Melanoma Inhibitory Activity and Melanoma Inhibitory Activity 2 as Novel Immunohistochemical Markers of Oral Epithelial Dysplasia.

Oral potentially malignant disorders are associated with the development of oral squamous cell carcinoma (OSCC). Most OSCCs are diagnosed via histopathology as oral epithelial dysplasia (OED), but the histologic diagnostic criteria remain non-uniform. Accordingly, the establishment of a diagnostic marker to assist in diagnosis could contribute towards cancer prevention. Melanoma inhibitory activity (MIA) and MIA2 are involved in tumor growth, invasion, and lymph node metastasis in various malignancies. The purpose of this study was to clarify the usefulness of MIA and MIA2 as diagnostic markers of oral mucosal lesions. The expression of MIA and MIA2 was analyzed immunohistochemically in 100 specimens (10 specimens with normal oral mucosa (NOM) and 30 specimens each with low-grade epithelial dysplasia (LED), high-grade epithelial dysplasia (HED), and OSCC). Immunohistochemical results were evaluated based on the Allred scoring system. Cytoplasmic expression of MIA and MIA2 increased in the order of LED, HED, and OSCC. All NOM specimens were negative for cytoplasmic expression. Significant differences were observed between the groups (NOM vs. HED, p < 0.05, NOM vs. OSCC, p < 0.001). These results demonstrate that MIA and MIA2 are expressed in the oral mucosa within early neoplastic lesions and suggest that MIA and MIA2 are useful novel immunohistochemical markers for discriminating between normal tissue and OED.

Utility of the sleep stage sequence preceding sleep onset REM periods for the diagnosis of narcolepsy: a study in a Japanese cohort.

BACKGROUND: The minimum narcolepsy criteria "mean sleep latency (MSL) ≤8 min and ≥2 sleep onset rapid eye movement (REM) periods (SOREMPs) on polysomnography (PSG) and the multiple sleep latency test (MSLT)," according to The International Classification of Sleep Disorders, Third Edition (ICSD-3), are not specific to narcolepsy. Recently, the characteristic sleep stage sequences preceding SOREMPs in narcolepsy have received attention, but their diagnostic utility remains unclear. METHODS: We retrospectively reviewed PSG/MSLT records and chart data for 102 Japanese patients with hypersomnia and at least one SOREMP. We examined the sporadic rates of two sleep stage sequences preceding the SOREMPs-wakefulness or stage 1 to REM (W/S1→R) and stage 2 to REM (S2→R)-comparing these between patient groups with narcolepsy type 1 (N = 28), narcolepsy type 2 (N = 19), and other hypersomnia (N = 55). We also examined the utility of three simple indices using the occurrence of W/S1→R SOREMPs for distinguishing between narcolepsy and other hypersomnia in patients who satisfied the minimum narcolepsy criteria. RESULTS: W/S1→R SOREMPs were significantly more frequent in narcolepsy than in other hypersomnia, and this tendency was also observed even in the patients who satisfied the minimum narcolepsy criteria. The three indices had moderate sensitivities and specificities for distinguishing between narcolepsy and other hypersomnia in patients satisfying the minimum narcolepsy criteria. CONCLUSIONS: The W/S1→R pattern was observed significantly more frequently in narcolepsy than in other hypersomnia, suggesting it may help with differentiating narcolepsy from other hypersomnia in patients demonstrating the narcolepsy criteria, although its ability to do so may be modest.

Stabilization Mechanism for a Nonfibrillar Amyloid ß Oligomer Based on Formation of a Hydrophobic Core Determined by Dissipative Particle Dynamics.

Neurotoxicity caused by nonfibrillar amyloid ß (Aß) oligomers in the brain is suggested to be associated with the onset of Alzheimer's disease (AD). Elucidating the structural features of Aß oligomers is critical for promoting drug discovery research for AD. One of the Aß oligomers, known as Aß*56, is a dodecamer that impairs memory when injected into healthy rats, suggesting that Aß*56 may contribute to cognitive deficits in AD patients. Another dodecamer structure, formed by 20-residue peptide segments derived from the Aß peptide (Aß17-36), has been revealed by X-ray crystallography. The structure of the Aß17-36 dodecamer is composed of trimer units and shows the oligomer antibody A11 reactivity, which are characteristic of Aß*56, indicating that Aß*56 and the Aß17-36 dodecamer share a similar structure. However, the structure of the C-terminal regions (Aß37-42) remains unclear. The C-terminal region, which is abundant in hydrophobic residues, is thought to play a key role in stabilizing the oligomer structure by forming a hydrophobic core. In this study, we employed dissipative particle dynamics, a coarse-grained simulation method with soft core potentials, utilizing the crystal structure information to unravel Aß dodecamer structures with C-terminal regions. The simulation results were validated by the reported experimental data. Hence, an analysis of the simulation results can provide structural insights into Aß oligomers. Our simulations revealed the stabilization mechanism of the dodecamer structure at the molecular level. We showed that C-terminal regions spontaneously form a hydrophobic core in the central cavity, contributing to stabilizing the dodecamer structure. Furthermore, four consecutive hydrophobic residues in the C-terminal region (i.e., Val39-Ala42) are important for core formation.

