The level of macrophage migration inhibitory factor is negatively correlated with the efficacy of PD-1 blockade immunotherapy combined with chemotherapy as a neoadjuvant therapy for esophageal squamous cell carcinoma.

PURPOSE: This study aimed to screen biomarkers to predict the efficacy of programmed cell death 1 (PD-1) blockade immunotherapy combined with chemotherapy as neoadjuvant therapy for esophageal squamous cell carcinoma (ESCC). METHODS: In the first stage of the study, the baseline concentrations of 40 tumor-related chemokines in the serum samples of 50 patients were measured to screen for possible biomarkers. We investigated whether the baseline concentration of the selected chemokine was related to the therapeutic outcomes and tumor microenvironment states of patients treated with the therapy. In the second stage, the reliability of the selected biomarkers was retested in 34 patients. RESULTS: The baseline concentration of macrophage migration inhibitory factor (MIF) was negatively correlated with disease-free survival (DFS) and overall survival (OS) in patients treated with the therapy. In addition, a low baseline expression level of MIF is related to a better tumor microenvironment for the treatment of ESCC. A secondary finding was that effective treatment decreased the serum concentration of MIF. CONCLUSION: Baseline MIF levels were negatively correlated with neoadjuvant therapy efficacy. Thus, MIF may serve as a predictive biomarker for this therapy. The accuracy of the prediction could be improved if the serum concentration of MIF is measured again after the patient received several weeks of treatment.

Characterizing HDAC Pathway Copy Number Variation in Pan-Cancer.

Background: Histone deacetylase (HDAC) plays a crucial role in regulating the expression and activity of a variety of genes associated with tumor progression and immunotherapeutic processes. The aim of this study was to characterize HDAC pathway copy number variation (CNV) in pan-cancer. Methods: A total of 10,678 tumor samples involving 33 types of tumors from The Cancer Genome Atlas (TCGA) were included in the study. Results: HDAC pathway CNV and CNV gain were identified as prognostic risk factors for pan-cancer species. The differences of tumor characteristics including tumor mutational burden, tumor neoantigen burden, high-microsatellite instability, and microsatellite stable between HDAC pathway CNV altered-type group and wild-type group varied among the various cancer species. In some cancer types, HDAC pathway CNV alteration was positively correlated with loss of heterozygosity, CNV burden, ploidy, and homologous recombination defect score markers, while it was significantly negatively correlated with immune score and stroma score. There were significant differences in immune characteristics such as major histocompatibility complex class I (MHC-I), MHC-II, chemokines, cytolytic-activity, and IFN-γ between the two groups. Immune cycle characteristics varied from one cancer type to another. Conclusion: This study reveals a tumor and immune profile of HDAC pathway CNV as well as its unlimited potential in immune prognosis.

Mid-pregnancy consumption of fruit, vegetable and fruit juice and the risk of gestational diabetes mellitus: A correlation study.

OBJECTIVE: To determine the potential association between mid-pregnancy consumption of fruit, vegetable and fruit juice and the risk of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: An observational study with 2987 pregnant women was conducted in China from June 2013 to June 2014. Fruit, vegetable and fruit juice consumption during weeks 13-28 of pregnancy was assessed by using 24 h dietary recall method and food frequency questionnaire. Cox proportional hazard model was used to assess the association between fruit, vegetable and fruit juice consumption (in quartiles) and GDM risks, and One-Way ANOVA was used to compare the incidences of GDM at various levels of fruit, vegetable and fruit juice consumption, adjusted for gestational age, family history of diabetes, physical activity, fiber and meat intake. RESULTS: Among all the 2987 pregnant women, 405 (13.6%) were diagnosed as GDM for the first time. There was no association between total fruit and vegetable consumption and GDM. Quantity of grape, melon, potatoes and fruit juice consumption were positively associated with the incidence of GDM. In contrast, quantity of apple, orange and vegetables other than potatoes were negatively associated with the incidence of GDM. CONCLUSIONS: Our findings indicate that appropriate quantity of fruit and vegetable intakes throughout pregnancy may have a beneficial effect on preventing the development of GDM, whereas excess consumption of fruits, potatoes and fruit juices is associated with an increased risk of GDM.

The Ratio of IP10 to IL-8 in Plasma Reflects and Predicts the Response of Patients With Lung Cancer to Anti-PD-1 Immunotherapy Combined With Chemotherapy.

Antibodies against checkpoint inhibitors such as anti-programmed cell death protein 1 (PD-1) and its ligand anti-programmed death ligand 1 (PD-L1) have shown clinical efficacy in the treatment of multiple cancers. However, there are only a few studies on biomarkers for these targeted immunotherapies, especially in peripheral blood. We first studied the role of interferon-induced protein-10 (IP10) combined with interleukin-8 (IL-8) in peripheral blood as a biomarker of immune-combined chemotherapy for lung cancer and multiple cancers. We used the high-throughput cytokine detection platform and performed bioinformatics analysis of blood samples from 67 patients with lung cancer and 24 with multiple cancers. We selected the ratio of IP-10 to IL-8 (S2/S0, ratio of changes at 10-12 weeks after treatment to baseline) to predict the response to immunotherapy combined with chemotherapy and evaluate the survival of lung cancer patients and mixed cancer patients. In patients treated with the combination therapy, the specificity and sensitivity of IL-8 and IP10 together as predictors were improved compared with those of IL-8 and IP10 alone. Our conclusion was verified in not only lung cancer but also multiple cancer research cohorts. We then further validated the predictive effect of biomarkers in different histologic types of NSCLC and chemotherapy combined with different PD-1 drug groups. Subsequent validation should be conducted with a larger number of patients. The proposed marker IP10 (S2/S0)/IL-8 (S2/S0), as a predictive immunotherapy biomarker, has broad prospects for future clinical applications in treating patients with multiple intractable neoplasms.

