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Squamous odontogenic tumor of the mandible: a case report demonstrating immunoexpression of Notch1, 3, 4, Jagged1 and Delta1

Siar CH, Nakano K, Ng KH, Tomida M, Nagatsuka H, Kawakami T

Eur J Med Res, 2010 Apr 08;15(4):180-4.
PMID: 20554499

BACKGROUND: Squamous odontogenic tumor (SOT) is a rare benign odontogenic epithelial neoplasm. A slow-growing painless expansive swelling is the common presenting symptom. Histopathologically, SOT can be easily misdiagnosed as an acanthomatous ameloblastoma. Although Notch receptors and ligands have been shown to play a role in cell fate decisions in ameloblastomas, the role of these cell signaling molecules in SOT is unknown.
CASE REPORT: This paper describes a case of SOT affecting the anterior mandible of a 10-year-old Indian female. The patient was treated by local surgical excision and there has been no follow-up clinical record of recurrence 5 years after primary treatment. Histo?pathological examination revealed a solid, locally-infiltrative neoplasm composed of bland-looking squamatoid islands scattered in a mature fibrous connective tissue stroma and the diagnosis was SOT. Immunohistochemical evaluation showed positive reactivity of varying intensity in the neoplastic epithelial cells for Notch1, Notch3, Notch4, and their ligands Jagged1 and Delta1. Expression patterns showed considerable overlap. No immunoreactivity was detected for Notch2 and Jagged2.
CONCLUSIONS: Present findings suggest that Notch receptors and their ligands play differential roles in the cytodifferentiation of SOT.
An unsuspected ameloblastoma in the subpontic region of the mandible with consideration of pathogenesis from the radiographic course

Siar CH, Nakano K, Chelvanayagam PI, Ng KH, Nagatsuka H, Kawakami T

Eur J Med Res, 2010 Mar 30;15(3):135-8.
PMID: 20452900

The purpose of this report is to document a case of unsuspected ameloblastoma involving the right man dibular subpontic region in a 38-year-old Cambodian female patient. This lesion was purportedly preceded by multiple radiolucencies which were diagnosed as radicular cysts and treated a few times in the past years by enucleation followed by endodontic therapy of the affected teeth. Bridgework restoration of the partially edentulous area was performed. This case report demonstrates radiographic changes that occurred in the periods before and after the diagnosis of ameloblastoma. The case may represent an example of radicular cysts and ameloblastoma occurring as a collision phenomenon, or the ameloblastoma may have arisen as a result of neoplastic transformation of the lining epithelium in an inflammatory odontogenic epithelial cyst.
Differential expression of canonical and non-canonical Wnt ligands in ameloblastoma

Siar CH, Nagatsuka H, Han PP, Buery RR, Tsujigiwa H, Nakano K, et al.

J Oral Pathol Med, 2012 Apr;41(4):332-9.
PMID: 22077561 DOI: 10.1111/j.1600-0714.2011.01104.x

Canonical and non-canonical Wnt signaling pathways modulate diverse cellular processes during embryogenesis and post-natally. Their deregulations have been implicated in cancer development and progression. Wnt signaling is essential for odontogenesis. The ameloblastoma is an odontogenic epithelial neoplasm of enamel organ origin. Altered expressions of Wnts-1, -2, -5a, and -10a are detected in this tumor. The activity of other Wnt members remains unclarified.
Notch4 overexpression in ameloblastoma correlates with the solid/multicystic phenotype

Siar CH, Nagatsuka H, Chuah KS, Rivera RS, Nakano K, Ng KH, et al.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2010 Aug;110(2):224-33.
PMID: 20659700 DOI: 10.1016/j.tripleo.2010.03.009

Notch signaling has been implicated in cell fate decisions during odontogenesis and tumorigenesis of some odontogenic neoplasms; however, its role in solid/multicystic (SA), unicystic (UA), and recurrent (RA) ameloblastoma remains unclear. The aim of this study was to determine Notch receptor and ligand expressions in these subtypes and to speculate on their significance.
Differential expression of Notch receptors and their ligands in desmoplastic ameloblastoma

Siar CH, Nakano K, Han PP, Nagatsuka H, Ng KH, Kawakami T

J Oral Pathol Med, 2010 Aug 1;39(7):552-8.
PMID: 20337864 DOI: 10.1111/j.1600-0714.2009.00871.x

