Between 1975 and 1990, 104 male patients with a total of 106 breast cancers were treated at Memorial Hospital or the Ochsner Clinic and their records reviewed. The patients were followed for a median of 67 months (range, 0.5 to 14.4 years). Analysis of the frequency distribution by stage showed that 16 (17%) patients were stage 0 and 26 (27%) patients were stage I. The median duration of symptoms before diagnosis was 18 weeks (mean, 5 weeks; range, 1 to 156 weeks). Modified radical mastectomy was undertaken in 71 (67%) patients. The actuarial 5-year relapse-free survival for the entire group was 68% and the actuarial 5-year overall survival was 85%. Relapse-free survival at 5 years for axillary node-negative patients was 87% and for node-positive patients was 30% (p less than 0.001). Overall survival figures for the same subsets showed a 5-year survival of 100% for the node-negative subset and 60% for the node-positive subset. On multivariate analysis, the most powerful predictor of outcome in men was the status of the axillary lymph nodes, and the only prognostic factor that added significantly to this predictive power was the duration of symptoms. Patients who sought treatment less than 6 months after the onset of symptoms experienced a significant survival advantage when compared with patients whose symptoms were present for more than 6 months (p = 0.03). The profile of the stages at diagnosis, the treatment approach, and the survival rates approximate those reported in series of female breast cancers, and overall, the two diseases are remarkably similar.

Memory formation requires de novo protein synthesis, and memory disorders may result from misregulated synthesis of critical proteins that remain largely unidentified. Plasma membrane ion channels and receptors are likely candidates given their role in regulating neuron excitability, a candidate memory mechanism. Here we conduct targeted molecular monitoring and quantitation of hippocampal plasma membrane proteins from mice with intact or impaired contextual fear memory to identify putative candidates. Here we report contextual fear memory deficits correspond to increased Trpc3 gene and protein expression, and demonstrate TRPC3 regulates hippocampal neuron excitability associated with memory function. These data provide a mechanistic explanation for enhanced contextual fear memory reported herein following knockdown of TRPC3 in hippocampus. Collectively, TRPC3 modulates memory and may be a feasible target to enhance memory and treat memory disorders.

Alzheimer’s disease (AD), the most common form of dementia in the elderly, has no cure. Thus, the identification of key molecular mediators of cognitive decline in AD remains a top priority. As aging is the most significant risk factor for AD, the goal of this study was to identify altered proteins and pathways associated with the development of ‘normal’ aging and AD memory deficits, and identify unique proteins and pathways that may contribute to AD-specific symptoms. We used contextual fear conditioning to diagnose 8-month-old 5XFAD and non-transgenic (Ntg) mice as having either intact or impaired memory, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify hippocampal membrane proteins across groups. Subsequent analysis detected 113 proteins differentially expressed relative to memory status (intact vs impaired) in Ntg mice and 103 proteins in 5XFAD mice. Thirty-six proteins, including several involved in neuronal excitability and synaptic plasticity (e.g., GRIA1, GRM3, and SYN1), were altered in both ‘normal’ aging and AD. Pathway analysis highlighted HDAC4 as a regulator of observed protein changes in both genotypes and identified the REST epigenetic regulatory pathway and Gi intracellular signaling as AD-specific pathways involved in regulating the onset of memory deficits. Comparing the hippocampal membrane proteome of Ntg versus AD, regardless of cognitive status, identified 138 differentially expressed proteins, including confirmatory proteins APOE and CLU. Overall, we provide a novel list of putative targets and pathways with therapeutic potential, including a set of proteins associated with cognitive status in normal aging mice or gene mutations that cause AD.

