Publications by authors named "Tim Chambers"

30 Publications

  • Page 1 of 1

How to tackle childhood obesity? Evidence and policy implications from a STOP series of systematic reviews.

Obes Rev 2021 Feb;22(2):e13181

Centre for Health Economics and Policy Innovation, Imperial College Business School, London, UK.

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http://dx.doi.org/10.1111/obr.13181DOI Listing
February 2021

Where do the children play? An objective analysis of children's use of green space.

Health Promot Int 2020 Oct 29. Epub 2020 Oct 29.

University of Otago, Wellington, 23A Mein street, Newtown, Wellington 6042, New Zealand.

Green space is important for health, yet, objective research on children's use of green space is sparse. This study aimed to objectively assess children's use of green space in both public and private settings during their summer leisure time, using wearable cameras. Images from cameras worn by 74 children were analysed for green space use over 4 days. Children spent an average of ∼1/10 h of leisure time in green space in the summer months, were physically active 68%, and with others 85%, of the time. Green spaces are important places for children's health because they are places they frequent and places where they are physically active and socialize. Wearable cameras provide an effective method for objective assessment of green space use.
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http://dx.doi.org/10.1093/heapro/daaa106DOI Listing
October 2020

An objective methodology capturing online commodity marketing and other harms.

Health Promot Int 2020 Dec;35(6):1312-1319

Health Promotion & Policy Research Unit, Department of Public Health, University of Otago, 23 Mein Street, Newtown, Wellington, New Zealand, 6242.

Increasingly life is lived online, yet little is known about the actual nature and extent of online content that people view due to the difficulty of recording real time exposure. This includes people's exposure to harmful commodity marketing. This study aimed to develop a methodology to assess the nature and extent of exposure to, and engagement with, unhealthy commodity marketing and other public health harms online, particularly children's exposure. A convenience sample of 16 young adult participants (aged 21-29) recorded their device usage for 2 days using Zoom software. Data were coded and analysed to assess the nature and extent of marketing for alcohol, gambling, junk food and smoking products. Four focus groups were conducted with participants to explore their data collection and coding experiences, and results assessed using thematic analysis. The study found that, with some modifications, this method was feasible for gathering real-time objective data from the online world that can be analysed for a range of public health harms, including marketing of unhealthy commodities. Larger studies are recommended to build global evidence for public health action in the online world.
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http://dx.doi.org/10.1093/heapro/daz131DOI Listing
December 2020

Alcohol Sponsorship and Esports: Reinforcing the Need for Legislative Restrictions on Alcohol Sponsorship.

Authors:
Tim Chambers

Alcohol Alcohol 2020 Mar;55(2):144-146

Imperial College London, Centre for Health Economics and Policy Innovation, School of Business, London, UK.

Alcohol sponsorship in esports is on the rise. Many esports athletes and viewers are children and young people. Alcohol sponsorship of esports places millions of children and young people at risk of alcohol-related harm. Action on alcohol sponsorship in esports may provide policy makers an opportunity for greater restrictions on all alcohol sports sponsorship.
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http://dx.doi.org/10.1093/alcalc/agz104DOI Listing
March 2020

Food store environment examination - FoodSee: a new method to study the food store environment using wearable cameras.

Glob Health Promot 2020 09 26;27(3):73-81. Epub 2019 Aug 26.

Health Promotion and Policy Research Unit, Department of Public Health, University of Otago, Wellington, New Zealand.

Introduction: Food environments shape food behaviours and are implicated in rising rates of obesity worldwide. Measurement of people's interactions with food stores is important to advance understanding of the associations between the food environment and in-store behaviour. This paper describes a new method, Food Store Environment Examination (FoodSee) to measure people's interaction with the food store environment in a feasibility study focused on convenience stores and children.

Methods: One hundred and sixty-eight randomly selected children (aged 11-13 years) recruited from 16 randomly selected schools in Wellington, New Zealand, used wearable cameras for 4 days that recorded images every 7 s. The study was conducted from July 2014 to June 2015. All images of convenience stores and service stations, and a sample of images from supermarkets, were evaluated to determine the feasibility of assessing food availability and marketing. The outcomes of interest assessed were: food product availability, placement, packaging, branding, price promotion, purchases and consumption.

Results: Thirty-seven children (22%) visited a convenience store or service station at least once during the study period. In total, there were 65 visits to 34 different stores. Seven hundred and nineteen images revealed the in-store environment. Of those, 86.1% were usable and able to be analysed for the outcomes of interest.

Conclusions: The FoodSee methodology provides a promising new method to study people's interaction with the in-store food environment. The evidence generated will be valuable in understanding and improving the food store environment within which people shop, and will contribute to efforts to address obesity globally.
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http://dx.doi.org/10.1177/1757975919859575DOI Listing
September 2020

Space-time analysis of unhealthy food advertising: New Zealand children's exposure and health policy options.

Health Promot Int 2020 Aug;35(4):812-820

Department of Public Health, University of Otago, Wellington, Wellington 6242, New Zealand.

