Endostar acts as a pneumonitis protectant in patients with locally advanced non-small cell lung cancer receiving concurrent chemoradiotherapy.

BACKGROUND: CCRT is presently the standard treatment for LA-NSCLC. RP is one of the main obstacles to the completion of thoracic radiation therapy, resulting in limited survival benefits in NSCLC patients. This research aims to explore the role of Endostar in the occurrence of grade≥2 RP and clinical curative effect in LA-NSCLC patients. METHODS: This study retrospectively analyzed 122 patients with stage III NSCLC who received CCRT from December 2008 to December 2017, or Endostar intravenous drip concurrently with chemoradiotherapy (Endostar + CCRT group). Standard toxicity of the pneumonitis endpoint was also collected by CTCAE V5.0. We further summarized other available studies on the role of Endostar in the prognosis of NSCLC patients and the incidence of RP. RESULTS: There were 76 cases in the CCRT group and 46 cases in the CCRT+ Endostar group. In the CCRT+ Endostar group, the occurrence of grade ≥2 RP in patients with V20Gy ≥25% was significantly higher than that in patients with V20Gy < 25% (p = 0.001). In the cohorts with V20Gy < 25%, 0 cases of 29 patients treated with Endostar developed grade ≥2 RP was lower than in the CCRT group (p = 0.026). The re-analysis of data from other available studies indicated that Endostar plus CCRT could be more efficient and safely in the occurrence of grade≥2 RP with LA-NSCLC. CONCLUSIONS: When receiving CCRT for LA-NSCLC patients, simultaneous combination of Endostar is recommended to enhance clinical benefit and reduce pulmonary toxicity.

Soluble CD147 regulates endostatin via its effects on the activities of MMP-9 and secreted proteasome 20S.

During progression of rheumatoid arthritis (RA), angiogenesis provides oxygen and nutrients for the cells' increased metabolic demands and number. To turn on angiogenesis, pro-angiogenic factors must outweigh anti-angiogenic factors. We have previously shown that CD147/extracellular matrix metalloproteinase inducer (EMMPRIN) can induce the expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and matrix metallopeptidase 9 (MMP-9) in a co-culture of the human HT1080 fibrosarcoma and U937 monocytic-like cell lines. However, whether CD147 influences anti-angiogenic factors was not known. We now show that relative to single cultures, the co-culture of these cells not only enhanced pro-angiogenic factors but also decreased the anti-angiogenic factors endostatin and thrombospondin-1 (Tsp-1), generally increasing the angiogenic potential as measured by a wound assay. Using anti-CD147 antibody, CD147 small interfering RNA (siRNA), and recombinant CD147, we demonstrate that CD147 hormetically regulates the generation of endostatin but has no effect on Tsp-1. Since endostatin is cleaved from collagen XVIII (Col18A), we applied different protease inhibitors and established that MMP-9 and proteasome 20S, but not cathepsins, are responsible for endostatin generation. MMP-9 and proteasome 20S collaborate to synergistically enhance endostatin generation, and in a non-cellular system, CD147 enhanced MMP-9 activity and hormetically regulated proteasome 20S activity. Serum samples obtained from RA patients and healthy controls mostly corroborated these findings, indicating clinical relevance. Cumulatively, these findings suggest that secreted CD147 mediates a possibly allosteric effect on MMP-9 and proteasome 20S activities and can serve as a switch that turns angiogenesis on or off, depending on its ambient concentrations in the microenvironment.

Antibody-Drug Conjugate αEGFR-E-P125A Reduces Triple-negative Breast Cancer Vasculogenic Mimicry, Motility, and Metastasis through Inhibition of EGFR, Integrin, and FAK/STAT3 Signaling.

