Balancing safety and efficacy of low-molecular-weight heparins in neonates: a systematic review.

The rising incidence of venous thromboembolism (VTE) in neonates has led to increased use of low-molecular-weight heparins (LMWHs), but optimal dosages remain uncertain. A serious adverse effect of LMWHs is major bleeding. Given the vulnerability of neonates to major bleeding, we aimed to review therapeutic and prophylactic LMWH dosages to achieve target anti-factor Xa ranges of 0.

[Hereditary thrombophilia; whom to test?].

Patients with thrombophilia show a higher incidence of VTE due to a disturbance in the hemostatic system. Hereditary thrombophilia can be identified by laboratory diagnostics, however most guidelines advise against thrombophilia testing in the majority of the patients with VTE, since the outcome rarely affects clinical decisions for the treatment. In this article we describe two cases in which hereditary thrombophilia testing could be considered.

Incidence and risk factors for postthrombotic syndrome in neonates and children in a single-center cohort study.

Background: Postthrombotic syndrome (PTS) is a chronic condition following deep vein thrombosis (DVT) and is associated with pain, swelling, and restricted use of the affected limb. In pediatric age groups, its incidence and risk factors are not well-known.

Methods: This observational cohort study of all consecutive children (≤18 years) with DVT treated at the Emma Children's Hospital Amsterdam between January 2001 and January 2021 was conducted to identify incidence and risk factors for PTS in neonates aged ≤2 months and children aged >2 months.

The association between lipoprotein(a) levels and ischemic stroke in children: A case-control study.

Background: Pediatric arterial ischemic stroke (AIS) is a rare disorder, associated with severe morbidity. In adults, elevated lipoprotein(a) (Lp(a)), a cholesterol-like particle, is associated with ischemic stroke. However, data on Lp(a) and pediatric AIS are scarce.

New Insights in ATP Synthesis as Therapeutic Target in Cancer and Angiogenic Ocular Diseases.

Lactate and ATP formation by aerobic glycolysis, the Warburg effect, is considered a hallmark of cancer. During angiogenesis in non-cancerous tissue, proliferating stalk endothelial cells (ECs) also produce lactate and ATP by aerobic glycolysis. In fact, all proliferating cells, both non-cancer and cancer cells, need lactate for the biosynthesis of building blocks for cell growth and tissue expansion.

Differential roles of eNOS in late effects of VEGF-A on hyperpermeability in different types of endothelial cells.

Vascular endothelial growth factor (VEGF)-A induces endothelial hyperpermeability, but the molecular pathways remain incompletely understood. Endothelial nitric oxide synthase (eNOS) regulates acute effects of VEGF-A on permeability of endothelial cells (ECs), but it remains unknown whether and how eNOS regulates late effects of VEGF-A-induced hyperpermeability. Here we show that VEGF-A induces hyperpermeability via eNOS-dependent and eNOS-independent mechanisms at 2 days after VEGF-A stimulation.

A high rate of post thrombotic complication in pediatric portal vein thrombosis.

Introduction: Portal vein thrombosis (PVT) is a rare disease in children and may be complicated by portal hypertension (PH), hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPHTN) but their incidence and risk factors are unknown.

Methods: An observational, retrospective cohort study of all consecutive children (≤18 years) with PVT treated at the Emma Children's Hospital Amsterdam University Medical Centers between January 1996 and January 2022 was conducted to identify the incidence and risk factors of these post thrombotic complications (PTC) in pediatric patients.

Results: In total 43/ 703 thrombosis patients had PVT (boys 72.

Disruption of cortical cell type composition and function underlies diabetes-associated cognitive decline.

Aims/hypothesis: Type 2 diabetes is associated with increased risk of cognitive decline although the pathogenic basis for this remains obscure. Deciphering diabetes-linked molecular mechanisms in cells of the cerebral cortex could uncover novel therapeutic targets.

Methods: Single-cell transcriptomic sequencing (scRNA-seq) was conducted on the cerebral cortex in a mouse model of type 2 diabetes (db/db mice) and in non-diabetic control mice in order to identify gene expression changes in distinct cell subpopulations and alterations in cell type composition.

Vitreous protein networks around ANG2 and VEGF in proliferative diabetic retinopathy and the differential effects of aflibercept versus bevacizumab pre-treatment.

