Phosphodiesterase 10A: a novel target for selective inhibition of colon tumor cell growth and ß-catenin-dependent TCF transcriptional activity.

The cyclic nucleotide phosphodiesterase 10A (PDE10) has been mostly studied as a therapeutic target for certain psychiatric and neurological conditions, although a potential role in tumorigenesis has not been reported. Here we show that PDE10 is elevated in human colon tumor cell lines compared with normal colonocytes, as well as in colon tumors from human clinical specimens and intestinal tumors from Apc(Min/+) mice compared with normal intestinal mucosa, respectively. An isozyme and tumor-selective role of PDE10 were evident by the ability of small-molecule inhibitors and small interfering RNA knockdown to suppress colon tumor cell growth with reduced sensitivity of normal colonocytes. Stable knockdown of PDE10 by short hairpin RNA also inhibits colony formation and increases doubling time of colon tumor cells. PDE10 inhibition selectively activates cGMP/cGMP-dependent protein kinase signaling to suppress ß-catenin levels and T-cell factor (TCF) transcriptional activity in colon tumor cells. Conversely, ectopic expression of PDE10 in normal and precancerous colonocytes increases proliferation and activates TCF transcriptional activity. These observations suggest a novel role of PDE10 in colon tumorigenesis and that inhibitors may be useful for the treatment or prevention of colorectal cancer.

Cementifying fibroma presenting as proptosis.

Cementifying fibromas are rare fibro-osseous tumors that arise from the periodontal ligament. These tumors are usually small, asymptomatic lesions noted on routine dental radiography, but they can develop into aggressive, expansile masses. The authors report the case of a 12-year-old boy with a tumor involving the maxillary, ethmoid, and frontal sinuses that extended to the right orbit, causing proptosis and disfigurement of the right side of his face. Removal of the tumor with facial reconstruction resulted in significant improvement of vision, despite long-standing disc edema and tension on the optic nerve. On histopathologic examination the lesion was found to be a cementifying fibroma.

Use of in vitro models of bovine corneal endothelial cells to determine the relative toxicity of viscoelastic agents.

Healon, Viscoat and Amvisc Plus (Amvisc+) are commercial preparations containing hyaluronic acids of different molecular weights and viscosities. Cytotoxicity of these preparations to the corneal endothelium may be a factor in postsurgical recovery of the cornea. Using different in vitro models of bovine corneal endothelial cells (BCEC), three experiments to compare the possible detrimental effects of these viscoelastic agents were designed. In the confluent model, confluent BCEC were exposed to viscoelastic agents and the control to Balanced Salt Solution Plus (BSS+) for one hour and the nuclear density (nuclei/mm2) was assessed at 24 and 168 hours. At both times, the BCEC exposed to Healon showed the highest nuclear densities. In the preconfluent model, BCEC were treated for one hour at 48 hours post-seeding. The nuclear density of the BCEC was assessed at 24 hours. The BCEC exposed to Healon showed the highest density, followed by those exposed to Amvisc+ and then Viscoat. In the proliferation model, BCEC were cultured in media containing 1%, 5%, and 10% viscoelastic agents. The growth curves based on nuclear densities at 0, 24, 72, 120, and 168 hours in all treatment groups did not differ significantly from the control. The results indicate that the undiluted Healon was significantly less toxic in the preconfluent and confluent BCEC models.

Apparent cytomegalovirus epithelial keratitis in a cardiac transplant recipient.

A 44-year-old immunosuppressed man developed initial symptoms of intermittent irritation of the left eye three months after cardiac transplantation. Symptoms increased, with decreased vision, photophobia, and lacrimation. Slit lamp examination showed slightly raised, swollen, grayish epithelium in a broad multibranching dendritic pattern associated with fine and medium punctate epithelial erosions that stained slightly with fluorescein. Histopathologic study of the corneal epithelial scraping demonstrated swollen epithelial cells with intranuclear and intracytoplasmic viral inclusions. Viral cultures manifested a cytopathic pattern characteristic of cytomegalovirus 14 days after inoculation on human embryonic lung cells (MRC-5). Pretransplantation cytomegalovirus IgM and IgG serologic titers were negative (less than 1:16 for IgG, no IgM noted) until the onset of symptoms. Subsequently, IgM titers rose against cytomegalovirus consistent with concurrent infection.

Muramyl tripeptide: an effective immunotherapy in the surgical setting for pediatric abdominal neoplasms.

A potential complication of intraperitoneal neoplasms is the occurrence of peritoneal metastases. This experiment hypothesizes that resident peritoneal macrophages, activated by muramyl tripeptide (MTP-PE), will destroy peritoneal tumor. MTP-PE is a lipophilic derivative of the mycobacteria cell wall component responsible for induction of cellular immunity and activation of macrophages to a tumoricidal state. A transplantable murine fibrosarcoma, MCA-F was utilized. Murine hosts were challenged intraperitoneally with 5 X 10(3) MCA-F cells. Treatment with MTP-PE micelles or liposome-encapsulated MTP-PE was initiated 48 hours prechallenge and on the day of tumor challenge and continued at 72 hour intervals for the subsequent 21 days. Hosts were observed for survival. At 45 days after tumor challenge, all untreated control animals had succumbed to overwhelming neoplastic disease. In contrast, 30% of the mice treated with liposome-encapsulated MTP-PE (P less than .05) and 50% of the animals treated with MTP-PE micelles (P less than .001) remained alive at 60 days. Followed for 120 days, 20% of MTP-PE micelle treated mice are long-term survivors. These results suggest that control of intraperitoneal seedings may be achieved with MTP-PE when the tumor burden is small.