Primary tumor growth and metastasis in triple-negative breast cancer (TNBC) require supporting vasculature, which develop through a combination of endothelial angiogenesis and vasculogenic mimicry (VM), a process associated with aggressive metastatic behavior in which vascular-like structures are lined by tumor cells. We developed αEGFR-E-P125A, an antibody-endostatin fusion protein that delivers a dimeric, mutant endostatin (E-P125A) payload that inhibits TNBC angiogenesis and VM in vitro and in vivo. To characterize the mechanisms associated with induction and inhibition of VM, RNA sequencing (RNA-seq) of MDA-MB-231-4175 TNBC cells grown in a monolayer (two-dimensional) was compared with cells plated on Matrigel undergoing VM [three-dimensional (3D)]. We then compared RNA-seq between TNBC cells in 3D and cells in 3D with VM inhibited by αEGFR-E-P125A (EGFR-E-P125A). Gene set enrichment analysis demonstrated that VM induction activated the IL6-JAK-STAT3 and angiogenesis pathways, which were downregulated by αEGFR-E-P125A treatment.Correlative analysis of the phosphoproteome demonstrated decreased EGFR phosphorylation at Y1069, along with decreased phosphorylation of focal adhesion kinase Y397 and STAT3 Y705 sites downstream of α5ß1 integrin. Suppression of phosphorylation events downstream of EGFR and α5ß1 integrin demonstrated that αEGFR-E-P125A interferes with ligand-receptor activation, inhibits VM, and overcomes oncogenic signaling associated with EGFR and α5ß1 integrin cross-talk. In vivo, αEGFR-E-P125A treatment decreased primary tumor growth and VM, reduced lung metastasis, and confirmed the inhibition of signaling events observed in vitro. Simultaneous inhibition of EGFR and α5ß1 integrin signaling by αEGFR-E-P125A is a promising strategy for the inhibition of VM, tumor growth, motility, and metastasis in TNBC and other EGFR-overexpressing tumors. SIGNIFICANCE: αEGFR-E-P125A reduces VM, angiogenesis, tumor growth, and metastasis by inhibiting EGFR and α5ß1 integrin signaling, and is a promising therapeutic agent for TNBC treatment, used alone or in combination with chemotherapy.

Multi-omics sequencing revealed endostar combined with cisplatin treated non small cell lung cancer via anti-angiogenesis.

BACKGROUND: Endostar, an anti-angiogenic drug, has been approved for treating non-small cell lung cancer (NSCLC). At present, endostar combined with radiotherapy or chemotherapy has achieved ideal results in the treatment of some tumors, but there is a lack of application and study in NSCLC. This study investigated the therapeutic effect and potential mechanism of endostar combined with cisplatin (EC) in NSCLC. METHODS: HE staining, TUNEL staining, immunofluorescence, colony formation ability, and cell migration ability were used to evaluate the anti-tumor activity of EC. The expressions of FMOD, VEGF, FGF-2, and PDGF-B were detected by western blotting and qPCR. The target of combination therapy was analyzed by m6A sequencing and RNA sequencing. METTL3 knockdown and overexpressed A549 cells were constructed and co-cultured with HUVECs to further evaluate the effect of METLL3 on combination therapy. RESULTS: Combination therapy significantly reduced the colony formation and migration ability of NSCLC cells, induced cell apoptosis, and inhibited the tube formation ability of HUVECs. The results of m6A sequencing and RNA sequencing showed that the EC could down-regulate the expression level of FMOD in tumor tissues, which might be related to the reduction of its m6A methylation modification regulatory enzyme METTL3. Restricting FMOD expression could reduce the expression of FGF2, TGF-ß1, VEGF and PDGF-B. Moreover, overexpression of METTLE almost abolished the anti-tumor effect of EC and promoted angiogenesis. CONCLUSIONS: Endostar combined with cisplatin might exert anti-tumor effects by down-regulating the expression of METTL3 and FMOD.

Microvascular damage, neuroinflammation and extracellular matrix remodeling in Col18a1 knockout mice as a model for early cerebral small vessel disease.

Collagen type XVIII (COL18) is an abundant heparan sulfate proteoglycan in vascular basement membranes. Here, we asked (i) if the loss of COL18 would result in blood-brain barrier (BBB) breakdown, pathological alterations of small arteries and capillaries and neuroinflammation as found in cerebral small vessel disease (CSVD) and (ii) if such changes may be associated with remodeling of synapses and neural extracellular matrix (ECM). We found that 5-month-old Col18a1-/- mice had elevated BBB permeability for mouse IgG in the deep gray matter, and intravascular erythrocyte accumulations were observed brain-wide in capillaries and arterioles. BBB permeability increased with age and affected cortical regions and the hippocampus in 12-month-old Col18a1-/- mice. None of the Col18a1-/- mice displayed hallmarks of advanced CSVD, such as hemorrhages, and did not show perivascular space enlargement. Col18a1 deficiency-induced BBB leakage was accompanied by activation of microglia and astrocytes, a loss of aggrecan in the ECM of perineuronal nets associated with fast-spiking inhibitory interneurons and accumulation of the perisynaptic ECM proteoglycan brevican and the microglial complement protein C1q at excitatory synapses. As the pathway underlying these regulations, we found increased signaling through the TGF-ß1/Smad3/TIMP-3 cascade. We verified the pivotal role of COL18 for small vessel wall structure in CSVD by demonstrating the protein's involvement in vascular remodeling in autopsy brains from patients with cerebral hypertensive arteriopathy. Our study highlights an association between the alterations of perivascular ECM, extracellular proteolysis, and perineuronal/perisynaptic ECM, as a possible substrate of synaptic and cognitive alterations in CSVD.

