Targeting endothelial coagulation signaling ameliorates liver obstructive cholestasis and dysfunctional angiogenesis.

Cholestatic fibrogenesis is a pathobiological process in which cumulative injury to the bile ducts coincides with progressive liver fibrosis. The pathobiologic mechanisms underlying fibrogenesis and disease progression remain poorly understood. Currently, there is no effective treatment for liver fibrosis. In this study, we discovered that components of the coagulation cascade were associated with the advanced progression of obstructive cholestasis, and anticoagulant therapy could improve liver cholestasis-induced fibrosis. In a mouse model of common bile duct ligation (BDL), which mimics cholestatic liver injury, RNA sequencing analysis revealed an increased expression of coagulation factors in endothelial cells. Pharmacological targeting of the coagulation signaling by hirudin, an anticoagulatory antagonist of thrombin, ameliorated obstructive cholestasis, and attenuated liver fibrosis symptoms. Hirudin attenuated fibrosis-associated angiogenesis, endothelial-to-mesenchymal transition (EndMT), and tissue hypoxia and reduced liver inflammation after BDL. Furthermore, hirudin suppressed YAP (Yes-associated protein) signaling and its downstream effectors in vascular endothelial cells, which are considered with profibrotic characteristics. In conclusion, we demonstrated that pharmacological targeting of coagulation signaling by hirudin has the potential to alleviate liver obstructive cholestasis and fibrosis.

Multifunctional Nanoplatform for Mild Microwave-Enhanced Thermal, Antioxidative, and Chemotherapeutic Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is usually associated with excessive proliferation of M1-type proinflammatory macrophages, resulting in severe hypoxia and excess reactive oxygen species (ROS) in the joint cavity. Inhibiting M1-type proinflammatory macrophages and/or repolarizing them into M2 phenotype anti-inflammatory cells by alleviating hypoxia and scavenging ROS could be a promising strategy for RA treatment. In this work, a microwave-sensitive metal-organic framework of UiO-66-NH2 is constructed for coating a nanoenzyme of cerium oxide (CeO2) and loading with the drug celastrol (Cel) to give UiO-66-NH2/CeO2/Cel, which is ultimately wrapped with hyaluronic acid (HA) to form a nanocomposite UiO-66-NH2/CeO2/Cel@HA (UCCH). With the microwave-susceptible properties of UiO-66-NH2, the thermal effect of microwaves can eliminate the excessive proliferation of inflammatory cells. In addition, superoxide-like and catalase-like activities originating from CeO2 in UCCH are boosted to scavenge ROS and accelerate the decomposition of H2O2 to produce O2 under microwave irradiation. The nonthermal effect of microwaves could synergistically promote the repolarization of M1-type macrophages into the M2 phenotype. Accompanied by the release of the anti-RA chemotherapeutic drug Cel, UCCH can efficiently ameliorate RA in vitro and in vivo through microwave-enhanced multisynergistic effects. This strategy could inspire the design of other multisynergistic platforms enhanced by microwaves to exploit new treatment modalities in RA therapies.

CDC6 is a prognostic biomarker and correlated with immune infiltrates in glioma.

BACKGROUND: Cell division cycle 6 (CDC6) has been proven to be associated with the initiation and progression of human multiple tumors. However, it's role in glioma, which is ranked as one of the common primary malignant tumor in the central nervous system and is associated with high morbidity and mortality, is unclear. METHODS: In this study, we explored CDC6 gene expression level in pan-cancer. Furthermore, we focused on the relationships between CDC6 expression, its prognostic value, potential biological functions, and immune infiltrates in glioma patients. We also performed vitro experiments to assess the effect of CDC6 expression on proliferative, apoptotic, migrant and invasive abilities of glioma cells. RESULTS: As a result, CDC6 expression was upregulated in multiple types of cancer, including glioma. Moreover, high expression of CDC6 was significantly associated with age, IDH status, 1p/19q codeletion status, WHO grade and histological type in glioma (all p < 0.05). Meanwhile, high CDC6 expression was associated with poor overall survival (OS) in glioma patients, especially in different clinical subgroups. Furthermore, a univariate Cox analysis showed that high CDC6 expression was correlated with poor OS in glioma patients. Functional enrichment analysis indicated that CDC6 was mainly involved in pathways related to DNA transcription and cytokine activity, and Gene Set Enrichment Analysis (GSEA) revealed that MAPK pathway, P53 pathway and NF-κB pathway in cancer were differentially enriched in glioma patients with high CDC6 expression. Single-sample gene set enrichment analysis (ssGSEA) showed CDC6 expression in glioma was positively correlated with Th2 cells, Macrophages and Eosinophils, and negative correlations with plasmacytoid dendritic cells, CD8 T cells and NK CD56bright cells, suggesting its role in regulating tumor immunity. Finally, CCK8 assay, flow cytometry and transwell assays showed that silencing CDC6 could significantly inhibit proliferation, migration, invasion, and promoted apoptosis of U87 cells and U251 cells (p < 0.05). CONCLUSION: In conclusion, high CDC6 expression may serve as a promising biomarker for prognosis and correlated with immune infiltrates, presenting to be a potential immune therapy target in glioma.

