Clinical implications and utility of field cancerization

Cancer begins with multiple cumulative epigenetic and genetic alterations that sequencially transform a cell, or a group of cells in a particular organ. The early genetic events might lead to clonal expansion of pre-neoplastic daughter cells in a particular tumor field. Subsequent genomic changes in some of these cells drive them towards the malignant phenotype. These transformed cells are diagnosed histopathologically as cancers owing to changes in cell morphology. Conceivably, a population of daughter cells with early genetic changes (without histopathology) remain in the organ, demonstrating the concept of field cancerization. With present technological advancement, including laser capture microdisection and high-throughput genomic technologies, carefully designed studies using appropriate control tissue will enable identification of important molecular signatures in these genetically transformed but histologically normal cells. Such tumor-specific biomarkers should have excellent clinical utility. This review examines the concept of field cancerization in several cancers and its possible utility in four areas of oncology; risk assessment, early cancer detection, monitoring of tumor progression and definition of tumor margins

Agricultural expansion in African savannas: effects on diversity and composition of trees and mammals

AbstractLand use change (LUC) is the leading cause of biodiversity loss worldwide. However, the global understanding of LUC's impact on biodiversity is mainly based on comparisons of land use endpoints (habitat vs non-habitat) in forest ecosystems. Hence, it may not generalise to savannas, which are ecologically distinct from forests, as they are inherently patchy, and disturbance adapted. Endpoint comparisons also cannot inform the management of intermediate mosaic landscapes. We aim to address these gaps by investigating species- and community-level responses of mammals and trees along a gradient of small scale agricultural expansion in the miombo woodlands of northern Mozambique. Thus, the case study represents the most common pathway of LUC and biodiversity change in the world's largest savanna. Tree abundance, mammal occupancy, and tree- and mammal-species richness showed a non-linear relationship with agricultural expansion (characterised by the Land Division Index, LDI). These occurrence and diversity metrics increased at intermediate LDI (0.3 to 0.7), started decreasing beyond LDI &gt; 0.7, and underwent high levels of decline at extreme levels of agricultural expansion (LDI &gt; 0.9). Despite similarities in species richness responses, the two taxonomic groups showed contrasting β-diversity patterns in response to increasing LDI: increased dissimilarity among tree communities (heterogenisation) and high similarity among mammals (homogenisation). Our analysis along a gradient of landscape-scale land use intensification allows a novel understanding of the impacts of different levels of land conversion, which can help guide land use and restoration policy. Biodiversity loss in this miombo landscape was lower than would be inferred from existing global syntheses of biodiversity-land use relations for Africa or the tropics, probably because such syntheses take a fully converted landscape as the endpoint. As, currently, most African savanna landscapes are a mosaic of savanna habitats and small scale agriculture, biodiversity loss is probably lower than in current global estimates, albeit with a trend towards further conversion. However, at extreme levels of land use change (LDI &gt; 0.9 or &lt; 15% habitat cover) miombo biodiversity appears to be more sensitive to LUC than inferred from the meta-analyses. To mitigate the worst effects of land use on biodiversity, our results suggest that miombo landscapes should retain &gt; 25% habitat cover and avoid LDI &gt; 0.75—after which species richness of both groups begin to decline. Our findings indicate that tree diversity may be easier to restore from natural restoration than mammal diversity, which became spatially homogeneous.</jats:p

The pseudo-mitochondrial genome influences mistakes in heteroplasmy interpretation

BACKGROUND: Nuclear mitochondrial pseudogenes (numts) are a potential source of contamination during mitochondrial DNA PCR amplification. This possibility warrants careful experimental design and cautious interpretation of heteroplasmic results. RESULTS: Here we report the cloning and sequencing of numts loci, amplified from human tissue and rho-zero (ρ(0)) cells (control) with primers known to amplify the mitochondrial genome. This paper is the first to fully sequence 46 paralogous nuclear DNA fragments that represent the entire mitochondrial genome. This is a surprisingly small number due primarily to the primer sets used in this study, because prior to this, BLAST searches have suggested that nuclear DNA harbors between 400 to 1,500 paralogous mitochondrial DNA fragments. Our results indicate that multiple numts were amplified simultaneously with the mitochondrial genome and increased the load of pseudogene signal in PCR reactions. Further, the entire mitochondrial genome was represented by multiple copies of paralogous nuclear sequences. CONCLUSION: These findings suggest that mitochondrial genome disease-associated biomarkers must be rigorously authenticated to preclude any affiliation with paralogous nuclear pseudogenes. Importantly, the common perception that mitochondrial template "swamps" numts loci precluding detectable amplification, depends on the region of the mitochondrial genome targeted by the PCR reaction and the number of pseudogene loci that may co-amplify. Cloning and relevant sequencing data will facilitate the correct interpretation. This is the first complete, wet-lab characterization of numts that represent the entire mitochondrial genome

Individual Recognition in Domestic Cattle (Bos taurus): Evidence from 2D-Images of Heads from Different Breeds

