Discovery of Natural Ah Receptor Antagonists from Salvia miltiorrhiza Bunge and Synthesis of Analogs for Tumor Immunotherapy.

IDO/TDO/Kyn/AhR signaling plays a crucial role in regulating innate and adaptive immunity, and targeting Ah receptor (AhR) inhibition can potentially redirect immune cells toward an antitumoral phenotype. Therefore, AhR is an attractive drug target for novel small molecule cancer immunotherapies. In this study, natural products tanshinolic A-D (1-4), the first adducts composed of ortho-naphthoquinone-type tanshinone and phenolic acid featuring a unique 1,4-benzodioxan hemiacetal structure, were isolated and characterized from the roots of Salvia miltiorrhiza Bunge. Luciferase reporter gene assay revealed that these adducts exhibited significant AhR inhibitory activity. A linear strategy was developed to construct a cis-3,4-disubstituted 1,4-benzodioxan hemiacetal structure. Encouragingly, in both in vitro and in vivo experiments, (±)-13e demonstrated the ability to inhibit tumor cell proliferation, promote INF-γ secretion in CD8+ T cells, and inhibit PD-1/PD-L1 signal transduction, which could exert tumor inhibition properties by inhibiting AhR activity, positioning it as a promising candidate for tumor immunotherapy.

Multilevel regulation of N6-methyladenosine RNA modifications: Implications in tumorigenesis and therapeutic opportunities.

N6-methyladenosine (m6A) RNA modification is widely perceived as the most abundant and common modification in transcripts. This modification is dynamically regulated by specific m6A "writers", "erasers" and "readers" and is reportedly involved in the occurrence and development of many diseases. Since m6A RNA modification was discovered in the 1970s, with the progress of relevant research technologies, an increasing number of functions of m6A have been reported, and a preliminary understanding of m6A has been obtained. In this review, we summarize the mechanisms through which m6A RNA modification is regulated from the perspectives of expression, posttranslational modification and protein interaction. In addition, we also summarize how external and internal environmental factors affect m6A RNA modification and its functions in tumors. The mechanisms through which m6A methylases, m6A demethylases and m6A-binding proteins are regulated are complicated and have not been fully elucidated. Therefore, we hope to promote further research in this field by summarizing these mechanisms and look forward to the future application of m6A in tumors.

Artificial neural network-based diagnostic models for lung cancer combining conventional indicators with tumor markers.

This study set out to establish a lung cancer diagnosis and prediction model uses conventional laboratory indicators combined with tumor markers, so as to help early screening and auxiliary diagnosis of lung cancer through a convenient, fast, and cheap way, and improve the early diagnosis rate of lung cancer. A total of 221 patients with lung cancer, 100 patients with benign pulmonary diseases, and 184 healthy subjects were retrospectively studied. General clinical data, the results of conventional laboratory indicators, and tumor markers were collected. Statistical Product and Service Solutions 26.0 was used for data analysis. The diagnosis and prediction model of lung cancer was established by artificial neural network - multilayer perceptron. After correlation and difference analysis, five comparison groups (lung cancer-benign lung disease group, lung cancer-health group, benign lung disease-health group, early-stage lung cancer-benign lung disease group, and early-stage lung cancer-health group) obtained 5, 28, 25, 16, and 25 valuable indicators for predicting lung cancer or benign lung disease, and then established five diagnostic prediction models, respectively. The area under the curve (AUC) of each combined diagnostic prediction model (0.848, 0.989, 0.949, 0.841, and 0.976) was higher than that of the diagnostic prediction model established only using tumor markers (0.799, 0.941, 0.830, 0.661, and 0.850), and the difference in the lung cancer-health group, the benign lung disease-health group, the early-stage lung cancer-benign lung disease group, and early-stage lung cancer-health group was statistically significant (P < 0.05). The artificial neural network-based diagnostic models for lung cancer combining conventional indicators with tumor markers have high performance and clinical significance in assisting the diagnosis of early lung cancer.

The risk factors of postoperative nausea and vomiting in patients undergoing laparoscopic sleeve gastrectomy and laparoscopic distal gastrectomy: a propensity score matching analysis.

Postoperative nausea and vomiting (PONV) is a common side effect after laparoscopic surgery. The aim of the study is to investigate the variables that could predict PONV in patients who underwent laparoscopic gastrectomy. We divided patients who underwent laparoscopic gastrectomy into PONV and No-PONV groups. Propensity score matching (PSM) was applied to adjust confounding factors for further validation, and ordinal logistic regression analysis was used to identify predictors for PONV. In the ordinal logistic regression analysis, the preoperative neutrophil-to-lymphocyte ratio (NLR) (odds ratio [OR]: 3.19, 95% confidence interval [CI]: 1.38-7.38; p < 0.01) was identified as an independent risk factor for the presence of PONV and a predictor of the severity of PONV (OR: 3.44, 95% CI: 1.67-5.20; p < 0.01) in 94 PSM patients. Besides, NLR was positively correlated with the PONV score (r = 0.534, p < 0.001). In the receiver-operating characteristic (ROC) curve analysis, an NLR with an optimal cutoff value of 1.59 predicted severe PONV with a sensitivity of 72% and specificity of 81%. The NLR was an independent risk factor for the presence of PONV, and a high NLR tends to be positively associated with the severity of PONV after laparoscopic gastrectomy.