Targeted inhibition of the immunoproteasome blocks endothelial MHC class II antigen presentation to CD4+ T cells in chronic liver injury.

Chronic or overwhelming liver injury is frequently associated with fibrosis, which is the main histological characteristic of non-alcoholic steatohepatitis (NASH). Currently, there is no effective treatment for liver fibrosis. Adaptive immunity is one of the perpetrators of liver inflammation and involves the antigen-specific activation of lymphocytes. Targeting adaptive immunity has been proposed as a novel therapeutic approach for NASH. In this study, we demonstrated that liver endothelial cells contribute to MHC class II (MHC-II) antigen presentation to CD4+ T cells after chronic liver injury. In human cirrhotic liver samples, we observed an increased expression of endothelial MHC-II and of the antigen presentation-associated protein LMP7, which is one of the proteolytically active subunits of the immunoproteasome. In a CCl4-induced chronic injury model or a diet- and chemical-induced NASH model, endothelial MHC-II and LMP7 expression was induced to increase. PR-957, a selective inhibitor of the immunoproteasome, inhibited MHC-II expression in endothelial cells and CD4+ T cell response after chronic liver injury. In vitro experiment demonstrated PR-957 also reversed IFN-γ-induced upregulation of MHC-II in endothelial cells. Furthermore, PR-957 treatment or CD4+ T cell depletion in chronic liver injury alleviated liver fibrosis and reduced inflammation, as indicated by the downregulation of inflammatory response markers (F4/80, IL-1, IL-6 and IL-18). In conclusion, targeted inhibition of the immunoproteasome blocks endothelial MHC-II antigen presentation to CD4+ T cells in chronic liver injury. In this regard, the PR-957 inhibitor is a promising candidate for the development of future therapies against NASH.

Long-Term Results of Partial Breast Irradiation After Breast-Conserving Surgery for Early Stage Breast Cancer: A Prospective Phase II Trial in China.

BACKGROUND: Partial breast radiotherapy (PBI) has emerged as an option after breast-conserving surgery for early stage breast cancer patients. METHODS: A total of 55 patients with early stage breast cancer between 2009 and 2013 were enrolled in this single-institutional phase II prospective clinical trial. All patients received adjuvant PBI-IMRT after lumpectomy, with the prescription of 48 Gy in 12 fractions at 4 Gy per fraction, 5 days a week. The primary endpoint was ipsilateral breast tumor recurrence (IBTR), the other endpoints were a regional nodal failure (RNF), distant metastasis (DM) rate, disease-free survival (DFS), and overall survival (OS). These endpoints were used to evaluate clinical outcomes. The cosmetic effects and the late toxicity were assessed according to Harvard standard scale and CTCAE 3.0, respectively. RESULTS: In our cohorts, the median age was 45.60 years old (range 31-65 years) and 29.09% of these patients were post-menopause (n = 16). Most patients were T1 stage (65.45%) or N0 stage (70.91%). 80% of patients were ER-positive, 67.27% PR positive, and 61.82% HER2 negative. At the median follow-up of 9.25 years, RNF was 0% and IBTR occurred in only one patient (1.82%) to the chest wall. Except for one patient (1.82%) had DM to lung and pleura and died from disease progression, the remaining patients were alive at the end of the 10-year follow-up. The 10-year DFS and OS were 94.55 and 98.18%. One patient (1.82%) was diagnosed with endometrial cancer after PBI. Except for 9 patients who declined the cosmetic assessment, the rest of the 46 patients (83.64%) were all rated as good and well-satisfied with the appearance of the irradiated breast. No breast retraction and fibrosis were observed in any of the patients. Additionally, only 4 patients experienced grade 1 late toxicity (7.28%). None had grade 3 or higher late toxicity. CONCLUSION: This is the first study to report the 10-year results of PBI after breast-conserving surgery in Chinese patients. Our study suggested that PBI had durable local control and maintained good cosmetic outcomes with minimal late toxicity at long term follow up for the early stage breast cancer patients.

