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Collagen (Col)-based composite hydrogels have attracted wide attention because of the additional properties that the second component brings to the hydrogel. Here we reported self-assembly of collagen and cross-linking of alginate with [Ca.sup.2+] to prepare a novel composite hydrogel with Tilapiaskin-derived collagen and alginate for efficient wound repairing as the wound dressing. The composite hydrogels exhibited higher water content, coupled with a significant increase in water retention rates upon the incorporation of alginate. As the concentration of alginate rose, the cross-linking network became tighter, thereby not only modifying the internal structure of the hydrogel but also enhancing its mechanical strength. Moreover, the collagen degradation rate in the composite hydrogels was greatly reduced through addition of alginate, and the collagen-alginate composite hydrogels exhibited low cytotoxicity, and improved wound healing efficacy, accelerating the maturation of skin attachments and the secretion of vascular endothelial growth factor (VEGF). These results suggested that the composite hydrogel formed by fish-derived collagen and alginate held promising potential as a wound dressing for challenging and refractory wounds. KEYWORDS alginate, characterization, collagen, composite hydrogel, wound dressing Highlights * Tilapia-skin-derived collagen/alginate hydrogels was prepared by selfassembly and cross-linking method. * The introduction of alginate improves the mechanical strength of collagen hydrogel. * The addition of alginate can slow down the degradation of collagen. * The composite hydrogels retain high water content and low cytotoxicity. * The composite hydrogels can promote wound healing significantly., 1 | INTRODUCTION Refractory wounds, such as severe frostbite, burns and ulcers, can cause full-thickness skin damage and are difficult to repair, (1,2) which brings great pain to patients, and [...]

This study aims to develop, characterize, and evaluate the best statin-loaded Collagen Silver nanoparticle-coated polycaprolactone nanofibers by electrospinning technique. The characterization and evaluation results reveal that nanofibers had shown an aligned Collagen Silver nanoparticle-coated polycaprolactone nanofibers distribution of fibers and aliment of collagen and silver nanoparticle coating material on the surface of the nanofibers. Furthermore, the electrospun nanofibers have shown no interaction between the drug and collagen and PCL polymeric material and have demonstrated controlled drug release for 360 h and significant degradation for 60 days of the study. In vitro, among the nanofiber treatment groups and the control groups, Pravastatin Collagen Silver nanoparticle-coated polycaprolactone nanofibers have shown cell proliferation and migration of NHDF cells and blood vessel development in the CAM assay and potential anti-bacterial activity against S. aureus and E. coli. In vivo, the Pravastatin Collagen Silver nanoparticle-coated polycaprolactone nanofibers have demonstrated improved wound recovery, reepithelization, fibroblast cell proliferation, angiogenesis, and ECM remodeling and enhanced VEGF-sprouting in the excised tissues of streptozotocin-induced diabetic rats for 7, 14, and 21 days of the study. Therefore, the developed Pravastatin Collagen Silver nanoparticle-coated polycaprolactone nanofibers could be a promising wound-dressing platform for effectively treating and managing diabetic wounds. Highlights * Nanofiber wound dressings provide numerous structural features in biomaterials. * Polycaprolactone can release the repurposed statin molecules into the wound site in a controlled manner. * In diabetic wounds, ECM tissue remodeling stimulates repair and vessel growth. * Pravastatin has been demonstrated to improve angiogenesis and ECM secretion for wound healing in diabetic conditions. KEYWORDS diabetic wounds, electrospinning, hypoxic microenvironment, nanofibers, pro-angiogenesis, re-epithelization, wound dressing, 1 | INTRODUCTION The most prevalent cause of death in diabetic individuals is diabetic wounds. Unfortunately, the bulk of the treatment options in the market do not entirely address how [...]

There is an ongoing search for novel biomarkers of endothelial damage, active disease, and organ dysfunction in systemic lupus erythematosus (SLE). We investigated the role of the vascular endothelial growth factor (VEGF) as a candidate biomarker by conducting a systematic review and meta-analysis of studies examining VEGF concentrations in SLE patients and healthy controls. We searched electronic databases (PubMed, Scopus, and Web of Science) from inception to 31 May 2024 (inclusion criteria: VEGF measurement in SLE patients and healthy controls and SLE patients with and without active disease or specific organ dysfunction in case–control studies, recruitment of adult participants, and availability of the full text in the English language; exclusion criteria: non-case–control studies, participants under 18 years, articles reporting duplicate or irrelevant data, and animal studies). We assessed the risk of bias and the certainty of evidence using the JBI Critical Appraisal Checklist and GRADE, respectively (PROSPERO registration number: CRD42024561636). Circulating VEGF concentrations were significantly higher in SLE patients than in controls (22 studies; standardised mean difference, SMD = 0.71, 95% CI 0.44 to 0.98, p < 0.001; low certainty of evidence). In SLE patients, VEGF concentrations were significantly higher in those with active disease (six studies; SMD = 1.10, 95% CI 0.27 to 1.92, p = 0.009; very low certainty of evidence) and lupus nephritis (four studies; SMD = 0.80, 95% CI 0.03 to 1.57, p = 0.042; very low certainty of evidence). Only one study reported VEGF concentrations in SLE patients with and without pulmonary arterial hypertension. The effect size of the differences in VEGF concentrations between SLE patients and controls was not associated with disease duration, use of glucocorticoids and immunosuppressors, biological matrix assessed, or analytical method used. However, it was significantly associated with the study's geographical location. The evidence was limited by the high but partially explainable heterogeneity and the presence of publication bias which was addressed with the "trim-and-fill" method (SLE presence), the high but partially explainable heterogeneity and lack of assessment of publication bias because of the limited study number (active disease), and the limited study number preventing the identification of sources of heterogeneity, sensitivity analysis, and assessment of publication bias (lupus nephritis). Our results highlight VEGF's potential role as a SLE biomarker and the need for further research, also given the aforementioned limitations, investigating VEGF concentrations in a wide range of SLE patient subgroups. [ABSTRACT FROM AUTHOR]

Background: We aimed to evaluate microaneurysms (MAs) after treatment with anti-vascular endothelial growth factor (anti-VEGF) therapy to understand causes of chronic edema and anti-VEGF resistance. Methods: Patients with non-proliferative diabetic retinopathy, with or without macular edema were recruited. Optical coherence tomography angiography (OCTA) MAs-related parameters were observed, including the maximum diameter of overall dimensions, material presence, and flow signal within the lumen. OCTA parameters also included central macular thickness (CMT), foveal avascular zone, superficial and deep capillary plexuses, and non-flow area measurements on the superficial retinal slab. Results: Overall, 48 eyes from 43 patients were evaluated. CMT differed significantly between the diabetic macular edema (DME) and non-DME (NDME) groups at 1st, 2nd, 3rd, and 6th months of follow-up (P < 0.001; <0.001; 0.003; <0.001, respectively). A total of 55 and 59 MAs were observed in the DME (mean = 99.40 ± 3.18 μm) and NDME (mean maximum diameter = 74.70 ± 2.86 μm) groups at baseline, respectively (significant between-group difference: P < 0.001). Blood flow signal was measurable for 46 (83.6%) and 34 (59.3%) eyes in the DME and NDME groups, respectively (significant between-group difference: P < 0.001). Conclusions: Compared to the NDME group, the DME group had larger MAs and a higher blood-flow signal ratio. Following anti-VEGF therapy, changes in the diameter of MAs were observed before changes in CMT thickness. Highlights: Microaneurysms (MAs) in diabetic macular edema (DME) are not fully understood. We utilized optical coherence tomography angiography (OCTA) to assess the parameters of MAs. Changes in MAs diameter reflected the therapeutic effects of Anti-Vascular Endothelial Growth Factor (anti-VEGF) therapeutic effects. A limited number of MAs exhibited wall reflex shifts, as well as low content and blood flow signals. Anti-VEGF therapy can enhance rich blood flow signals, however, it does not improved content proportion. [ABSTRACT FROM AUTHOR]

High-grade gliomas (HGG) comprising WHO grades 3 and 4 have a poor overall survival (OS) that has not improved in the past decade. Herein, markers representing four components of the tumor microenvironment (TME) were identified to define their linked expression in TME and predict the prognosis in HGG, namely, interleukin6 (IL6, inflammation), inducible nitric oxide synthase(iNOS), heat shock protein-70 (HSP70, hypoxia), vascular endothelial growth receptor (VEGF), and endothelin1 (ET1) (angiogenesis) and matrix metalloprotease-14 (MMP14) and intercellular adhesion molecule1 (ICAM1, extracellular matrix). To establish a non-invasive panel of biomarkers for precise prognostication in HGG. Eighty-six therapy-naive HGG patients with 45 controls were analyzed for the defined panel. Systemic expression of extracellular/secretory biomarkers was screened dot-immune assay (DIA), quantified by ELISA, and validated by immunocytochemistry (ICC). Expression of iNOS, HSP70, IL-6, VEGF, ET1, MMP14, and ICAM1 was found to be positively associated with grade. Quantification of circulating levels of the markers by ELISA and ICC presented a similar result. The biomarkers were observed to negatively correlate with OS (p < 0.0001). Cox-regression analysis yielded all biomarkers as good prognostic indicators and independent of confounders. On applying combination statistics, the biomarker panel achieved higher sensitivity than single markers to define survival. The intra-association of all seven biomarkers was significant, hinting of a cross-talk between the TME components and a hypoxia driven systemic inflammation upregulating the expression of other components. This is a first ever experimental study of a marker panel that can distinguish between histopathological grades and also delineate differential survival using liquid biopsy, suggesting that markers of hypoxia can be a cornerstone for personalized therapy. The panel of biomarkers of iNOS, HSP70, IL-6, VEGF, ET1, MMP14, and ICAM1 holds promise for prognostication in HGG. The cross-talk between the systemic biomarkers of four different partakers of tumor microenvironment [ABSTRACT FROM AUTHOR]

