A Comprehensive Assessment of Radial Scars on Core Needle Biopsy in Patients with or without Breast Cancer: Upgrade Rate and Implications on Management.

BACKGROUND: Radial scars/radial sclerosing lesions (RS) are benign breast lesions identified on core needle biopsy (CNB) which can upgrade to malignancy at excision. There is limited data on RS detection and upgrade rates with more sensitive imaging such as magnetic resonance imaging (MRI) and none during their detection for breast cancer workup and its implication on patient treatment decisions. METHODS: A retrospective institutional study of RS diagnosed on CNB between January 2008 and December 2017 was conducted. Clinicopathologic and radiologic features of RS, patient treatment decisions, upgrade rates and long-term follow-up were examined. RESULTS: We identified 133 patients with RS on CNB, of whom 106 opted for surgery for an upgrade rate to malignancy of 1.9%, 2 patients. Radial scar was diagnosed on mammogram in 60%, MRI in 25% and ultrasound in 15% of patients. In this cohort, 32 patients had their RS detected during breast cancer workup (coexistent group) and they were more likely to have their radial scar detected by MRI (60% vs. 14%, P < .001) and undergo more extensive surgery (94% vs. 75%, P = .02). Among the 27 patients electing observation of their RS, only one (3.7%) developed breast cancer. CONCLUSIONS: Our results show an extremely low upgrade rate to malignancy of RS, regardless if there is coexisting breast cancer elsewhere. Despite this, RS still prompted more extensive surgical excisions. The findings do not support excision of RS even among breast cancer patients when identified at a separate site from their cancer.

Neuronal morphology in MeCP2 mouse models is intrinsically variable and depends on age, cell type, and Mecp2 mutation.

Rett Syndrome (RTT), a progressive neurological disorder characterized by developmental regression and loss of motor and language skills, is caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MECP2). Neurostructural phenotypes including decreased neuronal size, dendritic complexity, and spine density have been reported in postmortem RTT brain tissue and in Mecp2 animal models. How these changes in neuronal morphology are related to RTT-like phenotype and MeCP2 function, and the extent to which restoration of neuronal morphology can be used as a cellular readout in therapeutic studies, however, remain unclear. Here, we systematically examined neuronal morphology in vivo across three Mecp2 mouse models representing Mecp2 loss-of-function, partial loss-of-function, and gain-of-function mutations, at developmental time points corresponding to early- and late-symptomatic RTT-like behavioral phenotypes. We found that in Mecp2 loss-of-function mouse models, dendritic complexity is reduced in a mild, age-dependent, and brain region-specific manner, whereas soma size is reduced consistently throughout development. Neither phenotype, however, is altered in Mecp2 gain-of-function mice. Our results suggest that, in the cell types we examined, the use of dendritic morphology as a cellular readout of RTT phenotype and therapeutic efficacy should be cautioned, as it is intrinsically variable. In contrast, soma size may be a robust and reliable marker for evaluation of MeCP2 function in Mecp2 loss-of-function studies.

Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses.

Mutations in the MECP2 gene cause the autism spectrum disorder Rett syndrome (RTT). One of the most common MeCP2 mutations associated with RTT occurs at threonine 158, converting it to methionine (T158M) or alanine (T158A). To understand the role of T158 mutations in the pathogenesis of RTT, we generated knockin mice that recapitulate the MeCP2 T158A mutation. We found a causal role for T158A mutation in the development of RTT-like phenotypes, including developmental regression, motor dysfunction, and learning and memory deficits. These phenotypes resemble those present in Mecp2 null mice and manifest through a reduction in MeCP2 binding to methylated DNA and a decrease in MeCP2 protein stability. The age-dependent development of event-related neuronal responses was disrupted by MeCP2 mutation, suggesting that impaired neuronal circuitry underlies the pathogenesis of RTT and that assessment of event-related potentials (ERPs) may serve as a biomarker for RTT and treatment evaluation.

Ultrastructural relationship between the mu opioid receptor and its interacting protein, GPR177, in striatal neurons.