Plasmid co-expressing siRNA-PD-1 and Endostatin carried by attenuated Salmonella enhanced the anti-melanoma effect via inhibiting the expression of PD-1 and VEGF on tumor-bearing mice.

Melanoma, the most perilous form of skin cancer, is known for its inherent resistance to chemotherapy. Even with advances in tumor immunotherapy, the survival of patients with advanced or recurrent melanomas remains poor. Over time, melanoma tumor cells may produce excessive angiogenic factors, necessitating the use of combinations of angiogenesis inhibitors, including broad-spectrum options, to combat melanoma. Among these inhibitors, Endostatin is one of the most broad-spectrum and least toxic angiogenesis inhibitors. We found Endostatin significantly increased the infiltration of CD8+ T cells and reduced the infiltration of M2 tumor-associated macrophages (TAMs) in the melanoma tumor microenvironment (TME). Interestingly, we also observed high expression levels of programmed death 1 (PD-1), an essential immune checkpoint molecule associated with tumor immune evasion, within the melanoma tumor microenvironment despite the use of Endostatin. To address this issue, we investigated the effects of a plasmid expressing Endostatin and PD-1 siRNA, wherein Endostatin was overexpressed while RNA interference (RNAi) targeted PD-1. These therapeutic agents were delivered using attenuated Salmonella in melanoma-bearing mice. Our results demonstrate that pEndostatin-siRNA-PD-1 therapy exhibits optimal therapeutic efficacy against melanoma. We found that pEndostatin-siRNA-PD-1 therapy promotes the infiltration of CD8+ T cells and the expression of granzyme B in melanoma tumors. Importantly, combined inhibition of angiogenesis and PD-1 significantly suppresses melanoma tumor progression compared with the inhibition of angiogenesis or PD-1 alone. Based on these findings, our study suggests that combining PD-1 inhibition with angiogenesis inhibitors holds promise as a clinical strategy for the treatment of melanoma.

Recombinant human endostatin as a potential anti-angiogenic agent: therapeutic perspective and current status.

Angiogenesis is the physiological process that results in the formation of new blood vessels develop from pre-existing vasculature and plays a significant role in several physiological and pathological processes. Inhibiting angiogenesis, a crucial mechanism in the growth and metastasis of cancer, has been proposed as a potential anticancer therapy. Different studies showed the beneficial effects of angiogenesis inhibitors either in patients suffering from different cancers, alone or in combination with conventional therapies. Even though there are currently a number of efficient anti-angiogenic drugs, including monoclonal antibodies and kinase inhibitors, the associated toxicity profile and their affordability constraints are prompting researchers to search for a safe and affordable angiostatic agent for cancer treatment. Endostatin is one of the endogenous anti-angiogenic candidates that have been extensively pursued for the treatment of cancer, but even over three decades after its discovery, we have not made much advancement in employing it as an anticancer therapeutic despite of its remarkable anti-angiogenic effect with low toxicity profile. A recombinant human endostatin (rh-Es) variant for non-small cell lung cancer was approved by China in 2006 and has since been used effectively. Several other successful clinical trials related to endostatin for various malignancies are either ongoing or have already been completed with promising results. Thus, in this review, we have provided an overview of existing anti-angiogenic drugs developed for cancer therapy, with a summary of tumour angiogenesis in the context of Endostatin, and clinical status of rh-Es in cancer treatment. Furthermore, we briefly discuss the various strategies to improve endostatin features (poor pharmacokinetic properties) for developing rh-Es as a safe and effective agent for cancer treatment.

A real-world study of recombinant human endostatin combined with PD-1/PD-L1 blockade and chemotherapy for patients with advanced non-small cell lung cancer negative for actionable molecular biomarkers.

