Breast cancer brain metastases: evidence for neuronal-like adaptation in a ‘breast-to-brain’ transition?

Abstract Brain metastases remain a significant challenge in the treatment of breast cancer patients due to the unique environment posed by the central nervous system. A better understanding of the biology of breast cancer cells that have metastasized to the brain is required to develop improved therapies. A recent Proceedings of the National Academy of Sciences article demonstrates that breast cancer cells in the brain microenvironment express γ-aminobutyric acid (GABA)-related genes, enabling them to utilize GABA as an oncometabolite, thus gaining a proliferative advantage. In this viewpoint, we highlight these findings and their potential impact on the treatment of breast cancer brain metastases

Efficacy and pharmacokinetics of a modified acid-labile docetaxel-PRINT ® nanoparticle formulation against non-small-cell lung cancer brain metastases

Particle Replication in Nonwetting Templates (PRINT®) PLGA nanoparticles of docetaxel and acid-labile C2-dimethyl-Si-Docetaxel were evaluated with small molecule docetaxel as treatments for non-small-cell lung cancer brain metastases

Design of an affordable electric snowmobile -Done Right

ABSTRACT The University of Alaska Fairbanks Nanook EV team's latest electric snowmobile has a 51.5 km (32 mi) range at 32 km/h (20 mi/h) under optimal snow conditions. Building on the 2011 competition success (winning Best Design with a Ski-Doo Tundra 300F), we started this project with a much improved chassis: a Ski-Doo Renegade Sport 550

Cre-dependent DREADD (Designer Receptors Exclusively Activated by Designer Drugs) mice: Conditional DREADD Mice

DREADDs, designer receptors exclusively activated by designer drugs, are engineered G protein-coupled receptors (GPCR) which can precisely control GPCR signaling pathways (for example, Gq, Gs and Gi). This chemogenetic technology for control of GPCR signaling has been successfully applied in a variety of in vivo studies, including in mice, to remotely control GPCR signaling, for example, in neurons, glia cells, pancreatic beta-cells, or cancer cells. In order to fully explore the in vivo applications of the DREADD technology we generated hM3Dq and hM4Di strains of mice which allow for Cre recombinase-mediated restricted expression of these pathway-selective DREADDs. With the many Cre driver lines now available, these DREADD lines will be applicable to studying a wide array of research and preclinical questions

Integrated RNA and DNA sequencing reveals early drivers of metastatic breast cancer

Breast cancer metastasis remains a clinical challenge, even within a single patient across multiple sites of the disease. Genome-wide comparisons of both the DNA and gene expression of primary tumors and metastases in multiple patients could help elucidate the underlying mechanisms that cause breast cancer metastasis. To address this issue, we performed DNA exome and RNA sequencing of matched primary tumors and multiple metastases from 16 patients, totaling 83 distinct specimens. We identified tumor-specific drivers by integrating known protein-protein network information with RNA expression and somatic DNA alterations and found that genetic drivers were predominantly established in the primary tumor and maintained through metastatic spreading. In addition, our analyses revealed that most genetic drivers were DNA copy number changes, the TP53 mutation was a recurrent founding mutation regardless of subtype, and that multiclonal seeding of metastases was frequent and occurred in multiple subtypes. Genetic drivers unique to metastasis were identified as somatic mutations in the estrogen and androgen receptor genes. These results highlight the complexity of metastatic spreading, be it monoclonal or multiclonal, and suggest that most metastatic drivers are established in the primary tumor, despite the substantial heterogeneity seen in the metastases

Comprehensive Analysis of the Immunogenomics of Triple-Negative Breast Cancer Brain Metastases From LCCC1419

