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PURPOSE: Cell-free circulating tumor DNA (ctDNA) has shown its potential as a quantitative biomarker for longitudinal monitoring of response to anticancer therapies. However, ctDNA dynamics have not been studied in patients with heavily pretreated, advanced solid tumors, for whom therapeutic responses can be weak. We investigated whether changes in ctDNA could predict clinical outcomes in such a cohort treated with combined poly(ADP-ribose) polymerase/vascular endothelial growth factor receptor inhibitor therapy. MATERIALS AND METHODS: Patients with metastatic pancreatic ductal adenocarcinoma (PDAC), triple-negative breast cancer (TNBC), small-cell lung cancer (SCLC), or non–small-cell lung cancer (NSCLC) received up to 7 days of cediranib 30 mg orally once daily monotherapy lead-in followed by addition of olaparib 200 mg orally twice daily. Patients had progressed on a median of three previous lines of therapy. Plasma samples were collected before and after cediranib monotherapy lead-in and on combination therapy at 7 days, 28 days, and every 28 days thereafter. ctDNA was quantified from plasma samples using a multigene mutation–based assay. Radiographic assessment was performed every 8 weeks. RESULTS: ctDNA measurements were evaluable in 63 patients. The median baseline ctDNA variant allele fractions (VAFs) were 20%, 28%, 27%, and 34% for PDAC, TNBC, SCLC, and NSCLC, respectively. No association was observed between baseline VAF and radiographic response, progression-free survival, or overall survival (OS). Similarly, no association was found between ctDNA decline and radiographic response or survival. However, an increase in ctDNA at 56 days of combination therapy was associated with disease progression and inferior OS in a landmark analysis. CONCLUSION: ctDNA levels or dynamics did not correlate with radiographic response or survival outcomes in patients with advanced metastatic malignancies treated with olaparib and cediranib. [ABSTRACT FROM AUTHOR]

New technologies have resulted in a better understanding of blood and lymphatic vascular heterogeneity at the cellular and molecular levels. However, we still need to learn more about the heterogeneity of the cardiovascular and lymphatic systems among different species at the anatomical and functional levels. Even the deceptively simple question of the functions of fish lymphatic vessels has yet to be conclusively answered. The most common interpretation assumes a similar dual setup of the vasculature in zebrafish and mammals: a cardiovascular circulatory system, and a lymphatic vascular system (LVS), in which the unidirectional flow is derived from surplus interstitial fluid and returned into the cardiovascular system. A competing interpretation questions the identity of the lymphatic vessels in fish as at least some of them receive their flow from arteries via specialised anastomoses, neither requiring an interstitial source for the lymphatic flow nor stipulating unidirectionality. In this alternative view, the 'fish lymphatics' are a specialised subcompartment of the cardiovascular system, called the secondary vascular system (SVS). Many of the contradictions found in the literature appear to stem from the fact that the SVS develops in part or completely from an embryonic LVS by transdifferentiation. Future research needs to establish the extent of embryonic transdifferentiation of lymphatics into SVS blood vessels. Similarly, more insight is needed into the molecular regulation of vascular development in fish. Most fish possess more than the five vascular endothelial growth factor (VEGF) genes and three VEGF receptor genes that we know from mice or humans, and the relative tolerance of fish to whole‐genome and gene duplications could underlie the evolutionary diversification of the vasculature. This review discusses the key elements of the fish lymphatics versus the SVS and attempts to draw a picture coherent with the existing data, including phylogenetic knowledge. [ABSTRACT FROM AUTHOR]

Objective: This study aimed at ascertaining the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with donafenib versus HAIC alone in the treatment of unresectable hepatocellular carcinoma (HCC). Methods: Seventy HCC patients were enrolled for our study, and they were randomized by simple randomization using computer‐generated random numbers into two groups: control group and observation group. Regular follow‐up reviews were conducted to assess the efficacy of treatments. The levels of apoptotic factors, the levels of hepatic fibrosis indices, the levels of serum tumor vascular factors and tumor markers, and the occurrence of adverse reactions in the two groups were recorded and compared. Results: Disease control rate, objective response rate, and progression‐free survival (PFS) of patients in the observation group were higher in contrast to the control group. After 12 weeks of treatment, lower mRNA expression of c‐mesenchymal‐epithelial transition factor, telomerase, and Fas Ligand and higher mRNA expression of Fas and Caspase‐3 were observed in HCC tissues of the observation group versus the control group (p < 0.05); lower detection values of serum laminin, hyaluronic acid, collage type IV, vascular endothelial growth factor receptor 2, and alpha‐fetal protein (AFP) were noted in HCC patients of the observation group in comparison to the control group (p < 0.05); there was no difference in the incidence of adverse reactions between the two groups. Conclusion: Donafenib combined with HAIC in the treatment of unresectable HCC patients can notably reduce serum AFP levels, improve hepatic fibrosis, enhance short‐term efficacy, prolong PFS, and have a favorable safety profile. [ABSTRACT FROM AUTHOR]

The high rate of recurrence after radiation therapy in triple-negative breast cancer (TNBC) indicates that novel approaches and targets are needed to enhance radiosensitivity. Here, we report that neuropilin-2 (NRP2), a receptor for vascular endothelial growth factor (VEGF) that is enriched on subpopulations of TNBC cells with stem cell properties, is an effective therapeutic target for sensitizing TNBC to radiotherapy. Specifically, VEGF/NRP2 signaling induces nitric oxide synthase 2 (NOS2) transcription by a mechanism dependent on Gli1. NRP2-expressing tumor cells serve as a hub to produce nitric oxide (NO), an autocrine and paracrine signaling metabolite, which promotes cysteine-nitrosylation of Kelch-like ECH-associated protein 1 (KEAP1) and, consequently, nuclear factor erythroid 2-related factor 2-mediated (NFE2L2-mediated) transcription of antioxidant response genes. Inhibiting VEGF binding to NRP2, using a humanized mAb, results in NFE2L2 degradation via KEAP1, rendering cell lines and organoids vulnerable to irradiation. Importantly, treatment of patient-derived xenografts with the NRP2 mAb and radiation resulted in significant tumor necrosis and regression compared with radiation alone. Together, these findings reveal a targetable mechanism of radioresistance, and they support the use of NRP2 mAb as an effective radiosensitizer in TNBC. [ABSTRACT FROM AUTHOR]

AbstractDiabetic foot ulcers (DFUs) are a severe microvascular complication. Platelet-rich plasma (PRP) pitches in DFU treatment. This study explored the mechanism of PRP facilitating wound repair in DFU mice via vascular endothelial growth factor A (VEGFA)/VEGF receptor 2 (VEGFR2)/extracellular signal-regulated kinase (ERK) pathway. The DFU mouse model was established, with wound skin injected with PRP, followed by the detections of wound area, histopathological changes, and CD31-positive cells. IL-6/TNF-α/VEGFA/VEGFR2/p-VEGFR2/(ERK1/2)/(p-ERK1/2) levels in wound tissue homogenates were assessed. VEGFA-VEGFR2 interaction was evaluated. PRP-treated DFU mice were simultaneously treated with fruquintinib/PD98059. PRP reduced wound area, IL-6 and TNF-α levels, elevated epidermal dermal thickness, CD31-positive cell number, and aligned tissue structure, which were mitigated by fruquintinib/PD98059. PRP promoted VEGFR2 phosphorylation. PRP and fruquintinib/PD98059 abated p-VEGFR2/VEGFR2 or p-ERK1/2/ERK1/2 levels in DFU mice. PRP activated the ERK pathway through VEGFA/VEGFR2. Collectively, PRP promoted VEGFR2 phosphorylation and activated the ERK pathway, thereby facilitating wound repair in DFU mice. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions The global pandemic of coronavirus disease 2019 (COVID‐19) represented a major public health concern. Growing evidence shows that plasma of COVID‐19 patients contains large numbers of circulating extracellular vesicles (cEVs) that correlate with disease severity and recovery. In this study, we sought to characterize the longitudinal cEV signature in critically ill COVID‐19 patients during hospitalization and its relation to mortality risk.cEVs were quantitatively and phenotypically analysed in hospitalized non‐surviving COVID‐19 patients at baseline (n = 42) and before exitus (n = 40) and in 40 healthy volunteers as a reference group by high sensitivity nano flow cytometry using specific markers for parental cell sources and activation.Levels of cEV subtypes differed between patients with severe COVID‐19 and healthy subjects, specifically those from platelets and endothelial, inflammatory and viral infected cells, which associate to high mortality risk. In the longitudinal analysis from baseline to the time point immediately preceding death, no changes were found for platelet, pan‐leukocyte, and lung epithelial cell‐shed cEVs, while endothelial cell releases of EVs (eEVs) significantly differed. Vascular endothelial growth factor receptor 2‐positive eEVs were significantly increased before death compared to admission whereas endoglin and E‐selectin‐containing eEVs did not change. Conversely, lymphocyte (ℓEV), monocyte, macrophage, pericyte and progenitor cell‐derived cEVs displayed significant reductions before exitus. Noteworthy, levels of CD45+/CD3+‐ℓEVs were significantly associated to the patient's survival time.An evolving cEV profile able to discriminate prompt risk of death during hospitalization has been defined suggesting a role for circulating and vascular cell‐derived EVs in COVID‐19 pathogenesis. [ABSTRACT FROM AUTHOR]