Fibronectin type III domain-containing protein 5 interacts with APP and decreases amyloid ß production in Alzheimer's disease.

The deposition of Amyloid-beta peptides (Aß) is detected at an earlier stage in Alzheimer's disease (AD) pathology. Thus, the approach toward Aß metabolism is considered to play a critical role in the onset and progression of AD. Mounting evidence suggests that lifestyle-related diseases are closely associated with AD, and exercise is especially linked to the prevention and the delayed progression of AD. We previously showed that exercise is more effective than diet control against Aß pathology and cognitive deficit in AD mice fed a high-fat diet; however, the underlying molecular mechanisms remain poorly understood. On the other hand, a report suggested that exercise induced expression of fibronectin type III domain-containing protein 5 (FNDC5) in the hippocampus of mice through PGC1α pathway. Thus, in the current study, we investigated a possibility that FNDC5 interacts with amyloid precursor protein (APP) and affects Aß metabolism. As a result, for the first time ever, we found the interaction between FNDC5 and APP, and forced expression of FNDC5 significantly decreased levels of both Aß40 and Aß42 secreted in the media. Taken together, our results indicate that FNDC5 significantly affects ß-cleavage of APP via the interaction with APP, finally regulating Aß levels. A deeper understanding of the mechanisms by which the interaction between APP and FNDC5 may affect Aß production in an exercise-dependent manner would provide new preventive strategies against the development of AD.

Structure-activity relationships of succinimidyl-Cys-C(O)-Glu derivatives with different near-infrared fluorophores as optical imaging probes for prostate-specific membrane antigen.

Prostate-specific membrane antigen (PSMA), which is overexpressed in malignant prostate cancer (PCa), is an ideal target for imaging and therapy of PCa. We previously reported a PSMA imaging probe, 800CW-SCE, based on succinimidyl-Cys-C(O)-Glu (SCE) for optical imaging of PCa. In this study, we investigated the structure-activity relationships of novel SCE derivatives with five different near-infrared (NIR) fluorophores (IRDye 680LT, IRDye 750, Indocyanine Green, Cyanine 5.5, and Cyanine 7) as optical imaging probes targeting PSMA. An in vitro binding assay revealed that 800CW-SCE, 680LT-SCE, and 750-SCE exhibited higher binding affinity than 2-PMPA, which is known as a PSMA inhibitor. These three SCE derivatives were internalized into PSMA-positive cells (LNCaP cells) but not into PSMA-negative cells (PC-3 cells). In the in vivo imaging study, 800CW-SCE and 750-SCE were highly accumulated in LNCaP tumors but not in PC-3 tumors, and the ratio of LNCaP/PC-3 accumulation of 800CW-SCE was higher than that of 750-SCE. The present study may provide valuable molecular design information for the future development of new PSMA imaging probes based on the SCE scaffold.

Core Binding Site of a Thioflavin-T-Derived Imaging Probe on Amyloid ß Fibrils Predicted by Computational Methods.

Development of new diagnostic imaging probes for Alzheimer's disease, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) probes, has been strongly desired. In this study, we investigated the most accessible amyloid ß (Aß) binding site of [123I]IMPY, a Thioflavin-T-derived SPECT probe, using experimental and computational methods. First, we performed a competitive inhibition assay with Orange-G, which recognizes the KLVFFA region in Aß fibrils, suggesting that IMPY and Orange-G bind to different sites in Aß fibrils. Next, we precisely predicted the IMPY binding site on a multiple-protofilament Aß fibril model using computational approaches, consisting of molecular dynamics and docking simulations. We generated possible IMPY-binding structures using docking simulations to identify candidates for probe-binding sites. The binding free energy of IMPY with the Aß fibril was calculated by a free energy simulation method, MP-CAFEE. These computational results suggest that IMPY preferentially binds to an interfacial pocket located between two protofilaments and is stabilized mainly through hydrophobic interactions. Finally, our computational approach was validated by comparing it with the experimental results. The present study demonstrates the possibility of computational approaches to screen new PET/SPECT probes for Aß imaging.

Advances in food composition tables in Japan-Standard Tables Of Food Composition in Japan - 2015 - (Seventh Revised Edition).

The latest version of the Standard Tables of Food Composition in Japan-2015- comprises the main food composition table (Standard Tables of Food Composition in Japan-2015-[Seventh revised Edition)) and three supplementary books. The supplementary books are Standard Tables of Food Composition in Japan - 2015 - (Seventh Revised Edition) - Amino Acids -, Standard Tables of Food Composition in Japan - 2015 - (Seventh Revised Edition) - Fatty Acids - and Standard Tables of Food Composition in Japan - 2015 - (Seventh Revised Edition) - Available Carbohydrates, Polyols and Organic Acids-. We believe understanding these food composition tables can give greater insight into Japan's gastronomic culture and changes in eating habits. We expect them to play important roles as part of the East Asia food composition tables.