Reducing children's exposure to unhealthy food advertising is an accepted strategy to end childhood obesity. This study aimed to (i) measure children's space-time exposures to unhealthy food advertising in public outdoor spaces, using GPS and wearable cameras; and (ii) test effectiveness of banning options. We compiled data (collected July 2014-June 2015) on 138 12-year-old children in Wellington, New Zealand, using wearable cameras and GPS devices worn over 4 days. In 2017-18, we linked 59 150 images taken in public outdoor spaces to GPS data. Of these, 1631 contained unhealthy food advertising exposures, defined as ≥50% of an advertisement observed in each image. We examined spatial patterns using kernel density mapping and graphed space-time trends. We interpolated a kriged exposure rate across Wellington to estimate exposure reductions for potential bans. Children were exposed to 7.4 (95% CI 7.0-7.8) unhealthy food advertisements/hour spent in outdoor public spaces. Exposures occurred in shopping centres, residential areas and sports facilities, commonly involving fast food, sugary drinks and ice cream. Peak exposure times were weekend afternoons/evenings and weekdays before/after school. In Wellington, we estimated that banning such advertising within 400 m of playgrounds would yield a 33% reduction in exposure, followed by in residential areas (27%), within 400 m of schools (25%), and 50% for a ban combining all above. This work documents the extent of children's exposure to unhealthy food advertising and the potential impact of bans. Given the ubiquity of advertising in public spaces, this New Zealand research offers innovative methods and findings likely relevant in other jurisdictions.
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http://dx.doi.org/10.1093/heapro/daz083DOI Listing
August 2020

Anti-metastatic Inhibitors of Lysyl Oxidase (LOX): Design and Structure-Activity Relationships.

J Med Chem 2019 06 23;62(12):5863-5884. Epub 2019 May 23.

Cancer Research UK Centre for Cancer Therapeutics , The Institute of Cancer Research , 15 Cotswold Road , London SM2 5NG , United Kingdom.

Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase that cross-links collagens and elastin in the extracellular matrix and is a critical mediator of tumor growth and metastatic spread. LOX is a target for cancer therapy, and thus the search for therapeutic agents against LOX has been widely sought. We report herein the medicinal chemistry discovery of a series of LOX inhibitors bearing an aminomethylenethiophene (AMT) scaffold. High-throughput screening provided the initial hits. Structure-activity relationship (SAR) studies led to the discovery of AMT inhibitors with sub-micromolar half-maximal inhibitory concentrations (IC) in a LOX enzyme activity assay. Further SAR optimization yielded the orally bioavailable LOX inhibitor CCT365623 with good anti-LOX potency, selectivity, pharmacokinetic properties, as well as anti-metastatic efficacy.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937593PMC
June 2019

Quantifying Children's Non-Supermarket Exposure to Alcohol Marketing via Product Packaging Using Wearable Cameras.

J Stud Alcohol Drugs 2019 03;80(2):158-166

Health Promotion & Policy Research Unit, University of Otago, Wellington, New Zealand.

Objective: The aim of this research was to quantify children's exposure to alcohol marketing via product packaging using wearable cameras, observing sociodemographic differences and contextual features of exposure.

Method: In Wellington, New Zealand, 167 children (ages 11-13; 53% girls) wore wearable cameras for 4 consecutive days. The cameras automatically captured images approximately every 7 seconds. Image data (n = 700,000 images) were coded through content analysis to determine the extent of children's exposure to alcohol marketing via product packaging. Negative binomial regression models were used to calculate rates of exposure per day and to examine differences between groups.

Results: Children were exposed to alcohol marketing via product packaging 7.7 times per day, on average. Product packaging contained limited health information and lacked defining features that could provide visual cues to children to differentiate alcohol from other commodities. No statistically significant differences by sociodemographic characteristics were detected.

Conclusions: Children are frequently exposed to alcohol marketing via product packaging. Such exposure normalizes alcohol in children's environments and fails to send accurate information to children about the health risks associated with alcohol consumption. Mandatory labeling on alcohol product packaging, including prominent health warnings (text, pictorial, and graphic), or plain packaging, provides governments an opportunity to substantially reduce children's overall exposure to alcohol marketing and potentially increase children's awareness of the risks associated with alcohol consumption.
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March 2019

Prime Minister for a day: children's views on junk food marketing and what to do about it.

N Z Med J 2019 03 29;132(1492):36-45. Epub 2019 Mar 29.

National Institute for Health Innovation, University of Auckland, Auckland.

Aims: This study explored children's awareness of and engagement with food marketing, and their views on action to address it.

Methods: A purposeful sample of 33 children (11-13 years) from the Wellington region of New Zealand were interviewed.

Results: Children were knowledgeable about food marketing, although most were not aware of the extent to which they were exposed. Children did not distinguish 'marketing to children' from other marketing. According to the children, they were frequently exposed to food marketing, and persuaded, against their better judgement, to purchase food they knew to be harmful to their health. As many children recognised the unhealthy nature of the food marketed to them, they agreed they would take action to reduce junk food marketing if they were Prime Minister for a day. Interventions included making food marketing honest, providing nutrition information, removing billboards and increasing the promotion of healthy food.

Conclusions: These findings suggest children's exposure to junk food marketing may cause them physical, mental and moral harm, in direct contradiction of the New Zealand self-regulatory code for marketing. The children's views align with the World Health Assembly's recent decision to endorse initiatives to end childhood obesity, including restricting marketing of unhealthy foods.
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March 2019

Are children smoke-free at home? Using wearable cameras to study children's exposure to smoking and smoking paraphernalia in private spaces.

Child Care Health Dev 2019 03 12;45(2):306-309. Epub 2018 Dec 12.

Department of Public Health, University of Otago, Wellington, New Zealand.

Background: There is limited evidence available on the nature of children's exposure to smoking and smoking paraphernalia in private spaces (homes and cars). We aimed to evaluate the extent and nature of children's exposure to smoking in these settings using image data captured by wearable cameras.

Methods: One-hundred and sixty-eight children wore wearable cameras for 4 days that automatically took pictures every 7 s. Images captured in private spaces (n = 140,818) by children living in households with a smoker (n = 34) were screened for instances of smoking and smoking paraphernalia.

