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1.  Vitamin E intake and the lung cancer risk among female nonsmokers: a report from the Shanghai Women’s Health Study 
Vitamin E includes several tocopherol isoforms which may reduce lung cancer risk, but past studies evaluating the association between vitamin E intake and lung cancer risk were inconsistent. We prospectively investigated the associations between tocopherol intake from diet and from supplements with lung cancer risk among 72,829 Chinese female nonsmokers aged 40-70 years and participating in the Shanghai Women’s Health Study (SWHS). Dietary and supplement tocopherol exposure was assessed by a validated food-frequency questionnaire at baseline, and also reassessed for change in intake during follow-up. Cox proportional hazards models with time-dependent covariates were used to calculate multivariate-adjusted hazard ratios (HRs) and 95% confidence interval (CIs) for lung cancer. After 12.02 years of follow-up, 481 women were diagnosed with lung cancer. Total dietary tocopherol was inversely associated with lung cancer risk among women meeting dietary guidelines for adequate intake (AI) of tocopherol (14 mg/day or more: HR: 0.78; 95% CI 0.60-0.99; compared to the category less than AI). The protective association between dietary tocopherol intake and lung cancer was restricted to women exposed to side-stream smoke in the home and workplace (HR=0.53 (0.29-0.97), p-trend = 0.04). In contrast, vitamin E supplement use was associated with increased lung cancer risk (HR: 1.33; 95% CI 1.01-1.73), more so for lung adenocarcinoma risk (HR: 1.79; 95% CI 1.23-2.60). In summary, dietary tocopherol intake may reduce the risk of lung cancer among female non-smokers, however supplements may increase lung adenocarcinoma risk and requires further investigation.
doi:10.1002/ijc.29016
PMCID: PMC4232456  PMID: 24916784
diet; dietary supplements; lung neoplasm; prospective study; tocopherols; women
2.  Constitutive mitochondrial DNA copy number in peripheral blood of melanoma families with and without CDKN2A mutations 
Journal of carcinogenesis & mutagenesis  2014;2014(Suppl 4):006.
Quantitative changes in mitochondrial DNA (mtDNA) have been associated with the risk of a number of human cancers; however, the relationship between constitutive mtDNA copy number in blood and the risk of familial cutaneous malignant melanoma (CMM) has not been reported. We measured mtDNA copy number using quantitative PCR in blood-derived DNA from 136 CMM cases and 302 controls in 53 melanoma-prone families (23 segregating CDKN2A germline mutations). MtDNA copy number did not vary by age, sex, pigmentation characteristics, or CMM status. However, germline CDKN2A mutation carriers had significantly higher mean mtDNA copy number compared to non-carriers, particularly among CMM cases (geometric mean mtDNA copy number of 144 and 111 for carrier versus non-carrier, respectively; P= 0.02). When adjusting for age, sex, and familial correlation, having increasing mtDNA copy number was significantly associated with CDKN2A mutation status among CMM cases (OR=1.47, Ptrend=0.024). In particular, individuals with specific CDKN2A mutations with the potential to inactivate or reduce the level of the p16-INK4 reactive oxygen species (ROS) protective function had significantly increased mtDNA copy number levels (P=0.035). Future research in prospective studies is required to validate these findings and to further investigate mtDNA copy number in both blood and melanoma tissues in relation to CMM risk and CDKN2A mutation status.
doi:10.4172/2157-2518.S4-006
PMCID: PMC4326067
Familial melanoma; CDKN2A; mtDNA copy number; peripheral blood
3.  A genome-wide association study of marginal zone lymphoma shows association to the HLA region 
Vijai, Joseph | Wang, Zhaoming | Berndt, Sonja I. | Skibola, Christine F. | Slager, Susan L. | de Sanjose, Silvia | Melbye, Mads | Glimelius, Bengt | Bracci, Paige M. | Conde, Lucia | Birmann, Brenda M. | Wang, Sophia S. | Brooks-Wilson, Angela R. | Lan, Qing | de Bakker, Paul I. W. | Vermeulen, Roel C. H. | Portlock, Carol | Ansell, Stephen M. | Link, Brian K. | Riby, Jacques | North, Kari E. | Gu, Jian | Hjalgrim, Henrik | Cozen, Wendy | Becker, Nikolaus | Teras, Lauren R. | Spinelli, John J. | Turner, Jenny | Zhang, Yawei | Purdue, Mark P. | Giles, Graham G. | Kelly, Rachel S. | Zeleniuch-Jacquotte, Anne | Ennas, Maria Grazia | Monnereau, Alain | Bertrand, Kimberly A. | Albanes, Demetrius | Lightfoot, Tracy | Yeager, Meredith | Chung, Charles C. | Burdett, Laurie | Hutchinson, Amy | Lawrence, Charles | Montalvan, Rebecca | Liang, Liming | Huang, Jinyan | Ma, Baoshan | Villano, Danylo J. | Maria, Ann | Corines, Marina | Thomas, Tinu | Novak, Anne J. | Dogan, Ahmet | Liebow, Mark | Thompson, Carrie A. | Witzig, Thomas E. | Habermann, Thomas M. | Weiner, George J. | Smith, Martyn T. | Holly, Elizabeth A. | Jackson, Rebecca D. | Tinker, Lesley F. | Ye, Yuanqing | Adami, Hans-Olov | Smedby, Karin E. | De Roos, Anneclaire J. | Hartge, Patricia | Morton, Lindsay M. | Severson, Richard K. | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Diver, W. Ryan | Vajdic, Claire M. | Armstrong, Bruce K. | Kricker, Anne | Zheng, Tongzhang | Holford, Theodore R. | Severi, Gianluca | Vineis, Paolo | Ferri, Giovanni M. | Ricco, Rosalia | Miligi, Lucia | Clavel, Jacqueline | Giovannucci, Edward | Kraft, Peter | Virtamo, Jarmo | Smith, Alex | Kane, Eleanor | Roman, Eve | Chiu, Brian C. H. | Fraumeni, Joseph F. | Wu, Xifeng | Cerhan, James R. | Offit, Kenneth | Chanock, Stephen J. | Rothman, Nathaniel | Nieters, Alexandra
Nature Communications  2015;6:5751.
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10−15) and HLA-B (rs2922994, P=2.43 × 10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
Marginal zone lymphoma (MZL) is a common subtype of B-cell non-Hodgkin lymphoma. Here the authors carry out a two-stage genome-wide association study in over 8,000 Europeans and identify two new MZL risk loci at chromosome 6p, implicating the major histocompatibility complex in the disease for the first time.
doi:10.1038/ncomms6751
PMCID: PMC4287989  PMID: 25569183
6.  IL10 and TNF variants and risk of non-Hodgkin lymphoma among three Asian populations 
Genetic variation in immune-related genes, such as IL10 and TNF, have been associated with the development of non-Hodgkin lymphoma (NHL) in Caucasian populations. To test the hypothesis that IL10 and TNF polymorphisms may be associated with NHL risk in Asian populations, we genotyped 20 single nucleotide polymorphisms (SNPs) within the IL10 and TNF/LTA loci in three independent case–control studies (2635 cases and 4234 controls). IL10 rs1800871, rs1800872, and rs1800896 were genotyped in all three studies, while 5 of the remaining SNPs were genotyped in two studies, and 12 in a single study. IL10 rs1800896 was associated with B cell lymphoma [per-allele odds ratio (OR) = 1.25, 95 % confidence interval (CI) 1.08–1.45; ptrend = 0.003], specifically diffuse large B cell lymphoma (DLBCL) (per-allele OR = 1.29, 95 % CI 1.08–1.53; ptrend = 0.004), as well as T cell lymphoma (per-allele OR = 1.44, 95 % CI 1.13–1.82; ptrend = 0.003). TNF rs1800629, which was genotyped in only two of our studies, was also associated with B cell lymphoma (per-allele OR = 0.77, 95 % CI 0.64–0.91; ptrend = 0.003), specifically DLBCL (per-allele OR = 0.69, 95 % CI 0.55–0.86; ptrend = 0.001). Our findings suggest that genetic variation in IL10 and TNF may also play a role in lymphomagenesis in Asian populations.