Both lymphatic vessels and macrophages are key factors influencing the inflammatory response. During the inflammatory response, lymphatic vessels undergo dilation and growth, playing a beneficial role in alleviating inflammation by facilitating the drainage of exudate, inflammatory mediators, and leukocytes. Consequently, the promotion of lymphangiogenesis has emerged as a novel therapeutic approach to treating inflammation. Macrophages play a crucial role in promoting lymphangiogenesis by secreting several pro‐lymphatic growth factors, including vascular endothelial growth factor (VEGF)‐C, and undergoing transdifferentiation into lymphatic endothelial cell progenitors (LECP), which integrate into newly formed lymphatic vessels. Macrophages exhibit heterogeneity and perform diverse functions based on their phenotypes. The regulation of macrophage polarization is crucial in inflammatory responses. Notably, macrophages promote lymphangiogenesis, while lymphatic vessels, in turn, serve as a conduit for macrophages to drain out inflamed tissue and also affect macrophage polarization. Thus, there is an interactive relationship between them. In this review, we discuss current work on the effects of macrophages on lymphangiogenesis as well as lymphatic vessel recruitment of macrophages and regulation of macrophage polarization. Furthermore, we explore the roles of lymphatic vessels and macrophages in various inflammation‐related diseases, emphasizing potential therapeutic targets within the context of lymphatic–macrophage interactions. [ABSTRACT FROM AUTHOR]

Background: Vascular endothelial growth factor (VEGF) is an important proangiogenic factor and has been considered as a key target of antiangiogenetic therapy in oral squamous cell carcinoma (OSCC). However, clinical application of bevacizumab, a specific VEGF antibody, didn't improve the survival rate of OSCC patients. One possible explanation is that VEGF gene expresses diverse isoforms, which associate with extracellular vesicles (EVs), and EVs potentially contribute to VEGF resistance to bevacizumab. However, clear solution is lacking in addressing this issue. Methods: Expression of VEGF isoforms in OSCC cells was confirmed by reverse transcription and polymerase chain reaction (RT-PCR) and western blot. EVs isolated from OSCC cell's conditioned medium (CM) were characterized by western blot, transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Flow cytometry, immunogold labeling and western blot were applied to study the VEGF on EVs. Tube formation assay and Matrigel plug angiogenesis assay were used for analyzing the angiogenesis capacity of EV-VEGF. Results: The most popular isoforms expressed by VEGF gene are VEGF121, VEGF165 and VEGF189. In this study, we demonstrated that all three isoforms of mRNA could be detected at varying levels in OSCC cells, while only VEGF165 and VEGF189 proteins were found. CM derived from OSCC cells, both soluble and non-soluble forms of VEGF could be detected. We further confirmed the presence of VGEF189 bound to EVs as a non-soluble form. EV-bound VEGF189 presented angiogenic activity, which could not be neutralized by bevacizumab. It was found that VEGF189 bound to EVs by heparan sulfate proteoglycans (HSPG). In addition, the angiogenic effect of EV-VEGF could be reversed by surfen, a kind of HSPG antagonist both in vitro and in vivo. Conclusion: Antagonists targeting HSPG might potentially overcome the resistance of EV-VEGF to bevacizumab and serve as an alternative for anti-VEGF therapy in OSCC. [ABSTRACT FROM AUTHOR]

Background: While drainage/removal of fluid and toxins from the brain by cerebrospinal fluid (CSF) directly into venous blood is well-known, a second drainage route has recently been (re)discovered—meningeal lymphatic vessels (mLVs)—which are responsible for up to half of total brain fluid/toxin drainage. The cytokine vascular endothelial growth factor (VEGF) increases mLV diameter and numbers to increase mLV drainage, resulting in increased mLV drainage. Alzheimer's disease (AD) is characterized by low plasma and CSF levels of VEGF. Objective: To determine if non-invasive transcranial radiofrequency wave treatment (TRFT), through modulation of VEGF levels in blood and CSF, can affect removal of toxins tau and amyloid-β (Aβ) from the brain. Methods: Eight mild/moderate AD subjects were given twice-daily 1-hour TRFT sessions at home by their caregivers. Blood and CSF samples were taken at baseline and following completion of 2 months of TRFT. Results: In plasma and/or CSF, strong baseline correlations between VEGF levels and AD markers (t-tau, p-tau, Aβ1-40, Aβ1-42) were eliminated by TRFT. This effect was primarily due to TRFT-induced increases in VEGF levels in AD subjects with low or unmeasurable "baseline" VEGF levels. These increased VEGF levels were associated with increased clearance/drainage of tau and Aβ from the brain, likely through VEGF's actions on mLVs. Conclusions: A new mechanism of TRFT is identified (facilitation of brain tau and Aβ clearance via VEGF) that is likely contributory to TRFT's reversal of cognitive impairment in AD subjects. TRFT may be particularly effective for cognitive benefit in AD subjects who have low VEGF levels. [ABSTRACT FROM AUTHOR]

Objective To explore the effects of vascular endothelial growth factor (VEGF), insulin-like growth factor 1(IGF-1) and neuromodulatory protein 1(NRG1) on first-episode schizophrenia patients. Meth- ods A total of 71 patients with first-episode schizophrenia admitted to the hospital from September 2021 to January 2023 were retrospectively selected as the study group, and 71 healthy volunteers who underwent phys- ical examination during the same period were selected as the control group. At the same time, according to the results ofpositive and negative symptom scale (PANSS) score results, the study group was divided into the high score subgroup(70 points, 33 cases) and the low score subgroup (<70 points, 38 cases). The study group was divided into cognitive dysfunction group (29 cases) and normal cognitive function group (42 cases) according to the results of MATRICS recognized cognitive battery(MCCB). The levels of serum VEGF, IGF1, and NRG1 in each group were compared, and their correlation with MCCB and PANSS scores was analyzed. Results The levels of serum VEGF, IGF1, and NRG1 in the study group were lower than those in the control group, and the differences were statistically significant (P<0.05). The levels of serum VEGF, IGF1, and NRG1 in the cognitive dysfunction subgroup were lower than those in the normal cognitive function sub- group, and the differences were statistically significant (P<0.05). The levels of serum VEGF, IGF1, and NRG1 in the low score subgroup were higher than those in the high score subgroup, and the differences were statistically significant (P<0.05). The levels of serum VEGF, IGF1, and NRG1 were positively correlated with MCCB and PANSS scores (P<0.05). Conclusion The levels of serum VEGF, IGF1 and NRG1 in pa- tients with schizophrenia are lower than those in healthy people, which are closely related to mental symptoms and cognitive function. [ABSTRACT FROM AUTHOR]

Anti-Mullerian hormone (AMH) has been implicated in the pathogenesis of preeclampsia. The present study was primarily designed to determine the placental tissue AMH, Anti-Mullerian hormone Receptor II (AMHRII), vascular endothelial growth factor (VEGF) and microRNA (miRNA) 26a/126/155/210 expressions and serum miRNA 26a/126/155/210 levels in patients with preeclampsia to examine their potential role in the pathogenesis of preeclampsia. Placental tissue samples from patients with preeclampsia (n = 20) and control subjects (n = 20) were examined by immunohistochemical staining and quantitative polymerase chain reaction (qPCR) for AMH, AMHRII, VEGF mRNA expression levels and miRNA 26a/126/155/210 expressions. Serum levels of miRNA 26a/126/155/210 were measured by qPCR. Patients with preeclampsia had lower AMH/AMHRII immunostaining, particularly in syncytiotrophoblastic cells compared to control subjects (p < 0.05). The relative mRNA expressions of AMH/AMHRII were increased (1.535 ± 0.121 and 1.155 ± 0.049 fold, p < 0.0002 and p < 0.033, respectively) and the relative mRNA expression of VEGF was decreased (4.878 ± 0.331 fold, p < 0.0002) in patients with preeclampsia compared to control subjects. The miR-26a expression was increased and miR-126 expression was decreased in serum samples of patients with preeclampsia compared to control subjects (p < 0.0002). miR-155 and miR-210 expressions were increased in serum and placental tissue samples of patients with preeclampsia compared to control subjects (p < 0.0002). In conclusion, reduced placental tissue immunostaining of AMH/AMHRII along with increased AMH/AMHRII mRNA expressions may indicate posttranscriptional dysregulation. Robust increase in expressions of hypoxia/inflammation-related miRNAs particularly miR-155 and miR-210 might have a role in this mechanistic pathway. Increased serum levels of miR 26a, 155 and 210 are potential early diagnostic markers for preeclampsia. [ABSTRACT FROM AUTHOR]

