A nomogram model of postoperative prognosis for metastatic lung adenocarcinoma: A study based on the SEER database.

We have observed that patients with metastatic lung adenocarcinoma can obtain survival benefits from surgical resection of the primary tumor. A model was developed to evaluate the prognosis of patients. The patients with metastatic lung adenocarcinoma were identified in the Surveillance, Epidemiology, and End Results database and divided into surgery group and non-surgical group. Through Kaplan-Meier analysis, the survival rate of the non-surgical group was found to be significantly lower no matter before or after propensity score matching. One thousand one hundred and seventy surgical patients were divided into a training group and a verification group. In the training group, univariate and multivariate Cox models were used to explore the prognostic factors, and logistic regression was used to establish a nomogram based on significant predictors. In total, 12,228 patients with metastatic lung adenocarcinoma were recognized; primary tumor surgery accounted for 9.5%. After propensity score matching, the median survival time of 2 groups was significantly different. For the training group, univariate and multivariate COX analysis was conducted, and a nomogram was constructed. Acceptable agreement has been achieved between the predicted and observed survival rates, and the nomogram can divide patients with metastatic lung adenocarcinoma into different risk groups and predict their prognostic survival rate.

Metabolic adaptation of ovarian tumors in patients treated with an IDO1 inhibitor constrains antitumor immune responses.

To uncover underlying mechanisms associated with failure of indoleamine 2,3-dioxygenase 1 (IDO1) blockade in clinical trials, we conducted a pilot, window-of-opportunity clinical study in 17 patients with newly diagnosed advanced high-grade serous ovarian cancer before their standard tumor debulking surgery. Patients were treated with the IDO1 inhibitor epacadostat, and immunologic, transcriptomic, and metabolomic characterization of the tumor microenvironment was undertaken in baseline and posttreatment tumor biopsies. IDO1 inhibition resulted in efficient blockade of the kynurenine pathway of tryptophan degradation and was accompanied by a metabolic adaptation that shunted tryptophan catabolism toward the serotonin pathway. This resulted in elevated nicotinamide adenine dinucleotide (NAD+), which reduced T cell proliferation and function. Because NAD+ metabolites could be ligands for purinergic receptors, we investigated the impact of blocking purinergic receptors in the presence or absence of NAD+ on T cell proliferation and function in our mouse model. We demonstrated that A2a and A2b purinergic receptor antagonists, SCH58261 or PSB1115, respectively, rescued NAD+-mediated suppression of T cell proliferation and function. Combining IDO1 inhibition and A2a/A2b receptor blockade improved survival and boosted the antitumor immune signature in mice with IDO1 overexpressing ovarian cancer. These findings elucidate the downstream adaptive metabolic consequences of IDO1 blockade in ovarian cancers that may undermine antitumor T cell responses in the tumor microenvironment.

The molecular mechanisms of the long noncoding RNA SBF2-AS1 in regulating the proliferation of oesophageal squamous cell carcinoma.

The long noncoding RNASBF2-AS1 can promote the occurrence and development of many kinds of tumours, but its role in oesophageal squamous cell carcinoma (ESCC) is unknown. We found that SBF2-AS1 was up-regulated in ESCC, and its expression was positively correlated with tumor size (P = 0.0001), but was not related to gender, age, TNM stage, histological grade, and lymphnode metastasis (P > 0.05). It was further found that the higher the expression of SBF2-AS1, the lower the survival rate. COX multivariate analysis showed that the expression of SBF2-AS1 was an independent prognostic factor. Functional experiments show that inhibition of SBF2-AS1 can inhibit the proliferation of ESCC through in vivo and in vitro, and overexpression of SBF2-AS1 can promote the proliferation of ESCC and inhibit its apoptosis. In mechanism, SBF2-AS1/miR-338-3P, miR-362-3P/E2F1 axis are involved in the regulation of ESCC growth. In general, SBF2-AS1 may be used as ceRNA to combine with miR-338-3P and miR-362-3P to up-regulate the expression ofE2F1, and ultimately play a role in promoting cancer. It may be used as a therapeutic target and a biomarker for prognosis.

Cancer Moonshot Immuno-Oncology Translational Network (IOTN): accelerating the clinical translation of basic discoveries for improving immunotherapy and immunoprevention of cancer.

Despite regulatory approval of several immune-based treatments for cancer in the past decade, a number of barriers remain to be addressed in order to fully harness the therapeutic potential of the immune system and provide benefits for patients with cancer. As part of the Cancer Moonshot initiative, the Immuno-Oncology Translational Network (IOTN) was established to accelerate the translation of basic discoveries to improve immunotherapy outcomes across the spectrum of adult cancers and to develop immune-based approaches that prevent cancers before they occur. The IOTN currently consists of 32 academic institutions in the USA. By leveraging cutting-edge preclinical research in immunotherapy and immunoprevention, open data and resource sharing, and fostering highly collaborative team science across the immuno-oncology ecosystem, the IOTN is designed to accelerate the generation of novel mechanism-driven immune-based cancer prevention and therapies, and the development of safe and effective personalized immuno-oncology approaches.

