ARK5 expression in colorectal cancer and its implications for tumor progression

A novel member of the human AMPK family, ARK5, was recently discovered to be a key molecule in mediating cancer cell migration activity in human pancreas cancer cell line PANC-1, and its activation was found to be induced by Akt-dependent phosphorylation at Ser 600. DNA array analysis with 241 paired cDNAs from 13 different types of tumors and corresponding normal tissues derived from cancer patients revealed ARK5 overexpression in the samples of colorectal cancer. ARK5 expression was measured and an in vitro invasion assay was performed in six human colorectal cancer cell lines, WiDr, HCT-15, DLD-1, SW620, LoVo, and SW480, and since high invasion activity was concordant with higher ARK5 expression, ARK5 expression was examined in relation to tumor progression and metastatic activity in clinical samples. In 56 clinical samples of primary colorectal cancers and their liver metastases, higher ARK5 expression was observed in the samples from more advanced cases, and much higher expression was observed in the liver metastases. In situ hybridization analysis showed ARK5 overexpression in tumor cells. Based on these findings, we propose that ARK5 overexpression is involved in tumor progression of colon cancer clinically.     

The vomeronasal chemosensory system as a route of neuroinvasion by herpes simplex virus

We have investigated the potential of neurotropic microbes to invade the central nervous system (CNS) via the peripheral nervous system. Herpes simplex virus type 1 (HSV-1) strain KH6 and herpes simplex virus type 2 (HSV-2) strain 186 were found to infect chemosensory neurons in the vomeronasal organ (the pheromone detector) following intranasal inoculation of mice. HSV-1 strain KH6 infection was further transmitted to the accessory olfactory bulb (first relay), the medial amygdala (second relay), and the bed nucleus of the stria terminalis and the ventromedial hypothalamus (third relay). HSV-1 strain KH6 also targeted the olfactory and trigeminal systems. HSV-2 strain 186 predominantly attacked the brainstem including the trigeminal system. While both viruses did not induce apoptosis in infected chemosensory neurons, they did in infected brain tissue. These results suggest that neurotropic viruses can invade the brain by infecting vomeronasal chemosensory neurons and that the restrained induction of apoptosis in the infected neurons may facilitate viral transmission to the CNS.     

A novel videoendoscopy system by using autofluorescence and reflectance imaging for diagnosis of esophagogastric cancers

BACKGROUND: Image quality of the prior autofluorescence (AF) imaging systems, including the fiber-optic endoscope, was not feasible for general clinical use. The use of AF image alone resulted in low specificity. The objective of the study was to evaluate the resolution and the sensitivity of the novel videoendoscopy system by using AF and reflectance imaging (AFI) in the diagnosis of early esophagogastric cancers. METHODS: This was a case series study. The setting was a pretreatment examination at a cancer center. Five patients with superficial esophageal cancers (SEC) and 21 patients with 22 early gastric cancers (EGC) were included in the study. The extent of the tumors was diagnosed by white light (WL), AF and chromoendoscopic observations. The main outcome measurement was the diagnostic accuracy of each observation in relation to the histologic mapping as a criterion standard. RESULTS: Two of 5 SECs (40%) were correctly diagnosed in the WL image and all (100%) in the AF image as purple or magenta color in a green background. EGCs in atrophic mucosa were observed as purple or magenta areas in a green background, while diffuse-type EGCs in fundic mucosa were observed as green areas in a purple background. Of the 22 EGCs, diagnostic accuracy of WL, AF, and chromoendoscopic observations were 36%: 95% CI [16%, 56%], 68%: 95% CI [49%, 88%], and 91%: 95% CI [79%, 100%], respectively. AFI could reveal flat or isochromatic extensions that were not detected in the WL images. The limitations of the study were ulcerations or inflammation that caused overdiagnosis in the AF observation. CONCLUSIONS: The resolution of the AFI at present is limited, but the image quality was acceptable. The current system of AFI does not equal to chromoendoscopy in sensitivity but has an advantage over standard WL videoendoscopy.     