Introduction: Vascular endothelial growth factor (VEGF) is key to wet age-related macular degeneration (wAMD). Anti-VEGF drugs are the main treatment in clinics. This study assessed ocular adverse events (AE) from anti-VEGF drugs in VigiAccess, WHO's database, and compared adverse drug reaction (ADR) profiles of four drugs to aid personalized treatment choices for optimal benefit and safety. Methods: The design was a descriptive retrospective study. We observed four anti-VEGF drugs commonly used in the clinical treatment of wAMD, and their ADR reports came from WHO-VigiAccess. The collected data included the age group, gender, and regional data, as well as the data of disease systems and symptoms caused by ADR recorded in the annual ADR reports and reports received by the WHO. We observed the overall characteristics of the ADR reports of these drugs, then explored the distribution of 27 SOCs of these drugs. Subsequently, we compared the most common ocular ADRs of the drugs. Finally, we compared the commonalities and differences of ocular ADRs related to the drugs. Results: Overall, 57,779 AE associated with the four anti-VEGF drugs were reported. The results showed that the number of females experiencing ADRs (67.83%) was significantly higher than males (32.17%), the age group with the highest reported incidence was over 75 years old. More than half of the ADR reports came from the Americas (50.86%). The five most common types of AE were: eye disorders (43.56%), general disorders and administration site conditions (34.47%), injury poisoning and procedural complications (13.36%), infections and infestations (11.61%), nervous system disorders (9.99%). Compared with the other three inhibitors, brolucizumab had a significantly higher rate of ocular ADR reports. The most common ocular ADRs of these four anti-VEGF drugs were mostly related to visual impairment, vision blurred, and blindness. However, there is still a disparity of ADRs between different drugs. Conclusion: The presence of ocular AEs when using anti-VEGF drugs to treat wAMD in clinical practice should attract clinical attention. Clinicians should use these expensive drugs more rationally based on the characteristics of ADRs and develop personalized treatment plans for patients. [ABSTRACT FROM AUTHOR]

Background & objective: Knee pain, related to osteoarthritis (OA) of the knees is a disease of middle to old age. The males are the predominant victims. It has been suggested that knee diseases may be related to inflammatory biomarkers such as vascular endothelial growth factor (VEGF-A) and interleukin-1 (IL-1Ra) receptor antagonists of synovial fluis cytokines. These biomarkers might provide diagnostic and prognostic information to the clinicians. We investigated the levels of VEGF-A and IL-1Ra in patients known to suffer from suffered from anterior cruciate ligament (ACL) injuries, meniscal tears, and cartilage damage. Materials and methods: A total of 76 Iraqi participants were diagnosed to be suffering from anterior cruciate ligament (ACL) injuries, meniscal tears, and/or cartilage damage during the period from November 2022 to May 2023. They were admitted to the Al-Furat Al-Awsat Private Hospital in the Al-Qadisiyah Governorate, Iraq. The patients were divided into three groups according to the duration of the disease: Group I included patients with injuries for less than 6 months, Group II with 6-12 months and Group III had patients with injuries for more than one year. The enzyme-linked immunosorbent assay (ELISA) technique was used to detect inflammatory markers VEGF-A and and IL-1Ra. Data were summarized, and Microsoft Office Excel 2013 and GraphPad Prism 9.2.0 were used to present the statistical analysis. Results: Patients in Group I showed a significantly elevated level of VEGF-A (372.2 ± 68.95 pg/mL) as compared to Group II (273.5 ± 53.47 pg/mL) and Group III (232.2 ± 28.22 pg/mL) (P < 0.0001). While the concentration of IL-1Ra declined in patients with Group III (162.1 ± 7.036 pg/mL), as compared with both Group II (173.1 ± 9.351 pg/mL) and Group I ( 200 ± 34.53 pg/mL) with significant differences (P < 0.0001). Conclusion: The current study identified two synovial fluid biomarkers, vascular endothelial growth factor (VEGF-A) and interleukin-1 (IL-1), receptor antagonists of synovial fluis cytokines, whose concentrations after anterior cruciate ligament injury differ depending on the duration of the injury. [ABSTRACT FROM AUTHOR]

• Folate and glutathione (GSH) increased after tumor resection in hepatocellular carcinoma (HCC). • Vascular endothelial growth factor (VEGF) showed a decreased trend during follow-up in HCC. • VEGF correlates with folate, GSH, and GSH-related antioxidant enzymes in HCC. • The pre-resection VEGF level is a potential independent marker to predict HCC recurrence. The associations of tumor angiogenesis with folate and antioxidant capacities in patients with hepatocellular carcinoma (HCC) and their effects on HCC recurrence have not yet been investigated. We investigated the changes and relationships of VEGF, folate, GSH, and GSH-related antioxidant enzymes in patients with HCC before tumor resection, as well as 1 month, 1 year, and 3 years after tumor resection, and their effects on HCC recurrence. 95 HCC patients who underwent tumor resection were recruited. Patients were followed up before tumor resection (pre-resection), 1 month after tumor resection (post-resection), 1 year, and 3 years of follow-up. The recurrence and survival status of patients were evaluated. Plasma VEGF concentrations decreased slightly during follow-up. Serum folate and GSH concentrations and plasma GPx and GR activities increased significantly from pre-resection to post-resection and remained stable at follow-up. Pre-resection plasma VEGF was positively correlated with GSH, GPx, and GR, but negatively correlated with folate and GST. The high pre-resection plasma VEGF was a significant predictor of a high HCC rate (hazard ratio = 1.05, p = 0.035), remaining significant after adjustments for folate, GSH, GPx, GR, and GST to diminish their interference with VEGF. Pre-tumor-resection plasma VEGF constitutes a potential independent marker for predicting HCC recurrence. However, the associations of plasma VEGF with folate and GSH-related antioxidant capacities in HCC patients cannot be ignored. This study followed 95 patients with HCC who underwent tumor resection. VEGF decreased slightly during follow-up. Folate, GSH, GPx, and GR increased significantly after tumor resection and remained steady. Pre-resection VEGF correlated with folate, GSH, GPx, and GR. High pre-resection VEGF levels independently predicted a high HCC recurrence rate. HCC, hepatocellular carcinoma; VEGF, vascular endothelial growth factor; GSH, glutathione; GPx, glutathione peroxidase; GR, glutathione reductase. [Display omitted] [ABSTRACT FROM AUTHOR]

Renal cell carcinoma accounts for a significant proportion of cancer diagnoses in Canadians. Over the past several years, the management of renal cell cancers has undergone rapid changes in all prognostic risk categories, resulting in improved oncologic outcomes. Novel strategies for metastatic disease make use of the synergy between checkpoints and angiogenesis inhibition. Moreover, combination checkpoint inhibition has demonstrated durable efficacy in some patients. Adjuvant immunotherapy has recently shown a survival benefit for the first time in select cases. Significant efforts are underway to explore new compounds or combinations for later-line diseases, such as inhibitors of hypoxia-inducible factors and radiolabeled biomolecules targeting tumor antigens within the neoplastic microenvironment for precise payload delivery. In this manuscript, we provide a comprehensive review of the available data addressing key therapeutic areas pertaining to systemic therapy for metastatic and localized disease, review the most relevant prognostic tools, describe local therapies and management of CNS disease, and discuss practice-changing trials currently underway. Finally, we focus on some of the practical aspects for general practitioners in oncology caring for patients with renal cell carcinoma. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF) and neuregulin1 (NRG1) are multifunctional trophic factors reported to be dysregulated in schizophrenia. However, the relationships between serum concentrations and schizophrenia symptoms have differed markedly across studies, possibly because schizophrenia is a highly heterogenous disorder. The aim of this study was to investigate the associations of serum VEGF and NRG1 with clinical symptoms and cognitive deficits specifically in male patients with chronic schizophrenia. The study included 79 male patients with chronic schizophrenia and 79 matched healthy individuals. Serum VEGF, NRG1β1, S100B, S100A8, and neuropilin1 were measured using the Luminex liquid suspension chip detection method, psychopathological symptom severity using the Positive and Negative Symptom Scale (PANSS), and cognitive dysfunction using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Serum VEGF and NRG1β1 concentrations were significantly lower in male chronic schizophrenic patients than healthy controls (P < 0.05), while serum S100B, S100A8, and neuropilin1 concentrations did not differ between groups (P > 0.05). Serum VEGF concentration was negatively correlated with PANSS negative subscore (beta = −0.220, t = −2.07, P = 0.042), general psychopathology subscore (beta = -0.269, t = −2.55, P = 0.013), and total score (beta = -0.234, t = −2.12, P = 0.038), and positively correlated with RBANS language score (beta = 0.218, t = 2.03, P = 0.045). Alternatively, serum NRG1β1 concentration was not correlated with clinical symptoms or cognitive deficits (all P > 0.05). Dysregulation of VEGF and NRG1β1 signaling may contribute to the pathogenesis of chronic schizophrenia in males. Moreover, abnormal VEGF signaling may contribute directly or through intermediary processes to neuropsychiatric and cognitive symptom expression. • Serum VEGF and NRG1 levels were reduced in male patients with chronic schizophrenia. • Reduced serum VEGF was associated with psychopathologic symptoms and language deficits. • Deficient VEGF signaling is a potential therapeutic target for schizophrenia treatment. [ABSTRACT FROM AUTHOR]

Background: To identify genotypes associated with neovascular age‐related macular degeneration (nAMD) and investigate the associations between genotype variations and anti‐vascular endothelial growth factor (VEGF) treatment response. Methods: This observational, retrospective, case series study enrolled patients diagnosed with nAMD who received anti‐VEGF treatment in National Taiwan University Hospital with at least one‐year follow‐up between 2012 and 2020. A genome‐wide association study (GWAS) was conducted on enrolled patients and controls. Correlations between the genotypes identified from GWAS and the treatment response of functional/anatomical biomarkers, including visual acuity (VA), presence of intraretinal or subretinal fluid (SRF), serous or fibrovascular pigmented epithelium detachment (PED), and disruption of the ellipsoid zone (EZ), were analysed. Results: In total, 182 patients with nAMD and 1748 controls were enrolled. GWAS revealed 16 single nucleotide polymorphisms (SNPs) as risk loci for nAMD, including seven loci in CFH and ARMS2/HTRA1 and nine novel loci, including rs117517872 and rs79835234(COPB2‐DT), rs7525578(RAP1A), rs2123738(LOC105376755), rs1374879(CNTN3), rs3812692(SAR1A), rs117501587(PRKCA), rs9965945(CNDP1), and rs189769231(MATK). Our study revealed rs800292(CFH), rs11200638(HTRA1), and rs2123738(LOC105376755) correlated with poor treatment response in VA (P = 0.005), SRF (P = 0.044), and fibrovascular PED (P = 0.007), respectively. Rs9965945(CNDP1) was correlated with poor response in disruption of EZ (P = 0.046) and serous PED (P = 0.049). Conclusions: Among the 16 SNPs found in the GWAS, four loci—CFH, ARMS2/HTRA1, and two novel loci—were correlated with the susceptibility of nAMD and anatomical/functional responses after anti‐VEGF treatment. [ABSTRACT FROM AUTHOR]

