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Collagen triple helix repeat-containing 1 (CTHRC1) is known to be aberrantly upregulated in most human solid tumors, although the functional roles of CTHRC1 in colorectal cancer remain unclear. In this study, we investigated the occurrence of CTHRC1 upregulation and its role in vivo and in vitro. The expression profile and clinical importance of CTHRC1 were examined by reverse transcription-polymerase chain reaction and immunohistochemical analyses in normal and tumor patient samples. CTHRC1 was detectable in normal tissues, but also was highly expressed in tumor specimens. CTHRC1 upregulation was significantly associated with demethylation of the CTHRC1 promoter in colon cancer cell lines and tumor tissues. Clinicopathologic analyses showed that nodal status and expression of CTHRC1 (95% CI 0.999–3.984, p=0.05) were significant prognostic factors for disease-free survival. Promoter CpG methylation and hypermethylation status were measured by bisulfite sequencing and pyrosequencing analysis. Furthermore, we showed that overexpression of CTHRC1 in the SW480 and HT-29 cell lines increased invasiveness, an effect mediated by extracellular signal-regulated kinase (ERK)-dependent upregulation of matrix metalloproteinase 9 (MMP9). Consistent with this, we found that knockdown of CTHRC1 attenuated ERK activation and cancer cell invasivity. These results demonstrate that CTHRC1 expression is elevated in human colon cancer cell lines and clinical specimens, and promotes cancer cell invasivity through ERK-dependent induction of MMP9 expression. Our results further suggest that high levels of CTHRC1 expression are associated with poor clinical outcomes.

e Brucella abortus is an intracellular pathogen that uses a crafty strategy to invade and proliferate within host cells, but the distinct signaling pathways associated with phagocytic mechanisms of B. abortus remain unclear. The present study was performed to test the hypothesis that Toll-like receptor 4 (TLR4)-linked signaling interacting with Janus kinase 2 (JAK2) plays an essential role in B. abortus phagocytosis by macrophages. The effects of TLR4-JAK2 signaling on B. abortus phagocytosis in murine macrophage RAW 264.7 cells were observed through an infection assay and confocal microscopy. We determined that the uptake of B. abortus was negatively affected by the dysfunction of TLR4 and JAK2. F-actin polymerization detected by flow cytometry and F-actin assay was amplified for B. abortus entry, whereas that event was attenuated by the disruption of TLR4 and JAK2. Importantly, JAK2 phosphorylation and actin skeleton reorganization were suppressed immediately after B. abortus infection in bone marrow-derived macrophages (BMDMs) from TLR4 ؊/؊ mice, showing the cooperation of JAK2 with TLR4. Furthermore, small GTPase Cdc42 participated in the intermediate pathway of TLR4-JAK2 signaling on B. abortus phagocytosis. Consequently, TLR4-associated JAK2 activation in the early cellular signaling events plays a pivotal role in B. abortus-induced phagocytic processes in macrophages, implying the pathogenic significance of JAK2-mediated entry. Here, we elucidate that this specific phagocytic mechanism of B. abortus might provide achievable strategies for inhibiting B. abortus invasion.

BACKGROUND:Pulmonary vein isolation (PVI) is effective for maintenance of sinus rhythm in 50% to 75% of patients with paroxysmal atrial fibrillation, and it is not uncommon for patients to require additional ablation after PVI. We prospectively evaluated the relative effectiveness of 2 post-PVI ablation strategies in paroxysmal atrial fibrillation. METHODS AND RESULTS:A total of 500 patients (mean age, 55.7±11.0 years; 74.6% male) were randomly assigned to undergo ablation by 2 different strategies after PVI: (1) elimination of non-PV triggers (group A, n=250) or (2) stepwise substrate modification including complex fractionated atrial electrogram or linear ablation until noninducibility of atrial tachyarrhythmia was achieved (group B, n=250). During a median follow-up of 26.0 months, 75 (32.2%) patients experienced at least 1 episode of recurrent atrial tachyarrhythmia after the single procedure in group A compared with 105 (43.8%) patients in group B (P value in log-rank test of Kaplan-Meier analysis: 0.012). Competing risk analysis showed that the cumulative incidence of atrial tachycardia was significantly higher in group B compared with group A (P=0.007). With the exception of total ablation time, there were no significant differences in fluoroscopic time or procedure-related complications between the 2 groups.CONCLUSIONS: Elimination of triggers as an end point of ablation in patients with paroxysmal atrial fibrillation decreased long-term recurrence of atrial tachyarrhythmia compared with a noninducibility approach achieved by additional empirical ablation. The post-PVI trigger test is thus a better end point of ablation for paroxysmal atrial fibrillation.