Citations

Abstract Introduction: Renal cell carcinoma (RCC) is the most common malignancy of the kidney, responsible for 13,000 deaths in the United States annually. Patients who present with the clear cell (ccRCC) variant of this disease demonstrate a worse prognosis as compared to other subtypes. Due to its asymptomatic nature, patients often do not demonstrate signs of illness until the disease has progressed to an advanced stage. It is estimated that 30% of patients present with metastatic disease at initial diagnosis, and 20-30% of patients with localized cases treated surgically relapse with metastatic disease likely due to the presence of undetectable micrometastases. The treatment for metastatic disease is limited due to its profound resistance against chemotherapy, radiation, and current FDA approved targeted therapies. Despite advances in treatment strategies for patients with metastatic RCC, there remains a need for identification of tumor-specific therapeutic targets. Additionally, elucidation of key signatures which contribute to the development of metastatic disease is paramount. Our group has identified secreted neuronal pentraxin 2 (NPTX2) as a novel oncogenic factor that is highly overexpressed specifically in ccRCC at all stages of disease, and facilitates tumor cell invasion through its interaction with the ionotropic glutamate receptor 4 subunit (GluR4). Methods: NPTX2 expression was evaluated by Affymetrix gene array and immunohistochemistry analysis of patient tumor tissue compared to matched normal samples. Nextbio meta-analysis was used to evaluate NPTX2 expression patterns among RCC subtypes and disease staging. Lentiviral mediated knock-down of NPTX2 and GluR4 was performed in representative ccRCC cell lines and resulting changes in proliferation, viability, morphology, and invasion were evaluated. NPTX2-GluR4 interactions were evaluated via immunoprecipitation, immunofluorescence, and intracellular calcium assays. Results: NPTX2 mRNA and protein is consistently elevated in the clear cell variant of RCC at all stages of disease, and is important for tumor cell viability. We correlate NPTX2 expression with an invasive phenotype, and demonstrate that over-expression of NPTX2 in tumor cells leads to actin cytoskeletal remodeling and increased invasion. We identify GluR4 as a mediator for NPTX2 activity which leads to increased intracellular calcium influx in tumor cells. Conclusions: NPTX2 is a tumor-specific factor that is consistently over-expressed in ccRCC. We further identify GluR4 as a downstream mediator of NPTX2 activity, whereby it modulates intracellular calcium levels, actin cytoskeletal remodeling, and tumor cell invasion. Inhibition of NPTX2 or GluR4 expression via shRNA leads to decreased tumor cell proliferation and invasion, and induces programed cell death. We propose NPTX2 as a new candidate for targeted therapy not previously described in cancer, whose inhibition may demonstrate a clinical benefit in patients suffering from metastatic ccRCC. Citation Format: Christina A. von Roemeling, Derek C. Radisky, Laura A. Marlow, Simon J. Cooper, Stefan K. Grebe, Panagiotis Z. Anastasiadis, Han W. Tun, John A. Copland. Neuronal Pentraxin 2: a novel tumor-specific molecular target that mediates clear cell renal cell carcinoma malignancy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-111. doi:10.1158/1538-7445.AM2014-LB-111

AbstractBackgroundThe European Alzheimer's Disease Consortium and Alzheimer's Disease Neuroimaging Initiative (ADNI) Harmonized Protocol (HarP) is a Delphi definition of manual hippocampal segmentation from magnetic resonance imaging (MRI) that can be used as the standard of truth to train new tracers, and to validate automated segmentation algorithms. Training requires large and representative data sets of segmented hippocampi. This work aims to produce a set of HarP labels for the proper training and certification of tracers and algorithms.MethodsSixty‐eight 1.5 T and 67 3 T volumetric structural ADNI scans from different subjects, balanced by age, medial temporal atrophy, and scanner manufacturer, were segmented by five qualified HarP tracers whose absolute interrater intraclass correlation coefficients were 0.953 and 0.975 (left and right). Labels were validated as HarP compliant through centralized quality check and correction.ResultsHippocampal volumes (mm3) were as follows: controls: left = 3060 (standard deviation [SD], 502), right = 3120 (SD, 897); mild cognitive impairment (MCI): left = 2596 (SD, 447), right = 2686 (SD, 473); and Alzheimer’s disease (AD): left = 2301 (SD, 492), right = 2445 (SD, 525). Volumes significantly correlated with atrophy severity at Scheltens' scale (Spearman's ρ = <−0.468, P = <.0005).Cerebrospinal fluid spaces (mm3) were as follows: controls: left = 23 (32), right = 25 (25); MCI: left = 15 (13), right = 22 (16); and AD: left = 11 (13), right = 20 (25). Five subjects (3.7%) presented with unusual anatomy.ConclusionsThis work provides reference hippocampal labels for the training and certification of automated segmentation algorithms. The publicly released labels will allow the widespread implementation of the standard segmentation protocol.

Significance Noninvasive brain imaging holds great promise for expanding our capabilities of treating human neurologic and psychiatric disorders. However, key limitations exist in human-only studies, and the ability to use animal models would greatly advance our understanding of human brain function. Mice offer sophisticated genetic and molecular methodology, but correlating these data to functional brain imaging in the mouse brain has remained a major hurdle. This study is the first, to our knowledge, to use whole-brain functional imaging to show large-scale functional architecture with structural correlates in the mouse. Perhaps more important is the finding of conservation in brain topology and default network among rodents and primates, thereby clearing the way for a bridge measurement between human and mouse models.

Abstract BAFF and a proliferation-inducing ligand (APRIL), which control B cell homeostasis, are therapeutic targets in autoimmune diseases. TACI-Fc (atacicept), a soluble fusion protein containing the extracellular domain of the BAFF–APRIL receptor TACI, was applied in clinical trials. However, disease activity in multiple sclerosis unexpectedly increased, whereas in systemic lupus erythematosus, atacicept was beneficial. In this study, we show that an endogenous soluble TACI (sTACI) exists in vivo. TACI proteolysis involved shedding by a disintegrin and metalloproteinase 10 releasing sTACI from activated B cells. The membrane-bound stub was subsequently cleaved by γ-secretase reducing ligand-independent signaling of the remaining C-terminal fragment. The shed ectodomain assembled ligand independently in a homotypic way. It functioned as a decoy receptor inhibiting BAFF- and APRIL-mediated B cell survival and NF-κB activation. We determined sTACI levels in autoimmune diseases with established hyperactivation of the BAFF–APRIL system. sTACI levels were elevated both in the cerebrospinal fluid of the brain-restricted autoimmune disease multiple sclerosis correlating with intrathecal IgG production, as well as in the serum of the systemic autoimmune disease systemic lupus erythematosus correlating with disease activity. Together, we show that TACI is sequentially processed by a disintegrin and metalloproteinase 10 and γ-secretase. The released sTACI is an immunoregulator that shares decoy functions with atacicept. It reflects systemic and compartmentalized B cell accumulation and activation.

Abstract Background:BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. Cancer Epidemiol Biomarkers Prev; 24(1); 308–16. ©2014 AACR.