Molecular classification and biomarkers of clinical outcome in breast ductal carcinoma in situ: Analysis of TBCRC 038 and RAHBT cohorts

Ductal carcinoma in situ; Tumor microenvironment; Whole genome sequencingCarcinoma ductal in situ; Microambiente tumoral; Secuenciación del genoma completoCarcinoma ductal in situ; Microambient tumoral; Seqüenciació del genoma completDuctal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We perform multiscale, integrated molecular profiling of DCIS with clinical outcomes by analyzing 774 DCIS samples from 542 patients with 7.3 years median follow-up from the Translational Breast Cancer Research Consortium 038 study and the Resource of Archival Breast Tissue cohorts. We identify 812 genes associated with ipsilateral recurrence within 5 years from treatment and develop a classifier that predicts DCIS or IBC recurrence in both cohorts. Pathways associated with recurrence include proliferation, immune response, and metabolism. Distinct stromal expression patterns and immune cell compositions are identified. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.This publication is part of the HTAN (Human Tumor Atlas Network) Consortium paper package. A list of HTAN members is available at humantumoratlas.org/htan-authors/. R01 CA185138-01 (E.S.H.); U2C CA-17-035 Pre-Cancer Atlas (PCA) Research Centers (E.S.H., R.B.W., C.M., K.P., G.A.C., K.O.); UO1 CA214183 (J.R.M.); DOD BC132057 (E.S.H., C.M.); BCRF 19-074 (E.S.H.); BCRF 19-028 (G.A.C.); PRECISION CRUK Grand Challenge (E.S.H.); R01CA193694 (R.B.W., G.A.C.), BCRF PPI-18-006 (R.B.W.). AEI RYC2019- 026576-I, "LaCaixa" Foundation LCF/PR/PR17/51120011 (J.A.S.). S.H.S. was supported by the Lundbeck Foundation (R288-2018-35) and the Danish Cancer Society (R229-A13616). K.E.H. was supported by a CIHR Banting Postdoctoral Fellowship. TBCRC 038 was conducted by the TBCRC, which receives major funding support from The Breast Cancer Research Foundation and Susan G. Komen. Some results in this paper are based upon data generated by the TCGA Research Network

Quantitative urban classification for malaria epidemiology in sub-Saharan Africa

<p>Abstract</p> <p>Background</p> <p>Although sub-Saharan Africa (SSA) is rapidly urbanizing, the terms used to classify urban ecotypes are poorly defined in the context of malaria epidemiology. Lack of clear definitions may cause misclassification error, which likely decreases the accuracy of continent-wide estimates of malaria burden, limits the generalizability of urban malaria studies, and makes identification of high-risk areas for targeted interventions within cities more difficult. Accordingly, clustering techniques were applied to a set of urbanization- and malaria-related variables in Kisumu, Kenya, to produce a quantitative classification of the urban environment for malaria research.</p> <p>Methods</p> <p>Seven variables with a known or expected relationship with malaria in the context of urbanization were identified and measured at the census enumeration area (EA) level, using three sources: a) the results of a citywide knowledge, attitudes and practices (KAP) survey; b) a high-resolution multispectral satellite image; and c) national census data. Principal components analysis (PCA) was used to identify three factors explaining higher proportions of the combined variance than the original variables. A k-means clustering algorithm was applied to the EA-level factor scores to assign EAs to one of three categories: "urban," "peri-urban," or "semi-rural." The results were compared with classifications derived from two other approaches: a) administrative designation of urban/rural by the census or b) population density thresholds.</p> <p>Results</p> <p>Urban zones resulting from the clustering algorithm were more geographically coherent than those delineated by population density. Clustering distributed population more evenly among zones than either of the other methods and more accurately predicted variation in other variables related to urbanization, but not used for classification.</p> <p>Conclusion</p> <p>Effective urban malaria epidemiology and control would benefit from quantitative methods to identify and characterize urban areas. Cluster analysis techniques were used to classify Kisumu, Kenya, into levels of urbanization in a repeatable and unbiased manner, an approach that should permit more relevant comparisons among and within urban areas. To the extent that these divisions predict meaningful intra-urban differences in malaria epidemiology, they should inform targeted urban malaria interventions in cities across SSA.</p

Significance of Travel to Rural Areas as a Risk Factor for Malarial Anemia in an Urban Setting

Disclaimer: This manuscript was published with the approval of the Director of the Kenya Medical Research Institute. The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the Centers for Disease Control and Prevention.The epidemiology of malaria in urban environments is poorly characterized, yet increasingly problematic. We conducted an unmatched case–control study of risk factors for malarial anemia with high parasitemia in urban Kisumu, Kenya, from June 2002 through February 2003. Cases (n = 80) were hospital patients with a hemoglobin level <= 8 g/dL and a Plasmodium parasite density ≥ 10,000/μL. Controls (n = 826) were healthy respondents to a concurrent citywide knowledge, attitude, and practice survey. Children who reported spending at least one night per month in a rural area were especially at risk (35% of cases; odds ratio = 9.3, 95% confidence interval [CI] = 4.4–19.7, P < 0.0001), and use of mosquito coils, bed net ownership, and house construction were non-significant, potentially indicating that malaria exposure during rural travel comprises an important element of risk. Control of severe malaria in an urban setting may be complicated by Plasmodium infections acquired elsewhere. Epidemiologic studies of urban malaria in low transmission settings should take travel history into account.This research was supported by CDC/KEMRI and by the University of Michigan through the Rackham Graduate School, the Center for Research on Ethnicity, Culture and Health, and the Global Health Program.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91955/1/2010 AJTMH Significance of Travel to Rural Areas as a Risk Factor for Malarial Anemia in an Urban Setting.pd

