Takaaki Ueno

Identification of IGFBP2 and IGFBP3 As Compensatory Biomarkers for CA19-9 in Early-Stage Pancreatic Cancer Using a Combination of Antibody-Based and LC-MS/MS-Based Proteomics.

Pancreatic cancer is one of the most lethal tumors, and reliable detection of early-stage pancreatic cancer and risk diseases for pancreatic cancer is essential to improve the prognosis. As 260 genes were previously reported to be upregulated in invasive ductal adenocarcinoma of pancreas (IDACP) cells, quantification of the corresponding proteins in plasma might be useful for IDACP diagnosis. Therefore, the purpose of the present study was to identify plasma biomarkers for early detection of IDACP by using two proteomics strategies: antibody-based proteomics and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics. Among the 260 genes, we focused on 130 encoded proteins with known function for which antibodies were available. Twenty-three proteins showed values of the area under the curve (AUC) of more than 0.8 in receiver operating characteristic (ROC) analysis of reverse-phase protein array (RPPA) data of IDACP patients compared with healthy controls, and these proteins were selected as biomarker candidates. We then used our high-throughput selected reaction monitoring or multiple reaction monitoring (SRM/MRM) methodology, together with an automated sample preparation system, micro LC and auto analysis system, to quantify these candidate proteins in plasma from healthy controls and IDACP patients on a large scale. The results revealed that insulin-like growth factor-binding protein (IGFBP)2 and IGFBP3 have the ability to discriminate IDACP patients at an early stage from healthy controls, and IGFBP2 appeared to be increased in risk diseases of pancreatic malignancy, such as intraductal papillary mucinous neoplasms (IPMNs). Furthermore, diagnosis of IDACP using the combination of carbohydrate antigen 19–9 (CA19-9), IGFBP2 and IGFBP3 is significantly more effective than CA19-9 alone. This suggests that IGFBP2 and IGFBP3 may serve as compensatory biomarkers for CA19-9. Early diagnosis with this marker combination may improve the prognosis of IDACP patients.

Plasma biomarker for detection of early stage pancreatic cancer and risk factors for pancreatic malignancy using antibodies for apolipoprotein-AII isoforms.

We recently reported that circulating apolipoprotein AII (apoAII) isoforms apoAII-ATQ/AT (C-terminal truncations of the apoAII homo-dimer) decline significantly in pancreatic cancer and thus might serve as plasma biomarkers for the early detection of this disease. We report here the development of novel enzyme-linked immunosorbent assays (ELISAs) for measurement of apoAII-ATQ/AT and their clinical applicability for early detection of pancreatic cancer. Plasma and serum concentrations of apoAII-ATQ/AT were measured in three independent cohorts, which comprised healthy control subjects and patients with pancreatic cancer and gastroenterologic diseases (n = 1156). These cohorts included 151 cases of stage I/II pancreatic cancer. ApoAII-ATQ/AT not only distinguished the early stages of pancreatic cancer from healthy controls but also identified patients at high risk for pancreatic malignancy. AUC values of apoAII-ATQ/AT to detect early stage pancreatic cancer were higher than those of CA19–9 in all independent cohorts. ApoAII-ATQ/AT is a potential biomarker for screening patients for the early stage of pancreatic cancer and identifying patients at risk for pancreatic malignancy (161 words).

Identification of highly sensitive biomarkers that can aid the early detection of pancreatic cancer using GC/MS/MS-based targeted metabolomics

BACKGROUND To improve prognosis of pancreatic cancer (PC) patients, the discovery of more reliable biomarkers for the early detection is desired. METHODS Blood samples were collected by 2 independent groups. The 1st set was included 55 early PC and 58 healthy volunteers (HV), and the 2nd set was included 16 PC and 16HV. The 16 targeted metabolites were quantitatively analyzed by gas chromatography/tandem mass spectrometry together with their corresponding stable isotopes. In the 1st set, the levels of these metabolites were evaluated, and diagnostic models were constructed via multivariate logistic regression analysis, leading to validation using the 2nd set. RESULTS In the 1st set, model X consisting of 4 candidates based on our previous report possessed higher sensitivity (74.1%) than carbohydrate antigen 19-9 (CA19-9). Model Y, consisting of 2 metabolites newly selected from 16 metabolites via stepwise method possessed higher sensitivity (70.4%) than CA19-9. Furthermore, combining model Y with CA19-9 increased its sensitivity (90.7%) and specificity (89.5%). In the 2nd set, combining model Y with CA19-9 displayed high sensitivity (81.3%) and specificity (93.8%). In particular, it displayed very high sensitivity (100%) for resectable PC. CONCLUSIONS Quantitative analysis confirmed that metabolomics-based diagnostic methods are useful for detecting PC early.