doi:10.1007/s12185-013-1345-5
PMCID: PMC4241501  PMID: 23640160
NHL; DLBCL; Subtype; Asia; IL10; TNF
7.  Combustion-derived nanoparticle exposure and household solid fuel use in Xuanwei and Fuyuan, China 
Combustion-derived nanoparticles (CDNPs) have not been readably measurable until recently. We conducted a pilot study to determine CDNP levels during solid fuel burning. The aggregate surface area of CDNP (μm2/cm3) was monitored continuously in 15 Chinese homes using varying fuel types (i.e. bituminous coal, anthracite coal, wood) and stove types (i.e. portable stoves, stoves with chimneys, firepits). Information on fuel burning activities was collected and PM2.5 levels were measured. Substantial exposure differences were observed during solid fuel burning (mean: 228.1 μm2/cm3) compared to times without combustion (mean: 14.0 μm2/cm3). The observed levels during burning were reduced by about four-fold in homes with a chimney (mean: 92.1 μm2/cm3; n = 9), and effects were present for all fuel types. Each home’s CDNP measurement was only moderately correlated with the respective PM2.5 measurements (r2 = 0.43; p = 0.11). Our results indicate that household coal and wood burning contributes to indoor nanoparticle levels, which are not fully reflected in PM2.5 measurements.
doi:10.1080/09603123.2012.684147
PMCID: PMC4231791  PMID: 22639822
coal; biomass; wood; stove; nanoparticle; respiratory
8.  Driver mutations among never smoking female lung cancer tissues in China identify unique EGFR and KRAS mutation pattern associated with household coal burning 
Respiratory medicine  2013;107(11):10.1016/j.rmed.2013.08.018.
Lung cancer in never smokers, which has been partially attributed to household solid fuel use (i.e coal), is etiologically and clinically different from lung cancer attributed to tobacco smoking. To explore the spectrum of driver mutations among lung cancer tissues from never smokers, specifically in a population where high lung cancer rates have been attributed to indoor air pollution from domestic coal use, multiplexed assays were used to detect >40 point mutations, insertions, and deletions (EGFR, KRAS, BRAF, HER2, NRAS, PIK3CA, MEK1, AKT1, and PTEN) among the lung tumors of confirmed never smoking females from Xuanwei, China [32 adenocarcinomas (ADCs), 7 squamous cell carcinomas (SCCs), 1 adenosquamous carcinoma (ADSC)]. EGFR mutations were detected in 35% of tumors. 46% of these involved EGFR exon 18 G719X, while 14% were exon 21 L858R mutations. KRAS mutations, all of which were G12C_34G>T, were observed in 15% of tumors. EGFR and KRAS mutations were mutually exclusive, and no mutations were observed in the other tested genes. Most point mutations were transversions and were also found in tumors from patients who used coal in their homes. Our high mutation frequencies in EGFR exon 18 and KRAS and low mutation frequency in EGFR exon 21 are strikingly divergent from those in other smoking and never smoking populations from Asia. Given that our subjects live in a region where coal is typically burned indoors, our findings provide new insights into the pathogenesis of lung cancer among never smoking females exposed to indoor air pollution from coal.
doi:10.1016/j.rmed.2013.08.018
PMCID: PMC3848251  PMID: 24055406
EGFR; KRAS; lung cancer; never smoking; China; driver mutations; tumor tissue
9.  Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 
Murray, Christopher J L | Ortblad, Katrina F | Guinovart, Caterina | Lim, Stephen S | Wolock, Timothy M | Roberts, D Allen | Dansereau, Emily A | Graetz, Nicholas | Barber, Ryan M | Brown, Jonathan C | Wang, Haidong | Duber, Herbert C | Naghavi, Mohsen | Dicker, Daniel | Dandona, Lalit | Salomon, Joshua A | Heuton, Kyle R | Foreman, Kyle | Phillips, David E | Fleming, Thomas D | Flaxman, Abraham D | Phillips, Bryan K | Johnson, Elizabeth K | Coggeshall, Megan S | Abd-Allah, Foad | Ferede, Semaw | Abraham, Jerry P | Abubakar, Ibrahim | Abu-Raddad, Laith J | Abu-Rmeileh, Niveen Me | Achoki, Tom | Adeyemo, Austine Olufemi | Adou, Arsène Kouablan | Adsuar, José C | Agardh, Emilie Elisabet | Akena, Dickens | Al Kahbouri, Mazin J | Alasfoor, Deena | Albittar, Mohammed I | Alcalá-Cerra, Gabriel | Alegretti, Miguel Angel | Alemu, Zewdie Aderaw | Alfonso-Cristancho, Rafael | Alhabib, Samia | Ali, Raghib | Alla, Francois | Allen, Peter J | Alsharif, Ubai | Alvarez, Elena | Alvis-Guzman, Nelson | Amankwaa, Adansi A | Amare, Azmeraw T | Amini, Hassan | Ammar, Walid | Anderson, Benjamin O | Antonio, Carl Abelardo T | Anwari, Palwasha | Ärnlöv, Johan | Arsenijevic, Valentina S Arsic | Artaman, Ali | Asghar, Rana J | Assadi, Reza | Atkins, Lydia S | Badawi, Alaa | Balakrishnan, Kalpana | Banerjee, Amitava | Basu, Sanjay | Beardsley, Justin | Bekele, Tolesa | Bell, Michelle L | Bernabe, Eduardo | Beyene, Tariku Jibat | Bhala, Neeraj | Bhalla, Ashish | Bhutta, Zulfiqar A | Abdulhak, Aref Bin | Binagwaho, Agnes | Blore, Jed D | Basara, Berrak Bora | Bose, Dipan | Brainin, Michael | Breitborde, Nicholas | Castañeda-Orjuela, Carlos A | Catalá-López, Ferrán | Chadha, Vineet K | Chang, Jung-Chen | Chiang, Peggy Pei-Chia | Chuang, Ting-Wu | Colomar, Mercedes | Cooper, Leslie Trumbull | Cooper, Cyrus | Courville, Karen J | Cowie, Benjamin C | Criqui, Michael H | Dandona, Rakhi | Dayama, Anand | De Leo, Diego | Degenhardt, Louisa | Del Pozo-Cruz, Borja | Deribe, Kebede | Jarlais, Don C Des | Dessalegn, Muluken | Dharmaratne, Samath D | Dilmen, Uğur | Ding, Eric L | Driscoll, Tim R | Durrani, Adnan M | Ellenbogen, Richard G | Ermakov, Sergey Petrovich | Esteghamati, Alireza | Faraon, Emerito Jose A | Farzadfar, Farshad | Fereshtehnejad, Seyed-Mohammad | Fijabi, Daniel Obadare | Forouzanfar, Mohammad H | Paleo, Urbano Fra. | Gaffikin, Lynne | Gamkrelidze, Amiran | Gankpé, Fortuné Gbètoho | Geleijnse, Johanna M | Gessner, Bradford D | Gibney, Katherine B | Ginawi, Ibrahim Abdelmageem Mohamed | Glaser, Elizabeth L | Gona, Philimon | Goto, Atsushi | Gouda, Hebe N | Gugnani, Harish Chander | Gupta, Rajeev | Gupta, Rahul | Hafezi-Nejad, Nima | Hamadeh, Randah Ribhi | Hammami, Mouhanad | Hankey, Graeme J | Harb, Hilda L | Haro, Josep Maria | Havmoeller, Rasmus | Hay, Simon I | Hedayati, Mohammad T | Pi, Ileana B Heredia | Hoek, Hans W | Hornberger, John C | Hosgood, H Dean | Hotez, Peter J | Hoy, Damian G | Huang, John J | Iburg, Kim M | Idrisov, Bulat T | Innos, Kaire | Jacobsen, Kathryn H | Jeemon, Panniyammakal | Jensen, Paul N | Jha, Vivekanand | Jiang, Guohong | Jonas, Jost B | Juel, Knud | Kan, Haidong | Kankindi, Ida | Karam, Nadim E | Karch, André | Karema, Corine Kakizi | Kaul, Anil | Kawakami, Norito | Kazi, Dhruv S | Kemp, Andrew H | Kengne, Andre Pascal | Keren, Andre | Kereselidze, Maia | Khader, Yousef Saleh | Khalifa, Shams Eldin Ali Hassan | Khan, Ejaz Ahmed | Khang, Young-Ho | Khonelidze, Irma | Kinfu, Yohannes | Kinge, Jonas M | Knibbs, Luke | Kokubo, Yoshihiro | Kosen, S | Defo, Barthelemy Kuate | Kulkarni, Veena S | Kulkarni, Chanda | Kumar, Kaushalendra | Kumar, Ravi B | Kumar, G Anil | Kwan, Gene F | Lai, Taavi | Balaji, Arjun Lakshmana | Lam, Hilton | Lan, Qing | Lansingh, Van C | Larson, Heidi J | Larsson, Anders | Lee, Jong-Tae | Leigh, James | Leinsalu, Mall | Leung, Ricky | Li, Yichong | Li, Yongmei | De Lima, Graça Maria Ferreira | Lin, Hsien-Ho | Lipshultz, Steven E | Liu, Shiwei | Liu, Yang | Lloyd, Belinda K | Lotufo, Paulo A | Machado, Vasco Manuel Pedro | Maclachlan, Jennifer H | Magis-Rodriguez, Carlos | Majdan, Marek | Mapoma, Christopher Chabila | Marcenes, Wagner | Marzan, Melvin Barrientos | Masci, Joseph R | Mashal, Mohammad Taufiq | Mason-Jones, Amanda J | Mayosi, Bongani M | Mazorodze, Tasara T | Mckay, Abigail Cecilia | Meaney, Peter A | Mehndiratta, Man Mohan | Mejia-Rodriguez, Fabiola | Melaku, Yohannes Adama | Memish, Ziad A | Mendoza, Walter | Miller, Ted R | Mills, Edward J | Mohammad, Karzan Abdulmuhsin | Mokdad, Ali H | Mola, Glen Liddell | Monasta, Lorenzo | Montico, Marcella | Moore, Ami R | Mori, Rintaro | Moturi, Wilkister Nyaora | Mukaigawara, Mitsuru | Murthy, Kinnari S | Naheed, Aliya | Naidoo, Kovin S | Naldi, Luigi | Nangia, Vinay | Narayan, K M Venkat | Nash, Denis | Nejjari, Chakib | Nelson, Robert G | Neupane, Sudan Prasad | Newton, Charles R | Ng, Marie | Nisar, Muhammad Imran | Nolte, Sandra | Norheim, Ole F | Nowaseb, Vincent | Nyakarahuka, Luke | Oh, In-Hwan | Ohkubo, Takayoshi | Olusanya, Bolajoko O | Omer, Saad B | Opio, John Nelson | Orisakwe, Orish Ebere | Pandian, Jeyaraj D | Papachristou, Christina | Caicedo, Angel J Paternina | Patten, Scott B | Paul, Vinod K | Pavlin, Boris Igor | Pearce, Neil | Pereira, David M | Pervaiz, Aslam | Pesudovs, Konrad | Petzold, Max | Pourmalek, Farshad | Qato, Dima | Quezada, Amado D | Quistberg, D Alex | Rafay, Anwar | Rahimi, Kazem | Rahimi-Movaghar, Vafa | Rahman, Sajjad Ur | Raju, Murugesan | Rana, Saleem M | Razavi, Homie | Reilly, Robert Quentin | Remuzzi, Giuseppe | Richardus, Jan Hendrik | Ronfani, Luca | Roy, Nobhojit | Sabin, Nsanzimana | Saeedi, Mohammad Yahya | Sahraian, Mohammad Ali | Samonte, Genesis May J | Sawhney, Monika | Schneider, Ione J C | Schwebel, David C | Seedat, Soraya | Sepanlou, Sadaf G | Servan-Mori, Edson E | Sheikhbahaei, Sara | Shibuya, Kenji | Shin, Hwashin Hyun | Shiue, Ivy | Shivakoti, Rupak | Sigfusdottir, Inga Dora | Silberberg, Donald H | Silva, Andrea P | Simard, Edgar P | Singh, Jasvinder A | Skirbekk, Vegard | Sliwa, Karen | Soneji, Samir | Soshnikov, Sergey S | Sreeramareddy, Chandrashekhar T | Stathopoulou, Vasiliki Kalliopi | Stroumpoulis, Konstantinos | Swaminathan, Soumya | Sykes, Bryan L | Tabb, Karen M | Talongwa, Roberto Tchio | Tenkorang, Eric Yeboah | Terkawi, Abdullah Sulieman | Thomson, Alan J | Thorne-Lyman, Andrew L | Towbin, Jeffrey A | Traebert, Jefferson | Tran, Bach X | Dimbuene, Zacharie Tsala | Tsilimbaris, Miltiadis | Uchendu, Uche S | Ukwaja, Kingsley N | Uzun, Selen Begüm | Vallely, Andrew J | Vasankari, Tommi J | Venketasubramanian, N | Violante, Francesco S | Vlassov, Vasiliy Victorovich | Vollset, Stein Emil | Waller, Stephen | Wallin, Mitchell T | Wang, Linhong | Wang, XiaoRong | Wang, Yanping | Weichenthal, Scott | Weiderpass, Elisabete | Weintraub, Robert G | Westerman, Ronny | White, Richard A | Wilkinson, James D | Williams, Thomas Neil | Woldeyohannes, Solomon Meseret | Wong, John Q | Xu, Gelin | Yang, Yang C | Yano, Yuichiro | Yentur, Gokalp Kadri | Yip, Paul | Yonemoto, Naohiro | Yoon, Seok-Jun | Younis, Mustafa | Yu, Chuanhua | Jin, Kim Yun | El Sayed Zaki, Maysaa | Zhao, Yong | Zheng, Yingfeng | Zhou, Maigeng | Zhu, Jun | Zou, Xiao Nong | Lopez, Alan D | Vos, Theo
Lancet  2014;384(9947):1005-1070.
Summary
Background
The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occurred since the Millennium Declaration.
Methods
To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010–13) of incidence, drug resistance, and coverage of insecticide-treated bednets.
Findings
Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990.
Interpretation
Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS’s estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action.