Results: A total of 37 incidents of smoking-four indoor, 21 outdoor, and two in-vehicles-and 62 incidents of smoking paraphernalia were observed. Most smoking incidents in homes (21 of 33) took place outdoors.

Conclusions: The findings support health promotion efforts to make smokers more aware that smoking paraphernalia may normalize smoking for children. The methodology (wearable cameras) appears to have high utility for studying health behaviours in private spaces.
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http://dx.doi.org/10.1111/cch.12631DOI Listing
March 2019

Children's healthy and unhealthy beverage availability, purchase and consumption: A wearable camera study.

Appetite 2019 02 20;133:240-251. Epub 2018 Nov 20.

University of Otago, 23a Mein St, Newtown, 6242, Wellington, New Zealand. Electronic address:

Children's sugar-sweetened beverages (SSBs) consumption presents significant risks for obesity, type 2 diabetes and dental health. But there is a lack of objective data on beverages in children's overall environments. This study aimed to determine the nature and extent of children's beverage availability, purchase and consumption, throughout their day, using wearable cameras for data collection. Data were sourced from 'Kids'Cam NZ', a study in which randomly-selected New Zealand children (n = 168; 11-14y, mean 12.6y) wore cameras for four days (Thursday-Sunday), automatically taking a photo every 7s. Using content analysis, Thursday and Saturday images (n = 700,201) were systematically analysed. On average, 18.9 (95% CI 16.8, 21.4) drinks/day were available to the children (n = 158), of which 7.5 (95% CI 5.8, 9.7; 39.7%) were non-core drinks, including 6.4 (95% CI 5.0, 8.3; 33.9%) SSBs. At school and home, core drinks (water and unflavoured milk) were the most available. In all other locations in which children spent time (e.g., recreation venues and food retail outlets) non-core drinks dominated, at rates 1.5-5 times that of core drinks availability. Almost all drinks (n = 17; 10.8%) the children purchased were non-core. On average, children (n = 111; 70.3%) consumed a drink 2.6 (95% CI 2.1, 3.1) times/day, including one (95% CI 0.7, 1.3) SSB. At school and home core drinks predominated. SSBs were available to most children in all locations in which they spent time, and dominated their drinks purchases and consumption. SSBs appear to be a typical feature of children's everyday environments, almost certainly making it difficult for children's beverage intakes to align with guidelines. The findings support calls for governments to urgently enact the SSB-related actions in the WHO Commission's Ending Childhood Obesity implementation plan and, in turn, improve child health.
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http://dx.doi.org/10.1016/j.appet.2018.11.004DOI Listing
February 2019

Sun protection and shade availability in New Zealand's outdoor recreation spaces.

N Z Med J 2018 10 26;131(1484):30-37. Epub 2018 Oct 26.

Professor, University of Otago, Wellington.

Aims: We aimed to investigate sun protection behaviours and shade availability in outdoor recreation spaces using images captured by children who, in 2014/15, wore wearable cameras for four consecutive days.

Methods: The 168 participants visited 16 outdoor recreation spaces between 10am and 4pm, capturing 378 images, on average, in each setting. People observed in the images (n=2,635) were coded for age, sex, clothing worn (38 clothing types) and shade used. Mean temperature and ultraviolet index (UVI) values were linked with the time-stamped and geo-referenced images.

Results: The UVI in most settings was high enough to warrant sun protection, but only 4.3% of people wore sun-protective hats (broad-brim, bucket and legionnaire styles) and 10.7% used shade. Areas most popular with children, including playground equipment, beach sand and pool areas, had little or no shade available.

Conclusions: Despite New Zealand having the highest incidence of melanoma skin cancer in the world, the results indicate that few New Zealanders wear hats and seek shade in outdoor recreation settings. The findings highlight the need to improve policy and environmental support for skin cancer prevention activities.
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October 2018

Quantifying the Nature and Extent of Children's Real-time Exposure to Alcohol Marketing in Their Everyday Lives Using Wearable Cameras: Children's Exposure via a Range of Media in a Range of Key Places.

Alcohol Alcohol 2018 Sep;53(5):626-633

National Institute for Health Innovation, University of Auckland, 261 Morrin Road, Glen Innes, Auckland, New Zealand.

Aims: Children's exposure to alcohol marketing is typically measured using self-report data, television viewing data or street marketing audits, which are subject to bias and often do not provide quantifiable measures of daily exposure. This article describes an innovative methodology to capture the world in which children live using wearable cameras.

Short Summary: Children wearing wearable cameras were exposed 4.5 times per day to alcohol marketing in multiple places and via a range of marketing media. The results reinforce calls for legislative restrictions and a global response to alcohol marketing in order to protect children and reduce alcohol-related harm.

Methods: Children aged 11-13 years (n = 167) wore cameras that automatically captured images approximately every 7 s for a 4-day period between June 2014 and July 2015. Content analysis of images (n = 700,000) was manually undertaken to assess children's exposure to alcohol marketing.

Results: On average, children were exposed to alcohol marketing 4.5 (95% CI: 3.3, 6.0) times per day, excluding within off-licence retailers, on screens and product packaging. Children were exposed at home (47%), on-licence alcohol retailers (19%), off-licence shop fronts (16%) and sporting venues (12%), and via sports sponsorship (31%) and shop front signage (31%) and merchandise (25%). The highest exposure rates were found among Māori (5.4 times higher than New Zealand European) and Pacific (3.0 times higher than New Zealand European), and boys (2.0 times higher than girls).

