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

GenomeVIP: A cloud platform for genomic variant discovery and interpretation

Identifying genomic variants is a fundamental first step toward the understanding of the role of inherited and acquired variation in disease. The accelerating growth in the corpus of sequencing data that underpins such analysis is making the data-download bottleneck more evident, placing substantial burdens on the research community to keep pace. As a result, the search for alternative approaches to the traditional “download and analyze” paradigm on local computing resources has led to a rapidly growing demand for cloud-computing solutions for genomics analysis. Here, we introduce the Genome Variant Investigation Platform (GenomeVIP), an open-source framework for performing genomics variant discovery and annotation using cloud- or local high-performance computing infrastructure. GenomeVIP orchestrates the analysis of whole-genome and exome sequence data using a set of robust and popular task-specific tools, including VarScan, GATK, Pindel, BreakDancer, Strelka, and Genome STRiP, through a web interface. GenomeVIP has been used for genomic analysis in large-data projects such as the TCGA PanCanAtlas and in other projects, such as the ICGC Pilots, CPTAC, ICGC-TCGA DREAM Challenges, and the 1000 Genomes SV Project. Here, we demonstrate GenomeVIP's ability to provide high-confidence annotated somatic, germline, and de novo variants of potential biological significance using publicly available data sets.</jats:p

TAML/H2O2 oxidative degradation of metaldehyde: Pursuing better water treatment for the most persistent pollutants.

The extremely persistent molluscicide, metaldehyde, widely used on farms and gardens, is often detected in drinking water sources of various countries at concentrations of regulatory concern. Metaldehyde contamination restricts treatment options. Conventional technologies for remediating dilute organics in drinking water, activated carbon and ozone, are insufficiently effective against metaldehyde. Some treatment plants have resorted to effective, but more costly UV/H2O2. Here we have examined if TAML/H2O2 can decompose metaldehyde under laboratory conditions to guide development of a better real world option. TAML/H2O2 slowly degrades metaldehyde to acetaldehyde and acetic acid. Nuclear magnetic resonance spectroscopy ((1)H NMR) was used to monitor the degradation-the technique requires a high metaldehyde concentration (60 ppm). Within the pH range of 6.5-9, the reaction rate is greatest at pH 7. Under optimum conditions, one aliquot of TAML 1a (400 nM) catalyzed 5% degradation over 10 hours with a turnover number of 40. Five sequential TAML aliquots (2 μM overall) effected a 31% removal over 60 hours. TAML/H2O2 degraded metaldehyde steadily over many hours, highlighting an important long-service property. The observation of metaldehyde decomposition under mild conditions provides a further indication that TAML catalysis holds promise for advancing water treatment. These results have turned our attention to more aggressive TAML activators in development, which we expect will advance the observed technical performance

Epigenetic regulation during cancer transitions across 11 tumour types

Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasi

Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease

Patient-derived xenograft (PDX) models in basic and translational breast cancer research

Patient-derived xenograft (PDX) models of a growing spectrum of cancers are rapidly supplanting long-established traditional cell lines as preferred models for conducting basic and translational preclinical research. In breast cancer, to complement the now curated collection of approximately 45 long-established human breast cancer cell lines, a newly formed consortium of academic laboratories, currently from Europe, Australia, and North America, herein summarizes data on over 500 stably transplantable PDX models representing all three clinical subtypes of breast cancer (ER+, HER2+, and "Triple-negative" (TNBC)). Many of these models are well-characterized with respect to genomic, transcriptomic, and proteomic features, metastatic behavior, and treatment response to a variety of standard-of-care and experimental therapeutics. These stably transplantable PDX lines are generally available for dissemination to laboratories conducting translational research, and contact information for each collection is provided. This review summarizes current experiences related to PDX generation across participating groups, efforts to develop data standards for annotation and dissemination of patient clinical information that does not compromise patient privacy, efforts to develop complementary data standards for annotation of PDX characteristics and biology, and progress toward "credentialing" of PDX models as surrogates to represent individual patients for use in preclinical and co-clinical translational research. In addition, this review highlights important unresolved questions, as well as current limitations, that have hampered more efficient generation of PDX lines and more rapid adoption of PDX use in translational breast cancer research

