Targeting epigenetics and lncRNAs in liver disease: From mechanisms to therapeutics.

Early onset and progression of liver diseases can be driven by aberrant transcriptional regulation. Different transcriptional regulation processes, such as RNA/DNA methylation, histone modification, and ncRNA-mediated targeting, can regulate biological processes in healthy cells, as well also under various pathological conditions, especially liver disease. Numerous studies over the past decades have demonstrated that liver disease has a strong epigenetic component. Therefore, the epigenetic basis of liver disease has challenged our knowledge of epigenetics, and epigenetics field has undergone an important transformation: from a biological phenomenon to an emerging focus of disease research. Furthermore, inhibitors of different epigenetic regulators, such as m6A-related factors, are being explored as potential candidates for preventing and treating liver diseases. In the present review, we summarize and discuss the current knowledge of five distinct but interconnected and interdependent epigenetic processes in the context of hepatic diseases: RNA methylation, DNA methylation, histone methylation, miRNAs, and lncRNAs. Finally, we discuss the potential therapeutic implications and future challenges and ongoing research in the field. Our review also provides a perspective for identifying therapeutic targets and new hepatic biomarkers of liver disease, bringing precision research and disease therapy to the modern era of epigenetics.

Cascade Reaction of Arylboronic Acids and 2'-Cyano-biaryl-2-aldehyde N-Tosylhydrazones: Access to Functionalized 9-Amino-10-arylphenanthrenes.

An efficient, general, and convenient protocol for the synthesis of functionalized 9-amino-10-arylphenanthrene derivatives using a catalyst-free cascade reaction of arylboronic acids and 2'-cyano-biaryl-2-aldehyde N-tosylhydrazones is described. The synthesis was carried out via simple experimental conditions using Na2CO3 in 1,4-dioxane as a solvent. Moreover, the 9-amino-10-arylphenanthrene compounds were also obtained on a gram scale and further derivatized to synthesize the fused phenanthrene derivatives.

Interference with HMGB1 increases the sensitivity to chemotherapy drugs by inhibiting HMGB1-mediated cell autophagy and inducing cell apoptosis.

Non-small cell lung cancer is commonly seen with higher morbidity and mortality. High-mobility group protein 1 (HMGB1) is a highly conserved nuclear protein, which is involved in multiple human diseases including cancers. However, the mechanisms of HMGB1 in non-small cell lung cancer remain unclear. The goal of the present study is to identify the relationship between HMGB1 and the progresssion of non-small cell lung cancer and investigate the molecular mechanism of HMGB1 in non-small lung cancer cell lines. Firstly, we detected the expression levels of HMGB1 by by real-time PCR and western blotting analysis, and the results demonstrated that HMGB1 was much higher expressed in non-small cell lung cancer cell lines, including A549, SPC-1-1, NCI-2170, SK-MES-1, and NCI-H1299, compared with that of WI-38. Next, 5 µM of adriamycin (AMD), 20 µM of cisplatin (DDP), and 50 µM of methotrexate (MTX) were used to treat A549 cells and SPC-A-1 cells for 48 h. The results showed that treatment with chemotherapy drugs significantly increased the levels of HMGB1 in A549 cells and SPC-A-1 cells. Moreover, the expression levels of HMGB1 increased in a time-dependent manner being treated with DDP. Then, the endogenous HMGB1 expression was successfully interferred with shRNA specific to HMGB1 in A549 and SPC-A-1 cells, which was detected by western blotting analysis. Then, the cisplatin-sensitive A549 cells and cisplatin-resistant A549/DDP cells were treated with increasing concentrations of cisplatin for 24, 48, and 72 h; cell viability were analyzed by MTT assay; and IC50 values were calculated. The results demonstrated that the expression level of HMGB1 in A549/DDP cells was much higher than that of A549 cells; moreover, transfection with HMGB1 shRNA in A549/DDP cells decreased the IC50 value of cisplatin in A549/DDP cells. The expression levels of autophagy-related proteins beclin-1 and LC3-II were significantly higher in A549/DDP cells or the A549 cells treated with chemotherapeutic drugs, compared with that in A549 cells. However, interference with endogenous HMGB1 obviously suppressed autophagy-related proteins and increased cell apoptosis rate and the expression of cleaved caspase-3 in A549/DDP cells. All of the data suggested that interference with the endogenous HMGB1 significantly inhibited cell autophagy and increased cell apoptosis of A549/DDP cells. Thus, the study on the resistance of chemotherapy drugs would provide a theoretical reference for clinical treatment of non-small cell lung cancer.