Bromodomain-containing protein 9 activates proliferation and epithelial-mesenchymal transition of colorectal cancer via the estrogen pathway in vivo and in vitro.

Background: Bromodomain-containing protein 9 (BRD9) has been reported to be upregulated in multiple malignancies and facilitate cancer progression. However, there is a paucity of data relating to its expression and biological role in colorectal cancer (CRC). Therefore, this current study examined the prognostic role of BRD9 in CRC and the underlying mechanisms involved. Methods: Real-time polymerase chain reaction (PCR) and Western blotting were used to examine the expression of BRD9 in paired fresh CRC and para-tumor tissues from colectomy patients (n=31). Immunohistochemistry (IHC) was performed to assess BRD9 expression in 524 paraffin-embedded archived CRC samples. The clinical variables are including age, sex, carcinoembryonic antigen (CEA), location of tumor, T stage, N stage, and TNM classification. The effect of BRD9 on the prognosis of CRC patients was explored by Kaplan-Meier and Cox regression analyses. Cell counting kit 8 (CCK-8), clone formation assay, transwell assay, and flow cytometry were used to determine CRC cell proliferation, migration, invasion, and apoptosis, respectively. Xenograft models in nude mice were established to investigate the role of the BRD9 in vivo. Results: BRD9 mRNA and protein expression levels were significantly upregulated in CRC cells compared to normal colorectal epithelial cells (P<0.001). IHC analysis of 524 paraffin-embedded archived CRC tissues showed that high BRD9 expression was significantly associated with TNM classifications, CEA, and lymphatic invasion (P<0.01). Univariate and multivariate analyses indicated that BRD9 [hazard ratio (HR): 3.04, 95% confidence interval (CI): 1.78-5.20; P<0.01] expression and sex (HR: 6.39, 95% CI: 3.94-10.37; P<0.01) were independent prognostic factors for overall survival in the entire cohort. Overexpressing BRD9 promoted CRC cell proliferation, while silencing BRD9 inhibited the proliferation of CRC cells. Furthermore, we showed that BRD9 silencing significantly inhibited epithelial-mesenchymal transition (EMT) via the estrogen pathway. Finally, we demonstrated that silencing BRD9 significantly inhibited the proliferation and tumorigenicity of SW480 and HCT116 cells in vitro and in vivo in nude mice (P<0.05). Conclusions: This study demonstrated that BRD9 high could be an independent prognostic risk factor for CRC. Furthermore, the BRD9/estrogen pathway may contribute to the proliferation of CRC cells and EMT, suggesting that BRD9 may be a novel molecular target in the therapeutic treatment of CRC.

C/EBPß enhances immunosuppression activity of myeloid-derived suppressor cells by a P300-mediated acetylation modification.

OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) are a major immunosuppressive population in the tumor microenvironment,inhibiting anti-tumor immune response and exerting pro-tumorigenic effect. CCAAT/enhancer-binding protein beta (C/EBPß), a key transcription factor indispensable for myelopoiesis, plays a fundamental role in regulating expansion and activation of MDSCs. Lysine acetylation can regulate functions of transcription factors. However, the role of C/EBPß acetylation modification in MDSCs has not been reported. MATERIALS AND METHODS: MDSCs derived from the spleens of tumor-bearing mice (TB-SP-MDSCs) were isolated by immunomagnetic beads. Bone marrow derived MDSCs were induced by IL-6 and GM-CSF. Western-blot was used to detect the expression of P300 and co-immunoprecipitation (CO-IP) was used to detect the C/EBPß acetylation in MDSCs. Inhibitor C646 was used to specificly inhibit P300 activity. RESULTS: In this study, we found that C/EBPß was acetylated by acetyltransferase P300 in MDSCs. A P300-mediated C/EBPß acetylation enhanced C/EBPß transactivation activity on arginase 1 (Arg-1) gene promoter. Inhibition of P300 activity downregulated the inhibitory effects of MDSCs in vitro and attenuated pro-tumorigenic effects of MDSCs in vivo. Additionally, IL-6 from tumor microenvironment could upregulate the expression of P300 and enhance C/EBPß acetylation in MDSCs. CONCLUSION: In general, a P300-mediated C/EBPß acetylation enhanced C/EBPß transactivation activity on Arg-1 promoter, thus promoting immunosuppressive function of MDSCs. In view of the critical role of P300 in regulating MDSCs, P300 might be a potential target of anti-tumor immunotherapy.

