Syed Ali Khurram

Functional expression of the chemokine receptor XCR1 on oral epithelial cells.

Chemokines are chemoattractant cytokines which act on specific receptors and play an important role in leukocyte migration as well as physiological and pathological processes. We investigated the role of the chemokine receptor XCR1 and its ligand lymphotactin (Lptn/XCL1) in the regulation of oral epithelial cell behaviour. In vitro XCR1 mRNA and cell surface protein expression was detected in normal oral keratinocytes and oral squamous cell carcinoma cell lines. Lymphotactin mediated intracellular activation of the ERK1/2 signalling pathway and stimulated migration, invasion, and proliferation of all cells through XCR1. Oral cancer cells showed a greater response to lymphotactin than normal keratinocytes and a direct relationship between receptor expression and migration, invasion, and proliferation was observed. Exposure of normal keratinocytes to lymphotactin resulted in increased adhesion to fibronectin but not collagen and stimulated MMP‐2 and MMP‐9 but not MMP‐7 release, whereas exposure of cancer cells resulted in increased adhesion to both collagen and fibronectin and stimulated production of MMP‐2, MMP‐9, and MMP‐7. We observed XCR1 but not lymphotactin to be expressed by epithelial cells in normal oral mucosa in vivo, whilst both were expressed and up‐regulated in inflammatory oral disease and oral cancer including primary and metastatic disease. Lymphotactin mRNA and constitutive intracellular protein were detected in normal keratinocytes and oral cancer cell lines in vitro. These findings show that XCR1 and its ligand, lymphotactin, are expressed by oral epithelial cells and suggest that they play a role in regulating the behaviour of these cells. Copyright

Epigenetic changes in histone acetylation underpin resistance to the topoisomerase I inhibitor irinotecan

Abstract The topoisomerase I (TOP1) inhibitor irinotecan triggers cell death by trapping TOP1 on DNA, generating cytotoxic protein-linked DNA breaks (PDBs). Despite its wide application in a variety of solid tumors, the mechanisms of cancer cell resistance to irinotecan remains poorly understood. Here, we generated colorectal cancer (CRC) cell models for irinotecan resistance and report that resistance is neither due to downregulation of the main cellular target of irinotecan TOP1 nor upregulation of the key TOP1 PDB repair factor TDP1. Instead, the faster repair of PDBs underlies resistance, which is associated with perturbed histone H4K16 acetylation. Subsequent treatment of irinotecan-resistant, but not parental, CRC cells with histone deacetylase (HDAC) inhibitors can effectively overcome resistance. Immunohistochemical analyses of CRC tissues further corroborate the importance of histone H4K16 acetylation in CRC. Finally, the resistant clones exhibit cross-resistance with oxaliplatin but not with ionising radiation or 5-fluoruracil, suggesting that the latter two could be employed following loss of irinotecan response. These findings identify perturbed chromatin acetylation in irinotecan resistance and establish HDAC inhibitors as potential therapeutic means to overcome resistance.

Solitary myofibroma of the adult mandible: a case report.

A 43-year-old woman presented with a swelling in the anterior mandible appearing radiographically as a well-defined radiolucency causing mobility of the anterior teeth. A clinical diagnosis of a radicular cyst led to removal of the lesion and the associated mobile teeth. Postoperative histopathology led to a diagnosis of intraosseous solitary myofibroma of the mandible. Solitary lesions of myofibroma are exceedingly rare in adult jaws, with only 3 previously documented cases.

The chemokine receptors CXCR1 and CXCR2 regulate oral cancer cell behaviour

BACKGROUND Chemokines regulate physiological and pathological leucocyte trafficking, and chemokine receptors play a role in tumorigenesis. Expression of interleukin-8 (IL-8) receptors CXCR1 and CXCR2 has been shown in oral squamous cell carcinoma (OSCC) but remains poorly characterised. This aim of this study was to investigate CXCR1 and CXCR2 expression on normal oral keratinocytes (NOKs) and oral cancer cell lines (OCCL) and their relative response when exposed to IL-8 and growth-related oncogene-α (which selectively binds CXCR2). METHODS mRNA and protein expression was studied using RT-PCR, immunocytochemistry and flow cytometry. ELISAs were used to investigate ERK1/2 phosphorylation and MMP production, whereas a MTS-based assay was employed to study proliferation. Migration assays were carried out using modified Boyden chambers with a matrigel coating used for invasion assays. RESULTS mRNA expression of CXCR1 and CXCR2 was seen in both NOKs and OCCL with significantly higher protein expression in OCCL. Exposure to IL-8 and GROα increased intracellular ERK phosphorylation, proliferation, migration and invasion with OCCL showing a greater response than NOKs. These effects were mediated through CXCR1 and CXCR2 (for IL-8) and CXCR2 (for GROα) as receptor-blocking antibodies significantly inhibited the responses. IL-8 and GROα also increased MMP-9 release from NOKs and OCCL with significantly higher amounts released by OCCL. However, an increase in MMP-7 production was only seen in OCCL. CONCLUSIONS Functional CXCR1 and CXCR2 exist on normal and cancerous oral epithelial cells, and our data suggests a role for these receptors in oral cancer biology.