Study protocol for an open-label, single-arm, phase Ib/II study of combination of toripalimab, nab-paclitaxel, and gemcitabine as the first-line treatment for patients with unresectable pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with a dismal response to single-use of immune checkpoint inhibitors (ICIs). ICIs combined with systemic therapy has shown efficacy and safety in various solid tumors. Nab-paclitaxel and gemcitabine (AG), as the standard first-line treatment for advanced PDAC, has been widely used in recent years. The combination of ICIs and AG chemotherapy appears to be a promising option in the treatment of PDAC. METHODS: This is an open-label, single-arm, and single-center phase Ib/II trial. The enrolled subjects are the unresectable (locally advanced or metastatic) PDAC patients without previous systemic treatments. All subjects receive an intravenous injection of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on day 1 and day 8, along with toripalimab 240 mg at day 1 every 3 weeks. The subjects may discontinue the treatment because of progression disease (PD), intolerable toxicities, requirements of patients or researchers. For local advanced patients who are evaluated as partial response (PR), surgeons need to assess the surgical possibility. The primary objective of this trial is to evaluate the safety and overall survival (OS) of this combination therapy; and the secondary objective is related to the assessment of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and the rate of resection or R0 resection after receiving toripalimab plus AG treatment. Besides, we expect to identify the predictive biomarkers (such as MMR protein and PD-L1 expression, the number of TILs, the small RNA of EBV and so on) and explore the correlation between these biomarkers and tumor response to this combined regimen. DISCUSSION: This trial is the first attempt to evaluate the efficacy and safety of the combination of toripalimab plus AG chemotherapy as a first-line treatment for unresectable PDAC patients. The results of this phase Ib/II study will provide preliminary evidence for further assessment of this combined therapeutic regimen for unresectable PDAC patients. TRIAL REGISTRATION: Trial registration: ChiCTR ( ChiCTR2000032293 ). Registered 25 April 2020 - Retrospectively registered.

Durable Response and Good Tolerance to the Triple Combination of Toripalimab, Gemcitabine, and Nab-Paclitaxel in a Patient With Metastatic Pancreatic Ductal Adenocarcinoma.

Background: The performance of immune checkpoint inhibitor (ICI) monotherapy was proved to be disappointing in pancreatic ductal adenocarcinoma (PDAC). Increasing evidence has shown the promising efficacy of ICIs combined with systemic therapy in the first-line treatment in solid tumors. Case presentation: We reported a case of a metastatic PDAC patient who had a long-term partial response and good tolerance to the combined approach of toripalimab (a novel PD-1 inhibitor) and gemcitabine plus nab-paclitaxel (GA). PD-L1 positive expression was detected in his liver metastases. Besides, we described a phenomenon of pseudo-progression of this patient during the course of therapy. Conclusion: As the first-line treatment of metastatic PDAC patients, GA plus toripalimab may provide a novel combined approach with favorable response and manageable toxicity. Further clinical trials are needed to confirm the results. Pseudo-progression requires special attention and to be differentiated with true progression in patients undergoing immunotherapy.

The Era of Radiogenomics in Precision Medicine: An Emerging Approach to Support Diagnosis, Treatment Decisions, and Prognostication in Oncology.

With the rapid development of new technologies, including artificial intelligence and genome sequencing, radiogenomics has emerged as a state-of-the-art science in the field of individualized medicine. Radiogenomics combines a large volume of quantitative data extracted from medical images with individual genomic phenotypes and constructs a prediction model through deep learning to stratify patients, guide therapeutic strategies, and evaluate clinical outcomes. Recent studies of various types of tumors demonstrate the predictive value of radiogenomics. And some of the issues in the radiogenomic analysis and the solutions from prior works are presented. Although the workflow criteria and international agreed guidelines for statistical methods need to be confirmed, radiogenomics represents a repeatable and cost-effective approach for the detection of continuous changes and is a promising surrogate for invasive interventions. Therefore, radiogenomics could facilitate computer-aided diagnosis, treatment, and prediction of the prognosis in patients with tumors in the routine clinical setting. Here, we summarize the integrated process of radiogenomics and introduce the crucial strategies and statistical algorithms involved in current studies.