Accelerated Loss of Islet β Cells in Sucrose-Fed Goto-Kakizaki Rats, a Genetic Model of Non-Insulin-Dependent Diabetes Mellitus

The Goto-Kakizaki (GK) rat is a spontaneously diabetic animal model of non-insulin-dependent diabetes mellitus, which is characterized by progressive loss of β cells in the pancreatic islets with fibrosis. In the present study, we examined the effects of sucrose feeding on the islet pathology in this model. Six-week-old GK rats were fed with 30% sucrose for 6 weeks to induce severe hyperglycemia, and their condition was compared with that of nontreated rats. Age-matched normal Wistar rats were also given sucrose for the same periods and used for comparison. The sucrose-treated GK rats showed elevated blood glucose levels on oral glucose tolerance tests at 60 minutes and 120 minutes, representing 123% and 127% of values in untreated GK rats, respectively. At the end of the study, the mean β-cell volume density in GK rats was 50% less than that in untreated Wistar rats. Sucrose feeding further reduced the volume densities of β cells to only 50% of the levels of age-matched GK rats. Apoptotic cells were found in islet β cells only in GK rats fed sucrose (mean 0.067%). There appeared to be more islets that immunohistochemically stained strongly positive with 8-hydroxy-deoxyguanosine as a marker of oxidative damage of DNA in GK rats fed sucrose compared with those not given sucrose. GK rats not fed sucrose showed significantly lower proliferative activity of β cells measured by 5-bromo-2′-deoxyuridine uptake and intensified expression of Bcl-2 immunoreactivities at 6 weeks of age compared with those in age-matched Wistar rats. These two indices were reduced in both GK and Wistar rats with increasing age and were not affected by sucrose feeding in either group. The present study thus indicated that sucrose feeding promoted the apoptosis of β cells in GK rats through increased oxidative stress without altering their proliferative activity.     

Basal insulin requirement in patients with type 1 diabetes depends on the age and body mass index

Aims/IntroductionTo investigate the basal insulin requirement in patients with type 1 diabetes who are on multiple daily injections (MDI) and to assess the patient characteristics that affect the percent of total daily basal insulin dose to the total daily insulin dose (%TBD/TDD).Materials and MethodsThe subjects of this study were 67 inpatients with type 1 diabetes who were served diabetic meals of 25–30 kcal/kg standard body weight during several weeks of hospitalization. The basal insulin requirement was adjusted to keep the blood glucose level from bedtime to before breakfast within a 30 mg/dL difference. The bolus insulin dose before the meal was adjusted to keep the blood glucose level below 140 and 200 mg/dL before and 2 h after each meal, respectively. The total daily insulin dose (TDD), the percent of total daily basal insulin dose (TBD) to TDD (%TBD/TDD), and clinical characteristics were collected.ResultsThe median (Q1, Q3) of TDD was 33.0 (26.0, 49.0) units, and the %TBD/TDD was 24.1 ± 9.8%. The %TBD/TDD was positively correlated with the body mass index (BMI) and negatively correlated with the age at the onset and at the examination according to a univariate analysis. However, the %TBD/TDD was dependent on the BMI (β = 0.340, P = 0.004) and the age at examination (β = −0.288, P = 0.012) according to the multiple regression analysis.ConclusionsThe average %TBD/TDD in patients with type 1 diabetes on MDI was approximately 24% under inpatient conditions. The basal insulin requirement was dependent on the BMI and the age at examination.     

Low Prevalence of Helicobacter pylori Infection in Patients with Hamartomatous Fundic Polyps

Helicobacter pylori infection of the gastricmucosal surface was investigated in patients withhamartomatous fundic polyps or hyperplastic polyps andin patients without endoscopic evidence of disease(healthy subjects). Presence of H. pylori infection wasdetermined by culture, histologic examination, and theendoscopic phenol red test. Adherence of H. pylori wasevaluated with scanning electron microscopic examination of antral biopsy specimens. Bothprevalence of H. pylori infection (P < 0.001) and H.pylori adherence (P < 0.05) were less in patientswith hamartomatous fundic polyps than in healthy subjects and patients with hyperplastic polyps.However, the percentages of plasma cells in gastricmucosa that contained IgA and of gastric epithelialcells that expressed Lewis b did not differsignificantly among the three groups. These findings suggestthat defense mechanisms against the attachment of H.pylori other than IgA or Lewis b antigen are present inpatients with hamartomarous fundic polyps.     

