YAP和Caspase在恶性肿瘤中的作用机制及其关联的研究进展

正常情况下细胞增殖与凋亡之间保持着动态平衡,维持着机体的生理状态,细胞异常增殖或凋亡抑制时细胞过度增殖组织异常生长导致肿瘤的发生。Hippo通路是最近发现的一条细胞信号传导通路,主要功能有调控器官体积、保持细胞增殖凋亡平衡、细胞接触性抑制的调节等。YAP是Hippo通路上的重要因子,YAP表达异常可导致Hippo通路不能正常发挥作用而细胞异常增殖导致肿瘤的发生。Caspase是与细胞凋亡密切相关的蛋白水解酶家族,一般以酶原形式存在,在凋亡信号的作用下激活启动型Caspase引发Caspase级联反应导致细胞凋亡,其功能异常导致各种相关疾病的发生。本文将介绍Hippo通路的主要组成及其作用机制,YAP和Caspase基因的作用机制及其与肿瘤发生发展的相关性。     

Sleep duration and body mass index in a rural population

BACKGROUND: A growing body of epidemiological evidence suggests an association between short sleep duration and obesity. Recently, potential hormonal links have been observed that may account for the relationship. The possible connection between sleep duration and body mass index (BMI) has not been explored in rural populations. Rural populations are of interest because obesity rates are high and lifestyle patterns of nutrition, physical activity, work hours, and sleep may differ from those in urban and suburban populations. We conducted this study to determine whether short sleep duration is related to BMI and obesity in a rural population in southeast Iowa. METHODS: We conducted a cross-sectional analysis of data collected in the Keokuk County Rural Health Cohort Study, 1999-2004. Study participants were from a population-based sample consisting of 990 employed adults in a rural community in southeastern Iowa. The main outcome measure was BMI. Multiple linear regression modeling was used to adjust for potential confounding variables. RESULTS: Self-reported sleep duration on weeknights was negatively correlated (beta = -0.42; 95% confidence interval, -0.77 to -0.07) with higher BMI after adjusting for sex, age, educational achievement, physical job demand, household income, depressive symptoms, marital status, alcohol consumption, and snoring. CONCLUSION: These data support an association between short sleep duration and higher BMI in this rural population, which is consistent with the relationship found in other settings.     

Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition

Combinations of MAP/ERK kinase (MEK) and phosphoinositide 3-kinase (PI3K) inhibitors have shown promise in preclinical cancer models, leading to the initiation of clinical trials cotargeting these two key cancer signaling pathways. GDC-0973, a novel selective MEK inhibitor, and GDC-0941, a class I PI3K inhibitor, are in early stage clinical trials as both single agents and in combination. The discovery of these selective inhibitors has allowed investigation into the precise effects of combining inhibitors of two major signaling branches downstream of RAS. Here, we investigated multiple biomarkers in the mitogen-activated protein kinase (MAPK) and PI3K pathway to search for points of convergence that explain the increased apoptosis seen in combination. Using washout studies in vitro and alternate dosing schedules in mice, we showed that intermittent inhibition of the PI3K and MAPK pathway is sufficient for efficacy in BRAF and KRAS mutant cancer cells. The combination of GDC-0973 with the PI3K inhibitor GDC-0941 resulted in combination efficacy in vitro and in vivo via induction of biomarkers associated with apoptosis, including Bcl-2 family proapoptotic regulators. Therefore, these data suggest that continuous exposure of MEK and PI3K inhibitors in combination is not required for efficacy in preclinical cancer models and that sustained effects on downstream apoptosis biomarkers can be observed in response to intermittent dosing.     

Topotecan and vincristine combination is effective against advanced bilateral intraocular retinoblastoma and has manageable toxicity

BACKGROUND:

New, effective chemotherapeutic agents are needed for intraocular retinoblastoma.

METHODS:

This institutional clinical trial sought to estimate the rate of response to 2 courses of vincristine and topotecan (VT) window therapy in patients with bilateral retinoblastoma and advanced disease (Reese‐Ellsworth group IV or V) in at least 1 eye. The topotecan dose started at 3 mg/m²/day for 5 days and was adjusted to target a systemic exposure of 140 ± 20 ng/mL · hour. The vincristine dose was 0.05 mg/kg for patients <12 months of age and 1.5 mg/m² for those >12 months of age at diagnosis.

RESULTS:

From February 2005 to June 2010, 27 patients received VT window therapy. Median age at enrollment was 8.1 months (range, 0.7‐22.1 months). Twenty‐four patients (88.9%) responded to window therapy (95% confidence interval = 71.3%‐96.9%). Hematologic toxicity comprised grade 4 neutropenia (n = 27), grade 3 anemia (n = 19), and grade 3/4 thrombocytopenia (n = 16). Thirteen patients had grade 3 nonhematologic toxicity. Granulocyte colony‐stimulating factor support was added after 10 patients had been treated, and it significantly reduced the duration of grade 4 neutropenia (median, 7 vs 24 days; P < .001). Pharmacokinetic studies showed rapid changes in topotecan clearance rates during the first year of life.

CONCLUSIONS:

The combination of topotecan and vincristine is effective for the treatment of advanced intraocular retinoblastoma. Granulocyte colony‐stimulating factor treatment alleviates the duration of grade 4 neutropenia. Appropriate topotecan starting doses for patients 0‐3, 3‐6, 6‐9, 9‐12, and >12 months of age are specified. Cancer 2012. © 2012 American Cancer Society.