Purpose: To compare the safety and efficacy of intravitreal injection of ranibizumab alone or ranibizumab combined with dexamethasone intravitreal implant in the treatment of macular edema secondary to retinal vein occlusion. Study design: A single center, case-controlled, prospective cohort study (Clinical Trail Registration Number: ChiCTR2400080048). Methods: A total of 44 patients were enrolled and randomized into the ranibizumab group (n = 23) and the combination group (ranibizumab combined with dexamethasone intravitreal implant) (n = 21). All patients received ranibizumab intravitreal injections in the first three months as the initial treatment. For the ranibizumab group, patients might receive repeat injections in case of the recurrence of macular edema; For the combination group, patients received an intravitreal injection of dexamethasone implant after the first injection of ranibizumab at the day 15. The main outcome was best-corrected visual acuity (BCVA) and reduction of central macular thickness. The secondary outcome were the numbers of recurrence, the average injection interval, and the numbers of injection. Adverse events were also recorded. Results: The BCVAs in both groups were significantly improved compared with the baselines (all p < 0.001), but more increment in BCVA was noticed at the 3-month in the combination group (p = 0.022). Both groups showed a reduction of central macular thickness at all time points (p < 0.05). However, the combination group did not exhibit higher central macular thickness-reducing effects than the ranibizumab group (p > 0.05). Compared with the combination group, the ranibizumab group suffered a higher number of recurrences of macular edema (p < 0.001), a lower interval of injection (p = 0.050), and a higher number of injection (p < 0.011). The incidence of adverse events was not significant between the two groups (p = 0.944). Conclusions: Ranibizumab combined with dexamethasone injection sustainably improved the BCVA of retinal vein occlusion patients with a good safety profile. [ABSTRACT FROM AUTHOR]

The use of tyrosine kinase inhibitors (TKI) has been growing in veterinary oncology and in the past few years several TKI have been tested in dogs. However, different from human medicine, we lack strategies to select patients to be treated with each TKI. Therefore, this study aimed to screen different tumor subtypes regarding TKI target immunoexpression as a predictor strategy to personalize the canine cancer treatment. It included 18 prostatic carcinomas, 36 soft tissue sarcomas, 20 mammary gland tumors, 6 urothelial bladder carcinomas, and 7 tumors from the endocrine system. A total of 87 patients with paraffin blocks were used to perform immunohistochemistry (IHC) of human epidermal growth factor receptor 2 (HER-2), epidermal growth factor receptors 1 (EGFR1), vascular endothelial growth factor receptor 2 (VEGFR-2), platelet derived growth factor receptor beta (PDGFR-β), c-KIT, and extracellular signal-regulated kinase 1/2 (ERK1/ERK2). The immunohistochemical screening revealed a heterogeneous protein expression among histological types with mesenchymal tumors showing the lowest expression level and carcinomas the highest expression. We have demonstrated by IHC screening that HER2, EGFR1, VEGFR-2, PDGFR-β and ERK1/ERK2 are commonly overexpressed in dogs with different carcinomas, and KIT expression is considered relatively low in the analyzed samples. [ABSTRACT FROM AUTHOR]

Tumor growth is intricately linked to the process of angiogenesis, with a key role played by vascular endothelial growth factor (VEGF) and its associated signaling pathways. Notably, these pathways also play a pivotal "housekeeping" role in renal physiology. Over the past decade, the utilization of VEGF signaling inhibitors has seen a substantial rise in the treatment of diverse solid organ tumors, diabetic retinopathy, age-related macular degeneration, and various ocular diseases. However, this increased use of such agents has led to a higher frequency of encountering renal adverse effects in clinical practice. This review comprehensively addresses the incidence, pathophysiological mechanisms, and current evidence concerning renal adverse events associated with systemic and intravitreal antiangiogenic therapies targeting VEGF-A and its receptors (VEGFR) and their associated signaling pathways. Additionally, we briefly explore strategies for mitigating potential risks linked to the use of these agents and effectively managing various renal adverse events, including but not limited to hypertension, proteinuria, renal dysfunction, and electrolyte imbalances. [ABSTRACT FROM AUTHOR]

Hyperglycaemia-induced retinal microvascular endothelial cell apoptosis is a critical and principle event in diabetic retinopathy (DR), which involves a series of complex processes such as mitochondrial dysfunction and oxidative stress. Ginsenoside Re (Re), a key ingredients of ginseng, is considered to have various pharmacologic functions, such as antioxidative, inhibition of inflammation and anti-apoptotic properties. However, the effects of Re in DR and the related mechanisms of endothelial cell injury induced by high glucose (HG) exposure remain unclear. The present study was designed to investigate and evaluate the ability of Re to ameliorate HG-induced retinal endothelial RF/6A cell injury and the potential mechanisms involved in the hypoxia-inducible factor-1-alpha (HIF-1α)/vascular endothelial growth factor (VEGF) signaling regulated by phosphoinositide 3-kinase (PI3K)/AKT pathway. Our results showed that preincubation with Re exerted cytoprotective effects by reversing the HG-induced decrease in RF/6A cell viability, downregulation of apoptosis rate and inhibition of oxidative-related enzymes, thereby reducing the excess intracellular reactive oxygen species (ROS) and HG-triggered RF/6A cell injury. In addition, Western blot analysis results showed ginsenoside Re significantly increased HIF-1α expression in the cytoplasm but decreased its expression in the nucleus, suggesting that it reduced the translocation of HIF-1α from the cytoplasm to the nucleus, and downregulated VEGF level. Moreover, this effect is involved in the activation of the PI3K/Akt pathway. LY294002, a PI3K inhibitor, was used to block the Akt pathway. Afterwards, the effects of Re on the regulation of apoptotic related proteins, VEGF and HIF-1α nuclear transcription was partially reversed. These findings suggested the exerting protective effects of ginsenoside Re were associated with regulating of PI3K/AKT and HIF-1α/VEGF signaling pathway, which indicates that ginsenoside Re may ameliorates HG-induced retinal angiogenesis and suggests the potential for the development of Re as a therapeutic for DR. [ABSTRACT FROM AUTHOR]

Angiogenesis, the natural mechanism by which fresh blood vessels develop from preexisting ones, is altered in arterial hypertension (AH), impacting renal function. Studies have shown that hypertension-induced renal damage involves changes in capillary density (CD), indicating alterations in vascularization. We aimed to elucidate the role of the apelin receptor (APLNR), neuronal nitric oxide synthase (nNOS), and vascular endothelial growth factor (VEGF) in hypertension-induced renal damage. We used two groups of spontaneously hypertensive rats aged 6 and 12 months, representing different stages of AH, and compared them to age-matched normotensive controls. The kidney tissue samples were prepared through a well-established protocol. All data analysis was conducted with a dedicated software program. APLNR was localized in tubular epithelial cells and the endothelial cells of the glomeruli, with higher expression in older SHRs. The localization of nNOS and VEGF was similar. The expression of APLNR and nNOS increased with AH progression, while VEGF levels decreased. CD was lower in young SHRs compared to controls and decreased significantly in older SHRs in comparison to age-matched controls. Our statistical analysis revealed significant differences in molecule expression between age groups and varying correlations between the expression of the three molecules and CD. [ABSTRACT FROM AUTHOR]

Erythropoietin (EPO) exerts non-canonical roles beyond erythropoiesis that are developmentally, structurally, and physiologically relevant for the heart as a paracrine factor. The role for paracrine EPO signalling and cellular crosstalk in the adult is uncertain. Here, we provided novel evidence showing cardiomyocyte restricted loss of function in Epo in adult mice induced hyper-compensatory increases in Epo expression by adjacent cardiac endothelial cells via HIF-2α independent mechanisms. These hearts showed concentric cellular hypertrophy, elevated contractility and relaxation, and greater resistance to ischemia-reperfusion injury. Voluntary exercise capacity compared to control hearts was improved independent of any changes to whole-body metabolism or blood O2 content or delivery (i.e., hematocrit). Our findings suggest cardiac EPO had a localized effect within the normoxic heart, which was regulated by cellspecific EPO-reciprocity between cardiomyocytes and endothelium. Within the heart, hyper-compensated endothelial Epo expression was accompanied by elevated Vegfr1 and Vegfb RNA, that upon pharmacological pan-inhibition of VEGF-VEGFR signaling, resulted in a paradoxical upregulation in whole-heart Epo. Thus, we provide the first evidence that a novel EPO-EPOR/VEGF-VEGFR axis exists to carefully mediate cardiac homeostasis via cardiomyocyteendothelial EPO crosstalk. [ABSTRACT FROM AUTHOR]