BackgroundTriple negative breast cancer (TNBC) is an aggressive variant of breast cancer that lacks the expression of estrogen and progesterone receptors (ER and PR) and HER2. Nearly 50% of patients with advanced TNBC will develop brain metastases (BrM), commonly with progressive extracranial disease. Immunotherapy has shown promise in the treatment of advanced TNBC; however, the immune contexture of BrM remains largely unknown. We conducted a comprehensive analysis of TNBC BrM and matched primary tumors to characterize the genomic and immune landscape of TNBC BrM to inform the development of immunotherapy strategies in this aggressive disease.MethodsWhole-exome sequencing (WES) and RNA sequencing were conducted on formalin-fixed, paraffin-embedded samples of BrM and primary tumors of patients with clinical TNBC (n = 25, n = 9 matched pairs) from the LCCC1419 biobank at UNC—Chapel Hill. Matched blood was analyzed by DNA sequencing as a comparison for tumor WES for the identification of somatic variants. A comprehensive genomics assessment, including mutational and copy number alteration analyses, neoantigen prediction, and transcriptomic analysis of the tumor immune microenvironment were performed.ResultsPrimary and BrM tissues were confirmed as TNBC (23/25 primaries, 16/17 BrM) by immunohistochemistry and of the basal intrinsic subtype (13/15 primaries and 16/19 BrM) by PAM50. Compared to primary tumors, BrM demonstrated a higher tumor mutational burden. TP53 was the most frequently mutated gene and was altered in 50% of the samples. Neoantigen prediction showed elevated cancer testis antigen- and endogenous retrovirus-derived MHC class I-binding peptides in both primary tumors and BrM and predicted that single-nucleotide variant (SNV)-derived peptides were significantly higher in BrM. BrM demonstrated a reduced immune gene signature expression, although a signature associated with fibroblast-associated wound healing was elevated in BrM. Metrics of T and B cell receptor diversity were also reduced in BrM.ConclusionsBrM harbored higher mutational burden and SNV-derived neoantigen expression along with reduced immune gene signature expression relative to primary TNBC. Immune signatures correlated with improved survival, including T cell signatures. Further research will expand these findings to other breast cancer subtypes in the same biobank. Exploration of immunomodulatory approaches including vaccine applications and immune checkpoint inhibition to enhance anti-tumor immunity in TNBC BrM is warranted

Effects of Acute Tryptophan Depletion on Brain Serotonin Function and Concentrations of Dopamine and Norepinephrine in C57BL/6J and BALB/cJ Mice

Acute tryptophan depletion (ATD) is a method of lowering brain serotonin (5-HT). Administration of large neutral amino acids (LNAA) limits the transport of endogenous tryptophan (TRP) across the blood brain barrier by competition with other LNAAs and subsequently decreases serotonergic neurotransmission. A recent discussion on the specificity and efficacy of the ATD paradigm for inhibition of central nervous 5-HT has arisen. Moreover, side effects such as vomiting and nausea after intake of amino acids (AA) still limit its use. ATD Moja-De is a revised mixture of AAs which is less nauseating than conventional protocols. It has been used in preliminary clinical studies but its effects on central 5-HT mechanisms and other neurotransmitter systems have not been validated in an animal model. We tested ATD Moja-De (TRP−) in two strains of mice: C57BL/6J, and BALB/cJ, which are reported to have impaired 5-HT synthesis and a more anxious phenotype relative to other strains of mice. ATD Moja-De lowered brain TRP, significantly decreased 5-HT synthesis as indexed by 5-HTP levels after decarboxlyase inhibition, and lowered 5-HT and 5-HIAA in both strains of mice, however more so in C57BL/6J than in BALB/cJ. Dopamine and its metabolites as well as norepinephrine were not affected. A balanced (TRP+) control mixture did not raise 5-HT or 5-HIAA. The present findings suggest that ATD Moja-De effectively and specifically suppresses central serotonergic function. These results also demonstrate a strain- specific effect of ATD Moja-De on anxiety-like behavior

Dopamine, Drugs, and Estradiol: The Roles of ERα and ERβ in the Mesencephalic Dopamine System and Dopamine-Mediated Behaviors of Mice