Circular RNA circ-Foxo3 inhibits esophageal squamous cell cancer progression via the miR-23a/PTEN axis.

Circ-Foxo3 is a circRNA encoded by the human FOXO3 gene and works as a sponge for potential microRNAs (miRNAs) to regulate cancer progression. However, the role of circ-Foxo3 in esophageal squamous cell cancer (ESCC) is not clear. In this study, circ-Foxo3 was lowly expressed in cell lines and ESCC tissues. Meanwhile, overexpression of circ-Foxo3 inhibited cell growth, migration, and invasion, whether in vivo or in vitro. Mechanically, we found a potential miRNA target, miR-23a, which negatively correlated with circ-Foxo3 in ESCC. Then, a luciferase assay confirmed the relationship between the circ-Foxo3 and miRNA. Moreover, circ-Foxo3 upregulation of PTEN occurred through "sponging" miR-23a. Taken together, these results indicated that the circ-Foxo3/miR-23a/PTEN pathway was critical for inhibiting the ESCC progression. This may provide a promising target for treat ESCC.

Rapid Detection and Characterisation of Triterpene Saponins from the Root of Pulsatilla chinensis (Bunge) Regel by HPLC-ESI-QTOF-MS/MS.

INTRODUCTION: Triterpene saponins are the major bioactive components in the root of Pulsatilla chinensis (Bunge) Regel (RPC), and have been reported to possess antitumor and immunological adjuvant activities. However, the isolation, purification and elucidation procedures of triterpene saponins from RPC are difficult and time consuming due to high polarity and structural similarity. OBJECTIVES: To develop an analytical strategy for discovering and elucidating triterpene saponins in RPC. METHODS: Methanolic extract of RPC is analysed by high-performance liquid chromatography coupled to electrospray ionisation and quadrupole time-of-flight-mass spectrometry (HPLC-ESI-QTOF-MS/MS). The MS and MS/MS experiments are conducted using the negative-ionisation mode, in order to provide molecular-mass information and production spectra for the structural elucidation of compounds. RESULTS: Based on retention times, accurate mass and mass spectrometric fragmentation, 24 triterpene saponins are identified or tentatively elucidated from RPC, of which nine triterpene saponins were not reported previously. CONCLUSION: The HPLC-ESI-QTOF-MS/MS could be employed as a rapid, effective technique to screen and identify triterpene saponins in RPC without tedious and time-consuming isolation of pure constituents. Copyright © 2016 John Wiley & Sons, Ltd.

Discovery and characterization of COVA322, a clinical-stage bispecific TNF/IL-17A inhibitor for the treatment of inflammatory diseases.

Biologic treatment options such as tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of inflammatory diseases, including rheumatoid arthritis. Recent data suggest, however, that full and long-lasting responses to TNF inhibitors are limited because of the activation of the pro-inflammatory TH17/interleukin (IL)-17 pathway in patients. Therefore, dual TNF/IL-17A inhibition is an attractive avenue to achieve superior efficacy levels in such diseases. Based on the marketed anti-TNF antibody adalimumab, we generated the bispecific TNF/IL-17A-binding FynomAb COVA322. FynomAbs are fusion proteins of an antibody and a Fyn SH3-derived binding protein. COVA322 was characterized in detail and showed a remarkable ability to inhibit TNF and IL-17A in vitro and in vivo. Through its unique mode-of-action of inhibiting simultaneously TNF and the IL-17A homodimer, COVA322 represents a promising drug candidate for the treatment of inflammatory diseases. COVA322 is currently being tested in a Phase 1b/2a study in psoriasis ( ClinicalTrials.gov Identifier: NCT02243787).

Linker length matters, fynomer-Fc fusion with an optimized linker displaying picomolar IL-17A inhibition potency.

Fynomers are small binding proteins derived from the human Fyn SH3 domain. Using phage display technology, Fynomers were generated inhibiting the activity of the proinflammatory cytokine interleukin-17A (IL-17A). One specific Fynomer called 2C1 inhibited human IL-17A in vitro with an IC50 value of 2.2 nm. Interestingly, when 2C1 was genetically fused to the Fc part of a human antibody via four different amino acid linkers to yield bivalent IL-17A binding proteins (each linker differed in length), the 2C1-Fc fusion protein with the longest linker displayed the most potent inhibitory activity. It blocked homodimeric IL-17A with an IC50 value of 21 pm, which corresponds to a hundredfold improved IC50 value as compared to the value obtained with monovalent Fynomer 2C1. In contrast, the 2C1-Fc fusion with the shortest linker showed only an ∼8-fold improved IC50 value of 260 pm. Furthermore, in a mouse model of acute inflammation, we have shown that the most potent 2C1-Fc fusion protein is able to efficiently inhibit IL-17A in vivo. With their suitable biophysical properties, Fynomer-Fc fusion proteins represent new drug candidates for the treatment of IL-17A mediated inflammatory conditions such as psoriasis, psoriatic arthritis, or rheumatoid arthritis.