Design, synthesis and biological evaluation of indazole derivatives as VEGFR-2 kinase inhibitors with anti-angiogenic properties.

The strategy of inhibiting angiogenesis, specifically by targeting vascular endothelial growth factor receptor 2 (VEGFR-2), has been proven effective in tumor treatment. In this study, we designed several VEGFR-2 kinase inhibitors based on an indazole scaffold. Among them, the most potent compound, 30, inhibits VEGFR-2 (IC50 = 1.24 nM) with subtle selectivity over other kinases. It demonstrates significant inhibitory activity against HUVEC angiogenesis and inhibits cell migration in a dose-dependent manner. Additionally, it exhibits low acute toxicity in mice. In vivo studies, compound 30 demonstrates favorable pharmacokinetic profiles. It suppresses tumor angiogenesis in the zebrafish subintestinal vessel model, indicating that it may be a potential angiogenesis inhibitor for further development.

Evaluation of the effectiveness and safety of combining PD-1/PD-L1 inhibitors with anti-angiogenic agents in unresectable hepatocellular carcinoma: a systematic review and meta-analysis.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally, particularly when diagnosed at an unresectable stage. Traditional treatments for advanced HCC have limited efficacy, prompting the exploration of combination therapies. This systematic review and meta-analysis evaluate the effectiveness and safety of combining PD-1/PD-L1 inhibitors with anti-angiogenic agents in patients with unresectable HCC. Methods: A comprehensive literature search was conducted in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science, including studies up to June 2024. Randomized controlled trials (RCTs) comparing combination therapy (PD-1/PD-L1 inhibitors with anti-angiogenic agents) to monotherapy or standard treatments in unresectable HCC patients were included. Data were synthesized using random-effects models, with pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and risk ratios (RRs) for objective response rate (ORR) and adverse events (AEs). Results: Five Phase III RCTs involving 1515 patients were included. Combination therapy significantly improved OS (HR: 0.71, 95% CI: 0.60-0.85) and PFS (HR: 0.64, 95% CI: 0.53-0.77) compared to monotherapy or standard treatments. The pooled OR for ORR was 1.27 (95% CI: 1.57-2.11), indicating a higher response rate with combination therapy. However, the risk of AEs was also higher in the combination therapy group (RR: 1.04, 95% CI: 1.02-1.06). Subgroup analyses revealed consistent benefits across different types of PD-1/PD-L1 inhibitors and anti-angiogenic agents, with no significant publication bias detected. Conclusions: The combination of PD-1/PD-L1 inhibitors with anti-angiogenic agents offers significant benefits in improving OS and PFS in patients with unresectable HCC, although it is associated with an increased risk of adverse events.

Analysis of clinicopathological characteristics and prognostic factors in 54 metaplastic breast carcinoma patients from northwest China.

Objective: Metaplastic breast carcinoma (MBC) is a special type of morphologically heterogeneous and aggressively invasive breast cancer. MBC is characterized by the transformation of tumor epithelium into squamous epithelium and/or mesenchymal components, including differentiation into spindle cells, chondrocytes, and osteocytes. Due to its rarity and invasiveness, there is a paucity of research on MBC prognosis. Furthermore, there are currently no treatment guidelines for MBC. This study analyzed the clinicopathological characteristics, immunophenotype, and prognostic features of MBC. Our aim was to better characterize MBC, thereby identifying potential prognostic factors and new treatment methods. Moreover, we also describe an MBC case treated experimentally with anti-vascular targeted therapy. Material and Methods: We retrospectively analyzed clinical pathological data on 54 female patients with MBC from Shaanxi Provincial People's Hospital and the XiJing Hospital of Air Force Medical University. These cases were diagnosed with MBC between January 1st, 2013, and October 1st, 2018. All patients were from the northwest region of China. The gross morphological, histological, and immunohistochemical features of MBC were analyzed. Kaplan-Meier analysis was used to calculate the survival rate, and univariate analysis was performed to identify significant prognostic factors. In addition, the treatment of an MBC patient with anti-angiogenic therapy was described, and a relevant literature review was conducted. Results: MBC was diagnosed in 32 left breasts and 22 right breasts from 54 women aged 21-76 years (median age of 57 years). The maximum tumor diameter ranged from 0.6 to 14 cm (average of 4.1 cm). Of the 54 patients, 47 underwent surgical treatment, with lymph node metastasis found in 17.0% (8/47). According to the World Health Organization classification criteria for breast tumors, the study cohort consisted of 15 cases of squamous cell carcinoma, ten cases of spindle cell carcinoma, nine cases of carcinoma with associated stromal differentiation, 18 cases of mixed carcinoma, and two cases of adenocarcinoma with squamous differentiation. Based on the American Joint Committee on Cancer clinical staging criteria, the patients were classified as Stage I (10 cases, 18.5%), Stage II (26 cases, 48.1%), Stage III (11 cases, 20.4%), and Stage IV (7 cases, 13.0%). Immunohistochemical analysis revealed that 94.4% of patients had triple-negative breast cancer (TNBC), 47 cases showed mutant tumor protein 53 (TP53) expression, 29 cases showed positive epidermal growth factor receptor (EGFR) expression, 43 cases showed positive E-cadherin expression, and 37 cases showed positive Cluster of Differentiation 24 expression. The Ki-67 index ranged from 20% to 90%. Univariate analysis showed that the Ki-67 index was not significantly associated with either progression-free survival (PFS) or overall survival (OS) in MBC patients. Patients with negative axillary lymph nodes had significantly better PFS and OS than those with positive nodes (P < 0.05), and patients with clinical stage I-II disease had better PFS and OS than those with stage III-IV disease (P < 0.05). Patients treated with anthracycline-containing chemotherapy had significantly better PFS than those who did not receive chemotherapy. Univariate analysis revealed that the high expression of EGFR correlated with worse PFS (P < 0.05). The type of surgical approach employed did not affect the prognosis of MBC patients. Following the application of anti-angiogenic therapy, a rapid partial response was observed in an MBC patient with carcinoma and associated stromal differentiation. This patient subsequently underwent surgery and radiation therapy and has now achieved over 6 years of PFS. Conclusion: MBC is a heterogeneous group of tumors with high malignancy and poor prognosis. The large majority is TNBC and exhibits unique immune phenotypes. The poor PFS of MBC patients may be related to EGFR expression, which could become a potential therapeutic target in these patients. Surgery remains the primary treatment method for MBC. The present study found that sentinel lymph node biopsy was feasible in appropriate patients, and that chemotherapy regimens incorporating anthracycline-class drugs did not appear to improve OS. Anti-angiogenic therapy holds promise as a potentially effective treatment approach for MBC, and the optimization of systemic treatment strategies should be a priority in the management of these patients.