The ongoing ENPOWER study exploring the efficacy and safety of the recombinant human endostatin (endostar) combined with programmed cell death 1 antibody sintilimab and chemotherapy showed encouraging efficacy and safety in advanced non-squamous non-small cell lung cancer. To evaluate the real-world efficacy and safety of endostar combined with immune checkpoint inhibitor and chemotherapy (EIC) for advanced non-squamous non-small cell lung cancer patients negative for actionable molecular biomarkers (NSCLCnm), patients with advanced NSCLCnm hospitalized to Zhejiang Provincial People's Hospital from January 2020 to December 2022 were screened for eligibility. The included patients were analyzed for the objective response rate (ORR) and disease control rate (DCR). The pre- and posttreatment expression levels of serum tumor associated biomarkers, chemokines and subpopulations of immune cells in peripheral blood were compared. For the 31 patients with advanced NSCLCnm treated with EIC, the median follow-up and treatment cycles were 18.0 months and 4, respectively. The ORR and DCR were 38.7% and 90.3%, respectively. For those who received EIC as first-line treatment, the ORR and DCR were 63.2% and 94.7%, respectively. EIC significantly decreased expression levels of carcinoma antigen 125, carcinoma embryonic antigen and cytokeratin 19 (P<0.05) in patients who were partial remission or stable disease. Among the 31 patients, 27 (87.1%) experienced at least 1 treatment-related adverse events, and 13 (41.9%) had the treatment-related adverse events of grade 3 or higher. No antiangiogenesis-related adverse events were observed. The current study showed that EIC was potentially effective for patients with NSCLCnm, especially when used as first-line therapy, and well tolerated.

Canagliflozin improves coronary microvascular vasodilation and increases absolute blood flow to the myocardium independent of angiogenesis.

OBJECTIVES: Sodium-glucose cotransporter-2 inhibitor, canagliflozin, improves myocardial perfusion to ischemic territory without accompanying changes in vascular density. We aimed to (1) characterize effects on angiogenic pathways, (2) use multiomics to identify gene expression and metabolite profiles relevant to regulation of myocardial blood flow, and (3) investigate drug effect on coronary microvascular reactivity. METHODS: A nondiabetic swine model of chronic myocardial ischemia and nondiabetic rat model were used to study functional and molecular effects of canagliflozin on myocardium and in vitro microvascular reactivity. RESULTS: Canagliflozin resulted in increased coronary microvascular vasodilation and decreased vasoconstriction (P < .05) without changes in microvascular density (P > .3). Expression of the angiogenic modulator, endostatin, increased (P = .008), along with its precursor, collagen 18 (P < .001), and factors that increase its production, including cathepsin L (P = .004). Endostatin and collagen 18 levels trended toward an inverse correlation with blood flow to ischemic territory at rest. Proangiogenic fibroblast growth factor receptor was increased (P = .03) and matrix metalloproteinase-9 was decreased (P < .001) with canagliflozin treatment. Proangiogenic vascular endothelial growth factor A (P = .13), Tie-2 (P = .10), and Ras (P = .18) were not significantly altered. Gene expression related to the cardiac renin-angiotensin system was significantly decreased. CONCLUSIONS: In chronic myocardial ischemia, canagliflozin increased absolute blood flow to the myocardium without robustly increasing vascular density or proangiogenic signaling. Canagliflozin resulted in altered coronary microvascular reactivity to favor vasodilation, likely through direct effect on vascular smooth muscle. Downregulation of cardiac renin-angiotensin system demonstrated local regulation of perfusion. VIDEO ABSTRACT.

Dan-Deng-Tong-Nao softgel capsule promotes angiogenesis of cerebral microvasculature to protect cerebral ischemia reperfusion injury via activating HIF-1α-VEGFA-Notch1 signaling pathway.

BACKGROUND: A proprietary Chinese herbal product called Dan-Deng-Tong-Nao softgel capsule (DDTNC) is used to treat ischemic stroke. However, the preventive mechanisms of DDTNC against cerebral ischemia reperfusion injury (CIRI) haven not been characterized. OBJECTIVE: To explore the mechanisms of protective effects of DDTNC against CIRI from both internal and external levels. METHODS: Chemical characterization was performed using UPLC. The potential protective mechanisms of DDTNC against CIRI were predicted using network pharmacology. Model of middle cerebral artery occlusion/reperfusion (MCAO/R) was established in rats. An model of brain microvascular endothelial cells (BMECs) induced by oxygen-glucose deprivation/reoxygenation (OGD/R) was also established. We evaluated neurological deficits, cerebral infarct volume, cortical neuron damage, and mitochondrial swelling in vivo. We evaluated the expression of VEGFR2, VEGFA, HIF-1α, CD31, and CD34 in ischemic cortex, and VEGF, bFGF, BDNF, angiostatin, and endostatin in serum of rats and in BMEC supernatants. We also evaluated cell viability, cytotoxicity, intracellular ROS, apoptosis, and migration ability in vitro. RESULTS: Seven components were detected in DDTNC. KEGG enrichment analysis showed that DDTNC may modulate angiogenesis via the HIF-1 signaling pathway. DDTNC treatment reduced neurological score and infarct volume, and improved cell morphology of damaged neurons. Transmission electron microscopy showed that DDTNC reduced mitochondria swelling in cortical neurons. Furthermore, DDTNC reduced intracellular ROS and inhibited apoptosis. DDTNC boosted the expression of CD31, CD34, VEGFR2, VEGFA and HIF-1α, highlighting its involvement in angiogenesis, according to immunofluorescence studies. Furthermore, DDTNC enhanced tube formation and migration of BMECs in vitro. ELISA and western blotting indicated that DDTNCCSF induced the expression of VEGF, BDNF and bFGF, reduced the level of angiostatin and endostatin, increased the protein expression of VEGFA, Notch1 and HIF-1α in vitro and in vivo. CONCLUSIONS: DDTNC promoted angiogenesis to protect brain tissue against MCAO/R, and exerted protective effects against OGD/R in BMECs via activating HIF-1α-VEGFA-NOTCH1 signal transduction pathway.