Conclusions: These findings highlight the urgent need to implement strict legislative restrictions on all forms of alcohol marketing to fulfil the World Health Organization Global Alcohol Strategy.
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http://dx.doi.org/10.1093/alcalc/agy053DOI Listing
September 2018

Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal.

Cell 2018 04 12;173(3):581-594.e12. Epub 2018 Apr 12.

Translational Cancer Therapeutics Laboratory, the Francis Crick Institute, London NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence London, University College London Cancer Institute, London WC1E 6DD, UK; Department of Medical Oncology, University College London Hospitals, London NW1 2BU, UK. Electronic address:

Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.
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http://dx.doi.org/10.1016/j.cell.2018.03.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938365PMC
April 2018

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.

Cell 2018 04 12;173(3):595-610.e11. Epub 2018 Apr 12.

Translational Cancer Therapeutics Laboratory, the Francis Crick Institute, London NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence London, University College London Cancer Institute, London WC1E 6DD, UK; Department of Medical Oncology, University College London Hospitals, London NW1 2BU, UK. Electronic address:

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.
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http://dx.doi.org/10.1016/j.cell.2018.03.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938372PMC
April 2018

Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.

Cell 2018 04 12;173(3):611-623.e17. Epub 2018 Apr 12.

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Department of Haematology, University of Cambridge, Cambridge CB2 2XY, UK. Electronic address:

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.
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http://dx.doi.org/10.1016/j.cell.2018.02.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927631PMC
April 2018

Corrigendum: Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

Authors:
Christopher Abbosh Nicolai J Birkbak Gareth A Wilson Mariam Jamal-Hanjani Tudor Constantin Raheleh Salari John Le Quesne David A Moore Selvaraju Veeriah Rachel Rosenthal Teresa Marafioti Eser Kirkizlar Thomas B K Watkins Nicholas McGranahan Sophia Ward Luke Martinson Joan Riley Francesco Fraioli Maise Al Bakir Eva Grönroos Francisco Zambrana Raymondo Endozo Wenya Linda Bi Fiona M Fennessy Nicole Sponer Diana Johnson Joanne Laycock Seema Shafi Justyna Czyzewska-Khan Andrew Rowan Tim Chambers Nik Matthews Samra Turajlic Crispin Hiley Siow Ming Lee Martin D Forster Tanya Ahmad Mary Falzon Elaine Borg David Lawrence Martin Hayward Shyam Kolvekar Nikolaos Panagiotopoulos Sam M Janes Ricky Thakrar Asia Ahmed Fiona Blackhall Yvonne Summers Dina Hafez Ashwini Naik Apratim Ganguly Stephanie Kareht Rajesh Shah Leena Joseph Anne Marie Quinn Phil A Crosbie Babu Naidu Gary Middleton Gerald Langman Simon Trotter Marianne Nicolson Hardy Remmen Keith Kerr Mahendran Chetty Lesley Gomersall Dean A Fennell Apostolos Nakas Sridhar Rathinam Girija Anand Sajid Khan Peter Russell Veni Ezhil Babikir Ismail Melanie Irvin-Sellers Vineet Prakash Jason F Lester Malgorzata Kornaszewska Richard Attanoos Haydn Adams Helen Davies Dahmane Oukrif Ayse U Akarca John A Hartley Helen L Lowe Sara Lock Natasha Iles Harriet Bell Yenting Ngai Greg Elgar Zoltan Szallasi Roland F Schwarz Javier Herrero Aengus Stewart Sergio A Quezada Karl S Peggs Peter Van Loo Caroline Dive C Jimmy Lin Matthew Rabinowitz Hugo J W L Aerts Allan Hackshaw Jacqui A Shaw Bernhard G Zimmermann Charles Swanton

Nature 2018 02 20;554(7691):264. Epub 2017 Dec 20.

This corrects the article DOI: 10.1038/nature22364.
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http://dx.doi.org/10.1038/nature25161DOI Listing
February 2018

Studying third-parties and environments: New Zealand sun-safety research.

Health Promot Int 2019 Jun;34(3):440-446

University of Otago, Wellington, New Zealand.

Wearable cameras have been used to study health behaviours, but their utility in assessing third-party behaviours and the built environment is uncertain. This paper reports on the feasibility of using wearable cameras for this purpose in a study of sun-protective behaviours and shade availability during school lunch-breaks. The Kids'Cam study provided 168 children (aged 11-13 years), recruited from 16 randomly selected schools in the Wellington region of New Zealand, with wearable cameras. The devices automatically captured images every 7 s from the child's perspective. Images captured during school lunch-breaks by a random sample of 15 children who took part during terms 4 and 1 (October 2014-April 2015) were selected and assessed for usability. The feasibility of studying third-party sun-protective behaviours and school shade availability was assessed for a subset of 320 images. Of the 3492 eligible lunch-break images, 96.4% were useable; the remainders were excluded due to obstruction, blurriness or unsuitable camera position. Overall, 1278 children and 108 shade structures were observed in the sample images. The use of shade, hats, sleeves, collars and sunglasses could be determined for 97.0%, 77.2%, 74.4%, 47.6% and 54.9% of children, respectively. All shade structures could be classified according to type, and canopy composition could be assessed for 95.4% of structures. Wearable cameras are a feasible tool for assessing sun-safety, particularly shade availability, hat wearing and shade use. This methodology could be used to objectively study other third-party health-related behaviours, and other features of the built environment.
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http://dx.doi.org/10.1093/heapro/dax094DOI Listing
June 2019

Sun Protection Among New Zealand Primary School Children.