BACKGROUND: In order to maintain cohesion of groups, social animals need to process social information efficiently. Visual individual recognition, which is distinguished from mere visual discrimination, has been studied in only few mammalian species. In addition, most previous studies used either a small number of subjects or a few various views as test stimuli. Dairy cattle, as a domestic species allow the testing of a good sample size and provide a large variety of test stimuli due to the morphological diversity of breeds. Hence cattle are a suitable model for studying individual visual recognition. This study demonstrates that cattle display visual individual recognition and shows the effect of both familiarity and coat diversity in discrimination. [br/]METHODOLOGY/PRINCIPAL FINDINGS: We tested whether 8 Prim'Holstein heifers could recognize 2D-images of heads of one cow (face, profiles, (3/4) views) from those of other cows. Experiments were based on a simultaneous discrimination paradigm through instrumental conditioning using food rewards. In Experiment 1, all images represented familiar cows (belonging to the same social group) from the Prim'Holstein breed. In Experiments 2, 3 and 4, images were from unfamiliar (unknown) individuals either from the same breed or other breeds. All heifers displayed individual recognition of familiar and unfamiliar individuals from their own breed. Subjects reached criterion sooner when recognizing a familiar individual than when recognizing an unfamiliar one (Exp 1: 3.1+/-0.7 vs. Exp 2: 5.2+/-1.2 sessions; Z = 1.99, N = 8, P = 0.046). In addition almost all subjects recognized unknown individuals from different breeds, however with greater difficulty. [br/] CONCLUSIONS/SIGNIFICANCE: Our results demonstrated that cattle have efficient individual recognition based on categorization capacities. Social familiarity improved their performance. The recognition of individuals with very different coat characteristics from the subjects was the most difficult task. These results call for studies exploring the mechanisms involved in face recognition allowing interspecies comparisons, including humans

Batch-produced, GIS-informed range maps for birds based on provenanced, crowd-sourced data inform conservation assessments.

Accurate maps of species ranges are essential to inform conservation, but time-consuming to produce and update. Given the pace of change of knowledge about species distributions and shifts in ranges under climate change and land use, a need exists for timely mapping approaches that enable batch processing employing widely available data. We develop a systematic approach of batch-processing range maps and derived Area of Habitat maps for terrestrial bird species with published ranges below 125,000 km2 in Central and South America. (Area of Habitat is the habitat available to a species within its range.) We combine existing range maps with the rapidly expanding crowd-sourced eBird data of presences and absences from frequently surveyed locations, plus readily accessible, high resolution satellite data on forest cover and elevation to map the Area of Habitat available to each species. Users can interrogate the maps produced to see details of the observations that contributed to the ranges. Previous estimates of Areas of Habitat were constrained within the published ranges and thus were, by definition, smaller-typically about 30%. This reflects how little habitat within suitable elevation ranges exists within the published ranges. Our results show that on average, Areas of Habitat are 12% larger than published ranges, reflecting the often-considerable extent that eBird records expand the known distributions of species. Interestingly, there are substantial differences between threatened and non-threatened species. Some 40% of Critically Endangered, 43% of Endangered, and 55% of Vulnerable species have Areas of Habitat larger than their published ranges, compared with 31% for Near Threatened and Least Concern species. The important finding for conservation is that threatened species are generally more widespread than previously estimated

The talar morphology of a hypochondroplasic dwarf: A case study from the Italian Late Antique period

This project aims to test whether geometric morphometric (GM) and trabecular analyses may be useful tools in identifying talar characteristics related to hypochondroplasia. We quantified the external and internal talar morphology of a hypochondroplasic dwarf (T17) from Modena (northern Italy) dated to the sixth century AD. External talar morphology of T17 was compared with a broad sample of modern human tali (n = 159) using GM methods. Additionally, a subsample of these tali (n = 41) was used to investigate whole talar trabecular changes in T17. Our results show that GM and trabecular analyses identify a combination of traits linked to the dwarfing disorder of hypochondroplasia. These traits include decreased scaled talar dimensions compared with normal-sized individuals, presence of an accessory antero-lateral talar facet, high bone volume fraction, and high anisotropy values throughout the entire talus. In our case study, hypochondroplasia does not appear to substantially modify external talar morphology probably due to the fast growth of the talus. We suggest that small talar dimensions are associated with hypochondroplasia. An antero-lateral talar facet may result from the talus and calcaneus coalition (i.e., talocalcaneal abnormal bridging) possibly related to an everted foot posture that was limited by overgrowth of the fibula. We suggest that high talar trabecular density and strut orientation provide insights into pathological development of the trabecular plates in T17. Finally, our study suggests that high talar trabecular density and strut orientation, and small talar dimensions, may be added as possible concomitant talar hallmarks for hypochondroplasia

Explore before you restore: Incorporating complex systems thinking in ecosystem restoration