Purpose: To understand factors affecting visual prognosis and the number of intravitreal antivascular endothelial growth factor (anti-VEGF) injections needed to stabilize wet age-related macular degeneration (AMD). Methods: In this retrospective cohort, 119 treatment-naïve wet AMD patients were followed for two years. In patients with bilateral disease, the eye with worse best-corrected visual acuity (BCVA) or that received more intravitreal injections was recruited as the study eye. In all visits, BCVA was recorded, ophthalmological examination was performed including macular optical coherence tomography imaging. Twenty health status/lifestyle questions were asked to the patients via phone as potential risk factors. All patients received 3 loading doses of intravitreal bevacizumab injections and received repeat injections of aflibercept or ranibizumab when the eye had a new, active neovascular lesion. Results: Patients who took regular micronutrition had similar visual outcome and injection numbers compared to the ones who did not. Patients with bilateral disease needed less intravitreal injections compared to unilateral AMD patients (p = 0.016) and women on hormone replacement therapy (HRT) required less injections compared to the women who were not (p = 0.024). Female patients had a mean gain of 2.7 letters while male patients lost 3.8 letters (p = 0.038). Wet AMD started at an earlier age in smokers (p = 0.002). Patients with a better education level presented earlier with better BCVA (p = 0.037). Conclusion: HRT and anti-VEGF injections to the fellow eye improved the prognosis of wet AMD, while male patients had slightly worse prognosis. Estrogen’s protective effects and potential contribution in wet AMD needs further attention. Retrospectively registered: 2020/0622. [ABSTRACT FROM AUTHOR]

Diabetic foot ulcers are a common and severe complication of diabetes mellitus, and a risk factor for amputation. Because of the vessel insufficiency in diabetic foot ulcers (DFU), vascular endothelial growth factor (VEGF) that simulates angiogenesis is of interest to promote wound healing. This systematic review evaluates the last 16 years of in‐vivo studies with VEGF stimulation as a treatment for DFU, developed based on the last published systematic article. A total of 961 articles were identified through databases in two phases. 947 articles were excluded by exclusion criteria, and four articles met our inclusion criteria and were included. The effects of VEGF on wound healing were analysed in all four studies. In three studies, the VEGF‐treated wounds showed statistically faster healing than those not treated with VEGF. In one study, the VEGF‐treated wounds revealed a positive trend toward faster healing. Furthermore, all four studies were in favor of using VEGF, but concluded that further research is needed. These studies showed a positive trend towards faster healing and was safe when using VEGF topically on humans. Furthermore, viral particles of VEGF seem to have a systematic effect when a dose exceeding 5.0 × 109 vp pr wound. Future research in using VEGF on DFU should focus on VEGF's relevant dosage, release rate, and specific mechanism. This review inspires further research, and a consistent study design is prerequisite such that results are more homogenic and comparable. Much effort is needed to translate the results into our clinical practice. [ABSTRACT FROM AUTHOR]

Two cases of complicated pain exist: posterior screw fixation and myofascial pain. Intramuscular pulsed radiofrequency (PRF) may be an alternative treatment for such patients. This is a two-stage animal study. In the first stage, two muscle groups and two nerve groups were subdivided into a high-temperature group with PRF at 58 °C and a regular temperature with PRF at 42 °C in rats. In the second stage, two nerve injury groups were subdivided into nerve injury with PRF 42 °C on the sciatic nerve and muscle. Blood and spinal cord samples were collected. In the first stage, the immunohistochemical analysis showed that PRF upregulated brain-derived neurotrophic factor (BDNF) in the spinal cord in both groups of rats. In the second stage, the immunohistochemical analysis showed significant BDNF and tropomyosin receptor kinase B (TrkB) expression within the spinal cord after PRF in muscles and nerves after nerve injury. The blood biomarkers showed a significant increase in BDNF levels. PRF in the muscle in rats could upregulate BDNF-TrkB in the spinal cord, similar to PRF on the sciatica nerve for pain relief in rats. PRF could be considered clinically for patients with complicated pain and this study also demonstrated the role of BDNF in pain modulation. The optimal temperature for PRF was 42 °C. [ABSTRACT FROM AUTHOR]

Laser photocoagulation (LPC) and/or intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections constitute the current standard treatment for retinopathy of prematurity (ROP). This network meta-analysis focus on whether a ranking of interventions may be established for different dose levels of intravitreal injection of anti-VEGF agents (aflibercept, bevacizumab, conbercept, ranibizumab) as primary treatments for ROP versus laser in terms of retreatment rate as primary outcome, and time to retreatment and refractive error as secondary endpoints, since best anti-VEGF dosage remains under debate. Sixty-eight studies (15 randomized control trials and 53 nonrandomized studies) of 12,356 eyes of 6445 infants were retrieved from databases (2005 Jan. – 2023 June). Studies were evaluated for model fit, risk of bias and confidence of evidence in Network Meta-Analysis (CINeMA). Bayesian NMA showed that anti-VEGF drugs were not inferior to laser in terms of retreatment rate. For intravitreal bevacizumab (IVB), doses half of the conventional infant dose showed a low risk of retreatment rate (risk ratio (RR) of 1.43; 95% credible interval (CrI): 0.508, 4.03). On probability ranking as surface under the cumulative ranking curve (SUCRA) plot, half dose of bevacizumab had a better position than conventional and augmented (1.2–2 times the regular dose) doses. A similar probability trend was observed for half vs. conventional doses of aflibercept and ranibizumab. Conventional infant dose of conbercept showed the lowest risk for retreatment (RR 0.846; 95% CrI: 0.245, 2.91). For secondary endpoints, lower doses of anti-VEGF agents were associated with shorter times to retreatment. The largest changes were noted for the augmented doses of bevacizumab and ranibizumab (0.3 mg) with means of 14.1 weeks (95% CrI: 6.65, 21.6) and 12.8 weeks (95% CrI: 3.19, 20.9), respectively. Finally, NMA demonstrated better refractive profile for anti-VEGF than laser therapy, especially for the conventional infant doses of bevacizumab and ranibizumab which exhibited a significantly better refractive profile than LPC, with mean differences of 1.67 (spherical equivalent - diopters) (95% CrI: 0.705, 2.67) and 2.19 (95% CrI: 0.782, 3.59), respectively. In the SUCRA plots, LPC had a markedly different position with a higher probability for myopia. Further clinical trials comparing different intravitreal doses of anti-VEGF agents are needed, but our findings suggest that low doses of these drugs retain efficacy and may reduce ocular and systemic undesired events. • ROP is a serious neovascular disorder caused by proliferation of abnormal fibrovascular tissue in premature infants. • Laser therapy is considered the standard treatment for ROP but the use of anti-VEGF agents has increasingly being recognized. • Anti-VEGF therapy has demonstrated some advantages but impact on organogenesis remains of concern. • Reduced doses of anti-VEGF seem to maintain efficacy while avoiding toxicity. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a systemic vascular disorder, is caused by an imbalance of pro- and anti-angiogenic factors that directly affect endothelial function. Vascular endothelial growth factor A (called VGF), a pro-angiogenic factor associated with endothelial dysfunction, plays an important role in the pathophysiology of PE. Therefore, we investigated the relationship between −2549 insertion/deletion (I/D) variant in the VEGF promoter region and PE in pregnant women in Turkey. A total of 100 patients diagnosed with PE and 118 healthy pregnants were recruited. To genotype the VEGF I/D variant, the PCR method was used. The results of analyses were evaluated for statistical significance. The weight of the PE group was found to be higher before and after pregnancy than the control group (p = 0.009, p = 0.012, respectively). The birth weight, and Apgar score (1 min and 5 min) of the PE group was lower than that of the control group (p= <0.001, p= <0.001, p= <0.001, respectively). The mean 24-h urine protein, ALT and AST levels in the PE group were higher than the control group (p= <0.001, p= <0.001, p= <0.001, respectively). There was no significant difference between the patients and the controls in terms of VEGF I/D genotype and allele distribution. There was no deviation from HWA for VEGF I/D variant in patient and control groups. In the patients carrying D/D genotype and the D allele had low gestational week and birth weight. Knowing the risk factors for PE is very important for its prevention and treatment. In conclusion, for the first time, our results supported that the VEGF I/D variant is not a risk factor for the development of PE in a group of Turkish populations. But VEGF I/D variant D/D genotype associated with low gestational week and birth weight while I/D genotype seems to be protective from high systolic blood pressure. [ABSTRACT FROM AUTHOR]

Haematopoiesis dysregulation with the presence of immature myeloid and erythroid immunosuppressive cells are key characteristics of the immune escape phase of tumour development. Here, the role of in vitro generated B16F10 tumour cell‐derived extracellular vesicles (tEVs) as indirect cellular communicators, participating in tumour‐induced dysregulation of haematopoiesis, was explored. The isolated tEVs displayed features of small EVs with a size range of 100–200 nm, expressed the common EV markers CD63, CD9, and Alix, and had a spherical shape with a lipid bilayer membrane. Proteomic profiling revealed significant levels of angiogenic factors, particularly vascular endothelial growth factor (VEGF), osteopontin, and tissue factor, associated with the tEVs. Systemic administration of these tEVs in syngeneic mice induced splenomegaly and disrupted haematopoiesis, leading to extramedullary haematopoiesis, expansion of splenic immature erythroid progenitors, reduced bone marrow cellularity, medullary expansion of granulocytic myeloid suppressor cells, and the development of anaemia. These effects closely mirrored those observed in tumour‐bearing mice and were not seen after heat inactivating the tEVs. In vitro studies demonstrated that tEVs independently induced the expansion of bone marrow granulocytic myeloid suppressor cells and B cells while reducing the frequency of cells in the erythropoietic lineage. These effects of tEVs were significantly abrogated by the blockade of VEGF or heat inactivation. Our findings underscore the important role of tEVs in dysregulating haematopoiesis during the immune escape phase of cancer immunoediting, suggesting their potential as targets for addressing immune evasion and reinstating normal hematopoietic processes. [ABSTRACT FROM AUTHOR]