Funding
Bill & Melinda Gates Foundation.
doi:10.1016/S0140-6736(14)60844-8
PMCID: PMC4202387  PMID: 25059949
10.  Identification of gene–environment interactions in cancer studies using penalization 
Genomics  2013;102(4):10.1016/j.ygeno.2013.08.006.
High-throughput cancer studies have been extensively conducted, searching for genetic markers associated with outcomes beyond clinical and environmental risk factors. Gene–environment interactions can have important implications beyond main effects. The commonly-adopted single-marker analysis cannot accommodate the joint effects of a large number of markers. The existing joint-effects methods also have limitations. Specifically, they may suffer from high computational cost, do not respect the “main effect, interaction” hierarchical structure, or use ineffective techniques. We develop a penalization method for the identification of important G × E interactions and main effects. It has an intuitive formulation, respects the hierarchical structure, accommodates the joint effects of multiple markers, and is computationally affordable. In numerical study, we analyze prognosis data under the AFT (accelerated failure time) model. Simulation shows satisfactory performance of the proposed method. Analysis of an NHL (non-Hodgkin lymphoma) study with SNP measurements shows that the proposed method identifies markers with important implications and satisfactory prediction performance.
doi:10.1016/j.ygeno.2013.08.006
PMCID: PMC3869641  PMID: 23994599
Gene–environment interaction; Penalized marker identification; Cancer prognosis
11.  Role of One-carbon Metabolizing Pathway Genes and Gene-Nutrient Interaction in the Risk of Non-Hodgkin Lymphoma 
Cancer causes & control : CCC  2013;24(10):1875-1884.
Purpose
Genetic polymorphisms in one-carbon metabolizing pathway genes have been associated with risk of malignant lymphoma. However, the results have been inconsistent. The objectives of this study were to examine the potential relationship between gene-nutrient interactions and the risk of non-Hodgkin lymphoma (NHL).
Methods
We examined 25 polymorphisms in 16 one-carbon metabolism genes for their main effect and gene-nutrient interactions in relation to NHL risk among 518 incident cases and 597 population-based controls of Connecticut women enrolled between 1996 and 2000.
Results
A significantly reduced risk of NHL was associated with the homozygous TT genotype in CBS (rs234706, Ex9+33C>T) (OR = 0.51, 95%CI, 0.31–0.84), the homozygous CC genotype in MBD2 (rs603097, −2176C>T) (OR = 0.37, 95%CI, 0.17–0.79), the heterozygote AG genotype in FTHFD (rs1127717, Ex21+31A>G) (OR = 0.73, 95%CI, 0.55–0.98), and a borderline significantly reduced risk of NHL was observed for the homozygous CC genotype in MTRR (rs161870, Ex5+136T>C) (OR = 0.23, 95%CI, 0.05–1.04). The reduced risk of NHL associated with these genotypes was predominately in those with higher dietary vitamin B6 and methionine intakes, as well as with higher dietary folate intake although results were less stable. A borderline significantly increased risk of NHL was also observed for CBS (rs1801181, Ex13+41C>T), FTHFD (rs2305230, Ex10-40G>T), SHMT1 (rs1979277, Ex12+138C>T), and SHMT1 (rs1979276, Ex12+236T>C), and these associations appeared to be contingent on dietary nutrient intakes.
Conclusion
Our results suggest that variation in several one-carbon metabolizing pathway genes may influence the risk of NHL through gene-nutrient interactions involving dietary nutrient intakes.
doi:10.1007/s10552-013-0264-3
PMCID: PMC3951097  PMID: 23913011
dietary nutrients; folate; one-carbon metabolizing genes; non-Hodgkin lymphoma; cancer
12.  Household air pollution and lung cancer in China: a review of studies in Xuanwei 
Chinese Journal of Cancer  2014;33(10):471-475.
Over half of the world's population is exposed to household air pollution from the burning of solid fuels at home. Household air pollution from solid fuel use is a leading risk factor for global disease and remains a major public health problem, especially in low- and mid-income countries. This is a particularly serious problem in China, where many people in rural areas still use coal for household heating and cooking. This review focuses on several decades of research carried out in Xuanwei County, Yunnan Province, where household coal use is a major source of household air pollution and where studies have linked household air pollution exposure to high rates of lung cancer. We conducted a series of case-control and cohort studies in Xuanwei to characterize the lung cancer risk in this population and the factors associated with it. We found lung cancer risk to vary substantially between different coal types, with a higher risk associated with smoky (i.e., bituminous) coal use compared to smokeless (i.e., anthracite) coal use. The installation of a chimney in homes resulted in a substantial reduction in lung cancer incidence and mortality. Overall, our research underscores the need among existing coal users to improve ventilation, use the least toxic fuel, and eventually move toward the use of cleaner fuels, such as gas and electricity.
doi:10.5732/cjc.014.10132
PMCID: PMC4198749  PMID: 25223911
Coal; household air pollution; lung cancer
13.  Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia 
Lan, Qing | Hsiung, Chao A | Matsuo, Keitaro | Hong, Yun-Chul | Seow, Adeline | Wang, Zhaoming | Hosgood, H Dean | Chen, Kexin | Wang, Jiu-Cun | Chatterjee, Nilanjan | Hu, Wei | Wong, Maria Pik | Zheng, Wei | Caporaso, Neil | Park, Jae Yong | Chen, Chien-Jen | Kim, Yeul Hong | Kim, Young Tae | Landi, Maria Teresa | Shen, Hongbing | Lawrence, Charles | Burdett, Laurie | Yeager, Meredith | Yuenger, Jeffrey | Jacobs, Kevin B | Chang, I-Shou | Mitsudomi, Tetsuya | Kim, Hee Nam | Chang, Gee-Chen | Bassig, Bryan A | Tucker, Margaret | Wei, Fusheng | Yin, Zhihua | Wu, Chen | An, She-Juan | Qian, Biyun | Lee, Victor Ho Fun | Lu, Daru | Liu, Jianjun | Jeon, Hyo-Sung | Hsiao, Chin-Fu | Sung, Jae Sook | Kim, Jin Hee | Gao, Yu-Tang | Tsai, Ying-Huang | Jung, Yoo Jin | Guo, Huan | Hu, Zhibin | Hutchinson, Amy | Wang, Wen-Chang | Klein, Robert | Chung, Charles C | Oh, In-Jae | Chen, Kuan-Yu | Berndt, Sonja I | He, Xingzhou | Wu, Wei | Chang, Jiang | Zhang, Xu-Chao | Huang, Ming-Shyan | Zheng, Hong | Wang, Junwen | Zhao, Xueying | Li, Yuqing | Choi, Jin Eun | Su, Wu-Chou | Park, Kyong Hwa | Sung, Sook Whan | Shu, Xiao-Ou | Chen, Yuh-Min | Liu, Li | Kang, Chang Hyun | Hu, Lingmin | Chen, Chung-Hsing | Pao, William | Kim, Young-Chul | Yang, Tsung-Ying | Xu, Jun | Guan, Peng | Tan, Wen | Su, Jian | Wang, Chih-Liang | Li, Haixin | Sihoe, Alan Dart Loon | Zhao, Zhenhong | Chen, Ying | Choi, Yi Young | Hung, Jen-Yu | Kim, Jun Suk | Yoon, Ho-Il | Cai, Qiuyin | Lin, Chien-Chung | Park, In Kyu | Xu, Ping | Dong, Jing | Kim, Christopher | He, Qincheng | Perng, Reury-Perng | Kohno, Takashi | Kweon, Sun-Seog | Chen, Chih-Yi | Vermeulen, Roel | Wu, Junjie | Lim, Wei-Yen | Chen, Kun-Chieh | Chow, Wong-Ho | Ji, Bu-Tian | Chan, John K C | Chu, Minjie | Li1, Yao-Jen | Yokota, Jun | Li, Jihua | Chen, Hongyan | Xiang, Yong-Bing | Yu, Chong-Jen | Kunitoh, Hideo | Wu, Guoping | Jin, Li | Lo, Yen-Li | Shiraishi, Kouya | Chen, Ying-Hsiang | Lin, Hsien-Chih | Wu, Tangchun | Wu, Yi-Long | Yang, Pan-Chyr | Zhou, Baosen | Shin, Min-Ho | Fraumeni, Joseph F | Lin, Dongxin | Chanock, Stephen J | Rothman, Nathaniel
Nature genetics  2012;44(12):1330-1335.
