Background Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder with a high prevalence, especially in industrialized countries. Dysbiosis of the intestinal microbiota has been observed in RA patients. For instance, new-onset untreated RA (NORA) is associated with the underrepresentation of the Clostridium cluster XIVa, including Lachnospiraceae, which are major butyrate producers, although the pathological relevance has remained obscure. Follicular regulatory T (T FR ) cells play critical regulatory roles in the pathogenesis of autoimmune diseases, including RA. Reduced number of circulating T FR cells has been associated with the elevation of autoantibodies and disease severity in RA. However, the contribution of commensal microbe-derived butyrate in controlling T FR cell differentiation remains unknown. Methods We examined the contribution of microbe-derived butyrate in controlling autoimmune arthritis using collagen-induced arthritis (CIA) and SKG arthritis models. We phenotyped autoimmune responses in the gut-associated lymphoid tissues (GALT) in the colon and joint-draining lymph nodes in the CIA model. We developed an in vitro CXCR5 + Bcl-6 + Foxp3 + T FR (iT FR ) cell culture system and examined whether butyrate promotes the differentiation of iT FR cells. Findings Microbe-derived butyrate suppressed the development of autoimmune arthritis. The immunization of type II collagen (CII) caused hypertrophy of the GALT in the colon by amplifying the GC reaction prior to the onset of the CIA. Butyrate mitigated these pathological events by promoting T FR cell differentiation. Butyrate directly induced the differentiation of functional T FR cells in vitro by enhancing histone acetylation in T FR cell marker genes. This effect was attributed to histone deacetylase (HDAC) inhibition by butyrate, leading to histone hyperacetylation in the promoter region of the T FR -cell marker genes. The adoptive transfer of the butyrate-treated iT FR cells reduced CII-specific autoantibody production and thus ameliorated the symptoms of arthritis. Interpretation Accordingly, microbiota-derived butyrate serves as an environmental cue to enhance T FR cells, which suppress autoantibody production in the systemic lymphoid tissue, eventually ameliorating RA. Our findings provide mechanistic insights into the link between the gut environment and RA risk. Funding This work was supported by (16gm1010...

Glioblastoma is the most aggressive type of brain tumor and has a poor prognosis. Increased levels of cholesteryl ester and simultaneous expression of acyl‑CoA:cholesterol acyltransferase 1 (ACAT1) in tumor cells indicated that cholesterol esterification is critical to tumor growth. The present study confirmed that human glioblastoma tissues as well as the glioblastoma cell line U251‑MG showed significant expression of ACAT1. ACAT1 expression in U251‑MG cells increased in a cell proliferation‑dependent manner. K604, a selective ACAT1 inhibitor, suppressed the proliferation of U251‑MG cells and downregulated the activation of Akt and extracellular signal‑regulated kinase in proliferating glioblastoma cells. These results suggested that ACAT1 may be a therapeutic target for the treatment of glioblastoma, with K604 as an effective therapeutic agent.

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Carcinoma with rhabdoid features is a rare malignant tumor with a poor prognosis whose molecular mechanism for aggressive behavior is unclear. We describe an undifferentiated pancreatic carcinoma with rhabdoid features that demonstrated extensive invasion and metastasis. Examination of a 63-year-old man with back pain disclosed a retroperitoneal tumor with multiple metastases. Lymph node biopsy revealed an undifferentiated carcinoma of unknown origin. Intensive chemotherapy was ineffective; the patient died 3 months after initial symptoms. Autopsy showed that the tumor displaced the retroperitoneal space: it diffusely invaded and destroyed the pancreas and duodenum. Histology demonstrated tumor cells with eccentric vesicular nuclei, large nucleoli, juxtanuclear eosinophilic inclusions, and poor cell adhesion. Immunohistochemistry showed that tumor cells expressed cytokeratin and vimentin, and electron microscopy confirmed a perinuclear mass of intermediate fibrils and lipid droplets, which indicated an undifferentiated carcinoma with rhabdoid features. Tumor tissue contained hyaluronan; tumor cells strongly expressed CD44, matrix metalloproteinase-9, hypoxia-inducible factor-1α, hyaluronan synthase 2, and acyl-CoA:cholesterol acyltransferase 1 and had a high Ki-67(+) ratio. Since hyaluronan is a ligand for CD44, formation of CD44-hyaluronan complex on the cell surface activates CD44 and this activation may explain why the tumor manifested aggressive invasion and metastasis throughout the clinical course.

The plasma membrane houses a complex mixture of membrane proteins and lipids, and is also the specific target of amphitropic proteins such as poreforming toxins. The activity of all of these proteins is exquisitely regulated