Citations

Abstract Migraine is increasingly understood to be a disorder of the brain. In susceptible individuals, a variety of ?triggers? may influence altered central excitability, resulting in the activation and sensitization of trigeminal nociceptive afferents surrounding blood vessels (i.e., the trigeminovascular system), leading to migraine pain. Transient receptor potential (TRP) channels are expressed in a subset of dural afferents, including those containing calcitonin gene related peptide (CGRP). Activation of TRP channels promotes excitation of nociceptive afferent fibers and potentially lead to pain. In addition to pain, allodynia to mechanical and cold stimuli can result from sensitization of both peripheral afferents and of central pain pathways. TRP channels respond to a variety of endogenous conditions including chemical mediators and low pH. These channels can be activated by exogenous stimuli including a wide range of chemical and environmental irritants, some of which have been demonstrated to trigger migraine in humans. Activation of TRP channels can elicit CGRP release, and blocking the effects of CGRP through receptor antagonism or antibody strategies has been demonstrated to be effective in the treatment of migraine. Identification of approaches that can prevent activation of TRP channels provides an additional novel strategy for discovery of migraine therapeutics.

Abstract Background: Autophagy and apoptosis regulate cancer cell viability in response to cytotoxic stress; however, the functional relationship between these processes is unclear. During autophagy, the multifunctional p62/sequestosome 1 protein shuttles ubiquitinated proteins to the lysosome. Previously, we found that ectopic p62 can promote chemotherapy-induced apoptosis. Since Bcl-2 can regulate both autophagy and apoptosis, we determined whether ABT-263-induced apoptosis is regulated by p62. Methods: Human colorectal cancer cell lines (HCT116, DLD1) were incubated with ABT-263 (0-2 μM) and caspase cleavage (immunoblotting), caspase-8 activation (luminescence), apoptosis (annexin V labeling), and autophagy (localization of GFP-LC3 by confocal microscopy) were analyzed. Caspase-8 was suppressed by siRNA or using caspase-8-deficient Jurkat cells. P62 mutants were generated by site-directed mutagenesis. Caspase-8 self aggregation and colocalization with p62 were studied in cells with lentiviral mCherry-p62, transfected with a non-cleavable caspase-8 fused with fluorescent Venus proteins (BiFC). Results: We demonstrate that ABT-263 induces autophagy and a caspase-8-mediated apoptosis, shown using caspase-8 siRNA or caspase-8-deficient cells. Regulation of this process by p62 was demonstrated by the ability of ectopic p62 expression to enhance apoptosis and caspase-8 activation that were disrupted by mutations at p62 functional domains. In contrast, p62 shRNA was shown to attenuate ABT-263-induced apoptosis. ABT-263 treatment enhanced binding between caspase-8 and p62, and triggered caspase-8 self aggregation that colocalized with p62, shown by Biomolecular Fluorescence Complementation (BiFC) assay using confocal microscopy. Consistent with ectopic p62, accumulation of p62 by the lysosomal autophagy inhibitors, chloroquine or bafilomycin A1, enhanced ABT-263-mediated caspase cleavage. Conclusion: p62 can regulate caspase-8 self aggregation/activation by ABT-263 to enable crosstalk between autophagy and apoptosis. Citation Format: Shengbing Huang, Jae Myung Park, Chunrong Yu, Frank A. Sinicrope. p62/sequestosome 1 regulates caspase-8 activation by the Bcl-2 antagonist ABT-263 to enable crosstalk between autophagy and apoptosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1733. doi:10.1158/1538-7445.AM2013-1733

Abstract Background: Fibroadenoma (FA) is a relatively common benign breast tumor that can occur in women of any age, with a peak incidence during the second and third decades. The only previous study of this lesion reported that FAs are associated with a 2.2 times increased risk of developing invasive breast cancer (BC) compared to matched controls [1]. This relative risk may increase to 3.1 among patients with complex FA, and remains elevated for decades after diagnosis. However, this study did not thoroughly account for other forms of concomitant risk factors. Our investigative team sought to examine breast cancer risk among women with non-complex and complex FA, overall and stratified by other BC risk factors. Materials and Methods: The study cohort included women between ages 18 to 85 in the Mayo Benign Breast Disease (BBD) Cohort who underwent excisional breast biopsy between 1967and1991 and were found to have a FA. FA was defined histologically as a combination of epithelial and stromal proliferation. Complex FA was defined as FA associated with any of the following features: sclerosing adenosis, epithelial calcifications, papillary apocrine change, and microcysts greater than 3.0 mm. The primary endpoint was a diagnosis of BC, determined using the Mayo medical record and questionnaire information from study participants. A single breast pathologist, blinded to the initial diagnosis and clinical outcome, performed pathology review. Observed vs. expected BC risk across levels of FA was assessed via standardized incidence ratios (SIRs), using age-stratified incidence rates from the Iowa Surveillance, Epidemiology, and End Results (SEER) registry. Analyses were carried out overall and within subgroups of involution status (none, partial, complete) and overall histology (non-proliferative disease [NP], proliferative disease without atypia [PDWA] or atypical hyperplasia [AH]). Results: Of 9097 women in the Mayo BBD Cohort, FA were identified in 2139- non-complex in 1903 (20.9%) and complex in 236 (2.6%). The greatest proportion of FA occurred in the 40–69 age range. The mean ages for women with non-complex FA and complex FA were 45.7 and 50.2 years respectively. The SIR of breast cancer in the overall BBD cohort was 1.5 (95% CI [1.4–1.6]). The SIR among women with non-complex FA was 1.5 (95% CI [1.3–1.8]), and for complex FA increased to 2.41 (95% CI [1.7–3.4]). However, women with complex FA were more likely to have other concomitant high-risk histologic features such as PDWA and incomplete involution. In stratified analyses accounting for involution status and PDWA, complex FA did not demonstrate an independent increase in BC risk. Conclusion: Complex FA does not confer an increased risk for BC beyond other established histologic features. Therefore, women with complex FA should be managed based upon a risk level consistent with the major histologic category of PDWA and/or AH. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-01-08.