GPR177, the mammalian ortholog of Drosophila Wntless/Evi/Sprinter, was recently identified as a novel mu-opioid receptor (MOR) interacting protein. GPR177 is a trans-membrane protein pivotal to mediating the secretion of Wnt signaling proteins. Wnt proteins, in turn, are essential in regulating neuronal development, a phenomenon inhibited upon chronic exposure to MOR agonists such as morphine and heroin. We previously showed that GPR177 and MOR are co-localized in the mouse dorsolateral striatum; however, the nature of this interaction was not fully elucidated. Therefore, in the present study, we examined cellular substrates for interactions between GPR177 and MOR using a combined immunogold-silver and peroxidase detection approach in coronal sections in the dorsolateral segment of the striatum. Semi-quantitative analysis of the ultrastructural distribution of GPR177 and MOR in striatal somata and in dendritic processes showed that, of the somata and dendritic processes exhibiting GPR177, 32% contained MOR immunolabeling while for profiles exhibiting MOR, 37% also contained GPR177 immunoreactivity. GPR177-labeled particles were localized predominantly along both the plasma membrane and within the cytoplasm of MOR-labeled dendrites. Somata and dendritic processes that contained both GPR177 and MOR more often received symmetric (inhibitory-type) synapses from unlabeled axon terminals. To further define the phenotype of GPR177 and MOR-containing cellular profiles, triple immunofluorescence detection showed that GPR177 and MOR are localized in neurons containing the opioid peptide, enkephalin, within the dorsolateral striatum. The results provide an anatomical substrate for interactions between MOR and its interacting protein, GPR177, in striatal opioid-containing neurons that may underlie the morphological alterations produced in neurons by chronic opiate use.

Contribution of limbic norepinephrine to cannabinoid-induced aversion.

RATIONALE: The cannabinoid system has risen to the forefront in the development of novel treatments for a number of pathophysiological processes. However, significant side effects have been observed in clinical trials raising concerns regarding the potential clinical utility of cannabinoid-based agents. Understanding the neural circuits and neurochemical substrates impacted by cannabinoids will provide a better means of gaging their actions within the central nervous system that may contribute to the expression of unwanted side effects. OBJECTIVES: In the present study, we investigated whether norepinephrine (NE) in the limbic forebrain is a critical determinant of cannabinoid receptor agonist-induced aversion and anxiety in rats. METHODS: An immunotoxin lesion approach was combined with behavioral analysis using a place conditioning paradigm and the elevated zero maze. RESULTS: Our results show that the non-selective CB1/CB2 receptor agonist, WIN 55,212-2, produced a significant place aversion in rats. Further, NE in the nucleus accumbens was critical for WIN 55,212-2-induced aversion but did not affect anxiety-like behaviors. Depletion of NE from the bed nucleus of the stria terminalis was ineffective in altering WIN 55,212-2-induced aversion and anxiety. CONCLUSIONS: These results indicate that limbic, specifically accumbal, NE is required for cannabinoid-induced aversion but is not essential to cannabinoid-induced anxiety.

Evidence for beta1-adrenergic receptor involvement in amygdalar corticotropin-releasing factor gene expression: implications for cocaine withdrawal.

We previously showed that betaxolol, a selective beta(1)-adrenergic receptor antagonist, administered during early phases of cocaine abstinence, ameliorated withdrawal-induced anxiety and blocked increases in amygdalar beta(1)-adrenergic receptor expression in rats. Here, we report the efficacy of betaxolol in reducing increases in gene expression of amygdalar corticotropin-releasing factor (CRF), a peptide known to be involved in mediating 'anxiety-like' behaviors during initial phases of cocaine abstinence. We also demonstrate attenuation of an amygdalar beta(1)-adrenergic receptor-mediated cell-signaling pathway following this treatment. Male rats were administered betaxolol at 24 and 44 h following chronic cocaine administration. Animals were euthanized at the 48-h time point and the amygdala was microdissected and processed for quantitative reverse transcriptase-polymerase chain reaction and/or western blot analysis. Results showed that betaxolol treatment during early cocaine withdrawal attenuated increases in amygdalar CRF gene expression and cyclic adenosine monophosphate-dependent protein kinase regulatory and catalytic subunit (nuclear fraction) protein expression. Our data also reveal that beta(1)-adrenergic receptors are on amygdalar neurons, which are immunoreactive for CRF. The present findings suggest that the efficacy of betaxolol treatment on cocaine withdrawal-induced anxiety may be related, in part, to its effect on amygdalar beta(1)-adrenergic receptor, modulation of its downstream cell-signaling elements and CRF gene expression.