Citations

Abstract Introduction: Breast cancer is a major cause of cancer mortality in American Indian and Alaska Native (AIAN) women. However regional differences are striking with lowers rates in Arizona and highest in Alaska with almost a three-fold difference in incidence and mortality between the two states. These differences may be due in part to varying levels of biologic tumor aggressiveness. To evaluate this, we compared a panel of biomarkers on consecutively diagnosed AIAN breast cancer cases from AZ (N=53) and AK (N=42). Methods: Retrospective analysis of tissue blocks measured expression levels for the following panel of biomarkers: ER and PR (ordinally coded as positive vs. negative); her2, BCL-2, and EGFR (coded 0.1.2. and 3+) and P53, MIB-1 and cyclin D (continuous percent of cells stained). Distributions of biomarker values were compared across state of residence using t-tests for continuous and ordinally scaled markers and chi-square tests of significance for binary markers. Age adjusted analyses were also carried out using linear and logistic regression models as appropriate to account for possible differences in age at diagnosis across states. Chart reviews recorded demographics and treatment characteristics. Results: The following demographics were observed with 95 cases of AIAN women with breast cancer analyzed. Average age at diagnosis was similar in the two states (mean, 58.4 for AZ vs. 56.1 for AK, t-test p value=0.45). 74% presented with a palpable mass. 32% had lumpectomy and axillary node dissection. 28% were premenopausal. 8% had a first-degree relative with breast cancer. 46% received adjuvant chemotherapy. 54% received adjuvant hormonal therapy. Cases from AK had higher levels of p53 staining (40.3 vs. 18.5, p=0.004) and lower levels of both EGFR (mean ordinal scaling 0.15 vs. 0.53, p=0.02) and Her2 (mean ordinal scaling 0.81 vs. 1.32, p=0.02) tan those from AZ. No differences in distribution were observed for MIB-1, Cyclin D, BCL-2, ER or PR. When examined together, the triple negative combination of ER/PR/Her2 also did not differ across states (12% for AK vs.13%forAZ, p=0.85). Conclusions: Our findings indicate that regional differences in biomarker expression levels of P53, EGFR and Her2 may exist in AIAN women. Further research is needed to confirm our results and determine to what extent these differences may explain the observed differences in mortality. Genetic testing for BRCA1,2 or other genetic associations with breast cancer have not been done in these populations and may also be useful to examine the reasons for differences in incidence and mortality. In addition, AIAN women are more likely to present with palpable masses representing higher risk stages of breast cancer. Outreach activities in this population continue to be highly important to change mortality. Supported in part by NCI U01 114609 Spirit of Eagles Community Network Program Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A55.

Here, we review progress by the Penn Biomarker Core in the Alzheimer's Disease Neuroimaging Initiative (ADNI) toward developing a pathological cerebrospinal fluid (CSF) and plasma biomarker signature for mild Alzheimer's disease (AD) as well as a biomarker profile that predicts conversion of mild cognitive impairment (MCI) and/or normal control subjects to AD. The Penn Biomarker Core also collaborated with other ADNI Cores to integrate data across ADNI to temporally order changes in clinical measures, imaging data, and chemical biomarkers that serve as mileposts and predictors of the conversion of normal control to MCI as well as MCI to AD, and the progression of AD. Initial CSF studies by the ADNI Biomarker Core revealed a pathological CSF biomarker signature of AD defined by the combination of Aβ1‐42 and total tau (T‐tau) that effectively delineates mild AD in the large multisite prospective clinical investigation conducted in ADNI. This signature appears to predict conversion from MCI to AD. Data fusion efforts across ADNI Cores generated a model for the temporal ordering of AD biomarkers which suggests that Aβ amyloid biomarkers become abnormal first, followed by changes in neurodegenerative biomarkers (CSF tau, F‐18 fluorodeoxyglucose‐positron emission tomography, magnetic resonance imaging) with the onset of clinical symptoms. The timing of these changes varies in individual patients due to genetic and environmental factors that increase or decrease an individual's resilience in response to progressive accumulations of AD pathologies. Further studies in ADNI will refine this model and render the biomarkers studied in ADNI more applicable to routine diagnosis and to clinical trials of disease modifying therapies.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) beginning in October 2004, is a 6‐year research project that studies changes of cognition, function, brain structure and function, and biomarkers in elderly controls, subjects with mild cognitive impairment, and subjects with Alzheimer's disease (AD). A major goal is to determine and validate MRI, PET images, and cerebrospinal fluid (CSF)/blood biomarkers as predictors and outcomes for use in clinical trials of AD treatments. Structural MRI, FDG PET, C‐11 Pittsburgh compound B (PIB) PET, CSF measurements of amyloid β (Aβ) and species of tau, with clinical/cognitive measurements were performed on elderly controls, subjects with mild cognitive impairment, and subjects with AD. Structural MRI shows high rates of brain atrophy, and has high statistical power for determining treatment effects. FDG PET, C‐11 Pittsburgh compound B PET, and CSF measurements of Aβ and tau were significant predictors of cognitive decline and brain atrophy. All data are available at UCLA/LONI/ADNI, without embargo. ADNI‐like projects started in Australia, Europe, Japan, and Korea. ADNI provides significant new information concerning the progression of AD.