Abstract Background: Optimal early detection and prevention strategies for breast cancer are predicated on our ability to accurately identify women at increased risk for disease. Current breast cancer risk prediction models rely on clinical and epidemiologic features. As demonstrated with other cancers, such as those of the cervix and colon, cancer risk assessment is enhanced when the tissue at risk is examined for evidence of premalignant abnormalities. Here, we present a multivariate model for individualized breast cancer risk prediction that incorporates tissue features identified from biopsies from women with benign breast disease (BBD). Methods: We used our cohort of more than 9000 women diagnosed with BBD at the Mayo Clinic from 1967–1991, and identified a nested case:control series of 377 women who developed cancer (cases) matched with 734 women who did not (controls). We identified a set of variables that either alone or in two-way interactions contributed to a multivariable risk prediction model. We combined this relative risk model with the baseline incidence of breast cancer and the baseline hazard of death from our full BBD cohort to develop a risk prediction tool that computes absolute risk estimates for breast cancer. We calculated 5-year risk predictions for these cases and controls using our model and using the Gail model and compared c-statistics from these risk predictions. We validated our model using an independent set of 378 breast cancer cases and 728 matched controls drawn from our BBD cohort. Results: Cases and controls in the model development data set differed significantly on a number of features when examined individually. Those included in a multivariable relative risk model for breast cancer among women with BBD are shown below. After including interactions between lobular involution, and histologic impression, with age at first live birth/number of children, and degree of involution with sclerosing adenosis, we devised a model that predicts the absolute risk of breast cancer. Predicted five-year risks in the model development series, we observed a c-statistic of 0.66, higher than the c-statistic of 0.61 for the Gail model. With risk prediction estimates from our validation series of cases and matched controls, the c-statistic of our model decreased to 0.59 and the c-statistic for the Gail model was 0.55. Conclusion: We have identified an initial risk prediction model for breast cancer in women with BBD. The identified model includes basic demographic information as well as a number of histologic features of the tissue samples. Its initial performance is promising, providing improved discrimination over the Gail model in our replication data set. Further work is needed to identify features which might provide additional predictive information for breast cancer risk. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-12-03.

Background—Nuclear reprogramming inculcates pluripotent capacity by which de novo tissue differentiation is enabled. Yet, introduction of ectopic reprogramming factors may desynchronize natural developmental schedules. This study aims to evaluate the effect of imposed transgene load on the cardiogenic competency of induced pluripotent stem (iPS) cells.Methods and Results—Targeted inclusion and exclusion of reprogramming transgenes (c-MYC,KLF4,OCT4, andSOX2) was achieved using a drug-inducible and removable cassette according to the piggyBac transposon/transposase system. Pulsed transgene overexpression, before iPS cell differentiation, hindered cardiogenic outcomes. Delayed in counterparts with maintained integrated transgenes, transgene removal enabled proficient differentiation of iPS cells into functional cardiac tissue. Transgene-free iPS cells generated reproducible beating activity with robust expression of cardiac α-actinin, connexin 43, myosin light chain 2a, α/β-myosin heavy chain, and troponin I. Although operational excitation–contraction coupling was demonstrable in the presence or absence of transgenes, factor-free derivatives exhibited an expedited maturing phenotype with canonical responsiveness to adrenergic stimulation.Conclusions—A disproportionate stemness load, caused by integrated transgenes, affects the cardiogenic competency of iPS cells. Offload of transgenes in engineered iPS cells ensures integrity of cardiac developmental programs, underscoring the value of nonintegrative nuclear reprogramming for derivation of competent cardiogenic regenerative biologics.

Phoneme duration control in utterances of various lengths was investigated in one apractic subject. Results indicate a loss of segment duration control and a speeding of intrasyllabic articulatory rates in apraxia. Findings are related to a theory of apractic speech dysfunction.

Twenty-seven schizophrenic patients free of any known neurologic deficit were tested with an aphasia test battery. The objective of the research was to derive a profile of schizophrenic language performance to permit its comparison with the profiles characteristic of aphasia, apraxia of speech, generalized intellectual impairment, and confused language. Results indicate that schizophrenic patients exhibit a profile of language performance distinctive from those found in aphasia, apraxia of speech, confusion, or generalized intellectual impairment and demonstrate that the disruption of language in schizophrenia is not aphasic in nature.

This study investigated the practicality of developing short forms of the Porch Index of Communicative Ability (PICA). Stepwise regression procedures were performed using data from 222 complete administrations of the PICA to determine the accuracy of prediction of overall scores on the basis of data from either fewer subtests or fewer items. Results indicated that the PICA is highly redundant and that it may be possible to develop useful shorter forms of it.

Two short versions (SPICAs) of the Porch Index of Communicative Ability (PICA)were developed and investigated, with specific attention to their ability to predict standard PICA overall scores of patients with aphasia. Ninety-three patients were administered three versions of the test in randomized order. Results indicate that SPICAs predict overall scores by standard administration at acceptable confidence levels in approximately one-third of the time required for the administration of the standard PICA.