Copyright of Current Research in Dental Sciences is the property of Ataturk University Coordinatorship of Scientific Journals and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: We previously developed a novel therapy with low-intensity pulsed ultrasound (LIPUS) that ameliorates cognitive decline through upregulation of endothelial nitric oxide synthase (eNOS) in mouse models of Alzheimer's disease (AD). In a randomized, double-blind, placebo-controlled pilot trial, we demonstrated that whole-brain LIPUS therapy is safe and tends to suppress the cognitive decline in early AD patients. We herein report the findings of our basic experiments that we performed for the pilot trial in order to apply whole-brain LIPUS therapy to humans, as well. Methods: First, we examined the relationship between bone density/thickness and ultrasound transmittance using human temporal bone. Next, based on the results of ultrasound transmittance, we further examined mRNA expression of VEGF, FGF2, and eNOS in response to variable ultrasound frequencies, duty cycles, and sound pressures. Results: There was a significant correlation between bone thickness and transmittance (1.0 MHz, P < 0.001), while there was no significant correlation between bone density and transmittance (1.0 MHz, P = 0.421). At a frequency of 0.5 MHz, the optimum duty cycle was considered to be up to 20%. When the tissue amplitude was in the range of 0.05–0.5 MPa, VEGF, FGF2, and eNOS were significantly upregulated by LIPUS. Thus, the conditions necessary for LIPUS therapy for the human brain were identified as sound pressure just below the probe 1.3 MPa (tissue amplitude 0.15 MPa), duty cycle 5%, and frequency 0.5 MHz. Conclusion: We successfully identified the optimal treatment conditions for LIPUS therapy for patients with AD. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Modern Laboratory Medicine is the property of Journal of Modern Laboratory Medicine Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Angiogenesis is one of the most important steps during pregnancy for placental and fetal development. Based on the hypothesis that vascular insufficiency and altered angiogenesis may lead to early pregnancy loss, the present study was aimed to understand the role of Vascular endothelial growth factor (VEGFA) and Placental growth factor (PLGF) gene expression in placental angiogenesis in the pathogenesis of Recurrent pregnancy loss (RPL). Gene expression analysis of VEGFA and PLGF was carried out in the placental tissue collected from 30 women with recurrent pregnancy loss and compared with the placenta obtained from 16 women with medically terminated pregnancy. The mRNA expression of both VEGFA and PLGF genes were significantly downregulated in the placenta of recurrent pregnancy loss in comparison to the placenta of medically terminated pregnancies. In conclusion the results of the present study suggest that altered expression of VEGFA and PLGF genes in placenta disturb the angiogenesis and contribute to the pathogenesis of recurrent pregnancy loss. [ABSTRACT FROM AUTHOR]

Background and Objectives: In this study, our objective was to assess and compare the changes in visual and structural outcomes among patients with neovascular age-related macular degeneration (nAMD) who were switched from intravitreal aflibercept (IVA) to either intravitreal brolucizumab (IVBr) or intravitreal faricimab (IVF) injections in a clinical setting. Materials and Methods: This observational clinical study included 20 eyes of 20 patients switched to brolucizumab and 15 eyes of 14 patients switched to faricimab from aflibercept in eyes with nAMD. We measured the structural outcome (central macular thickness (CMT)) and the visual outcome (best-corrected visual acuity (BCVA); logMAR) as follows: just before the most recent IVA injection (B0), one month after the most recent IVA injection (B1), just before the first IVBr or IVF injection (A0), one month after (A1) and three months after (A3) the first IVBr or IVF injection. Results: BCVA showed significant improvement at A1 (0.25 ± 0.34) and at A3 (0.19 ± 0.24) compared to A0 (0.38 ± 0.35) in the IVBr group (p = 0.0156, p = 0.0166, respectively). CMT (μm) was significantly thinner at A1 (IVBr: 240.55 ± 51.82, IVF: 234.91 ± 47.29) and at A3 (IVBr: 243.21 ± 76.15, IVF: 250.50 ± 72.61) compared to at A0 (IVBr: 303.55 ± 79.18, IVF: 270.33 ± 77.62) in the IVBr group (A1: p = 0.0093, A3: p = 0.0026) and in the IVF group (A1: p = 0.0161, A3: p = 0.0093). There was no significant difference in BCVA and CMT improvement observed between two groups at any time point (p > 0.05 for all). Conclusions: Switching from aflibercept to either brolucizumab or faricimab has a significant anatomical effect in eyes with nAMD and both treatments appear to be effective short-term treatment options. There is a trend towards greater visual improvements and reductions in CMT with brolucizumab. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma accounts for a significant proportion of cancer diagnoses in Canadians. Over the past several years, the management of renal cell cancers has undergone rapid changes in all prognostic risk categories, resulting in improved oncologic outcomes. Novel strategies for metastatic disease make use of the synergy between checkpoints and angiogenesis inhibition. Moreover, combination checkpoint inhibition has demonstrated durable efficacy in some patients. Adjuvant immunotherapy has recently shown a survival benefit for the first time in select cases. Significant efforts are underway to explore new compounds or combinations for later-line diseases, such as inhibitors of hypoxia-inducible factors and radiolabeled biomolecules targeting tumor antigens within the neoplastic microenvironment for precise payload delivery. In this manuscript, we provide a comprehensive review of the available data addressing key therapeutic areas pertaining to systemic therapy for metastatic and localized disease, review the most relevant prognostic tools, describe local therapies and management of CNS disease, and discuss practice-changing trials currently underway. Finally, we focus on some of the practical aspects for general practitioners in oncology caring for patients with renal cell carcinoma.

Abstract Background Vascular endothelial growth factor (VEGF) is an important proangiogenic factor and has been considered as a key target of antiangiogenetic therapy in oral squamous cell carcinoma (OSCC). However, clinical application of bevacizumab, a specific VEGF antibody, didn’t improve the survival rate of OSCC patients. One possible explanation is that VEGF gene expresses diverse isoforms, which associate with extracellular vesicles (EVs), and EVs potentially contribute to VEGF resistance to bevacizumab. However, clear solution is lacking in addressing this issue. Methods Expression of VEGF isoforms in OSCC cells was confirmed by reverse transcription and polymerase chain reaction (RT-PCR) and western blot. EVs isolated from OSCC cell’s conditioned medium (CM) were characterized by western blot, transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Flow cytometry, immunogold labeling and western blot were applied to study the VEGF on EVs. Tube formation assay and Matrigel plug angiogenesis assay were used for analyzing the angiogenesis capacity of EV-VEGF. Results The most popular isoforms expressed by VEGF gene are VEGF121, VEGF165 and VEGF189. In this study, we demonstrated that all three isoforms of mRNA could be detected at varying levels in OSCC cells, while only VEGF165 and VEGF189 proteins were found. CM derived from OSCC cells, both soluble and non-soluble forms of VEGF could be detected. We further confirmed the presence of VGEF189 bound to EVs as a non-soluble form. EV-bound VEGF189 presented angiogenic activity, which could not be neutralized by bevacizumab. It was found that VEGF189 bound to EVs by heparan sulfate proteoglycans (HSPG). In addition, the angiogenic effect of EV-VEGF could be reversed by surfen, a kind of HSPG antagonist both in vitro and in vivo. Conclusion Antagonists targeting HSPG might potentially overcome the resistance of EV-VEGF to bevacizumab and serve as an alternative for anti-VEGF therapy in OSCC.

Objective To establish a nomogram model to predict the survival of elderly patients with colon cancer after radical resection, and to verify the predictive value of this model. Methods A total of 118 elderly patients with colon cancer who underwent radical surgery at the Xinjiang Medical University Affiliated Traditional Chinese Medicine Hospital from January 2015 to December 2017 were selected as the research subjects. The prognostic indicators of elderly patients with colorectal cancer after radical surgery were analyzed by univariate Cox regression analysis. The meaningful indicators with P0.05). Conclusion The nomogram model combined with differentiation degree, TNM/T staging, lymph node metastasis and VEGF can accurately predict postoperative disease-free survival and overall survival of elderly patients with colon cancer.

AIM: To observe the effect of human umbilical cord mesenchymal stem cells (hUCMSCs) secretions on the relevant factors in mouse retinal astrocytes, and to investigate the effect of hUCMSCs on the expression of vascular endothelial growth factor-A (VEGF-A) and to observe the therapeutic effect on the mouse model of retinopathy of prematurity (ROP). METHODS: Cultured hUCMSCs and extracted exosomes from them and then retinal astrocytes were divided into control group and hypoxia group. MTT assay, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used to detect related indicators. Possible mechanisms by which hUCMSCs exosomes affect VEGF-A expression in hypoxia-induced mouse retinal astrocytes were explored. At last, the efficacy of exosomes of UCMSCs in a mouse ROP model was explored. Graphpad6 was used to comprehensively process data information. RESULTS: The secretion was successfully extracted from the culture supernatant of hUCMSCs by gradient ultracentrifugation. Reactive oxygen species (ROS) and hypoxia inducible factor-1α (HIF-1α) of mice retinal astrocytes under different hypoxia time and the expression level of VEGF-A protein and VEGF-A mRNA increased, and the ROP cell model was established after 6h of hypoxia. The secretions of medium and high concentrations of hUCMSCs can reduce ROS and HIF-1α, the expression levels of VEGF-A protein and VEGF-A mRNA are statistically significant and concentration dependent. Compared with the ROP cell model group, the expression of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signal pathway related factors in the hUCMSCs exocrine group is significantly decreased. The intravitreal injection of the secretions of medium and high concentrations of hUCMSCs can reduce VEGF-A and HIF-1α in ROP model tissues. HE staining shows that the number of retinal neovascularization in ROP mice decreases with the increase of the dose of hUCMSCs secretion. CONCLUSION: In a hypoxia induced mouse retinal astrocyte model, hUCMSCs exosomes are found to effectively reduce the expression of HIF-1α and VEGF-A, which are positively correlated with the concentration of hUCMSCs exosomes. HUCMSCs exosomes can effectively reduce the number of retinal neovascularization and the expression of HIF-1α and VEGF-A proteins in ROP mice, and are positively correlated with drug dosage. Besides, they can reduce the related factors on the PI3K/AKT/mTOR signaling pathway.

