Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation.

Microcephaly is a neurodevelopmental disorder causing significantly reduced cerebral cortex size. Many known microcephaly gene products localize to centrosomes, regulating cell fate and proliferation. Here, we identify and characterize a nuclear zinc finger protein, ZNF335/NIF-1, as a causative gene for severe microcephaly, small somatic size, and neonatal death. Znf335 null mice are embryonically lethal, and conditional knockout leads to severely reduced cortical size. RNA-interference and postmortem human studies show that ZNF335 is essential for neural progenitor self-renewal, neurogenesis, and neuronal differentiation. ZNF335 is a component of a vertebrate-specific, trithorax H3K4-methylation complex, directly regulating REST/NRSF, a master regulator of neural gene expression and cell fate, as well as other essential neural-specific genes. Our results reveal ZNF335 as an essential link between H3K4 complexes and REST/NRSF and provide the first direct genetic evidence that this pathway regulates human neurogenesis and neuronal differentiation.

Incidence of osteonecrosis of the jaw in patients with multiple myeloma and breast or prostate cancer on intravenous bisphosphonate therapy.

PURPOSE: Osteonecrosis of the jaw (ONJ) has been observed recently in patients with cancer who are receiving intravenous bisphosphonate (BP) therapy. The incidence of BP-associated ONJ has not been well established. The purpose of this study was to determine the incidence of ONJ in a cohort of patients with multiple myeloma (MM), breast cancer (BC), or prostate cancer (PC) who were receiving BP therapy. PATIENTS AND METHODS: A retrospective chart review was performed. Medical record numbers were identified by ICD-9 codes: 203.0, 203.01, 174.9, and 185.0 for active MM, MM in remission, BC, and PC, respectively. Patients were included if they were evaluated and/or treated between January 1, 2000, and December 31, 2005, and had received zoledronic acid and/or pamidronate. Patients were excluded if they had a history of radiation therapy to the jaws or of tumors or cysts. ONJ was defined as clinical evidence of "exposed necrotic bone" in the mouth. RESULTS: Through evaluation of 1,086 patient medical records, it was determined that 447 subjects met the inclusion criteria: 11 of 292 patients with MM (3.8%; 95% confidence interval [CI], 1.6%, 6.0%) had ONJ, as did 2.5% of 81 patients with BC (0%, 6.9%) and 2.9% of 69 patients with PC (0%, 5.9%). CONCLUSION: The incidence of ONJ associated with intravenous BPs was at least 3.8 per 100 patients with MM, 2.5 per 100 patients with BC, and 2.9 per 100 patients with PC during the 5-year study period. The next phase of this study involves assessment of risk factors that differentiate these patients from those treated with BPs who do not develop ONJ.