Health Educ Behav 2018 10 3;45(5):800-807. Epub 2017 Dec 3.

1 University of Otago, Wellington, New Zealand.

Schools are an important setting for raising skin cancer prevention awareness and encouraging sun protection. We assessed the clothes worn and shade used by 1,278 children in eight schools in the Wellington region of New Zealand. These children were photographed for the Kids'Cam project between September 2014 and March 2015 during school lunch breaks. Children's mean clothing coverage (expressed as a percentage of body area covered) was calculated. Data on school sun-safety policies were obtained via telephone. Mean total body clothing coverage was 70.3% (95% confidence interval = 66.3%, 73.8%). Body regions with the lowest mean coverage were the head (15.4% coverage), neck (36.1% coverage), lower arms (46.1% coverage), hands (5.3% coverage), and calves (30.1% coverage). Children from schools with hats as part of the school uniform were significantly more likely to wear a hat (52.2%) than children from schools without a school hat (2.7%). Most children (78.4%) were not under the cover of shade. Our findings suggest that New Zealand children are not sufficiently protected from the sun at school. Schools should consider comprehensive approaches to improve sun protection, such as the provision of school hats, sun-protective uniforms, and the construction of effective shade.
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http://dx.doi.org/10.1177/1090198117741943DOI Listing
October 2018

Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis.

Lancet Oncol 2017 08 7;18(8):1009-1021. Epub 2017 Jul 7.

Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, London, UK; Department of Medical Oncology, University College London Hospitals, London, UK. Electronic address:

Background: The focus of tumour-specific antigen analyses has been on single nucleotide variants (SNVs), with the contribution of small insertions and deletions (indels) less well characterised. We investigated whether the frameshift nature of indel mutations, which create novel open reading frames and a large quantity of mutagenic peptides highly distinct from self, might contribute to the immunogenic phenotype.

Methods: We analysed whole-exome sequencing data from 5777 solid tumours, spanning 19 cancer types from The Cancer Genome Atlas. We compared the proportion and number of indels across the cohort, with a subset of results replicated in two independent datasets. We assessed in-silico tumour-specific neoantigen predictions by mutation type with pan-cancer analysis, together with RNAseq profiling in renal clear cell carcinoma cases (n=392), to compare immune gene expression across patient subgroups. Associations between indel burden and treatment response were assessed across four checkpoint inhibitor datasets.

Findings: We observed renal cell carcinomas to have the highest proportion (0·12) and number of indel mutations across the pan-cancer cohort (p<2·2 × 10), more than double the median proportion of indel mutations in all other cancer types examined. Analysis of tumour-specific neoantigens showed that enrichment of indel mutations for high-affinity binders was three times that of non-synonymous SNV mutations. Furthermore, neoantigens derived from indel mutations were nine times enriched for mutant specific binding, as compared with non-synonymous SNV derived neoantigens. Immune gene expression analysis in the renal clear cell carcinoma cohort showed that the presence of mutant-specific neoantigens was associated with upregulation of antigen presentation genes, which correlated (r=0·78) with T-cell activation as measured by CD8-positive expression. Finally, analysis of checkpoint inhibitor response data revealed frameshift indel count to be significantly associated with checkpoint inhibitor response across three separate melanoma cohorts (p=4·7 × 10).

Interpretation: Renal cell carcinomas have the highest pan-cancer proportion and number of indel mutations. Evidence suggests indels are a highly immunogenic mutational class, which can trigger an increased abundance of neoantigens and greater mutant-binding specificity.

Funding: Cancer Research UK, UK National Institute for Health Research (NIHR) at the Royal Marsden Hospital National Health Service Foundation Trust, Institute of Cancer Research and University College London Hospitals Biomedical Research Centres, the UK Medical Research Council, the Rosetrees Trust, Novo Nordisk Foundation, the Prostate Cancer Foundation, the Breast Cancer Research Foundation, the European Research Council.
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http://dx.doi.org/10.1016/S1470-2045(17)30516-8DOI Listing
August 2017

Clothing Protection from Ultraviolet Radiation: A New Method for Assessment.

Photochem Photobiol 2017 11 25;93(6):1513-1518. Epub 2017 Jul 25.

University of Otago, Wellington, New Zealand.

Clothing modifies ultraviolet radiation (UVR) exposure from the sun and has an impact on skin cancer risk and the endogenous synthesis of vitamin D. There is no standardized method available for assessing body surface area (BSA) covered by clothing, which limits generalizability between study findings. We calculated the body cover provided by 38 clothing items using diagrams of BSA, adjusting the values to account for differences in BSA by age. Diagrams displaying each clothing item were developed and incorporated into a coverage assessment procedure (CAP). Five assessors used the CAP and Lund & Browder chart, an existing method for estimating BSA, to calculate the clothing coverage of an image sample of 100 schoolchildren. Values of clothing coverage, inter-rater reliability and assessment time were compared between CAP and Lund & Browder methods. Both methods had excellent inter-rater reliability (>0.90) and returned comparable results, although the CAP method was significantly faster in determining a person's clothing coverage. On balance, the CAP method appears to be a feasible method for calculating clothing coverage. Its use could improve comparability between sun-safety studies and aid in quantifying the health effects of UVR exposure.
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http://dx.doi.org/10.1111/php.12803DOI Listing
November 2017

Measuring Blue Space Visibility and 'Blue Recreation' in the Everyday Lives of Children in a Capital City.

Int J Environ Res Public Health 2017 05 26;14(6). Epub 2017 May 26.

Department of Public Health, University of Otago, Wellington 6242, New Zealand.

