Risk of Cancer After Diagnosis of Cardiovascular Disease

BACKGROUND: Cardiovascular disease (CVD) and cancer share several risk factors. Although preclinical models show that various types of CVD can accelerate cancer progression, clinical studies have not determined the impact of atherosclerosis on cancer risk. OBJECTIVES: The objective of this study was to determine whether CVD, especially atherosclerotic CVD, is independently associated with incident cancer. METHODS: Using IBM MarketScan claims data from over 130 million individuals, 27 million cancer-free subjects with a minimum of 36 months of follow-up data were identified. Individuals were stratified by presence or absence of CVD, time-varying analysis with multivariable adjustment for cardiovascular risk factors was performed, and cumulative risk of cancer was calculated. Additional analyses were performed according to CVD type (atherosclerotic vs nonatherosclerotic) and cancer subtype. RESULTS: Among 27,195,088 individuals, those with CVD were 13% more likely to develop cancer than those without CVD (HR: 1.13; 95% CI: 1.12-1.13). Results were more pronounced for individuals with atherosclerotic CVD (aCVD), who had a higher risk of cancer than those without CVD (HR: 1.20; 95% CI: 1.19-1.21). aCVD also conferred a higher risk of cancer compared with those with nonatherosclerotic CVD (HR: 1.11; 95% CI: 1.11-1.12). Cancer subtype analyses showed specific associations of aCVD with several malignancies, including lung, bladder, liver, colon, and other hematologic cancers. CONCLUSIONS: Individuals with CVD have an increased risk of developing cancer compared with those without CVD. This association may be driven in part by the relationship of atherosclerosis with specific cancer subtypes, which persists after controlling for conventional risk factors

Alterations of renal phenotype and gene expression profiles due to protein overload in NOD-related mouse strains

BACKGROUND: Despite multiple causes, Chronic Kidney Disease is commonly associated with proteinuria. A previous study on Non Obese Diabetic mice (NOD), which spontaneously develop type 1 diabetes, described histological and gene expression changes incurred by diabetes in the kidney. Because proteinuria is coincident to diabetes, the effects of proteinuria are difficult to distinguish from those of other factors such as hyperglycemia. Proteinuria can nevertheless be induced in mice by peritoneal injection of Bovine Serum Albumin (BSA). To gain more information on the specific effects of proteinuria, this study addresses renal changes in diabetes resistant NOD-related mouse strains (NON and NOD.B10) that were made to develop proteinuria by BSA overload. METHODS: Proteinuria was induced by protein overload on NON and NOD.B10 mouse strains and histology and microarray technology were used to follow the kidney response. The effects of proteinuria were assessed and subsequently compared to changes that were observed in a prior study on NOD diabetic nephropathy. RESULTS: Overload treatment significantly modified the renal phenotype and out of 5760 clones screened, 21 and 7 kidney transcripts were respectively altered in the NON and NOD.B10. Upregulated transcripts encoded signal transduction genes, as well as markers for inflammation (Calmodulin kinase beta). Down-regulated transcripts included FKBP52 which was also down-regulated in diabetic NOD kidney. Comparison of transcripts altered by proteinuria to those altered by diabetes identified mannosidase 2 alpha 1 as being more specifically induced by proteinuria. CONCLUSION: By simulating a component of diabetes, and looking at the global response on mice resistant to the disease, by virtue of a small genetic difference, we were able to identify key factors in disease progression. This suggests the power of this approach in unraveling multifactorial disease processes

Stem Cell Pluripotency Genes Klf4 and Oct4 Regulate Complex SMC Phenotypic Changes Critical in Late-Stage Atherosclerotic Lesion Pathogenesis

Background: Rupture and erosion of advanced atherosclerotic lesions with a resultant myocardial infarction or stroke are the leading worldwide cause of death. However, we have a limited understanding of the identity, origin, and function of many cells that make up late-stage atherosclerotic lesions, as well as the mechanisms by which they control plaque stability. Methods: We conducted a comprehensive single-cell RNA sequencing of advanced human carotid endarterectomy samples and compared these with single-cell RNA sequencing from murine microdissected advanced atherosclerotic lesions with smooth muscle cell (SMC) and endothelial lineage tracing to survey all plaque cell types and rigorously determine their origin. We further used chromatin immunoprecipitation sequencing (ChIP-seq), bulk RNA sequencing, and an innovative dual lineage tracing mouse to understand the mechanism by which SMC phenotypic transitions affect lesion pathogenesis. Results: We provide evidence that SMC-specific Klf4- versus Oct4-knockout showed virtually opposite genomic signatures, and their putative target genes play an important role regulating SMC phenotypic changes. Single-cell RNA sequencing revealed remarkable similarity of transcriptomic clusters between mouse and human lesions and extensive plasticity of SMC- and endothelial cell-derived cells including 7 distinct clusters, most negative for traditional markers. In particular, SMC contributed to a Myh11 -, Lgals3 +population with a chondrocyte-like gene signature that was markedly reduced with SMC-Klf4 knockout. We observed that SMCs that activate Lgals3 compose up to two thirds of all SMC in lesions. However, initial activation of Lgals3 in these cells does not represent conversion to a terminally differentiated state, but rather represents transition of these cells to a unique stem cell marker gene-positive, extracellular matrix-remodeling, "pioneer" cell phenotype that is the first to invest within lesions and subsequently gives rise to at least 3 other SMC phenotypes within advanced lesions, including Klf4-dependent osteogenic phenotypes likely to contribute to plaque calcification and plaque destabilization. Conclusions: Taken together, these results provide evidence that SMC-derived cells within advanced mouse and human atherosclerotic lesions exhibit far greater phenotypic plasticity than generally believed, with Klf4 regulating transition to multiple phenotypes including Lgals3 +osteogenic cells likely to be detrimental for late-stage atherosclerosis plaque pathogenesis