Basement membrane product, endostatin, as a link between inflammation, coagulation and vascular permeability in COVID-19 and non-COVID-19 acute respiratory distress syndrome.

Background: Immune cell recruitment, endothelial cell barrier disruption, and platelet activation are hallmarks of lung injuries caused by COVID-19 or other insults which can result in acute respiratory distress syndrome (ARDS). Basement membrane (BM) disruption is commonly observed in ARDS, however, the role of newly generated bioactive BM fragments is mostly unknown. Here, we investigate the role of endostatin, a fragment of the BM protein collagen XVIIIα1, on ARDS associated cellular functions such as neutrophil recruitment, endothelial cell barrier integrity, and platelet aggregation in vitro. Methods: In our study we analyzed endostatin in plasma and post-mortem lung specimens of patients with COVID-19 and non-COVID-19 ARDS. Functionally, we investigated the effect of endostatin on neutrophil activation and migration, platelet aggregation, and endothelial barrier function in vitro. Additionally, we performed correlation analysis for endostatin and other critical plasma parameters. Results: We observed increased plasma levels of endostatin in our COVID-19 and non-COVID-19 ARDS cohort. Immunohistochemical staining of ARDS lung sections depicted BM disruption, alongside immunoreactivity for endostatin in proximity to immune cells, endothelial cells, and fibrinous clots. Functionally, endostatin enhanced the activity of neutrophils, and platelets, and the thrombin-induced microvascular barrier disruption. Finally, we showed a positive correlation of endostatin with soluble disease markers VE-Cadherin, c-reactive protein (CRP), fibrinogen, and interleukin (IL)-6 in our COVID-19 cohort. Conclusion: The cumulative effects of endostatin on propagating neutrophil chemotaxis, platelet aggregation, and endothelial cell barrier disruption may suggest endostatin as a link between those cellular events in ARDS pathology.

Macrophage-Derived Cathepsin S Remodels the Extracellular Matrix to Promote Liver Fibrogenesis.

BACKGROUND & AIMS: Liver fibrosis is an intrinsic wound-healing response to chronic injury and the major cause of liver-related morbidity and mortality worldwide. However, no effective diagnostic or therapeutic strategies are available, owing to its poorly characterized molecular etiology. We aimed to elucidate the mechanisms underlying liver fibrogenesis. METHODS: We performed a quantitative proteomic analysis of clinical fibrotic liver samples to identify dysregulated proteins. Further analyses were performed on the sera of 164 patients with liver fibrosis. Two fibrosis mouse models and several biochemical experiments were used to elucidate liver fibrogenesis. RESULTS: We identified cathepsin S (CTSS) up-regulation as a central node for extracellular matrix remodeling in the human fibrotic liver by proteomic screening. Increased serum CTSS levels efficiently predicted liver fibrosis, even at an early stage. Secreted CTSS cleaved collagen 18A1 at its C-terminus, releasing endostatin peptide, which directly bound to and activated hepatic stellate cells via integrin α5ß1 signaling, whereas genetic ablation of Ctss remarkably suppressed liver fibrogenesis via endostatin reduction in vivo. Further studies identified macrophages as the main source of hepatic CTSS, and splenectomy effectively attenuated macrophage infiltration and CTSS expression in the fibrotic liver. Pharmacologic inhibition of CTSS ameliorated liver fibrosis progression in the mouse models. CONCLUSIONS: CTSS functions as a novel profibrotic factor by remodeling extracellular matrix proteins and may represent a promising target for the diagnosis and treatment of liver fibrosis.

Increased plasma endostatin and GDF15 in indolent non-Hodgkin lymphoma.