Shenqi fuzheng injection attenuates irradiation-induced brain injury in mice via inhibition of the NF-κB signaling pathway and microglial activation.

AIM: Radiation-induced brain injury (RIBI) is the most common and severe adverse effect induced by cranial radiation therapy (CRT). In the present study, we examined the effects of the traditional Chinese medicine Shenqi Fuzheng Injection (SFI) on RIBI in mice, and explored the underlying mechanisms. METHODS: C57BL/6J mice were subjected to a single dose of 20-Gy CRT. The mice were treated with SFI (20 mL·kg(-1)·d(-1), ip) for 4 weeks. Morris water maze test was used to assess the cognitive changes. Evans blue leakage and a horseradish peroxidase (HRP) assay were used to evaluate the integrity of the blood-brain barrier (BBB). The expression of inflammatory factors and microglial activation in brain tissues were detected using RT-PCR, Western blotting and immunofluorescence staining. RESULTS: CRT caused marked reductions in the body weight and life span of the mice, and significantly impaired their spatial learning. Furthermore, CRT significantly increased the BBB permeability, number of activated microglia, expression levels of TNF-α and IL-1ß, and the levels of phosphorylated p65 and PIDD-CC (the twice-cleaved fragment of p53-induced protein with a death domain) in the brain tissues. Four-week SFI treatment (administered for 2 weeks before and 2 weeks after CRT) not only significantly improved the physical status, survival, and spatial learning in CRT-treated mice, but also attenuated all the CRT-induced changes in the brain tissues. Four-week SFI pretreatment (administered for 4 weeks before CRT) was less effective. CONCLUSION: Administration of SFI effectively attenuates irradiation-induced brain injury via inhibition of the NF-κB signaling pathway and microglial activation.

[Preliminary Analysis of the Genetic Loci of SAG1 and SAG3, the Surface Antigens of Toxoplasma gondii, in HIV-positive People in Dali of Yunnan Province].

OBJECTIVE: To identify the genotypes of Toxoplasma gondii that infects HIV-positive people in Dali of Yunnan Province through analyzing the genetic loci of the surface antigens SAG1 and SAG3. METHODS: A total of 291 blood samples from HIV-positive cases were collected from the HIV/AIDS Prevention and Control Institution in Yunnan. Nested PCR was used to amplify SAGI and SAG3 genes in the blood samples. The products were digested with restriction enzymes Sau96 I, Hae II and Nci I, and sequenced. RESULTS: Of the 291 HIV-positive blood samples, 64 showed successful amplification of SAGI gene, and 42 of SAG3 gene, with product sizes of 390 bp and 225 bp, respectively. Enzymetic digestion of the PCR products resulted in fragments of 350 bp and 50 bp for SAGI, and -200 bp band for SAG3, consistent with RH, a particular type I strain of T. gondii. Sequencing of the SAG1 and SAG3 PCR products showed that their sequence identities with SAGI (Accession No. GQ253073) and SAG3 (Accession No. JX218225.1) of the type I strain of T. gondii were 99.98%-100% and 99.96% -99.98% respectively. CONCLUSION: The Toxoplasma gondii in HIV-positive cases in Dali of Yunnan Province is the type I strain of T. gondii.

