Synovial sarcoma of the temporomandibular joint area: report of a case.

Synovial cell sarcoma is a relatively rare tumor of mesenchymal origin. It is a high-grade neoplasm that microscopically shows a monophasic or biphasic cellular pattern and includes epithelial features as well as supporting tissue features. Surgical excision is the primary mode of treatment. Postoperative radiotherapy and chemotherapy also is seen to be helpful. Between 3% and 10% of cases originate in the head and neck. A review of relevant literature shows less than 10 cases of synovial cell sarcoma of the temporomandibular joint area reported in the English literature. We report an additional case of biphasic synovial cell sarcoma arising in the temporomandibular joint area, which caused ear pain, tinnitus, and hearing loss, and we further discuss the clinical features, histopathology, differential diagnosis, and treatment modality.     

Engineering and characterization of the long‐acting glucagon‐like peptide‐1 analogue LY2189265, an Fc fusion protein

Background

Glucagon‐like peptide‐1 (GLP‐1) receptor agonists are novel agents for type 2 diabetes treatment, offering glucose‐dependent insulinotropic effects, reduced glucagonemia and a neutral bodyweight or weight‐reducing profile. However, a short half‐life (minutes), secondary to rapid inactivation by dipeptidyl peptidase‐IV (DPP‐IV) and excretion, limits the therapeutic potential of the native GLP‐1 hormone. Recently, the GLP‐1 receptor agonist exenatide injected subcutaneously twice daily established a novel therapy class. Developing long‐acting and efficacious GLP‐1 analogues represents a pivotal research goal. We developed a GLP‐1 immunoglobulin G (IgG4) Fc fusion protein (LY2189265) with extended pharmacokinetics and activity.

Methods

In vitro and in vivo activity of LY2189265 was characterized in rodent and primate cell systems and animal models.

Results

LY2189265 retained full receptor activity in vitro and elicited insulinotropic activity in islets similar to native peptide. Half‐life in rats and cynomolgus monkeys was 1.5–2 days, and serum immunoreactivity representing active compound persisted > 6 days. In rats, LY2189265 enhanced insulin responses during graded glucose infusion 24 h after one dose. LY2189265 increased glucose tolerance in diabetic mice after one dose and lowered weight and delayed hyperglycaemia when administered twice weekly for 4 weeks. In monkeys, LY2189265 significantly increased glucose‐dependent insulin secretion for up to a week after one dose, retained efficacy when administered subchronically (once weekly for 4 weeks) and was well tolerated.

Conclusions

LY2189265 retains the effects of GLP‐1 with increased half‐life and efficacy, supporting further evaluation as a once‐weekly treatment of type 2 diabetes. Copyright © 2010 John Wiley & Sons, Ltd.     

Cyclin D1 genotype in areca-associated oral squamous cell carcinoma

BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most common malignancy in areca-chewing regions, accounting for up to 50% of malignant tumors in some South Asian countries. Amplification and/or over-expression of cyclin D1 (CCND1) is a frequent event in human malignancies, including OSCC. CCND1 G870A polymorphism (codon 242) gives rise to two isoforms of the protein. The objective of the present study was to evaluate if the risk, onset, and prognosis of areca-associated OSCC is related to CCND1 genotypes. METHODS: We analyzed the CCND1 genotype in 70 OSCC cases and 93 control Taiwanese using single-strand conformation polymorphism techniques. RESULTS: Statistical analysis showed that CCND1 genotype had no impact on the risk, onset, or survival of areca-associated OSCC. However, buccal squamous cell carcinoma (BSCC) appeared to be less frequently associated with AA genotype than non-BSCC (P = 0.02). In addition, amplification of CCND1 was significantly more prevalent in OSCC cases (22%) than in control subjects (2%, P < 0.01). CONCLUSION: This study demonstrates that the CCND1 genotype may confer different risks for BSCC and non-BSCC.     

Dynamic cellular and molecular modulations of diabetes mediated head and neck carcinogenesis

Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent neoplasms worldwide. While numerous potent dietary insults were considered as oncogenic players for HNSCC development, the impact of metabolic imbalance was less emphasized during HNSCC carcinogenesis. Previous preclinical and epidemiological investigations showed that DM could possibly be correlated with greater incidence and poorer prognosis in HNSCC patients; however, the outcomes from different groups are contradictive and underlying mechanisms remains elusive. In the present study, the changes of cellular malignancy in response to prolonged glucose incubation in HNSCC cells were examined. The results demonstrated that hyperglycemia enhanced HNSCC cell malignancy over time through suppression of cell differentiation, promotion of cell motility, increased resistance to cisplatin, and up-regulation of the nutrient-sensing Akt/AMPK-mTORC1 pathway. Further analysis showed that a more aggressive tongue neoplastic progression was found under DM conditions compared to non-DM state whereas DM pathology led to a higher percentage of cervical lymph node metastasis and poorer prognosis in HNSCC patients. Taken together, the present study confirms that hyperglycemia and DM could enhance HNSCC malignancy and the outcomes are of great benefit in providing better anti-cancer treatment strategy for DM patients with HNSCC.     

