Oxidized LDL Receptor 1 (OLR1) as a Possible Link between Obesity, Dyslipidemia and Cancer

Recent studies have linked expression of lectin-like ox-LDL receptor 1 (OLR1) to tumorigenesis. We analyzed microarray data from Olr1 knockout (KO) and wild type (WT) mice for genes involved in cellular transformation and evaluated effects of OLR1 over-expression in normal mammary epithelial cells (MCF10A) and breast cancer cells (HCC1143) in terms of gene expression, migration, adhesion and transendothelial migration. Twenty-six out of 238 genes were inhibited in tissues of OLR1 KO mice; the vast majority of OLR1 sensitive genes contained NF-κB binding sites in their promoters. Further studies revealed broad inhibition of NF-kB target genes outside of the transformation-associated gene pool, with enrichment themes of defense response, immune response, apoptosis, proliferation, and wound healing. Transcriptome of Olr1 KO mice also revealed inhibition of de novo lipogenesis, rate-limiting enzymes fatty acid synthase (Fasn), stearoyl-CoA desaturase (Scd1) and ELOVL family member 6 (Elovl6), as well as lipolytic phospholipase A2 group IVB (Pla2g4b). In studies comparing MCF10A and HCC1143, the latter displayed 60% higher OLR1 expression. Forced over-expression of OLR1 resulted in upregulation of NF-κB (p65) and its target pro-oncogenes involved in inhibition of apoptosis (BCL2, BCL2A1, TNFAIP3) and regulation of cell cycle (CCND2) in both cell lines. Basal expression of FASN, SCD1 and PLA2G4B, as well as lipogenesis transcription factors PPARA, SREBF2 and CREM, was higher in HCC1143 cells. Over-expression of OLR1 in HCC1143 cells also enhanced cell migration, without affecting their adherence to TNFα-activated endothelium or transendothelial migration. On the other hand, OLR1 neutralizing antibody inhibited both adhesion and transmigration of untreated HCC1143 cells. We conclude that OLR1 may act as an oncogene by activation of NF-kB target genes responsible for proliferation, migration and inhibition of apoptosis and de novo lipogenesis genes

Gender-specific association of body composition with inflammatory and adipose-related markers in healthy elderly Europeans from the NU-AGE study

Objectives: The aim of this work was to examine the cross-sectional relationship between body composition (BC) markers for adipose and lean tissue and bone mass, and a wide range of specific inflammatory and adipose-related markers in healthy elderly Europeans. Methods: A whole-body dual-energy X-ray absorptiometry (DXA) scan was made in 1121 healthy (65–79 years) women and men from five European countries of the “New dietary strategies addressing the specific needs of elderly population for a healthy aging in Europe” project (NCT01754012) cohort to measure markers of adipose and lean tissue and bone mass. Pro-inflammatory (IL-6, IL-6Rα, TNF-α, TNF-R1, TNF-R2, pentraxin 3, CRP, alpha-1-acid glycoprotein, albumin) and anti-inflammatory (IL-10, TGF-β1) molecules as well as adipose-related markers such as leptin, adiponectin, ghrelin, and resistin were measured by magnetic bead-based multiplex-specific immunoassays and biochemical assays. Results: BC characteristics were different in elderly women and men, and more favorable BC markers were associated with a better adipose-related inflammatory profile, with the exception of skeletal muscle mass index. No correlation was found with the body composition markers and circulating levels of some standard pro- and anti-inflammatory markers like IL-6, pentraxin 3, IL-10, TGF-β1, TNF-α, IL-6Rα, glycoprotein 130, TNF-α-R1, and TNF-α-R2. Conclusions: The association between BC and inflammatory and adipose-related biomarkers is crucial in decoding aging and pathophysiological processes, such as sarcopenia. DXA can help in understanding how the measurement of fat and muscle is important, making the way from research to clinical practice. Key Points: • Body composition markers concordantly associated positively or negatively with adipose-related and inflammatory markers, with the exception of skeletal muscle mass index. • No correlation was found with the body composition markers and circulating levels of some standard pro- and anti-inflammatory markers like IL-6, pentraxin 3, IL-10, TGF-β1, TNF-α, IL-6Rα, gp130, TNF-α-R1, and TNF-α-R2. • Skeletal muscle mass index (SMI) shows a good correlation with inflammatory profile in age-related sarcopenia

Kinetochore fiber formation in animal somatic cells : dueling mechanisms come to a draw

Author Posting. © The Author, 2005. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Chromosoma 114 (2005): 310-318, doi:10.1007/s00412-005-0028-2.The attachment to and movement of a chromosome on the mitotic spindle is mediated by the formation of a bundle of microtubules (MTs) that tethers the kinetochore on the chromosome to a spindle pole. The origin of these “kinetochore fibers” (K-fibers) has been investigated for over 125 years. As noted in 1944 by Schrader, there are only three possible ways to form a K-fiber: either it a) grows from the pole until it contacts the kinetochore; b) grows directly from the kinetochore; or c) it forms as a result of an interaction between the pole and the chromosome. Since Schrader’s time it has been firmly established that K-fibers in centrosome-containing animal somatic cells form as kinetochores capture MTs growing from the spindle pole (route a). It is now similarly clear that in cells lacking centrosomes, including plants and many animal oocytes, K-fibers “self-assemble” from MTs generated by the chromosomes (route b). Can animal somatic cells form K-fibers in the absence of centrosomes by the “self-assembly” pathway? In 2000 the answer to this question was shown to be a resounding “yes”. With this result, the next question became whether the presence of a centrosome normally suppresses K-fiber self-assembly, or if this route works concurrently with centrosome-mediated K-fiber formation. This question, too, has recently been answered: observations on untreated live animal cells expressing GFP-tagged tubulin clearly show that kinetochores can nucleate the formation of their associated MTs in the presence of functional centrosomes. The concurrent operation of these two “dueling” routes for forming K-fibers in animals helps explain why the attachment of kinetochores and the maturation of K-fibers occur as quickly as it does on all chromosomes within a cell.The work is sponsored by NIH grant GMS 40198

Development and Psychometric Properties of a New Questionnaire to Assess Mental Health and Concerning Behaviors in Children and Young People with Autism Spectrum Disorder (ASD):The Assessment of Concerning Behavior (ACB) Scale

Although 70% of autistic children and young people meet criteria for co-occurring psychiatric conditions, there are few screening measures specifically for autistic individuals. We describe the development and validation of the Assessment of Concerning Behavior (ACB), an instrument co-developed with the autistic community to assess mental health and problematic/risky behaviors. Items include descriptions to facilitate symptom recognition by autistic people, and carers/professionals. The ACB was completed by 255 parents, 149 autistic children and young people and 30 teachers. Internal consistency, stability and validity was assessed. The ACB parent-version fit a two-factor model (internalizing and externalizing problems) and showed adequate test–retest reliability, internal consistency and construct validity. The ACB is a promising new measure for research and clinical use in autism