Background: Increased microvascular density correlates with more advanced disease and unfavorable overall survival in non-Hodgkin lymphoma (NHL), suggesting that angiogenesis is important for disease progression. However, studies of anti-angiogenic agents in NHL patients, have generally not shown favorable outcomes. The aim of this study was to investigate whether plasma levels of a subset of angiogenesis-associated proteins are increased in indolent B-cell derived NHL (B-NHL) and to investigate whether the levels differ between patients with asymptomatic versus symptomatic disease. Methods: Plasma levels of growth differentiation factor 15 (GDF15), endostatin, matrix metalloproteinase 9 (MMP9), neutrophil gelatinase-associated lipocalin (NGAL), long pentraxin 3 (PTX3), and galectin 3 (GAL-3) were measured by ELISA in 35 patients with symptomatic indolent B-NHL, 41 patients with asymptomatic disease, and 62 healthy controls. Bootstrap t-tests were used to assess the relative differences in biomarker levels between groups. Group differences were visualized using a principal component plot. Results: Mean plasma endostatin and GDF15 levels were significantly higher in symptomatic and asymptomatic lymphoma patients than in controls. Symptomatic patients had higher mean MMP9 and NGAL than controls. Conclusions: The finding of increased plasma endostatin and GDF15 in patients with asymptomatic indolent B-NHL suggests that increased angiogenic activity is an early event in indolent B-NHL disease progression.

Performance of Pretreatment MRI-Based Radiomics in Recombinant Human Endostatin Plus Concurrent Chemoradiotherapy Response Prediction in Nasopharyngeal Carcinoma: A Retrospective Study.

PURPOSE: To investigate the capability of an Magnetic resonance imaging (MRI) radiomics model based on pretreatment texture features in predicting the short-term efficacy of recombinant human endostatin (RHES) plus concurrent chemoradiotherapy (CCRT) for nasopharyngeal carcinoma (NPC). METHODS: We retrospectively enrolled 65 patients newly diagnosed as having NPC and treated with RHES + CCRT. A total of 144 texture features were extracted from the MRI before RHES + CCRT treatment of all the NPC patients. The maximum relevance minimum redundancy (mRMR) method was used to remove redundant, irrelevant texture features, and calculate the Rad score of the primary tumor. Multivariable logistic regression was used to select the most predictive features subset, and prediction models were constructed. The performance of the 3 models in predicting the early response of RHES + CCRT for NPC was explored. RESULTS: The diagnostic efficiency of combined model and radiomics model in distinguishing between the effective and the ineffective groups of patients was found to be moderate. The area under the ROC curve (AUC) of the combined model and radiomics model was 0.74 (95% confidence interval [CI]: 0.62-0.86) and 0.71 (95% CI: 0.58-0.84), respectively, with both being higher than the AUC of the clinics model (0.63, 95% CI: 0.49-0.78). Compared with the radiomics model, the combined model showed marginally improved diagnostic performance in predicting RHES + CCRT treatment response. The accuracy of combined model and radiomics model for RHES + CCRT response assessment in NPC were higher than those of the clinics model (0.723, 0.723 vs 0.677). CONCLUSION: The pretreatment MRI-based radiomics may be a noninvasive and effective method for the prediction of RHES + CCRT early response in patients with NPC.

The mechanism of rh-endostatin-induced cardiotoxicity and its protection by dihydromyricetin[in vivo/in vitro, C57BL/6 mice, AC16 and hiPSC-CMs].

Recombinant human endostatin (rh-endostatin) is an anti-angiogenic drug, which is used for the treatment of advanced non-small-cell lung cancer (NSCLC) and other cancers. However, its side effects, especially the cardiotoxicity with unclear mechanisms limit its wide application in clinical practice. In this study, human cardiomyocyte cell line AC16 and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated with different doses of rh-endostatin were used to analyze its effect on cardiac cell toxicity. The results revealed that rh-endostatin dose-dependently enhanced cardiomyocyte apoptosis through Apaf-1 apoptotic factor and apoptosis-related proteins such as p53. rh-endostatin-induced changes of mitochondrial function and mitophagy were involved in rh-endostatin-mediated cardiac cell toxicity. Rh-endostatin-induced cardiotoxicity was further verified in vivo in mice. Interestingly, Rh-endostatin-induced cardiotoxicity was inhibited by dihydromyricetin (DHM) both in cultured cells in vitro and in mouse hearts in vivo. The study provides new inside into rh-endostatin-induced cardiotoxicity and identified a novel potential medication DHM to overcome the serious adverse effect.

Can endocan serve as a molecular "hepatostat" in liver regeneration?