Triplet Chemotherapy (FOLFOXIRI) Plus Bevacizumab Versus Doublet Chemotherapy (FOLFOX/FOLFIRI) Plus Bevacizumab in Conversion Therapy for Metastatic Colorectal Cancer: a Meta-Analysis.

BACKGROUND/AIMS: Conversion therapy can convert unresectable metastatic colorectal cancer (mCRC) into resectable. However, the optimal conversion regimen was not yet defined. This meta-analysis aimed to compare the efficacy and safety of the triplet chemotherapy (FOLFOXIRI) plus bevacizumab (Bev) with doublet chemotherapy (FOLFOX/FOLFIRI) plus Bev in conversion therapy. METHODS: Randomized controlled trials (RCTs) from databases, including Pubmed, EMBASE, Cochrane clinical trials, clinicaltrial.gov and some conferences, were searched from the inception to November 2017. The R0 resection, objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and the incidence of adverse events were pooled with the use of hazard ratio (HR) or risk ratio (RR). RESULTS: Four RCTs with 1013 patients were included. FOLFOXIRI plus Bev regimen significantly improved the overall R0 resection rate (RR 1.41, 95% confidence interval (CI) 1.07-1.85, I2=37%), liver R0 resection rate (RR 2.28, 95% CI 1.34-3.89, I2=0%), ORR (RR 1.20, 95% CI 1.09-1.32, I2=0%), PFS (HR 0.72, 95% CI 0.62-0.84, I2=36%) and OS (HR 0.80, 95% CI 0.66-0.97, I2=0%). There was no significant difference in any Grade≥3 adverse event (RR 1.08, 95% CI 0.99-1.17, I2=0%) between two regimens. FOLFOXIRI-Bev was associated with a higher risk of neutropenia (RR 1.77, 95% CI 1.13-2.79, I2=68%) and diarrhea (RR 1.65, 95% CI 1.17-2.32, I2=0%). CONCLUSIONS: Triplet chemotherapy plus Bev significantly improved the R0 resection rates, ORR, PFS and OS in comparison with doublet chemotherapy plus Bev in conversion therapy for mCRC patients, with a higher risk of neutropenia and diarrhea.

Identification of N-Acetyldopamine Dimers from the Dung Beetle Catharsius molossus and Their COX-1 and COX-2 Inhibitory Activities.

Recent studies focusing on identifying the biological agents of Catharsius molossus have led to the identification of three new N-acetyldopamine dimers molossusamide A-C (1-3) and two known compounds 4 and 5. The structures of the new compounds were identified by comprehensive spectroscopic evidences. Compound 4 was found to have inhibitory effects towards COX-1 and COX-2.

Fructopyrano-(1→4)-glucopyranose inhibits the proliferation of liver cancer cells and angiogenesis in a VEGF/VEGFR dependent manner.

PURPOSE: To investigate whether fructopyrano-(1→4)-glucopyranose (FG) inhibits the proliferation of liver cancer cells and angiogenesis in a vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) dependent manner. METHODS: Bel-7402, HepG2 and SMMC-7721 cells with high expression of VEGF and VEGFR were screened. Bel-7402 cells and human microvascular endothelial cells (HMEC) were treated with FG for 48 h. CCK-8 assay was used to detect cell proliferation. Wound healing assay was used to investigate effect of FG on the migration of HMECs. Tube formation assay was done to test influence of FG on the angiogenesis of HMECs, and qRT-PCR and western blot assay were performed to detect mRNA and protein expression of VEGF, Fit-1 and KDR. Nude mice were inoculated with Bel-7402 cells, and influence of FG on tumor growth, microvessel density (MVD) and VEGF expression in tumor was investigated. RESULTS: Bel-7402 cells had a significantly higher expression of VEGF and VEGFR when compared with HepG2 cells and SMMC-7721 cells. FG could markedly reduce the mRNA and protein expressions of VEGF, Fit-1 and KDR in Bel-7402 cells and inhibit the proliferation of Bel-7402 cells in a concentration dependent manner. In addition, FG was able to remarkably inhibit the proliferation, migration and angiogenesis of HMECs, exerting anti-angiogenetic effect. In cancer-bearing nude mice, FG was found to inhibit the tumor growth, reduce MVD in tumors and decrease the VEGF in tumors. CONCLUSIONS: FG can inhibit proliferation of liver cancer cells and suppression angiogenesis in liver cancer in a VEGF/VEGFR dependent manner.