Two naturally derived small molecules disrupt the sineoculis homeobox homolog 1-eyes absent homolog 1 (SIX1-EYA1) interaction to inhibit colorectal cancer cell growth.

BACKGROUND: Emerging evidence indicates that the sineoculis homeobox homolog 1-eyes absent homolog 1 (SIX1-EYA1) transcriptional complex significantly contributes to the pathogenesis of multiple cancers by mediating the expression of genes involved in different biological processes, such as cell-cycle progression and metastasis. However, the roles of the SIX1-EYA1 transcriptional complex and its targets in colorectal cancer (CRC) are still being investigated. This study aimed to investigate the roles of SIX1-EYA1 in the pathogenesis of CRC, to screen inhibitors disrupting the SIX1-EYA1 interaction and to evaluate the efficiency of small molecules in the inhibition of CRC cell growth. METHODS: Real-time quantitative polymerase chain reaction and western blotting were performed to examine gene and protein levels in CRC cells and clinical tissues (collected from CRC patients who underwent surgery in the Department of Integrated Traditional and Western Medicine, West China Hospital of Sichuan University, between 2016 and 2018, n = 24). In vivo immunoprecipitation and in vitro pulldown assays were carried out to determine SIX1-EYA1 interaction. Cell proliferation, cell survival, and cell invasion were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, clonogenic assay, and Boyden chamber assay, respectively. The Amplified Luminescent Proximity Homogeneous Assay Screen (AlphaScreen) method was used to obtain small molecules that specifically disrupted SIX1-EYA1 interaction. CRC cells harboring different levels of SIX1/EYA1 were injected into nude mice to establish tumor xenografts, and small molecules were also injected into mice to evaluate their efficiency to inhibit tumor growth. RESULTS: Both SIX1 and EYA1 were overexpressed in CRC cancerous tissues (for SIX1, 7.47 ±â€Š3.54 vs.1.88 ±â€Š0.35, t = 4.92, P = 0.008; for EYA1, 7.61 ±â€Š2.03 vs. 2.22 ±â€Š0.45, t = 6.73, P = 0.005). The SIX1/EYA1 complex could mediate the expression of two important genes including cyclin A1 (CCNA1) and transforming growth factor beta 1 (TGFB1) by binding to the myocyte enhancer factor 3 consensus. Knockdown of both SIX1 and EYA1 could decrease cell proliferation, cell invasion, tumor growth, and in vivo tumor growth (all P < 0.01). Two small molecules, NSC0191 and NSC0933, were obtained using AlphaScreen and they could significantly inhibit the SIX1-EYA1 interaction with a half-maximal inhibitory concentration (IC50) of 12.60 ±â€Š1.15 µmol/L and 83.43 ±â€Š7.24 µmol/L, respectively. Administration of these two compounds could significantly repress the expression of CCNA1 and TGFB1 and inhibit the growth of CRC cells in vitro and in vivo. CONCLUSIONS: Overexpression of the SIX1/EYA1 complex transactivated the expression of CCNA1 and TGFB1, causing the pathogenesis of CRC. Pharmacological inhibition of the SIX1-EYA1 interaction with NSC0191 and NSC0933 significantly inhibited CRC cell growth by affecting cell-cycle progression and metastasis.

Modified Van Assche magnetic resonance imaging-based score for assessing the clinical status of anal fistulas.

The modified Van Assche magnetic resonance imaging (MRI)-based score is a feasible system to assess the clinical status of anal fistulas in Crohn disease. In this study, we evaluated this score's association with clinical status in patients with anal fistulas (AFs).We included all patients with AF who underwent contrast-enhanced pelvic MRI and surgery between January 2011 and December 2016. The score was evaluated retrospectively preoperatively and 1, 3, and 6 months postoperatively. Univariate and multivariate analyses of the risk factors for AF recurrence were also performed.We retrospectively analyzed data for 104 patients. Twelve (11.5%) patients developed AF recurrence. We classified patients' preoperative clinical status into three grades: 52 (50.0%) grade A, 31 (29.8%) grade B, and 21 (20.2%) grade C. The preoperative MRI-based score was significantly correlated with patients' preoperative clinical status grade (Pearson correlation: 0.547; P < .001). The 3 preoperative clinical status grades showed significant (F = 23.303, P < .001) tendencies for associations with lower respective MRI-based scores. The incidence of AF recurrence decreased with the MRI-based score to 1-month postoperatively, then gradually increased (F = 60.863, P = .000). Long duration of disease, prior interventions, and high MRI-based score were independent risk factors for AF recurrence.The MRI-based score objectively assessed the clinical status and disease activity of patients with AFs, with a high score being associated with severe clinical status and long recovery time.

Effect of lateral internal sphincterotomy in patients undergoing excisional hemorrhoidectomy.

BACKGROUND: Excisional hemorrhoidectomy (EH) is the major surgical option for high-grade symptomatic hemorrhoids, but it has some shortcomings, especially postoperative pain. This study was performed to assess the effect of lateral internal sphincterotomy (LIS) in patients undergoing excisional hemorrhoidectomy. METHODS: A systematic literature search (Medline, Embase, Cochrane Library, Science Citation Index, Science Direct, Springer Link, Ovid Journals, and EBSCO) was performed to identify all eligible articles. Randomized controlled trials (RCTs) published until July 7, 2017 comparing EH combined with LIS (experimental group) with EH only (control group) were eligible for inclusion. The primary outcome of interest was postoperative pain. RESULTS: Ten RCTs involving 1560 patients were identified for inclusion. The pooled analysis revealed that patients undergoing EH and LIS were associated with lower pain score [standardized mean difference (SMD), -0.75; 95% confidence interval (CI), -1.14 to -0.36; z = 3.76; P = .0002] and resting anal pressure [odds ratio (OR), -17.19; 95% CI, -25.66 to -8.72; z = 3.98; P < .0001], and lower incidence of anal stricture (OR, 0.12; 95% CI, 0.03-0.53; z = 2.85; P = .004). However, the differences of urinary retention, bleeding and length of hospital stay were similar between the 2 methods. CONCLUSION: Our meta-analysis suggests that LIS effectively relieves postoperative pain and reduces patient's postoperative analgesic requirements. LIS also reduces the incidence of anal stenosis but increases the incidence of fecal incontinence.