Introduction: Activated vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs) and c-Kit have been shown to be involved in the growth, invasion and metastasis of non-rhabdomyosarcoma soft tissue sarcoma tumor (NRSTS) with promising results for targeted therapy. Our aim was to assess the expression of these markers among different histological types and correlate with outcomes. Material and methods: This retrospective study included pediatric patients aged ≤ 18 years diagnosed with high-grade NRSTS who were treated at Children Cancer Hospital Egypt 57357 as per the COG NRSTS protocol (ARST0332). Expression of VEGFR2, PDGFRs (α and β) and c-Kit in tumor tissue was assessed by immunohistochemistry and correlated with clinical outcome. Results: Of 113 patients, 96 were eligible for the analysis with a median age of 11 years. Overall, 32.3% demonstrated high expression of PDGFRα, 17.7% for PDGFRβ, 19.8% for VEGFR2 and 8.3% exhibited positive expression for c-kit on the tumor cells. Most cases of synovial sarcoma (45.8%) and 43.7% of patients with undifferentiated sarcoma exhibited high expression of PDGFRα while 41.6% of MPNST showed high expression to PDGFRβ. The 5-year overall survival (OS), event free survival and relapse free survival (RFS) for the whole cohort were 59%, 54% and 60% respectively. In univariate analyses, only PDGFRα had a negative prognostic impact on relapse free survival (RFS) (p =0.03). In multivariate analyses, VEGFR2 was found to have a negative prognostic impact for OS (p = 0.02). Conclusion: Our findings indicated that tyrosine kinase receptors are upregulated in NRSTS and exhibited a distinct expression pattern within various subgroups. High expression of VEGFR2 and PDGFRα significantly correlated with reduced survival and may guide targeted therapy approaches for this poor prognosis group of patients. [ABSTRACT FROM AUTHOR]

The hematopoietic system of Drosophila is a well‐established genetic model for studying hematopoiesis mechanisms, which are strictly regulated by multiple signaling pathways. Autophagy‐related 2 (Atg2) protein is involved in autophagosome formation through its lipid transfer function; however, other functions in animal development, especially the role of Atg2 in maintaining hematopoietic homeostasis, are unclear. Here, we show that Atg2 knockdown in the cortical zone (CZ) induced the proliferation and differentiation of mature plasmatocytes and disrupted progenitor maintenance in the medullary zone (MZ). We also observed the differentiation of lamellocytes among circulating hemocytes and in the lymph gland, which is rarely observed in healthy larvae. The above results on hematopoiesis disorders are due to Atg2 regulating the Drosophila PDGF/VEGF receptor (PVR) and target of rapamycin (TOR) in the CZ of lymph gland. In conclusion, we identified Atg2 as a previously undescribed regulator of hematopoiesis. Understanding the mechanism of maintenance of hematopoietic homeostasis in Drosophila will help us better evaluate human blood disorder‐related diseases. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to elucidate the differential immunological mechanisms and characteristics of hypertension induced by VEGF inhibitors (VEGFi) and VEGF receptor inhibitors (VEGFRi), with the goal of optimizing monitoring strategies and treatment protocols. Methods: We investigated the risk of immune-related adverse events associated with VEGFi/VEGFRi-induced hypertension by analyzing the FDA Adverse Event Reporting System (FAERS) database. Findings were corroborated with blood pressure characteristics observed in clinical patients and preclinical models exposed to various VEGF/VEGFRi. Clinical and preclinical studies were conducted to compare immunological responses and hypertension profiles between inhibitor classes. An integrative analysis across cancer types and species was performed, focusing on key signaling pathways. Results: Analysis of FAERS data, in conjunction with clinical observations, revealed that both VEGFi and VEGFRi significantly elevated the risk of immune-mediated, blood pressure-related adverse events (ROR=7.75, 95% CI: 7.76-7.95). Subsequent clinical and preclinical studies demonstrated differential immunological responses and hypertension profiles between inhibitor classes. VEGFRi exhibited a more rapid onset, greater blood pressure elevation, and higher incidence of immune-mediated adverse events compared to VEGFi (Systolic BP: ROR=0 for VEGFi vs. ROR=12.25, 95% CI: 6.54-22.96 for VEGFRi; Diastolic BP: ROR=5.09, 95% CI: 0.60-43.61 for VEGFi vs. ROR=12.90, 95% CI: 3.73-44.55 for VEGFRi). Integrative analysis across cancer types and species, focusing on key signaling pathways, revealed that VEGF/VEGFRi-induced blood pressure elevation was associated with immunomodulation of the mitogen activated protein kinase (MAPK) pathway (R=-0.379, P=0.0435), alterations in triglyceride metabolism (R=-0.664, P=0.0001), modulation of myo-inositol 1,4,5-trisphosphate-sensitive calcium release channel activity (R=0.389, P=0.0378), and dysregulation of nitric oxide eNOS activation and metabolism (R=-0.439, P=0.0179). Discussion: The temporal dynamics of these effects demonstrated greater significance than dose-dependent responses. Both VEGFi and VEGFRi significantly augmented the risk of immune-mediated, blood pressure-related adverse events, with VEGFRi inducing a more rapid and pronounced onset of blood pressure elevation and a higher incidence of immune-related, blood pressure-associated adverse events compared to VEGFi. [ABSTRACT FROM AUTHOR]

Context: Glioblastoma (GBM), well known as grade 4 tumors due to its progressive malignant features such as vascular proliferation and necrosis, is the most aggressive form of primary brain tumor found in adults. Mutations and amplifications in the vascular endothelial growth factor receptor (VEGFR) contribute to almost 25% of GBM tumors. And thus, VEGFR has been declared the primary target in glioblastoma therapeutic strategies. However, many studies have been previously reported that include GBM as global therapeutics challenge, but they lack the molecular level insights that could help in understanding the biological function of a therapeutically important protein playing a major role in the disease and design the best strategies to develop the potential drugs. Methods: Therefore, to the best of our knowledge, the present study is the first time of kind, which involves multi-in silico approaches to predict the inhibition potential of withanolides from Withania coagulan against VEGFR. The study is actually based on determining the mode of action of five isolates: withanolide J, withaperuvin, 27-hydroxywithanolide I, coagule E, and coagule E, along with their respective binding energies. Molecular docking simulations revealed primarily four ligands, withanolide J (− 7.33 kJ/mol), 27-withanolide (− 7.01 kJ/mol), ajugine, withaperuvin (− 6.89 kJ/mol), and ajugine E (− 6.39 kJ/mol), to have significant binding potencies against the protein. Ligand binding was found to enhance the confirmational stability of the protein revealed through RMSD analysis, and RMSF assessment revealed the protein residues especially from 900–1000 surrounding the binding of the protein. Structural and dynamics of the protein via dynamics cross-correlation movement (DCCM) and principal component analysis (PCA) in both the unbound form and complexed with most potent ligand, withanolide J, reveal the ligand binding affecting the entire conformational integrity of the protein stabilized by hydrogen bonds and electrostatic attractions. Free energy of binding estimations by means of molecular mechanics Poisson-Boltzmann surface area (MMPBSA) method further revealed the withanolide J to have maximum binding potency of the all ligands. Withanolide J in final was also found to have suitable molecular characterizations to cross the blood–brain barrier (BBB +) and reasonable human intestinal absorption ability determined by ADMET profiling via admetSAR tools. [ABSTRACT FROM AUTHOR]

