Shui-Yi Tung

Magnifying colonoscopy in differentiating neoplastic from nonneoplastic colorectal lesions

OBJECTIVE:Because the medical management of persons with adenomatous colorectal polyps differs from that of those with hyperplastic polyps, accuracy of diagnosis is essential. This study reports our experience using a magnifying colonoscope combined with indigocarmine dye to diagnose colorectal polyps, emphasizing its ability to differentiate neoplastic from nonneoplastic lesions.METHODS:The materials consisted of 175 polyps. A 0.2% indigocarmine solution was sprayed, and the colonoscope zoom apparatus performed a magnified observation after an ordinary colonoscopy identified the lesions. The pit patterns were classified into six categories: I, II, IIIL, IIIs, IV, and V according to Kudos modified classification.RESULTS:The percentages of neoplastic changes in the lesions with pit pattern I, II, IIIL, IIIs, IV, and V were 0, 12.2, 69.7, 80, 84.4, and 100%, respectively. The diagnostic sensitivity of neoplastic lesions was 93.8% and specificity was 64.6% when types I and II represented the pit pattern of nonneoplastic lesions and types IIIL, IIIs, IV, and V represented neoplastic lesions. The overall diagnostic accuracy in differentiating neoplastic from nonneoplastic lesions was 80.1%. The diagnostic accuracy is not influenced by the size and shape of the lesions. The six neoplastic lesions that were misjudged to be nonneoplastic were histologically adenoma with only mild atypia.CONCLUSIONS:The pit pattern analysis of colorectal lesions by magnifying colonoscopy is a useful and objective tool for differentiating neoplastic from nonneoplastic lesions of the large bowel. In its current state of development, however, this technique is not a substitute for histology.

Resistin-induced stromal cell-derived factor-1 expression through Toll-like receptor 4 and activation of p38 MAPK/ NFκB signaling pathway in gastric cancer cells

BackgroundStromal cell-derived factor-1 (SDF-1) (CXC chemokine ligand-12)/CXC chemokine receptor 4 (CXCR4) is involved in the carcinogenesis of human gastric cancer, where it stimulates angiogenesis and favors metastasis of tumor cells to distant organs. In addition, resistin is suggested to be an important link between obesity and the development of gastric cancer. Resistin has identified as an important player in inflammatory responses, and emerged as a mediator in inflammation-associated cancer. A limited number of studies have investigated the association of resistin and SDF-1 with gastric cancer. Herein, we investigated the molecular mechanisms by which resistin influences the expression of SDF-1 in gastric carcinoma cells.ResultsHuman gastric cancer cell lines were exposed to doses of resistin; SDF-1 expression and secretion levels were then determined. Real-time polymerase chain reaction and western blotting analyses were performed to clarify molecular changes. Inhibition of Toll-like receptor 4 (TLR4) by a competitive antagonist inhibited resistin-induced SDF-1 expression. Pharmacological inhibitors and small interfering RNA (siRNA) demonstrated that activation of the p38 mitogen-activated protein kinase (MAPK) pathway is critical for resistin-induced SDF-1 expression mediated by TLR4. The promoter activity and transcription factor enzyme-linked immunosorbent assay revealed that resistin induced expression of SDF-1 mediated by NF-κB in gastric cancer cells. Inhibition of p38 MARK activation blocked the SDF-1-induced expression and the SDF-1 promoter activity in the cancer gastric cells. Chromatin immunoprecipitation assay revealed that inhibition of p38 MARK activation also blocked the resistin-increased NF-κB-DNA-binding activity.ConclusionsResistin-induced SDF-1 upregulation by activation of TLR4, p38 MARK and NF-κB may explain a new role of resistin in the link of obesity and gastric cancer.

Routine blood tests to predict liver fibrosis in chronic hepatitis C.