In mammals, the Notch gene family encodes four receptors (Notch1-4), and all of them are important for cell fate decisions. Notch signaling pathway plays an essential role in tooth development. The ameloblastoma, a benign odontogenic epithelial neoplasm, histologically recapitulates the enamel organ at bell stage. Notch has been detected in the plexiform and follicular ameloblastoma. Its activity in the desmoplastic ameloblastoma is unknown.
Angiogenic squamous dysplasia-like phenomenon in oral epithelial precursor lesions

Siar CH, Oo VP, Nagatsuka H, Nakano K, Ng KH, Kawakami T

Eur J Med Res, 2009 Jul 22;14(7):315-9.
PMID: 19661015

STATEMENT OF THE PROBLEM: Dysplasia, the morphological yardstick of epithelial precursor lesions, is the collective term for a variety of architectural and cytological changes within the altered oral epithelium. Angiogenic squamous dysplasia (ASD), a distinct morphological characteristic in pre-invasive bronchial lesions, describes the presence of capillary tufts that are closely juxtaposed to and projecting into the dysplastic bronchial epithelium.
OBJECTIVE: To determine whether ASD-like phenomenon occurs in oral epithelial precursor lesions, and to speculate on its relevance.
METHODS: Twenty cases each of mild, moderate and severe oral dysplasia (inclusive of carcinoma-in-situ), and 10 normal oral mucosa (normal controls) were serial sectioned for H and E staining, and for microvessel density (MVD) scoring with CD31, CD34 and CD105. Microcapillary pattern images were digitally captured for 3-D reconstruction.
RESULTS: Oral ASD foci consisting of CD31- and CD34-positive capillary loops abutting onto the overlying dysplastic oral epithelium (and causing it to assume an irregular or papillary surface configuration) were identified in moderate (3/20; 15%) and severe dysplasia (13/20; 65%), but not in normal oral mucosa and mild dysplasia. MVD score demonstrated increasing vascularity as epithelium progressed from normal to severe dysplasia (p<0.05). CD105 demonstrated increase neovascularization in all dysplasia grades (p<0.05).
CONCLUSIONS: These preliminary findings taken together suggest that: 1. ASD-like phenomenon may be an important intermediary biomarker in oral precursor lesions; and 2. architectural alterations of the entire disturbed mucosa may be a more useful pre-malignancy index.
Notch signaling and ghost cell fate in the calcifying cystic odontogenic tumor

Siar CH, Kawakami T, Buery RR, Nakano K, Tomida M, Tsujigiwa H, et al.

Eur J Med Res, 2011 Nov 10;16(11):501-6.
PMID: 22027644

Notch signaling is an evolutionarily conserved mechanism that enables adjacent cells to adopt different fates. Ghost cells (GCs) are anucleate cells with homogeneous pale eosinophilic cytoplasm and very pale to clear central areas (previous nucleus sites). Although GCs are present in a variety of odontogenic lesions notably the calcifying cystic odontogenic tumor (CCOT), their nature and process of formation remains elusive. The aim of this study was to investigate the role of Notch signaling in the cell fate specification of GCs in CCOT. Immunohistochemical staining for four Notch receptors (Notch1, Notch2, Notch3 and Notch4) and three ligands (Jagged1, Jagged2 and Delta1) was performed on archival tissues of five CCOT cases. Level of positivity was quantified as negative (0), mild (+), moderate (2+) and strong (3+). Results revealed that GCs demonstrated overexpression for Notch1 and Jagged1 suggesting that Notch1-Jagged1 signaling might serve as the main transduction mechanism in cell fate decision for GCs in CCOT. Protein localizations were largely membranous and/or cytoplasmic. Mineralized GCs also stained positive implicating that the calcification process might be associated with upregulation of these molecules. The other Notch receptors and ligands were weak to absent in GCs and tumoral epithelium. Stromal endothelium and fibroblasts were stained variably positive.
Strawberry gingivitis as the first presenting sign of Wegener's granulomatosis: report of a case

Siar CH, Yeo KB, Nakano K, Nagatsuka H, Tsujigiwa H, Tomida M, et al.