IgG4-related sclerosing disease clinically mimicking oral squamous cell carcinoma

IgG4-related sclerosing disease is a distinct clinicopathologic entity known to involve the maxillofacial region, particularly the salivary, lacrimal, and pituitary glands. We report a case with lesions involving the tongue and palatine tonsil with associated skin lesions. A 45-year-old female patient presented with a history of soreness, dysphagia, and an asymptomatic rash involving the upper trunk. The initial clinical diagnosis of her oral lesions was squamous cell carcinoma. The diagnosis of an IgG4-related lesion was confirmed by histologic examination of the oral and skin lesions as well as confirmation of raised serum IgG4 levels. Tapering systemic corticosteroid therapy resulted in complete resolution of the lesions. This is the first report of IgG4-related sclerosing disease presenting as concurrent oral and skin lesions, with the oral lesion clinically resembling oral squamous cell carcinoma. Such lesions present a diagnostic challenge, but the outcome is very favorable.

Diagnostic difficulties in lesions of the minor salivary glands

A wide range of lesions arise from the intra-oral salivary glands, and often present a diagnostic challenge to specialists and generalists alike. Of the salivary neoplasms, pleomorphic adenoma is the most common, but its morphological diversity may bring several other entities to mind, notably polymorphous adenocarcinoma, particularly in a small incisional biopsy. Polymorphous adenocarcinoma in turn shares features with adenoid cystic carcinoma. Immunohistochemistry and molecular cytogenetic studies can assist diagnosis in the face of overlapping morphology. The other salivary neoplasms most likely to be encountered in the oral cavity are canalicular adenoma, mucoepidermoid carcinoma, secretory carcinoma and acinic cell carcinoma. Of the non-neoplastic conditions, necrotising sialometaplasia is most likely to be misdiagnosed as neoplastic on both clinical and histological grounds. However, careful consideration of the clinicopathological features of an adequate tissue specimen will enable correct diagnosis.

Oral potentially malignant disorders: risk of progression to malignancy

Oral potentially malignant disorders (OPMDs) have a statistically increased risk of progressing to cancer, but the risk varies according to a range of patient- or lesion-related factors. It is difficult to predict the risk of progression in any individual patient, and the clinician must make a judgment based on assessment of each case. The most commonly encountered OPMD is leukoplakia, but others, including lichen planus, oral submucous fibrosis, and erythroplakia, may also be seen. Factors associated with an increased risk of malignant transformation include sex; site and type of lesion; habits, such as smoking and alcohol consumption; and the presence of epithelial dysplasia on histologic examination. In this review, we attempt to identify important risk factors and present a simple algorithm that can be used as a guide for risk assessment at each stage of the clinical evaluation of a patient.

Plate-guided distraction osteogenesis to recreate two-thirds of the mandible including symphysis

We report a case of plate-guided distraction osteogenesis to reconstruct a large mandibular defect caused by recurrence of an ameloblastoma in a 17-year-old male patient who had previously had reconstruction using a fibula bone graft.

Adenoid dysplasia of the oral mucosa

OBJECTIVE To describe an unusual variant of oral epithelial dysplasia and to provide an appraisal of its immunohistochemical profile. STUDY DESIGN An unusual form of epithelial dysplasia, which we have termed adenoid dysplasia, was evaluated for staining of cytokeratins AE1/AE3, vimentin, E-cadherin, and β-catenin. The immunohistochemical results were compared with those observed in moderate epithelial dysplasia, moderately differentiated squamous cell carcinoma, and acantholytic squamous cell carcinoma. RESULTS The immunoprofile of adenoid dysplasia was similar to that of acantholytic squamous cell carcinoma. Cytokeratin positivity within the acantholytic dysplastic cells confirmed their epithelial nature, and upregulation of vimentin was suggestive of epithelial-mesenchymal transition. The most distinctive finding was a loss of E-cadherin expression within the discohesive cells, accompanied by increased cytosolic expression of β-catenin. CONCLUSIONS This report presents the histomorphologic features of a unique form of oral epithelial dysplasia, termed adenoid dysplasia.

Crystal storing histiocytosis of the tongue as the initial presentation of multiple myeloma

Crystal-storing histiocytosis (CSH) is a rare consequence of abnormal accumulation of immunoglobulins which may arise in a number of different clinical scenarios. In this report, we describe the case of a male patient who presented with an apparently innocuous lesion on the dorsum of tongue which showed the typical features of CSH. Subsequent investigations revealed an associated plasmacytoma, and the patient developed further systemic lesions. The rarity of such lesions presents diagnostic difficulties, yet accurate diagnosis underpins the timely implementation of appropriate therapy.