Gossypol acetic acid regulates leukemia stem cells by degrading LRPPRC via inhibiting IL-6/JAK1/STAT3 signaling or resulting mitochondrial dysfunction.

BACKGROUND: Leukemia stem cells (LSCs) are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia (AML), as they are protected by the bone marrow microenvironment (BMM) against conventional therapies. Gossypol acetic acid (GAA), which is extracted from the seeds of cotton plants, exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2. AIM: To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism. METHODS: In this study, LSCs were magnetically sorted from AML cell lines and the CD34+CD38- population was obtained. The expression of leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) and forkhead box M1 (FOXM1) was evaluated in LSCs, and the effects of GAA on malignancies and mitochondrial function were measured. RESULTS: LRPPRC was found to be upregulated, and GAA inhibited cell proliferation by degrading LRPPRC. GAA induced LRPPRC degradation and inhibited the activation of interleukin 6 (IL-6)/janus kinase (JAK) 1/signal transducer and activator of transcription (STAT) 3 signaling, enhancing chemosensitivity in LSCs against conventional chemotherapies, including L-Asparaginase, Dexamethasone, and cytarabine. GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC. Furthermore, GAA induced reactive oxygen species accumulation, disturbed mitochondrial homeostasis, and caused mitochondrial dysfunction. By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC, GAA resulted in the elimination of LSCs. Meanwhile, GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage. CONCLUSION: Taken together, the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.

Intratumoral Delivery of Interleukin 9 via Oncolytic Vaccinia Virus Elicits Potent Antitumor Effects in Tumor Models.

The success of cancer immunotherapy is largely associated with immunologically hot tumors. Approaches that promote the infiltration of immune cells into tumor beds are urgently needed to transform cold tumors into hot tumors. Oncolytic viruses can transform the tumor microenvironment (TME), resulting in immunologically hot tumors. Cytokines are good candidates for arming oncolytic viruses to enhance their function in this transformation. Here, we used the oncolytic vaccinia virus (oVV) to deliver interleukin-9 (IL-9) into the tumor bed and explored its antitumor effects in colon and lung tumor models. Our data show that IL-9 prolongs viral persistence, which is probably mediated by the up-regulation of IL-10. The vvDD-IL-9 treatment elevated the expression of Th1 chemokines and antitumor factors such as IFN-γ, granzyme B, and perforin. IL-9 expression increased the percentages of CD4+ and CD8+ T cells in the TME and decreased the percentage of oVV-induced immune suppressive myeloid-derived suppressor cells (MDSC), leading to potent antitumor effects compared with parental virus treatment. The vvDD-IL-9 treatment also increased the percentage of regulatory T cells (Tregs) in the TME and elevated the expression of immune checkpoint molecules such as PD-1, PD-L1, and CTLA-4, but not GITR. The combination therapy of vvDD-IL-9 and the anti-CTLA-4 antibody, but not the anti-GITR antibody, induced systemic tumor-specific antitumor immunity and significantly extended the overall survival of mice, indicating a potential translation of the IL-9-expressing oncolytic virus into a clinical trial to enhance the antitumor effects elicited by an immune checkpoint blockade for cancer immunotherapy.

Anti-PD-1/PD-L1 therapy for colorectal cancer: Clinical implications and future considerations.

Colorectal cancer (CRC) is the third most prevalent cancer in the world. The PD-1/PD-L1 pathway plays a crucial role in modulating immune response to cancer, and PD-L1 expression has been observed in tumor and immune cells within the tumor microenvironment of CRC. Thus, immunotherapy drugs, specifically checkpoint inhibitors, have been developed to target the PD-1/PD-L1 signaling pathway, thereby inhibiting the interaction between PD-1 and PD-L1 and restoring T-cell function in cancer cells. However, the emergence of resistance mechanisms can reduce the efficacy of these treatments. To counter this, monoclonal antibodies (mAbs) have been used to improve the efficacy of CRC treatments. mAbs such as nivolumab and pembrolizumab are currently approved for CRC treatment. These antibodies impede immune checkpoint receptors, including PD-1/PD-L1, and their combination therapy shows promise in the treatment of advanced CRC. This review presents a concise overview of the use of the PD-1/PD-L1 blockade as a therapeutic strategy for CRC using monoclonal antibodies and combination therapies. Additionally, this article outlines the function of PD-1/PD-L1 as an immune response suppressor in the CRC microenvironment as well as the potential advantages of administering inflammatory agents for CRC treatment. Finally, this review analyzes the outcomes of clinical trials to examine the challenges of anti-PD-1/PD-L1 therapeutic resistance.