Expression Analysis of the Theileria parva Subtelomere-Encoded Variable Secreted Protein Gene Family

Background The intracellular protozoan parasite Theileria parva transforms bovine lymphocytes inducing uncontrolled proliferation. Proteins released from the parasite are assumed to contribute to phenotypic changes of the host cell and parasite persistence. With 85 members, genes encoding subtelomeric variable secreted proteins (SVSPs) form the largest gene family in T. parva. The majority of SVSPs contain predicted signal peptides, suggesting secretion into the host cell cytoplasm. Methodology/Principal Findings We analysed SVSP expression in T. parva-transformed cell lines established in vitro by infection of T or B lymphocytes with cloned T. parva parasites. Microarray and quantitative real-time PCR analysis revealed mRNA expression for a wide range of SVSP genes. The pattern of mRNA expression was largely defined by the parasite genotype and not by host background or cell type, and found to be relatively stable in vitro over a period of two months. Interestingly, immunofluorescence analysis carried out on cell lines established from a cloned parasite showed that expression of a single SVSP encoded by TP03_0882 is limited to only a small percentage of parasites. Epitope-tagged TP03_0882 expressed in mammalian cells was found to translocate into the nucleus, a process that could be attributed to two different nuclear localisation signals. Conclusions Our analysis reveals a complex pattern of Theileria SVSP mRNA expression, which depends on the parasite genotype. Whereas in cell lines established from a cloned parasite transcripts can be found corresponding to a wide range of SVSP genes, only a minority of parasites appear to express a particular SVSP protein. The fact that a number of SVSPs contain functional nuclear localisation signals suggests that proteins released from the parasite could contribute to phenotypic changes of the host cell. This initial characterisation will facilitate future studies on the regulation of SVSP gene expression and the potential biological role of these enigmatic proteins

Mismatches in Scale Between Highly Mobile Marine Megafauna and Marine Protected Areas

Marine protected areas (MPAs), particularly large MPAs, are increasing in number and size around the globe in part to facilitate the conservation of marine megafauna under the assumption that large-scale MPAs better align with vagile life histories; however, this alignment is not well established. Using a global tracking dataset from 36 species across five taxa, chosen to reflect the span of home range size in highly mobile marine megafauna, we show most MPAs are too small to encompass complete home ranges of most species. Based on size alone, 40% of existing MPAs could encompass the home ranges of the smallest ranged species, while only \u3c 1% of existing MPAs could encompass those of the largest ranged species. Further, where home ranges and MPAs overlapped in real geographic space, MPAs encompassed \u3c 5% of core areas used by all species. Despite most home ranges of mobile marine megafauna being much larger than existing MPAs, we demonstrate how benefits from MPAs are still likely to accrue by targeting seasonal aggregations and critical life history stages and through other management techniques

Mismatches in Scale Between Highly Mobile Marine Megafauna and Marine Protected Areas

Marine protected areas (MPAs), particularly large MPAs, are increasing in number and size around the globe in part to facilitate the conservation of marine megafauna under the assumption that large-scale MPAs better align with vagile life histories; however, this alignment is not well established. Using a global tracking dataset from 36 species across five taxa, chosen to reflect the span of home range size in highly mobile marine megafauna, we show most MPAs are too small to encompass complete home ranges of most species. Based on size alone, 40% of existing MPAs could encompass the home ranges of the smallest ranged species, while only \u3c 1% of existing MPAs could encompass those of the largest ranged species. Further, where home ranges and MPAs overlapped in real geographic space, MPAs encompassed \u3c 5% of core areas used by all species. Despite most home ranges of mobile marine megafauna being much larger than existing MPAs, we demonstrate how benefits from MPAs are still likely to accrue by targeting seasonal aggregations and critical life history stages and through other management techniques

Interleukin-1 beta has atheroprotective effects in advanced atherosclerotic lesions of mice