To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10-18), 6q22.2 (rs9387478, P = 4.14 × 10-10) and 6p21.32 (rs2395185, P = 9.51 × 10-9). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.
doi:10.1038/ng.2456
PMCID: PMC4169232  PMID: 23143601
14.  Global, regional, and national levels of neonatal, infant, and under-5 mortality during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 
Wang, Haidong | Liddell, Chelsea A | Coates, Matthew M | Mooney, Meghan D | Levitz, Carly E | Schumacher, Austin E | Apfel, Henry | Iannarone, Marissa | Phillips, Bryan | Lofgren, Katherine T | Sandar, Logan | Dorrington, Rob E | Rakovac, Ivo | Jacobs, Troy A | Liang, Xiaofeng | Zhou, Maigeng | Zhu, Jun | Yang, Gonghuan | Wang, Yanping | Liu, Shiwei | Li, Yichong | Ozgoren, Ayse Abbasoglu | Abera, Semaw Ferede | Abubakar, Ibrahim | Achoki, Tom | Adelekan, Ademola | Ademi, Zanfina | Alemu, Zewdie Aderaw | Allen, Peter J | AlMazroa, Mohammad AbdulAziz | Alvarez, Elena | Amankwaa, Adansi A | Amare, Azmeraw T | Ammar, Walid | Anwari, Palwasha | Cunningham, Solveig Argeseanu | Asad, Majed Masoud | Assadi, Reza | Banerjee, Amitava | Basu, Sanjay | Bedi, Neeraj | Bekele, Tolesa | Bell, Michelle L | Bhutta, Zulfiqar | Blore, Jed | Basara, Berrak Bora | Boufous, Soufiane | Breitborde, Nicholas | Bruce, Nigel G | Bui, Linh Ngoc | Carapetis, Jonathan R | Cárdenas, Rosario | Carpenter, David O | Caso, Valeria | Castro, Ruben Estanislao | Catalá-Lopéz, Ferrán | Cavlin, Alanur | Che, Xuan | Chiang, Peggy Pei-Chia | Chowdhury, Rajiv | Christophi, Costas A | Chuang, Ting-Wu | Cirillo, Massimo | Leite, Iuri da Costa | Courville, Karen J | Dandona, Lalit | Dandona, Rakhi | Davis, Adrian | Dayama, Anand | Deribe, Kebede | Dharmaratne, Samath D | Dherani, Mukesh K | Dilmen, Uğur | Ding, Eric L | Edmond, Karen M | Ermakov, Sergei Petrovich | Farzadfar, Farshad | Fereshtehnejad, Seyed-Mohammad | Fijabi, Daniel Obadare | Foigt, Nataliya | Forouzanfar, Mohammad H | Garcia, Ana C | Geleijnse, Johanna M | Gessner, Bradford D | Goginashvili, Ketevan | Gona, Philimon | Goto, Atsushi | Gouda, Hebe N | Green, Mark A | Greenwell, Karen Fern | Gugnani, Harish Chander | Gupta, Rahul | Hamadeh, Randah Ribhi | Hammami, Mouhanad | Harb, Hilda L | Hay, Simon | Hedayati, Mohammad T | Hosgood, H Dean | Hoy, Damian G | Idrisov, Bulat T | Islami, Farhad | Ismayilova, Samaya | Jha, Vivekanand | Jiang, Guohong | Jonas, Jost B | Juel, Knud | Kabagambe, Edmond Kato | Kazi, Dhruv S | Kengne, Andre Pascal | Kereselidze, Maia | Khader, Yousef Saleh | Khalifa, Shams Eldin Ali Hassan | Khang, Young-Ho | Kim, Daniel | Kinfu, Yohannes | Kinge, Jonas M | Kokubo, Yoshihiro | Kosen, Soewarta | Defo, Barthelemy Kuate | Kumar, G Anil | Kumar, Kaushalendra | Kumar, Ravi B | Lai, Taavi | Lan, Qing | Larsson, Anders | Lee, Jong-Tae | Leinsalu, Mall | Lim, Stephen S | Lipshultz, Steven E | Logroscino, Giancarlo | Lotufo, Paulo A | Lunevicius, Raimundas | Lyons, Ronan Anthony | Ma, Stefan | Mahdi, Abbas Ali | Marzan, Melvin Barrientos | Mashal, Mohammad Taufiq | Mazorodze, Tasara T | McGrath, John J | Memish, Ziad A | Mendoza, Walter | Mensah, George A | Meretoja, Atte | Miller, Ted R | Mills, Edward J | Mohammad, Karzan Abdulmuhsin | Mokdad, Ali H | Monasta, Lorenzo | Montico, Marcella | Moore, Ami R | Moschandreas, Joanna | Msemburi, William T | Mueller, Ulrich O | Muszynska, Magdalena M | Naghavi, Mohsen | Naidoo, Kovin S | Narayan, KM Venkat | Nejjari, Chakib | Ng, Marie | Ngirabega, Jean de Dieu | Nieuwenhuijsen, Mark J | Nyakarahuka, Luke | Ohkubo, Takayoshi | Omer, Saad B | Caicedo, Angel J Paternina | Wyk, Victoria Pillay-van | Pope, Dan | Prabhakaran, Dorairaj | Rahman, Sajjad UR | Rana, Saleem M | Reilly, Robert Quentin | Rojas-Rueda, David | Ronfani, Luca | Rushton, Lesley | Saeedi, Mohammad Yahya | Salomon, Joshua | Sampson, Uchechukwu | Santos, Itamar S | Sawhney, Monika | Schmidt, Jürgen C | Nazarova, Marina Shakh | She, Jun | Sheikhbahaei, Sara | Shibuya, Kenji | Shin, Hwashin Hyun | Shishani, Kawkab | Shiue, Ivy | Sigfusdottir, Inga Dora | Singh, Jasvinder A | Skirbekk, Vegard | Sliwa, Karen | Soshnikov, Sergey S | Sposato, Luciano A | Stathopoulou, Vasiliki Kalliopi | Stroumpoulis, Konstantinos | Tabb, Karen M | Talongwa, Roberto Tchio | Teixeira, Carolina Maria | Terkawi, Abdullah Sulieman | Thomson, Alan J | Lyman, Andrew L Thorne | Toyoshima, Hideaki | Dimbuene, Zacharie Tsala | Uwaliraye, Parfait | Uzun, Selen Begüm | Vasankari, Tommi J | Vasconcelos, Ana Maria Nogales | Vlassov, Vasiliy Victorovich | Vollset, Stein Emil | Vos, Theo | Waller, Stephen | Wan, Xia | Weichenthal, Scott | Weiderpass, Elisabete | Weintraub, Robert G | Westerman, Ronny | Wilkinson, James D | Williams, Hywel C | Yang, Yang C | Yentur, Gokalp Kadri | Yip, Paul | Yonemoto, Naohiro | Younis, Mustafa | Yu, Chuanhua | Jin, Kim Yun | Zaki, Maysaa El Sayed | Zhu, Shankuan | Lopez, Alan D | Murray, Christopher J L
Lancet  2014;384(9947):957-979.