Eur J Med Res, 2011 Jul 25;16(7):331-4.
PMID: 21813375

Wegener's granulomatosis is a rare multi-system disease characterized by the classic triad of necrotizing granulomas affecting the upper and lower respiratory tracts, disseminated vasculitis and glomerulonephritis. Oral lesions as a presenting feature are only encountered in 2% of these cases. Hyperplastic gingival lesions or strawberry gingivitis, is a characteristic sign of Wegener's granulomatosis. The latter consists of reddish-purple exophytic gingival swellings with petechial haemorrhages thus resembling strawberries. Recognition of this feature is of utmost importance for timely diagnosis and definitive management of this potentially fatal disease. A case of strawberry gingivitis as the first presenting sign of Wegener's granulomatosis affecting a 50-year-old Malay male is reported here. The differential diagnosis of red lesions that may present in the gingiva is discussed.
Immunolocalization of notch signaling protein molecules in a maxillary chondrosarcoma and its recurrent tumor

Siar CH, Ha KO, Aung LO, Nakano K, Tsujigiwa H, Nagatsuka H, et al.

Eur J Med Res, 2010 Oct 25;15(10):456-60.
PMID: 21156405

BACKGROUND: notch receptors are critical determinants of cell fate in a variety of organisms. Notch signaling is involved in the chondrogenic specification of neural crest cells. Aberrant Notch activity has been implicated in numerous human diseases including cancers; however its role in chondrogenic tumors has not been clarified.
METHOD: tissue samples from a case of primary chondrosarcoma of the maxilla and its recurrent tumor were examined immunohistochemically for Notch1-4 and their ligands (Jagged1, Jagged2 and Delta1) expression.
RESULTS: both primary and recurrent tumors were histopathologically diagnosed as conventional hyaline chondrosarcoma (WHO Grade I). Hypercellular tumor areas strongly expressed Notch3 and Jagged1 in spindle and pleomorphic cells suggesting up-regulation of these protein molecules at sites of tumor proliferation. Expression patterns were distinct with some overlap. Differentiated malignant and atypical chondrocytes demonstrated variable expression levels of Jagged1, and weak to absent staining for Notch1, 4 and Delta1. Protein immunolocalization was largely membranous and cytoplasmic, sometimes outlining the lacunae of malignant chondrocytes. Hyaline cartilage demonstrated a diffuse or granular precipitation of Jagged1 suggesting presence of soluble Jagged1 activity at sites of abnormal chondrogenesis. No immunoreactivity for the other Notch members was observed. Calcified cartilage was consistently Notch-negative indicating down-regulation of Notch with cartilage maturation. Stromal components namely endothelial cells and fibroblasts variably expressed Notch1, 3 and Jagged1 but were mildly or non-reactive for the other members.
CONCLUSIONS: Results indicate that Notch signaling pathway may participate in cellular differentiation and proliferation in chondrosarcoma. Findings implicate Notch3 and Jagged1 as key molecules that influence the differentiation and maturation of cells of chondrogenic lineage.
Fulltext Design and synthesis of chalcone derivatives as inhibitors of the ferredoxin - ferredoxin-NADP+ reductase interaction of Plasmodium falciparum: pursuing new antimalarial agents

Suwito H, Jumina, Mustofa, Pudjiastuti P, Fanani MZ, Kimata-Ariga Y, et al.

Molecules, 2014 Dec 19;19(12):21473-88.
PMID: 25532844 DOI: 10.3390/molecules191221473

Some chalcones have been designed and synthesized using Claisen-Schmidt reactions as inhibitors of the ferredoxin and ferredoxin-NADP+ reductase interaction to pursue a new selective antimalaria agent. The synthesized compounds exhibited inhibition interactions between PfFd-PfFNR in the range of 10.94%-50%. The three strongest inhibition activities were shown by (E)-1-(4-aminophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (50%), (E)-1-(4-aminophenyl)-3-(2,4-dimethoxyphenyl)prop-2-en-1-one (38.16%), and (E)-1-(4-aminophenyl)-3-(2,3-dimethoxyphenyl)prop-2-en-1-one (31.58%). From the docking experiments we established that the amino group of the methoxyamino chlacone derivatives plays an important role in the inhibition activity by electrostatic interaction through salt bridges and that it forms more stable and better affinity complexes with FNR than with Fd.