Bruton's tyrosine kinase inhibition suppresses pathological retinal angiogenesis.

BACKGROUND AND PURPOSE: Pathological retinal angiogenesis is a typical manifestation of vision-threatening ocular diseases. Many patients exhibit poor response or resistance to anti-vascular endothelial growth factor (VEGF) agents. Bruton's tyrosine kinase (BTK) controls the proliferation and function of immune cells. Therefore, we examined the anti-inflammatory and anti-angiogenic effects of BTK inhibition on retinal angiogenesis. EXPERIMENTAL APPROACH: Retinal neovascularisation and vascular leakage in oxygen-induced retinopathy in C57/BL6J mice were assessed by whole-mount retinal immunofluorescence. PLX5622 was used to deplete microglia and Rag1-knockout mice were used to test the contribution of lymphocytes to the effects of BTK inhibition. The cytokines, activation markers, inflammatory and immune-regulatory activities of retinal microglia/macrophages were detected using qRT-PCR and immunofluorescence. NLRP3 was detected by western blotting, and the effects of BTK inhibition on the co-culture of microglia and human retinal microvascular endothelial cells (HRMECs) were examined. KEY RESULTS: BTK inhibition suppressed pathological angiogenesis and vascular leakage, and significantly reduced retinal inflammation, which involved microglia/macrophages but not lymphocytes. BTK inhibition increased anti-inflammatory factors and reduced pro-inflammatory cytokines that resulted from NLRP3 inflammasome activation. BTK inhibition suppressed the inflammatory activity of microglia/macrophages, and acted synergistically with anti-VEGF without retinal toxicity. Moreover, the supernatant of microglia incubated with BTK-inhibitor reduced the proliferation, tube formation and sprouting of HRMECs. CONCLUSION AND IMPLICATIONS: BTK inhibition suppressed retinal neovascularisation and vascular leakage by modulating the inflammatory activity of microglia and macrophages. Our study suggests BTK inhibition as a novel and promising approach for alleviating pathological retinal angiogenesis.

Intermanufacturer assessment of diagnostic performance of angiogenic ratio vs glycosylated fibronectin in women with suspected pre-eclampsia.

