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Scientific Reports Jun 2024Age-related macular degeneration (AMD) is one of the major causes of blindness in the elderly worldwide. Anti-vascular endothelial growth factor (VEGF) drugs have been...
Age-related macular degeneration (AMD) is one of the major causes of blindness in the elderly worldwide. Anti-vascular endothelial growth factor (VEGF) drugs have been widely used to treat the neovascular type of AMD (nAMD). However, VEGF acts not only as a pro-angiogenic factor but also as an anti-apoptotic factor in the eyes. In this study, we found that anti-VEGF drugs, including bevacizumab (Bev), ranibizumab (Ran), and aflibercept (Afl), induced epithelial-mesenchymal transition (EMT) in ARPE-19 cells in vitro, accompanied by the induction of CCN2, a potent pro-fibrotic factor. Similarly, intravitreal injection of Afl into mouse eyes resulted in EMT in the retinal pigmented epithelium (RPE). Co-treatment with CCN5, an anti-fibrotic factor that down-regulates CCN2 expression, significantly attenuated the adverse effects of the anti-VEGF drugs both in vitro and in vivo. Inhibition of the VEGF signaling pathway with antagonists of VEGF receptors, SU5416 and ZM323881, induced EMT and up-regulated CCN2 in ARPE-19 cells. Additionally, knock-down of CCN2 with siRNA abolished the adverse effects of the anti-VEGF drugs in ARPE-19 cells. Collectively, these results suggest that anti-VEGF drugs induce EMT in RPE through the induction of CCN2 and that co-treatment with CCN5 attenuates the adverse effects of anti-VEGF drugs in mouse eyes.
Topics: Epithelial-Mesenchymal Transition; Retinal Pigment Epithelium; Animals; Humans; Mice; Vascular Endothelial Growth Factor A; Macular Degeneration; Cell Line; Bevacizumab; CCN Intercellular Signaling Proteins; Angiogenesis Inhibitors; Ranibizumab; Recombinant Fusion Proteins; Signal Transduction; Repressor Proteins; Receptors, Vascular Endothelial Growth Factor
PubMed: 38886213
DOI: 10.1038/s41598-024-63565-z -
Ophthalmology Science 2024To evaluate the safety and efficacy of CBT-001, a multitarget tyrosine kinase inhibitor eyedrop, for pterygia.
A Phase IIa Multicenter, Randomized, Vehicle-Controlled, Dose Escalating Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of CBT-001 Ophthalmic Solution in Patients With Primary or Recurrent Pterygium.
PURPOSE
To evaluate the safety and efficacy of CBT-001, a multitarget tyrosine kinase inhibitor eyedrop, for pterygia.
DESIGN
Phase II clinical trial. Stage 1 was a single center, open-labeled, vehicle-controlled study. Stage 2 was a multicenter, randomized, double-masked, vehicle-controlled trial.
PARTICIPANTS
Patients with primary or recurrent pterygia.
MAIN OUTCOME MEASURES
The primary efficacy end point was lesion vascularity based on masked grading of photographs by an independent reading center. Other end points included dimensions of pterygia and safety.
METHODS
In stage 1, 24 eyes of 24 patients received 1 drop of CBT-001 in a dose escalation fashion (0.02%, 0.05%, and 0.2%) to determine the maximally tolerated dose based on adverse events (AEs) and blood drug levels. In stage 2, subjects were randomly assigned to receive the maximally tolerated dose of CBT-001 or vehicle dosed 3 times a day for 4 weeks with a 20-week follow-up.