Blocking the MIF-CD74 axis augments radiotherapy efficacy for brain metastasis in NSCLC via synergistically promoting microglia M1 polarization.

BACKGROUND: Brain metastasis is one of the main causes of recurrence and death in non-small cell lung cancer (NSCLC). Although radiotherapy is the main local therapy for brain metastasis, it is inevitable that some cancer cells become resistant to radiation. Microglia, as macrophages colonized in the brain, play an important role in the tumor microenvironment. Radiotherapy could activate microglia to polarize into both the M1 and M2 phenotypes. Therefore, searching for crosstalk molecules within the microenvironment that can specifically regulate the polarization of microglia is a potential strategy for improving radiation resistance. METHODS: We used databases to detect the expression of MIF in NSCLC and its relationship with prognosis. We analyzed the effects of targeted blockade of the MIF/CD74 axis on the polarization and function of microglia during radiotherapy using flow cytometry. The mouse model of brain metastasis was used to assess the effect of targeted blockade of MIF/CD74 axis on the growth of brain metastasis. RESULT: Our findings reveals that the macrophage migration inhibitory factor (MIF) was highly expressed in NSCLC and is associated with the prognosis of NSCLC. Mechanistically, we demonstrated CD74 inhibition reversed radiation-induced AKT phosphorylation in microglia and promoted the M1 polarization in combination of radiation. Additionally, blocking the MIF-CD74 interaction between NSCLC and microglia promoted microglia M1 polarization. Furthermore, radiation improved tumor hypoxia to decrease HIF-1α dependent MIF secretion by NSCLC. MIF inhibition enhanced radiosensitivity for brain metastasis via synergistically promoting microglia M1 polarization in vivo. CONCLUSIONS: Our study revealed that targeting the MIF-CD74 axis promoted microglia M1 polarization and synergized with radiotherapy for brain metastasis in NSCLC.

Vision matters for shape representation: Evidence from sculpturing and drawing in the blind.

Shape is a property that could be perceived by vision and touch, and is classically considered to be supramodal. While there is mounting evidence for the shared cognitive and neural representation space between visual and tactile shape, previous research tended to rely on dissimilarity structures between objects and had not examined the detailed properties of shape representation in the absence of vision. To address this gap, we conducted three explicit object shape knowledge production experiments with congenitally blind and sighted participants, who were asked to produce verbal features, 3D clay models, and 2D drawings of familiar objects with varying levels of tactile exposure, including tools, large nonmanipulable objects, and animals. We found that the absence of visual experience (i.e., in the blind group) led to stronger differences in animals than in tools and large objects, suggesting that direct tactile experience of objects is essential for shape representation when vision is unavailable. For tools with rich tactile/manipulation experiences, the blind produced overall good shapes comparable to the sighted, yet also showed intriguing differences. The blind group had more variations and a systematic bias in the geometric property of tools (making them stubbier than the sighted), indicating that visual experience contributes to aligning internal representations and calibrating overall object configurations, at least for tools. Taken together, the object shape representation reflects the intricate orchestration of vision, touch and language.

[Genotypes of Toxoplasma gondii isolates from HIV positive patients in Yunnan Province].