OBJECTIVE: To compare the diagnostic performance of different manufacturers' immunoassays for the soluble fms-like tyrosine kinase-1 (sFlt-1)-to-placental growth factor (PlGF) ratio with that of a point-of-care test for glycosylated fibronectin (GlyFn) in women with suspected pre-eclampsia (PE). METHODS: This was a prospective, single-center, double-blinded, non-interventional study of East Asian women with a singleton pregnancy who presented with hypertension with or without clinical features of PE after 20 weeks' gestation between January 2020 and March 2022. Maternal serum samples were collected at the time of presentation, and subsequent management followed the departmental protocol, based on gestational age, severity of hypertension, fetal condition and presence of severe PE features. Women diagnosed with PE at presentation were excluded. PE was diagnosed according to the 2018 International Society for the Study of Hypertension in Pregnancy classification. Levels of sFlt-1 and PlGF were measured using the Cobas e411 (Roche Diagnostics), BRAHMS KRYPTOR (ThermoFisher Scientific) and iMAGIN 1800 (Ningbo-Aucheer) platforms. GlyFn levels were measured using the Lumella™ GlyFn PoC test (Diabetomics). The predictive performance of each test to rule out PE within 7 days and rule in PE within 28 days from the date of presentation was assessed. Based on the PROGNOSIS study, a sFlt-1/PlGF ratio of ≤ 38 on the Roche platform was used to predict the absence of PE within 7 days. The sFlt-1/PlGF ratio was classified as high or low using platform-specific thresholds equivalent to a Roche sFlt-1/PlGF ratio of 38, which were derived using Passing-Bablok regression. GlyFn was categorized as high or low using two reported clinical management thresholds (263 µg/mL and 510 µg/mL). RESULTS: Overall, 236 women with suspected PE were included, of whom 70 (29.7%) were diagnosed with PE; 36 (51.4%) and 70 (100%) developed PE within 7 days and 28 days, respectively. Eighty-eight (37.3%) women had a sFlt-1/PlGF ratio of > 38 on the Roche platform, 79 (33.5%) women had a sFlt-1/PlGF ratio of > 55 on the KRYPTOR platform and 96 (40.7%) women had a sFlt-1/PlGF ratio of > 40 on the iMAGIN 1800 platform. Furthermore, 62 (26.3%) and four (1.7%) women had a GlyFn level of > 263 µg/mL and > 510 µg/mL, respectively. The negative predictive value (NPV) of the sFlt-1/PlGF ratio measured on the Roche, KRYPTOR and iMAGIN 1800 platforms to rule out PE within 7 days after presentation was 83.3%, 82.0% and 82.9%, respectively, while that for GlyFn > 263 µg/mL and > 510 µg/mL was 82.6% and 70.4%, respectively. The corresponding positive predictive values (PPV) to rule in PE within 28 days after presentation were 50.5%, 52.3% and 46.7%, respectively, for the sFlt-1/PlGF ratio, and 35.4% and 50.0%, respectively, for GlyFn > 263 µg/mL and > 510 µg/mL. CONCLUSIONS: The predictive performance of different manufacturers' assays for the sFlt-1/PlGF ratio to rule in and rule out PE were similar once standardized to a common threshold. Our findings suggest that the sFlt-1/PlGF ratio and GlyFn using a cut-off of 263 µg/mL can both be utilized to rule out PE within 7 days after assessment, with a moderate NPV. The PPV for ruling in PE within 28 days remains poor. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Gut microbiome influences efficacy of Endostatin combined with PD-1 blockade against colorectal cancer.

The combination of anti-angiogenic drugs and immune checkpoint inhibitors (ICIs) in the treatment of tumors is emerging as a way to improve ICIs-resistant tumor therapy. In addition, gut microbes (GMs) are involved in angiogenesis in the tumor microenvironment and are also associated with the antitumor function of immune checkpoint inhibitors. However, it is unclear whether gut microbes have a role in anti-tumor function in the combination of anti-angiogenic drugs and immune checkpoint inhibitors for cancer treatment. Endostatin, an angiogenesis inhibitor, has been widely used as an antiangiogenic therapy for cancer. We showed that combined therapy with an adenovirus encoding human endostatin, named Ad-E, and PD-1 blockade dramatically abrogated MC38 tumor growth. The structure of intestinal microbes in mice was changed after combination treatment. We found that the antitumor function of combination therapy was inhibited after the elimination of intestinal microbes. In mice with depleted microbiota, oral gavage of Bacteroides fragilis salvaged the antitumor effects of combination Ad-E and αPD-1 monoclonal antibody (mAb) to a certain extent. Further, Bacteroides fragilis could improve CD3+T cells, NK cells, and IFNγ+CD8+ T cells in the tumor microenvironment to inhibit tumor growth. Besides, Bacteroides fragilis might restore antitumor function by down-regulating isobutyric acid (IBA). Our results suggested that GMs may be involved in the combination of Ad-E and αPD-1 mAb for cancer treatment, which has oncological implications for tumor growth dynamics and cancer immune surveillance.

[Effectiveness and safety of brolucizumab in the treatment of neovascular age-related macular degeneration]. / Effektivnost' i bezopasnost' brolutsizumaba v lechenii neovaskulyarnoi vozrastnoi makulyarnoi degeneratsii.

