APC1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development

This is the publisher's version, also available electronically from "http://genesdev.cshlp.org".The adenomatous polyposis coli (APC) gene is considered as the true gatekeeper of colonic epithelial proliferation: It is mutated in the majority of colorectal tumors, and mutations occur at early stages of tumor development in mouse and man. These mutant proteins lack most of the seven 20-amino-acid repeats and all SAMP motifs that have been associated with down-regulation of intracellular β-catenin levels. In addition, they lack the carboxy-terminal domains that bind to DLG, EB1, and microtubulin. APC also appears to be essential in development because homozygosity for mouse Apcmutations invariably results in early embryonic lethality. Here, we describe the generation of a mouse model carrying a targeted mutation at codon 1638 of the mouse Apc gene, Apc1638T, resulting in a truncated Apc protein encompassing three of the seven 20 amino acid repeats and one SAMP motif, but missing all of the carboxy-terminal domains thought to be associated with tumorigenesis. Surprisingly, homozygosity for the Apc1638T mutation is compatible with postnatal life. However, homozygous mutant animals are characterized by growth retardation, a reduced postnatal viability on the B6 genetic background, the absence of preputial glands, and the formation of nipple-associated cysts. Most importantly,Apc 1638T/1638T animals that survive to adulthood are tumor free. Although the full complement of Apc1638T is sufficient for proper β-catenin signaling, dosage reductions of the truncated protein result in increasingly severe defects in β-catenin regulation. The SAMP motif retained in Apc1638T also appears to be important for this function as shown by analysis of the Apc1572T protein in which its targeted deletion results in a further reduction in the ability of properly controlling β-catenin/Tcf signaling. These results indicate that the association with DLG, EB1, and microtubulin is less critical for the maintenance of homeostasis by APC than has been suggested previously, and that proper β-catenin regulation by APC appears to be required for normal embryonic development and tumor suppression

Assignment of the gene for cytosolic alanine aminotransferase (AAT1) to human chromosome 8

The segregation of human cytosolic alanine aminotransferase (AAT1) and the individual human chromosomes has been studied in 27 secondary and tertiary rat hepatoma-human (liver) fibroblast hybrids. The staining solution used to visualize AAT activity on starch gels was specific for AAT since it was visualized only when all components of the stain were present. The locus for human AAT1 has been assigned to chromosome 8

DNA polymorphism in the 5′ flanking region of the human carbonic anhydrase II gene on chromosome 8

A restriction-fragment-length polymorphism (RFLP) is described which is associated with the human carbonic anhydrase II gene ( CA2 ) that codes for one of the three genetically distinct carbonic anhydrase isozymes, CA I, CA II, and CA III. The isolated DNA was cleaved with several restriction enzymes and subjected to Southern blot hybridization analysis using a DNA probe containing the 5′ end of the human CA II gene. A two allele RFLP which was detected with the restriction endonuclease, Taq I, is expressed phenotypically on Southern blots as either a 5.4 kilobase (kb) fragment or as 4.0 and 1.4 kb fragments. These fragments result from the presence or absence of a Taq I recognition site in the 5′ flanking region approximately 1.0kb from the initiation codon of the CA II gene. Segregation analysis showed that the alleles are inherited in a Mendelian fashion, with a frequency of 50%.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47613/1/439_2004_Article_BF00291652.pd

Genomic assessment of invasion dynamics of SARS-CoV-2 Omicron BA.1

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) now arise in the context of heterogeneous human connectivity and population immunity. Through a large-scale phylodynamic analysis of 115,622 Omicron BA.1 genomes, we identified >6,000 introductions of the antigenically distinct VOC into England and analyzed their local transmission and dispersal history. We find that six of the eight largest English Omicron lineages were already transmitting when Omicron was first reported in southern Africa (22 November 2021). Multiple datasets show that importation of Omicron continued despite subsequent restrictions on travel from southern Africa as a result of export from well-connected secondary locations. Initiation and dispersal of Omicron transmission lineages in England was a two-stage process that can be explained by models of the country’s human geography and hierarchical travel network. Our results enable a comparison of the processes that drive the invasion of Omicron and other VOCs across multiple spatial scales

Association of respiratory symptoms and lung function with occupation in the multinational Burden of Obstructive Lung Disease (BOLD) study

Background Chronic obstructive pulmonary disease has been associated with exposures in the workplace. We aimed to assess the association of respiratory symptoms and lung function with occupation in the Burden of Obstructive Lung Disease study. Methods We analysed cross-sectional data from 28 823 adults (≥40 years) in 34 countries. We considered 11 occupations and grouped them by likelihood of exposure to organic dusts, inorganic dusts and fumes. The association of chronic cough, chronic phlegm, wheeze, dyspnoea, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)/FVC with occupation was assessed, per study site, using multivariable regression. These estimates were then meta-analysed. Sensitivity analyses explored differences between sexes and gross national income. Results Overall, working in settings with potentially high exposure to dusts or fumes was associated with respiratory symptoms but not lung function differences. The most common occupation was farming. Compared to people not working in any of the 11 considered occupations, those who were farmers for ≥20 years were more likely to have chronic cough (OR 1.52, 95% CI 1.19–1.94), wheeze (OR 1.37, 95% CI 1.16–1.63) and dyspnoea (OR 1.83, 95% CI 1.53–2.20), but not lower FVC (β=0.02 L, 95% CI −0.02–0.06 L) or lower FEV1/FVC (β=0.04%, 95% CI −0.49–0.58%). Some findings differed by sex and gross national income. Conclusion At a population level, the occupational exposures considered in this study do not appear to be major determinants of differences in lung function, although they are associated with more respiratory symptoms. Because not all work settings were included in this study, respiratory surveillance should still be encouraged among high-risk dusty and fume job workers, especially in low- and middle-income countries.publishedVersio