RESULTS
In stage 1, the plasma maximum concentration values for all doses of CBT-001 were at or below the limit of detection (0.01 ng/ml). The most commonly reported AEs were mild foreign body sensation and irritation. CBT-001 0.2% was evaluated in stage 2. Baseline demographic characteristics were similar between patients receiving CBT-001 (n = 25) and vehicle (n = 23). After 4 weeks of dosing, the mean change from baseline in pterygium vascularity scores was -0.8 ± 0.7 (mean ± standard deviation) in subjects receiving CBT-001 0.2% and 0.0 ± 0.5 in subjects receiving vehicle ( < 0.001; 95% confidence interval: -1.12, -0.40). Pterygium vascularity scores remained significantly decreased, after the 4-week dosing period, at weeks 8 and 16, but not at week 24. The mean changes from baseline in the length of the pterygia were also significantly lower in subjects receiving CBT-001 compared with vehicle at weeks 2, 4, and 8 ( ≤ 0.014). The most commonly reported AEs were ocular, mild in severity, resolved after therapy, and did not result in discontinuation.
CONCLUSIONS
CBT-001 0.2% decreased pterygia vascularity and lesion length after 4 weeks of dosing with a prolonged effect after dosing. The drug was well tolerated with minimal detected systemic drug levels.
FINANCIAL DISCLOSURES
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PubMed: 38883924
DOI: 10.1016/j.xops.2024.100502 -
Frontiers in Public Health 2024Progressive glioblastoma (GBM) is a malignancy with extremely poor prognosis. Chemotherapy is one of the approved systemic treatment modalities. The aim of this study is...
BACKGROUND
Progressive glioblastoma (GBM) is a malignancy with extremely poor prognosis. Chemotherapy is one of the approved systemic treatment modalities. The aim of this study is to assess the cost-effectiveness of using bevacizumab (BEV) in combination with lomustine (LOM) regimen for the treatment of progressive glioblastoma in China.
METHODS
The estimation results are derived from a multicenter randomized phase III trial, which demonstrated improved survival in GBM patients receiving BEV+LOM combination therapy. To calculate the incremental cost-effectiveness ratio (ICER) from the perspective of Chinese society, a Markov model was established. Univariate deterministic analysis and probabilistic sensitivity analysis were employed to address the uncertainties within the model.
RESULTS
Compared to LOM monotherapy, the total treatment cost for BEV+LOM combination therapy increased from $2,646.70 to $23,650.98. The health-adjusted life years (QALYs) for BEV+LOM combination therapy increased from 0.26 QALYs to 0.51 QALYs, representing an increment of 0.25 QALYs. The incremental cost-effectiveness ratio (ICER) was $84,071.12. The cost-effectiveness curve indicates that within the willingness-to-pay (WTP) range of $35,906 per QALY, BEV+LOM combination therapy is not a cost-effective treatment option for unresectable malignant pleural mesothelioma patients.
CONCLUSIONS
Taken as a whole, the findings of this study suggest that, from the perspective of payers in China, BEV+LOM combination therapy as a first-line treatment for GBM is not a cost-effective option. However, considering the survival advantages this regimen may offer for this rare disease, it may still be one of the clinical treatment options for this patient population.
Topics: Bevacizumab; Glioblastoma; Humans; Cost-Benefit Analysis; Lomustine; Markov Chains; China; Antineoplastic Combined Chemotherapy Protocols; Quality-Adjusted Life Years; Brain Neoplasms; Cost-Effectiveness Analysis
PubMed: 38883194
DOI: 10.3389/fpubh.2024.1410355 -
Regenerative Therapy Jun 2024Hair loss is one of the common clinical conditions in modern society. Although it is not a serious disease that threatens human life, it brings great mental stress and...
INTRODUCTION
Hair loss is one of the common clinical conditions in modern society. Although it is not a serious disease that threatens human life, it brings great mental stress and psychological burden to patients. This study investigated the role of dendrobium officinale polysaccharide (DOP) in hair follicle regeneration and hair growth and its related mechanisms.
METHODS
After in vitro culture of mouse antennal hair follicles and mouse dermal papilla cells (DPCs), and mouse vascular endothelial cells (MVECs), the effects of DOP upon hair follicles and cells were evaluated using multiple methods. DOP effects were evaluated by measuring tentacle growth, HE staining, immunofluorescence, Western blot, CCK-8, ALP staining, tube formation, scratch test, and Transwell. LDH levels, WNT signaling proteins, and therapeutic mechanisms were also analyzed.
