Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine released from T-cells and macrophages. Although a detailed understanding of the biological functions of MIF has not yet been clarified, it is known that MIF catalyzes the tautomerization of a nonphysiological molecule, D-dopachrome. Using a structure-based computer-assisted search of two databases of commercially available compounds, we have found 14 novel tautomerase inhibitors of MIF whose K(i) values are in the range of 0.038-7.4 microM. We also have determined the crystal structure of MIF complexed with the hit compound 1. It showed that the hit compound is located in the active site of MIF containing the N-terminal proline which plays an important role in the tautomerase reaction and forms several hydrogen bonds and undergoes hydrophobic interactions. A crystallographic study also revealed that there is a hydrophobic surface which consists of Pro-33, Tyr-36, Trp-108, and Phe-113 at the rim of the active site of MIF, and molecular modeling studies indicated that several more potent hit compounds have the aromatic rings which can interact with this hydrophobic surface. To our knowledge, our compounds are the most potent tautomerase inhibitors of MIF. One of these small, drug-like molecules has been cocrystallized with MIF and binds to the active site for tautomerase activity. Molecular modeling also suggests that the other hit compounds can bind in a similar fashion.

Aim: The purpose of this retrospective study was to evaluate the clinicopathological features of 64 patients with keratocystic odontogenic tumor (KCOT). Materials and Methods: The patients ranged in age at the time of diagnosis from 8 to 74 years (mean: 38.20 ± 16.71). Postoperative follow-up period was 3-8 years (mean time 4.76 ± 1.10). This research was carried out on panoramic radiographs and histopathological samples. Data such as gender, age, treatment methods, location of the tumor, presence of impacted teeth and its histological features were subjected to descriptive statistical analyses with the statistical software program. Results: Of the 64 analyzed cases of KCOT, 68.8% of them were men and 31.2% were females (male-to-female ratio was 2.2:1). It was observed that KCOT peaked in the third and fifth decade of life (23.4%-20.3%). The incidence of KCOT was higher in the mandible than in the maxilla (76.6%-23.4%). There was recurrence in nine out of 64 subjects (14.1%) in the follow-up period. The recurrence was more often found in posterior mandible. It is noteworthy that in 9 recurrent subjects, 7 lesions were parakeratotic and 4 lesions were associated with daughter cysts. Conclusion: Although there are several studies about KCOT in the literature, the choice of treatment modalities remains controversial. In recurrent subjects, more aggressive therapy approaches should be considered. Periodic controls and aggressive treatment approaches may be effective in the prevention of recurrences.

Expression of podoplanin in AMs is considered to be associated with neoplastic odontogenic tissues; this molecule might play a role in the collective cell migration of tumor nests in AMs. The pattern of expression of E-cadherin and vimentin suggests that invasion in AMs occurs in the absence of EMT. The migration and invasion mediated by podoplanin in AMs could be related to cytoskeletal reorganization.

Human podoplanin, a type-1 transmembrane sialomucin-like glycoprotein, is involved in cell migration, tumor cell invasion, and metastasis. However, the role of the protein in squamous cell carcinoma (SCC) has been unclear and immunohistochemical reactivity for podoplanin differs from organ-to-organ. In the present study, immunohistochemical and molecular biological analyses were performed to examine the importance of podoplanin expression in oral precancerous and cancerous lesions and metastases. We immunohistochemically investigated the expression of podoplanin in 103 precancerous lesions, 69 primary oral squamous cell carcinomas (OSCCs), and 32 metastases, and that of E-cadherin and vimentin in primary OSCCs with metastasis. Furthermore, human OSCC-derived cell lines preincubated with fibrous growth factor-basic, epidermal growth factor (EGF), and tumor growth factor-β1 were subjected to real-time reverse transcription polymerase chain reaction. Immunoreactivity for podoplanin was detected in 89 (86.4%) of the precancerous lesions and the intensity was correlated with the degree of epithelial dysplasia (P = 0.016). Enhanced podoplanin expression was observed in 66 (95.7%) of the OSCCs and was significantly associated with a poor pathologic grade of differentiation (P = 0.020). Epithelial-mesenchymal transition was observed in 18 (58.1%) of the primary OSCCs with metastasis to regional lymph nodes. Messenger RNA for podoplanin was markedly increased after treatment with EGF in three OSCC cell lines. The present findings suggest that podoplanin is associated with tumor development via the oral dysplasia-carcinoma sequence and could be involved in a signaling pathway governing tumor growth and invasion in OSCC.

The number of published cases of adenomatoid odontogenic tumor (AOT) has steadily increased, and about half were reported in Asian populations. Although the clinicopathologic profile of AOT has been extensively reported, factual knowledge of its pathogenesis is rudimentary at best, and there is controversy as to precisely which odontogenic epithelium it arises from. AOT is a successional tooth-associated lesion which develops during the mixed dentition. The permanent successor differs from its deciduous predecessor in that it has an eruptive pathway from the dental follicle to the gingiva, the gubernaculum dentis. With this background in mind, the present review focuses mainly on the early development of AOT. We successfully demonstrated a close spatial relationship between AOT and the gubernaculum dentis in a typical case. From further observations of the same AOT in which an enclosed permanent canine showed enamel hypoplasia, it is possible to pinpoint areas around the crown of a developing successional tooth in continuity with the gubernaculum dentis as starting points. In addition, we discuss the unifying histogenetic concept of three clinical variants, namely, pericoronal (follicular), extracoronal (extrafollicular), (see Article note) and peripheral.