Precision delivery of RAS-inhibiting siRNA to KRAS driven cancer via peptide-based nanoparticles

Over 95% of pancreatic adenocarcinomas (PDACs), as well as a large fraction of other tumor types, such as colorectal adenocarcinoma, are driven by KRAS activation. However, no direct RAS inhibitors exist for cancer therapy. Furthermore, the delivery of therapeutic agents of any kind to PDAC in particular has been hindered by the extensive desmoplasia and resultant drug delivery challenges that accompanies these tumors. Small interfering RNA (siRNA) is a promising modality for anti-neoplastic therapy due to its precision and wide range of potential therapeutic targets. Unfortunately, siRNA therapy is limited by low serum half-life, vulnerability to intracellular digestion, and transient therapeutic effect. We assessed the ability of a peptide based, oligonucleotide condensing, endosomolytic nanoparticle (NP) system to deliver siRNA to KRAS-driven cancers. We show that this peptide-based NP is avidly taken up by cancer cell

GeneLink: a database to facilitate genetic studies of complex traits

BACKGROUND: In contrast to gene-mapping studies of simple Mendelian disorders, genetic analyses of complex traits are far more challenging, and high quality data management systems are often critical to the success of these projects. To minimize the difficulties inherent in complex trait studies, we have developed GeneLink, a Web-accessible, password-protected Sybase database. RESULTS: GeneLink is a powerful tool for complex trait mapping, enabling genotypic data to be easily merged with pedigree and extensive phenotypic data. Specifically designed to facilitate large-scale (multi-center) genetic linkage or association studies, GeneLink securely and efficiently handles large amounts of data and provides additional features to facilitate data analysis by existing software packages and quality control. These include the ability to download chromosome-specific data files containing marker data in map order in various formats appropriate for downstream analyses (e.g., GAS and LINKAGE). Furthermore, an unlimited number of phenotypes (either qualitative or quantitative) can be stored and analyzed. Finally, GeneLink generates several quality assurance reports, including genotyping success rates of specified DNA samples or success and heterozygosity rates for specified markers. CONCLUSIONS: GeneLink has already proven an invaluable tool for complex trait mapping studies and is discussed primarily in the context of our large, multi-center study of hereditary prostate cancer (HPC). GeneLink is freely available at

Contrasting environmental drivers of adult and juvenile growth in a marine fish: implications for the effects of climate change

Many marine fishes have life history strategies that involve ontogenetic changes in the use of coastal habitats. Such ontogenetic shifts may place these species at particular risk from climate change, because the successive environments they inhabit can differ in the type, frequency and severity of changes related to global warming. We used a dendrochronology approach to examine the physical and biological drivers of growth of adult and juvenile mangrove jack (Lutjanus argentimaculatus) from tropical north-western Australia. Juveniles of this species inhabit estuarine environments and adults reside on coastal reefs. The Niño-4 index, a measure of the status of the El Niño-Southern Oscillation (ENSO) had the highest correlation with adult growth chronologies, with La Niña years (characterised by warmer temperatures and lower salinities) having positive impacts on growth. Atmospheric and oceanographic phenomena operating at ocean-basin scales seem to be important correlates of the processes driving growth in local coastal habitats. Conversely, terrestrial factors influencing precipitation and river runoff were positively correlated with the growth of juveniles in estuaries. Our results show that the impacts of climate change on these two life history stages are likely to be different, with implications for resilience and management of populations

Multiwavelength Observations of 1ES 1959+650, One Year After the Strong Outburst of 2002

In April-May 2003, the blazar 1ES 1959+650 showed an increased level of X-ray activity. This prompted a multiwavelength observation campaign with the Whipple 10 m gamma-ray telescope, the Rossi X-ray Timing Explorer, the Bordeaux Optical Observatory, and the University of Michigan Radio Astrophysical Observatory. We present the multiwavelength data taken from May 2, 2003 to June 7, 2003 and compare the source characteristics with those measured during observations taken during the years 2000 and 2002. The X-ray observations gave a data set with high signal-to-noise light curves and energy spectra; however, the gamma-ray observations did not reveal a major TeV gamma-ray flare. Furthermore, we find that the radio and optical fluxes do not show statistically significant deviations from those measured during the 2002 flaring periods. While the X-ray flux and X-ray photon index appear correlated during subsequent observations, the apparent correlation evolved significantly between the years 2000, 2002, and 2003. We discuss the implications of this finding for the mechanism that causes the flaring activity.Comment: 17 pages, 6 figures, 2 table