<p>Sex differences in drug addiction are mediated in part by effects of the ovarian hormone estradiol (E2) within the ascending dopamine (DA) system from the midbrain to the striatum. Estradiol enhances the effects of psychostimulants, but the exact underlying mechanisms are unknown. Mice could serve as an ideal genetically-tractable model for mechanistic studies into sex and hormone effects within the DA system but have been under-utilized. This study sought to: 1) characterize psychostimulant-induced behavior in mice as an indirect but quantifiable measure of DA neurotransmission, and 2) elucidate the mechanism underlying E2's enhancement of psychostimulant effects in females using surgical, pharmacological, and genetic manipulations. The spontaneous behavior of mice during habituation to a novel environment and after the psychostimulants d-amphetamine (AMPH; 1, 2.5, and/or 5 mg/kg) and cocaine (COC; 5, 15, and/or 30 mg/kg) were assessed in open field chambers using both automated photobeam interruptions and behavioral observations. Behaviors were assessed in the following groups of mice: intact males and females; ovariectomized mice replaced with either E2 for 2 days or 30 minutes or with estrogen receptor-selective agonists; and female mice lacking either ER&alpha; (&alpha;ERKO) or ER&beta; (&beta;ERKO) versus wildtype (WT) littermates. Brain psychostimulant concentrations and tissue content of DA and its metabolites were determined at the time of maximum behavioral stimulation. Psychostimulants induced behavioral activation in mice including both increased locomotion as detected with an automated system and a sequence of behaviors progressing from stereotyped sniffing at low doses to patterned locomotion and rearing at high doses. Intact female mice exhibited more patterned locomotion and a shift towards higher behavior scores after psychostimulants despite having lower AMPH and equivalent COC brain levels as males. Actively ovariectomized mice exhibited fewer ambulations and lower behavior scores during habituation and after psychostimulants than Sham females. Two days but not 30 minutes of E2 replacement restored COC-induced behavioral responses to Sham levels. ER&alpha;-selective PPT replacement in ovariectomized mice and genetic ablation of ER&alpha; in &alpha;ERKO mice altered COC-stimulated behavior. Immunohistochemistry revealed that midbrain DA neurons in mice express ER&beta; but not ER&alpha;, and that non-DA cells in the midbrain and the striatum express ER&alpha;. These results indicate that E2 enhances COC-stimulated locomotion in mice through an indirect effect of ER&alpha;. ER&alpha; may alter behavior through presynaptic effects on DA neuron activity and/or through postsynaptic effects on transcription and signal transduction pathways within striatal neurons.</p>Dissertatio

State-and-transition simulation modeling to compare outcomes of alternative management scenarios under two natural disturbance regimes in a forested landscape in northeastern Wisconsin, USA

Comparisons of the potential outcomes of multiple land management strategies and an understanding of the influence of potential increases in climate-related disturbances on these outcomes are essential for long term land management and conservation planning. To provide these insights, we developed an approach that uses collaborative scenario development and state-and-transition simulation modeling to provide land managers and conservation practitioners with a comparison of potential landscapes resulting from alternative management scenarios and climate conditions, and we have applied this approach in the Wild Rivers Legacy Forest (WRLF) area in northeastern Wisconsin. Three management scenarios were developed with input from local land managers, scientists, and conservation practitioners: 1) continuation of current management, 2) expanded working forest conservation easements, and 3) cooperative ecological forestry. Scenarios were modeled under current climate with contemporary probabilities of natural disturbance and under increased probability of windthrow and wildfire that may result from climate change in this region. All scenarios were modeled for 100 years using the VDDT/TELSA modeling suite. Results showed that landscape composition and configuration were relatively similar among scenarios, and that management had a stronger effect than increased probability of windthrow and wildfire. These findings suggest that the scale of the landscape analysis used here and the lack of differences in predominant management strategies between ownerships in this region play significant roles in scenario outcomes. The approach used here does not rely on complex mechanistic modeling of uncertain dynamics and can therefore be used as starting point for planning and further analysis