AIM To verify the usefulness of FibroQ for predicting fibrosis in patients with chronic hepatitis C, compared with other noninvasive tests. METHODS This retrospective cohort study included 237 consecutive patients with chronic hepatitis C who had undergone percutaneous liver biopsy before treatment. FibroQ, aspartate aminotransferase (AST)/alanine aminotransferase ratio (AAR), AST to platelet ratio index, cirrhosis discriminant score, age-platelet index (API), Pohl score, FIB-4 index, and Loks model were calculated and compared. RESULTS FibroQ, FIB-4, AAR, API and Loks model results increased significantly as fibrosis advanced (analysis of variance test: P < 0.001). FibroQ trended to be superior in predicting significant fibrosis score in chronic hepatitis C compared with other noninvasive tests. CONCLUSION FibroQ is a simple and useful test for predicting significant fibrosis in patients with chronic hepatitis C.

Hericium erinaceus mycelium and its isolated erinacine A protection from MPTP-induced neurotoxicity through the ER stress, triggering an apoptosis cascade

BackgroundHericium erinaceus is an edible mushroom; its various pharmacological effects which have been investigated. This study aimed to demonstrate whether efficacy of oral administration of H. erinaceus mycelium (HEM) and its isolated diterpenoid derivative, erinacine A, can act as an anti-neuroinflammatory agent to bring about neuroprotection using an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson’s disease, which results in motor disturbances, in addition to elucidating the mechanisms involved.MethodsMice were treated with and without HEM or erinacine A, after MPTP injection for brain injuries by the degeneration of dopaminergic nigrostriatal neurons. The efficacy of oral administration of HEM improved MPTP-induced loss of tyrosine hydroxylase positive neurons and brain impairment in the substantia nigra pars compacta as measured by brain histological examination.ResultsTreatment with HEM reduced MPTP-induced dopaminergic cell loss, apoptotic cell death induced by oxidative stress, as well as the level of glutathione, nitrotyrosine and 4-hydroxy-2-nonenal (4-HNE). Furthermore, HEM reversed MPTP-associated motor deficits, as revealed by the analysis of rotarod assessment. Our results demonstrated that erinacine A decreases the impairment of MPP-induced neuronal cell cytotoxicity and apoptosis, which were accompanied by ER stress-sustained activation of the IRE1α/TRAF2, JNK1/2 and p38 MAPK pathways, the expression of C/EBP homologous protein (CHOP), IKB-β and NF-κB, as well as Fas and Bax.ConclusionThese physiological and brain histological changes provide HEM neuron-protective insights into the progression of Parkinson’s disease, and this protective effect seems to exist both in vivo and in vitro.

Risk factors for colorectal adenomas among immediate family members of patients with colorectal cancer in Taiwan: a case-control study

OBJECTIVES:The incidence of colorectal cancer or adenoma among first-degree relatives of patients with colorectal cancer is significantly high. However, a well defined screening and surveillance consensus has not been developed for these families in Taiwan. We conducted this study to evaluate the colorectal adenoma prevalence pattern in screened immediate family members in Taiwan, and to derive implications for future screening programs.METHODS:A total of 234 immediate family members (aged 51.6 ± 21.5 yr) of 186 patients with colorectal cancer were offered a colonoscopy. Each relative examined was then paired with two control subjects for age, sex, and symptoms. The prevalence of colorectal adenomas was then compared using multiple logistic regression analysis.RESULTS:The estimated risk of developing adenomas among immediate family members of patients with colorectal cancer was significantly increased (OR = 2.33; 95% CI, 1.43–3.78; p < 0.001). This trend was more striking for men (OR = 2.46; 95% CI, 1.40–4.31; p= 0.001). Immediate family members were at an increased risk for high-risk adenomas (≥1.0 cm, with a villous component, and/or with severe dysplasia) (OR = 4.5; 95% CI, 1.91–10.60; p= 0.002), and developed adenomas at an earlier age than did controls. Individuals with index cancer relatives diagnosed at <50 yr of age or male relatives posed a higher risk of developing colorectal adenomas.CONCLUSIONS:The prevalence of colorectal adenoma in persons with a colorectal cancer family history in Taiwan is similar to that reported in Western countries. This high-risk population should be offered a screening colonoscopy beginning at 40 yr of age.

