Genome-wide studies using cells from patients with Cornelia de Lange Syndrome reveal a role for cohesin in regulating gene expression in human cells.

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BackgroundGene expression studies of peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE) have demonstrated a type I interferon signature and increased expression of inflammatory cytokine genes. Studies of patients with Aicardi Goutières syndrome, commonly cited as a single gene model for SLE, have suggested that accumulation of non-coding RNAs may drive some of the pathologic gene expression, however, no RNA sequencing studies of SLE patients have been performed. This study was designed to define altered expression of coding and non-coding RNAs and to detect globally altered RNA processing in SLE.MethodsPurified monocytes from eight healthy age/gender matched controls and nine SLE patients (with low-moderate disease activity and lack of biologic drug use or immune suppressive treatment) were studied using RNA-seq. Quantitative RT-PCR was used to validate findings. Serum levels of endotoxin were measured by ELISA.ResultsWe found that SLE patients had diminished expression of most endogenous retroviruses and small nucleolar RNAs, but exhibited increased expression of pri-miRNAs. Splicing patterns and polyadenylation were significantly altered. In addition, SLE monocytes expressed novel transcripts, an effect that was replicated by LPS treatment of control monocytes. We further identified increased circulating endotoxin in SLE patients.ConclusionsMonocytes from SLE patients exhibit globally dysregulated gene expression. The transcriptome is not simply altered by the transcriptional activation of a set of genes, but is qualitatively different in SLE. The identification of novel loci, inducible by LPS, suggests that chronic microbial translocation could contribute to the immunologic dysregulation in SLE, a new potential disease mechanism.

Purpose To determine if phosphodiesterase 5 (PDE5) inhibitors can augment immune function in head and neck cancer patients through inhibition of myeloid derived suppressor cells (MDSCs). Experimental Design We performed a randomized, prospective, double blinded, placebo controlled, phase II clinical trial to determine the in vivo effects of systemic PDE5 inhibition on immune function in head and neck squamous cell carcinoma (HNSCC) patients. Results Tadalafil augmented immune response, increasing ex vivo T cell expansion to a mean 2.4 fold increase compared to 1.1 fold in control patients (P= 0.01), reducing peripheral MDSC numbers to mean 0.81 fold change compared to a 1.26 fold change in control patients (P=0.001), and increasing general immunity as measured by delayed type hypersensitivity response (P=0.002). Tumor specific immunity in response to HNSCC tumor lysate was augmented in tadalafil treated patients (P=0.04). Conclusions These findings demonstrate that tadalafil augments general and tumor-specific immunity in HNSCC patients and has therapeutic potential in HNSCC. Evasion of immune surveillance and suppression of systemic and tumor specific immunity is a significant feature of head and neck cancer development. This study demonstrates that a PDE5 inhibitor, tadalafil, can reverse tumor specific immune suppression in head and neck cancer patients, with potential for therapeutic application.

Background: Sorafenib is the first agent that has demonstrated an improved overall survival benefit in advanced hepatocellular carcinoma (HCC), setting a new standard for first-line treatment. However, no one has yet been able to predict sensitivity to sorafenib. Pre-treatment pERK level has been shown to be associated with favorable response to such therapy in a phase II clinical study, indicating that pERK may be a potential biomarker for treatment of HCC with sorafenib.

This research was supported by Grant (81571417) from the National Science Foundation of China and Grant (2015GSF118092) from the Technology Development Plan of Shandong Province. The authors report no conflict of interest.

BackgroundMultidrug resistance remains a major obstacle to successful treatment for patients with gastric cancer (GC). Recently, glycosylation has been demonstrated to play a vital role in the acquisition of multidrug resistance. As a potent inhibitor of glycosylation, tunicamycin (Tu) has shown marked antitumor activities in various cancers. In the present study, we attempted to determine the exact effect of Tu on the chemoresistance of GC.MethodsThe cytotoxic effects of drugs on GC cells were evaluated by cell viability assays, and apoptosis was detected by flow cytometry. PCR, western blot analysis, immunofluorescence staining and canonical inhibitors were employed to identify the underlying mechanisms of the specific effects of Tu on multidrug-resistant (MDR) GC cells.ResultsFor the first time, we found that MDR GC cells were more sensitive to Tu-induced cell death than the parental cells and that the increased sensitivity might correlate with basal endoplasmic reticulum (ER) stress. In addition, Tu dramatically increased chemotherapy-induced apoptosis by evoking ER stress in GC cells, particularly MDR cells. Further study indicated that these effects were highly dependent on glycosylation inhibition by Tu, rather than its role as a canonical ER stress inducer. Besides, autophagy was markedly triggered by Tu, and blocking autophagy enhanced the combined effects of Tu and chemotherapy on MDR GC cells.ConclusionsOur results suggest that tumor-targeted glycosylation inhibition may be a feasible strategy to reverse chemoresistance in GC patients.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0935-8) contains supplementary material, which is available to authorized users.

Comparison of DNA methylation, together with mRNA levels, revealed significant differences between AMD versus normal retinas. The evidence presented suggests that GSTM1 and GSTM5 undergo epigenetic repression in AMD RPE/choroid, which may increase susceptibility to oxidative stress in AMD retinas.