One hundred and fifty serum samples of HIV positive patients were collected in western Yunnan Province from September 2011 to December 2012. Toxoplasma gondii B1 gene was amplified by nested PCR. Genotyping of T. gondii isolates were performed by restriction fragment length polymorphism (RFLP) with Pm1 I and Xho I. 13 samples were found positive with the B1 gene (530 bp) amplification and belonged to type I. The sequencing results showed that 4 T. gondii B1 gene positive samples were identical, with 3 nucleotide variation compared with T. gondii strain RH (type I) B1 gene (GenBank No. AF179871), and in the other sample a "G --> A" mutation at 230bp was detected. The results indicated that the genotype of Toxoplasma gondii in HIV positive patients in Yunnan Province is type I.

Oncolytic virotherapy in cancer treatment: challenges and optimization prospects.

Oncolytic viruses (OVs) are emerging cancer therapeutics that offer a multifaceted therapeutic platform for the benefits of replicating and lysing tumor cells, being engineered to express transgenes, modulating the tumor microenvironment (TME), and having a tolerable safety profile that does not overlap with other cancer therapeutics. The mechanism of OVs combined with other antitumor agents is based on immune-mediated attack resistance and might benefit patients who fail to achieve durable responses after immune checkpoint inhibitor (ICI) treatment. In this Review, we summarize data on the OV mechanism and limitations of monotherapy, which are currently in the process of combination partner development, especially with ICIs. We discuss some of the hurdles that have limited the preclinical and clinical development of OVs. We also describe the available data and provide guidance for optimizing OVs in clinical practice, as well as a summary of approved and promising novel OVs with clinical indications.

Radiation therapy in the era of immune treatment for hepatocellular carcinoma.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment in recent years and provide new opportunities to treat hepatocellular carcinoma (HCC). To date, several ICIs have been approved by the FDA for advanced HCC in first-line or second-line therapy. Downstaging conversion therapy for potentially resectable HCC to provide opportunities for surgical intervention is challenging. ICIs have become a hot spot in this field due to their high response rate. However, HCC has various etiologies and can evade the immune system through multiple mechanisms, which limit the efficacy of ICI monotherapy and demand novel combination strategies. Radiation therapy (RT) is also a candidate for conversion therapy in HCC and is currently gaining increasing attention as a good combination partner with ICIs due to its ability to modulate the tumor microenvironment. In this review, we illustrate the current indications for ICIs and RT in HCC, the rationale for their synergistic combination, and the current clinical trials in combination therapy. We also speculate on predictive biomarkers and novel future strategies to further enhance the efficacy of this combination. This review aims to provide references for future research on radiation and immunotherapy to arrive at a promising new era of HCC treatment.

LncRNAs in colorectal cancer: Biomarkers to therapeutic targets.

Colorectal cancer (CRC) is the third leading cause of cancer-related death in men and women worldwide. As early detection is associated with lower mortality, novel biomarkers are urgently needed for timely diagnosis and appropriate management of patients to achieve the best therapeutic response. Long noncoding RNAs (lncRNAs) have been reported to play essential roles in CRC progression. Accordingly, the regulatory roles of lncRNAs should be better understood in general and for identifying diagnostic, prognostic and predictive biomarkers in CRC specifically. In this review, the latest advances on the potential diagnostic and prognostic lncRNAs as biomarkers in CRC samples were highlighted, Current knowledge on dysregulated lncRNAs and their potential molecular mechanisms were summarized. The potential therapeutic implications and challenges for future and ongoing research in the field were also discussed. Finally, novel insights on the underlying mechanisms of lncRNAs were examined as to their potential role as biomarkers and therapeutic targets in CRC. This review may be used to design future studies and advanced investigations on lncRNAs as biomarkers for the diagnosis, prognosis and therapy in CRC.

Case report: A rare case of neutropenia caused by pembrolizumab in squamous lung cancer and literature review.