Continuous treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitor + immunotherapy against the PD1 is one option for upfront treatment of metastatic renal cell carcinoma, but this is characterised by toxicity leading to treatment interruption or discontinuation. The TIDE-A investigated the axitinib withdrawal and avelumab maintenance in patients achieving a response during the combo treatment, reporting resolution of axitinib-related toxicity. The median progression-free survival was 23.8 mo, while the duration of treatment interruption was 16 wk. Combinations of VEGFR-TKIs plus ICI against PD1/PD-L1 are the standard first-line therapy for patients with mRCC, irrespective of the prognostic class. This study aims to investigate the feasibility and safety of withdrawing the VEGFR-TKI but continuing the anti- PD1/PD-L1 in patients who achieve response to their combination. This was a single-arm phase 2 trial in patients with treatment naïve mRCC with prior nephrectomy, without symptomatic/bulky disease and no liver metastases. Enrolled patients received axitinib+avelumab, after 36 weeks of therapy those who achieved tumor response interrupted axitinib and continued avelumab maintenance until disease progression. The primary endpoint was the rate of patients without progression eight weeks after the axitinib interruption. Secondary endpoints were the median value for progression free (mPFS) and overall survival (mOS) and the safety in the overall population. 79 patients were enrolled and 75 evaluated for efficacy. A total of 29 (38%) patients had axitinib withdrawn, as per the study design, with 72% of them having no progression after eight weeks and thus achieving the primary endpoint. The mPFS of the overall population was 24 months while the mOS was not reached. The ORR was 76% (12% CR, 64% PR), with 19% of patients having stable disease. In the patients who discontinued axitinib, the incidence of AEs of any grade was 59% and 3% for grade 3 or 4. This study was limited by the lack of the comparative arm. The TIDE-A study demonstrates that the withdrawal of VEGFR-TKI with ICI maintenance is feasible for selected mRCC patients with evidence of response to the VEGFR-TKI+ICI combination employed in first-line therapy. Axitinib interruption with avelumab maintenance led to decreased side effects and should be further investigated as a new strategy to delay tumor progression. [ABSTRACT FROM AUTHOR]

The article in the JNCI: Journal of the National Cancer Institute celebrates Glenn Algire's 1945 pioneering contribution to antiangiogenic therapy for cancer. Algire's observations on tumor angiogenesis laid the foundation for Judah Folkman's idea in 1971 that angiogenesis inhibitors could be used to treat cancer. The article discusses the development of VEGF inhibitors and other antiangiogenic drugs, as well as the challenges and potential future directions in antiangiogenic cancer therapy. It emphasizes the complexity of tumor angiogenesis regulation and the need to explore new strategies beyond VEGF-targeted therapies to improve efficacy in cancer treatment. [Extracted from the article]

Despite breakthroughs of immunotherapy synergistically combined with blockade of vascular endothelial growth factor receptor, several patients with advanced non‐small cell lung cancer (NSCLC) experience non‐response or followed relapse. Organized lymphoid aggregates, termed tertiary lymphoid structures (TLSs), are found to be associated with improved response to immunotherapy. Here, we explore the landscapes of TLSs in tumour tissues from a real‐world retrospective study. Our investigation showed that with a median follow‐up of 11.2 months, the ORR was 28.6% (18/63, 95% CI 17.9–41.3) and the median PFS was 6.1 (95% CI 5.5–6.6) months in NSCLC patients treated with PD‐1 blockade combined with anlotinib. By multiplex immunofluorescence (mIF) analysis, spatially, more TLSs and high CD20+ B‐cell ratio in TLSs were associated with higher ORR. High density of intratumoral CD8+ T cells showed better ORR and PFS. The numbers of CD8+ T cells with a distance within 20 μm and 20–50 μm between tumour cells were higher in responders than non‐responders. But responders had significantly higher TLSs within 20 μm rather than within 20–50 μm of tumour cells than non‐responders. The inflamed immunophenotyping occupied higher proportions in responders and was associated with better PFS. Besides, tumour cells in non‐responders were found more temporal cell‐in‐cell structures than responders, which could protect inner cells from T‐cell attacks. Taken together, landscape of TLSs and proximity architecture may imply superior responses to PD‐1 blockade combined with anlotinib for patients with advanced non‐small cell lung cancer. [ABSTRACT FROM AUTHOR]

Nicotine acts as an angiogenic factor by stimulating endogenous cholinergic pathways. Several subtypes of nicotinic acetylcholine receptors (nAChRs) have been demonstrated to be closely correlated to the formation and progression of different types of cancers. Recently, several studies have found that nicotinic acetylcholine receptors α9 (α9-nAChRs) are highly expressed in breast tumors, especially in tumors derived from patients diagnosed at advanced stages. In vitro studies have demonstrated that activation of α9-nAChRs is associated with increased proliferation and migration of breast cancer. To study the tumor-promoting role of α9-nAChRs in breast cancers, we generated a novel anti-α9-nAChR and methoxy-polyethylene glycol (mPEG) bispecific antibody (α9 BsAb) for dissecting the molecular mechanism on α9-nAChR-mediated tumor progression. Unexpectedly, we discovered the angiogenic role of α9-nAChR in nicotine-induced neovascularization of tumors. It revealed α9 BsAbs reduced nicotine-induced endothelial cell tube formation, blood vessel development in Matrigel plug assay and angiogenesis in microtube array membrane murine model (MTAMs). To unbraid the molecular mechanism of α9-nAChR in nicotine-mediated angiogenesis, the α9 BsAbs were applied and revealed the inhibitory roles in nicotine-induced production of hypoxia-inducible factor-2 alpha (HIF-2α), vascular endothelial growth factor A (VEGF-A), phosphorylated vascular endothelial growth factor receptor 2 (p-VEGFR2), vascular endothelial growth factor receptor 2 (VEGFR2) and matrix metalloproteinase-9 (MMP9) from triple-negative breast cancer cells (MDA-MB-231), suggesting α9-nAChRs played an important role in nicotine-induced angiogenesis. To confirm our results, the shRNA targeting α9-nAChRs was designed and used to silence α9-nAChR expression and then evaluated the angiogenic role of α9-nAChRs. The results showed α9 shRNA also played an inhibitory effect in blocking the nicotine-induced angiogenic signaling. Taken together, α9-nAChR played a critical role in nicotine-induced angiogenesis and this bispecific antibody (α9 BsAb) may serve as a potential therapeutic candidate for treatments of the α9 positive cancers. [ABSTRACT FROM AUTHOR]

Fine-tuning angiogenesis, the development of new blood vessels, is essential for maintaining a healthy circulatory and lymphatic system. The small glycoprotein vascular endothelial growth factors (VEGF) are the key mediators in this process, binding to their corresponding membrane-bound VEGF receptors (VEGFRs) to activate angiogenesis signaling pathways. These pathways are crucial throughout human life as they are involved in lymphatic and vascular endothelial cell permeability, migration, proliferation, and survival. Neovascularization, the formation of abnormal blood vessels, occurs when there is a dysregulation of angiogenesis and can result in debilitating disease. Hence, VEGFRs have been widely studied to understand their role in disease-causing angiogenesis. VEGFR1, also known as Fms-like tyrosine kinase-1 (FLT-1), is also found in a soluble form, soluble FLT-1 or sFLT-1, which is known to act as a VEGF neutralizer. It is incorporated into anti-VEGF therapy, designed to treat diseases caused by neovascularization. Here we review the journey of sFLT-1 discovery and delve into the alternative splicing mechanism that creates the soluble receptor, its prevalence in disease states, and its use in current and future potential therapies. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionCrimean-Congo hemorrhagic fever (CCHF), an acute viral hemorrhagic fever disease, has a high mortality rate among humans. Hemorrhagic propensity is caused by coagulation malfunction and increased capillary permeability brought on by the resultant vascular injury. Vascular endothelial growth factor (VEGF) and VEGF receptor-2, or KDR (kinase insert domain containing receptor), are effective in vasculogenesis and angiogenesis. CCHF was stated to have endothelial dysfunction. This study aimed to evaluate whether the VEGF and KDR gene variants contribute to the development of CCHF in the Turkish population.A total of 101 subjects, including 51 CCHF patients and 50 healthy controls, were included in the study. The polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method was used to genotype VEGF 936 C > T (rs3025039) and KDR − 604 T > C (rs2071559) variants. The results were statistically analyzed.The VEGF 936 C > T genotype and allele distributions did differ significantly between the patients and the controls. The subjects carrying the C/C genotype and C allele had a higher risk of developing CCHF than the control group (p˂0.05). There was a statistically significant association between the controls and the patients in terms of VEGF 936 C > T C/C versus C/T + T/T (p˂0.05, OR:3.273, 95%Cl: 1.44–7.63). The KDR − 604 T > C variant’s allele and genotype distribution were not significantly different between the patients and controls.This study suggests the VEGF 936 C > T variant is a genetic marker of sensitivity to CCHF among the Turkish population and may help protect against the disease. [ABSTRACT FROM AUTHOR]