PURPOSE: This study analyzes the effectiveness and safety of brolucizumab in the treatment of neovascular age-related macular degeneration (nAMD) in real clinical practice. MATERIAL AND METHODS: The study included patients with nAMD who received brolucizumab treatment and evaluated the changes in best-corrected visual acuity (BCVA), central retinal thickness (CRT), macular volume, as well as the number of injections and adverse events. RESULT: The group of previously treated patients included 28 subjects (28 eyes) that were switched to brolucizumab with a loading phase. By 12 months, BCVA changed from 0.43±0.29 to 0.33±0.27 LogMAR (p=0.11), CRT decreased from 281.5±58.2 to 239.9±45.6 µm (p=0.02). The group of previously untreated patients included 29 subjects (29 eyes). By 12 months, BCVA changed from 0.47±0.32 to 0.40±0.30 LogMAR (p=0.09), CRT decreased from 333.2±77.3 to 226.2±49.6 µm (p<0.001). Patients received 6.3±0.7 injections. In this group, baseline choroidal thickness showed a statistically significant correlation with final visual acuity (r=0.54; p<0.05) and CRT (r= -0.5; p<0.05). The group of previously treated patients switched without a loading phase included 18 patients (18 eyes). By 6 months, BCVA changed from 0.42±0.2 to 0.37±0.26 LogMAR (p=0.42). CRT remained stable at 285.6±56.9 µm (p=0.97). No adverse events related to intraocular inflammation were reported during the course of 385 injections. CONCLUSION: Brolucizumab therapy helps achieve significant anatomical and functional improvements in real clinical practice both in patients switched from previous treatments and in treatment-naïve patients. Greater baseline choroidal thickness may be associated with better anatomical and functional outcomes with brolucizumab treatment.

Angiogenic biomarkers of response to treatment with peptide receptor radionuclide therapy in neuroendocrine tumours.

BACKGROUND: Neuroendocrine tumours (NETs) are a heterogeneous group of tumours, which is characterized by rich vascularization. The role of angiogenesis in NETs has been widely researched. Peptide receptor radionuclide therapy (PRRT) is an effective treatment method for patients with disease progression in NETs. Due to the heterogeneousness of NETs, the response to treatment varies. Currently, the finding of efficient markers helpful in assessing the response to treatment in NETs is crucial. The aim of this study was to assess chromogranin A (CgA) and angiogenic factors in gastro-entero-pancreatic (GEP) and broncho-pulmonary (BP) NET patients treated with PRRT. MATERIAL AND METHODS: The study group included 40 patients with GEP NETs and BP NETs who completed four cycles of PRRT. Serum levels of CgA and angiogenic factors such as vascular endothelial growth factor (VEGF), its receptors (VEGF-R1, VEGF-R2, VEGF-R3), were assessed before and after four cycles of PRRT. All tests were determined using ELISA. RESULTS: The concentration of CgA, VEGF-R1 and VEGF-R2 decreased significantly, whereas VEGF-R3 increased significantly after PRRT. PRRT did not affect VEGF, it was similar before and after the radioisotope treatment. Based on AUROC, only for VEGF-R1 AUC was a consequence of 0.7 which can be considered as a good response to PRRT treatment. CONCLUSIONS: VEGF-R1 may be a potential biomarker useful in assessing the effectiveness of PRRT in NET patients.

Circulating CD31+ Angiogenic T cells are reduced in prediabetes and increase with exercise training.

AIMS: To investigate circulating angiogenic cells in adults with prediabetes and the effect of a structured exercise program. METHODS: A cohort of adults with overweight/obesity and either normal glucose (NG) or prediabetes were randomised to receive exercise (Exercise) (as twice weekly supervised combined high intensity aerobic exercise and progressive resistance training, and once weekly home-based aerobic exercise) or an unsupervised stretching intervention (Control) for 12 weeks. Circulating angiogenic T cells, muscle strength, and cardiovascular disease risk factors, including blood lipids, arterial stiffness, central haemodynamic responses, and cardiorespiratory fitness (VO2peak) in those with prediabetes (n = 35, 16 Control, 19 Exercise) and NG (n = 37, 17 Control, 20 Exercise) were analysed at baseline and after the 12-week intervention. RESULTS: At baseline, compared with NG those with prediabetes demonstrated reduced VO2peak, angiogenic CD31+CD8+ T cells and VEGFR2+CD4+ T cells, and increased systolic blood pressure. CD31+ T cells were negatively correlated with cardiovascular disease (CVD) risk. Compared with Control, exercise training increased muscle strength, VO2peak, and CD31+CD4+ and CD31+CD8+ T cells in NG and prediabetes. CONCLUSIONS: Circulating angiogenic CD31+ T cells are decreased in people with prediabetes and are enhanced with exercise training. Exercise increases CD31+ T cells, and through this mechanism it is proposed that it may reduce CVD risk. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry number: ACTRN12617000552381.

Sulfamoylated Estradiol Analogs Targeting the Actin and Microtubule Cytoskeletons Demonstrate Anti-Cancer Properties In Vitro and In Ovo.