Endoscopic Treatment of Colorectal Polyps and Early Cancer

To analyze the efficacy and outcome of colonoscopic resection for colorectal neoplastic lesions, we retrospectively reviewed 338 colorectal lesions from 232 patients regarding the clinical profiles, colonoscopic findings, histological findings, complications, and outcome. Morphologically, these lesions were classified into three categories: pedunculated (n = 140), sessile (n = 176); and flat (n = 22). Histological findings of lesions included adenoma (n = 248), carcinoma in situ (n = 17), submucosal carcinoma (n = 2), hyperplastic polyp (n = 57), and inflammatory polyp (n = 14). Neoplastic lesions are generally larger than nonneoplastic lesions (χ2 test, P < 0.05). The incidence of carcinoma was 5.6% of 338 resected lesions. The rate of cancer or high-grade dysplasia in flat polyps was greater than in pedunculated and sessile polyps (13.6 vs 4.54 vs 5.71%; P < 0.05). There were no perforations or deaths after colonoscopic treatment, and only mild bleeding occured in two patients. To date, 19 patients with early colorectal cancer were treated successfully by endoscopy with no recurrence or metastasis. To reduce the incidence and mortality of colorectal cancer, colonoscopic resection is a simple and safe procedure for removing neoplastic lesions. Detailed histological examinations are essential to decide the indications of surgery.

Increased Abundance of Clostridium and Fusobacterium in Gastric Microbiota of Patients with Gastric Cancer in Taiwan

Helicobacter pylori is recognised as a main risk factor for gastric cancer. However, approximately half of the patients with gastritis are negative for H. pylori infection, and the abundance of H. pylori decreases in patients with cancer. In the current study, we profiled gastric epithelium-associated bacterial species in patients with gastritis, intestinal metaplasia, and gastric cancer to identify additional potential pathogenic bacteria. The overall composition of the microbiota was similar between the patients with gastritis and those with intestinal metaplasia. H. pylori was present in half of the non-cancer group, and the dominant bacterial species in the H. pylori-negative patients were Burkholderia, Enterobacter, and Leclercia. The abundance of those bacteria was similar between the cancer and non-cancer groups, whereas the frequency and abundance of H. pylori were significantly lower in the cancer group. Instead, Clostridium, Fusobacterium, and Lactobacillus species were frequently abundant in patients with gastric cancer, demonstrating a gastric cancer-specific bacterial signature. A receiver operating characteristic curve analysis showed that Clostridium colicanis and Fusobacterium nucleatum exhibited a diagnostic ability for gastric cancer. Our findings indicate that the gastric microenvironment is frequently colonised by Clostridium and Fusobacterium in patients with gastric cancer.

The Association of CXC Receptor 4 Mediated Signaling Pathway with Oxaliplatin-Resistant Human Colorectal Cancer Cells.

The stromal cell–derived factor-1 (SDF-1)/CXC receptor 4 (CXCR4) axis plays an important role in tumor angiogenesis and invasiveness in colorectal cancer (CRC) progression. In addition, metastatic CRC remains one of the most difficult human malignancies to treat because of its chemoresistant behavior. However, the mechanism by which correlation occurs between CXCR4 and the clinical response of CRC to chemotherapy remains unknown. We generated chemoresistant cells with increasing doses of oxaliplatin (OXA) and 5-Fluorouracil (5FU) to develop resistance at a clinical dose. We found that the putative markers did not change in the parental cells, but HCT-116/OxR and HCT-116/5-FUR were more aggressive and had higher tumor growth (demonstrated by wound healing, chemotaxis assay, and a nude mice xenograft model) with the use of oxaliplatin. Apoptosis induced by oxaliplatin treatment was significantly decreased in HCT-116/OxR compared to the parental cells. Moreover, HCT-116/OxR cells displayed increased levels of p-gp, p-Akt p-ERK, p-IKBβ, CXCR4, and Bcl-2, but they also significantly inhibited the apoptotic pathways when compared to the parental strain. We evaluated the molecular mechanism governing the signaling pathway associated with anti-apoptosis activity and the aggressive status of chemoresistant cells. Experiments involving specific inhibitors demonstrated that the activation of the pathways associated with CXCR4, ERK1/2 mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)/Akt is critical to the functioning of the HCT-116/OxR and HCT-116/5-FUR characteristics of chemosensitivity. These findings elucidate the mechanism of CXCR4/PI3K/Akt downstream signaling and provide strategies to inhibit CXCR4 mediated signaling pathway in order to overcome CRC’s resistance to chemotherapy.