Blue spaces (water bodies) may promote positive mental and physical health through opportunities for relaxation, recreation, and social connections. However, we know little about the nature and extent of everyday exposure to blue spaces, particularly in settings outside the home or among children, nor whether exposure varies by individual or household characteristics. Wearable cameras offer a novel, reliable method for blue space exposure measurement. In this study, we used images from cameras worn over two days by 166 children in Wellington, New Zealand, and conducted content and blue space quantification analysis on each image ( = 749,389). Blue space was identified in 24,721 images (3.6%), with a total of 23 blue recreation events. Visual exposure and participation in blue recreation did not differ by ethnicity, weight status, household deprivation, or residential proximity to the coastline. Significant differences in both visual exposure to blue space and participation in blue recreation were observed, whereby children from the most deprived schools had significantly higher rates of blue space exposure than children from low deprivation schools. Schools may be important settings to promote equitable blue space exposures. Childhood exposures to blue space may not follow the expected income inequality trends observed among adults.
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http://dx.doi.org/10.3390/ijerph14060563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486249PMC
May 2017

Kids'Cam: An Objective Methodology to Study the World in Which Children Live.

Am J Prev Med 2017 Sep 25;53(3):e89-e95. Epub 2017 Apr 25.

National Institute for Health Innovation, University of Auckland, Auckland, New Zealand.

Introduction: This paper reports on a new methodology to objectively study the world in which children live. The primary research study (Kids'Cam Food Marketing) illustrates the method; numerous ancillary studies include exploration of children's exposure to alcohol, smoking, "blue" space and gambling, and their use of "green" space, transport, and sun protection.

Methods: One hundred sixty-eight randomly selected children (aged 11-13 years) recruited from 16 randomly selected schools in Wellington, New Zealand used wearable cameras and GPS units for 4 days, recording imagery every 7 seconds and longitude/latitude locations every 5 seconds. Data were collected from July 2014 to June 2015. Analysis commenced in 2015 and is ongoing. Bespoke software was used to manually code images for variables of interest including setting, marketing media, and product category to produce variables for statistical analysis. GPS data were extracted and cleaned in ArcGIS, version 10.3 for exposure spatial analysis.

Results: Approximately 1.4 million images and 2.2 million GPS coordinates were generated (most were usable) from many settings including the difficult to measure aspects of exposures in the home, at school, and during leisure time. The method is ethical, legal, and acceptable to children and the wider community.

Conclusions: This methodology enabled objective analysis of the world in which children live. The main arm examined the frequency and nature of children's exposure to food and beverage marketing and provided data on difficult to measure settings. The methodology will likely generate robust evidence facilitating more effective policymaking to address numerous public health concerns.
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http://dx.doi.org/10.1016/j.amepre.2017.02.016DOI Listing
September 2017

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

Authors:
Christopher Abbosh Nicolai J Birkbak Gareth A Wilson Mariam Jamal-Hanjani Tudor Constantin Raheleh Salari John Le Quesne David A Moore Selvaraju Veeriah Rachel Rosenthal Teresa Marafioti Eser Kirkizlar Thomas B K Watkins Nicholas McGranahan Sophia Ward Luke Martinson Joan Riley Francesco Fraioli Maise Al Bakir Eva Grönroos Francisco Zambrana Raymondo Endozo Wenya Linda Bi Fiona M Fennessy Nicole Sponer Diana Johnson Joanne Laycock Seema Shafi Justyna Czyzewska-Khan Andrew Rowan Tim Chambers Nik Matthews Samra Turajlic Crispin Hiley Siow Ming Lee Martin D Forster Tanya Ahmad Mary Falzon Elaine Borg David Lawrence Martin Hayward Shyam Kolvekar Nikolaos Panagiotopoulos Sam M Janes Ricky Thakrar Asia Ahmed Fiona Blackhall Yvonne Summers Dina Hafez Ashwini Naik Apratim Ganguly Stephanie Kareht Rajesh Shah Leena Joseph Anne Marie Quinn Phil A Crosbie Babu Naidu Gary Middleton Gerald Langman Simon Trotter Marianne Nicolson Hardy Remmen Keith Kerr Mahendran Chetty Lesley Gomersall Dean A Fennell Apostolos Nakas Sridhar Rathinam Girija Anand Sajid Khan Peter Russell Veni Ezhil Babikir Ismail Melanie Irvin-Sellers Vineet Prakash Jason F Lester Malgorzata Kornaszewska Richard Attanoos Haydn Adams Helen Davies Dahmane Oukrif Ayse U Akarca John A Hartley Helen L Lowe Sara Lock Natasha Iles Harriet Bell Yenting Ngai Greg Elgar Zoltan Szallasi Roland F Schwarz Javier Herrero Aengus Stewart Sergio A Quezada Karl S Peggs Peter Van Loo Caroline Dive C Jimmy Lin Matthew Rabinowitz Hugo J W L Aerts Allan Hackshaw Jacqui A Shaw Bernhard G Zimmermann Charles Swanton

Nature 2017 04;545(7655):446-451

Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6DD, UK.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.
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http://dx.doi.org/10.1038/nature22364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812436PMC
April 2017

Tracking the Evolution of Non-Small-Cell Lung Cancer.

N Engl J Med 2017 06 26;376(22):2109-2121. Epub 2017 Apr 26.