The microtubule-disrupting agent 2-methoxyestradiol (2-ME) displays anti-tumor and anti-angiogenic properties, but its clinical development is halted due to poor pharmacokinetics. We therefore designed two 2-ME analogs in silico-an ESE-15-one and an ESE-16 one-with improved pharmacological properties. We investigated the effects of these compounds on the cytoskeleton in vitro, and their anti-angiogenic and anti-metastatic properties in ovo. Time-lapse fluorescent microscopy revealed that sub-lethal doses of the compounds disrupted microtubule dynamics. Phalloidin fluorescent staining of treated cervical (HeLa), metastatic breast (MDA-MB-231) cancer, and human umbilical vein endothelial cells (HUVECs) displayed thickened, stabilized actin stress fibers after 2 h, which rearranged into a peripheral radial pattern by 24 h. Cofilin phosphorylation and phosphorylated ezrin/radixin/moesin complexes appeared to regulate this actin response. These signaling pathways overlap with anti-angiogenic, extra-cellular communication and adhesion pathways. Sub-lethal concentrations of the compounds retarded both cellular migration and invasion. Anti-angiogenic and extra-cellular matrix signaling was evident with TIMP2 and P-VEGF receptor-2 upregulation. ESE-15-one and ESE-16 exhibited anti-tumor and anti-metastatic properties in vivo, using the chick chorioallantoic membrane assay. In conclusion, the sulfamoylated 2-ME analogs displayed promising anti-tumor, anti-metastatic, and anti-angiogenic properties. Future studies will assess the compounds for myeloproliferative effects, as seen in clinical applications of other drugs in this class.

Correlation between Periostin Expression and Pro-Angiogenic Factors in Non-Small-Cell Lung Carcinoma.

The role of periostin (POSTN) in remodeling the microenvironment surrounding solid tumors and its effect on the tumor cells in non-small-cell lung carcinoma (NSCLC) have not yet been fully understood. The aim of this study was to determine the relationship between POSTN expression (in tumor cells [NSCLC cells] and the tumor stroma) and pro-angiogenic factors (CD31, CD34, CD105, and VEGF-A) and microvascular density (MVD) in NSCLC. In addition, these associations were analyzed in individual histological subtypes of NSCLC (SCC, AC, and LCC) and their correlations with clinicopathological factors and prognosis were examined. Immunohistochemistry using tissue microarrays (TMAs) was used to assess the expression of POSTN (in tumor cells and cancer-associated fibroblasts [CAFs]) and the pro-angiogenic factors. A significant positive correlation was found between the expression of POSTN (in cancer cells/CAFs) and the expression of the analyzed pro-angiogenic factors (CD31, CD34, CD105, and VEGF-A) and MVD in the entire population of patients with NSCLC and individual histological subtypes (AC, SCC). In addition, this study found that POSTN expression (in tumor cells/CAFs) increased with tumor size (pT), histopathological grade (G), and lymph-node involvement (pN). In addition, a high expression of POSTN (in tumor cells and CAFs) was associated with shorter survival among patients with NSCLC. In conclusion, a high expression of POSTN (in cancer cells and CAFs) may be crucial for angiogenesis and NSCLC progression and can constitute an independent prognostic factor for NSCLC.

Surgery-based radiation-free multimodality treatment for locally advanced cervical cancer.

The current review described a 55-year woman using 28 months to finish her surgery-based radiation-free multimodality treatment journey to fight International Federation of Gynaecology & Obstetrics (FIGO) 2018 clinical stage IIA2 (cT2aN0M0) squamous cell carcinoma (SCC) of the cervix. She received six cycles of perioperative adjuvant therapy, including three cycles of neoadjuvant therapy (NAT) and three cycles of postoperative adjuvant therapy by using combination of dose-dense chemotherapy (CT, weekly paclitaxel 80 mg/m2+triweekly cisplatin 40 mg/m2), immunotherapy (IO, triweekly pembrolizumab 200 mg) and half-dose anti-angiogenic agent (triweekly bevacizumab 7.5 mg/kg) plus interval radical surgery (radical hysterectomy + bilateral salpingo-oophorectomy + bilateral pelvic lymph node dissection + para-aortic lymph node sampling) and following maintenance therapy with monthly 22 cycles of half-dose of IO (pembrolizumab 100 mg) and concomitant 4 cycles of single-agent CT (paclitaxel 175 mg/m2) and 18 cycles of half-dose anti-angiogenic agent (bevacizumab 7.5 mg/kg). During the cervical SCC fighting journey, two unwanted adverse events (AEs) occurred. One was pseudo-progressive disease during the NAT treatment and pathology-confirmed upgrading FIGO stage IIIC1p (ypT2a1N1M0) after radical surgery and the other was the occurrence of hypothyroidism during the post operative adjuvant therapy. Based on this case we presented, we review the recent trend in the management of women with locally advanced cervical cancer (LACC) using the radiation-free but surgery-based multimodality strategy and highlight the strengths and limitations about perioperative adjuvant therapy with dose-dense CT + IO + half-dose anti-angiogenic agent and maintenance treatment of half-dose IO combining with short-term single agent CT and following long-term half-dose anti-angiogenic agent. All underscore the possibility that women with LACC have an opportunity to receive surgery-based RT-free multi-modality strategy to manage their diseases with satisfactory results. Additionally, the evolving role of IO plus CT with/without anti-angiogenic agent functioning as either primary treatment or adjuvant therapy for the treatment of advanced CC has been in process continuously. Moreover, the patient's positive response to IO, pembrolizumab as an example, both during the primary and maintenance therapy, highlights the importance of integrating IO into CT regimens for CC, especially in cases where conventional therapies, RT as an example, are insufficient or who do not want to receive RT-based treatment. The sustained disease-free status of the patient over several years reinforces the potential of IO to significantly increase long-term survival outcomes in CC patients, particularly for those with LACC.