Species of Allocreadiidae are an important component of the parasite fauna of freshwater vertebrates, particularly fishes, and yet their systematic relationships with other trematodes have not been clarified. Partial sequences of the 18S and 28S ribosomal RNA genes from 3 representative species of Allocreadiidae, i.e., Crepidostomum cooperi, Bunodera mediovitellata, and Polylekithum ictaluri, and from 79 other taxa representing 78 families of trematodes obtained from GenBank, were used in a phylogenetic analysis to address the relationships of Allocreadiidae with other plagiorchiiforms/plagiorchiidans. Maximum parsimony and Bayesian analyses of combined 18S and 28S rRNA gene sequence data place 2 of the allocreadiids, Crepidostomum cooperi and Bunodera mediovitellata, in a clade with species of Callodistomidae and Gorgoderidae, which, in turn is sister to a clade containing Polylekithum ictaluri and representatives of Encyclometridae, Dicrocoelidae, and Orchipedidae, a grouping supported by high bootstrap values. These results suggest that Polylekithum ictaluri is not an allocreadiid, a conclusion that is supported by reported differences between its cercaria and that of other allocreadiids. Although details of the life cycle of callodistomids, the sister taxon to Allocreadiidae, remain unknown, the relationship of Allocreadiidae and Gorgoderidae is consistent with their larval development in bivalve, rather than gastropod, molluscs, and with their host relationships (predominantly freshwater vertebrates). The results also indicate that, whereas Allocreadiidae is not a basal taxon, it is not included within the suborder Plagiorchiata. No support was found for a direct relationship between allocreadiids and opecoelids either.

Hyperglycemia is a critical factor in the development of vascular endothelial dysfunction in type 2 diabetes mellitus (T2DM). While hyperglycemic states are an independent risk factor for endothelial dysfunction, a pro‐inflammatory environment during diabetes is demonstrated to serve as a priming factor for hyperglycemia‐induced vascular damage. Whether hyperglycemic states result in a disruption of similar cellular pathways under both diabetic and non‐diabetic states, remains largely unknown. This study aimed to address this gap in knowledge through molecular and functional characterization of primary cardiac microvascular endothelial cells (RCMVECs) derived from the spontaneously T2DM Goto‐Kakizaki (GK) rat model in comparison to the control Wistar Kyoto (WKY) rat model under normal and hyperglycemic conditions. GK and WKY RCMVECs were cultured under both normal (NG; 4.5 mM) and high glucose (HG; 25 mM) conditions for two weeks, followed by tandem mass spectrometry (MS/MS), qPCR, tube formation assay (TFA), microplate based fluorimetry for reactive oxygen species (ROS), and mitochondrial respiration analyses. Following enrichment and pathway analyses of the tandem MS/MS and qPCR datasets, several molecular targets involved in angiogenic, redox and metabolic functions were significantly altered (FC>2; p<0.05) in the GK RCMVEC response to HG, but not in the WKY RCMVECs. Glycolytic enzymes were markedly reduced, and PMA‐induced superoxide production was enhanced in GK RCMVECs (HG vs NG; p<0.05). Additionally, insulin resistance genes were markedly altered in GK RCMVECs under HG conditions (p<0.05). While HG caused reduction in TFA parameters in WKY RCMVECs, GK RCMVECs exhibited fractured tubes under baseline conditions regardless of glycemic condition. Through the integration of high‐throughput tandem MS/MS analysis, bioinformatics analyses, transcriptomic analysis and in vitro functional assays, we identified a wide spectrum of molecular derangements in endothelial cells that were triggered by environmental (hyperglycemic) and/or genetic (diabetic permissive) determinants. We infer that the consequence of an incapacitated glycolytic machinery could well result in a greater reliance on the OXPHOS pathway in GK HG RCMVECs. This may lead to a significant superoxide burden and a spike in the levels of pro‐atherogenic factors. In conclusion, a hyperglycemia microenvironment exhibited distinct changes in the diabetic endothelial response as compared to those observed in healthy states. Support or Funding Information Support for this project has been provided by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (K01‐DK105043 to BRH) and the Department of Biomedical Engineering at the Medical College of Wisconsin and Marquette University, Milwaukee, WI, USA. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.