From the Cancer Research UK Lung Cancer Centre of Excellence (M.J.-H., G.A.W., N. McGranahan, N.J.B., S.V., S.S., D.H.J., R.R., S.-M.L., M.D.F., C.A., S.M.J., C.D., C.S.), London and Manchester, Good Clinical Laboratory Practice Facility, University College London (UCL) Experimental Cancer Medicine Centre (H.L.L., J.A.H.), Bill Lyons Informatics Centre (J.H.), and Cancer Immunology Unit (S.A.Q.), UCL Cancer Institute, the Translational Cancer Therapeutics Laboratory (G.A.W., N. McGranahan, N.J.B., T.B.K.W., A.R., T.C., S. Turajlic, H.X., C.T.H., C.S.), Department of Bioinformatics and Biostatistics (R.M., M.S., S.H., M.E., A.S.), Advanced Sequencing Facility (N. Matthews), and Cancer Genomics Laboratory (S.D., P.V.L.), Francis Crick Institute, the Renal and Skin Units, Royal Marsden Hospital (S. Turajlic), the Departments of Medical Oncology (M.J.-H., S.-M.L., M.D.F., T.A., C.A., C.S.), Pathology (M.F., E.B., T.M.), Cardiothoracic Surgery (D.L., M.H., S. Kolvekar, N.P.), Respiratory Medicine (S.M.J., R.T.), and Radiology (A.A.), UCL Hospitals, Lungs for Living, UCL Respiratory, UCL (S.M.J.), the Department of Radiotherapy, North Middlesex University Hospital (G.A.), the Department of Respiratory Medicine, Royal Free Hospital (S. Khan), and UCL Cancer Research UK and Cancer Trials Centre (N.I., H.B., Y.N., A.H.), London, Cancer Studies, University of Leicester (D.A.M., D.A.F., J.A.S., J.L.Q.), the Department of Thoracic Surgery, Glenfield Hospital (A.N., S.R.), and the Medical Research Center Toxicology Unit (J.L.Q.), Leicester, the Institute of Cancer Studies, University of Manchester (F.B.), the Christie Hospital (F.B., Y.S.), the Departments of Cardiothoracic Surgery (R.S.) and Pathology (L.J., A.M.Q.) and the North West Lung Centre (P.A.C.), University Hospital of South Manchester, and Cancer Research UK Manchester Institute (C.D.), Manchester, the Departments of Thoracic Surgery (B.N.) and Cellular Pathology (G.L., S. Trotter), Birmingham Heartlands Hospital, Molecular Pathology Diagnostic Services, Queen Elizabeth Hospital (P.T., B.O.), and Institute of Immunology and Immunotherapy, University of Birmingham (G.M.), Birmingham, the Departments of Medical Oncology (M.N.), Cardiothoracic Surgery (H.R.), Pathology (K.K.), Respiratory Medicine (M.C.), and Radiology (L.G.), Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen, the Department of Respiratory Medicine, Barnet and Chase Farm Hospitals, Barnet (S. Khan), the Department of Respiratory Medicine, Princess Alexandra Hospital, Harlow (P.R.), the Department of Clinical Oncology, St. Luke's Cancer Centre, Guildford (V.E.), the Departments of Pathology (B.I.), Respiratory Medicine (M.I.-S.), and Radiology (V.P.), Ashford and St. Peters' Hospitals, Surrey, the Department of Clinical Oncology, Velindre Hospital (J.F.L.), the Departments of Radiology (H.A.) and Respiratory Medicine (H.D.), University Hospital Llandough, the Departments of Pathology (R.A.) and Cardiothoracic Surgery (M.K.), University Hospital of Wales, and Cardiff University (R.A.), Cardiff, and Wellcome Trust Sanger Institute, Hinxton, and Big Data Institute, University of Oxford, Oxford (S.D.) - all in the United Kingdom; the Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby (Z.S.); the Computational Health Informatics Program, Boston Children's Hospital and Harvard Medical School, Boston (Z.S.); MTA-SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary (Z.S.); Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine, Berlin (R.F.S.); and the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.).

Background: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC.

Methods: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival.

Results: We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10), which remained significant in multivariate analysis.

Conclusions: Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).
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http://dx.doi.org/10.1056/NEJMoa1616288DOI Listing
June 2017

Alcohol sponsorship of a summer of sport: a frequency analysis of alcohol marketing during major sports events on New Zealand television.

N Z Med J 2017 Jan 13;130(1448):27-33. Epub 2017 Jan 13.

School of Medicine, University of Otago, Dunedin.

Aims: This research aims to assess the nature and extent of alcohol marketing through sport sponsorship over a summer of televised sport in New Zealand.

Methods: Frequency analysis of New Zealand television broadcasts of five international sporting events during the summer of 2014-2015. Broadcasts were analysed to identify the percentage of time when alcohol brands were visible during game-play. The number of independent alcohol brand exposures was recorded.

Results: Alcohol brands were observed during every televised event. Audiences were exposed to between 1.6 and 3.8 alcohol brand exposures per minute. Alcohol brands were visible between 42 and 777 times across the games examined. For three out of the five events alcohol brands were visible for almost half of the game.

Conclusion: Alcohol sponsorship was prevalent in international sport on New Zealand television. Given the popularity of broadcast sport, especially with children, there is an urgent need for regulation of alcohol sponsorship of sport. There are viable models of alcohol sponsorship replacement but their implementation requires the will of both sporting organisations and politicians. This research adds weight to arguments to implement recommendations to remove all alcohol sponsorship of sport.
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January 2017

Distinctive subdomains in the resorbing surface of osteoclasts.

PLoS One 2013 21;8(3):e60285. Epub 2013 Mar 21.

Division of Basic Medical Sciences, St George's, University of London, Cranmer Terrace, Tooting, London, United Kingdom.