Abstract Rationale Idiopathic pulmonary fibrosis (IPF) and other idiopathic interstitial pneumonias (IIPs) have similar clinical and radiographic features, but their histopathology, response to therapy, and natural history differ. A surgical lung biopsy is often required to distinguish between these entities. Objectives We sought to determine if clinical variables could predict a histopathologic diagnosis of IPF in patients without honeycomb change on high-resolution computed tomography (HRCT). Methods Data from 97 patients with biopsy-proven IPF and 38 patients with other IIPs were examined. Logistic regression models were built to identify the clinical variables that predict histopathologic diagnosis of IPF. Measurements and Main Results Increasing age and average total HRCT interstitial score on HRCT scan of the chest may predict a biopsy confirmation of IPF. Sex, pulmonary function, presence of desaturation, or distance walked during a 6-minute walk test did not help discriminate pulmonary fibrosis from other IIPs. Conclusions Clinical data may be used to predict a diagnosis of IPF over other IIPs. Validation of these data with a prospective study is needed.

Tobacco use is predicted to result in over 1 billion deaths worldwide by the end of the 21 st century. How genetic variation contributes to the observed differential predisposition in the human population to drug dependence is unknown. The zebrafish ( Danio rerio ) is an emerging vertebrate model system for understanding the genetics of behavior. We developed a nicotine behavioral assay in zebrafish and applied it in a forward genetic screen using gene-breaking transposon mutagenesis. We used this method to molecularly characterize bdav /cct8 and hbog /gabbr1.2 as mutations with altered nicotine response. Each have a single human ortholog, identifying two points for potential scientific, diagnostic, and drug development for nicotine biology and cessation therapeutics. We show this insertional method generates mutant alleles that are reversible through Cre-mediated recombination, representing a conditional mutation system for the zebrafish. The combination of this reporter-tagged insertional mutagen approach and zebrafish provides a powerful platform for a rich array of questions amenable to genetic-based scientific inquiry, including the basis of behavior, epigenetics, plasticity, stress, memory, and learning.

Abstract The insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) are receptor tyrosine kinases that participate in mitogenic and antiapoptotic signaling in normal and neoplastic epithelia. In the present study, immunoblotting and reverse transcription-PCR demonstrated expression of IGF1R and IR isoform A in acute myelogenous leukemia (AML) cell lines as well as in >80% of clinical AML isolates. Treatment with insulin enhanced signaling through the Akt and MEK1/2 pathways as well as survival of serum-starved AML cell lines. Conversely, treatment with BMS-536924, a dual IGF1R/IR kinase inhibitor that is undergoing preclinical testing, inhibited constitutive receptor phosphorylation as well as downstream signaling through MEK1/2 and Akt. These changes inhibited proliferation and, in some AML cell lines, induced apoptosis at submicromolar concentrations. Likewise, BMS-536924 inhibited leukemic colony formation in CD34+ clinical AML samples in vitro. Collectively, these results not only indicate that expression of IGF1R and IR isoform A is common in AML but also show that interruption of signaling from these receptors inhibits proliferation in clinical AML isolates. Accordingly, further investigation of IGF1R/IR axis as a potential therapeutic target in AML appears warranted. [Cancer Res 2009;69(19):7635–43]

Abstract Activating epidermal growth factor receptor (EGFR) mutations are common in many cancers including glioblastoma. However, clinical responses to EGFR inhibitors are infrequent and short-lived. We show that the Src family kinases (SFK) Fyn and Src are effectors of oncogenic EGFR signaling, enhancing invasion and tumor cell survival in vivo. Expression of a constitutively active EGFR mutant, EGFRvIII, resulted in activating phosphorylation and physical association with Src and Fyn, promoting tumor growth and motility. Gene silencing of Fyn and Src limited EGFR- and EGFRvIII-dependent tumor cell motility. The SFK inhibitor dasatinib inhibited invasion, promoted tumor regression, and induced apoptosis in vivo, significantly prolonging survival of an orthotopic glioblastoma model expressing endogenous EGFRvIII. Dasatinib enhanced the efficacy of an anti-EGFR monoclonal antibody (mAb 806) in vivo, further limiting tumor growth and extending survival. Examination of a large cohort of clinical samples showed frequent coactivation of EGFR and SFKs in glioblastoma patients. These results establish a mechanism linking EGFR signaling with Fyn and Src activation to promote tumor progression and invasion in vivo and provide rationale for combined anti-EGFR and anti-SFK targeted therapies. [Cancer Res 2009;69(17):6889–98]