TGF-ß signaling promotes desmoid tumor formation via CSRP2 upregulation.

Desmoid tumors (DTs), also called desmoid-type fibromatoses, are locally aggressive tumors of mesenchymal origin. In the present study, we developed a novel mouse model of DTs by inducing a local mutation in the Ctnnb1 gene, encoding ß-catenin in PDGFRA-positive stromal cells, by subcutaneous injection of 4-hydroxy-tamoxifen. Tumors in this model resembled histologically clinical samples from DT patients and showed strong phosphorylation of nuclear SMAD2. Knockout of SMAD4 in the model significantly suppressed tumor growth. Proteomic analysis revealed that SMAD4 knockout reduced the level of Cysteine-and-Glycine-Rich Protein 2 (CSRP2) in DTs, and treatment of DT-derived cells with a TGF-ß receptor inhibitor reduced CSRP2 RNA levels. Knockdown of CSRP2 in DT cells significantly suppressed their proliferation. These results indicate that the TGF-ß/CSRP2 axis is a potential therapeutic target for DTs downstream of TGF-ß signaling.

Differences in clinical and cost-effectiveness between cefmetazole and flomoxef for the prevention of surgical site infection in elective colorectal surgery: A single-center, retrospective cohort study.

INTRODUCTION: Surgical site infection (SSI) is associated with increased morbidity and mortality rates, postoperative length of stay (pLOS), and medical costs. In colorectal surgery, cefmetazole (CMZ) and flomoxef (FMOX) are predominantly used in Japan, and they have almost the same spectrum of antibiotic activity against SSI pathogens, and an approximately four-fold cost difference (CMZ: ∼4$, FMOX: ∼16$). However, the difference between these antibiotics in SSI prophylaxis in colorectal surgery remains poorly understood. METHODS: We performed a single-center retrospective cohort study to investigate the prophylactic effects of these antibiotics, pLOS, and hospitalization costs. Patients who underwent elective colorectal surgery between April 2016 and March 2020 were considered for this study. RESULTS: Of the 634 patients, 316 (49.8%) were eligible. The SSI rates in the CMZ and FMOX groups were 14.7% and 12.5%, respectively. The incidence of organ/space SSI was approximately two-fold lower in the CMZ group than in the FMOX group (4.4% vs. 9.4%). Multivariable regression analysis revealed that CMZ was not significantly related to SSI, with an adjusted odds ratio of 1.21 (95% confidence interval [CI]: 0.52-2.82) and did not induce a significant difference in pLOS (difference ratio: 0.951 [95% CI: 0.868-1.041]). Hospitalization costs were reduced in the CMZ group (difference ratio, 0.951 [95% CI: 0.907-0.998], p = 0.042). The sensitivity analysis also showed results similar to the above findings. CONCLUSION: Our study showed that CMZ could be a cost-effective antibiotic with similar efficacy for SSI prophylaxis in colorectal surgery, compared with FMOX.

Establishment of a mouse model of troglitazone-induced liver injury and analysis of its hepatotoxic mechanism.

Drug-induced liver injury is a major problem in drug development and clinical drug therapy. Troglitazone (TGZ), a thiazolidinedione antidiabetic drug for the treatment of type II diabetes mellitus, was found to induce rare idiosyncratic severe liver injury in patients, which led to its withdrawal in 2000. However, in normal experimental animals in vivo TGZ has never induced liver injury. To explore TGZ hepatotoxic mechanism, we established a novel mouse model of TGZ-induced liver injury. Administration of BALB/c female mice with a single intraperitoneal TGZ dose (300 mg/kg) significantly elevated alanine aminotransferase and aspartate aminotransferase levels 6 hours after the treatment. The ratio of oxidative stress marker glutathione/disulfide glutathione was significantly decreased. The increased hepatic mRNA levels of inflammation- and oxidative stress-related factors were observed in TGZ-treated mice. Subsequently, hepatic transcriptome profiles of TGZ-exposed liver were compared with those of non-hepatotoxic rosiglitazone. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was activated in TGZ-induced liver injury. The activation of the JAK/STAT pathway promoted phosphorylation of STAT3 in TGZ-treated mice. Consequently, upregulation of STAT3 activation increased mRNA levels of its downstream genes. In conclusion, a single intraperitoneal dose of TGZ exposure could induce liver injury in BALB/c female mice and, by a hepatic transcriptomic analysis, we found that the activation of JAK/STAT pathway might be related to TGZ-induced hepatotoxicity.

Comparative hepatic transcriptome analyses revealed possible pathogenic mechanisms of fasiglifam (TAK-875)-induced acute liver injury in mice.

Fasiglifam (TAK-875), a G protein-coupled receptor 40 (GPR40) agonist, was a drug candidate for type 2 diabetes. However, its development was terminated in phase 3 trials due to liver safety concerns. Although TAK-875 was reported to inhibit hepatobiliary transporters and disturb bile acid disposition, pathogenic mechanisms of TAK-875-induced liver injury are not fully understood. In this study, we sought to identify the mechanisms with a hepatic genome-wide transcriptomic analysis in a murine model. We demonstrated that, among the three GPR40 agonists, TAK-875, AMG-837, and TUG-770, only TAK-875 induced acute liver injury in mice. Transcriptome profiles of TAK-875-exposed liver was compared with those of non-hepatotoxic analogues AMG-837 and TUG-770 as negative controls and those of classical hepatotoxicants concanavalin A and carbon tetrachloride as positive controls. The comparative hepatic transcriptome analyses revealed the enrichment of genes involved in inflammation, endoplasmic reticulum (ER) stress, apoptosis, and hepatic lipid accumulation, suggesting that these events play pathophysiologic roles in the development of TAK-875-induced liver injury. These results were validated by quantitative PCR with significant changes in chemokines, danger signals, ER stress mediators, proapoptotic factors, and hepatic steatosis markers only in TAK-875-exposed liver. Pretreatment of TAK-875-administered mice with an ER stress inhibitor 4-phenylbutyric acid (4-PBA) alleviated the liver injury. Consistent with the in vivo study, pretreatment of HepG2 cells with 4-PBA significantly improved the decrease of cell viability induced by TAK-875. In conclusion, by a comprehensive transcriptomic analysis, we found multiple possible processes that contribute to TAK-875-induced acute liver injury in mice.