontrolled cell proliferation and development of hepatocellular carcinoma (HCC). Stem cell factor (SCF), epidermal growth factor (EGF) and Angiopietin-2 (Ang-2) have been shown to be extremely important in the pathogenesis of liver diseases, and given their role in hepatitis B (HBV) or C virus (HCV), HCC and nonalcoholic fatty liver disease (NAFLD), they seem to be potential targets for future research into antifibrotic drugs. The role of SCF receptor c-kit in the liver is debatable, as it has impact on both liver regeneration and liver disease. EGF is a potential indicator of the survival of patients with HCC and can be a biomarker and therapeutic target structure in HCC. Further research is needed to investigate the potential role of Ang-2 for NAFLD associated with liver damage as a non-invasive circulating biomarker.

Angiopoietin-2 (Ang-2) has been implicated in the development of several types of cancer, including lung malignancy. In the present study, we examined the impact of Ang-2 serum concentration on the development, dissemination, and 5-year overall survival of NSCLC and SCLC. A total of 99 patients with lung cancer were tested. The OS of NSCLC and SCLC patients was estimated using Kaplan–Meier curves and compared through log-rank test. The median serum level of Ang-2 at baseline in both NSCLC and SCLC patients was significantly higher than that of controls (p < 0.0001). The Ang-2 serum concentration was not related to metastasis, neither in NSCLC nor in SCLC cases. The OS was found to be significantly shorter for stage IIIβ NSCLC patients with a high baseline Ang-2 serum concentration (p = 0.012), while Cox regression analysis showed that Ang-2 is a significant independent factor for poor prognosis for stage IIIβ NSCLC (hazard ratio = 2.97, 95% CI: 1.05–8.40, p = 0.04). The concentration of Ang-2 has no impact on the prognosis of SCLC. Ang-2 could be considered as a significant molecular marker that enables the prediction of NSCLC and SCLC development, and is involved in the poor prognosis of stage IIIβ NSCLC.

Abstract Background Malaria-associated acute respiratory distress syndrome (MA-ARDS) is an understudied complication of malaria and is characterized by pulmonary inflammation and disruption of the alveolar-capillary membrane. Its pathogenesis remains poorly understood. Since endothelial activation plays an important role in other malarial complications, the expression of two endothelial activation markers, von Willebrand factor (VWF) and angiopoietin-2 (ANG-2), was investigated in the lungs of patients with MA-ARDS. Methods Post-mortem lung sections of Plasmodium falciparum-infected patients without alveolar oedema (NA), P. falciparum-infected patients with alveolar oedema (MA-ARDS), and uninfected people who died accidentally with no pathological changes to the lungs (CON) were immunohistochemically stained for VWF and ANG-2, and were evaluated with semi-quantitative analysis. Results Alveolar oedematous VWF and ANG-2 and intravascular VWF staining were significantly increased in patients with MA-ARDS versus infected and uninfected control groups. The levels of VWF in the alveolar septa and endothelial lining of large blood vessels of patients with MA-ARDS was significantly decreased compared to controls. ANG-2 expression was increased in the alveolar septa of malaria patients without alveolar oedema versus control patients, while ANG-2+ leukocytes were increased in the alveoli in both infected patient groups. Conclusions This study documents a high level of VWF and ANG-2, two endothelial activation markers in the oedematous alveoli of post-mortem lung sections of Thai patients with MA-ARDS. Decreased detection of VWF in the endothelial lining of blood vessels, in parallel with an increased presence of intravascular VWF staining suggests marked endothelial activation and Weibel–Palade body release in the lungs of patients with MA-ARDS.