Summary
Background
Remarkable financial and political efforts have been focused on the reduction of child mortality during the past few decades. Timely measurements of levels and trends in under-5 mortality are important to assess progress towards the Millennium Development Goal 4 (MDG 4) target of reduction of child mortality by two thirds from 1990 to 2015, and to identify models of success.
Methods
We generated updated estimates of child mortality in early neonatal (age 0–6 days), late neonatal (7–28 days), postneonatal (29–364 days), childhood (1–4 years), and under-5 (0–4 years) age groups for 188 countries from 1970 to 2013, with more than 29 000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non-sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030.
Findings
We estimated that 6·3 million (95% UI 6·0–6·6) children under-5 died in 2013, a 64% reduction from 17·6 million (17·1–18·1) in 1970. In 2013, child mortality rates ranged from 152·5 per 1000 livebirths (130·6–177·4) in Guinea-Bissau to 2·3 (1·8–2·9) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from −6·8% to 0·1%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000–13 than during 1990–2000. In 2013, neonatal deaths accounted for 41·6% of under-5 deaths compared with 37·4% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 1·4 million more child deaths, and rising income per person and maternal education led to 0·9 million and 2·2 million fewer deaths, respectively. Changes in secular trends led to 4·2 million fewer deaths. Unexplained factors accounted for only −1% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone.
Interpretation
Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030.
Funding
Bill & Melinda Gates Foundation, US Agency for International Development.
doi:10.1016/S0140-6736(14)60497-9
PMCID: PMC4165626  PMID: 24797572
15.  A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010 
Lim, Stephen S | Vos, Theo | Flaxman, Abraham D | Danaei, Goodarz | Shibuya, Kenji | Adair-Rohani, Heather | Amann, Markus | Anderson, H Ross | Andrews, Kathryn G | Aryee, Martin | Atkinson, Charles | Bacchus, Loraine J | Bahalim, Adil N | Balakrishnan, Kalpana | Balmes, John | Barker-Collo, Suzanne | Baxter, Amanda | Bell, Michelle L | Blore, Jed D | Blyth, Fiona | Bonner, Carissa | Borges, Guilherme | Bourne, Rupert | Boussinesq, Michel | Brauer, Michael | Brooks, Peter | Bruce, Nigel G | Brunekreef, Bert | Bryan-Hancock, Claire | Bucello, Chiara | Buchbinder, Rachelle | Bull, Fiona | Burnett, Richard T | Byers, Tim E | Calabria, Bianca | Carapetis, Jonathan | Carnahan, Emily | Chafe, Zoe | Charlson, Fiona | Chen, Honglei | Chen, Jian Shen | Cheng, Andrew Tai-Ann | Child, Jennifer Christine | Cohen, Aaron | Colson, K Ellicott | Cowie, Benjamin C | Darby, Sarah | Darling, Susan | Davis, Adrian | Degenhardt, Louisa | Dentener, Frank | Des Jarlais, Don C | Devries, Karen | Dherani, Mukesh | Ding, Eric L | Dorsey, E Ray | Driscoll, Tim | Edmond, Karen | Ali, Suad Eltahir | Engell, Rebecca E | Erwin, Patricia J | Fahimi, Saman | Falder, Gail | Farzadfar, Farshad | Ferrari, Alize | Finucane, Mariel M | Flaxman, Seth | Fowkes, Francis Gerry R | Freedman, Greg | Freeman, Michael K | Gakidou, Emmanuela | Ghosh, Santu | Giovannucci, Edward | Gmel, Gerhard | Graham, Kathryn | Grainger, Rebecca | Grant, Bridget | Gunnell, David | Gutierrez, Hialy R | Hall, Wayne | Hoek, Hans W | Hogan, Anthony | Hosgood, H Dean | Hoy, Damian | Hu, Howard | Hubbell, Bryan J | Hutchings, Sally J | Ibeanusi, Sydney E | Jacklyn, Gemma L | Jasrasaria, Rashmi | Jonas, Jost B | Kan, Haidong | Kanis, John A | Kassebaum, Nicholas | Kawakami, Norito | Khang, Young-Ho | Khatibzadeh, Shahab | Khoo, Jon-Paul | Kok, Cindy | Laden, Francine | Lalloo, Ratilal | Lan, Qing | Lathlean, Tim | Leasher, Janet L | Leigh, James | Li, Yang | Lin, John Kent | Lipshultz, Steven E | London, Stephanie | Lozano, Rafael | Lu, Yuan | Mak, Joelle | Malekzadeh, Reza | Mallinger, Leslie | Marcenes, Wagner | March, Lyn | Marks, Robin | Martin, Randall | McGale, Paul | McGrath, John | Mehta, Sumi | Mensah, George A | Merriman, Tony R | Micha, Renata | Michaud, Catherine | Mishra, Vinod | Hanafiah, Khayriyyah Mohd | Mokdad, Ali A | Morawska, Lidia | Mozaff arian, Dariush | Murphy, Tasha | Naghavi, Mohsen | Neal, Bruce | Nelson, Paul K | Nolla, Joan Miquel | Norman, Rosana | Olives, Casey | Omer, Saad B | Orchard, Jessica | Osborne, Richard | Ostro, Bart | Page, Andrew | Pandey, Kiran D | Parry, Charles D H | Passmore, Erin | Patra, Jayadeep | Pearce, Neil | Pelizzari, Pamela M | Petzold, Max | Phillips, Michael R | Pope, Dan | Pope III, C Arden | Powles, John | Rao, Mayuree | Razavi, Homie | Rehfuess, Eva A | Rehm, Jürgen T | Ritz, Beate | Rivara, Frederick P | Roberts, Thomas | Robinson, Carolyn | Rodriguez-Portales, Jose A | Romieu, Isabelle | Room, Robin | Rosenfeld, Lisa C | Roy, Ananya | Rushton, Lesley | Salomon, Joshua A | Sampson, Uchechukwu | Sanchez-Riera, Lidia | Sanman, Ella | Sapkota, Amir | Seedat, Soraya | Shi, Peilin | Shield, Kevin | Shivakoti, Rupak | Singh, Gitanjali M | Sleet, David A | Smith, Emma | Smith, Kirk R | Stapelberg, Nicolas J C | Steenland, Kyle | Stöckl, Heidi | Stovner, Lars Jacob | Straif, Kurt | Straney, Lahn | Thurston, George D | Tran, Jimmy H | Van Dingenen, Rita | van Donkelaar, Aaron | Veerman, J Lennert | Vijayakumar, Lakshmi | Weintraub, Robert | Weissman, Myrna M | White, Richard A | Whiteford, Harvey | Wiersma, Steven T | Wilkinson, James D | Williams, Hywel C | Williams, Warwick | Wilson, Nicholas | Woolf, Anthony D | Yip, Paul | Zielinski, Jan M | Lopez, Alan D | Murray, Christopher J L | Ezzati, Majid
Lancet  2012;380(9859):2224-2260.
Summary
Background
Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time.
Methods
We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden.
Findings
In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2–7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5–7·0]), and alcohol use (5·5% [5·0–5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8–9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6–8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4–6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2–10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water we and sanitation accounting for 0·9% (0·4–1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania.