RESULTS
DOP promoted tentacle hair follicle and DPCs growth in mice and the angiogenic, migratory and invasive capacities of MVECs. Meanwhile, DOP was also capable of enhancing angiogenesis and proliferation-related protein expression. Mechanistically, DOP activated the WNT signaling and promoted the expression level of β-catenin, a pivotal protein of the pathway, and the pathway target proteins Cyclin D1, C-Myc, and LDH activity. The promotional effects of DOP on the biological functions of DPCs and MVECs could be effectively reversed by the WNT signaling pathway inhibitor IWR-1.
CONCLUSION
DOP advances hair follicle and hair growth via the activation of the WNT signaling. This finding provides a mechanistic reference and theoretical basis for the clinical use of DOP in treating hair loss.
PubMed: 38883148
DOI: 10.1016/j.reth.2024.04.014 -
Frontiers in Pharmacology 2024Celastrol (Cel) is a widely used main component of Chinese herbal medicine with strong anti-inflammatory, antiviral and antitumor activities. In the present study, we...
Celastrol (Cel) is a widely used main component of Chinese herbal medicine with strong anti-inflammatory, antiviral and antitumor activities. In the present study, we aimed to elucidate the cellular molecular protective mechanism of Cel against diabetes-induced inflammation and endothelial dysfunction. Type 2 diabetes (T2DM) was induced by db/db mice, and osmotic pumps containing Cel (100 μg/kg/day) were implanted intraperitoneally and were calibrated to release the drug for 28 days. In addition, human umbilical vein endothelial cells (HUVECs) were cultured in normal or high glucose and palmitic acid-containing (HG + PA) media in the presence or absence of Cel for 48 h. Cel significantly ameliorated the hyperglycemia-induced abnormalities in nuclear factor (erythroid-derived 2)-like protein 2 (Nrf2) pathway activity and alleviated HG + PA-induced oxidative damage. However, the protective effect of Cel was almost completely abolished in HUVECs transfected with short hairpin (sh)RNA targeting Nrf2, but not by nonsense shRNA. Furthermore, HG + PA reduced the phosphorylation of AMP-activated protein kinase (AMPK), the autophagic degradation of p62/Kelch-like ECH-associated protein 1 (Keap1), and the nuclear localization of Nrf2. However, these catabolic pathways were inhibited by Cel treatment in HUVECs. In addition, compound C (AMPK inhibitors) and reduced Cel-induced Nrf2 activation and angiogenesis in db/db mice. Taking these findings together, the endothelial protective effect of Cel in the presence of HG + PA may be at least in part attributed to its effects to reduce reactive oxygen species (ROS) and inflammation through p62/Keap1-mediated Nrf2 activation.
PubMed: 38881873
DOI: 10.3389/fphar.2024.1360177 -
Scientific Reports Jun 2024We assessed the short-term effects of switching from intravitreal aflibercept (IVA) to intravitreal faricimab (IVF) on ocular blood flow in patients with...
We assessed the short-term effects of switching from intravitreal aflibercept (IVA) to intravitreal faricimab (IVF) on ocular blood flow in patients with treatment-resistant diabetic macular edema (DME). The medical records of 15 patients with DME who had received IVA injection ≥ 3 months before were retrospectively reviewed. The best-corrected visual acuity, central macular thickness (CMT) on optical coherence tomography, and mean blur rate (MBR) of all disc areas on laser speckle flowgraphy were measured before, 1 week after, and 4 weeks after IVA and IVF, respectively. The changes in visual acuity showed no significant difference after switching from IVA to IVF (P = 0.732). The mean CMT decreased significantly during the follow-up period (both P < 0.001). MBR showed no significant difference during the follow-up period (P = 0.26). However, it decreased significantly 4 weeks after IVF (P = 0.01) compared with the baseline value, but not 4 weeks after IVA (P = 0.074). A significant association was observed between decreased MBR and decreased CMT in patients who received IVF (correlation coefficient: 0.501, P = 0.005) but not in those who received IVA (P = 0.735). Thus, IVF maintained ocular blood flow reduction, although no significant differences in visual acuity and CMT changes were observed compared to IVA.
