Downregulation of tumor suppressor signaling plays an important role in the pathogenesis of hepatocellular carcinoma (HCC). Here, we report that downregulation of the angiopoietin-like protein is associated with vascular invasion, tumor thrombus, metastasis, and poor prognosis in HCC. Ectopic expression of in HCC cells effectively decreased their and tumorigenicity, cell motility, and angiogenesis. shRNA-mediated depletion of exerted opposing effects. promoted apoptosis via inhibition of the STAT3/Bcl-2-mediated antiapoptotic pathway and decreased cell migration and invasion via downregulation of transcription factors SNAIL and SLUG. Furthermore, inhibited angiogenesis by attenuating ERK and AKT signaling and interacted with integrin α1β1 receptor to suppress the downstream FAK/Src-JAK-STAT3 signaling pathway. Taken together, these results suggest as a prognostic biomarker and novel therapeutic agent in HCC. .
The tumor microenvironment (TME) of nasopharyngeal carcinoma (NPC) harbors a heterogeneous and dynamic stromal population. A comprehensive understanding of this tumor-specific ecosystem is necessary to enhance cancer diagnosis, therapeutics, and prognosis. However, recent advances based on bulk RNA sequencing remain insufficient to construct an in-depth landscape of infiltrating stromal cells in NPC. Here we apply single-cell RNA sequencing to 66,627 cells from 14 patients, integrated with clonotype identification on T and B cells. We identify and characterize five major stromal clusters and 36 distinct subpopulations based on genetic profiling. By comparing with the infiltrating cells in the non-malignant microenvironment, we report highly representative features in the TME, including phenotypic abundance, genetic alternations, immune dynamics, clonal expansion, developmental trajectory, and molecular interactions that profoundly influence patient prognosis and therapeutic outcome. The key findings are further independently validated in two single-cell RNA sequencing cohorts and two bulk RNA-sequencing cohorts. In the present study, we reveal the correlation between NPC-specific characteristics and progression-free survival. Together, these data facilitate the understanding of the stromal landscape and immune dynamics in NPC patients and provides deeper insights into the development of prognostic biomarkers and therapeutic targets in the TME.
Brown cotton fiber is the major raw material for colored cotton industry. Previous studies have showed that the brown pigments in cotton fiber belong to proanthocyanidins (PAs). To clarify the details of PA biosynthesis pathway in brown cotton fiber, gene expression profiles in developing brown and white fibers were compared via digital gene expression profiling and qRT-PCR. Compared to white cotton fiber, all steps from phenylalanine to PA monomers (flavan-3-ols) were significantly up-regulated in brown fiber. Liquid chromatography mass spectrometry analyses showed that most of free flavan-3-ols in brown fiber were in 2, 3-trans form (gallocatechin and catechin), and the main units of polymeric PAs were trihydroxylated on B ring. Consistent with monomeric composition, the transcript levels of flavonoid 3′, 5′-hydroxylase and leucoanthocyanidin reductase in cotton fiber were much higher than their competing enzymes acting on the same substrates (dihydroflavonol 4-reductase and anthocyanidin synthase, respectively). Taken together, our data revealed a detailed PA biosynthesis pathway wholly activated in brown cotton fiber, and demonstrated that flavonoid 3′, 5′-hydroxylase and leucoanthocyanidin reductase represented the primary flow of PA biosynthesis in cotton fiber.
Serum amyloid A (SAA), a major acute-phase protein, has potent cytokine-like activities in isolated phagocytes and synovial fibroblasts. SAA-induced proinflammatory cytokine gene expression requires transcription factors such as NF-κB; however, the associated epigenetic regulatory mechanism remains unclear. Here we report that Jmjd3, a histone H3 lysine 27 (H3K27) demethylase, is highly inducible in SAA-stimulated macrophages and plays an important role in the induction of inflammatory cytokine genes. SAA-induced Jmjd3 expression leads to reduced H3K27 trimethylation. Silencing of Jmjd3 expression significantly inhibited SAA-induced expression of proinflammatory cytokines including IL-23p19, G-CSF and TREM-1, along with up-regulation of H3K27 trimethylation levels on their promoters. Depletion of Jmjd3 expression also attenuated the release of proinflammatory cytokine genes in a peritonitis model and ameliorated neutrophilia in SAA-stimulated mice. Finally, we observed that Jmjd3 is essential for SAA-enhanced macrophage foam cell formation by oxidized LDL. Taken together, these results illustrate a Jmjd3-dependent epigenetic regulatory mechanism for proinflammatory cytokine gene expression in SAA-stimulate macrophages. This mechanism may be subject to therapeutic intervention for sterile inflammation and atherosclerosis.
Macrophages affect the magnitude and duration of inflammatory response in a functionally heterogeneous manner. The phenotype of macrophages is maintained through a reversible homeostatic mechanism. A number of determinants that modulate macrophage plasticity have been identified, although the precise mechanisms are not fully understood. Here we report that stimulation of isolated human blood monocytes and mouse bone marrow-derived macrophages with human serum amyloid A (SAA), a major acute-phase protein, leads to induced expression of macrophage M2 markers including IL-10, Ym1, Fizz-1, MRC1, IL-1Rn and CCL17. The same effect was observed with macrophages exposed to SAA in peritoneal cavity. SAA also increases arginase 1 activity and enhances macrophage efferocytosis of apoptotic neutrophils in mouse macrophages. The induction of M2 markers requires MyD88 and the activation of multiple signaling pathways, but is independent of Stat6. SAA induces IRF4 expression and increases its DNA-binding activity. Silencing IRF4 by siRNA abrogates SAA-induced expression of the M2 markers. These results suggest a potential role for SAA to alter macrophage phenotype and modulate macrophage functions through a MyD88-dependent mechanism that involves IRF4-mediated transcription.