Interpretation
Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children.
Funding
Bill & Melinda Gates Foundation.
doi:10.1016/S0140-6736(12)61766-8
PMCID: PMC4156511  PMID: 23245609
16.  History of lung disease and risk of lung cancer in a population with high household fuel combustion exposures in rural China 
Lung cancer (Amsterdam, Netherlands)  2013;81(3):10.1016/j.lungcan.2013.06.019.
History of chronic lung diseases and household coal use for heating and cooking are established risk factors of lung cancer; however, few studies have been able to explore these risk factors simultaneously. Xuanwei, China, has some of the highest rates of lung cancer in China and most residents experience substantial in-home coal smoke exposures. Using a population-based case-control study of 498 lung cancer cases and 498 age-matched controls, we evaluated the risk of lung cancer in relation to coal smoke exposure and history of chronic lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, tuberculosis (TB), chronic bronchitis, and emphysema. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by conditional logistic regression adjusting for potential confounders. We observed an increased risk of lung cancer with history of any chronic lung disease among males (OR=14.2; 95%CI =4.3 to 46.9), females (OR=2.6; 95%CI =1.1 to 6.3), smokers (OR=12.7; 95%CI =3.5 to 45.8), and nonsmokers (OR=2.6; 95%CI =1.1 to 6.4). Specifically, TB (OR=83.7; 95%CI =11.0 to 634.7), COPD (OR=3.2; 95%CI =1.7 to 6.0), and emphysema and chronic bronchitis (OR=3.3; 95%CI =1.7 to 6.4) were associated with increased risks. These findings suggest that history of chronic lung diseases may also increase risk of lung cancer in populations with indoor coal smoke exposures.
doi:10.1016/j.lungcan.2013.06.019
PMCID: PMC3845667  PMID: 23891511
Chronic lung disease; lung cancer; never smoking; Xuanwei; China
17.  Polymorphisms in JAK/STAT Signaling Pathway Genes and Risk of Non-Hodgkin Lymphoma 
Leukemia research  2013;37(9):1120-1124.
Impaired function of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway genes leads to immunodeficiency and various hematopoietic disorders. We evaluated the association between genetic polymorphisms (SNPs) in 12 JAK/STAT pathway genes (JAK3, STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6, SCOS1, SCOS2, SCOS3, and SCOS4) and NHL risk in a population-based case-control study of Connecticut women. We identified three SNPs in STAT3 (rs12949918 and rs6503695) and STAT4 (rs932169) associated with NHL risk after adjustment for multiple comparison. Our results suggest that genetic variation in JAK/STAT pathway genes may play a role in lymphomagenesis and warrants further investigation.
doi:10.1016/j.leukres.2013.05.003
PMCID: PMC3998836  PMID: 23768868
JAK/STAT signaling pathway; Non-Hodgkin Lymphoma; polymorphism; case-control study
18.  Glioblastoma microvesicles promote endothelial cell proliferation through Akt/beta-catenin pathway 
Glioblastoma tumor cells release microvesicles, which contain mRNA, miRNA and angiogenic proteins. These tumor-derived microvesicles transfer genetic information and proteins to normal cells. Previous reports demonstrated that the increased microvesicles in cerebrospinal fluid (CSF) of patients with glioblastoma up-regulate procoagulant activity. The concentration of microvesicles was closely related to thromboembolism incidence and clinical therapeutic effects of glioblastoma patients. However, it is still not clear how CSF microvesicles and what factors affect glioblastoma development. In this study, we collected the plasma and CSF from glioblastoma patients and healthy volunteers. Microvesicles acquired from serum or CSF were added to cultured endothelial cells. And the effects of these microvesicles on endothelial cells were examined. Our results showed that microvesicles from CSF of patients, but not from circulating blood, promoted endothelial cells migration and proliferation in vitro. In addition, the degree of endothelial cell proliferation triggered by microvesicles from CSF was reduced when treated with siRNA targeting Akt/beta-catenin, suggesting that the Akt/beta-catenin pathway is involved in the microvesicle-initiated endothelial cell proliferation. In conclusion, glioblastoma mainly affects microvesicles within CSF without showing significant impact on microvesicles in circulating blood. Microvesicles from the CSF of glioblastoma patients may initiate endothelial cell growth and thus promote cell invasion. This effect may be directly exerted by activated Akt/beta-catenin pathway.
PMCID: PMC4152046  PMID: 25197356
Microvesicles; glioblastoma; Akt/beta-catenin; endothelial cells
19.  Single nucleotide polymorphisms in genes encoding for CC chemokines were not associated with the risk of Non-Hodgkin Lymphoma 
Background
Chemokines play a pivotal role in immune regulation and response, and previous studies suggest an association between immune deficiency and Non-Hodgkin lymphoma (NHL).
Methods
We evaluated the association between NHL and polymorphisms in 18 genes (CCL1, CCL2, CCL5, CCL7, CCL8, CCL11, CCL13, CCL18, CCL20, CCL24, CCL26, CCR1, CCR3, CCR4, CCR6, CCR7, CCR8 and CCR9) encoding for the CC chemokines using data from a population-based case-control study of NHL conducted in Connecticut women.
Results
CCR8 was associated with diffuse large B-cell lymphoma (DLBCL) (p = 0.012) and CCL13 was associated with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) (p = 0.003) at gene level. After adjustment for multiple comparisons, none of the genes or SNPs were associated with risk of overall NHL or NHL subtypes.
Conclusions
Our results suggest that the genes encoding for CC chemokines are not significantly associated with the risk of NHL, and further studies are needed to verify these findings.
Impact
Our data indicate that CC chemokine genes were not associated with NHL risk.
doi:10.1158/1055-9965.EPI-13-0328
PMCID: PMC3753095  PMID: 23640258
Non-Hodgkin lymphoma; CC chemokine gene; Single nucleotide polymorphism
20.  Polymorphisms in DNA Repair Pathway Genes, Body Mass Index, and Risk of Non-Hodgkin Lymphoma 
American journal of hematology  2013;88(7):606-611.
We conducted a population-based case-control study in Connecticut women to test the hypothesis that genetic variations in DNA repair pathway genes may modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL). Compared to those with BMI < 25, women with BMI ≥ 25 had significantly increased risk of NHL among women who carried BRCA1 (rs799917) CT/TT, ERCC2 (rs13181) AA, XRCC1 (rs1799782) CC, and WRN (rs1801195) GG genotypes, but no increase in NHL risk among women who carried BRCA1 CC, ERCC2 AC/CC, XRCC1 CT/TT, and WRN GT/TT genotypes. A significant interaction with BMI was only observed for WRN (rs1801195, P=0.004) for T-cell lymphoma and ERCC2 (rs13181, P=0.002) for diffuse large B-cell lymphoma. The results suggest that common genetic variation in DNA repair pathway genes may modify the association between BMI and NHL risk.
doi:10.1002/ajh.23463
PMCID: PMC3902049  PMID: 23619945
Non-Hodgkin lymphoma; BMI; polymorphisms; DNA repair genes
21.  Quercetin sensitizes human glioblastoma cells to temozolomide in vitro via inhibition of Hsp27 
Acta Pharmacologica Sinica  2014;35(6):832-838.
Aim:
Quercetin is an effective Hsp27 inhibitor and has been reported to facilitate tumor cell apoptosis. The aim of this study was to investigate whether quercetin could sensitize human glioblastoma cells to temozolomide (TMZ) in vitro.
