T-helper 17 (Th17) cells have important functions in adaptor immunity and have also been implicated in inflammatory disorders. The bromodomain and extraterminal domain (BET) family proteins regulate gene transcription during lineage-specific differentiation of naïve CD4 T cells to produce mature T-helper cells. Inhibition of acetyl-lysine binding of the BET proteins by pan-BET bromodomain (BrD) inhibitors, such as JQ1, broadly affects differentiation of Th17, Th1, and Th2 cells that have distinct immune functions, thus limiting their therapeutic potential. Whether these BET proteins represent viable new epigenetic drug targets for inflammatory disorders has remained an unanswered question. In this study, we report that selective inhibition of the first bromodomain of BET proteins with our newly designed small molecule MS402 inhibits primarily Th17 cell differentiation with a little or almost no effect on Th1 or Th2 and Treg cells. MS402 preferentially renders Brd4 binding to Th17 signature gene loci over those of housekeeping genes and reduces Brd4 recruitment of p-TEFb to phosphorylate and activate RNA polymerase II for transcription elongation. We further show that MS402 prevents and ameliorates T-cell transfer-induced colitis in mice by blocking Th17 cell overdevelopment. Thus, selective pharmacological modulation of individual bromodomains likely represents a strategy for treatment of inflammatory bowel diseases.

Nitric oxide derived from iNOS in activated T cells negatively regulates Th17 cell differentiation.

Lung DCs induce the expression of gut-homing molecules on T cells, resulting in their migration to the GI tract and protection against Salmonella infection after immunization

Tumour heterogeneity poses a significant challenge for treatment stratification. The goals of this study were to quantify heterogeneity in hepatocellular carcinoma (HCC) using multiparametric magnetic resonance imaging (mpMRI), and to report preliminary data correlating quantitative MRI parameters with advanced histopathology and gene expression in a patient subset. Thirty-two HCC patients with 39 HCC lesions underwent mpMRI including diffusion-weighted imaging (DWI), blood-oxygenation-level-dependent (BOLD), tissue-oxygenation-level-dependent (TOLD) and dynamic contrast-enhanced (DCE)-MRI. Histogram characteristics [central tendency (mean, median) and heterogeneity (standard deviation, kurtosis, skewness) MRI parameters] in HCC and liver parenchyma were compared using Wilcoxon signed-rank tests. Histogram data was correlated between MRI methods in all patients and with histopathology and gene expression in 14 patients. HCCs exhibited significantly higher intra-tissue heterogeneity vs. liver with all MRI methods (P < 0.030). Although central tendency parameters showed significant correlations between MRI methods and with each of histopathology and gene expression, heterogeneity parameters exhibited additional complementary correlations between BOLD and DCE-MRI and with histopathologic hypoxia marker HIF1α and gene expression of Wnt target GLUL, pharmacological target FGFR4, stemness markers EPCAM and KRT19 and immune checkpoint PDCD1. Histogram analysis combining central tendency and heterogeneity mpMRI features is promising for non-invasive HCC characterization on the imaging, histologic and genomics levels.

Post-translational modifications have been identified to be of great importance in cancers and lysine acetylation, which can attract the multifunctional transcription factor BRD4, has been identified as a potential therapeutic target. In this paper, we identify that BRD4 has an important role in colorectal cancer; and that its inhibition substantially wipes out tumor cells. Treatment with inhibitor MS417 potently affects cancer cells, although such effects were not always outright necrosis or apoptosis. We report that BRD4 inhibition also limits distal metastasis by regulating several key proteins in the progression of epithelial-to-mesenchymal transition (EMT). This effect of BRD4 inhibitor is demonstrated via liver metastasis in animal model as well as migration and invasion experiments in vitro. Together, our results demonstrate a new application of BRD4 inhibitor that may be of clinical use by virtue of its ability to limit metastasis while also being tumorcidal.

Cirrhosis and hepatocellular carcinoma are the prototypic complications of chronic hepatitis C virus infection in the liver. However, hepatitis C virus also affects a variety of other organs that may lead to significant morbidity and mortality. Extrahepatic manifestations of hepatitis C infection include a multitude of disease processes affecting the small vessels, skin, kidneys, salivary gland, eyes, thyroid, and immunologic system. The majority of these conditions are thought to be immune mediated. The most documented of these entities is mixed cryoglobulinemia. Morphologically, immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney. Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis. This paper highlights the histomorphologic features of these processes, which are typically characterized by chronic inflammation, immune complex deposition, and immunoproliferative disease in the affected organ.

Purpose To assess the correlation between intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) metrics in hepatocellular carcinoma (HCC) and liver parenchyma. Materials and Methods Twenty-five patients with HCC (M/F 23/2, mean age 58 years) underwent abdominal MRI at 1.5 or 3.0T, including IVIM-DWI (with 16 b-values) and DCE-MRI (3D FLASH sequence, mean temporal resolution of 2.3 sec). IVIM-DWI parameters (pseudodiffusion coefficient, D*, diffusion coefficient, D, and perfusion fraction, PF) were quantified in HCC lesions and liver parenchyma using a Bayesian fitting algorithm. DCE-MRI parameters (arterial flow, Fa, portal flow, Fp, total flow, Ft, mean transit time, MTT, distribution volume, DV, and arterial fraction, ART) were quantified using a dual-input single-compartment model. Correlations between IVIM-DWI and DCE-MRI parameters were assessed using a Spearman correlation test. Results Thirty-three HCC lesions (average size 5.0 ± 3.6 cm) were analyzed. D, D*, and PF were all significantly lower in HCC vs. liver (P < 0.05). Significantly higher Fa and ART and lower Fp were observed in HCC vs. liver (P < 0.001). Significant moderate to strong negative correlations were observed between ART and D* (r = −0.443, P = 0.028), ART and PF (r = −0.536, P = 0.006), ART and PFxD* (r = −0.655, P < 0.001), Fa and PF (r = 0.455, P = 0.023), and Fa and PFxD* (r = −0.475, P = 0.018) in liver parenchyma. There was no significant correlation between IVIM-DWI and DCE-MRI metrics in HCC lesions. Conclusion IVIM-DWI and DCE-MRI provide nonredundant information in HCC, while they correlate in liver parenchyma. These findings may be secondary to predominant portal inflow in the liver and tortuous vasculature and tissue heterogeneity in tumors.

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