BACKGROUND: Altered cadherin expression plays a vital role in tumorigenesis, angiogenesis and tumor progression. However, the function of protocadherin 17 (PCDH17) in breast cancer remains unclear. OBJECTIVE: Our target is to explore PCDH17 gene expression in breast carcinoma tissues and its relation to serum angiopoietin-2 (Ang-2), carbonic anhydrase IX (CAIX) and % of circulating CD34 + cells in breast cancer patients (BCPs). METHODS: This study included Fifty female BCPs and 50 healthy females as control group. Cancerous and neighboring normal breast tissues were collected from BCPs as well as blood samples at diagnosis. PCDH17 gene expression was evaluated by RT-PCR. Serum Ang-2, CAIX levels were measured by ELISA and % CD34 + cells were assessed by flow cytometry. RESULTS: PCDH17 was downregulated in cancerous breast tissues and its repression was significantly correlated with advanced stage and larger tumor size. Low PCDH17 was significantly correlated with serum Ang-2, % CD34 + cells and serum CAIX levels. Serum CAIX, Ang-2 and % CD34 + cells levels were highly elevated in BCPs and significantly correlated with clinical stage. CONCLUSIONS: PCDH17 downregulation correlated significantly with increased angiogenic and hypoxia biomarkers. These results explore the role of PCDH17 as a tumor suppressor gene inhibiting tumor growth and proliferation. [ABSTRACT FROM AUTHOR]

Hyperglycemia in pregnancy (HIP) occurs in up to 8–17% of pregnancies. Unfavorable impact of the pregnancy induced hyperglycemia on both maternal and fetal tissues is associated with adverse pregnancy outcomes. Vascular growth factors, especially in the early phase of gestation, are considered as one of the most significant molecules that regulate pregnancy course and their serum expression may be altered in patients affected with HIP. Fifty-five consecutive pregnant patients who underwent elective cesarean section were incorporated into this study. During the surgery, maternal and cord blood samples were collected. Serum expression levels of vascular growth factors: PlGF, VEGF, THBS-2 and Ang-2 were compared among non-HIP and pregnancies affected by gestational diabetes. Subsequently, laboratory results were correlated with obstetric outcomes. There were no statistical differences in maternal characteristics, neonatal outcomes and maternal or neonatal serum levels between study and control groups. However, our results revealed significant differences between fetal and maternal levels of VEGF (p =.028 and.0001), THBS-2 (p =.013 and.0014) and Ang-2 (p =.035 and.048) for HIP and non-HIP group, respectively. Similar serum expressions of vascular growth factors in and non-HIP and HIP pregnancies point that normal glycemia due to thorough prenatal surveillance may result in normal angio- and vasculogenesis associated with good pregnancy outcomes. [ABSTRACT FROM AUTHOR]

The underlying mechanisms of human umbilical cord mesenchymal stem cells (hucMSCs) and their exosomes (hucMSC-Exs), which play significant roles in skin wound healing, remain poorly understood. By using a rat model of deep second-degree burn injury, the roles of hucMSC-Exs in angiogenesis and cutaneous wound healing in vivo were investigated. We found that hucMSC-Exs accelerated skin wound healing and angiogenesis, inducing a higher wound-closure rate and increased expression of CD31 in vivo. We also discovered that hucMSC-Exs contained angiopoietin-2 (Ang-2), and treatment with hucMSC-Exs enhanced the expression of the Ang-2 protein in the wound area and human umbilical vein endothelial cells (HUVECs) through exosomal-mediated Ang-2 transfer. Moreover, hucMSC-Exs promoted the proliferative, migratory, and tube-forming ability of HUVECs. Furthermore, overexpression of Ang-2 in hucMSC-Exs further enhanced HUVEC migration and tube formation and exerted therapeutic and proangiogenic effects in cutaneous wounds in rats, whereas knockdown of Ang-2 in hucMSC-Exs abrogated these therapeutic and proangiogenic effects. Taken together, our results indicated that hucMSC-Ex-derived Ang-2 plays a significant role in tube formation of HUVECs and promotion of angiogenesis, and further suggested that hucMSC-Ex-based therapy may serve as a promising therapeutic approach for promoting cutaneous wound healing. [ABSTRACT FROM AUTHOR]