CXCL10 promotes melanoma angiogenesis and tumor growth.

Upregulation of CXC motif chemokine 10 (CXCL10) in melanoma patients has been found to be associated with melanoma progression. However, the role of endogenous CXCL10 from the host in melanoma tumor growth remains unclear. In the present study, we found that host-derived endogenous CXCL10 production was dramatically augmented during subcutaneous B16F10 melanoma tumor growth and that host ablation of CXCL10 in Cxcl10-/- mice showed a decrease in both angiogenesis and tumor growth of B16F10 melanoma in vivo. Several signaling pathways involved in production of pro-angiogenic factors and tumor growth were activated by CXCL10 in B16F10 melanoma cells. CXCL10 increased expression of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor subunit-B (PDGF-B), fibroblast growth factor 2 (FGF2), hepatocyte growth factor (HGF), and angiopoietin 2 (Angpt2), in B16F10 melanoma cells, resulting in enhanced tube formation and proliferation of human umbilical vein endothelial cells in vitro. In addition, CXCL10 directly enhanced B16F10 melanoma tumor growth in an in vitro three-dimensional cell culture system. Together, our findings reveal that amplified host-derived endogenous CXCL10 is critical for B16F10 melanoma angiogenesis and tumor growth. Therefore, CXCL10 might represent a therapeutic target for melanoma.

Dendrimer-mediated targeting of angiogenic biomarkers: therapeutic intervention against cancer.

INTRODUCTION: Development of novel vascular networks is a fundamental requirement for tumor growth and progression. In the last decade, biomarkers and underlying molecular pathways of angiogenesis have been intensely investigated to disrupt the initiation and progression of tumor angiogenesis. However, the clinical applications of anti-angiogenic agents are constrained due to toxic side effects, acquired drug resistance, and unavailability of validated biomarkers. AREA COVERED: This review discusses the development of dendrimeric nanocarriers that could be a promising domain to explore for the eradication of current challenges associated with angiogenesis-based cancer therapy. Novel drug-delivery approaches with subtle readouts and better understanding of molecular mechanisms have revealed that dendrimers comprise innate anti-angiogenic activity and incorporation of anti-angiogenic agents or gene-silencing RNA could lead to synergistic anti-angiogenic and anticancer effects with reduced side effects. EXPERT OPINION: Dendrimer-mediated targeting of angiogenic biomarkers has efficiently led to the vascular normalization, and rational linking of dendrimers with anti-angiogenic agent or siRNA or both might be a potential area to eradicate the current challenges of angiogenesis-based cancer therapy. However, drawbacks associated with the dendrimers-mediated targeting of angiogenic biomarkers, such as poor stability or small expression of these biomarkers on the normal cells, limit their application at market scale.

Deep reinforcement learning control of combined chemotherapy and anti-angiogenic drug delivery for cancerous tumor treatment.

By virtue of the chronic and dangerous nature of cancer, researchers have explored various approaches to managing the abnormal cell growth associated with this disease using novel treatment methods. This study introduces a control system based on normalized advantage function reinforcement learning. It aims to boost the body's immune response against cancer cell proliferation. This control approach is applied to provide a combination of both chemotherapy and anti-angiogenic drugs for the first time without the need for complex, predefined mathematical models. It employs a model-free reinforcement learning technique that adaptively adjusts to individual patients to determine optimal drug administration with minimum injection rates. In this regard, a comprehensive and realistic simulation and training environment is employed, with the concentrations of normal cells, cancer cells, and endothelial cells, as well as the levels of chemotherapy and anti-angiogenic agents, as state variables. Furthermore, high levels of disturbances are considered in the simulation to investigate the robustness of the proposed method against probable uncertainties in the treatment process or patient parameters. A practical reward function has also been devised in alignment with medical objectives to ensure effective and safe treatment outcomes. The results demonstrate robustness and superior performance compared to the existing methods. Simulations show that the proposed approach is a dependable strategy for effectively reducing the concentration of cancer cells in the shortest duration using minimal doses of chemotherapy and anti-angiogenic drugs.

Soluble fms-like tyrosine kinase-1/placental growth factor ratio at 36 weeks' gestation: association with spontaneous onset of labor and intrapartum fetal compromise in low-risk pregnancies.