Topics: Humans; Macular Edema; Male; Female; Intravitreal Injections; Recombinant Fusion Proteins; Receptors, Vascular Endothelial Growth Factor; Middle Aged; Diabetic Retinopathy; Aged; Retrospective Studies; Visual Acuity; Tomography, Optical Coherence; Angiogenesis Inhibitors; Regional Blood Flow; Eye
PubMed: 38877041
DOI: 10.1038/s41598-024-63435-8 -
PloS One 2024Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far,...
BACKGROUND
Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far, there are no biomarkers that reliably predict resistance to anti-VEGF mAbs like bevacizumab. A biomarker-guided strategy for early and accurate assessment of resistance could avoid the use of non-effective treatment and improve patient outcomes. We hypothesized that repeated analysis of multiple cytokines and angiogenic growth factors (CAFs) before and during treatment using machine learning could provide an accurate and earlier, i.e., 100 days before conventional radiologic staging, prediction of resistance to first-line mCRC treatment with FOLFOX plus bevacizumab.
PATIENTS AND METHODS
15 German and Austrian centers prospectively recruited 50 mCRC patients receiving FOLFOX plus bevacizumab as first-line treatment. Plasma samples were collected every two weeks until radiologic progression (RECIST 1.1) as determined by CT scans performed every 2 months. 102 pre-selected CAFs were centrally analyzed using a cytokine multiplex assay (Luminex, Myriad RBM).
RESULTS
Using random forests, we developed a predictive machine learning model that discriminated between the situations of "no progress within 100 days before radiological progress" and "progress within 100 days before radiological progress". We could further identify a combination of ten out of the 102 CAF markers, which fulfilled this task with 78.2% accuracy, 71.8% sensitivity, and 82.5% specificity.
CONCLUSIONS
We identified a CAF marker combination that indicates treatment resistance to FOLFOX plus bevacizumab in patients with mCRC within 100 days prior to radiologic progress.
Topics: Humans; Colorectal Neoplasms; Bevacizumab; Leucovorin; Antineoplastic Combined Chemotherapy Protocols; Female; Organoplatinum Compounds; Male; Fluorouracil; Middle Aged; Aged; Drug Resistance, Neoplasm; Prospective Studies; Adult; Neoplasm Metastasis; Biomarkers, Tumor
PubMed: 38875244
DOI: 10.1371/journal.pone.0304324 -
Immunity, Inflammation and Disease Jun 2024The heterogeneity of tumor endothelial cells (TECs) hinders the efficacy of antiangiogenic therapies (AATs). Only a small percentage of angiogenic TECs are considered...
BACKGROUND
The heterogeneity of tumor endothelial cells (TECs) hinders the efficacy of antiangiogenic therapies (AATs). Only a small percentage of angiogenic TECs are considered effective targets for AATs. Immunomodulatory ECs (IMECs), as a newly focused functional subgroup of endothelial cells (ECs), are being evaluated for their ability to regulate tumor immune balance and influence existing AATs.
METHODS
Based on single-cell transcriptome data from colorectal cancer in a publicly available database, we conducted a wide array of bioinformatic approaches to study EC subsets that meet the IMECs definition. Our investigation encompassed the gene expression signatures of these subsets, cellular composition differences, cell-cell interactions.
RESULTS
Two subsets that meet the IMECs definition were found in tumors and para-cancerous tissues. Combined with the results of gene ontological analysis and interaction with CD4 T cells, we found that IMECs can present MHC-II antigens to mature CD4 T cells. There were differences in the level of interaction between IMECs and different types of mature CD4 T cell subsets. In addition, IMEC subsets had different expression levels of angiogenesis related genes. The angiogenesis score of IMECs decreased after patients received immunotherapy. IMEC subsets do not depend on a single proangiogenic receptor and are involved in regulating angiogenesis, which may reduce the efficacy of AATs. The adverse effects of specific IMEC subsets on AATs were validated in the RNA-seq dataset of the bevacizumab treatment group.
