The recently developed siRNA oligonucleotides are an attractive alternative to antisense as a therapeutic modality because of their robust, gene selective silencing of drug target protein expression. To achieve therapeutic success, however, several hurdles must be overcome including rapid clearance, nuclease degradation, and inefficient intracellular localization. In this presentation, we discuss design strategies for development of self-assembling nanoscale carriers for neovasculature targeted delivery of siRNA inhibiting tumor or ocular angiogenesis. D

Objective This study aimed to describe the implementation of preoperative geriatric assessment (GA) in patients undergoing major cancer surgery and to determine predictors of postoperative delirium. Summary Background Data Geriatric surgical patients have unique vulnerabilities and are at increased risk of developing postoperative delirium. Methods Geriatricians at Memorial Sloan Kettering Cancer Center risk-stratify surgical patients with solid tumors, aged ≥ 75 years using preoperative GA, which includes basic and instrumental activities of daily living (ADLs, IADLs), cognition (Mini-Cog Test), history of falls, nutritional state, and comorbidities (Charlson Comorbidity Index [CCI]). The Geriatrics Service evaluates patients for postoperative delirium using the Confusion Assessment Method (CAM). A retrospective review was performed. The associations between GA and postoperative outcomes were evaluated. Univariate logistic regression analysis was performed to determine the predictive value of GA for postoperative delirium, and a multivariate model was built. Results In total, 416 patients who received preoperative evaluation by the Geriatrics Service between September 1, 2010, and December 31, 2011, were included. Delirium occurred in 19% of patients. Patients with delirium had longer length of hospital stay (P<0.001) and greater likelihood of discharge to a rehabilitation facility (P<0.001). CCI score, history of falls, dependent on IADL, and abnormal Mini-Cog Test results predicted postoperative delirium on univariate analysis. Developed using a stepwise selection method, a multivariate model to predict delirium is presented including CCI score (P=0.032), dependence IADLs (P=0.011) and falls history (P=0.056). Conclusions Preoperative GA is feasible and may achieve a better understanding of older patients’ perioperative risks, including delirium.

BackgroundPrevious association studies examining the relationship between the APOC1 polymorphism and susceptibility to Alzheimer’s disease (AD) have shown conflicting results, and it is not clear if an APOC1 variant acts as a genetic risk factor in AD etiology across multiple populations.MethodsTo confirm the risk association between APOC1 and AD, we designed a case-control study and also performed a meta-analysis of previously published studies.ResultsSeventy-nine patients with AD and one hundred fifty-six unrelated controls were included in case-control study. No association was found between the variation of APOC1 and AD in stage 1 of our study. However, our meta-analysis pooled a total of 2092 AD patients and 2685 controls. The APOC1 rs11568822 polymorphism was associated with increased AD risk in Caucasians, Asians and Caribbean Hispanics, but not in African Americans. APOE ε4 carriers harboring the APOC1 insertion allele, were more prevalent in AD patients than controls (χ2 = 119.46, OR = 2.79, 95% CI = 2.31–3.36, P<0.01).ConclusionsThe APOC1 insertion allele, in combination with APOE ε4, likely serves as a potential risk factor for developing AD.

Oxidative stress plays a critical role in the pathophysiology of contrast-induced nephropathy (CIN). Since the specific treatment of CIN remains an unmet medical need, it is imperative to find an effective strategy against the clinical management of CIN. The transcription factor Nrf2 is known to regulate antioxidative stress response. The aim of the present study was to assess the effects of tert-butylhydroquinone (t-BHQ), an activator of Nrf2, in the prevention of CIN and elucidate the underlying mechanism of its action in vitro and in vivo. We established a rat model of CIN and treated the animals with t-BHQ (25 mg/kg). The effects of t-BHQ treatment on CIN rats were elucidated by assessing renal function, HE staining, immunohistochemistry, and western blotting. We also studied the activity of oxidative stress-related markers, such as intracellular ROS level, MDA level, SOD2 activity, and GSH/GSSG ratio. We validated our results by siRNA-mediated silencing of Nrf2 in HK-2 cells exposed to the radiocontrast agent. Treatment with t-BHQ significantly ameliorated the renal function and the histopathological lesions in CIN rats. Further, pretreatment with t-BHQ significantly increased the SOD2 activity and GSH/GSSG ratio and decreased the levels of ROS and MDA in animals subjected to ioversol exposure. In addition, t-BHQ treatment increased the expression of Nrf2, Sirt3, and SOD2 and concomitantly decreased the expression of acetylated-SOD2. When Nrf2-silenced HK-2 cells were exposed to radiocontrast agent, they suffered severe cell oxidative stress, exhibited lower expression of Sirt3 and SOD2, and expressed higher levels of acetylated-SOD2; however, t-BHQ treatment did not affect the protein expression of these indicators in si-Nrf2 HK-2 cells. Our findings suggested that Nrf2 plays an important role in the regulation of the Sirt3/SOD2 antioxidative pathway, and t-BHQ may be a potential agent to ameliorate radiocontrast-induced nephropathy via activating the Nrf2/Sirt3/SOD2 signaling pathway in vitro and in vivo.