Brain metastases (BM) are an ever-increasing challenge in oncology, threatening quality of life and survival of many cancer patients. The majority of BM originate from lung adenocarcinoma, and stage III patients have a risk of 40–50% to develop BM in the first years of disease onset. As therapeutic options are limited, prevention of their occurrence is an attractive concept. Here we investigated whether Nintedanib (BIBF 1120), a tyrosine kinase inhibitor (TKI) targeting the VEGF pathway approved for lung adenocarcinoma, and the dual anti-VEGF-A/Ang2 nanobody BI836880 have the potential to prevent BM formation. A mouse model of brain metastasis from lung adenocarcinoma was used in which tumor cells were injected intracardially. Metastases formation occurred inside and outside of the brain and was followed by MRI, IVIS, and immunohistochemistry. BM were reduced in volume and number by both Nintedanib and the dual anti-VEGF-A/Ang2 nanobody, which translated into improved survival. Both compounds were able to normalize cerebral blood vessels at the site of brain metastatic lesions. Extracranial metastases, however, were not reduced, and meningeal metastases only partially. Interestingly, unspecific control IgG also lead to brain vessel normalization and reduction of brain and meningeal metastases. This data indicates a brain-specific group effect of antiangiogenic compounds with respect to metastasis prevention, most likely by preventing an early angiogenic switch. Thus, Nintedanib and BI836880 are promising candidates for future BM preventive study concepts in lung adenocarcinoma patients. [ABSTRACT FROM AUTHOR]

Background: Forkhead box C2 (FOXC2) is a crucial factor involving in various cancers. However, its functions in hepatocellular carcinoma (HCC) is unknown. Here, we explored the role of FOXC2 in the progression of HCC and its potential mechanisms. Methods: FOXC2 expression in HCC tissue and cells were detected by immunohistochemistry or western blot and real-time PCR. CCK8, wound healing and transwell assay were used to measure cell growth and invasion. Tumor formation experiment was carried out to assess the tumorigenicity of HCC cells. Regulation of FOXC2 on Ang-2 was validated by luciferase assay and complementary experiments. Results: Increased FOXC2 expression was found to be associated positively with more aggressive clinicopathologic features. HCC patients with higher FOXC2 expression had significantly shorter overall survival. FOXC2 expression was indentified as an independent risk factor for resectable HCC. Increased FOXC2 expression accelerated the migration and invasion of HCC cells, accompanied by enhanced Ang-2 expression. Likewise, FOXC2 knockdown yielded opposite results. Moreover, FOXC2 stimulated the activation of the Ang-2 promoter. Suppression of Ang-2 expression hindered the FOXC2-mediated EMT processs, cell migration and invasion of HCC. Conclusions: FOXC2 is a novel prognostic predictor for HCC and may facilitate the growth and invasion through Ang-2. [ABSTRACT FROM AUTHOR]

Objective: Determine the effect of bradykinin on solute permeability and cellular junctional proteins in human dermis microvascular endothelial cells. Methods: Cells were characterized by immunofluorescence and fluorescence‐activated cell sorting. Macromolecular transport of dextran and albumin was monitored. Junctional protein expression and phosphorylation were determined by immunoblot analyses. Intracellular calcium and cAMP levels were evaluated. Target gene expression at mRNA and protein levels was determined. Results: Human dermis microvascular endothelial cells comprised 97% lymphatic endothelial cells. Bradykinin increased the permeability to dextran in a concentration‐dependent manner, while reduced the permeability to albumin. Bradykinin treatment down‐regulated VE‐cadherin expression and affected its phosphorylation status at Tyr731. It also down‐regulated claudin‐5 expression at the transcriptional level through bradykinin‐2‐receptor signaling. An increase in the intracellular calcium levels and a reduction in the cAMP concentration were associated effects. Finally, bradykinin induced the up‐regulation of vascular endothelial growth factor‐C protein which was found increased in BK‐induced human dermis microvascular endothelial cells culture supernates. Conclusions: Human dermis microvascular endothelial cells represent a model of lymphatic endothelial cells, in which bradykinin‐2‐receptor is expressed. Bradykinin‐induced bradykinin‐2‐receptor signaling through intracellular calcium mobilization and reduction in cAMP levels, triggered changes in solute permeability and cellular junction expression. It further up‐regulated vascular endothelial growth factors‐C protein expression, which is a key modulator of lymphatic vessels function and lymphangiogenesis. [ABSTRACT FROM AUTHOR]