Combination TIGIT/PD-1 blockade enhances the efficacy of neoantigen vaccines in a model of pancreatic cancer

BackgroundCancer neoantigens are important targets of cancer immunotherapy and neoantigen vaccines are currently in development in pancreatic ductal adenocarcinoma (PDAC) and other cancer types. Immune regulatory mechanisms in pancreatic cancer may limit the efficacy of neoantigen vaccines. Targeting immune checkpoint signaling pathways in PDAC may improve the efficacy of neoantigen vaccines.MethodsWe used KPC4580P, an established model of PDAC, to test whether neoantigen vaccines can generate therapeutic efficacy against PDAC. We focused on two immunogenic neoantigens associated with genetic alterations in the CAR12 and CDK12 genes. We tested a neoantigen vaccine comprised of two 20-mer synthetic long peptides and poly IC, a Toll-like receptor (TLR) agonist. We investigated the ability of neoantigen vaccine alone, or in combination with PD-1 and TIGIT signaling blockade to impact tumor growth. We also assessed the impact of TIGIT signaling on T cell responses in human PDAC.ResultsNeoantigen vaccines induce neoantigen-specific T cell responses in tumor-bearing mice and slow KPC4580P tumor growth. However, KPC4580P tumors express high levels of PD-L1 and the TIGIT ligand, CD155. A subset of neoantigen-specific T cells in KPC4580P tumors are dysfunctional, and express high levels of TIGIT. PD-1 and TIGIT signaling blockade in vivo reverses T cell dysfunction and enhances neoantigen vaccine-induced T cell responses and tumor regression. In human translational studies, TIGIT signaling blockade in vitro enhances neoantigen-specific T cell function following vaccination.ConclusionsTaken together, preclinical and human translational studies support testing neoantigen vaccines in combination with therapies targeting the PD-1 and TIGIT signaling pathways in patients with PDAC

The Energy Spectrum of TeV Gamma-Rays from the Crab Nebula as measured by the HEGRA system of imaging air Cherenkov telescopes

The Crab Nebula has been observed by the HEGRA (High-Energy Gamma-Ray Astronomy) stereoscopic system of imaging air Cherenkov telescopes (IACTs) for a total of about 200 hrs during two observational campaigns: from September 1997 to March 1998 and from August 1998 to April 1999. The recent detailed studies of system performance give an energy threshold and an energy resolution for gamma-rays of 500 GeV and ~ 18%, respectively. The Crab energy spectrum was measured with the HEGRA IACT system in a very broad energy range up to 20 TeV, using observations at zenith angles up to 65 degrees. The Crab data can be fitted in the energy range from 1 to 20 TeV by a simple power-law, which yields dJg/dE = (2.79+/-0.02 +/- 0.5) 10^{-7} E^{-2.59 +/- 0.03 +/- 0.05}, ph m^{-2} s^{-1} TeV^{-1} The Crab Nebula energy spectrum, as measured with the HEGRA IACT system, agrees within 15% in the absolute scale and within 0.1 units in the power law index with the latest measurements by the Whipple, CANGAROO and CAT groups, consistent within the statistical and systematic errors quoted by the experiments. The pure power-law spectrum of TeV gamma-rays from the Crab Nebula constrains the physics parameters of the nebula environment as well as the models of photon emission.Comment: to appear in ApJ, 29 pages, 6 figure

Direct measurement of stellar angular diameters by the VERITAS Cherenkov Telescopes

The angular size of a star is a critical factor in determining its basic properties. Direct measurement of stellar angular diameters is difficult: at interstellar distances stars are generally too small to resolve by any individual imaging telescope. This fundamental limitation can be overcome by studying the diffraction pattern in the shadow cast when an asteroid occults a star, but only when the photometric uncertainty is smaller than the noise added by atmospheric scintillation. Atmospheric Cherenkov telescopes used for particle astrophysics observations have not generally been exploited for optical astronomy due to the modest optical quality of the mirror surface. However, their large mirror area makes them well suited for such high-time-resolution precision photometry measurements. Here we report two occultations of stars observed by the VERITAS Cherenkov telescopes with millisecond sampling, from which we are able to provide a direct measurement of the occulted stars' angular diameter at the $\leq0.1$ milliarcsecond scale. This is a resolution never achieved before with optical measurements and represents an order of magnitude improvement over the equivalent lunar occultation method. We compare the resulting stellar radius with empirically derived estimates from temperature and brightness measurements, confirming the latter can be biased for stars with ambiguous stellar classifications.Comment: Accepted for publication in Nature Astronom