Method of establishing breast cancer brain metastases affects brain uptake and efficacy of targeted, therapeutic nanoparticles

HER2‐targeted therapies effectively control systemic disease, but their efficacy against brain metastases is hindered by their low penetration of the blood‐brain and blood‐tumor barriers (BBB and BTB). We investigate brain uptake and antitumor efficacy of transferrin receptor (TfR)‐targeted, therapeutic nanoparticles designed to transcytose the BBB/BTB in three murine models. Two known models involving intracranial (IC) or intracardiac (ICD) injection of human breast cancer cells were employed, as was a third model developed here involving intravenous (IV) injection of the cells to form whole‐body tumors that eventually metastasize to the brain. We show the method of establishing brain metastases significantly affects therapeutic BBB/BTB penetration. Free drug accumulates and delays growth in IC‐ and ICD‐formed brain tumors, while non‐targeted nanoparticles show uptake and inhibition only in IC‐established metastases. TfR‐targeted nanoparticles accumulate and significantly delay growth in all three models, suggesting the IV model maintains a more intact BBB/BTB than the other models

Method of establishing breast cancer brain metastases affects brain uptake and efficacy of targeted, therapeutic nanoparticles

HER2‐targeted therapies effectively control systemic disease, but their efficacy against brain metastases is hindered by their low penetration of the blood‐brain and blood‐tumor barriers (BBB and BTB). We investigate brain uptake and antitumor efficacy of transferrin receptor (TfR)‐targeted, therapeutic nanoparticles designed to transcytose the BBB/BTB in three murine models. Two known models involving intracranial (IC) or intracardiac (ICD) injection of human breast cancer cells were employed, as was a third model developed here involving intravenous (IV) injection of the cells to form whole‐body tumors that eventually metastasize to the brain. We show the method of establishing brain metastases significantly affects therapeutic BBB/BTB penetration. Free drug accumulates and delays growth in IC‐ and ICD‐formed brain tumors, while non‐targeted nanoparticles show uptake and inhibition only in IC‐established metastases. TfR‐targeted nanoparticles accumulate and significantly delay growth in all three models, suggesting the IV model maintains a more intact BBB/BTB than the other models

Dissecting the regulatory strategies of NF-kB RelA target genes in the inflammatory response reveals differential transactivation logics

Nuclear factor κB (NF-κB) RelA is the potent transcriptional activator of inflammatory response genes. We stringently defined a list of direct RelA target genes by integrating physical (chromatin immunoprecipitation sequencing [ChIP-seq]) and functional (RNA sequencing [RNA-seq] in knockouts) datasets. We then dissected each gene’s regulatory strategy by testing RelA variants in a primary-cell genetic-complementation assay. All endogenous target genes require RelA to make DNA-base-specific contacts, and none are activatable by the DNA binding domain alone. However, endogenous target genes differ widely in how they employ the two transactivation domains. Through model-aided analysis of the dynamic time-course data, we reveal the gene-specific synergy and redundancy of TA1 and TA2. Given that post-translational modifications control TA1 activity and intrinsic affinity for coactivators determines TA2 activity, the differential TA logics suggests context-dependent versus context-independent control of endogenous RelA-target genes. Although some inflammatory initiators appear to require co-stimulatory TA1 activation, inflammatory resolvers are a part of the NF-κB RelA core response

Wild raccoons demonstrate flexibility and individuality in innovative problem-solving

Cognitive skills, such as innovative problem-solving, are hypothesized to aid animals in urban environments. However, the significance of innovation in wild populations, and its expression across individuals and socio-ecological conditions, is poorly understood. To identify how and when innovation arises in urban-dwelling species, we used advanced technologies and new testing and analytical methods to evaluate innovative problem-solving abilities of wild raccoons (Procyon lotor). We deployed multi-compartment puzzle boxes with either one or multiple solution types and identified raccoons using radio frequency identification. Raccoons solved these novel extractive foraging tasks, and their success was influenced by age and exploratory diversity. Successful raccoons always discovered multiple different solution types, highlighting flexible problem-solving. Using a unique, comparative sequence analysis approach, we found that variation in raccoon solving techniques was greater between individuals than within individuals, and this self-similarity intensified during times of competition. Finally, the inclusion of an easier solution in the multi-solution trials enabled previously unsuccessful raccoons to bootstrap their learning and successfully open multiple difficult solutions. Our study suggests that innovative problem-solving is probably influenced by many factors and has provided novel field and analytical methods, as well as new insights on the socio-ecological dynamics of urban populations

High-throughput genomic technology in research and clinical management of breast cancer. Plasma-based proteomics in early detection and therapy

Abstract Protein-based breast cancer biomarkers are a promising resource for breast cancer detection at the earliest and most treatable stages of the disease. Plasma is well suited to proteomic-based methods of biomarker discovery because it is easily obtained, is routinely used in the diagnosis of many diseases, and has a rich proteome. However, due to the vast dynamic range in protein concentration and the often uncertain tissue and cellular origin of plasma proteins, proteomic analysis of plasma requires special consideration compared with tissue and cultured cells. This review briefly touches on the search for plasma-based protein biomarkers for the early detection and treatment of breast cancer. Outlin