Safety and curative ability of endoscopic submucosal dissection for superficial esophageal cancers at least 50 mm in diameter

Background and Aim: Limited data are available regarding the use of endoscopic submucosal dissection (ESD) for superficial esophageal cancers ≥50 mm in diameter. The aim of the present study was to investigate the safety and success of ESD for superficial esophageal cancers ≥50 mm. Methods: A total of 39 patients with superficial esophageal squamous cell carcinoma ≥50 mm were treated with ESD at Osaka Medical Center for Cancer and Cardiovascular Diseases between January 2004 and April 2011, and were analyzed in a retrospective study. Results: En bloc resection was achieved in all patients. One mediastinal emphysema without perforation occurred during the procedure. Stricture developed in 11 of 39 patients, requiring a median of five endoscopic balloon dilatation procedures. Thirty‐three clinical epithelial or lamina propria mucosal cancers were treated by ESD with curative intent, of which invasion into the muscularis mucosa or deeper was detected in seven and lymphovascular involvement in three. The en bloc resection rate was 100% with a tumor‐free margin achieved in 92% of lesions. The curative resection and complication rates during ESD were 70% and 2.5%, respectively. Conclusion: ESD achieved a high en bloc resection rate of 92% with a tumor‐free margin. Curative resection rate of ESD in patients with clinical epithelial or lamina propria mucosal cancers was not low at 70%. However, the risk of stricture must be taken into account when considering the use of ESD in lesions ≥50 mm.     

Acarbose treatments improve arterial stiffness in patients with type 2 diabetes mellitus

Aims/Introduction: Although the improvement of postprandial hyperglycemia by an alpha‐glucosidase inhibitor (α‐GI) has been associated with a risk reduction of cardiovascular events, the relationship between postprandial hyperglycemia and arterial stiffness has not been well understood. We therefore examined whether ameliorating the postprandial state by α‐GI leads to an improvement in arterial stiffness. Materials and Methods: A total of 22 patients with type 2 diabetes mellitus were treated with acarbose. Cardio‐ankle vascular index (CAVI) as the arterial stiffness was measured by using a VaSera CAVI instrument before and 12 months after acarbose treatment. Serum high‐sensitivity C‐reactive protein (hs‐CRP), pentraxin‐3 (PTX3) and matrix metalloproteinase (MMP) ‐2, ‐9 were measured at the same time points. Furthermore, circulating peripheral blood mononuclear cells were examined for the frequencies of CD14 positive cells expressing membrane type‐1 MMP (MT1‐MMP) at the single cell level using flow cytometry. Results: After acarbose treatment, postprandial glucose and glycosylated hemoglobin (HbA_1c) were significantly decreased. Serum levels of hs‐CRP, PTX3, MMP‐2 and MMP‐9 were significantly decreased. CAVI showed a significant reduction, although the changes were not significant in blood pressure and heart rate. MT1‐MMP expression was significantly decreased by acarbose treatment. In multivariate analysis, improvement of blood glucose, decrease of PTX3 levels and MT1‐MMP expression were independent predictors of beneficial change in CAVI. Conclusions: The present study showed that the beneficial effects of acarbose on arterial stiffness are mediated by an improvement of postprandial hyperglycemia and vascular remodeling markers. In conclusion, acarbose treatment might reduce the risk of cardiovascular diseases by altering the arterial stiffness in postprandial hyperglycemic status. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00079.x , 2010)     

Fusobacterium nucleatum confers chemoresistance by modulating autophagy in oesophageal squamous cell carcinoma

Background Fusobacterium nucleatum (F. nucleatum) is a gut microbe implicated in gastrointestinal tumorigenesis. Predicting the chemotherapeutic response is critical to developing personalised therapeutic strategies for oesophageal cancer patients. The present study investigated the relationship between F. nucleatum and chemotherapeutic resistance in oesophageal squamous cell carcinoma (ESCC).Methods We examined the relationship between F. nucleatum and chemotherapy response in 120 ESCC resected specimens and 30 pre-treatment biopsy specimens. In vitro studies using ESCC cell lines and co-culture assays further uncovered the mechanism underlying chemotherapeutic resistance.Results ESCC patients with F. nucleatum infection displayed lesser chemotherapeutic response. The infiltration and subsistence of F. nucleatum in the ESCC cells were observed by transmission electron microscopy and laser scanning confocal microscopy. We also observed that F. nucleatum modulates the endogenous LC3 and ATG7 expression, as well as autophagosome formation to induce chemoresistance against 5-FU, CDDP, and Docetaxel. ATG7 knockdown resulted in reversal of F. nucleatum-induced chemoresistance. In addition, immunohistochemical studies confirmed the correlation between F. nucleatum infection and ATG7 expression in 284 ESCC specimens.Conclusions F. nucleatum confers chemoresistance to ESCC cells by modulating autophagy. These findings suggest that targeting F. nucleatum, during chemotherapy, could result in variable therapeutic outcomes for ESCC patients.Subject terms: Tumour biomarkers, Oesophageal cancer