Sex-biased ceRNA networks reveal that OSCAR can promote proliferation and migration of lung adenocarcinoma in women.

Lung adenocarcinoma (LUAD) is one of several malignant tumours with the highest incidence rates. Currently, there is an urgent need for effective diagnostic and therapeutic targets for LUAD in clinical practice. Numerous studies have shown that there may be differences in the development pattern of LUAD between male and female patients, leading to the need for differential treatment. At the same time, previous studies have shown that competitive endogenous (ce)RNA plays an important role in the development of LUAD, but there is no relevant research on whether there is a gender difference in the ceRNA network of LUAD. In this study, we constructed gender-independent, male-specific, and female-specific ceRNA networks using RNA sequencing results from TCGA database. Subsequently, through analysis of the core genes of the ceRNA network, we determined that the male and female ceRNA networks indeed display different features. In addition, we also found that the osteoclast-associated receptor (OSCAR) gene was a potential diagnostic target for detecting LUAD in females, and that increased expression of this gene promoted the proliferation and migration of A549 and H1975 LUAD cell lines; more specifically, A549 and H1975 are male and female LUAD cell lines, respectively. This suggests that the OSCAR gene has the potential to serve as target molecule for the diagnosis and treatment of female-specific LUADs.

The clinical and prognostic significance of CD14(+)HLA-DR(-/low) myeloid-derived suppressor cells in hepatocellular carcinoma patients receiving radiotherapy.

Myeloid-derived suppressor cells (MDSCs) are key player in mediating systemic immunosuppression, and their accumulation and expansion in the periphery and tumor have been iteratively observed in patients with various types of cancer. It has been reported that CD14(+)HLA-DR(-/low) MDSCs are increased in hepatocellular carcinoma (HCC) patients; however, the clinical significance of MDSC alteration in HCC patients after treatment is poorly studied. In this study, we examined the frequency of MDSCs in 92 HCC patients, 14 chronic liver disease patients without HCC, and 22 healthy controls by flow cytometric analysis. The associations between the clinical features and the frequency of MDSCs were analyzed. In particular, we further examined the prognostic impact of MDSCs on the overall survival of HCC patients receiving radiation therapy. The frequency of MDSCs in HCC patients was significantly increased and correlated with tumor stage, size, burden, and Child-Pugh classification but not with biochemical parameters of liver function. In HCC patients who received radiation therapy, the frequency of MDSCs after treatment significantly decreased and was inversely correlated with overall survival time. In multivariate analysis, only post-treatment MDSC ratio and Child-Pugh classification were correlated with the prognosis of HCC patients. Patients with a high frequency of MDSCs after radiotherapy should be closely followed, and the inhibition of MDSCs may improve the prognosis of patients.

Mer receptor tyrosine kinase is frequently overexpressed in human non-small cell lung cancer, confirming resistance to erlotinib.

Mer is a receptor tyrosine kinase (RTK) with oncogenic properties that is often overexpressed or activated in various malignancies. Using both immunohistochemistry and microarray analyses, we demonstrated that Mer was overexpressed in both tumoral and stromal compartments of about 70% of non-small cell lung cancer (NSCLC) samples relative to surrounding normal lung tissue. This was validated in freshly harvested NSCLC samples; however, no associations were found between Mer expression and patient features. Although Mer overexpression did not render normal lung epithelial cell tumorigenic in vivo, it promoted the in vitro cell proliferation, clonogenic colony formation and migration of normal lung epithelial cells as well as NSCLC cells primarily depending on MAPK and FAK signaling, respectively. Importantly, Mer overexpression induced resistance to erlotinib (EGFR inhibitor) in otherwise erlotinib-sensitive cells. Furthermore, Mer-specific inhibitor rendered erlotinib-resistant cells sensitive to erlotinib. We conclude that Mer enhances malignant phenotype and pharmacological inhibition of Mer overcomes resistance of NSCLC to EGFR-targeted agents.

Oncogenicity of LHX4 in colorectal cancer through Wnt/ß-catenin/TCF4 cascade.

The LHX genes play an important role in a number of developmental processes. Potential roles of LHXs have been demonstrated in various neoplastic tissues as tumor suppressors or promoters depending on tumor status and types. The aim of this study was to investigate the function role of LHXs in the human colorectal cancer (CRC). The gene expression changes of LHXs in CRC tissues compared with noncancerous colorectal tissues was detected using real-time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) analysis and immunohositochemistry. And we identified the gene LHX4 that were significantly upregulated in CRC by QRT-PCR analysis and immunohistochemistry. Furthermore, we discovered that LHX4 promoted cancer cell proliferation in vitro, and LHX4 expression correlated with elevated ß-catenin levels in CRC and ß-catenin function was required for LHX4's oncogenic effects. Mechanistically, LHX4 facilitate TCF4 to bind to ß-catenin and form a stable LHX4/TCF4/ß-catenin complex and transactive its downstream target gene. LHX4 mutations that disrupt the LHX4-ß-catenin interaction partially prevent its function in tumor cells. All in all, LHX4 is a commonly activated tumor promoter that activate Wnt/ß-catenin signaling in cancer cells of CRC.