Extracellular signalling proteins interact in networks rather than in isolation. In this context we investigated vitreous protein levels, including placental growth factor (PlGF), angiopoietin-2 (ANG2) and vascular endothelial growth factor (VEGF), in patients with proliferative diabetic retinopathy (PDR) with variable disease severities, and after anti-VEGF pre-treatment. Vitreous samples of 112 consecutive patients undergoing vitrectomy for PDR and of 52 non-diabetic patients with macular holes as controls were studied.

Quantitative Assessment of the Apical and Basolateral Membrane Expression of VEGFR2 and NRP2 in VEGF-A-stimulated Cultured Human Umbilical Vein Endothelial Cells.

Endothelial cells (ECs) form a precisely regulated polarized monolayer in capillary walls. Vascular endothelial growth factor-A (VEGF-A) induces endothelial hyperpermeability, and VEGF-A applied to the basolateral side, but not the apical side, has been shown to be a strong barrier disruptor in blood-retinal barrier ECs. We show here that VEGF-A presented to the basolateral side of human umbilical vein ECs (HUVECs) induces higher permeability than apical stimulation, which is similar to results obtained with bovine retinal ECs.

miRNA Levels as a Biomarker for Anti-VEGF Response in Patients with Diabetic Macular Edema.

Background: The aim of this study was to investigate whether miRNA levels in the circulation could serve as a predictive biomarker for responsiveness to anti-vascular endothelial growth factor (VEGF) therapy in patients with diabetic macular edema.

Methods: Whole blood samples were collected at baseline from 135 patients who were included in the BRDME study, a randomized controlled comparative trial of monthly bevacizumab or ranibizumab treatment for 6 months in patients with diabetic macular edema (Trialregister.nl, NTR3247).

PDGF as an Important Initiator for Neurite Outgrowth Associated with Fibrovascular Membranes in Proliferative Diabetic Retinopathy.

Purpose: The formation of fibrovascular membranes (FVMs) is a serious sight-threatening complication of proliferative diabetic retinopathy (PDR) that may result in retinal detachment and eventual blindness. During the formation of these membranes, neurite/process outgrowth occurs in retinal neurons and glial cells, which may both serve as a scaffold and have guiding or regulatory roles. To further understand this process, we investigated whether previously identified candidate proteins, from vitreous of PDR patients with FVMs, could induce neurite outgrowth in an experimental setting.

Exploring the choroidal vascular labyrinth and its molecular and structural roles in health and disease.

The choroid is a key player in maintaining ocular homeostasis and plays a role in a variety of chorioretinal diseases, many of which are poorly understood. Recent advances in the field of single-cell RNA sequencing have yielded valuable insights into the properties of choroidal endothelial cells (CECs). Here, we review the role of the choroid in various physiological and pathophysiological mechanisms, focusing on the role of CECs.

The Role of Heparan Sulfate and Neuropilin 2 in VEGFA Signaling in Human Endothelial Tip Cells and Non-Tip Cells during Angiogenesis In Vitro.

During angiogenesis, vascular endothelial growth factor A (VEGFA) regulates endothelial cell (EC) survival, tip cell formation, and stalk cell proliferation via VEGF receptor 2 (VEGFR2). VEGFR2 can interact with VEGFR2 co-receptors such as heparan sulfate proteoglycans (HSPGs) and neuropilin 2 (NRP2), but the exact roles of these co-receptors, or of sulfatase 2 (SULF2), an enzyme that removes sulfate groups from HSPGs and inhibits HSPG-mediated uptake of very low density lipoprotein (VLDL), in angiogenesis and tip cell biology are unknown. In the present study, we investigated whether the modulation of binding of VEGFA to VEGFR2 by knockdown of or affects sprouting angiogenesis, tip cell formation, proliferation of non-tip cells, and EC survival, or uptake of VLDL.

Effectiveness and Safety of Nadroparin Therapy in Preterm and Term Neonates with Venous Thromboembolism.

Introduction: Optimal neonatal nadroparin dosages to treat venous thromboembolism (VTE) are unknown.

Objective: To evaluate therapeutic nadroparin dosages to reach therapeutic target ranges (TTR: 0.5-1.

Angiogenesis in gynecological cancers and the options for anti-angiogenesis therapy.

Angiogenesis is required in cancer, including gynecological cancers, for the growth of primary tumors and secondary metastases. Development of anti-angiogenesis therapy in gynecological cancers and improvement of its efficacy have been a major focus of fundamental and clinical research. However, survival benefits of current anti-angiogenic agents, such as bevacizumab, in patients with gynecological cancer, are modest.

microRNA Expression Profile in the Vitreous of Proliferative Diabetic Retinopathy Patients and Differences from Patients Treated with Anti-VEGF Therapy.

