Spinocerebellar ataxia type 3 (SCA3) is an autosomal-dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the ataxin-3 gene. The resulting mutant ataxin-3 protein forms intraneuronal inclusions that lead to neurodegeneration in the cerebellum and other brain regions. This study aimed to develop a novel nonhuman primate model of SCA3 to address the limitations of existing knock-in and transgenic models using an adeno-associated virus (AAV) to deliver the mutant gene. AAV viral vectors carrying mutant ataxin-3 were stereotaxically injected into the cerebellum of monkeys. The animals were monitored over an 8-week period, during which behavioral and neuroimaging assessments were conducted. This was followed by a detailed pathological examination. The AAV vector successfully spread throughout the cerebellum, and the expression of mutant ataxin-3 was confirmed. Neuroimaging revealed a reduction in N-acetylaspartate (NAA) levels, whereas histological analysis showed significant damage to the Purkinje cell layer. Notably, the monkeys exhibited sleep disturbances, a prodromal symptom commonly observed in human patients with SCA3. AAV-mediated delivery of mutant ataxin-3 can effectively replicate the key pathological and clinical features of SCA3 in primates. This approach offers a promising new model for studying disease mechanisms and evaluating potential therapies.

OBJECTIVE: To determine the reliable perfusion parameters in dynamic contrast-enhanced MRI (DCE-MRI) for the monitoring antiangiogenic treatment in mice. MATERIALS AND METHODS: Mice, with U-118 MG tumor, were treated with either saline (n = 3) or antiangiogenic agent (sunitinib, n = 8). Before (day 0) and after (days 2, 8, 15, 25) treatment, DCE examinations using correlations of perfusion parameters (Kep, Kel, and AH from two compartment model; time to peak, initial slope and % enhancement from time-intensity curve analysis) were evaluated. RESULTS: Tumor growth rate was found to be 129% +/- 28 in control group, -33% +/- 11 in four mice with sunitinib-treatment (tumor regression) and 47% +/- 15 in four with sunitinib-treatment (growth retardation). Kep (r = 0.80) and initial slope (r = 0.84) showed strong positive correlation to the initial tumor volume (p < 0.05). In control mice, tumor regression group and growth retardation group animals, Kep (r : 0.75, 0.78, 0.81, 0.69) and initial slope (r : 0.79, 0.65, 0.67, 0.84) showed significant correlation with tumor volume (p < 0.01). In four mice with tumor re-growth, Kep and initial slope increased 20% or greater at earlier (n = 2) than or same periods (n = 2) to when the tumor started to re-grow with 20% or greater growth rate. CONCLUSION: Kep and initial slope may a reliable parameters for monitoring the response of antiangiogenic treatment.
Angiogenesis Inhibitors/therapeutic use ; Animals ; Contrast Media/*diagnostic use ; Female ; Heterografts ; Indoles/*therapeutic use ; Longitudinal Studies ; Magnetic Resonance Imaging/*methods ; Mice ; Mice, Inbred BALB C ; Neoplasm Transplantation ; Neoplasms, Experimental/*diagnosis/drug therapy/pathology ; Pyrroles/*therapeutic use ; Reproducibility of Results ; Tumor Burden

PURPOSE: Bone loss resulting from cancer treatment is an emerging problem among cancer survivors. However, the mechanism and treatment of cancer treatment-induced bone loss (CTIBL) is not fully understood. The purpose of this article was to review the recent advances in CTIBL. METHODS: A comprehensive review of the literature was conducted. RESULTS: Risk factors for CTIBL that are unique to or commonly found in cancer survivors include chemotherapy-induced menopause, anti-estrogen and anti-androgen therapies, gonadotropin-releasing hormone suppression of gonadal function, and use of glucocorticoids. Assessment of CTIBL is performed using dual X-ray absorptiometry testing for measurement of BMD levels, Fracture Risk Assessment Tool, and bone turnover markers. Initial strategies for prevention of CTIBL include lifestyle modifications such as exercise, an adequate intake of calcium and vitamin D, avoiding tobacco use, and limiting alcohol intake. Pharmacologic therapy should be considered for patients at high risk for bone loss or fracture. CONCLUSIONS: Prevention of CTIBL may be the best way to decrease morbidity and financial costs associated with osteoporosis and/or fractures. Oncology nurses should be well prepared to identify cancer survivors at risk of CTIBL, and to provide them with education regarding prevention and treatment of CTIBL.
Absorptiometry, Photon ; Breast Neoplasms ; Breast* ; Calcium ; Education ; Female ; Fractures, Bone ; Glucocorticoids ; Gonadotropin-Releasing Hormone ; Gonads ; Health Promotion ; Humans ; Life Style ; Menopause ; Osteoporosis ; Prostate* ; Prostatic Neoplasms* ; Risk Assessment ; Risk Factors ; Survivors ; Tobacco ; Vitamin D