BACKGROUND: Intriguingly, liver regeneration after injury does not induce uncontrolled growth and the underlying mechanisms of such a "hepatostat" are still not clear. Endocan, a proteoglycan, was implicated in liver regeneration. It can support the function of hepatocyte growth factor/scatter factor in tissue repair after injury. Endostatin, a 20 kDa C-terminal fragment of collagen XVIII, may modulate the cessation of liver regeneration. eEF2K, a protein kinase that regulates protein synthesis, can regulate angiogenesis. Thus, we investigated the role of endocan, endostatin and eEF2K during normal liver regeneration. METHODS: Serum samples and regenerating remnant liver tissues were obtained on various days after partial hepatectomy in rats. mRNA expression levels of Vegf and Pcna were analyzed in addition to immunohistochemical evaluations. Liver tissue protein levels of endostatin, endocan and p-eEF2K/eEF2K were determined with Western blot. Serum levels of endostatin and endocan were assessed with ELISA. RESULTS: Pcna expression level in residual liver tissues peaked on day-1, while Vegf expression reached its highest level on days 1-3 after partial hepatectomy (70%). Endocan activity declined gradually on days 1-7. The decrease in liver endocan expression was accompanied by an increase in serum endocan levels. Partial hepatectomy induced a rapid increase in liver endostatin levels. Following its surge on day-1, endostatin expression gradually declined, which was accompanied by a peak in serum endostatin. Finally, partial hepatectomy was shown to regulate eEF2K; thus, increasing protein translation. CONCLUSIONS: We revealed possible mechanistic insights into liver regeneration by examining the associations of Pcna, Vegf, endocan, endostatin, eEF2K with hepatic regeneration after partial hepatectomy. Indeed, endocan might serve as a useful biomarker to monitor clinical prognosis in a plethora of conditions such as recovery of donor's remaining liver after living-donor liver transplant. Whether endocan might represent a strategy to optimize liver regeneration when given therapeutically needs to be investigated in future studies.

Efficacy and safety of immune checkpoint inhibitors combined with recombinant human endostatin and chemotherapy as the first-line treatment of advanced non-small-cell lung cancer.

Aim: To assess the efficacy and safety of combination of PD-1 inhibitors, recombinant human endostatin (Rh-endostatin) and chemotherapy as first-line treatment for advanced non-small-cell lung cancer (NSCLC). Methods: A total of 100 patients with advanced NSCLC were retrospectively reviewed and analyzed (58 in the group receiving PD-1 inhibitors plus Rh-endostatin and chemotherapy; 42 in the group receiving Rh-endostatin and chemotherapy). The primary end point was progression-free survival. Results: Patients in the group receiving PD-1 inhibitors plus Rh-endostatin and chemotherapy had significantly improved progression-free survival (10.2 vs 6.5 months; p < 0.001) and objective response rate (67.2 vs 42.9%; p = 0.015), with acceptable toxicity. Conclusion: Our study showed the superiority of combination therapy of PD-1 inhibitors and Rh-endostatin as first-line treatment for advanced NSCLC.

This study retrospectively analyzed the effectiveness and safety of PD-1 inhibitors combined with recombinant human endostatin (Rh-endostatin) and chemotherapy as first-line treatment for advanced non-small-cell lung cancer. Among them, 58 patients received a PD-1 inhibitor combined with Rh-endostatin and chemotherapy (treatment group), and 42 patients received Rh-endostatin combined with chemotherapy (control group). Patients in the treatment group had a significantly improved objective response rate (67.2 vs 42.9%; p = 0.015) and prolonged survival without their disease getting worse (10.2 vs 6.5 months; p < 0.001). No significant differences were found in the adverse events between the two groups.

Cardiac rehabilitation in coronary artery bypass grafting patients: Effect of eight weeks of moderate-intensity continuous training versus high-intensity interval training.

BACKGROUND: Physical training in patients with heart failure can affect hemodynamic, cardiac and angiogenesis parameters. OBJECTIVE: The aim of the present study was to investigate the effects of traditional moderate-intensity rehabilitation training and interval training on some angiogenesis factors in coronary artery bypass graft (CABG) patients. METHODS: Thirty CABG patients (mean age±SD, 55±3 years) were randomly assigned to one of three groups: high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT) or the control group. After the initial assessments, eligible patients in the experimental groups (HIIT and MICT) performed exercise training for 8 weeks, while the control group did not. Angiogenesis and angiostatic indices, including pro-adrenomedullin (pro-ADM), basic fibroblast growth factor (bFGF), and endostatin, were then measured. RESULTS: The results showed no significant difference between pro-ADM in the HIIT and MICT groups (P = 0.99), but a significant difference was found between MICT and the control group and between HIIT and the control group (P = 0.001). There is also no significant difference between the bFGF levels in the HIIT and MICT training groups (P = 1.00), but the changes in this factor between the training groups and the control group were significant (P = 0.001). There was a significant difference between the levels of endostatin in all three groups. CONCLUSIONS: Two methods of cardiac rehabilitation (HIIT and MICT) may be useful for the recovery of patients with coronary artery bypass grafting. This improvement manifested itself in changes in angiogenesis and angiostatic indices in this study. However, more extensive studies are needed to investigate the effects of these two types of rehabilitation programs on other indicators of angiogenesis and angiostatic.