BACKGROUND: Previous evidence showed that placental dysfunction triggers spontaneous preterm or term births and intrapartum fetal compromise and often requires urgent delivery, thereby exposing both the fetus and the mother to significant risks. Predicting spontaneous labor onset and intrapartum fetal compromise could improve obstetrical management and outcomes, but this is currently difficult, particularly in low-risk populations. OBJECTIVE: The objective of this study was to examine whether placental dysfunction, as assessed at 36 weeks' gestation by the soluble fms-like tyrosine kinase-1 to placental growth factor ratio, is associated with the interval to spontaneous onset of labor and intrapartum fetal compromise that requires cesarean delivery in a routinely examined population. STUDY DESIGN: This was a retrospective analysis of prospectively collected data of women with singleton pregnancies who underwent routine assessment at 35+0 to 36+6 weeks' gestation at the King's College Hospital (London, England). Using a general linear model, the study examined the outcomes related to the soluble fms-like tyrosine kinase-1/placental growth factor ratio, including the time interval from testing to spontaneous onset of labor and the subsequent rate of fetal compromise that required a cesarean delivery. Patients who underwent induction of labor or prelabor cesarean deliveries were excluded from the study. Competing risks regression and Cox regression models were used to estimate the cumulative incidence and the risk of the outcomes of interest. RESULTS: In the screened population of 45,375 patients, 23,831 (52.5%) had spontaneous onset of labor and were included in the analysis. Cases with an soluble fms-like tyrosine kinase-1/placental growth factor ratio >50 delivered about 1 week earlier than those with a ratio of ≤50 (39.2 vs 40.0 weeks' gestation; P<.001). The general linear model showed that a larger soluble fms-like tyrosine kinase-1/placental growth factor ratio was associated with earlier spontaneous onset of labor (P<.001), particularly among multiparous women. The soluble fms-like tyrosine kinase-1/placental growth factor ratio was significantly associated, as expected, with cases of preeclampsia and advanced maternal age. The cumulative incidence of spontaneous onset of labor was significantly higher in cases with an soluble fms-like tyrosine kinase-1/placental growth factor ratio >50 than in those with a ratio 50 (P<.001). Cox regression showed that the risk for spontaneous onset of labor increased with an soluble fms-like tyrosine kinase-1/placental growth factor ratio >50 (hazard ratio, 1.424; 95% confidence interval, 1.253-1.618; P<.001) and, as expected, the risk was mitigated over time from when the soluble fms-like tyrosine kinase-1/placental growth factor ratio was measured to spontaneous labor onset (P<.001). Cases with intrapartum fetal compromise had a higher mean soluble fms-like tyrosine kinase-1/placental growth factor ratio than those without intrapartum fetal compromise (21.79 vs 17.67; P<.001). Qualitative addition of fetal compromise to the general linear model showed a higher soluble fms-like tyrosine kinase-1/placental growth factor ratio in cases with fetal compromise than in those without fetal compromise (P=.014). Competing risks regression showed a positive dose-response effect for fetal compromise with increasing soluble fms-like tyrosine kinase-1/placental growth factor ratios (P<.001). Above and below the optimal cutoff of 50, the quoted cumulative incidences were 6.7% and 4.7%, respectively (P<.001). The effect of the soluble fms-like tyrosine kinase-1/placental growth factor ratio remained significant even after adjusting for preeclampsia, which is a well-known major risk factor for fetal compromise. Finally, the proportion of cases with intrapartum fetal compromise who had an soluble fms-like tyrosine kinase-1/placental growth factor ratio >50 decreased from 35% to 0% with advancing gestation. CONCLUSION: This study showed that an increased soluble fms-like tyrosine kinase-1/placental growth factor ratio at 36 weeks' gestation is associated with an earlier gestational age at spontaneous onset of labor and higher rates of intrapartum fetal compromise. There are 2 major implications, namely an soluble fms-like tyrosine kinase-1/placental growth factor ratio >50 indicates imminent labor onset with about a 40% mean risk increase and immediate clinical translation for term pregnancy monitoring. In addition, an increased soluble fms-like tyrosine kinase-1/placental growth factor ratio increases the risk for intrapartum fetal compromise, although outcome variability indicates reassessment within multimarker models.

Advances in Predictive Biomarkers for Anti-Angiogenic Therapy in Non-Small Cell Lung Cancer.

This study aimed to explore advances in biomarkers related to anti-angiogenic therapy in patients with non-small cell lung cancer (NSCLC), thereby enhancing treatment selection, advancing personalized and precision medicine to improve treatment outcomes and patient survival rates. This article reviews key discoveries in predictive biomarkers for anti-angiogenic therapy in NSCLC in recent years, such as (1) liquid biopsy predictive biomarkers: studies have identified activated circulating endothelial cells (aCECs) via liquid biopsy as potential predictive biomarkers for the efficacy of anti-angiogenic therapy; (2) imaging biomarkers: advanced imaging technologies, such as dynamic contrast-enhanced integrated magnetic resonance positron emission tomography (MR-PET), are used to assess tumor angiogenesis in patients with NSCLC and evaluate the clinical efficacy of anti-angiogenic drugs; (3) genetic predictive biomarkers: research has explored polymorphisms of Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1) and vascular endothelial growth factor-A (VEGF-A), as well as how plasma levels of VEGF-A can predict the outcomes and prognosis of patients with non-squamous NSCLC undergoing chemotherapy combined with bevacizumab. Despite progress in identifying biomarkers related to anti-angiogenic therapy, several challenges remain, including limitations in clinical trials, heterogeneity in NSCLC, and technical hurdles. Future research will require extensive clinical validation and in-depth mechanistic studies to fully exploit the potential of these biomarkers for personalized treatment.

