The Importance of Acquisition Learning on Nicotine and Varenicline Drug Substitution in a Drug-Discriminated Goal-Tracking Task

Nicotine and varenicline (Chantix®; the leading non-nicotine cessation pharmacotherapy) can come to control appetitive behaviors such as goal-tracking. We tested rats (N = 48) in a drug-discriminated goal-tracking (DGT) task where each rat received daily subcutaneous injections of either nicotine (0.4 mg/kg) or saline (0.9% [w/v]) interspersed across the acquisition phase (Phase 1). On saline days, sucrose was intermittently available. On nicotine days, sucrose was withheld. All rats acquired the discrimination with increased goal-tracking rates on saline days relative to nicotine days. Following acquisition, rats were separated into four groups to assess drug-substitution and discrimination reversal in Phase 2. The first group maintained the stimulus-reinforcer relation from acquisition (NIC−). The reversal group was now given access to sucrose on nicotine days (NIC+). The substitution group replaced nicotine with varenicline (1 mg/kg) while maintaining the acquisition stimulus-reinforcer relation (VAR−). The substitution and reversal group had nicotine replaced by varenicline and the stimulus-reinforcer relation reversed (VAR+). Rats in all groups learned or maintained their Phase 1 discriminations. For Phase 2, the reversal groups (+ conditions) acquired their discriminations within 10 sessions. The VAR−group displayed a pattern of disrupted discrimination at the outset of Phase 2 but was reestablished after continued training. In substitution testing, VAR groups received nicotine and NIC groups received varenicline. The NIC−and VAR−groups displayed full substitution of the test stimulus whereas the NIC+ and VAR+ groups displayed partial substitution of the test stimulus. Rats underwent nicotine extinction in Phase 3. Initial responding for each group mimicked Phase 2 training (i.e., higher responding by the reversal groups). All rats maintained similarly low levels of responding after six sessions. In conclusion, initial learning history with nicotine (i.e., + or −) influenced drug-stimulus substitution and the rate at which new learning (e.g., reversal) occurs with the varenicline and nicotine interoceptive stimuli

Mapping genomic and transcriptomic alterations spatially in epithelial cells adjacent to human breast carcinoma.

Almost all genomic studies of breast cancer have focused on well-established tumours because it is technically challenging to study the earliest mutational events occurring in human breast epithelial cells. To address this we created a unique dataset of epithelial samples ductoscopically obtained from ducts leading to breast carcinomas and matched samples from ducts on the opposite side of the nipple. Here, we demonstrate that perturbations in mRNA abundance, with increasing proximity to tumour, cannot be explained by copy number aberrations. Rather, we find a possibility of field cancerization surrounding the primary tumour by constructing a classifier that evaluates where epithelial samples were obtained relative to a tumour (cross-validated micro-averaged AUC = 0.74). We implement a spectral co-clustering algorithm to define biclusters. Relating to over-represented bicluster pathways, we further validate two genes with tissue microarrays and in vitro experiments. We highlight evidence suggesting that bicluster perturbation occurs early in tumour development

A new classification of cardio-oncology syndromes

Abstract Increasing evidence suggests a multifaceted relationship exists between cancer and cardiovascular disease (CVD). Here, we introduce a 5-tier classification system to categorize cardio-oncology syndromes (COS) that represent the aspects of the relationship between cancer and CVD. COS Type I is characterized by mechanisms whereby the abrupt onset or progression of cancer can lead to cardiovascular dysfunction. COS Type II includes the mechanisms by which cancer therapies can result in acute or chronic CVD. COS Type III is characterized by the pro-oncogenic environment created by the release of cardiokines and high oxidative stress in patients with cardiovascular dysfunction. COS Type IV is comprised of CVD therapies and diagnostic procedures which have been associated with promoting or unmasking cancer. COS Type V is characterized by factors causing systemic and genetic predisposition to both CVD and cancer. The development of this framework may allow for an increased facilitation of cancer care while optimizing cardiovascular health through focused treatment targeting the COS type

Identification of genes expressed by immune cells of the colon that are regulated by colorectal cancer-associated variants.