Despite decades of research, our understanding of the processes controlling late-stage atherosclerotic plaque stability remains poor. A prevailing hypothesis is that reducing inflammation may improve advanced plaque stability, as recently tested in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial, in which post-myocardial infarction subjects were treated with an IL-1β antibody. Here, we performed intervention studies in which smooth muscle cell (SMC) lineage-tracing Apoe-/- mice with advanced atherosclerosis were treated with anti-IL-1β or IgG control antibodies. Surprisingly, we found that IL-1β antibody treatment between 18 and 26 weeks of Western diet feeding induced a marked reduction in SMC and collagen content, but increased macrophage numbers in the fibrous cap. Moreover, although IL-1β antibody treatment had no effect on lesion size, it completely inhibited beneficial outward remodeling. We also found that SMC-specific knockout of Il1r1 (encoding IL-1 receptor type 1) resulted in smaller lesions nearly devoid of SMCs and lacking a fibrous cap, whereas macrophage-selective loss of IL-1R1 had no effect on lesion size or composition. Taken together, these results show that IL-1β has multiple beneficial effects in late-stage murine atherosclerosis, including promotion of outward remodeling and formation and maintenance of an SMC- and collagen-rich fibrous cap

Blood Parasites in Owls with Conservation Implications for the Spotted Owl (Strix occidentalis)

The three subspecies of Spotted Owl (Northern, Strix occidentalis caurina; California, S. o. occidentalis; and Mexican, S. o. lucida) are all threatened by habitat loss and range expansion of the Barred Owl (S. varia). An unaddressed threat is whether Barred Owls could be a source of novel strains of disease such as avian malaria (Plasmodium spp.) or other blood parasites potentially harmful for Spotted Owls. Although Barred Owls commonly harbor Plasmodium infections, these parasites have not been documented in the Spotted Owl. We screened 111 Spotted Owls, 44 Barred Owls, and 387 owls of nine other species for haemosporidian parasites (Leucocytozoon, Plasmodium, and Haemoproteus spp.). California Spotted Owls had the greatest number of simultaneous multi-species infections (44%). Additionally, sequencing results revealed that the Northern and California Spotted Owl subspecies together had the highest number of Leucocytozoon parasite lineages (n = 17) and unique lineages (n = 12). This high level of sequence diversity is significant because only one Leucocytozoon species (L. danilewskyi) has been accepted as valid among all owls, suggesting that L. danilewskyi is a cryptic species. Furthermore, a Plasmodium parasite was documented in a Northern Spotted Owl for the first time. West Coast Barred Owls had a lower prevalence of infection (15%) when compared to sympatric Spotted Owls (S. o. caurina 52%, S. o. occidentalis 79%) and Barred Owls from the historic range (61%). Consequently, Barred Owls on the West Coast may have a competitive advantage over the potentially immune compromised Spotted Owls

Incremental grouping of image elements in vision

One important task for the visual system is to group image elements that belong to an object and to segregate them from other objects and the background. We here present an incremental grouping theory (IGT) that addresses the role of object-based attention in perceptual grouping at a psychological level and, at the same time, outlines the mechanisms for grouping at the neurophysiological level. The IGT proposes that there are two processes for perceptual grouping. The first process is base grouping and relies on neurons that are tuned to feature conjunctions. Base grouping is fast and occurs in parallel across the visual scene, but not all possible feature conjunctions can be coded as base groupings. If there are no neurons tuned to the relevant feature conjunctions, a second process called incremental grouping comes into play. Incremental grouping is a time-consuming and capacity-limited process that requires the gradual spread of enhanced neuronal activity across the representation of an object in the visual cortex. The spread of enhanced neuronal activity corresponds to the labeling of image elements with object-based attention

The Atypical Calpains: Evolutionary Analyses and Roles in Caenorhabditis elegans Cellular Degeneration

The calpains are physiologically important Ca2+-activated regulatory proteases, which are divided into typical or atypical sub-families based on constituent domains. Both sub-families are present in mammals, but our understanding of calpain function is based primarily on typical sub-family members. Here, we take advantage of the model organism Caenorhabditis elegans, which expresses only atypical calpains, to extend our knowledge of the phylogenetic evolution and function of calpains. We provide evidence that a typical human calpain protein with a penta EF hand, detected using custom profile hidden Markov models, is conserved in ancient metazoans and a divergent clade. These analyses also provide evidence for the lineage-specific loss of typical calpain genes in C. elegans and Ciona, and they reveal that many calpain-like genes lack an intact catalytic triad. Given the association between the dysregulation of typical calpains and human degenerative pathologies, we explored the phenotypes, expression profiles, and consequences of inappropriate reduction or activation of C. elegans atypical calpains. These studies show that the atypical calpain gene, clp-1, contributes to muscle degeneration and reveal that clp-1 activity is sensitive to genetic manipulation of [Ca2+]i. We show that CLP-1 localizes to sarcomeric sub-structures, but is excluded from dense bodies (Z-disks). We find that the muscle degeneration observed in a C. elegans model of dystrophin-based muscular dystrophy can be suppressed by clp-1 inactivation and that nemadipine-A inhibition of the EGL-19 calcium channel reveals that Ca2+ dysfunction underlies the C. elegans MyoD model of myopathy. Taken together, our analyses highlight the roles of calcium dysregulation and CLP-1 in muscle myopathies and suggest that the atypical calpains could retain conserved roles in myofilament turnover