Choroidal neovascularization (CNV) underlies the crux of many angiogenic eye disorders. Although medications that target vascular endothelial growth factor (VEGF) are approved for treating CNV, their effectiveness in destroying new blood vessels is limited, and invasive intravitreal administration is required. Additionally, other drugs that destroy established neovessels, such as combretastatin A‐4, may have systemic side effects that limit their therapeutic benefits. To overcome these shortcomings, a two‐pronged anti‐vascular approach is presented for CNV treatment using a photoactivatable nanoparticle system that can release a VEGF receptor inhibitor and a vascular disrupting agent when irradiated with 690 nm light. The nanoparticles can be injected intravenously to enable anti‐angiogenic and vascular disrupting combination therapy for CNV through light irradiation to the eyes. This approach can potentiate therapeutic effects while maintaining a favorable biosafety profile for choroidal vascular diseases. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is typically characterized by rich vascularity, with angiogenesis playing a crucial role in its growth and invasion. Molecular imaging of specific receptors in blood vessels is crucial in HCC diagnosis. In particular, in vivo imaging utilizing the second near‐infrared (NIR‐II) window offers improved tissue penetration, reduced light scattering, and lower autofluorescence. Despite the great potential of the NIR‐II window, developing safe and effective probes to provide better imaging performance for HCC is urgently needed. In this study, NIR‐II imaging integrated with a vascular endothelial growth factor receptor (VEGFR)‐targeted probe generated by combining a VEGFR‐targeted peptide with indocyanine green (ICG) is used to characterize HCC‐related angiogenesis at a resolution of 56.0 µm. For the first time, liver metabolic curves and parameters of liver function reserve (LFR) are obtained by fitting NIR‐II fluorescence signals with high spatiotemporal resolution, showing significant differences between HCC mice and controls. Moreover, unlike ICG, the targeting probe has a targeted effect on blood vessels in vivo. The tumor‐to‐normal (T/N) ratio in NIR‐II imaging reaches up to 3.30 after post‐injection of the targeting probe. The results indicate that the VEGFR‐targeted probe is a powerful tool for NIR‐II fluorescence imaging to enhance early diagnosis of HCC. [ABSTRACT FROM AUTHOR]

Lung squamous cell carcinoma (LUSC) is the second most common pathological type of non-small cell lung cancer (NSCLC). However, compared with lung adenocarcinoma (LUAD), the incidence of driver gene mutations in LUSC is relatively lower and treatment options for LUSC patients are very limited. We described a LUSC patient with a novel FGFR3-IER5L fusion revealed by next generation sequencing in this report. The patient refused surgery, radiotherapy or chemotherapy and received anlotinib treatment. Anlotinib is a small molecular multi-target tyrosine kinase inhibitor, which can inhibit the activity of kinases including vascular endothelial growth factor receptor 2/3 (VEGFR2/3), fibroblast growth factor receptor 1-4 (FGFR1-4), platelet-derived growth factor receptor a/ b (PDGFRa/b), and c-Kit. The patient achieved partial response and the progression-free survival was 3.8 months. [ABSTRACT FROM AUTHOR]

Background and Aims: Anti‐angiogenic therapies prolong patient survival in some malignancies but not glioblastoma. We focused on the relationship between the differentiation of glioma stem like cells (GSCs) into tumor derived endothelial cells (TDECs) and, anti‐angiogenic therapy resistance. Especially we aimed to elucidate the mechanisms of drug resistance of TDECs to anti‐angiogenic inhibitors and identify novel anti‐angiogenic drugs with clinical applications. Results: The mouse GSCs, 005, were differentiated into TDECs under hypoxic conditions, and TDECs had endothelial cell characteristics independent of the vascular endothelial growth factor (VEGF) pathway. In vivo, inhibition of the VEGF pathway had no anti‐tumor effect and increased the percentage of TDECs in the 005 mouse model. Novel anti‐angiogenic drugs for glioblastoma were evaluated using a tube formation assay and a drug repositioning strategy with existing blood–brain barrier permeable drugs. Drug screening revealed that the antidepressant sertraline inhibited tube formation of TDECs. Sertraline was administered to differentiated TDECs in vitro and 005 mouse models in vivo to evaluate genetic changes by RNA‐Seq and tumor regression effects by immunohistochemistry and MRI. Sertraline reduced Lama4 and Ang2 expressions of TDEC, which play an important role in non‐VEGF‐mediated angiogenesis in tumors. The combination of a VEGF receptor inhibitor axitinib, and sertraline improved survival and reduced tumor growth in the 005 mouse model. Conclusion: Collectively, our findings showed the diversity of tumor vascular endothelial cells across VEGF and non‐VEGF pathways led to anti‐angiogenic resistance. The combination of axitinib and sertraline can represent an effective anti‐angiogenic therapy for glioblastoma with safe, low cost, and fast availability. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGF) play important role in breast tumor growth, invasion, metastasis, patient survival and drug resistance. The aim of this study was to evaluate the protein expression status of EGFR and VEGF-A, as well as their association with hormone receptor status and histopathological characteristics in the invasive type of female breast cancer among Ethiopians. Method: The primary breast tumor tissues were obtained from 85 Ethiopian invasive breast cancer cases that underwent modified radical mastectomy (MRM) from June 2014 to June 2015. Their FFPE blocks were analyzed for EGFR and VEGF protein expressions using immunohistochemical techniques. The expressions were also correlated with histopathologic features. Result: Epidermal growth factor receptor over-expression was observed in 22% of the tumor samples. VEGF-A expression was negative in 13.41%, low in 63.41%, moderate in 20.73%, and high in 2.44%. EGFR expression, but not VEGF-A, showed a significant inverse correlation with both estrogen receptor (ER) (P = 0.01) and progesterone receptor (PR) statuses (P = 0.04). EGFR and VEGF expressions did not show significant association with tumor size, grade, lymph node status or age at diagnosis. Conclusion: Epidermal growth factor receptor expression was most likely associated with ER and PR negative tumors. Assessments of multiple molecular markers aid to understand the biological behavior of the disease in Ethiopian population. It might also help to predict which group of patients might get more benefit from the selected treatment strategies and which are not. [ABSTRACT FROM AUTHOR]

ABSTRACT Due to its intricate molecular and structural characteristics, vascular endothelial growth factor receptor 2 (VEGFR‐2) is essential for the development of new blood vessels in various pathological processes and conditions, especially in cancers. VEGFR‐2 inhibitors have demonstrated significant anticancer effects by blocking many signaling pathways linked to tumor growth, metastasis, and angiogenesis. Several small compounds, including the well‐tolerated sunitinib and sorafenib, have been approved as VEGFR‐2 inhibitors. However, the widespread side effects linked to these VEGFR‐2 inhibitors—hypertension, epistaxis, proteinuria, and upper respiratory infection—motivate researchers to search for new VEGFR‐2 inhibitors with better pharmacokinetic profiles. The key molecular interactions required for the interaction of the small molecules with the protein target to produce the desired pharmacological effects are identified using computer‐aided drug design (CADD) methods such as pharmacophore and QSAR modeling, structure‐based virtual screening, molecular docking, molecular dynamics (MD) simulation coupled with MM/PB(GB)SA, and other computational strategies. This review discusses the applications of these methods for VEGFR‐2 inhibitor design. Future VEGFR‐2 inhibitor designs may be influenced by this review, which focuses on the current trends of using multiple screening layers to design better inhibitors. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors are cornerstones of first-line treatment for advanced renal cell carcinoma; however, optimal treatment sequencing after progression is unknown. This study aimed to assess clinical outcomes of tivozanib–nivolumab versus tivozanib monotherapy in patients with metastatic renal cell carcinoma who have progressed following one or two lines of therapy in the post-ICI setting. TiNivo-2 is a multicentre, randomised, open-label, phase 3 trial at 190 sites across 16 countries, in Australia, Europe, North America, and South America. Patients with advanced renal cell carcinoma and progression during or after one to two previous lines of therapy (including one ICI) were randomised 1:1 to tivozanib (0·89 mg per day, orally) plus nivolumab (480 mg every 4 weeks, intravenously) or tivozanib (1·34 mg per day, orally). Randomisation was stratified by immediate previous therapy (ICI or non-ICI) and International Metastatic Renal Cell Carcinoma Database Consortium risk category. The primary endpoint was progression-free survival (PFS), defined as the time from randomisation to first documentation of objective progressive disease according to RECIST 1·1 or death from any cause, whichever came first, by independent radiology review. Efficacy was evaluated in the intention-to-treat population, and safety was assessed in patients who received one or more doses of the study drug. This trial was registered on ClinicalTrials.gov (NCT04987203) and is active and not recruiting. From Nov 4, 2021, to June 16, 2023, 343 patients were randomly assigned to tivozanib–nivolumab (n=171) or tivozanib monotherapy (n=172). Median follow-up was 12·0 months. Median PFS was 5·7 months (95% CI 4·0–7·4) with tivozanib–nivolumab and 7·4 months (5·6–9·2) with tivozanib monotherapy (hazard ratio 1·10, 95% CI 0·84–1·43; p=0·49). Among those with an ICI as their immediate previous therapy (n=244), median PFS was 7·4 months (95% CI 5·6–9·6) with tivozanib–nivolumab and 9·2 months (7·4–10·0) with tivozanib monotherapy. With non-ICIs as the most recent therapy, lower median PFS was observed, with no difference between groups (tivozanib–nivolumab 3·7 months [95% CI 2·7–5·4] and with tivozanib monotherapy 3·7 months [1·9–7·2]). Serious adverse events occurred in 54 (32%) of 168 patients receiving tivozanib–nivolumab and 64 (37%) of 171 patients receiving tivozanib monotherapy. One (<1%) treatment-related death occurred (tivozanib group). These data further support that ICI rechallenge should be discouraged in patients with advanced renal cell carcinoma. Furthermore, these data suggest that tivozanib monotherapy has efficacy in the post-ICI setting. Aveo Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Purpose: In this study, we evaluated 66 patients diagnosed with adenoid cystic carcinoma (ACC) enrolled in two Korean Cancer Study Group trials to investigate the response and progression patterns in recurrent and/or metastatic ACC treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). Materials and Methods: We evaluated 66 patients diagnosed with ACC who were enrolled in the Korean Cancer Study Group trials. The tumor measurements, clinical data, treatment outcomes, and progression patterns of therapy were analyzed. Results: In the 66 patients (53 receiving axitinib and 13 receiving nintedanib), the disease control rate was 61%, and three patients achieved partial response. The median follow-up, median progression-free survival (PFS), overall survival, and 6-month PFS rate were 27.6%, 12.4%, and 18.1% months and 62.1%, respectively. Among 42 patients who experienced progression, 27 (64.3%) showed target lesion progression. Bone metastasis was an independent poor prognostic factor. Conclusion: Overall, most patients demonstrated stable disease with prolonged PFS; however, prominent target lesion progression occurred in some patients. Thus, PFS may capture VEGFR-TKI efficacy better than the objective response rate. [ABSTRACT FROM AUTHOR]