A locus on human chromosome 11q23 tagged by marker rs3802842 was associated with colorectal cancer (CRC) in a genome-wide association study; this finding has been replicated in case-control studies worldwide. In order to identify biologic factors at this locus that are related to the etiopathology of CRC, we used microarray-based target selection methods, coupled to next-generation sequencing, to study 103 kb at the 11q23 locus. We genotyped 369 putative variants from 1,030 patients with CRC (cases) and 1,061 individuals without CRC (controls) from the Ontario Familial Colorectal Cancer Registry. Two previously uncharacterized genes, COLCA1 and COLCA2, were found to be co-regulated genes that are transcribed from opposite strands. Expression levels of COLCA1 and COLCA2 transcripts correlate with rs3802842 genotypes. In colon tissues, COLCA1 co-localizes with crystalloid granules of eosinophils and granular organelles of mast cells, neutrophils, macrophages, dendritic cells and differentiated myeloid-derived cell lines. COLCA2 is present in the cytoplasm of normal epithelial, immune and other cell lineages, as well as tumor cells. Tissue microarray analysis demonstrates the association of rs3802842 with lymphocyte density in the lamina propria (p = 0.014) and levels of COLCA1 in the lamina propria (p = 0.00016) and COLCA2 (tumor cells, p = 0.0041 and lamina propria, p = 6 × 10(-5)). In conclusion, genetic, expression and immunohistochemical data implicate COLCA1 and COLCA2 in the pathogenesis of colon cancer. Histologic analyses indicate the involvement of immune pathways

DNA replication stress restricts ribosomal DNA copy number

Ribosomal RNAs (rRNAs) in budding yeast are encoded by ~100–200 repeats of a 9.1kb sequence arranged in tandem on chromosome XII, the ribosomal DNA (rDNA) locus. Copy number of rDNA repeat units in eukaryotic cells is maintained far in excess of the requirement for ribosome biogenesis. Despite the importance of the repeats for both ribosomal and non-ribosomal functions, it is currently not known how “normal” copy number is determined or maintained. To identify essential genes involved in the maintenance of rDNA copy number, we developed a droplet digital PCR based assay to measure rDNA copy number in yeast and used it to screen a yeast conditional temperature-sensitive mutant collection of essential genes. Our screen revealed that low rDNA copy number is associated with compromised DNA replication. Further, subculturing yeast under two separate conditions of DNA replication stress selected for a contraction of the rDNA array independent of the replication fork blocking protein, Fob1. Interestingly, cells with a contracted array grew better than their counterparts with normal copy number under conditions of DNA replication stress. Our data indicate that DNA replication stresses select for a smaller rDNA array. We speculate that this liberates scarce replication factors for use by the rest of the genome, which in turn helps cells complete DNA replication and continue to propagate. Interestingly, tumors from mini chromosome maintenance 2 (MCM2)-deficient mice also show a loss of rDNA repeats. Our data suggest that a reduction in rDNA copy number may indicate a history of DNA replication stress, and that rDNA array size could serve as a diagnostic marker for replication stress. Taken together, these data begin to suggest the selective pressures that combine to yield a “normal” rDNA copy number

The places parents go: understanding the breadth, scope, and experiences of activity spaces for parents

The final publication is available at Springer via https://doi.org/10.1007/s10708-015-9690-yNeighborhood environments are related to parenting behaviors, which in turn have a life-long effect on children’s health and well-being. Activity spaces, which measure individual routine patterns of movement, may be helpful in assessing how physical and social environments shape parenting. In this study we use qualitative data and GIS mapping from four California cities to examine parental activity spaces. Parents described a number of factors that shape their activity spaces including caregiving status, the age of their children, and income. Parental activity spaces also varied between times (weekends vs. weekdays) and places (adult-only vs. child-specific places). Knowing how to best capture and study parental activity spaces could identify mechanisms by which environmental factors influence parenting behaviors and child health

Erratum: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

This corrects the article DOI: 10.1038/sdata.2017.179