Palmitate inhibits arthritis by inducing t-bet and gata-3 mRNA degradation in iNKT cells via IRE1α-dependent decay.

Long chain fatty acids (LCFAs) exert pro-inflammatory effects in vivo. However, little is known regarding the effect of LCFAs on invariant (i) NKT cell functions. Here, we report an inhibitory effect of saturated LCFAs on transcription factors in iNKT cells. Among the saturated LCFAs, palmitic acid (PA) specifically inhibited IL-4 and IFN-γ production and reduced gata-3 and t-bet transcript levels in iNKT cells during TCR-mediated activation. In iNKT cells, PA was localized and induced dilation in the endoplasmic reticulum and increased the mRNA levels of downstream molecules of IRE1α RNase. Moreover, PA increased the degradation rates of gata-3 and t-bet mRNA, which was restored by IRE1α inhibition or transfection with mutant gata-3 or t-bet, indicating that gata-3 and t-bet are cleaved via regulated IRE1α-dependent decay (RIDD). A PA-rich diet and PA injection suppressed IL-4 and IFN-γ production by iNKT cells in C57BL/6, but not Jα18 knockout mice, which was restored by injection of STF083010, an IRE1α-specific inhibitor. Furthermore, a PA-rich diet and PA injection attenuated arthritis in an iNKT cell-dependent manner. Taken together, our experiments demonstrate that a saturated LCFA induced RIDD-mediated t-bet and gata-3 mRNA degradation in iNKT cells, thereby suppressing arthritis.

Expression of c-MET in Invasive Meningioma.

BACKGROUND: Meningiomas show high recurrence rates even after curative tumor removal. The invasiveness of meningiomas may contribute to their high recurrence rates. Recently, c-MET and hepatocyte growth factor (HGF) have been reported to be involved in cancer invasion. METHODS: We examined the immunohistochemical expression of c-MET and HGF in 100 cases of patients with meningiomas who have undergone complete tumor removal. RESULTS: c-MET(-High) and HGFHigh were found in 17% and 13% of meningiomas, respectively. Brain invasion was observed in 17.6% of c-MET(-High) meningiomas, but in only 2.4% of c-MET(-Low) meningiomas (p=.033). Bone/soft tissue invasion was observed in 23.5% of c-MET(-High) meningiomas and in 9.6% of c-MET(-Low) meningiomas (p=.119). HGF(-High) did not show statistical association with brain invasion or bone/soft tissue invasion. c-MET(-High) demonstrated shorter recurrence-free survival (RFS, 93.5±8.2 months vs 96.1±1.9 months); however, this difference was not statistically significant (p=.139). There was no association of HGF(-High) with RFS. CONCLUSIONS: This study demonstrates that c- MET(-High) is associated with brain invasion of meningiomas, and that c-MET expression may be a useful predictive marker for meningioma recurrence. Patients with invasive meningiomas with high expressions of c-MET may be good candidates for targeted therapy using c-MET inhibitors.

Tumor Growth Suppression and Enhanced Radioresponse by an Exogenous Epidermal Growth Factor in Mouse Xenograft Models with A431 Cells.

PURPOSE: The purpose of this study was to evaluate whether an exogenous epidermal growth factor (EGF) could induce anti-tumor and radiosensitizing effects in vivo. MATERIALS AND METHODS: BALB/c-nu mice that were inoculated with A431 (human squamous cell carcinoma) cells in the right hind legs were divided into five groups: I (no treatment), II (EGF for 6 days), III (EGF for 20 days), IV (radiotherapy [RT]), and V (RT plus concomitant EGF). EGF was administered intraperitoneally (5 mg/kg) once a day and the RT dose was 30 Gy in six fractions. Hematoxylin and eosin (H&E) stained sections of tumor, liver, lung, and kidney tissues were investigated. Additionally, tumors were subjected to immunohistochemistry staining with caspase-3. RESULTS: EGF for 6 days decreased tumor volume, but it approached the level of the control group at the end of follow-up (p=0.550). The duration of tumor shrinkage was prolonged in group V while the slope of tumor re-growth phase was steeper in group IV (p=0.034). EGF for 20 days decreased tumor volume until the end of the observation period (p < 0.001). Immunohistochemistry revealed that mice in group V showed stronger intensity than those in group IV. There were no abnormal histological findings upon H&E staining of the normal organs. CONCLUSION: EGF-induced anti-tumor effect was ascertained in the xenograft mouse models with A431 cells. Concomitant use of EGF has the potential role as a radiosensitizer in the design of fractionated irradiation.

Pulmonary subsolid nodules: what radiologists need to know about the imaging features and management strategy.