AIM: To examine the regulatory role of microRNA-204 (miR-204) on silent information regulator 1 (SIRT1) and vascular endothelial growth factor (VEGF) under high-glucose-induced metabolic memory in human retinal pigment epithelial (hRPE) cells. METHODS: Cells were cultured with either normal (5 mmol/L) or high D-glucose (25 mmol/L) concentrations for 8d to establish control and high-glucose groups, respectively. To induce metabolic memory, cells were cultured with 25 mmol/L D-glucose for 4d followed by culture with 5 mmol/L D-glucose for 4d. In addition, exposed in 25 mmol/L D-glucose for 4d and then transfected with 100 nmol/L miR-204 control, miR-204 inhibitor or miR-204 mimic in 5 mmol/L D-glucose for 4d. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was used to detect miR-204 mRNA levels. SIRT1 and VEGF protein levels were assessed by immunohistochemical and Western blot. Flow cytometry was used to investigate apoptosis rate. RESULTS: It was found that high glucose promoted miR-204 and VEGF expression, and inhibited SIRT1 activity, even after the return to normal glucose culture conditions. Upregulation of miR-204 promoted apoptosis inhibiting SIRT1 and increasing VEGF expression. However, downregulation of miR-204 produced the opposite effects. CONCLUSION: The study identifies that miR-204 is the upstream target of SIRT1and VEGF, and that miR-204 can protect hRPE cells from the damage caused by metabolic memory through increasing SIRT1 and inhibiting VEGF expression.

BACKGROUND: Multitargeted tyrosine kinase inhibitors (TKIs) of the vascular endothelial growth factor receptor (VEGFR) pathway have activity in differentiated thyroid cancer (DTC). Lenalidomide demonstrated preliminary efficacy in DTC, but its safety and efficacy in combination with VEGFR-targeted TKIs is unknown. We sought to determine the safety and efficacy of cediranib, a VEGFR-targeted TKI, with or without lenalidomide, in the treatment of iodine 131-refractory DTC. PATIENTS AND METHODS: In this multicenter, open-label, randomized, phase II clinical trial, 110 patients were enrolled and randomized to cediranib alone or cediranib with lenalidomide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, duration of response, toxicity, and overall survival (OS). Patients (≥18 years of age) with DTC who were refractory to further surgical or radioactive iodine (RAI) therapy as reviewed at a multispecialty tumor board conference, and evidence of disease progression within the previous 12 months and no more than one prior line of systemic therapy were eligible. RESULTS: Of the 110 patients, 108 started therapy and were assessable for efficacy. The median PFS was 14.8 months [95% confidence interval (CI) 8.5-23.8 months] in the cediranib arm and 11.3 months (95% CI 8.7-18.9 months) in the cediranib with lenalidomide arm (P = 0.36). The 2-year OS was 64.8% (95% CI 43.3% to 86.4%) and 75.3% (95% CI 59.4% to 91.0%), respectively (P = 0.80). The serious adverse event rate was 41% in the cediranib arm and 46% in the cediranib with lenalidomide arm. CONCLUSIONS: Single-agent therapy with cediranib showed promising efficacy in RAI-refractory DTC similar to other VEGFR-targeted TKIs, while the addition of lenalidomide did not result in clinically meaningful improvements in outcomes.

BACKGROUND: Previous studies showed that extracts of Sambucus adnata Wall. have the ability to promote the proliferation and differentiation of osteoblasts, fracture healing, anti-inflammatory and antioxidant effects, which can effectively alleviate the development of osteoarthritis. Vascular endothelial growth factor, on the other hand, is a biomarker for the evaluation of osteoarthritis severity. OBJECTIVE: To investigate the effect and mechanism of two extracts of Sambucus adnata Wall. (methanol extract SAW-ME and dichloromethane extract SAWDCE) on angiogenesis in osteoarthritis. METHODS: (1) Rat models of osteoarthritis were established using anterior cruciate ligament transection and given SAW-ME and SAW-DCE. A sham group was set as a control. Immunohistochemistry and immunofluorescence were used to detect the changes of articular vascular endothelial growth factor A in joint tissue and vascular endothelial growth factor and “H” type blood vessels in serum of osteoarthritis rats. (2) Vascular endothelial cells EA.hy926 were used as the research object and intervened with SAW-ME and SAW-DCE. Cell proliferation was then detected by MTT assay. Vascular endothelial growth factor was used to induce EA.hy926 cells, and the model of angiogenesis was replicated. Cell scratch assay and tube formation assay were performed to study the role and mechanism. (3) EA.hy926 cells were used for transcriptome sequencing to analyze the characteristic changes of cell differential genes and related functions after SAW-DCE intervention. RESULTS AND CONCLUSION: (1) SAW-ME and SAW-DCE downregulated the expression of vascular endothelial growth factor A in the rat knee cartilage and reduced the formation of “H” type vessels in osteoarthritis rats. SAW-ME could significantly decrease the level of vascular endothelial growth factor in serum of osteoarthritis rats (P < 0.05). SAW-DCE could also decrease the level of vascular endothelial growth factor in serum of osteoarthritis rats, but there was no significant change. (2) Both SAW-ME and SAW-DCE significantly inhibited vascular endothelial cell migration and tube formation, and downregulated the expression of Ang1 and Tie2 proteins. (3) Transcriptome sequencing analysis found that abnormal angiogenesis in osteoarthritis was related to the PI3K/AKT signaling pathway. (4) To conclude, SAW-ME and SAW-DCE can inhibit angiogenesis in the rat model of osteoarthritis, and the mechanism may be related to the Ang1/Tie2 and PI3K/AKT signaling pathways. [ABSTRACT FROM AUTHOR]

BACKGROUND: In recent years, increasing studies have shown that low-intensity pulsed ultrasound can promote the healing of acute tendon injuries, but the specific mechanism is still unclear. OBJECTIVE: To observe the effect of low-intensity pulsed ultrasound on early angiogenesis after acute tendon injury, and to detect the regulatory relationship of low-intensity pulsed ultrasound with vascular endothelial growth factor-related signaling pathways, so as to reveal its potential mechanism of action. METHODS: Animal models of acute Achilles tendon injury were established using local injection of type I collagenase for 3 days in SPF male Sprague-Dawley rats aged 8-12 weeks, and were then randomly divided into ultrasound group and control group. In the ultrasound group, low-intensity pulsed ultrasound was treated daily with a small ultrasonic probe with an effective radiation area of 1 cm2 perpendicular to the Achilles tendon. No intervention was performed in the control group. Ultrasound imaging examination was performed 2 weeks later to observe the early healing of the tendon. Hematoxylin-eosin staining and CD31 immunohistochemical staining were performed to observe the changes in the number of blood vessels in the tissues after 1 and 2 weeks of treatment. The expression of vascular endothelial growth factor-related signaling pathway molecules in Achilles tendon tissues was detected by western blot or qRT-PCR. RESULTS AND CONCLUSION: Compared with the control group, the Achilles tendon in the ultrasound group was more continuous, the echo intensity was lower and more uniform, and the tendon thickness was significantly reduced (P < 0.05). Hematoxylin-eosin staining and CD31 immunohistochemical staining results showed that after 2 weeks of treatment, the number of new vessels in the ultrasound group was significantly increased compared with the control group (P < 0.05). Western blot and qRT-PCR results showed that after 2 weeks of continuous ultrasound intervention, the protein or mRNA expressions of vascular endothelial growth factor, Yes-associated protein, angiopoietin-2 and cysteine-rich angiogenic inducer 61 in the Achilles tendon of the ultrasound group were significantly higher than those of the control group (P < 0.05). These finding indicate that low-intensity pulsed ultrasound significantly increases the number of blood vessels in the early stage of acute tendon injury and accelerate tendon healing by up-regulating vascular endothelial growth factor expression. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mesenchymal stem cells are susceptible to senescence during in vitro expansion, which greatly hinders their application in vivo and in vitro. How to improve the replicative senescence of mesenchymal stem cells is an urgent problem to be solved in tissue engineering. OBJECTIVE: To determine whether vascular endothelial growth factor combined with basic fibroblast growth factor can improve the aging of bone marrow mesenchymal stem cells caused by replicative passage. METHODS: Rat bone marrow mesenchymal stem cells were extracted by whole bone marrow adhesion method. Passage 2 cells were selected as normal control group. Passage 7 and later algebraic cells were selected as aging model group. Vascular endothelial growth factor (50 μg/L), basic fibroblast growth factor (10 μg/L), and their combination were administered. Cell proliferation was detected by CCK-8 assay. Cell senescence was observed by β-galactosidase activity staining. Cytoskeleton size and colony formation ability were observed by phalloidine staining and Giemsa staining, respectively, and the levels of senescence-related genes P16, P21, and P53 were detected by qRT-PCR. Gene expression levels of P16, P21, and P53 were tested by qRT-PCR. RESULTS AND CONCLUSION: (1) Vascular endothelial growth factor combined with basic fibroblast growth factor could promote the proliferation of aged bone marrow mesenchymal stem cells, which began to enter the plateau stage on day 9, and the absorbance value of the combined intervention group was significantly higher than that of the model group on day 9 (P < 0.05). (2) The phenotypic markers of the cells in the combined intervention group did not change, and the cell morphology changed from broad to slender. (3) Compared with the model group, the positive rate of β-galactosidase was significantly decreased (P < 0.01); the number of nuclei increased (P < 0.001); the total area of cytoskeleton increased (P < 0.01); colony formation ability was enhanced (P < 0.05); expression level of P16 was decreased (P < 0.01) in the combined intervention group. These results indicate that vascular endothelial growth factor combined with basic fibroblast growth factor can improve the senescence of bone marrow mesenchymal stem cells caused by replicative passage without changing the cell phenotype. [ABSTRACT FROM AUTHOR]