Background: Cerebral ischemic disease is a common cerebrovascular disease, especially ischemic stroke. Exercise has protective functions on brain tissues following cerebral ischemia‐reperfusion injury (CIRI), but its preventive effects and mechanisms in CIRI remain unclear. We aimed to investigate the effects and mechanisms of exercise preconditioning on CIRI. Methods: The middle cerebral artery occlusion (MCAO) operation was prepared to establish CIRI rats. All rats were randomized into the MCAO, exercise (exercise preconditioning plus MCAO operation), vector (exercise preconditioning, MCAO operation plus intraventricular injection of empty vector), and tissue inhibitor of metalloprotease 1 overexpression (OE‐TIMP1, exercise preconditioning, MCAO operation plus intraventricular injection of OE‐TIMP1) groups. Results: The results indicated that exercise preconditioning suppressed approximately 66.67% of neurological deficit scores and 73.79% of TIMP1 mRNA expression in MCAO rats, which were partially offset by OE‐TIMP1. The protective effects of exercise against neuron death status and cerebral infarction size in MCAO rats were reversed by OE‐TIMP1. It also confirmed that exercise weakened apoptosis and oxidative stress damage, with notable increases of B‐cell lymphoma‐2, superoxide dismutase, and glutathione peroxidase production, and evident decreases of BCL2‐associated X, caspase 3, and malondialdehyde in MCAO rats, while these effects were partially reversed by OE‐TIMP1. Additionally, the inhibitory effects of exercise on the protein levels of TIMP1, hypoxia‐inducible factor‐alpha, vascular endothelial growth factor receptor 2, vascular endothelial growth factor, and neurogenic locus notch homolog protein 1 in MCAO rats were partially reversed by OE‐TIMP1. Conclusion: Altogether, exercise preconditioning had protective effects on CIRI by restraining TIMP1, which provided new therapeutic strategies for preventing CIRI. [ABSTRACT FROM AUTHOR]

In the era of immunotherapy, lenvatinib (LEN) still holds an important position in the sequential treatment of advanced hepatocellular carcinoma (HCC). However, the sustained therapeutic effect of LEN is not sufficient, and there is a need to address the development of resistance. Neuropilin-1 (NRP1) is known to act as a coreceptor for epidermal growth factor receptor (EGFR), Met, and vascular endothelial growth factor receptor 2 (VEGFR2), which have been reported to be involved in LEN resistance. In this study, we used cell culture and in vivo xenograft models to evaluate the contribution of NRP1 in the acquisition of LEN resistance in HCC as well as the potential of NRP1 as a therapeutic target. LEN resistance increased EGF/EGFR and hepatocyte growth factor (HGF)/Met signaling in liver cancer cells and VEGFA/VEGFR2 and HGF/Met signaling in vascular endothelial cells, thereby promoting cell proliferation, cell migration, and angiogenesis. We found that activation of NRP1 is essential for the enhancement of these signaling. In addition, NRP1 inhibition combined with LEN therapy synergistically improved the antitumor effects against LEN-resistant HCC, indicating that NRP1 is an attractive therapeutic target. [ABSTRACT FROM AUTHOR]

Because host kinases are key regulators of multiple signaling pathways in response to viral infections, we previously screened a kinase inhibitor library using rhabdomyosarcoma cells and human intestinal organoids in parallel to identify potent inhibitors against EV-A71 infection. We found that Rho-associated coiled-coil-containing protein kinase (Rock) inhibitor efficiently suppressed the EV-A71 replication and further revealed Rock1 as a novel EV-A71 host factor. In this study, subsequent analysis found that a variety of vascular endothelial growth factor receptor (VEGFR) inhibitors also had potent antiviral effects. Among the hits, Pazopanib, with a selectivity index as high as 254, which was even higher than that of Pirodavir, a potent broad-spectrum picornavirus inhibitor targeting viral capsid protein VP1, was selected for further analysis. We demonstrated that Pazopanib not only efficiently suppressed the replication of EV-A71 in a dose-dependent manner, but also exhibited broad-spectrum anti-enterovirus activity. Mechanistically, Pazopanib probably induces alterations in host cells, thereby impeding viral genome replication and transcription. Notably, VEGFR2 knockdown and overexpression suppressed and facilitated EV-A71 replication, respectively, indicating that VEGFR2 is a novel host dependency factor for EV-A71 replication. Transcriptome analysis further proved that VEGFR2 potentially plays a crucial role in combating EV-A71 infection through the TSAd-Src-PI3K-Akt pathway. These findings expand the range of potential antiviral candidates of anti-enterovirus therapeutics and suggest that VEGFR2 may be a key host factor involved in EV-A71 replication, making it a potential target for the development of anti-enterovirus therapeutics. [ABSTRACT FROM AUTHOR]

The phosphatidyl-inositol 3-kinase/serine-threonine kinase (PI3K/AKT) signaling pathway constitutes a classical phosphorylation cascade that integrates tyrosine, lipid, and serine acid-threonine phosphorylation, affecting cell function. The pathway is vulnerable to viral infection. Newcastle disease virus (NDV) poses a significant threat to the global poultry industry; however, its mechanism of early viral cell invasion and pathogenesis remain unclear. Previous in vivo and in vitro studies have shown that NDV infection activates PI3K/AKT signaling; however, it remains unclear whether NDV establishes infection through endocytosis regulated by this pathway. This study aimed to examine whether different genotypes of NDV strains could activate the PI3K/AKT signaling pathway within 2 h of in vitro infection. This activation, which relies on PI3K phosphorylation, remains unaffected by the phosphorylation-phosphatase and tensin homolog/phosphatase and tensin homolog (p-PTEN/PTEN) signaling pathway. Moreover, inhibition of PI3K activity impedes NDV replication. Additionally, interfering with the PI3K regulatory subunit p85 has no significant effect on NDV replication. Conversely, the tyrosine kinase activity upstream of PI3K can influence AKT activation and viral replication, particularly through vascular endothelial growth factor receptor 2 (VEGFR2). Additionally, NDV F protein primarily mediates PI3K and AKT phosphorylation to activate the PI3K/AKT signaling pathway. NDV F and VEGFR2 proteins, along with the PI3K p85α subunit, interact and co-localize at the cell membrane. NDV-induced PI3K/AKT signaling pathway activation impacts clathrin-mediated endocytosis, with VEGFR2 playing a pivotal role. In conclusion, this study shows that NDV infection is established early through F protein binding to VEGFR2, activating the PI3K/AKT signaling pathway and inducing clathrin-mediated endocytosis, supporting infection prevention and control measures. [ABSTRACT FROM AUTHOR]

