@article {1298, title = {Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.}, journal = {Ann Neurol}, volume = {69}, year = {2011}, month = {2011 Jun}, pages = {928-39}, abstract = {

OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.

METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.

RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 {\texttimes} 10(-9) ; p(replication) = 1.3 {\texttimes} 10(-7) ; p(combined) = 4.0 {\texttimes} 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 {\texttimes} 10(-9) ), rs11869977 (p = 5.7 {\texttimes} 10(-9) ), rs936393 (p = 6.8 {\texttimes} 10(-9) ), rs3744017 (p = 7.3 {\texttimes} 10(-9) ), and rs1055129 (p = 4.1 {\texttimes} 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8\% of the overall mean WMH burden in the sample).

INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

}, keywords = {Aged, Aged, 80 and over, Cerebral Cortex, Chromosomes, Human, Pair 17, Cognition Disorders, Cohort Studies, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Middle Aged, Movement Disorders, Nerve Fibers, Myelinated, Polymorphism, Single Nucleotide, Residence Characteristics, RNA, Messenger}, issn = {1531-8249}, doi = {10.1002/ana.22403}, author = {Fornage, Myriam and Debette, Stephanie and Bis, Joshua C and Schmidt, Helena and Ikram, M Arfan and Dufouil, Carole and Sigurdsson, Sigurdur and Lumley, Thomas and DeStefano, Anita L and Fazekas, Franz and Vrooman, Henri A and Shibata, Dean K and Maillard, Pauline and Zijdenbos, Alex and Smith, Albert V and Gudnason, Haukur and de Boer, Renske and Cushman, Mary and Mazoyer, Bernard and Heiss, Gerardo and Vernooij, Meike W and Enzinger, Christian and Glazer, Nicole L and Beiser, Alexa and Knopman, David S and Cavalieri, Margherita and Niessen, Wiro J and Harris, Tamara B and Petrovic, Katja and Lopez, Oscar L and Au, Rhoda and Lambert, Jean-Charles and Hofman, Albert and Gottesman, Rebecca F and Garcia, Melissa and Heckbert, Susan R and Atwood, Larry D and Catellier, Diane J and Uitterlinden, Andr{\'e} G and Yang, Qiong and Smith, Nicholas L and Aspelund, Thor and Romero, Jose R and Rice, Kenneth and Taylor, Kent D and Nalls, Michael A and Rotter, Jerome I and Sharrett, Richey and van Duijn, Cornelia M and Amouyel, Philippe and Wolf, Philip A and Gudnason, Vilmundur and van der Lugt, Aad and Boerwinkle, Eric and Psaty, Bruce M and Seshadri, Sudha and Tzourio, Christophe and Breteler, Monique M B and Mosley, Thomas H and Schmidt, Reinhold and Longstreth, W T and DeCarli, Charles and Launer, Lenore J} } @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} }