The efficacy and toxicity of angiogenesis inhibitors for ovarian cancer: a meta-analysis of randomized controlled trials.

PURPOSE: To evaluate the efficacy and toxicity of angiogenesis inhibitors for the treatment of ovarian cancer patients, we conducted a meta-analysis of the published literature on this subject. METHODS: In this meta-analysis, we searched PubMed, EMBASE, Web of Science, and Cochrane Library databases for randomized controlled trials (RCTs). The literature search was performed up to August 12, 2019. The risk of bias of the included studies was evaluated using The Cochrane Collaboration's tool, and the statistical analyses were performed using RevMan 5.3 software. The sensitivity analysis was performed with Stata 12.0 software. RESULTS: 22 RCTs with 11,254 patients were included. Our meta-analysis demonstrates that angiogenesis inhibitors therapy can significantly improve progression-free survival (PFS) (hazard ratio [HR] 0.71, 95% CI 0.63-0.79, I2 = 80%, P < 0.00001) and overall survival (OS) (HR 0.95, 95% CI 0.90-0.99, I2 = 0%, P = 0.03) in ovarian cancer patients. The subgroups results suggest differences in the benefit in OS in first-line treatment (HR 1.00, 95% CI 0.93-1.08, I2 = 0%, P = 0.90) compared with treatment at relapse (HR 0.87, 95% CI 0.81-0.95, I2 = 0%, P = 0.0008). The PFS improved both in first-line treatment (HR 0.87, 95% CI 0.79-0.95, I2 = 60%, P = 0.003) and recurrent treatment (HR 0.60, 95% CI 0.53-0.67, I2 = 57% P < 0.0001) patients. The PFS and OS in recurrent group were prolonged both in the platinum-resistant group(PFS: HR 0.50, 95% CI 0.42-0.60, I2 = 0%, P < 0.00001; OS: HR 0.76, 95% CI 0.62-0.93, I2 = 0%, P = 0.007) and the platinum-sensitive group (PFS: HR 0.58, 95% CI 0.49-0.69, I2 = 64%, P < 0.00001; OS: HR 0.88, 95% CI 0.79-0.99, I2 = 0%, P = 0.03). However, this therapy is associated with a higher risk of common adverse events of grade ≥ 3 (risk ratio [RR]: 1.12; 95% CI 1.07-1.17; I2 = 0%, P = 0.68) such as arterial thromboembolic disease, ascites, diarrhea, gastrointestinal perforations, headache, hemorrhagic, hypertension, hypokalemia, leucopenia, pain, proteinuria, thrombocytopenia, and thrombosis or embolism. CONCLUSION: This meta-analysis suggests angiogenesis inhibitors may significantly improve PFS and OS of ovarian cancer patients and increase the incidence of common adverse events.

Engineering of an enhanced synthetic Notch receptor by reducing ligand-independent activation.

Notch signaling is highly conserved in most animals and plays critical roles during neurogenesis as well as embryonic development. Synthetic Notch-based systems, modeled from Notch receptors, have been developed to sense and respond to a specific extracellular signal. Recent advancement of synNotch has shown promise for future use in cellular engineering to treat cancers. However, synNotch from Morsut et al. (2016) has a high level of ligand-independent activation, which limits its application. Here we show that adding an intracellular hydrophobic sequence (QHGQLWF, named as RAM7) present in native Notch, significantly reduced ligand-independent activation. Our enhanced synthetic Notch receptor (esNotch) demonstrates up to a 14.6-fold reduction in ligand-independent activation, without affecting its antigen-induced activation efficiency. Our work improves a previously reported transmembrane receptor and provides a powerful tool to develop better transmembrane signaling transduction modules for further advancement of eukaryotic synthetic biology.

Clinical Analysis of Patients with Primary Blepharospasm: A Report of 100 Cases in China.

PURPOSE: This study explored the clinical characteristics, diagnosis and treatments of primary blepharospasm. METHODS: In this retrospective analysis, 100 patients with blepharospasm were enrolled. Data were collected from medical records and face-to-face interviews with patients and their families. RESULTS: The age of onset was 56.4 ± 2.7 (range, 32-76 years). The duration between onset and accurate diagnosis was 38.7 ± 36.0 months (range, 2-120 months). Dry eyes occurred in 54% of the patients. The initial diagnostic accuracy was 10%. Dry eye syndrome, conjunctivitis/keratitis and myasthenia gravis caused the most confusion in the differential diagnosis. Regular botulinum toxin type A injections improved both eyelid spasms and subjective ocular symptoms in all patients. CONCLUSIONS: Regular botulinum toxin type A injections improved both eyelid spasms and subjective ocular symptoms in blepharospasm patients. The differentiation of primary blepharospasm differentiation from dry eye syndrome, conjunctivitis/keratitis and myasthenia gravis must be improved.