@article {8558, title = {Systems biology approach to late-onset Alzheimer{\textquoteright}s disease genome-wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments.}, journal = {Alzheimers Dement}, volume = {13}, year = {2017}, month = {2017 Oct}, pages = {1133-1142}, abstract = {

INTRODUCTION: We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer{\textquoteright}s disease (LOAD) loci.

METHODS: We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions.

RESULTS: We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aβ toxicity, and NDUFS3, SLC25A11, ATP5H, and APP were differentially expressed in the temporal cortex.

DISCUSSION: Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex.

}, keywords = {Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Animals, Genetically Modified, Antigens, Neoplasm, Caenorhabditis elegans, Disease Models, Animal, Early Growth Response Protein 1, Female, Gene Expression Regulation, Genome-Wide Association Study, Heparin-binding EGF-like Growth Factor, Humans, Male, Membrane Transport Proteins, Mitochondrial ADP, ATP Translocases, NADH Dehydrogenase, Polymorphism, Single Nucleotide, Protein Interaction Maps, RNA Interference, Systems Biology, Temporal Lobe}, issn = {1552-5279}, doi = {10.1016/j.jalz.2017.01.016}, author = {Mukherjee, Shubhabrata and Russell, Joshua C and Carr, Daniel T and Burgess, Jeremy D and Allen, Mariet and Serie, Daniel J and Boehme, Kevin L and Kauwe, John S K and Naj, Adam C and Fardo, David W and Dickson, Dennis W and Montine, Thomas J and Ertekin-Taner, Nilufer and Kaeberlein, Matt R and Crane, Paul K} } @article {9252, title = {CD133 as a Biomarker for an Autoantibody-to-ImmunoPET Paradigm for the Early Detection of Small Cell Lung Cancer.}, journal = {J Nucl Med}, volume = {63}, year = {2022}, month = {2022 Nov}, pages = {1701-1707}, abstract = {

Small cell lung cancer (SCLC) is a deadly neuroendocrine tumor for which there are no screening methods sensitive enough to facilitate early, effective intervention. We propose targeting the neuroendocrine tumor neoantigen CD133 via antibody-based early detection and PET (immunoPET) to facilitate earlier and more accurate detection of SCLC. RNA sequencing datasets, immunohistochemistry, flow cytometry, and Western blots were used to quantify CD133 expression in healthy and SCLC patients. CD133 was imaged using near-infrared fluorescence (NIRF) immunoimaging, and Zr immunoPET. Anti(α)-CD133 autoantibody levels were measured in SCLC patient plasma using antibody microarrays. Across 6 publicly available datasets, CD133 messenger RNA was found to be higher in SCLC tumors than in other tissues, including healthy or normal adjacent lung and non-SCLC samples. Critically, the upregulation of CD133 messenger RNA in SCLC was associated with a significant increase (hazard ratio, 2.62) in death. CD133 protein was expressed in primary human SCLC, in SCLC patient-derived xenografts, and in both SCLC cell lines tested (H82 and H69). Using an H82 xenograft mouse model, we first imaged CD133 expression with NIRF. Both and NIRF clearly showed that a fluorophore-tagged αCD133 homed to lung tumors. Next, we validated the noninvasive visualization of subcutaneous and orthotopic H82 xenografts via immunoPET. An αCD133 antibody labeled with the positron-emitting radiometal Zr demonstrated significant accumulation in tumor tissue while producing minimal uptake in healthy organs. Finally, plasma αCD133 autoantibodies were found in subjects from cohort studies up to 1 year before SCLC diagnosis. In light of these findings, we conclude that the presence of αCD133 autoantibodies in a blood sample followed by CD133-targeted Zr-immunoPET could be an effective early detection screening strategy for SCLC.

}, keywords = {Animals, Autoantibodies, Biomarkers, Cell Line, Tumor, Disease Models, Animal, Early Detection of Cancer, Humans, Lung Neoplasms, Mice, Mice, Nude, Neuroendocrine Tumors, Positron-Emission Tomography, RNA, Messenger, Small Cell Lung Carcinoma}, issn = {1535-5667}, doi = {10.2967/jnumed.121.263511}, author = {Kunihiro, Andrew G and Sarrett, Samantha M and Lastwika, Kristin J and Solan, Joell L and Pisarenko, Tatyana and Kein{\"a}nen, Outi and Rodriguez, Cindy and Taverne, Lydia R and Fitzpatrick, Annette L and Li, Christopher I and Houghton, A McGarry and Zeglis, Brian M and Lampe, Paul D} }