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Context-specific emergence and growth of the SARS-CoV-2 Delta variant

The SARS-CoV-2 Delta (Pango lineage B.1.617.2) variant of concern spread globally, causing resurgences of COVID-19 worldwide1,2. The emergence of the Delta variant in the UK occurred on the background of a heterogeneous landscape of immunity and relaxation of non-pharmaceutical interventions. Here we analyse 52,992 SARS-CoV-2 genomes from England together with 93,649 genomes from the rest of the world to reconstruct the emergence of Delta and quantify its introduction to and regional dissemination across England in the context of changing travel and social restrictions. Using analysis of human movement, contact tracing and virus genomic data, we find that the geographic focus of the expansion of Delta shifted from India to a more global pattern in early May 2021. In England, Delta lineages were introduced more than 1,000 times and spread nationally as non-pharmaceutical interventions were relaxed. We find that hotel quarantine for travellers reduced onward transmission from importations; however, the transmission chains that later dominated the Delta wave in England were seeded before travel restrictions were introduced. Increasing inter-regional travel within England drove the nationwide dissemination of Delta, with some cities receiving more than 2,000 observable lineage introductions from elsewhere. Subsequently, increased levels of local population mixing-and not the number of importations-were associated with the faster relative spread of Delta. The invasion dynamics of Delta depended on spatial heterogeneity in contact patterns, and our findings will inform optimal spatial interventions to reduce the transmission of current and future variants of concern, such as Omicron (Pango lineage B.1.1.529)

Economic evaluation of shortened, bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis (STREAM stage 2) : a within-trial analysis of a randomised controlled trial

Background: The STREAM stage 2 trial assessed two bedaquiline-containing regimens for rifampicin-resistant tuberculosis: a 9-month all-oral regimen and a 6-month regimen containing an injectable drug for the first 2 months. We did a within-trial economic evaluation of these regimens. Methods: STREAM stage 2 was an international, phase 3, non-inferiority randomised trial in which participants with rifampicin-resistant tuberculosis were randomly assigned (1:2:2:2) to the 2011 WHO regimen (terminated early), a 9-month injectable-containing regimen (control regimen), a 9-month all-oral regimen with bedaquiline (oral regimen), or a 6-month regimen with bedaquiline and an injectable for the first 2 months (6-month regimen). We prospectively collected direct and indirect costs and health-related quality of life data from trial participants until week 76 of follow-up. Cost-effectiveness of the oral and 6-month regimens versus control was estimated in four countries (oral regimen) and two countries (6-month regimen), using health-related quality of life for cost-utility analysis and trial efficacy for cost-effectiveness analysis. This trial is registered with ISRCTN, ISRCTN18148631. Findings: 300 participants were included in the economic analyses (Ethiopia, 61; India, 142; Moldova, 51; Uganda, 46). In the cost-utility analysis, the oral regimen was not cost-effective in Ethiopia, India, Moldova, and Uganda from either a provider or societal perspective. In Moldova, the oral regimen was dominant from a societal perspective. In the cost-effectiveness analysis, the oral regimen was likely to be cost-effective from a provider perspective at willingness-to-pay thresholds per additional favourable outcome of more than US$4500 in Ethiopia,$1900 in India, $3950 in Moldova, and$7900 in Uganda, and from a societal perspective at thresholds of more than $15 900 in Ethiopia,$3150 in India, and $4350 in Uganda, while in Moldova the oral regimen was dominant. In Ethiopia and India, the 6-month regimen would cost tuberculosis programmes and participants less than the control regimen and was highly likely to be cost-effective in both cost-utility analysis and cost-effectiveness analysis. Reducing the bedaquiline price from$1·81 to $1·00 per tablet made the oral regimen cost-effective in the provider-perspective cost-utility analysis in India and Moldova and dominate over the control regimen in the provider-perspective cost-effectiveness analysis in India. Interpretation: At current costs, the oral bedaquiline-containing regimen for rifampicin-resistant tuberculosis is unlikely to be cost-effective in many low-income and middle-income countries. The 6-month regimen represents a cost-effective alternative if injectable use for 2 months is acceptable. Funding: USAID and Janssen Research & Development

Cohort Profile: Burden of Obstructive Lung Disease (BOLD) study

The Burden of Obstructive Lung Disease (BOLD) study was established to assess the prevalence of chronic airflow obstruction, a key characteristic of chronic obstructive pulmonary disease, and its risk factors in adults (≥40 years) from general populations across the world. The baseline study was conducted between 2003 and 2016, in 41 sites across Africa, Asia, Europe, North America, the Caribbean and Oceania, and collected high-quality pre- and post-bronchodilator spirometry from 28 828 participants. The follow-up study was conducted between 2019 and 2021, in 18 sites across Africa, Asia, Europe and the Caribbean. At baseline, there were in these sites 12 502 participants with high-quality spirometry. A total of 6452 were followed up, with 5936 completing the study core questionnaire. Of these, 4044 also provided high-quality pre- and post-bronchodilator spirometry. On both occasions, the core questionnaire covered information on respiratory symptoms, doctor diagnoses, health care use, medication use and ealth status, as well as potential risk factors. Information on occupation, environmental exposures and diet was also collected