Objective: Axitinib is a tyrosine kinase inhibitor characterized by a strong affinity for Vascular Endothelial Growth Factor Receptors (VEGFRs). It was approved in 2012 by Food and Drug Administration and European Medicines Agency as a second line treatment for advanced renal cell carcinoma and is currently under evaluation in clinical trial for the treatment of other cancers. Glioblastoma IDH‐wild type (GBM) is a highly malignant brain tumor characterized by diffusely infiltrative growth pattern and by a prominent neo‐angiogenesis. In GBM, axitinib has demonstrated a limited effectiveness as a monotherapy, while it was recently shown to significantly improve its efficacy in combination treatments. In preclinical models, axitinib has been reported to trigger cellular senescence both in tumor as well as in normal cells, through a mechanism involving intracellular reactive oxygen species (ROS) accumulation and activation of Ataxia Telangiectasia Mutated kinase (ATM). Limiting axitinib‐dependent ROS increase by antioxidants prevents senescence specifically in normal cells, without affecting tumor cells. Methods: We used brain tumor xenografts obtained by engrafting Glioma Stem Cells (GSCs) into the brain of immunocompromised mice, to investigate the hypothesis that the antioxidant molecule N‐Acetyl‐L‐Cysteine (NAC) might be used to reduce senescence‐associated adverse effects of axitinib treatment without altering its anti‐tumor activity. Results: We demonstrate that the use of the antioxidant molecule N‐Acetyl‐Cysteine (NAC) in combination with axitinib stabilizes tumor microvessels in GBM tumor orthotopic xenografts, eventually resulting in vessel normalization, and protects liver vasculature from axitinib‐dependent toxicity. Conclusion: Overall, we found that NAC co‐treatment allows vessel normalization in brain tumor vessels and exerts a protective effect on liver vasculature, therefore minimizing axitinib‐dependent toxicity. [ABSTRACT FROM AUTHOR]

Chordomas are rare sarcomas arising from notochordal tissue and occur most commonly in the spine. The standard of care for chordomas without evidence of metastatic disease generally consists of en bloc resection followed by adjuvant radiotherapy. However, long-term (20-year) survival rates are approximately 30%. Chordomas are generally considered as chemo resistant. Therefore, systemic therapies have rarely been employed. Novel immunotherapies, including antibody therapy and tumor vaccines, have shown promise in early trials, leading to extended progression-free survival and symptom relief. However, the outcomes of larger trials using these vectors are heterogeneous. The aim of this review is to summarize novel chordoma treatments in immune-targeted therapies. The current merits, trial outcomes, and toxicities of these novel immune and targeted therapies, including those targeting vascular endothelial growth factor receptor (VEGFR) targets and the epidermal growth factor receptor (EGFR), will be discussed. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) is the second most commonly diagnosed cancer in men worldwide, with metastasis, particularly to bone, being the primary cause of mortality. Currently, prognostic markers like PSA levels and Gleason classification are limited in predicting metastasis, emphasizing the need for novel clinical biomarkers. New molecules predicting tumor progression have been identified over time. Some, such as the immune checkpoint inhibitors (ICIs) PD-1/PD-L1, have become valid markers as theranostic tools essential for prognosis and drug target therapy. However, despite the success of ICIs as an anti-cancer therapy for solid tumors, their efficacy in treating bone metastases has mainly proven ineffective, suggesting intrinsic resistance to this therapy in the bone microenvironment. This study explores the potential of immunological intratumoral biomarkers, focusing on placental growth factor (PlGF), Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), and Programmed Cell Death Protein 1 (PD-1), in predicting bone metastasis formation. Methods: we analyzed PCa samples from patients with and without metastasis by immunohistochemical analysis. Results: Results revealed that PlGF expression is significantly higher in primary tumors of patients that developed metastasis within five years from the histological diagnosis. Additionally, PlGF expression correlates with increased VEGFR1 and PD-1 levels, as well as the presence of intratumoral M2 macrophages. Conclusions: These findings suggest that PlGF contributes to an immunosuppressive environment, thus favoring tumor progression and metastatic process. Results here highlight the potential of integrating these molecular markers with existing prognostic tools to enhance the accuracy of metastasis prediction in PCa. By identifying patients at risk for metastasis, clinicians can tailor treatment strategies more effectively, potentially improving survival outcomes and quality of life. This study underscores the importance of further research into the role of intratumoral biomarkers in PCa management. [ABSTRACT FROM AUTHOR]

Objectives: Preeclampsia (PE) is a leading cause of maternal death worldwide, which is one of the most major pregnancy complications. The effects of vascular endothelial growth factor (VEGF) and lncRNA-loc391533 on PE were evaluated in the present study. Material and methods: Expression of VEGF in pregnant women with PE was determined using immunohistochemical and enzyme linked immunosorbent assay (ELISA). The effects of lncRNA-loc391533 knockdown and overexpression on VEGF expression was detected using quantitative polymerase chain reaction (qPCR) and western blotting. Loss/gain-of-function assays were performed to evaluate the role of lncRNA-loc391533 on proliferation, cell cycle and migration of trophoblasts HTR-8/SVneo cells. Results: We found that VEGF and its receptor VEGFR1/2 were low expressed in PE. Knockdown of lncRNA-loc391533 enhanced VEGF expression, while overexpression of lncRNA-loc391533 downregulated VEGF. Moreover, lncRNA-loc391533 was required for proliferation and migration of HTR-8/SVneo cells. Conclusions: In conclusion, our findings emphasized that lncRNA-loc391533 exhibited a critical role in progression of PE through VEGF, which might as a novel therapeutic target for PE treatment. [ABSTRACT FROM AUTHOR]

BACKGROUND: Endometrial receptivity is a key factor in embryo implantation in northwest Tibetan cashmere goats, and the expression of genes related to endometrial receptivity and their variable splicing are still unclear. OBJECTIVE: To analyze and explore genes and variable splicing events related to endometrial receptivity in northwest Tibetan cashmere goats. METHODS: On days 5 and 15 of pregnancy (representing pre receptive endometrium group and receptive endometrium group), three northwest Tibetan cashmere goats were randomly selected. Endometrial tissue was collected and stained with hematoxylin and eosin to observe tissue morphology. Immunohistochemical staining was used to detect the expression of endometrial receptive marker proteins leukemia inhibitory factor and vascular endothelial growth factor. After the total RNA was extracted and the quality test was qualified, transcriptome sequencing was performed to search differentially expressed mRNAs, lncRNAs, circRNAs, and miRNAs, perform functional prediction, and analyze alternative splicing mRNAs and lncRNAs related to endometrial receptivity. RESULTS AND CONCLUSION: (1) Compared with the pre receptive endometrium group, the expression levels of leukemia inhibitory factor and vascular endothelial growth factor proteins in the endometrial tissue of the receptive endometrium group were significantly increased. (2) The sequencing results showed that the differentially expressed genes were mostly mRNA and lncRNA genes, including 250 upregulated mRNAs, 193 upregulated lncRNAs, 135 downregulated mRNAs, and 123 downregulated lncRNAs, which were significantly enriched in the Wnt, Hedgehog, and Hippo signaling pathways. (3) Alternative splicing event analysis uncovered 8 differentially expressed variable splicing transcripts, which were all mRNA transcripts, including 2 downregulated and 6 upregulated, and were significantly associated with vascular endothelial growth factor receptor signaling, cell motility, and embryonic development. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a common malignant tumor of digestive tract with an increasing incidence and mortality worldwide, and most patients have lost the opportunity of surgical treatment once diagnosed. With the continuous development of precision targeted therapy, anti-angiogenesis targeted drugs have achieved good therapeutic effect in the treatment of advanced CRC. Regorafenib is a multi-target oral tyrosine kinase inhibitor, which can improve the tumor immune microenvironment by regulating tumor-associated macrophage, vascular endothelial growth factor receptor, and has a synergistic effect with immunotherapy. This article reviews the progress of basic and clinical research on regorafenib in the field of CRC.