CIL-102-Induced Cell Cycle Arrest and Apoptosis in Colorectal Cancer Cells via Upregulation of p21 and GADD45

CIL-102 (1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone) is a well-known, major active agent of the alkaloid derivative of Camptotheca acuminata with valuable biological properties, including anti-tumorigenic activity. In this study, we investigated the molecular mechanisms by which CIL-102 mediated the induction of cell death, and we performed cell cycle G2/M arrest to clarify molecular changes in colorectal cancer cells (CRC). Treatment of DLD-1 cells with CIL-102 resulted in triggering the extrinsic apoptosis pathway through the activation of Fas-L, caspase-8 and the induction of Bid cleavage and cytochrome c release in a time-dependent manner. In addition, CIL-102 mediated apoptosis and G2/M arrest by phosphorylation of the Jun N-terminus kinase (JNK1/2) signaling pathway. This resulted in the expression of NFκB p50, p300 and CREB-binding protein (CBP) levels, and in the induction of p21 and GADD45 as well as the decreased association of cdc2/cyclin B. Furthermore, treatment with the JNK1/2 (SP600125), NFκB (PDTI) or the p300/CBP (C646) inhibitors abolished CIL-102-induced cell cycle G2/M arrest and reversed the association of cdc2 with cyclin B. Therefore, we demonstrated that there was an increase in the cellular levels of p21 and GADD45 by CIL-102 reduction in cell viability and cell cycle arrest via the activation of the JNK1/2, NFκB p50, p300 and CBP signaling modules. Collectively, our results demonstrated that CIL-102 induced cell cycle arrest and apoptosis of colon cancer cells by upregulating p21 and GADD45 expression and by activating JNK1/2, NFκB p50 and p300 to provide a new mechanism for CIL-102 treatment.

Interleukin-17 induces CC chemokine receptor 6 expression and cell migration in colorectal cancer cells.

The CC chemokine receptor 6 (CCR6) and its ligand CCL20 are involved in human colorectal cancer (CRC) carcinogenesis and can promote the progression of CRC. In addition, interleukin‐17 (IL‐17), produced by a T cell subset named “Th17,” has been identified as an important player in inflammatory responses, and has emerged as a mediator in inflammation‐associated cancer. However, the relevance of IL‐17 in the development and progression of CRC still remains to be explored. This study aimed to investigate the effect of IL‐17 on the cell migration of CRC cells. Human CRC HCT‐116 cells were used to study the effect of IL‐17 on CCR6 expression and cell migration in CRC cells. IL‐17 treatment induced migration of HCT‐116 cells across the Boyden chamber membrane and increased the expression level of the CCR6. Inhibition of CCR6 by small interfering RNA (siRNA) and neutralizing antibody inhibited IL‐17‐induced cell migration. By using specific inhibitors and short hairpin RNA (shRNA), we demonstrated that the activation of ERK and p38 pathways are critical for IL‐17‐induced CCR6 expression and cell migration. Promoter activity and transcription factor ELISA assays showed that IL‐17 increased NF‐κB‐DNA binding activity in HCT‐116 cells. Inhibition of NF‐κB activation by specific inhibitors and siRNA blocked the IL‐17‐induced CCR6 expression. Our findings support the hypothesis that CCR6 up‐regulation stimulated by IL‐17 may play an active role in CRC cell migration. J. Cell. Physiol. 230: 1430–1437, 2015.