Pulmonary subsolid nodules (SSNs) refer to pulmonary nodules with pure ground-glass nodules and part-solid ground-glass nodules. SSNs are frequently encountered in the clinical setting, such as screening chest computed tomography (CT). The main concern regarding pulmonary SSNs, particularly when they are persistent, has been lung adenocarcinoma and its precursors. The CT manifestations of SSNs help radiologists and clinicians manage these lesions. However, the management plan for SSNs has not previously been standardized. Recently, the Fleischner Society published recommendations for the management of incidentally detected SSNs. The guidelines reflect the new lung adenocarcinoma classification system proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) and include six specific recommendations according to the nodule size, solid portion and multiplicity. This review aims to increase the understanding of SSNs and the imaging features of SSNs according to their histology, natural course, possible radiologic interventions, such as biopsy, localization prior to surgery, and current management.

Clinical outcomes of patients with microsatellite-unstable colorectal carcinomas depend on L1 methylation level.

BACKGROUND: The prognostic significance of microsatellite instability (MSI) in colorectal cancers (CRCs) has been addressed in many studies since the initial description of better survival rates in MSI-positive (MSI+) tumors than in MSI-negative (MSI-) tumors. Recent studies have demonstrated that a higher degree of hypomethylation of long interspersed nuclear element-1 (L1) is related to poor prognosis of CRCs and that a wide variation of L1 methylation levels exist within MSI+ CRCs. Our aim was to identify whether L1 and Alu methylation status could predict clinical outcomes within MSI+ CRCs. METHODS: We analyzed 207 MSI+ CRCs for their methylation levels in L1 and Alu repetitive DNA elements using pyrosequencing and correlated them with clinicopathological information including survival data. RESULTS: Univariate survival analysis showed that low Alu methylation status (<18.60%) and low L1 methylation status (<53.00%) were significantly associated with shorter overall survival time (log-rank test, P = 0.009 and P < 0.001, respectively). Multivariate analysis using nine parameters (Alu methylation status, L1 methylation status, patient's age, disease stage [tumor, node, metastasis staging system], differentiation, Crohn-like lymphoid reaction, KRAS/BRAF mutation status, CpG island methylator phenotype [CIMP] status, and peritumoral lymphocytic infiltration), which were significantly prognostic in MSI+ CRCs, revealed that low L1 methylation status was an independent prognostic factor of MSI+ CRCs (P = 0.009), whereas low Alu methylation status was not. CONCLUSIONS: Clinical outcomes of MSI+ CRCs depend on L1 methylation status, suggesting that lower L1 methylation status serves as a significant prognostic parameter of adverse prognosis in MSI+ CRCs.

Differential clinicopathological features in microsatellite instability-positive colorectal cancers depending on CIMP status.

Microsatellite instability-positive (MSI+) colorectal cancers (CRCs) are divided into CpG island methylator phenotype-positive (CIMP+) and CpG island methylator phenotype-negative (CIMP-) tumors. The repertoire of inactivated genes in CIMP+/MSI+ CRCs overlaps with but is likely to differ from that of CIMP-/MSI+ CRCs. Because epigenotypic differences are likely to be manifested as phenotypic differences, CIMP+/MSI+ CRCs are expected to differ from CIMP-/MSI+ CRCs in some clinicopathological features. This study aimed to characterize both common and different features between the two subtypes. A total of 72 MSI+ CRCs were analyzed for their methylation status in eight CIMP panel markers using MethyLight assay. CIMP+/MSI+ and CIMP-/MSI+ CRCs were compared regarding clinicopathologic features and mutation in KRAS/BRAF. An independent set of MSI+ CRCs (n = 97) was analyzed for their relationship of CIMP+ status with clinical outcome. Eighteen cases (25%) were CIMP+, and this CIMP+ subtype was highly correlated with older age (P < 0.001). Polypoid gross appearance without ulceration was observed only in CIMP-/MSI+ CRCs (18.5%, P = 0.057). CIMP+/MSI+ CRCs were closely associated with poor differentiation, medullary appearance, signet ring cell appearance, and acinar-form appearance, whereas the CIMP-/MSI+ subtype was closely associated with intraglandular eosinophilic mucin and stratified nuclei (all P values <0.05). Patients with CIMP+/MSI+ CRCs showed worse overall survival than patients with CIMP-/MSI+ CRCs. Our results demonstrate heterogeneity in the clinicopathological features of MSI+ CRCs depending on CIMP status. The observation that CIMP+ and CIMP- subtypes showed different clinical behaviors may provide a clue for establishing subtype-specific therapeutic strategies for these two subtypes.