Methods:
Both U251 and U87 human glioblastoma cells were treated with quercetin and/or TMZ for 48 h. Cell viability was detected using the MTT assay. Cell apoptosis was analyzed with caspase-3 activity kits and flow cytometry. Hsp27 expression and phosphorylation were examined using Western blot analysis. RNA interference using Hsp27 siRNA oligos was performed to knock down the gene expression of Hsp27.
Results:
TMZ (200 or 400 μmol/L) alone effectively inhibited the viability of U251 and U87 cells. When combined with quercetin (30 μmol/L), TMZ (100 μmol/L) significantly inhibited the cell viability, and the inhibition of TMZ (200 and 400 μmol/L) was enhanced. TMZ or quercetin anole did not affect caspase-3 activity and cell apoptosis, while TMZ combined with quercetin significantly increased caspase-3 activity and induced cell apoptosis. TMZ anole significantly increased Hsp27 phosphorylation in U251 and U87 cells, while quercetin or Hsp27 siRNA oligos combined with TMZ attenuated TMZ-induced Hsp27 phosphorylation and significantly inhibited Hsp27 expression.
Conclusion:
Combined treatment with TMZ and quercetin efficiently suppressed human glioblastoma cell survival in vitro.
doi:10.1038/aps.2014.22
PMCID: PMC4086384  PMID: 24902789
glioma; quercetin; temozolomide; chemotherapy; apoptosis; caspase-3; heat shock protein 27; RNA interference
22.  A prospective study of leukocyte telomere length and risk of renal cell carcinoma 
Background
It has been hypothesized that genomic instability related to telomere dysfunction may contribute to carcinogenesis. There is some evidence from case-control studies suggesting that short leukocyte telomere length (TL) may be associated with an increased risk of renal cell carcinoma (RCC); however, this association has not been investigated prospectively.
Methods
We conducted a nested case-control study (209 cases, 410 controls) of RCC risk in relation to pre-diagnostic leukocyte TL in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression.
Results
Leukocyte TL was not significantly associated with future risk of RCC (highest quartile vs. lowest: OR=0.8, 95% CI=0.5–1.5; Ptrend=0.6). Analyses stratified by sex, age, and time from blood collection to RCC diagnosis were similarly null.
Conclusions
The results of this study, to our knowledge the first prospective investigation of its kind, do not support an association between pre-diagnostic leukocyte TL and risk of RCC.
Impact
In contrast to some earlier reports, our findings add to the evidence that leukocyte TL is not a biomarker of risk related to the etiology of RCC.
doi:10.1158/1055-9965.EPI-13-0142
PMCID: PMC3655903  PMID: 23513041
telomeres; telomere length; renal cell carcinoma; kidney cancer
23.  Characterization of Changes in Gene Expression and Biochemical Pathways at Low Levels of Benzene Exposure 
PLoS ONE  2014;9(5):e91828.
Benzene, a ubiquitous environmental pollutant, causes acute myeloid leukemia (AML). Recently, through transcriptome profiling of peripheral blood mononuclear cells (PBMC), we reported dose-dependent effects of benzene exposure on gene expression and biochemical pathways in 83 workers exposed across four airborne concentration ranges (from <1 ppm to >10 ppm) compared with 42 subjects with non-workplace ambient exposure levels. Here, we further characterize these dose-dependent effects with continuous benzene exposure in all 125 study subjects. We estimated air benzene exposure levels in the 42 environmentally-exposed subjects from their unmetabolized urinary benzene levels. We used a novel non-parametric, data-adaptive model selection method to estimate the change with dose in the expression of each gene. We describe non-parametric approaches to model pathway responses and used these to estimate the dose responses of the AML pathway and 4 other pathways of interest. The response patterns of majority of genes as captured by mean estimates of the first and second principal components of the dose-response for the five pathways and the profiles of 6 AML pathway response-representative genes (identified by clustering) exhibited similar apparent supra-linear responses. Responses at or below 0.1 ppm benzene were observed for altered expression of AML pathway genes and CYP2E1. Together, these data show that benzene alters disease-relevant pathways and genes in a dose-dependent manner, with effects apparent at doses as low as 100 ppb in air. Studies with extensive exposure assessment of subjects exposed in the low-dose range between 10 ppb and 1 ppm are needed to confirm these findings.
doi:10.1371/journal.pone.0091828
PMCID: PMC4006721  PMID: 24786086
24.  Alterations in serum immunoglobulin levels in workers occupationally exposed to trichloroethylene 
Carcinogenesis  2012;34(4):799-802.
Trichloroethylene (TCE) has been associated with a variety of immunotoxic effects and may be associated with an increased risk of non-Hodgkin lymphoma (NHL). Altered serum immunoglobulin (Ig) levels have been reported in NHL patients and in animals exposed to TCE. Recently, we reported that occupational exposure to TCE is associated with immunosuppressive effects and immune dysfunction, including suppression of B-cell counts and activation, even at relatively low levels. We hypothesized that TCE exposure would also affect Ig levels in humans. We measured serum levels of IgG, IgM and IgE, by enzyme-linked immunosorbent assay, in TCE-exposed workers (n = 80) and unexposed controls (n = 45), matched by age and gender, in a cross-sectional, molecular epidemiology study of occupational exposure to TCE in Guangdong, China. Exposed workers had about a 17.5% decline in serum levels of IgG compared with unexposed controls (P = 0.0002). Similarly, serum levels of IgM were reduced by about 38% in workers exposed to TCE compared with unexposed controls (P < 0.0001). Serum levels of both IgG and IgM were significantly decreased in workers exposed to TCE levels below 12 p.p.m., the median exposure level. Adjustment for B-cell counts had minimal impact on our findings. IgE levels were not significantly different between exposed and control subjects. These results provide further evidence that TCE is immunotoxic at relatively low exposure levels and provide additional biologic plausibility for the reported association of TCE with NHL.
doi:10.1093/carcin/bgs403
PMCID: PMC3616671  PMID: 23276795
25.  Alternative Polyadenylation in Glioblastoma Multiforme and Changes in Predicted RNA Binding Protein Profiles 
Abstract
Alternative polyadenylation (APA) is widely present in the human genome and plays a key role in carcinogenesis. We conducted a comprehensive analysis of the APA products in glioblastoma multiforme (GBM, one of the most lethal brain tumors) and normal brain tissues and further developed a computational pipeline, RNAelements (http://sysbio.zju.edu.cn/RNAelements/), using covariance model from known RNA binding protein (RBP) targets acquired by RNA Immunoprecipitation (RIP) analysis. We identified 4530 APA isoforms for 2733 genes in GBM, and found that 182 APA isoforms from 148 genes showed significant differential expression between normal and GBM brain tissues. We then focused on three genes with long and short APA isoforms that show inconsistent expression changes between normal and GBM brain tissues. These were myocyte enhancer factor 2D, heat shock factor binding protein 1, and polyhomeotic homolog 1 (Drosophila). Using the RNAelements program, we found that RBP binding sites were enriched in the alternative regions between the first and the last polyadenylation sites, which would result in the short APA forms escaping regulation from those RNA binding proteins. To the best of our knowledge, this report is the first comprehensive APA isoform dataset for GBM and normal brain tissues. Additionally, we demonstrated a putative novel APA-mediated mechanism for controlling RNA stability and translation for APA isoforms. These observations collectively lay a foundation for novel diagnostics and molecular mechanisms that can inform future therapeutic interventions for GBM.
doi:10.1089/omi.2012.0098
PMCID: PMC3603499  PMID: 23421905

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