Angiogenesis is a biological process that involves the formation of new blood vessels from the existing vasculature, and it plays a fundamental role in the development and progression of several types of cancer, including lung cancer. The angiopoietin/Tie2 ligand/receptor system orchestrates vascular integrity. In particular, Angiopoietin-1 activates the endothelial cell (EC)-specific receptor tyrosine kinase,Tie2,which is essential for preserving endothelial quiescence. On the other hand, Angiopoietin-2 acts as an inhibitor of the Angiopoietin-1/Tie2 signaling pathways, thus facilitating the destabilization of quiescent endothelium in cases of inflammation and cancer. Clinical studies have proven that high levels of Angiopoietin-2 indicate the development of non-small-cell lung carcinomas (NSCLC), while high levels of Angiopoietin-2 are strongly related to tumor angiogenesis, lymphangiogenesis, metastasis, and poor prognosis. Interestingly, the association of Angiopoietin-2 levels with the type of surgical approach makes Angiopoietin-2 a valuable factor in selecting the most suitable therapeutic strategy for lung cancer patients. The role of the Angiopoietin-1 and Angiopoietin-4 levels in NSCLC development requires further investigation. The present review focuses on the clinical impact of the Angiopoietin-1, Angiopoietin-2, and Angiopoietin-4 levels in patients diagnosed with NSCLC, emphasizing the interaction between them, and how they affect the development, progression, and metastasis of lung disease. Finally, it estimates the role of angiopoietins levels in the effective therapy of lung cancer patients.

Non-alcoholic fatty liver disease is the most common liver disorder worldwide, and its progressive form non-alcoholic steatohepatitis (NASH) is a growing cause of liver cirrhosis and hepatocellular carcinoma (HCC). Lifestyle changes, which are capable of improving the prognosis, are hard to achieve, whereas a pharmacologic therapy able to combine efficacy and safety is still lacking. Looking at the pathophysiology of various liver diseases, such as NASH, fibrosis, cirrhosis, and HCC, the process of angiogenesis is a key mechanism influencing the disease progression. The relationship between the worsening of chronic liver disease and angiogenesis may suggest a possible use of drugs with antiangiogenic activity as a tool to stop or slow the progression of the disorder. In this review, we highlight the available preclinical data supporting a role of known antiangiogenic drugs (e.g., sorafenib), or phytotherapeutic compounds with multiple mechanism of actions, including also antiangiogenic activities (e.g., berberine), in the treatment of NASH.

Introduction: Faricimab is a bispecific antibody that acts to reduce neoangiogenesis in exudative retinal vascular disorders. It is approved for use in neovascular age-related macular degeneration and diabetic macular edema. We review the published efficacy and safety of faricimab in clinical settings., Areas Covered: A comprehensive literature review was conducted. Based on the 14 published real-world studies, 1127 patients (1204 eyes) were treated with faricimab. The majority of studies (14) included pre-treated patients. Most studies (13) showed central macular thickness improvement. However visual acuity improved in only half of the studies analyzed. Four studies demonstrated an extension of the treatment. Only 4 eyes (0.33%) reported intraocular inflammation and 3 eyes (0.24%) reported retinal pigment epithelial tear., Expert Opinion: The clinical experience with faricimab to date has the potential to provide a stable visual outcome with reduced treatment burden in cases that are resistant to other approved anti-VEGF agents. There are no major safety concerns based on this data analysis.