Background: Immune checkpoint inhibitors, including anti-PD-1 therapies, have prolonged overall survival in patients with a variety of cancers, and immunotherapy is sometimes associated with immune-related adverse events (irAEs); however, hematological toxicity, especially neutropenia, is rare. Case presentation: A 78-year-old man with squamous lung cancer, with brain metastasis, was treated with pembrolizumab and albumin-bound paclitaxel as first-line treatment for one cycle and changed to pembrolizumab plus anlotinib at the second cycle. After two therapy cycles, grade 4 neutropenia developed, which mainly contributed to irAEs. The patient was started on granulocyte colony-stimulating factor (G-CSF) but did not improve; he was then treated with corticosteroids, and neutrophil counts gradually returned to normal levels. However, the patient eventually died because of neurological problems. Conclusion: Grade 4 neutropenia associated with ICI, although rare, is often severe and presents with infectious complications; it needs to be diagnosed early, and clinicians should ensure prompt and proper management to such patients.

T Cell-Mediated Tumor Killing-Related Classification of the Immune Microenvironment and Prognosis Prediction of Lung Adenocarcinoma.

BACKGROUND: Although immune checkpoint inhibitors (ICI) are a promising therapeutic strategy for lung adenocarcinoma (LUAD), individual subgroups that might benefit from them are yet to be identified. As T cell-mediated tumor killing (TTK) is an underlying mechanism of ICI, we identified subtypes based on genes associated with TTK sensitivity and assessed their predictive significance for LUAD immunotherapies. METHODS: Using high-throughput screening techniques, genes regulating the sensitivity of T cell-mediated tumor killing (GSTTK) with differential expression and associations with prognosis were discovered in LUAD. Furthermore, patients with LUAD were divided into subgroups using unsupervised clustering based on GSTTK. Significant differences were observed in the tumor immune microenvironment (TIME), genetic mutation and immunotherapy response across subgroups. Finally, the prognostic significance of a scoring algorithm based on GSTTK was assessed. RESULTS: A total of 6 out of 641 GSTTK exhibited differential expression in LUAD and were associated with prognosis. Patients were grouped into two categories based on the expression of the six GSTTK, which represented different TTK immune microenvironments in LUAD. Immune cell infiltration, survival difference, somatic mutation, functional enrichment and immunotherapy responses also varied between the two categories. Additionally, a scoring algorithm accurately distinguished overall survival rates across populations. CONCLUSIONS: TTK had a crucial influence on the development of the varying TIME. Evaluation of the varied TTK modes of different tumors enhanced our understanding of TIME characteristics, wherein the changes in T cell activity in LUAD are reflected. Thus, this study guides the development of more effective therapeutic methods.

Efficacy and safety of recombinant human endostatin combined with whole-brain radiation therapy in patients with brain metastases from non-small cell lung cancer.

BACKGROUND AND PURPOSE: Brain metastasis (BM) is the leading cause of poor prognosis in non-small cell lung cancer (NSCLC) patients. To date, whole-brain radiation therapy (WBRT) is a standard treatment for patients with multiple BMs, while its effectiveness is currently unsatisfactory. This study aimed to investigate the effects of Rh-endostatin combined with WBRT on NSCLC patients with BMs. MATERIALS AND METHODS: A total of 43 patients with BM were randomly divided into two groups. The Rh-endostatin combination group (n = 19) received Rh-endostatin combined with WBRT, and the radiation group (n = 24) received WBRT only. The primary endpoint of the study was progression-free survival (PFS), and the secondary endpoints were intracranial progressionfree survival (iPFS), overall survival (OS), objective response rate (ORR), and changes in the cerebral blood volume (CBV) and cerebral blood flow (CBF). RESULTS: Median PFS (mPFS) was 8.1 months in the Rh-endostatin combination group and 4.9 months in the radiation group (95%CI 0.2612-0.9583, p = 0.0428). Besides, the median iPFS was 11.6 months in the Rh-endostatin combination group and 4.8 months in the radiation group (95%CI 0.2530-0.9504, p = 0.0437). OS was 14.2 months in the Rh-endostatin combination group and 6.4 months in the radiation group (95%CI 0.2508-1.026, p = 0.0688). CBV and CBF in the Rh-endostatin combination group were better improved than that in the radiation group, which indicated that Rh-endostatin might improve local blood supply and microcirculation. CONCLUSION: Rh-endostatin showed better survival and improved cerebral perfusion parameters, which may provide further insights into the application of Rh-endostatin for NSCLC patients with BMs.

