RNAi-Mediated PD-L1 Inhibition for Pancreatic Cancer Immunotherapy.

The recent past has seen impressive progress in the treatment of various malignancies using immunotherapy. One of the most promising approaches involves immune checkpoint inhibitors. However, the clinical results with these agents have demonstrated variability in the response. Pancreatic cancer, in particular, has proven resistant to initial immunotherapy approaches. Here, we describe an alternative strategy that relies on combining gemcitabine and a novel programmed death-ligand 1 (PD-L1) inhibitor, termed MN-siPDL1. MN-siPDL1 incorporates small interfering RNA against PD-L1 (siPDL1) conjugated to a magnetic nanocarrier (MN). We show that noninvasive magnetic resonance imaging (MRI) could be used to monitor therapeutic response. Combination therapy consisting of gemcitabine and MN-siPDL1 in a syngeneic murine pancreatic cancer model resulted in a significant reduction in tumor growth and an increase in survival. Following optimization, a 90% reduction in tumor volume was achieved 2 weeks after the beginning of treatment. Whereas 100% of the control animals had succumbed to their tumors by week 6 after the beginning of treatment, there was no mortality in the experimental group by week 5, and 67% of the experimental animals survived for 12 weeks. This method could provide therapeutic benefit against an intractable disease for which there are no effective treatments and which is characterized by a mere 1% 5-year survival.

Oral calcium supplements do not affect the progression of aortic valve calcification or coronary artery calcification.

BACKGROUND: The use of oral calcium supplementation among the elderly for prevention and treatment of osteoporosis and osteopenia is increasing. The incidence of aortic valve disease and coronary artery disease also is increasing. No study thus far has been done to demonstrate whether this affects the progression of calcification in both the valves and vasculature. We sought to determine whether ingestion of oral calcium supplementation has an effect on aortic valve calcification (AVC) and coronary artery calcification (CAC). METHODS: We performed an independent assessment of AVC, CAC, and calcium supplementation among patients enrolled in the Epidemiology of Coronary Artery Calcification study who were >60 years of age and had baseline and 4-year follow-up AVC data. In this population-based study of Olmsted County (Minnesota) residents, AVC and CAC scores were determined prospectively by electron beam computed tomography. We evaluated baseline demographic data and analyzed whether those patients using calcium supplementation had a higher rate of progression of both AVC and CAC. RESULTS: We identified 257 patients (mean age, 67.8+/-5.2 years), 144 of whom were women. Twenty-five patients (all women) reported using calcium supplements. Analysis of the 144 women (25 taking calcium supplementation) showed there was no difference in the progression of AVC (mean difference in baseline and follow-up AVC score; no supplement versus supplement, 30+/-9 vs 39+/-28; P=.73) or CAC (mean difference in baseline and follow-up CAC score; no supplement vs supplement, 47+/-15 vs 112+/-22; P=.154). There were no significant differences between the 2 groups with regard to baseline AVC, serum calcium, renal function, diabetes, hypertension, cholesterol, or body mass index. CONCLUSION: In this community-based observational study with a 4-year follow-up, no significant increased progression of AVC or CAC was found in women taking oral calcium supplementation. Larger prospective, randomized studies are needed to confirm these findings.

Evaluation and clinical implications of aortic valve calcification measured by electron-beam computed tomography.

BACKGROUND: Electron-beam computed tomography (EBCT) is used to measure coronary calcification but not for aortic valve calcification (AVC). Its accuracy, association with aortic stenosis (AS) severity, and diagnostic and prognostic value with respect to AVC are unknown. METHODS AND RESULTS: In 30 explanted aortic valves, the AVC score by EBCT (1125+/-1294 Agatston units [AU]) showed a strong linear correlation (r=0.96, P<0.0001) with valvular calcium weight (653+/-748 mg) by pathology that allowed estimation of calcium weight as AVC score/1.7, with a small standard error of the estimate (53 mg). In 100 consecutive clinical patients, we measured AVC by EBCT and AS severity by echocardiographic aortic valve area (AVA). The AVC score was 1316+/-1749 AU (range 0 to 7226 AU). Intraobserver and interobserver variabilities were excellent (4+/-4% and 4+/-10%, respectively). AVC and AVA were strongly associated (r=0.79, P<0.0001) but had a curvilinear relationship that suggested that AVC and AVA provide complementary information. AVC score > or =1100 AU provided 93% sensitivity and 82% specificity for diagnosis of severe AS (AVA <1 cm2), with a receiver operator characteristic curve area of 0.89. AVC assessment by echocardiography was often more severe than by EBCT (P<0.0001). During follow-up, 22 patients either died, developed heart failure, or required surgery. With adjustment for age, sex, symptoms, ejection fraction, and AVA, the AVC score was independently predictive of event-free survival (risk ratio 1.06 per 100-AU increment [1.02 to 1.10], P<0.001), even after adjustment for echocardiographic calcifications. CONCLUSIONS: AVC is accurately and reproducibly measured by EBCT and shows a strong association and diagnostic value for severe AS. The curvilinear relationship between AVC and AVA suggests these measures are complementary, and indeed, AVC provides independent outcome information. Thus, AVC is an important measurement in the evaluation of patients with AS.