Ectopic high endothelial venules in pancreatic ductal adenocarcinoma: A unique site for targeted delivery

BACKGROUND: Nanomedicine offers an excellent opportunity to tackle treatment-refractory malignancies by enhancing the delivery of therapeutics to the tumor site. High endothelial venules (HEVs) are found primarily in lymph nodes or formed de novo in peripheral tissues during inflammatory responses. They express peripheral node addressin (PNAd), which is recognized by the monoclonal antibody MECA79. METHODS: Here, we demonstrated that HEVs form de novo in human pancreatic ductal adenocarcinoma (PDAC). We engineered MECA79 coated nanoparticles (MECA79-NPs) that recognize these ectopic HEVs in PDAC. FINDINGS: The trafficking of MECA79-NPs following intravenous delivery to human PDAC implanted in a humanized mouse model was more robust than non-conjugated NPs. Treatment with MECA79-Taxol-NPs augmented the delivery of Paclitaxel (Taxol) to the tumor site and significantly reduced the tumor size. This effect was associated with a higher apoptosis rate of PDAC cells and reduced vascularization within the tumor. INTERPRETATION: Targeting the HEVs of PDAC using MECA79-NPs could lay the ground for the localized delivery of a wide variety of drugs including chemotherapeutic agents. FUND: National Institutes of Health (NIH) grants: T32-EB016652 (B.B.), NIH Cancer Core Grant CA034194 (L.D.S.), National Institute of Allergy and Infectious Diseases grants R01-AI126596 and R01-HL141815 (R.A.)

Mo-doped TiO2 photoanodes using [Ti4Mo2O8(OEt)10]2 bimetallic oxo cages as a single source precursor

Photoelectrochemical solar water splitting is a promising and sustainable technology for producing solar fuels such as clean hydrogen from water. A widely studied photoanode semiconductor for this application is TiO2, but it suffers from a large band gap (3.2 eV) and fast recombination of electrons and holes. Herein, we present a novel, facile and rapid strategy to develop Mo-doped TiO2 (Mo:TiO2) mixed anatase–rutile photoanodes using [Ti4Mo2O8(OEt)10]2 bimetallic oxo cages as a single source precursor. These cages dissolved in tetrahydrofuran deposit by spray pyrolysis at 150 C forming films with hierarchical porosity on the micrometer and nanometer scale. XPS, EDXS and UV-Vis spectroscopy reveal Mo atoms evaporate during annealing in air at temperatures 650–800 C, contributing to the formation of nanostructures and porosity. XPS depth profiling, XRD, EDXS, Raman, and electron paramagnetic resonance indicate that the remaining Mo atoms are well spread and incorporated in the TiO2 lattice, at interstitial or substitutional sites of the rutile or anatase phases depending on the annealing temperature. Photocurrent measurements show that Mo:TiO2 photoanodes optimized at 700 C outperform a TiO2 photoanode prepared in a similar manner by a factor of two at 1.23 VRHE. Finally, UV-Vis spectroscopy, conduction and valence band calculations, and incident-to-photon efficiency measurements show these Mo:TiO2 photoanodes possess a narrower band gap than TiO2 and higher efficiency in the visible light range (5% at 400 nm). These outcomes open a new avenue in the exploitation of titanium oxo cages and advance the development of photoelectrodes for water splitting and energy application

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events