Purpose: microRNAs (miRNAs) mediate the pathological mechanisms of diabetic retinopathy. In this study, we compared miRNA expression profiles in the vitreous between patients with proliferative diabetic retinopathy (PDR) and patients with a macular hole as non-diabetic controls, and between PDR patients treated with anti-vascular endothelial growth factor (VEGF) therapy and untreated PDR patients.

Methods: Vitreous samples of non-diabetic and PDR patients were screened for miRNAs with quantitative polymerase chain reaction (qPCR) panels.

The Effect of Internal Limiting Membrane Cleaning on Epiretinal Membrane Formation after Vitrectomy for Proliferative Diabetic Retinopathy.

Purpose: We hypothesised that cleaning the internal limiting membrane (ILM) with a flexible nitinol loop following diabetic vitrectomy without peeling may reduce the common occurrence of postoperative epiretinal membrane (ERM) formation.

Methods: Consecutive patients undergoing vitrectomy for proliferative diabetic retinopathy by one surgeon from 2015 to 2019 were studied and divided into 2 cohorts: the control group underwent standard surgery, and the ILM clean group underwent additional cleaning of the macular retina using a flexible nitinol loop after vitrectomy. Masked comparison of ERM on optical coherence tomography was performed at 3 months, and visual acuity (VA) was measured until 12 months postoperatively.

IGF-binding proteins 3 and 4 are regulators of sprouting angiogenesis.

Purpose: We have previously identified insulin-like growth factor 2 (IGF2) and insulin-like growth factor 1 receptor (IGF1R) as essential proteins for tip cell maintenance and sprouting angiogenesis. In this study, we aim to identify other IGF family members involved in endothelial sprouting angiogenesis.

Methods: Effects on sprouting were analyzed in human umbilical vein endothelial cells (HUVECs) using the spheroid-based sprouting model, and were quantified as mean number of sprouts per spheroid and average sprout length.

The role of glycolysis and mitochondrial respiration in the formation and functioning of endothelial tip cells during angiogenesis.

During sprouting angiogenesis, an individual endothelial tip cell grows out from a pre-existing vascular network and guides following and proliferating stalk cells to form a new vessel. Metabolic pathways such as glycolysis and mitochondrial respiration as the major sources of adenosine 5'-triphosphate (ATP) for energy production are differentially activated in these types of endothelial cells (ECs) during angiogenesis. Therefore, we studied energy metabolism during angiogenesis in more detail in tip cell and non-tip cell human umbilical vein ECs.

Endothelial tip cells in vitro are less glycolytic and have a more flexible response to metabolic stress than non-tip cells.

Formation of new blood vessels by differentiated endothelial tip cells, stalk cells, and phalanx cells during angiogenesis is an energy-demanding process. How these specialized endothelial cell phenotypes generate their energy, and whether there are differences between these phenotypes, is unknown. This may be key to understand their functions, as (1) metabolic pathways are essentially involved in the regulation of angiogenesis, and (2) a metabolic switch has been associated with angiogenic endothelial cell differentiation.

Venous Thrombosis in Children with Acute Lymphoblastic Leukemia Treated on DCOG ALL-9 and ALL-10 Protocols: The Effect of Fresh Frozen Plasma.

 Venous thromboembolism (VTE) is an important complication for treatment of acute lymphoblastic leukemia (ALL) in children. Especially, ALL treatment, with therapeutics such as asparaginase and steroids, increases the thrombotic risk by reduction in procoagulant and anticoagulant proteins. Replacement of deficient natural anticoagulants by administration of fresh frozen plasma (FFP) may have a preventive effect on the occurrence of VTE.

Anti-angiogenic effects of crenolanib are mediated by mitotic modulation independently of PDGFR expression.

Background: Crenolanib is a tyrosine kinase inhibitor targeting PDGFR-α, PDGFR-β and Fms related tyrosine kinase-3 (FLT3) that is currently evaluated in several clinical trials. Although platelet-derived growth factor receptor (PDGFR) signalling pathway is believed to play an important role in angiogenesis and maintenance of functional vasculature, we here demonstrate a direct angiostatic activity of crenolanib independently of PDGFR signalling.

Methods: The activity of crenolanib on cell viability, migration, sprouting, apoptosis and mitosis was assessed in endothelial cells, tumour cells and fibroblasts.