Proteomic aptamer analysis reveals serum markers that characterize preclinical systemic sclerosis (SSc) patients at risk for progression toward definite SSc.

BACKGROUND: The study of molecular mechanisms characterizing disease progression may be relevant to get insights into systemic sclerosis (SSc) pathogenesis and to intercept patients at very early stage. We aimed at investigating the proteomic profile of preclinical systemic sclerosis (PreSSc) via a discovery/validation two-step approach. METHODS: SOMAcan aptamer-based analysis was performed on a serum sample of 13 PreSSc (discovery cohort) according to 2001 LeRoy and Medsger criteria (characterized solely by Raynaud phenomenon plus a positive nailfold capillaroscopy and SSc-specific antibodies without any other sign of definite disease) and 8 healthy controls (HCs) age, gender, and ethnicity matched. Prospective data were available up to 4±0.6 years to determine the progression to definite SSc according to the EULAR/ACR 2013 classification criteria. In proteins with relative fluorescence units (RFU) > |1.5|-fold vs HCs values, univariate analysis was conducted via bootstrap aggregating models to determine the predicting accuracy (progression vs non-progression) of categorized baseline protein values. Gene Ontologies (GO terms) and Reactome terms of significant proteins at the adjusted 0.05 threshold were explored. Significant proteins from the discovery cohort were finally validated via ELISAs in an independent validation cohort of 50 PreSSc with clinical prospective data up to 5 years. Time-to-event analysis for interval-censored data was used to evaluate disease progression. RESULTS: In the discovery cohort, 286 out of 1306 proteins analyzed via SomaScan, were differentially expressed versus HCs. Ten proteins were significantly associated with disease progression; analysis through GO and Reactome showed differentially enriched pathways involving angiogenesis, endothelial cell chemotaxis, and endothelial cell chemotaxis to fibroblast growth factor (FGF). In the validation cohort, endostatin (HR=10.23, CI95=2.2-47.59, p=0.003) was strongly associated with disease progression, as well as bFGF (HR=0.84, CI95=0.709-0.996, p=0.045) and PAF-AHß (HR=0.372, CI95=0.171-0.809, p=0.013) CONCLUSIONS: A distinct protein profile characterized PreSSc from HCs and proteins associated with hypoxia, vasculopathy, and fibrosis regulation are linked with the progression from preclinical to definite SSc. These proteins, in particular endostatin, can be regarded both as markers of severity and molecules with pathogenetic significance as well as therapeutic targets.

Cardiac Dysfunction Biomarkers Are Associated With Potential for Successful Separation From Extracorporeal Membrane Oxygenation in Children.

Biomarkers of cardiac dysfunction may aid in decision making about organ recovery and optimal timing of separation from extracorporeal membrane oxygenation (ECMO). We conducted a prospective observational study of children from 0 to <18 years who underwent ECMO between 7/2010 and 6/2015 in a single center. In this pilot study, we aimed to determine whether Suppression of tumorigenicity 2 (ST2), N -terminal pro-B-type natriuretic peptide (NT-proBNP), galectin-3, and endostatin were associated with ability to separate from ECMO. Fifty neonatal and pediatric participants supported on venoarterial ECMO were included (median age 13 days, 50% male). Twelve (24%) participants were unable to separate from extracorporeal support. Plasma ST2 concentrations at cannulation were higher in children who were ultimately unable to separate versus those who successfully separated from ECMO (median 395.3 ng/mL vs. 207.4 ng/mL, p = 0.012). ST2 and NT-proBNP concentrations decreased significantly from the first to the last ECMO day in patients successfully separated from ECMO ( p < 0.0001 and p = 0.017, respectively). Endostatin concentrations increased significantly from the first to the last ECMO day in both groups. Galectin-3 concentrations were not associated with the ability to separate from ECMO. Cardiac dysfunction biomarkers, particularly ST2, may aid in decannulation decision-making in pediatric ECMO patients. These results should be validated with a larger study.