Comorbidities and Angiogenic Regulators Affect Endothelial Progenitor Cell Subtype Numbers in a Healthy Volunteer Control Group.

Endothelial progenitor cells (EPCs) are stem cells that can repair injured blood vessels through neovascularisation. This is achieved through secretion of growth factors and endothelial maturation. EPC numbers and function have been studied to determine their diagnostic, prognostic and therapeutic potential in many ischaemic diseases such as stroke. However their activation homing and migration is not definitively understood in stroke patients. In this study, we profiled the non-stroke control group recruited into the Dunhill Medical Trust Endothelial Progenitor Cell Study. Demographic, clinical and plasma levels of angiogenic regulators of participants were analysed to determine if there was any correlation with EPC numbers, subtypes and function. Participants with diabetes had significantly supressed EPC numbers (CD45-CD34 + CD133 + KDR+) and CD34 + KDR + and KDR + EPC subtypes. Male participants had significantly lower EPC numbers compared to female participants and the proliferative capacity of endothelial colony forming cells significantly decreased with increasing participant age. Pro-angiogenic proteins such as granulocyte colony-stimulating factor and stromal cell-derived factor were positively correlated with both undifferentiated and endothelial-committed EPC subtype numbers (CD133+, KDR+, CD34 + CD133+, CD34 + KDR+), whereas anti-angiogenic proteins such as thrombospondin-1 showed a negative correlation with undifferentiated EPC subtypes (CD133+, CD34 + CD133+) but a positive correlation with endothelial-committed EPC subtype numbers (KDR+, CD34 + KDR+). These results show that EPC numbers and subtypes are affected by many factors and larger studies which can analyse and deconvolute the interactions between comorbidities, plasma biomarker levels and EPC are needed.

A Splice Form of VEGF, a Potential Anti-Angiogenetic Form of Head and Neck Squamous Cell Cancer Inhibition.

Angiogenesis, primarily mediated by vascular endothelial growth factor (VEGF), is a fundamental step in the progression and metastasis of head and neck squamous cell carcinoma (HNSCC). Traditional anti-angiogenic therapies that target the VEGF pathway have shown promise but are often associated with significant side effects and variable efficacy due to the complexity of the angiogenic signaling pathway. This review highlights the potential of a specific VEGF splice form, VEGF165b, as an innovative therapeutic target for HNSCC. VEGF165b, unlike standard VEGF, is a natural inhibitor that binds to VEGF receptors without triggering pro-angiogenic signaling. Its distinct molecular structure and behavior suggest ways to modulate angiogenesis. This concept is particularly relevant when studying HNSCC, as introducing VEGF165b's anti-angiogenic properties offers a novel approach to understanding and potentially influencing the disease's dynamics. The review synthesizes experimental evidence suggesting the efficacy of VEGF165b in inhibiting tumor-induced angiogenesis and provides insight into a novel therapeutic strategy that could better manage HNSCC by selectively targeting aberrant vascular growth. This approach not only provides a potential pathway for more targeted and effective treatment options but also opens the door to a new paradigm in anti-angiogenic therapy with the possibility of reduced systemic toxicity. Our investigation is reshaping the future of HNSCC treatment by setting the stage for future research on VEGF splice variants as a tool for personalized medicine.

The Efficacy and Safety of Apatinib and Anlotinib in Advanced Non-Small Cell Lung Cancer.

Background: Anlotinib and apatinib, both vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), are clinically established in the treatment of advanced non-small cell lung cancer (NSCLC) in China, with anlotinib emerging as a standard treatment strategy. This study was conducted to evaluate the efficacy and safety of apatinib and anlotinib, and to compare their differences in treating patients with advanced NSCLC. Patients and Methods: We retrospectively analyzed the data of patients with advanced NSCLC treated with apatinib or anlotinib at a hospital in Eastern China from January 2017 to December 2021. The primary endpoint was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profile. Results: A total of 145 patients were included in this study. Median PFS (mPFS) was 3.53 months for the apatinib group and 5.3 months for the anlotinib group (HR = 0.59, 95% CI: 0.41-0.84; P = 0.004), and median OS (mOS) was 7.6 months versus 15.6 months (HR = 0.68, 95% CI: 0.46-1.00; P = 0.048), which all showed significant differences after adjusting for confounders (P < 0.05). Subgroup analysis revealed that the presence or absence of bone metastases significantly influenced PFS in both treatment groups. The ORR was 3.03% in the anlotinib group versus 10.13% in the apatinib group (P = 0.12), the DCR was 72.73% versus 51.90% (P = 0.21). No unanticipated adverse events (AEs) were observed. The incidence of grade 3-4 AEs was significantly higher in the apatinib group (31.65% vs 13.64%, P < 0.05). Conclusion: Anlotinib demonstrated greater efficacy and safety compared to apatinib in the treatment of advanced NSCLC, particularly in patients with bone metastases and EGFR(-).