CONCLUSION
Our study suggests the potential MHC-II antigen presentation capacity of IMECs and the enhanced angiogenesis characteristics within tumors. The function of IMECs in the vascular network may have a potentially adverse effect on AATs. Controlling the functional properties of IMECs may be a new angle for tumor therapy.
Topics: Humans; Colorectal Neoplasms; Endothelial Cells; Single-Cell Analysis; Transcriptome; Antigen Presentation; Neovascularization, Pathologic; Drug Resistance, Neoplasm; Gene Expression Profiling; Angiogenesis Inhibitors; Immunomodulation; CD4-Positive T-Lymphocytes
PubMed: 38874280
DOI: 10.1002/iid3.1311 -
Oncology Letters Aug 2024Skin metastasis from ovarian cancer is rare, and its prognosis is poor. Effective therapeutic strategies are currently lacking, but the combination of various treatment...
Skin metastasis from ovarian cancer is rare, and its prognosis is poor. Effective therapeutic strategies are currently lacking, but the combination of various treatment methods shrink the tumor and relieve symptoms. The present study reports a rare case of advanced ovarian cancer with skin metastases and intestinal wall thickening, along with a BRCA1 DNA repair associated (BRCA1) mutation. After standard first-line treatment and non-standard second-line treatment, the patient developed skin metastases. The patient's skin itching, pain and lesions were completely relieved after administering bevacizumab in combination with paclitaxel and carboplatin. After 4 months, skin metastases recurred along with anal distension during maintenance treatment with oral poly(ADP ribose) polymerase (PARP) inhibitors. The patient was treated again with bevacizumab combined with docetaxel, and the anal distension was significantly relieved. Angiogenesis therapy combined with chemotherapy is effective, but that the disease-free survival time is short, and PARP inhibitor maintenance effect is limited even in cases with a BRCA1 gene mutation.
PubMed: 38872856
DOI: 10.3892/ol.2024.14481 -
Cancer Medicine Jun 2024Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 2 probably cannot tolerate chemotherapy or other antitumor therapies. Some studies have...
Immunotherapy combined with antiangiogenic therapy as third- or further-line therapy for stage IV non-small cell lung cancer patients with ECOG performance status 2: A retrospective study.
BACKGROUND
Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 2 probably cannot tolerate chemotherapy or other antitumor therapies. Some studies have reported that immunotherapy combined with antiangiogenic therapy is well-tolerated and shows good antitumor activity. However, the efficacy of this combination as a later-line therapy in patients with ECOG PS 2 is unclear. This study evaluated the effectiveness and safety of this combination strategy as third- or further-line therapy in stage IV non-small cell lung cancer (NSCLC) patients with ECOG PS 2.
METHODS
In this retrospective study, patients treated with camrelizumab plus antiangiogenic therapy (bevacizumab, anlotinib, or recombinant human endostatin) were included. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), quality of life (QOL) assessed by ECOG PS, and safety were analyzed.
RESULTS
Between January 10, 2019, and February 28, 2024, a total of 59 patients were included. The ORR was 35.6% (21/59) and the DCR was 86.4%. With a median follow-up of 10.5 months (range: 0.7-23.7), the median PFS was 5.5 months (95% confidence interval [CI]: 3.8-7.3) and the median OS was 10.5 months (95% CI: 11.2-13.6). QOL was improved (≥1 reduction in ECOG PS) in 39 patients (66.1%). The most common Grade 3-4 treatment-related adverse events were hepatic dysfunction (6 [10%]), hypertension (5 [8%]), and hypothyroidism (3 [5%]). There were no treatment-related deaths.
CONCLUSIONS
Third- or further-line immunotherapy combined with antiangiogenic therapy is well-tolerated and shows good antitumor activity in stage IV NSCLC patients with ECOG PS 2. Future large-scale prospective studies are required to confirm the clinical benefits of this combination therapy.
Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Endostatins; Immunotherapy; Indoles; Lung Neoplasms; Neoplasm Staging; Quality of Life; Quinolines; Retrospective Studies
PubMed: 38872402
DOI: 10.1002/cam4.7349