We employed a novel technique to inspect the substrate-apposed surface of activated osteoclasts, the cells that resorb bone, in the scanning electron microscope. The surface revealed unexpected complexity. At the periphery of the cells were circles and crescents of individual or confluent nodules. These corresponded to the podosomes and actin rings that form a 'sealing zone', encircling the resorptive hemivacuole into which protons and enzymes are secreted. Inside these rings and crescents the osteoclast surface was covered with strips and patches of membrane folds, which were flattened against the substrate surface and surrounded by fold-free membrane in which many orifices could be seen. Corresponding regions of folded and fold-free membrane were found by transmission electron microscopy in osteoclasts incubated on bone. We correlated these patterns with the distribution of several proteins crucial to resorption. The strips and patches of membrane folds corresponded in distribution to vacuolar H+-ATPase, and frequently co-localized with F-actin. Cathepsin K localized to F-actin-free foci towards the center of cells with circular actin rings, and at the retreating pole of cells with actin crescents. The chloride/proton antiporter ClC-7 formed a sharply-defined band immediately inside the actin ring, peripheral to vacuolar H+-ATPase. The sealing zone of osteoclasts is permeable to molecules with molecular mass up to 10,000. Therefore, ClC-7 might be distributed at the periphery of the resorptive hemivacuole in order to prevent protons from escaping laterally from the hemivacuole into the sealing zone, where they would dissolve the bone mineral. Since the activation of resorption is attributable to recognition of the αVβ3 ligands bound to bone mineral, such leakage would, by dissolving bone mineral, release the ligands and so terminate resorption. Therefore, ClC-7 might serve not only to provide the counter-ions that enable proton pumping, but also to facilitate resorption by acting as a 'functional sealing zone'.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060285PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605329PMC
September 2013

Bone is not essential for osteoclast activation.

PLoS One 2010 Sep 17;5(9). Epub 2010 Sep 17.

Division of Basic Medical Sciences, St George's, University of London, London, UK.

Background: The mechanism whereby bone activates resorptive behavior in osteoclasts, the cells that resorb bone, is unknown. It is known that α(v)β(3) ligands are important, because blockade of α(v)β(3) receptor signaling inhibits bone resorption, but this might be through inhibition of adhesion or migration rather than resorption itself. Nor is it known whether α(v)β(3) ligands are sufficient for resorption the consensus is that bone mineral is essential for the recognition of bone as the substrate appropriate for resorption.

Methodology/principal Findings: Vitronectin- but not fibronectin-coated coverslips induced murine osteoclasts to secrete tartrate-resistant acid phosphatase, as they do on bone. Osteoclasts incubated on vitronectin, unlike fibronectin, formed podosome belts on glass coverslips, and these were modulated by resorption-regulating cytokines. Podosome belts formed on vitronectin-coated surfaces whether the substrates were rough or smooth, rigid or flexible. We developed a novel approach whereby the substrate-apposed surface of cells can be visualized in the scanning electron microscope. With this approach, supported by transmission electron microscopy, we found that osteoclasts on vitronectin-coated surfaces show ruffled borders and clear zones characteristic of resorbing osteoclasts. Ruffles were obscured by a film if cells were incubated in the cathepsin inhibitor E64, suggesting that removal of the film represents substrate-degrading behavior. Analogously, osteoclasts formed resorption-like trails on vitronectin-coated substrates. Like bone resorption, these trails were dependent upon resorbogenic cytokines and were inhibited by E64. Bone mineral induced actin rings and surface excavation only if first coated with vitronectin. Fibronectin could not substitute in any of these activities, despite enabling adhesion and cell spreading.

Conclusions/significance: Our results show that ligands α(v)β(3) are not only necessary but sufficient for the induction of resorptive behavior in osteoclasts; and suggest that bone is recognized through its affinity for these ligands, rather than by its mechanical or topographical attributes, or through a putative 'mineral receptor'.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0012837PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2941467PMC
September 2010

Shameful comment.

Authors:
Tim Chambers

Lancet 2009 Feb;373(9664):632

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http://dx.doi.org/10.1016/S0140-6736(09)60399-8DOI Listing
February 2009

WASp deficiency in mice results in failure to form osteoclast sealing zones and defects in bone resorption.

Blood 2004 May 15;103(9):3552-61. Epub 2004 Jan 15.

The Randall Centre for Molecular Mechanisms of Cell Function, New Hunt's House, King's College London, Guy's Campus, London, United Kingdom.

No defects related to deficiency of the Wiskott-Aldrich Syndrome protein (WASp) have been described in osteoclasts. Here we show that there are significant morphologic and functional abnormalities. WASp-null cells spread over a much larger surface area and are highly polykaryotic. In their migratory phase, normal cells assemble clusters of podosomes behind their leading edges, whereas during the bone resorptive phase multiple podosomes are densely aggregated in well-defined actin rings forming the sealing zone. In comparison, WASp-null osteoclasts in either phase are markedly depleted of podosomes. On bone surfaces, this results in a failure to form actin rings at sealing zones. Complementation of WASp-null osteoclasts with an enhanced green fluorescent protein (eGFP)-WASp fusion protein restores normal cytoarchitecture. These structural disturbances translate into abnormal patterns of bone resorption both in vitro on bone slices and in vivo. Although physiologic steady-state levels of bone resorption are maintained, a major impairment is observed when WASp-null animals are exposed to a resorptive challenge. Our results provide clear evidence that WASp is a critical component of podosomes in osteoclasts and indicate a nonredundant role for WASp in the dynamic organization of these actin structures during bone resorption.
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http://dx.doi.org/10.1182/blood-2003-04-1259DOI Listing
May 2004