A census-weighted, spatially-stratified household sampling strategy for urban malaria epidemiology

<p>Abstract</p> <p>Background</p> <p>Urban malaria is likely to become increasingly important as a consequence of the growing proportion of Africans living in cities. A novel sampling strategy was developed for urban areas to generate a sample simultaneously representative of population and inhabited environments. Such a strategy should facilitate analysis of important epidemiological relationships in this ecological context.</p> <p>Methods</p> <p>Census maps and summary data for Kisumu, Kenya, were used to create a pseudo-sampling frame using the geographic coordinates of census-sampled structures. For every enumeration area (EA) designated as urban by the census (n = 535), a sample of structures equal to one-tenth the number of households was selected. In EAs designated as rural (n = 32), a geographically random sample totalling one-tenth the number of households was selected from a grid of points at 100 m intervals. The selected samples were cross-referenced to a geographic information system, and coordinates transferred to handheld global positioning units. Interviewers found the closest eligible household to the sampling point and interviewed the caregiver of a child aged < 10 years. The demographics of the selected sample were compared with results from the Kenya Demographic and Health Survey to assess sample validity. Results were also compared among urban and rural EAs.</p> <p>Results</p> <p>4,336 interviews were completed in 473 of the 567 study area EAs from June 2002 through February 2003. EAs without completed interviews were randomly distributed, and non-response was approximately 2%. Mean distance from the assigned sampling point to the completed interview was 74.6 m, and was significantly less in urban than rural EAs, even when controlling for number of households. The selected sample had significantly more children and females of childbearing age than the general population, and fewer older individuals.</p> <p>Conclusion</p> <p>This method selected a sample that was simultaneously population-representative and inclusive of important environmental variation. The use of a pseudo-sampling frame and pre-programmed handheld GPS units is more efficient and may yield a more complete sample than traditional methods, and is less expensive than complete population enumeration.</p

Let-7 microRNA controls invasion-promoting lysosomal changes via the oncogenic transcription factor myeloid zinc finger-1

Cancer cells utilize lysosomes for invasion and metastasis. Myeloid Zinc Finger1 (MZF1) is an ErbB2-responsive transcription factor that promotes invasion of breast cancer cells via upregulation of lysosomal cathepsins B and L. Here we identify let-7 microRNA, a well-known tumor suppressor in breast cancer, as a direct negative regulator of MZF1. Analysis of primary breast cancer tissues reveals a gradual upregulation of MZF1 from normal breast epithelium to invasive ductal carcinoma and a negative correlation between several let-7 family members and MZF1 mRNA, suggesting that the inverse regulatory relationship between let-7 and MZF1 may play a role in the development of invasive breast cancer. Furthermore, we show that MZF1 regulates lysosome trafficking in ErbB2-positive breast cancer cells. In line with this, MZF1 depletion or let-7 expression inhibits invasion-promoting anterograde trafficking of lysosomes and invasion of ErbB2-expressing MCF7 spheres. The results presented here link MZF1 and let-7 to lysosomal processes in ErbB2-positive breast cancer cells that in non-cancerous cells have primarily been connected to the transcription factor EB. Identifying MZF1 and let-7 as regulators of lysosome distribution in invasive breast cancer cells, uncouples cancer-associated, invasion-promoting lysosomal alterations from normal lysosomal functions and thus opens up new possibilities for the therapeutic targeting of cancer lysosomes.Peer reviewe

Summaries of plenary, symposia, and oral sessions at the XXII World Congress of Psychiatric Genetics, Copenhagen, Denmark, 12-16 October 2014

The XXII World Congress of Psychiatric Genetics, sponsored by the International Society of Psychiatric Genetics, took place in Copenhagen, Denmark, on 12-16 October 2014. A total of 883 participants gathered to discuss the latest findings in the field. The following report was written by student and postdoctoral attendees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported

Recent acquisition of Helicobacter pylori by Baka Pygmies

Both anatomically modern humans and the gastric pathogen Helicobacter pylori originated in Africa, and both species have been associated for at least 100,000 years. Seven geographically distinct H. pylori populations exist, three of which are indigenous to Africa: hpAfrica1, hpAfrica2, and hpNEAfrica. The oldest and most divergent population, hpAfrica2, evolved within San hunter-gatherers, who represent one of the deepest branches of the human population tree. Anticipating the presence of ancient H. pylori lineages within all hunter-gatherer populations, we investigated the prevalence and population structure of H. pylori within Baka Pygmies in Cameroon. Gastric biopsies were obtained by esophagogastroduodenoscopy from 77 Baka from two geographically separated populations, and from 101 non-Baka individuals from neighboring agriculturalist populations, and subsequently cultured for H. pylori. Unexpectedly, Baka Pygmies showed a significantly lower H. pylori infection rate (20.8%) than non-Baka (80.2%). We generated multilocus haplotypes for each H. pylori isolate by DNA sequencing, but were not able to identify Baka-specific lineages, and most isolates in our sample were assigned to hpNEAfrica or hpAfrica1. The population hpNEAfrica, a marker for the expansion of the Nilo-Saharan language family, was divided into East African and Central West African subpopulations. Similarly, a new hpAfrica1 subpopulation, identified mainly among Cameroonians, supports eastern and western expansions of Bantu languages. An age-structured transmission model shows that the low H. pylori prevalence among Baka Pygmies is achievable within the timeframe of a few hundred years and suggests that demographic factors such as small population size and unusually low life expectancy can lead to the eradication of H. pylori from individual human populations. The Baka were thus either H. pylori-free or lost their ancient lineages during past demographic fluctuations. Using coalescent simulations and phylogenetic inference, we show that Baka almost certainly acquired their extant H. pylori through secondary contact with their agriculturalist neighbors

Explaining illness with evil::Pathogen prevalence fosters moral vitalism

Pathogens represent a significant threat to human health leading to the emergence of strategies designed to help manage their negative impact. We examined how spiritual beliefs developed to explain and predict the devastating effects of pathogens and spread of infectious disease. Analysis of existing data in studies 1 and 2 suggests that moral vitalism (beliefs about spiritual forces of evil) is higher in geographical regions characterized by historical higher levels of pathogens. Furthermore, drawing on a sample of 3140 participants from 28 countries in study 3, we found that historical higher levels of pathogens were associated with stronger endorsement of moral vitalistic beliefs. Furthermore, endorsement of moral vitalistic beliefs statistically mediated the previously reported relationship between pathogen prevalence and conservative ideologies, suggesting these beliefs reinforce behavioural strategies which function to prevent infection. We conclude that moral vitalism may be adaptive: by emphasizing concerns over contagion, it provided an explanatory model that enabled human groups to reduce rates of contagious disease.</p

Explaining illness with evil: pathogen prevalence fosters moral vitalism

Pathogens represent a significant threat to human health leading to the emergence of strategies designed to help manage their negative impact. We examined how spiritual beliefs developed to explain and predict the devastating effects of pathogens and spread of infectious disease. Analysis of existing data in studies 1 and 2 suggests that moral vitalism (beliefs about spiritual forces of evil) is higher in geographical regions characterized by historical higher levels of pathogens. Furthermore, drawing on a sample of 3140 participants from 28 countries in study 3, we found that historical higher levels of pathogens were associated with stronger endorsement of moral vitalis- tic beliefs. Furthermore, endorsement of moral vitalistic beliefs statistically mediated the previously reported relationship between pathogen prevalence and conser- vative ideologies, suggesting these beliefs reinforce behavioural strategies which function to prevent infection. We conclude that moral vitalism may be adaptive: by emphasizing concerns over contagion, it provided an explanatory model that enabled human groups to reduce rates of contagious disease

Global maps of soil temperature

Research in global change ecology relies heavily on global climatic grids derived from estimates of air temperature in open areas at around 2 m above the ground. These climatic grids do not reflect conditions below vegetation canopies and near the ground surface, where critical ecosystem functions occur and most terrestrial species reside. Here, we provide global maps of soil temperature and bioclimatic variables at a 1-km² resolution for 0–5 and 5–15 cm soil depth. These maps were created by calculating the difference (i.e., offset) between in-situ soil temperature measurements, based on time series from over 1200 1-km² pixels (summarized from 8500 unique temperature sensors) across all the world’s major terrestrial biomes, and coarse-grained air temperature estimates from ERA5-Land (an atmospheric reanalysis by the European Centre for Medium-Range Weather Forecasts). We show that mean annual soil temperature differs markedly from the corresponding gridded air temperature, by up to 10°C (mean = 3.0 ± 2.1°C), with substantial variation across biomes and seasons. Over the year, soils in cold and/or dry biomes are substantially warmer (+3.6 ± 2.3°C) than gridded air temperature, whereas soils in warm and humid environments are on average slightly cooler (-0.7 ± 2.3°C). The observed substantial and biome-specific offsets emphasize that the projected impacts of climate and climate change on near-surface biodiversity and ecosystem functioning are inaccurately assessed when air rather than soil temperature is used, especially in cold environments. The global soil-related bioclimatic variables provided here are an important step forward for any application in ecology and related disciplines. Nevertheless, we highlight the need to fill remaining geographic gaps by collecting more in-situ measurements of microclimate conditions to further enhance the spatiotemporal resolution of global soil temperature products for ecological applications