Background: Cancer is uncontrolled cell proliferation that has the potential to invade other tissues and cells. The first three most prevalent cancers are breast, lung, and colon cancer. The widest family of kinase enzymes is receptor tyrosine kinases (RTKs) which are aimed by several chemotherapy medicines. The vascular endothelial growth factor (VEGFR), a well-known type IV tyrosine kinase receptor, is an effective biological target for the development of angiogenesis-related cancer treatments. The hepatocyte growth factor (also known as mesenchymal–epithelial transition factor) triggers the activation of the c-Met tyrosine kinase receptor, which controls several biological processes including cell division, survival, and proliferation. Main body: In this review, we summarized the various dual inhibitors of VEGFR and c-MET receptors which are active for therapeutic action against cancer. Combination of some VEGFR and c-Met inhibitors also shows synergistic action. The developed dual inhibitors of VEGFR and c-MET such as quinolones and quinazolines derivatives, pyridine and pyrimidine derivatives, oxindole moiety and triazine derivatives are most potent for the same. Dual inhibitors of VEGFR and c-MET hold significant promise in improving cancer therapy by enhancing treatment efficacy, reducing resistance, and potentially improving patient outcomes. Clinical trials are currently being conducted on a few of them and other compounds are being under investigation. Inhibiting VEGFR and c-Met pathway activity will be discussed as novel therapeutic strategies for advanced development in treating cancer. The research progress in this review is fetched up to the current year. Conclusion: Apart from the development of cancer treatment still cancer is listed as a deadly disease, due to its toxicity and resistance to treatment. Hence, the novel approach is necessary to overcome the cancer. The VEGFR and c-MET inhibitors as dual inhibitors may be more significant in future clinical anticancer treatments. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor receptor inhibitors (VEGFRis) improve cancer survival but are associated with treatment-limiting hypertension, often attributed to endothelial cell (EC) dysfunction. Using phosphoproteomic profiling of VEGFRi-treated ECs, drugs were screened for mitigators of VEGFRi-induced EC dysfunction and validated in primary aortic ECs, mice, and canine cancer patients. VEGFRi treatment significantly raised systolic blood pressure (SBP) and increased markers of endothelial and renal dysfunction in mice and canine cancer patients. a-Adrenergic-antagonists were identified as drugs that most oppose the VEGFRi proteomic signature. Doxazosin, one such a-antagonist, prevented EC dysfunction in murine, canine, and human aortic ECs. In mice with sorafenib-induced-hypertension, doxazosin mitigated EC dysfunction but not hypertension or glomerular endotheliosis, while lisinopril mitigated hypertension and glomerular endotheliosis without impacting EC function. Hence, reversing EC dysfunction was insufficient to mitigate VEGFRi-induced-hypertension in this mouse model. Canine cancer patients with VEGFRi-induced-hypertension were randomized to doxazosin or lisinopril and both agents significantly decreased SBP. The canine clinical trial supports safety and efficacy of doxazosin and lisinopril as antihypertensives for VEGFRi-induced-hypertension and the potential of trials in canines with spontaneous cancer to accelerate translation. The overall findings demonstrate the utility of phosphoproteomics to identify EC-protective agents to mitigate cardio-oncology side effects. [ABSTRACT FROM AUTHOR]

The vascular endothelium, a specialized monolayer of endothelial cells (ECs), is crucial for maintaining vascular homeostasis by controlling the passage of substances and cells. In the tumor microenvironment, Vascular Endothelial Growth Factor A (VEGF-A) drives tumor angiogenesis, leading to endothelial anergy and vascular immunosuppression—a state where ECs resist cytotoxic CD8+ T cell infiltration, hindering immune surveillance. Immunotherapies have shown clinical promise. However, their effectiveness is significantly reduced by tumor EC anergy. Anti-angiogenic treatments aim to normalize tumor vessels and improve immune cell infiltration. Despite their potential, these therapies often cause significant systemic toxicities, necessitating new treatments. The small GTPase Rap1B emerges as a critical regulator of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) signaling in ECs. Our studies using EC-specific Rap1B knockout mice show that the absence of Rap1B impairs tumor growth, alters vessel morphology, and increases CD8+ T cell infiltration and activation. This indicates that Rap1B mediates VEGF-A's immunosuppressive effects, making it a promising target for overcoming vascular immunosuppression in cancer. Rap1B shares structural and functional similarities with RAS oncogenes. We propose that targeting Rap1B could enhance therapies' efficacy while minimizing adverse effects by reversing endothelial anergy. We briefly discuss strategies successfully developed for targeting RAS as a model for developing anti-Rap1 therapies. [ABSTRACT FROM AUTHOR]

Aims: To investigate the impact of intravitreal injection of conbercept, a recombinant fusion protein with decoy receptors for the vascular endothelial growth factor (VEGF) family, on intraocular concentrations of angiogenic and inflammatory mediators in patients with proliferative diabetic retinopathy (PDR), analyzed its potential impact on surgical outcomes. Methods: Forty eyes from 40 patients with PDR were included in this prospective study. Patients received intravitreal injection of conbercept followed by vitrectomy or phacovitrectomy in 1 week. Aqueous humor samples were collected before and 1 week after the conbercept injection. The concentrations of angiogenic and inflammatory cytokines and chemokines were measured by flow cytometry. Follow‐up clinical data were collected and analyzed. Results: Intravitreal conbercept injection significantly decreased aqueous concentrations of VEGF (325.5 (baseline) versus 22.3 pg/mL (postinjection), p < 0.0001), PlGF (39.5 versus 24.5 pg/mL, p < 0.0001), and PDGF‐A (54.1 versus 47.0 pg/mL, p = 0.0016), while no impact on bFGF levels. For inflammatory mediators, the concentration of TNF‐α (0.79 versus 0.45 pg/mL, p = 0.0004) and IL‐8 (180.6 versus 86 pg/mL, p < 0.0001) were decreased, while IL‐6 (184.1 versus 333.7 pg/mL, p = 0.0003) and IL‐10 (1.1 versus 1.5 pg/mL, p = 0.0032) were increased. No significant changes in IFN‐γ or MCP‐1 were detected. Three months after surgery, the mean best‐corrected visual acuity improved from a baseline of 1.8 ± 0.1 logMAR to 0.7 ± 0.1 logMAR (p < 0.0001), with 36 eyes (90%) achieving an improvement of visual function. Conclusions: Intravitreal conbercept injection presents dual effects of antiangiogenesis and anti‐inflammation and can be served as an adjuvant treatment to vitrectomy for PDR patients. [ABSTRACT FROM AUTHOR]

AIM: To investigate the effects of sodium selenite (SS) on viability, migration and angiogenesis of human non-small-cell lung cancer (NSCLC) H520 and A549 cells. METHODS: The H520 cells, A549 cells, and human umbilical vein endothelial cells (HUVEC) were divided into control group (0 μmol/L SS), low dose group (5 μmol/L SS), middle dose group (10 μmol/L SS), and high dose group (20 μmol/L SS). Cell viability was assessed using the CCK-8 assay, and the half-maximal inhibitory concentration (IC50) was calculated. Cell migration and invasion abilities were determined through wound healing and Transwell assays. The regulatory effects of SS on angiogenesis, vasculogenic mimicry and "mosaic" vascular formation between HUVEC and NSCLC cells were detected using vessel forming assays. The expression of vascular endothelial growth factor (VEGF) in the supernatant of lung cancer cells in each group was detected using chemiluminescence. RT-qPCR was used to assess the mRNA expression of VEGF, vascular endothelial growth factor receptor 2 (VEGFR2) and angiotensin II (Ang II). Western blot was used to examine the protein levels of VEGF, p-PI3K, and p-Akt in H520 and A549 cells. RESULTS : The IC50 values of SS to HUVEC, A549 cells and H520 cells for 48 h were 6. 762, 9. 003 and 7. 356 μmol/L, respectively. Compared with control group, the wound healing rate was significantly decreased in each group treated with SS for 48 h (p<0. 01). In HUVEC, the number of migrating cells in middle dose and high dose groups decreased (p<0. 01), whereas in lung cancer cells, the number of migrating cells in each group decreased after SS treatment (p<0. 01). The mRNA expression levels of VEGF, VEGFR2 and Ang II were lower in high-dose SS group than those in control group (p<0. 05 or p<0. 01). In H520 cells, compared with control group, the protein levels of VEGF, p-PI3K and p-Akt in SS treatment groups were significantly decreased (p<0. 05 or p< 0. 01). CONCLUSION: Sodium selenite inhibits the viability and migration of HUVEC, H520 cells and A549 cells, and inhibits the formation of vasculogenic mimicry and mosaic vessels in NSCLC cells. This mechanism may be related to the inhibition of PI3K-Akt signaling pathway activation and regulation of VEGF. [ABSTRACT FROM AUTHOR]