BACKGROUND: Heterotopic ossification is a dynamic growth process. Diverse heterotopic ossification subtypes have diverse etiologies or induction factors, but they exhibit a similar clinical process in the intermediate and later phases of the disease. Acquired heterotopic ossification produced by trauma and other circumstances has a high incidence. OBJECTIVE: To summarize the molecular biological mechanisms linked to the occurrence and progression of acquired heterotopic ossification in recent years. METHODS: The keywords “molecular biology, heterotopic ossification, mechanisms” were searched in CNKI, Wanfang, PubMed, Embase, Web of Science, and Google Scholar databases for articles published from January 2016 to August 2022. Supplementary searches were conducted based on the obtained articles. After the collected literature was screened, 131 articles were finally included and summarized. RESULTS AND CONCLUSION: (1) The occurrence and development of acquired heterotopic ossification is a dynamic process with certain concealment, making diagnosis and treatment of the disease difficult. (2) By reviewing relevant literature, it was found that acquired heterotopic ossification involves signaling pathways such as bone morphogenetic protein, transforming growth factor-β, Hedgehog, Wnt, and mTOR, as well as core factors such as Runx-2, vascular endothelial growth factor, hypoxia-inducing factor, fibroblast growth factor, and Sox9. The core mechanism may be the interaction between different signaling pathways, affecting the body’s osteoblast precursor cells, osteoblast microenvironment, and related cytokines, thereby affecting the body’s bone metabolism and leading to the occurrence of acquired heterotopic ossification. (3) In the future, it is possible to take the heterotopic ossification-related single-cell osteogenic homeostasis as the research direction, take the osteoblast precursor cells-osteogenic microenvironment-signaling pathways and cytokines as the research elements, explore the characteristics of each element under different temporal and spatial conditions, compare the similarities and differences of the osteogenic homeostasis of different types and individuals, observe the regulatory mechanism of the molecular signaling network of heterotopic ossification from a holistic perspective. It is beneficial to the exploration of new methods for the future clinical prevention and treatment of heterotopic ossification. (4) Meanwhile, the treatment methods represented by traditional Chinese medicine and targeted therapy have become research hotspots in recent years. How to link traditional Chinese medicine with the osteogenic homeostasis in the body and combine it with targeted therapy is also one of the future research directions. (5) At present, the research on acquired heterotopic ossification is still limited to basic experimental research and the clinical prevention and treatment methods still have defects such as uncertain efficacy and obvious side effects. The safety and effectiveness of relevant targeted prevention and treatment drugs in clinical application still need to be verified. Future research should focus on clinical prevention and treatment based on basic experimental research combined with the mechanism of occurrence and development. [ABSTRACT FROM AUTHOR]

Objective(s): Methotrexate (MTX) is a drug with anti-inflammatory and immunosuppressive effects and is also a folic acid antagonist. Our aim in this study is to determine the molecular mechanisms of cardiotoxicity caused by MTX, a chemotherapeutic drug, and to evaluate the protective effects of vitamin B12 on this toxicity. Materials and Methods: A total of 32 rats were used in our study and 4 groups were formed. Control group, Vit B12 group (3 μg/kg B12 for 15 days, IP), MTX group (20 mg/kg MTX single dose on day 8 of the experiment, IP), MTX +Vit B12 group (3 μg/kg, IP ), Vit B12 throughout the 15 days, and a single dose of 20 mg/kg MTX (IP) on day 8 of the experiment. Immunohistochemically, expressions of hypoxia-inducible factor 1α (HIF1-α), vascular endothelial growth factor receptor-2 (VEGFR-2), erythropoietin (EPO), and interleukin-6 (IL-6) were evaluated in the heart tissue. Total catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA) levels were measured in the heart tissue. At the same time, ANP and NT-proBNP levels were measured in the blood serum.Results: In the study, the expression of HIF1-α and VEGFR-2 increased significantly in the MTX group, while IL-6 and EPO significantly decreased. At the same time, CAT and SOD levels were significantly decreased and MDA levels increased significantly in the MTX group. While vitamin B12 significantly corrected all these values, it also greatly reduced the increases in ANP and NT-proBNP levels caused by MTX.Conclusion: It is important to use Vit B12 before and after MTX administration to replace the folate that MTX has reduced.

The aim of this study was to determine the tissue expressions of vascular endothelial growth factor (VEGF) and endocan in adrenal cortical tumors and the factors associated with them. The study included 6 subjects with adrenocortical adenoma (ACA), 7 subjects with adrenocortical carcinoma (ACC), and 13 control subjects with a normal adrenal cortex. The status of VEGF and endocan expression was determined by the proportions of cells staining on a scale ranging from negative (not staining at all) to strongly positive. VEGF expression was detected in 1 (16.7%) of 6 subjects in the ACA group and in 6 (85.7%) of 7 subjects in the ACC group. VEGF expression was not detected in any of the subjects in the control group. Endocan expression was detected in 6 (100%) of 6 subjects in the ACA group and in 7 (100%) of 7 subjects in the ACC group, while it was detected in only 4 (30.7%) of 13 subjects in the control group. VEGF was expressed with a high frequency in subjects with ACC and with a low frequency in subjects with ACA, but it was not expressed in subjects with normal adrenal cortex tissue. Although endocan was expressed with a higher frequency in subjects with ACC and ACA, it was also expressed in subjects with normal adrenal cortex tissue. The percentage of cells expressed endocan in subjects with ACC was also significantly higher than in subjects with both ACA and normal adrenal cortex.

Abstract Diabetic retinopathy (DR) is a multifactorial disease displaying vascular-associated pathologies, including vascular leakage and neovascularization, ultimately leading to visual impairment. However, animal models accurately reflecting these pathologies are lacking. Vascular endothelial growth factor A (VEGF-A) is an important factor in the development of micro- and macro-vascular pathology in DR. In this study, we evaluated the feasibility of using a cumate-inducible lentivirus (LV) mediated expression of vegf-a to understand DR pathology in vitro and in vivo. Retinal pigment epithelial cells (ARPE-19) were transduced with cumate-inducible LV expressing vegf-a, with subsequent analysis of vegf-a expression and its impact on cell proliferation, viability, motility, and permeability. Cumate tolerability in adult Wistar rat eyes was assessed as an initial step towards a potential DR animal model development, by administering cumate via intravitreal injections (IVT) and evaluating consequent effects by spectral domain optical coherence tomography (SD-OCT), flash electroretinography (fERG), ophthalmic examination (OE), and immunohistochemistry. Transduction of ARPE-19 cells with cumate-inducible LV resulted in ~ 2.5-fold increase in vegf-a mRNA and ~ threefold increase in VEGF-A protein secretion. Transduced cells displayed enhanced cell proliferation, viability, permeability, and migration in tube-like structures. However, IVT cumate injections led to apparent retinal toxicity, manifesting as retinal layer abnormalities, haemorrhage, vitreous opacities, and significant reductions in a- and b-wave amplitudes, along with increased microglial activation and reactive gliosis. In summary, while cumate-inducible LV-mediated vegf-a expression is valuable for in vitro mechanistic studies in cellular drug discovery, its use is not a feasible approach to model DR in in vivo studies due to cumate-induced retinal toxicity.

Abstract Background Gastrointestinal tract (GIT) cancers are complex disorders affecting millions of people worldwide. The vascular endothelial growth factor (VEGF) helps in the development of different GIT cancers by promoting abnormal angiogenesis in cancer cells. The role of VEGF-2549I/D polymorphism in influencing GIT cancer susceptibility has been studied in different populations with inconclusive results. Therefore, the relationship between VEGF-2549I/D polymorphism with GIT susceptibility was studied by performing a meta-analysis study. Methods Various online databases were used for identifying the articles. Based on study selection criteria, five studies on different GIT cancers including 1178 patients and 1520 controls were included in the meta-analysis. The accuracy of the study results was determined by performing a trial sequential analysis. Results In this study, the VEGF-2549I/D polymorphism did not influence the GIT cancer susceptibility in the overall analysis as well as when stratified according to ethnicity (p > 0.05). Stratification of all the studies based on the different GIT cancers reported an increased susceptibility to gastric cancer under different genetic models including allele contrast (OR = 1.67, CI = 1.294–2.157, p = 0.00008), recessive (OR = 1.68, CI = 1.056–2.660, p = 0.029), dominant (OR = 2.49, CI = 1.617–3.823, p = 0.00003), over-dominant (OR = 1.52, CI = 1.055–2.177, p = 0.025), II vs DD (OR = 2.97, CI = 1.692–5.208, p = 0.00015) and ID vs DD model (OR = 2.35, CI = 1.501–3.669, p = 0.00018). Conclusion There was no relationship between VEGF-2549I/D promoter polymorphism and GIT cancer susceptibility in the overall population and also in different ethnic groups. Stratification analysis revealed higher susceptibility towards gastric cancer development with VEGF-2549I/D polymorphism.