Objectives:The aim of the current study was to differentiate between neural activity that represents neural anomalies that are responsible for persistent developmental stuttering (PDS) from the activity that is a result of compensating for stuttering. This was done by investigating alterations to the intrinsic functional architecture of speech-language processes of patients with PDS before and after a short-term intervention. Methods:The resting-state functional connectivity (RSFC) and cortical thickness were examined before and after the intervention. The structural data were used to validate the functional results. Fifteen stuttering patients who received intervention (PDSϩ), 13 stuttering patients who did not receive intervention (PDSϪ), and 13 fluent controls participated.Results: Before the intervention, both groups of PDS patients showed significant RSFC and cortical thickness reductions in the left pars-opercularis (PO) and RSFC increases in the cerebellum, as compared to fluent controls. The intervention was effective in reducing stuttering in PDSϩ patients and lowering their RSFC in the cerebellum to the level of fluent controls. The intervention effect was specific to the PDSϩ group (it was not evident in the PDSϪ group). The intervention did not change RSFC and cortical thickness in the left PO, which remained at its preintervention level. Conclusions:The results suggest that the left PO is a locus where the intrinsic functional architecture of speech-language processes is altered in PDS patients, suggesting an etiologic role of this region in PDS. The cerebellum showed intervention-induced neural reorganization, suggesting a compensatory response when stuttering occurs. Neurology ® 2012;79:625-632 GLOSSARY AFNI ϭ Analysis of Functional NeuroImages; BA ϭ Brodmann area; EPI ϭ echoplanar image; IC ϭ independent component; ICA ϭ independent component analysis; IFC ϭ inferior frontal cortex; MFG ϭ middle frontal gyrus; OASES ϭ Overall Assessment of the Speaker's Experience of Stuttering; PDS ϭ persistent developmental stuttering; PDS؊ ϭ stuttering patients who did not receive intervention; PDS؉ ϭ stuttering patients who received intervention; PO ϭ pars-opercularis; ROI ϭ region of interest; RSFC ϭ resting-state functional connectivity; SMA ϭ supplementary motor area; SSI-3 ϭ Stuttering Severity Instrument version III; TE ϭ echo time; TR ϭ repetition time.
Background-Previous studies have suggested that systematic ablation of ganglionated plexi (GP) could increase the shortterm success rate of radiofrequency ablation for atrial fibrillation, but the long-term efficacy of this approach is not fully established. Methods and Results-Twenty-four mongrel dogs were divided into 3 groups: epicardial GP ablation group 1 (n=8), epicardial GP ablation group 2 (n=8), and a sham operation group (n=8). In the 2 epicardial GP ablation groups, the 4 major GP and the ligament of Marshall were systematically ablated. The effective refractory period and inducibility of tachyarrhythmias were measured before and immediately after GP ablation in epicardial GP ablation group 1 and 8 weeks later in the other 2 groups. Tyrosine hydroxylase and choline acetyltransferase expressions were also determined immunohistochemically 8 weeks later in the latter groups. Compared with epicardial GP ablation group 1 and the sham operation group, epicardial GP ablation group 2 had the shortest atrial and ventricular effective refractory period and the highest inducibility of atrial tachyarrhythmias. The inducibility of ventricular tachyarrhythmias among the 3 groups was comparable. The density of tyrosine hydroxylase-and choline acetyltransferase-positive nerves in the atrium was the highest in epicardial GP group 2, whereas there were no significant intergroup differences in the densities of these 2 types of nerves in the ventricle. Conclusions-After 8 weeks of healing, epicardial GP ablation without additional atrial ablation was potentially proarrhythmic, which may be attributable to decreased atrial effective refractory period and hyper-reinnervation involving both sympathetic and parasympathetic nerves. Methods Animal PreparationAll animal studies were reviewed and approved by the Institutional Animal Care and Use Committee at our institution. Twenty-four adult mongrel dogs (18-25 kg) were divided into 3 groups: epicardial GP ablation group 1 (n=8), epicardial GP ablation group 2 (n=8), and a sham operation group (n=8). All dogs were anesthetized with 5% sodium pentobarbital (2-3 mL/kg) given intravenously, followed by an additional dose of 1 mL/kg at the end of each hour. A tracheal cannula was inserted, and intermittent positive pressure ventilation with room air was delivered by a respirator. A 6-lead frontal ECG was recorded continuously during the procedure (filter, 0.05-30 Hz). After left thoracotomy at the fourth intercostal space, the heart was exposed in a pericardial cradle. GP AblationIn the 2 epicardial GP ablation groups, the LOM and the fat pads that contain the superior left GP and inferior left GP were exposed by left thoracotomy. After the superior left GP, inferior left GP, and LOM were ablated, the fat pads that contain the anterior right GP and inferior right GP were exposed by lifting up the pericardium, and the anterior right GP and inferior right GP were ablated sequentially through the left incision. The GP was localized by applying high-frequency stimulation (HFS; 20 Hz; ...
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