Introduction: Hyperglycemia in pregnancy (HIP) occurs in up to 8-17% of pregnancies. Unfavorable impact of the pregnancy induced hyperglycemia on both maternal and fetal tissues is associated with adverse pregnancy outcomes. Vascular growth factors, especially in the early phase of gestation, are considered as one of the most significant molecules that regulate pregnancy course and their serum expression may be altered in patients affected with HIP.Material and Methods: Fifty-five consecutive pregnant patients who underwent elective cesarean section were incorporated into this study. During the surgery, maternal and cord blood samples were collected. Serum expression levels of vascular growth factors: PlGF, VEGF, THBS-2 and Ang-2 were compared among non-HIP and pregnancies affected by gestational diabetes. Subsequently, laboratory results were correlated with obstetric outcomes.Results: There were no statistical differences in maternal characteristics, neonatal outcomes and maternal or neonatal serum levels between study and control groups. However, our results revealed significant differences between fetal and maternal levels of VEGF (p = .028 and .0001), THBS-2 (p = .013 and .0014) and Ang-2 (p = .035 and .048) for HIP and non-HIP group, respectively.Conclusions: Similar serum expressions of vascular growth factors in and non-HIP and HIP pregnancies point that normal glycemia due to thorough prenatal surveillance may result in normal angio- and vasculogenesis associated with good pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Objective To explore the changes in serum angiopoietin 2 (Ang-2), Krebs von den lungen 6 (KL- 6), surfactant protein D (SP-D), von Willebrand factor (vWF) and lnterleukin-8 (IL-8) in peripheral blood of patients with acute respiratory distress syndrome (ARDS) and evaluate their clinical value in diagnosis and mortality predication of ARDS. Methods In this prospective study, 49 ARDS patients and 50 non-ARDS were enrolled in two intensive care units (ICUs). Blood samples collected from the participants at admission to ICU (T1) and the time-point when diagnosed for ARDS (T2 ) were tested for the five serum biomarkers by enzyme-linked immunosorbent assay. Receiver operating characteristic curve (ROC) was used to evaluate the performance of the biomarkers in ARDS diagnosis and mortality prediction. Results The levels of all the five serum biomarkers were elevated in ARDS patients compared with non-ARDS ones (P<0.05). At T2 time-point the serum concentrations of the five biomarkers in ARDS patients were significantly higher than those at T1 time-point (P<0.05). The dead patients (n=17) in ARDS group had higher levels of Ang-2, KL-6, SP-D and IL-8 than the survivors (n=32) (P< 0.05). With regard to the diagnosis of ARDS, at T1 time-point the largest areas under the receiver operating characteristic curve (AUCs) for single biomarker and combination were 0.816 [95% confidence interval (CI): 0.730, 0.902] (KL-6) and 0.869 (95% CI: 0.795, 0.942) (KL-6+Ang-2), respectively. The best predictive AUCs [ABSTRACT FROM AUTHOR]

Angiopoietin-2 (Ang-2) has been reported to be involved in the development of type 2 diabetes (T2D) and accelerates micro and macro vascular complication. The current study aimed to investigate serum Ang-2 levels in Saudi patients with type 2 diabetes and its complications. In this observational cross-sectional study, serum was collected from 329 T2D subjects aged 34–79 years. All subjects were evaluated for fasting blood glucose (FBG), HbA1c, lipid profile, and kidney profile. Serum concentration of Ang-2 was assayed by ELISA-based method. Mean serum Ang-2 level was significantly higher in female T2D subjects (2881 ± 1550 pg/ml) compared with male T2D subjects (2450 ± 1477 pg/ml). The mean serum Ang-2 levels in female T2D subjects significantly increased with increase in their age and BMI, while mean serum Ang-2 levels did not significantly increase among the male with their age and BMI. A significantly higher level of Ang-2 was found in patients with diabetic complications like neuropathy (3293 ± 1728 pg/ml), retinopathy (2986 ± 1645 pg/ml), and vascular complications (3152 ± 1571 pg/ml). The study has established comprehensive Ang-2 levels in various subsets of adults with diabetes. While interpreting Ang-2 levels, the differences in age and sex need to be taken into account. Diabetic patients with higher Ang-2 levels should be monitored closely and level of serum Ang-2 should be served as a marker to identify patients at high risk of diabetic complications. [ABSTRACT FROM AUTHOR]