Localized Degradation of Neutrophil Extracellular Traps by Photoregulated Enzyme Delivery for Cancer Immunotherapy and Metastasis Suppression.

Extrusion of neutrophil extracellular traps (NETs), a fundamental host innate immune defense against pathogens, has recently been linked to cancer resistance to immunotherapy and distant metastasis. These findings highlight interesting areas of cancer-elicited inflammation and potential therapeutic strategies. Disrupting existing NETs with DNase I has been proved to enhance the therapeutic efficacy of tumor immunotherapy and attenuate metastatic spread. However, systemic biodistribution of DNase I raises safety issues, potentially impairing host defense against infection. Hence, tumor-specific delivery and metastatic niche-targeted effects are attractive options for localized degradation of NETs. We have engineered a nanoplatform with a plasmonic gold blackbody (AuPB) core with broad-spectrum photo activity and a mesoporous polydopamine (mPDA) shell for efficient loading and photoregulated release of DNase I. The on-demand released DNase I triggered by the second near-infrared (NIR-II) light irradiation breaks the "NET-mediated physical barrier", thereby increasing the contact of immune cytotoxic cells with tumor cells in living mice and sensitizing immune checkpoint therapy of primary colorectal cancer (CRC). Moreover, the deposition and light-controlled cargo release from systemically delivered AuPB@mPDA carriers in liver, the most frequent site of CRC metastasis, abolished NET-mediated capture of circulating tumor cells and hence metastatic seeding. Our findings indicate that the localized, light-regulated release of DNase I by photoactive carriers in the NIR-II window represent a translational route for immune-mediated tumor regression and metastasis inhibition.

Sp1 inhibition-mediated upregulation of VEGF 165 b induced by rh-endostatin enhances antiangiogenic and anticancer effect of rh-endostatin in A549.

Recombinant human endostatin (rh-endostatin), a potential antiangiogenic agent, is used in non-small cell lung carcinoma treatment and represses vascular endothelial cell growth factor (VEGF) levels in tumor cell. However, precise affection of rh-endostatin on the proangiogenic VEGF isoforms (VEGF(165)) or antiangiogenic VEGF isoforms (VEGF(165)b) is not clear. We therefore tested the hypothesis that rh-endostatin could alter expression of these isoforms to regulate tumor growth. A549 cells were exposed to rh-endostatin, and the expression of VEGF(165) and VEGF(165)b was detected. The role of SP1 as a regulator of isoform expression was investigated. We then examined the anticancer and antiangiogenic efficacy of rh-endostatin in combination with exogenous VEGF(165)b against A549 cells, EA.HY 926 cells and xenograft model of human lung cancer. rh-Endostatin reduced VEGF(165) and induced VEGF(165)b as well as inhibited SP1 in A549 cells. SP1 inhibitor (betulinic acid) also developed those changes. VEGF(165)b-rh-endostatin combination was highly synergistic and inhibited growth, survival, and migration of A549 cells, VEGF-mediated VEGFR2 phosphorylation in EA.HY 926 cells, and tumor growth in xenograft model of human lung cancer. rh-Endostatin downregulates proangiogenic vascular endothelial growth factor A (VEGFA) isoform and upregulates antiangiogenic VEGFA isoform, possibly through inhibition of SP1. Furthermore, VEGF(165)b sensitizes A549 to rh-endostatin treatment and enhances the anticancer effect of rh-endostatin.