This document is a letter to the editor of the journal Thyroid discussing the prevalence of erectile dysfunction (ED) in patients with RET-altered thyroid cancer who are treated with selpercatinib. The authors conducted a retrospective cohort study of 25 male patients and found that 92% of them reported ED. The study suggests that ED may be a common side effect of selpercatinib treatment and that phosphodiesterase-5 inhibitors (PDE-5i) may be effective in managing this adverse event. Further research is needed to confirm these findings and explore optimal management strategies. The authors acknowledge the support of Eli Lilly and Company in reviewing the study. [Extracted from the article]

Dysregulation of melanogenesis contributes to the development of skin hyperpigmentation diseases, which poses a treatment challenge. Following the establishment of CRTC3 screening methods to explore small molecules inhibiting melanogenesis for the topical treatment of hyperpigmentation diseases, we identified a candidate molecule, semaxanib. To explore the antimelanogenic effects of semaxanib, a vascular endothelial growth factor receptor (VEGFR) 2 inhibitor, for potential applications in hyperpigmentation management and to unravel the role of VEGF signaling in melanocyte biology by investigating mechanism of action of semaxanib. Mouse-derived spontaneously immortalized melanocytes, B16F10, and normal human primary epidermal melanocytes cells were treated with semaxanib, and cellular responses were assessed using cell viability assays and melanin content measurements. Molecular mechanisms were investigated using transcriptional activity assays, reverse-transcription polymerase chain reaction, and immunoblotting analysis. In vivo studies were conducted using an epidermis-humanized transgenic mouse model and ex vivo human skin tissues. Semaxanib ameliorated melanin content in cultured melanocytes by downregulating the expression of melanogenesis-associated genes by suppressing the CRTC3/microphthalmia-associated transcription factors. Topical application of semaxanib reduced melanin accumulation in the ultraviolet B–stimulated ex vivo human epidermis and tail of K14-stem cell factor transgenic mice. Mechanistically, the antimelanogenic effect induced by semaxanib was associated with SIK2-CRTC3-MITF rather than VEGF signaling in melanocytes. Semaxanib emerges as a promising candidate for the development of therapeutics for hyperpigmentation, potentially working independently of VEGF signaling in human melanocytes. • Semaxanib dose-dependently suppresses melanin production in cultured melanocytes. • Topical application of semaxanib reduces melanin content in human and mouse skin. • VEGF does not affect melanogenesis in melanocytes alone and in co-culture models. • Semaxanib-mediated suppression of melanogenesis was independent of VEGF signaling. • Semaxanib suppresses MITF expression by promoting CRTC3 hyperphosphorylation. [ABSTRACT FROM AUTHOR]

Laryngeal cancer (LC) is the second most common head and neck cancer and has a decreasing 5-year survival rate worldwide. Circular RNAs (circRNAs) regulate cancer development in diverse ways based on their distinct biogenesis mechanisms and expansive regulatory roles. However, currently, there is little research on how exosomal circRNAs are involved in the development of LC. Here, we demonstrated that circPVT1, a circRNA derived from the well-studied long noncoding RNA PVT1, is correlated with disease progression in LC and promotes angiogenesis both in vivo and in vitro. Mechanistically, circPVT1 is loaded into LC cell-secreted exosomes and taken up by vascular epithelium cells. By sponging miR-30c-5p, exosomal circPVT1 promotes Rap1b expression, which dramatically enhances vascular endothelial growth factor receptor 2 and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation, ultimately resulting in the induction of angiogenesis. Furthermore, our xenograft models demonstrated that the combination of short hairpin RNA-circPVT1 and cetuximab showed high efficacy in inhibiting tumor growth and angiogenesis. Collectively, these findings uncover a novel mechanism of exosomal circRNA-mediated angiogenesis modulation and provide a preclinical rationale for testing this analogous combination in patients with LC. [ABSTRACT FROM AUTHOR]

This document is a summary of a thesis on the ophthalmological manifestations of thyroid disorders and thyroid eye disease (TED). The thesis includes several studies that investigate the association between thyroid disorders and exudative age-related macular degeneration (AMD), as well as the incidence of TED and its ophthalmological sequelae. The thesis also examines the use of topical anesthesia in strabismus surgery for patients with TED. The findings suggest a possible association between thyroid disorders and exudative AMD, provide valuable information on the incidence and characteristics of TED, and support the use of topical anesthesia in strabismus surgery for patients with TED. The thesis emphasizes the need for further research and highlights the clinical implications of the findings. [Extracted from the article]

Exudative (wet) age-related macular degeneration can be treated with the vascular endothelial growth factor (VEGF)-inhibiting monoclonal antibody bevacizumab. Currently, bevacizumab therapy is associated with known skin-related side effects, such as rash, mucosal hemorrhage, and hemorrhagic ulcers. While subungual "splinter" hemorrhage is a documented side effect of VEGF receptor antagonists and Raf protein inhibitors, there are no prior reports of bevacizumab-induced subungual hemorrhage to the best of our knowledge. Thus, we present the case of a 71-year-old female diagnosed with bilateral agerelated macular degeneration, who, during six months of intravitreal bevacizumab treatment, began noticing fingernail discoloration, described as similar to that of a bruise. Given our patient's history of bevacizumab therapy and the documented reports of bevacizumab-associated mucosal and ulcerative hemorrhage, we hypothesize that the discoloration and hemorrhage are likely unreported adverse effects associated with bevacizumab therapy. [ABSTRACT FROM AUTHOR]

ORF virus (ORFV) causes contagious ecthyma ("ORF"), a disease of sheep and goats characterized by lesions ranging from vesicles and pustules to atypical papilloma-like and angiomatous lesions in the skin and mucosae. The authors investigated the molecular factors leading to the ORF-associated atypical tumor-like changes. Fifteen lambs, 15 kids, and an adult ram clinically affected by natural ORFV infection were enrolled in the study and examined by several methods. ORFV was detected by viral culture or real-time polymerase chain reaction (RT-PCR) in the lesioned tissues and in the blood of the clinically affected sheep and goats. Surprisingly, ORFV was also detected in the blood of healthy goats from an affected herd. Microscopically, they found a pseudo-papillomatous proliferation of the epithelium, while the dermis and lamina propria were expanded by a proliferating neovascular component that highly expressed the viral vascular endothelial growth factor (vVEGF) and its host receptor vascular endothelial growth factor receptor 2 (VEGFR2). Immunohistochemistry, immunofluorescence, and in situ hybridization for mRNA showed that epidermal growth factor receptor (EGFR) was expressed in the fibrovascular component, in the infiltrating CD163+ macrophages, and in the basal stratum of the epidermis. Confocal immunofluorescence microscopy demonstrated that CD163+ macrophages were associated with VEGF and VEGFR2. Finally, they found by quantitative RT-PCR the overexpression of the interleukin-6 and VEGFR2 genes in the lesioned tissues. These findings suggest that ORFV activates an inflammatory reaction characterized by CD163+ macrophages expressing EGFR and VEGFR2, which might play an oncogenic role through synergistic action with vVEGF signaling. [ABSTRACT FROM AUTHOR]

The article discusses a study which performed transcriptome-wide association study (TWAS) for the outcome of idiopathic pulmonary fibrosis (IPF) survival. Topics include reason that extracting biological insight from genome-wide association study (GWAS) is challenging, genes identified that were significant in TWAS analysis for both lung and whole body (WB), and validation analyses to explore the two significant TWAS genes further.

Catechins, a class of polyphenolic compounds found in tea, have attracted significant attention due to their numerous health benefits, particularly for the treatment and protection of hypertension. However, the potential targets and mechanisms of action of catechins in combating hypertension remain unclear. This study systematically investigates the anti-hypertensive mechanisms of tea catechins using network pharmacology, molecular docking, and molecular dynamics simulation techniques. The results indicate that 23 potential anti-hypertensive targets for eight catechin components were predicted through public databases. The analysis of protein–protein interaction (PPI) identified three key targets (MMP9, BCL2, and HIF1A). KEGG pathway and GO enrichment analyses revealed that these key targets play significant roles in regulating vascular smooth muscle contraction, promoting angiogenesis, and mediating vascular endothelial growth factor receptor signaling. The molecular docking results demonstrate that the key targets (MMP9, BCL2, and HIF1A) effectively bind with catechin components (CG, GCG, ECG, and EGCG) through hydrogen bonds and hydrophobic interactions. Molecular dynamics simulations further confirmed the stability of the binding between catechins and the targets. This study systematically elucidates the potential mechanisms by which tea catechins treat anti-hypertension and provides a theoretical basis for the development and application of tea catechins as functional additives for the prevention of hypertension. [ABSTRACT FROM AUTHOR]