Introduction: Preeclampsia affects 3-5% of pregnancies worldwide and is the primary cause of maternal-fetal and neonatal mortality. Previous studies show that alterations in maternal concentrations of angiogenic factors, such as PlGF, PDGF AA, ANG-1, and ANG-2, may play fundamental roles in the pathophysiology of the disease.Objective: Determine whether the PlGF, PDGF AA, ANG-1, and ANG-2 are predictors of preeclampsia occurrence in a prenatal cohort study.Patients and Methods: This is a case-control study associated with a prospective cohort of pregnant women, with gestational ages between 20 and 25 weeks, composed of 30 pregnant women with preeclampsia (PE) and 90 healthy pregnant women (HP). The plasma concentrations of the markers were determined using the ELISA method. The comparison between the case and control groups was performed using the t test on the SAS® 9.4 software. Also, ROC curves were constructed to evaluate the predictive potential of the biomarkers.Results: Differences in the concentrations of PlGF, PDGF AA, ANG-1 and ANG-2, and the ANG-1/ANG-2 ratio were not observed between the PE and the HP groups. The predictive capacity of the biomarkers was assessed using ROC curves, in which the area under the curve for PlGF AUC = 0.55; PDGF AA AUC = 0.55; ANG-1 AUC = 0.47; ANG-2 AUC = 0.51, and the ANG-1/ANG-2 ratio AUC = 0.57.Conclusion: In pregnant women, with gestational ages between 20 and 25 weeks significant differences in biomarker concentrations between groups PE and HP were not observed. The ROC curves showed that the biomarkers were ineffective as preeclampsia predictors in the analyzed cohort. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis is critical for the growth and metastasis of solid tumors and is, therefore, an important therapeutic target. Despite the great research advances in tumor therapies targeting vascular endothelial growth factor (VEGF), drug resistance frequently occurs, and further strategies targeting the tumor vasculature are of primary concern. Purpose: The present study aimed to determine whether a combination of small interfering RNAs (siRNAs) targeting VEGF-A and angiopoietin-2 (Ang-2) inhibited the biologic mechanisms of endometrial cancer more effectively compared to either one alone, in vitro and in vivo. Methods: VEGF-A and Ang-2 were silenced by siRNA in Ishikawa endometrial cancer cells. Cell growth, apoptosis, metastasis, and tumor angiogenesis were measured in vitro and in vivo. Results: There was no difference observed in cell apoptosis rate; however, combined silencing of VEGF-A and Ang-2 resulted in a stronger inhibition of cell proliferation and invasion (P<0.05). Similarly, a greater reduction of tumor size and angiogenesis was seen with the concurrent administration of siRNAs targeting VEGF-A and Ang-2 in nude mice (P<0.05). Conclusion: Our data indicated that simultaneous blockade of VEGF-A and Ang-2 may serve as a novel and effective therapeutic strategy in endometrial cancer. [ABSTRACT FROM AUTHOR]

Sepsis represents one the main cause of death in patients admitted to the intensive care. Biomarkers offer an alternative approach to the diagnostic and prognostic evaluation and improve the outcomes. Angiopoietin 2 (Ang-2) and Tyrosine kinase 2 (Tie-2) are biomarkers which may be involved in sepsis, Ang-2 being responsible for vascular remodelling while Tie-2 is their endothelial receptor.

Obesitas abdominal (Ob-Ab) merupakan komponen utama resistensi insulin (RI) yaitu kekutan pendorong utama untuk terjadinya diabetes mellitus (DM) tipe-2. Kadar angiopoietin-2 (Ang-2) plasma dilaporkan mengalami peningkatan pada penderita Ob-Ab dan diduga bahwa Ang-2 berpengaruh untuk terjadinya RI. Tujuan penelitian ini adalah untuk mengetahui korelasi kadar Ang-2, Inflamasi dan RI pada penderita Ob-Ab. Dilakukan penelitian secara cross-sectional analitik pada 81 penderita dengan Ob-Ab. Kadar TNF-α, sTNFR1 dan Ang-2 plasma diukur menggunakan metode ELISA. RI diukur menggunakan HOMA-IR. Analisis varian (ANOVA) dipergunakan untuk mengetahui persamaan variabel kontinyu. Analisis multivariat dipergunakan untuk mengetahui peran kadar TNF-α, s-TNFR-1, Ang-2 terhadap RI. Model analisis jalur (path analysis) dipergunakan untuk mengetahui pengaruh faktor risiko terjadinya RI. Hasil penelitian menunjukkan bahwa kadar TNF-α plasma tidak berkorelasi dengan HOMA-IR, sedangkan sTNFR-1 dan Ang-2 plasma berkorelasi positif bermakna dengan HOMA-IR (masing-masing r=0,323; p=0,003 dan r=0,641; p=