Gaining Insight into the Design of Oxidation Catalysts by Comparing the Rate and Equilibrium Constants That Define the Technical Performance of a Suite of TAML Activators Including Design Related Studies for Environmental Performance

<p>Iron tetraamido macrocylic ligand complexes (TAMLs) have been found to catalyze the oxidation of micropollutants by H2O2 under mild conditions. TAML development has long been focused on the design of environmentally benign catalysts. </p

Unifying Evaluation of the Technical Performances of Iron-Tetra-amido Macrocyclic Ligand Oxidation Catalysts

The main features of iron-tetra-amido macrocyclic ligand complex (a sub-branch of TAML) catalysis of peroxide oxidations are rationalized by a two-step mechanism: Fe^III + H₂O₂ → Active catalyst (Ac) (<i>k</i>_I), and Ac + Substrate (S) → Fe^III + Product (<i>k</i>_II). TAML activators also undergo inactivation under catalytic conditions: Ac → Inactive catalyst (<i>k</i>_i). The recently developed relationship, ln­(<i>S</i>₀/<i>S</i>_∞) = (<i>k</i>_II/<i>k</i>_i)­[Fe^III]_tot, where <i>S</i>₀ and <i>S</i>_∞ are [S] at time <i>t</i> = 0 and ∞, respectively, gives access to <i>k</i>_i under any conditions. Analysis of the rate constants <i>k</i>_I, <i>k</i>_II, and <i>k</i>_i at the environmentally significant pH of 7 for a broad series of TAML activators has revealed a 6 orders of magnitude reactivity differential in both <i>k</i>_II and <i>k</i>_i and 3 orders differential in <i>k</i>_I. Linear free energy relationships linking <i>k</i>_II with <i>k</i>_i and <i>k</i>_I reveal that the reactivity toward substrates is related to the instability of the active TAML intermediates and suggest that the reactivity in all three processes derives from a common electronic origin. The reactivities of TAML activators and the horseradish peroxidase enzyme are critically compared

Zebrafish assays as developmental toxicity indicators in the green design of TAML oxidation catalysts

TAML activators promise a novel water treatment approach by efficiently catalysing peroxide-based degradation of chemicals of high concern at environmental concentrations. Green design ethics demands an exploration of TAML toxicity. Exposure to high concentrations of certain activators caused adverse effects in zebrafish. At typical TAML operational concentrations, development was not perturbed

TAML/H₂O₂ Oxidative Degradation of Metaldehyde: Pursuing Better Water Treatment for the Most Persistent Pollutants

The extremely persistent molluscicide, metaldehyde, widely used on farms and gardens, is often detected in drinking water sources of various countries at concentrations of regulatory concern. Metaldehyde contamination restricts treatment options. Conventional technologies for remediating dilute organics in drinking water, activated carbon, and ozone, are insufficiently effective against metaldehyde. Some treatment plants have resorted to effective, but more costly UV/H₂O₂. Here we have examined if TAML/H₂O₂ can decompose metaldehyde under laboratory conditions to guide development of a better real world option. TAML/H₂O₂ slowly degrades metaldehyde to acetaldehyde and acetic acid. Nuclear magnetic resonance spectroscopy (¹H NMR) was used to monitor the degradationthe technique requires a high metaldehyde concentration (60 ppm). Within the pH range of 6.5–9, the reaction rate is greatest at pH 7. Under optimum conditions, one aliquot of TAML <b>1a</b> (400 nM) catalyzed 5% degradation over 10 h with a turnover number of 40. Five sequential TAML aliquots (2 μM overall) effected a 31% removal over 60 h. TAML/H₂O₂ degraded metaldehyde steadily over many hours, highlighting an important long-service property. The observation of metaldehyde decomposition under mild conditions provides a further indication that TAML catalysis holds promise for advancing water treatment. These results have turned our attention to more aggressive TAML activators in development, which we expect will advance the observed technical performance