The global movement for ecosystem restoration has gained momentum in response to the Bonn Challenge (2010) and the UN Decade on Ecosystem Restoration (UNDER, 2021–2030). While several science-based guidelines exist to aid in achieving successful restoration outcomes, significant variation remains in the outcomes of restoration projects. Some of this disparity can be attributed to unexpected responses of ecosystem components to planned interventions.Given the complex nature of ecosystems, we propose that concepts from Complex Systems Science (CSS) that are linked to non-linearity, such as regime shifts, ecological resilience and ecological feedbacks, should be employed to help explain this variation in restoration outcomes from an ecological perspective.Our framework, Explore Before You Restore, illustrates how these concepts impact restoration outcomes by influencing degradation and recovery trajectories. Additionally, we propose incorporating CSS concepts into the typical restoration project cycle through a CSS assessment phase and suggest that the need for such assessment is explicitly included in the guidelines to improve restoration outcomes.To facilitate this inclusion and make it workable by practitioners, we describe indicators and methods available for restoration teams to answer key questions that should make up such CSS assessment. In doing so, we identify key outstanding science and policy tasks that are needed to further operationalize CSS assessment in restoration.Synthesis and applications. By illustrating how key Complex Systems Science (CSS) concepts linked to non-linear threshold behaviour can impact restoration outcomes through influencing recovery trajectories, our framework Explore Before You Restore demonstrates the need to incorporate Complex Systems thinking in ecosystem restoration. We argue that inclusion of CSS assessment into restoration project cycles, and more broadly, into international restoration guidelines, may significantly improve restoration outcomes

Facile whole mitochondrial genome resequencing from nipple aspirate fluid using MitoChip v2.0

<p>Abstract</p> <p>Background</p> <p>Mutations in the mitochondrial genome (mtgenome) have been associated with many disorders, including breast cancer. Nipple aspirate fluid (NAF) from symptomatic women could potentially serve as a minimally invasive sample for breast cancer screening by detecting somatic mutations in this biofluid. This study is aimed at 1) demonstrating the feasibility of NAF recovery from symptomatic women, 2) examining the feasibility of sequencing the entire mitochondrial genome from NAF samples, 3) cross validation of the Human mitochondrial resequencing array 2.0 (MCv2), and 4) assessing the somatic mtDNA mutation rate in benign breast diseases as a potential tool for monitoring early somatic mutations associated with breast cancer.</p> <p>Methods</p> <p>NAF and blood were obtained from women with symptomatic benign breast conditions, and we successfully assessed the mutation load in the entire mitochondrial genome of 19 of these women. DNA extracts from NAF were sequenced using the mitochondrial resequencing array MCv2 and by capillary electrophoresis (CE) methods as a quality comparison. Sequencing was performed independently at two institutions and the results compared. The germline mtDNA sequence determined using DNA isolated from the patient's blood (control) was compared to the mutations present in cellular mtDNA recovered from patient's NAF.</p> <p>Results</p> <p>From the cohort of 28 women recruited for this study, NAF was successfully recovered from 23 participants (82%). Twenty two (96%) of the women produced fluids from both breasts. Twenty NAF samples and corresponding blood were chosen for this study. Except for one NAF sample, the whole mtgenome was successfully amplified using a single primer pair, or three pairs of overlapping primers. Comparison of MCv2 data from the two institutions demonstrates 99.200% concordance. Moreover, MCv2 data was 99.999% identical to CE sequencing, indicating that MCv2 is a reliable method to rapidly sequence the entire mtgenome. Four NAF samples contained somatic mutations.</p> <p>Conclusion</p> <p>We have demonstrated that NAF is a suitable material for mtDNA sequence analysis using the rapid and reliable MCv2. Somatic mtDNA mutations present in NAF of women with benign breast diseases could potentially be used as risk factors for progression to breast cancer, but this will require a much larger study with clinical follow up.</p

Genetic Variants of APOL1 Are Major Determinants of Kidney Failure in People of African Ancestry With HIV

INTRODUCTION: Variants of the APOL1 gene are associated with chronic kidney disease (CKD) in people of African ancestry, although evidence for their impact in people with HIV are sparse. METHODS: We conducted a cross-sectional study investigating the association between APOL1 renal risk alleles and kidney disease in people of African ancestry with HIV in the UK. The primary outcome was end-stage kidney disease (ESKD; estimated glomerular filtration rate [eGFR] of 30 mg/mmol), and biopsy-proven HIV-associated nephropathy (HIVAN). Multivariable logistic regression was used to estimate the associations between APOL1 high-risk genotypes (G1/G1, G1/G2, G2/G2) and kidney disease outcomes. RESULTS: A total of 2864 participants (mean age 48.1 [SD 10.3], 57.3% female) were genotyped, of whom, 354 (12.4%) had APOL1 high-risk genotypes, and 99 (3.5%) had ESKD. After adjusting for demographic, HIV, and renal risk factors, individuals with APOL1 high-risk genotypes were at increased odds of ESKD (odds ratio [OR] 10.58, 95% CI 6.22–17.99), renal impairment (OR 5.50, 95% CI 3.81–7.95), albuminuria (OR 3.34, 95% CI 2.00–5.56), and HIVAN (OR 30.16, 95% CI 12.48–72.88). An estimated 49% of ESKD was attributable to APOL1 high-risk genotypes. CONCLUSION: APOL1 high-risk genotypes were strongly associated with kidney disease in people of African ancestry with HIV and accounted for approximately half of ESKD cases in this cohort