DNA demethylase activity maintains intestinal cells in an undifferentiated state following loss of APC.

Although genome-wide hypomethylation is a hallmark of many cancers, roles for active DNA demethylation during tumorigenesis are unknown. Here, loss of the APC tumor suppressor gene causes upregulation of a DNA demethylase system and the concomitant hypomethylation of key intestinal cell fating genes. Notably, this hypomethylation maintained zebrafish intestinal cells in an undifferentiated state that was released upon knockdown of demethylase components. Mechanistically, the demethylase genes are directly activated by Pou5f1 and Cebpß and are indirectly repressed by retinoic acid, which antagonizes Pou5f1 and Cebpß. Apc mutants lack retinoic acid as a result of the transcriptional repression of retinol dehydrogenase l1 via a complex that includes Lef1, Groucho2, Ctbp1, Lsd1, and Corest. Our findings imply a model wherein APC controls intestinal cell fating through a switch in DNA methylation dynamics. Wild-type APC and retinoic acid downregulate demethylase components, thereby promoting DNA methylation of key genes and helping progenitors commit to differentiation.

A Survey of Current Blepharospasm Treatment Patterns Among Oculoplastic Surgeons.

PURPOSE: To determine the current practice pattern of ASOPRS members injecting onabotulinumtoxinA for Blepharospasm. METHODS: An invitation to participate in a web-based, anonymous survey was sent to current members of American Society of Ophthalmic Plastic and Reconstructive Surgeons (ASOPRS) via e-mail. The survey consisted of 9 questions and used the Research Electronic Data Capture online application. Institutional Review board approval was obtained for this study. RESULTS: Forty-one percent of ASOPRS members invited responded to the survey. The mean initial dose of onabotulinumtoxinA used was 22.5 units per side and the most common number of injection sites was greater than 7 per side. Only 12 of the 247 responding surgeons who treat benign essential blepharospasm with onabotulinumtoxinA reported that their initial injection pattern is with 3 or fewer sites per side as per the Food and Drug Administration (FDA)-approved recommendations. CONCLUSIONS: Survey of current trends in the management of blepharospasm with onabotulinumtoxinA by ASOPRS members showed that the mean initial dose used to treat blepharospasm patients was 22.5 (standard deviation ± 9.5 units, range 2.5 to 50 units per side). There is significant variation in the treatment doses. The majority of ASOPRS members do not follow the FDA-approved recommendation for dosing.

Erotic asphyxiation: May have you seeing double.

PURPOSE: If not recognized and treated promptly, nontraumatic orbital subperiosteal hemorrhage (NTSOH) can have serious sequelae including compressive optic neuropathy and permanent vision loss. The following case establishes erotic asphyxiation as a cause of NTSOH. OBSERVATIONS: A 29 year-old patient presented with diplopia and periorbital edema and ecchymosis. Complete ophthalmologic exam showed no optic neuropathy. Computed tomography of the orbits revealed a subperiosteal fluid collection in the right orbit. The patient had no risk factors for NTSOH, but after detailed questioning she admitted to participating in erotic asphyxiation prior to the onset of her symptoms. She was observed and subsequently lost to follow up. CONCLUSIONS AND IMPORTANCE: To the authors' knowledge, erotic asphyxiation as a cause of orbital subperiosteal hematoma has not been previously reported. Lack of knowledge about erotic asphyxiation amongst healthcare providers may contribute to hesitance to directly question patients about the practice. Clinicians should be aware of erotic asphyxiation as a potential cause of orbital subperiosteal hemorrhage.

Primary Epithelioid Sarcoma of Orbit: A Case Report and Review of the Literature.

Epithelioid sarcoma is a rare high-grade malignancy identified by Enzinger in 1970. It accounts for 1% of all reported soft tissue sarcomas and presents most commonly in distal upper extremities in young adults with a male predominance. At this time, there are only 5 previously reported cases of primary epithelioid sarcoma of the orbit. We present a primary orbital epithelioid sarcoma case of a patient who underwent orbital exenteration followed by external beam radiation treatment. Because the literature is limited, this is to our knowledge the largest descriptive analysis of cases of orbital epithelioid sarcoma. We also provide a detailed review of all the previously reported primary orbital epithelioid sarcoma cases, as well as a discussion on the use of postoperative radiation therapy for patients with epithelioid sarcoma. Surgical resection followed by adjuvant radiation therapy appears to be a safe option for local treatment of this rare malignancy, but further future studies are needed of this rare clinical situation in order to better understand and optimize treatment for patients with orbital epithelioid sarcoma.

New perspectives on APC control of cell fate and proliferation in colorectal cancer.

Aberrant Wnt/beta-catenin signaling following loss of the tumor suppressor adenomatous polyposis coli (APC) is thought to initiate colon adenoma formation. Considerable evidence for this model has come from mouse models of Apc truncation where nuclear beta-catenin is detectable soon after loss of Apc. However, examination of tumors from familial adenomatous polyposis coli (FAP) patients has failed to confirm the presence of nuclear beta-catenin in early lesions following APC loss despite robust staining in later lesions. This observation presents the possibility that colon adenomas arise through a beta-catenin-independent function of APC. Additionally, there is a well established role for inflammation and specifically COX-2 and prostaglandin E2 in the progression of colorectal cancer. Here we review the current literature regarding the functions of APC in regulating WNT/beta-catenin signaling as well as its control of intestinal cell fate and differentiation. Further, we provide a brief commentary on our current understanding of the role that inflammation plays in colorectal tumorigenesis and how it fits in with APC dysfunction. Though there are currently contrasting models to explain colon tumorigenesis, our goal is to begin to reconcile data from multiple different model systems and provide a functional view into the initiation and progression of colon cancer.