RESUMO
Src family kinases (SFKs), an important group of non-receptor tyrosine kinases, are suggested to be excessively activated during various types of tissue fibrosis. The present study investigated the effect of KF-1607, an orally active and a newly synthesized Src kinase inhibitor (SKI) with proposed low toxicity, in preventing the progression of renal interstitial fibrosis. Unilateral ureteral obstruction (UUO) surgery was performed in 6-week-old male C57BL/6 mice to induce renal interstitial fibrosis. Either KF-1607 (30 mg/kg, oral gavage) or PP2 (2 mg/kg, intraperitoneal injection), a common experimental SKI, was administered to mice for seven days, started one day prior to surgery. UUO injury-induced SFK expression, including Src, Fyn, and Lyn kinase. SFK inhibition by KF-1607 prevented the progression of tubular injury in UUO mice, as indicated by decreases in albuminuria, urinary KIM-1 excretion, and kidney NGAL protein expression. Renal tubulointerstitial fibrosis was attenuated in response to KF-1607, as shown by decreases in α-SMA, collagen I and IV protein expression, along with reduced Masson’s trichrome and collagen-I staining in kidneys. KF-1607 also inhibited inflammation in the UUO kidney, as exhibited by reductions in F4/80 positive-staining and protein expression of p-NFκB and ICAM. Importantly, the observed effects of KF-1607 were similar to those of PP2. A new pan Src kinase inhibitor, KF-1607, is a potential pharmaceutical agent to prevent the progression of renal interstitial fibrosis.
RESUMO
PURPOSE: The 2017 international consensus guidelines (ICG) for intraductal papillary mucinous neoplasm (IPMN) of the pancreas were recently released. Important changes included the addition of worrisome features such as elevated serum CA 19-9 and rapid cyst growth (>5 mm over 2 years). We aimed to clinically validate the 2017 ICG and compare the diagnostic performance between the 2017 and 2012 ICG. METHODS: This was a retrospective cohort study. During January 2000–January 2017, patients who underwent complete surgical resection and had pathologic confirmation of branch-duct or mixed-type IPMN were included. To evaluate diagnostic performance, the areas under the receiver operating curves (AUCs) were evaluated. RESULTS: A total of 448 patients were included. The presence of mural nodule (hazard ratio [HR], 9.12; 95% confidence interval [CI], 4.60–18.09; P = 0.001), main pancreatic duct dilatation (>5 mm) (HR, 5.32; 95% CI, 2.67–10.60; P = 0.001), thickened cystic wall (HR, 3.40; 95% CI, 1.51–7.63; P = 0.003), and elevated CA 19-9 level (>37 unit/mL) (HR, 5.25; 95% CI, 2.05–13.42; P = 0.001) were significantly associated with malignant IPMN. Malignant lesions showed a cyst growth rate >5 mm over 2 years more frequently than benign lesions (60.9% vs. 29.7%, P = 0.012). The AUC was higher for the 2017 ICG than the 2012 ICG (0.784 vs. 0.746). CONCLUSION: The new 2017 ICG for IPMN is clinically valid, with a superior diagnostic performance to the 2012 ICG. The inclusion of elevated serum CA 19-9 level and cyst growth rate to the 2017 ICG is appropriate.