Testicular relapse in childhood acute lymphocytic leukemia during bone marrow remission.

Seven children with acute lymphocytic leukemia developed testicular swelling during bone marrow remission. Needle biopsies and one orchiectomy specimen revealed leukemic infiltration. Another patient encountered concurrent medullary and testicular relapses. The leukemic nature of the testicular infiltration can be readily confirmed on needle biopsies. Orchiectomy should be discouraged. The leukemic infiltration mainly took place in the interstitial spaces. The seminiferous tubules were atrophic and lined by Sertoli cells. Occasional spermatogenic cells could be found in some cases. The leukemic cells were also observed to invade and accumulate beneath the Sertoli cell layer. Destruction of the tubules by the infiltrate was seen in advanced cases. Postradiation biopsies were characterized by fibrosis. The sigeveloped subsequent marrow relapse despite the effective control of the testicular relapse by irradiation. Another important observation is the high incidence of testicular relapse (16.2% so far).     

Tumor necrosis factor-α promoter polymorphism is associated with susceptibility to oral squamous cell carcinoma

BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the leading cancers in most Asian countries. Alterations of immune function have been detected in OSCC patients. The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is a central mediator of the immune response involved in a wide range of immuno-inflammatory and infectious diseases. Polymorphism of the TNF-alpha gene has been intensively studied as a potential determinant of susceptibility to numerous cancers. METHODS: We genotyped 192 patients with OSCC and 146 healthy case controls by using polymerase chain reaction-double restriction fragment length polymorphism with amplification-created restriction sites to assess allelic determinants at the TNF-alpha polymorphic sites -308 and -238 in the promoter region. Genotype frequencies were evaluated with Fisher's test. RESULTS: The -308 TNFG (tumor necrosis factor G) allele genotype was higher in patients with OSCC (91.2% vs. 82.2%; P = 0.02) and TNFG/A was lower (8.3% vs. 11.8%; P = 0.02); the -238 TNFG/A allele genotype was lower in patient with OSCC (2.1% vs. 6.9%; P = 0.02). CONCLUSION: This is the first report that the TNF-alpha polymorphism is associated with the risk for OSCC in Taiwan.     

Ripe areca nut extract induces G1 phase arrests and senescence-associated phenotypes in normal human oral keratinocyte

Around 200-600 million Asians chew areca (also called betel), which contains a mixture of areca nut and other ingredients. Epidemiological evidences indicated that areca use is tightly linked to oral carcinogenesis. This study investigated the effects of ripe areca nut extract (ANE) on cultured normal human oral keratinocyte (NHOK). Acute subtoxic ANE treatment inhibited DNA synthesis and induced cell cycle arrest at G1 phase in early passage (< 4th passage) cells. This was accompanied by a slight increase in the sub-G1 cellular fraction. O6-Methylguanine-DNA methyltransferase (MGMT), Hsp27 and p38MAPK was upregulated. p16 and p21 were remarkably upregulated early and declined afterwards. In contrast, the increase of dephosphorylated Rb seemed to be secondary to the episodes of p16 and p21 upregulation. To simulate the chronic areca exposure in vivo, constant ANE treatment in serial NHOK culture was performed. It resulted in a significant decrease in the population doubling, increase in senescence-associated beta-galactosidase (SA-beta-Gal) and decrease in cell proliferation in NHOK of late passages (> or = 4th passage). Induction of senescence-associated phenotypes, G2/M accumulation and genomic instability following long-term ANE treatment were also observed in a low-grade oral carcinoma cell. ANE-treated NHOK also had a higher nuclear factor-kappaB (NF-kappaB) fraction and a lower cytosolic IkappaBalpha level relative to the control in late passages. Moreover, electrophoretic mobility shift assay (EMSA) indicated that ANE treatment shifted the NF-kappaB complex from high mobility position to lower mobility position in late-passaged NHOK. ANE treatment also upregulated IL-6 and cyclooxygenase-2 (COX-2) mRNA expressions in late-passaged NHOK. In summary, our findings suggest that ANE induces the cell cycle arrest at G1/S phase and the occurrence of senescence-associated phenotypes of NHOK. The upregulation of p38MAPK, p16, p21, NF-kappaB, IL-6 and COX-2 are likely to participate in the control of these impacts.     

miR-372 inhibits p62 in head and neck squamous cell carcinoma in vitro and in vivo

Here we showed that exogenous miR-372 expression and knockdown of p62 (sequestosome1 or SQSTM1), both increased migration of head and neck squamous cell carcinoma (HNSCC) cells. p62 induced phase II detoxification enzyme NADPH quinone oxidoreductase 1 (NQO1), which decreased ROS levels and cell migration. Also, miR-372 decreased p62 during hypoxia, thus increasing cell migration. Levels of miR-372 and p62 inversely correlated in human HNSCC tissues. Plasma levels of miR-372 was associated with advanced tumor stage and patient mortality. Both plasma and salivary miR-372 levels were decreased after tumor resection. We conclude that miR-372 decreases p62, thus increasing ROS and motility in HNSCC cells.