Comparison of the Biological Impacts of the Fluoride Compounds by Graphical Risk Visualization Map Technique

Various fluoride compounds are widely used in industry. The present risk assessment study was conducted using a series of inorganic binary fluorides of the type XFn, where Xn = Na+, K+, Li+, Mg2+, Ca2+, Sr2+, Ba2+, Al3+, Nd3+, La3+, Ce3+, Sm3+, Gd3+, Y3+, Yb2+, and Zn2+. The aqueous solutions of these salts were orally administrated to 16 experimental groups (one for each of the salts tested). The levels of fluoride, N-acetyl-β-d-glucosaminidase in cumulative 24-h urine samples and creatinine clearance were measured to assess possible acute renal damages. The levels of fluoride, alanine aminotransferase, and aspartate aminotransferase were also determined in serum samples to assess possible acute hepatic damages. The results reveal that sodium fluoride (NaF), potassium fluoride (KF), and zinc fluoride tetrahydrate (ZnF2.4H2O) can carry the fluoride ion into the bloodstream and that it is excreted via urine more readily than the other compounds tested. These fluorides were assigned the highest risk impact factor. Most of the rare earth fluorides are insoluble in water while those groups 2 and 13 of the periodic table are slightly soluble, so that they do not have a significant negative risk. These findings suggest that the biological impact of fluoride depends on the accompanying counter ion and its solubility. The risk map obtained in the present study shows that the graphical visualization map technique employed is a valuable new tool to assess the toxicological risk of chemical compounds.

Osteogenic capacity of mixed-acid and heat-treated titanium mesh prepared by a selective laser melting technique

The practical use of additive manufacturing to create artificial bone as a material for repairing complex bone defects is currently attracting attention. In this study, we compared the osteogenic capacity of materials composited by the method developed by Kokubo et al. of treating 3D-printed titanium (Ti) mesh with a mixture of H2SO4 and HCl and heating (mixed-acid and heat treatment) with that of materials subjected to conventional chemical treatment. Ti plates treated with this method have been found to promote highly active bone formation on their surface when inserted into rabbit tibial bone defects. No previous study has compared this method with other surface treatment methods. In this study, we used histological and other observations to compare the bone formation process in bone defects when Ti meshes prepared by the selective laser melting technique (SLM) and treated either with mixed acids and heat or with conventional chemical Ti surface treatments were implanted in a rat calvarial bone defect model. We found that both micro-computed tomography and observations of undecalcified ground sections showed that the best bone formation was observed in rats implanted with mesh treated with mixed acids and heat. Our results suggest that mixed-acid and heat-treated Ti mesh prepared by SLM may have a high osteogenic capacity in bone defects.

Candida is a protractive factor of chronic oral ulcers among usual outpatients

Summary Although many oral ulcers have similar clinical appearances, their etiologies can range from reactive to neoplastic to oral manifestations of dermatological diseases. In patients with an HIV infection, fungal diseases may cause ulceration in the oral cavity; however, there have been few studies of oral ulcerative lesions associated with Candida in patients without an HIV infection. Nevertheless, we encountered chronic oral ulcer associated with Candida among our frequent outpatients without an HIV infection. The present article reviews the causes of oral ulcers, focusing on Candida as a protractive factor for chronic oral ulcers, and it is recommended that Candida involvement be considered in diagnosis of a certain chronic oral ulcer, that remains of unknown origin even if some examinations have been performed.

The use of only one hand for the reduction of a temporomandibular joint dislocation: a technique suitable for self-reduction

Dear Editor, We read with interest the case report on temporomandibular joint (TMJ) dislocation by Baur et al. We believe that a surgical intervention is one of the options for the long-term dislocation case. However, once an acute dislocation of the TMJ has been established, attempts at manual reduction should be made as soon as possible. Previously reported methods of manual reduction, including Hippocrates’ Int. J. Oral Maxillofac. Surg. 2014; 43: 663–665 available online at http://www.sciencedirect.com