Breakthroughs of the year 2010

1. Anaplastic Lymphoma Kinase Inhibition in Non-Small-Cell Lung Cancer

E. L. Kwak, Y. J. Bang, D. R. Camidge, A. T. Shaw, B. Solomon, R. G. Maki, S. H. I. Ou, B. J. Dezube, P. A. Janne, D. B. Costa, M. Varella-Garcia, W. H. Kim, T. J. Lynch, P. Fidias, H. Stubbs, J. A. Engelman, L. V. Sequist, W. W. Tan, L. Gandhi, M. Mino-Kenudson, G. C. Wei, S. M. Shreeve, M. J. Ratain, J. Settleman, J. G. Christensen, D. A. Haber, K. Wilner, R. Salgia, G. I. Shapiro, J. W. Clark and A. J. Iafrate

N Engl J Med.2010 Oct;363(18):1693-1703.

Abstract: BACKGROUND Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. METHODS After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. RESULTS Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. CONCLUSIONS The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients.

Keywords: eml4-alk fusion gene, activating mutations, 2nd-line treatment, egfr, mutations, phase-ii, gefitinib, alk, identification, tumors, immunohistochemistry

*Times Cited: 634

PMID: 20979469


2. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis

K. Matsushita, M. van der Velde, B. C. Astor, M. Woodward, A. S. Levey, P. E. de Jong, J. Coresh, R. T. Gansevoort and C. Chronic Kidney Dis Prognosis

Lancet.2010 Jun;375(9731):2073-2081.

Abstract: Background Substantial controversy surrounds the use of estimated glomerular filtration rate (eGFR) and albuminuria to define chronic kidney disease and assign its stages. We undertook a meta-analysis to assess the independent and combined associations of eGFR and albuminuria with mortality. Methods In this collaborative meta-analysis of general population cohorts, we pooled standardised data for all-cause and cardiovascular mortality from studies containing at least 1000 participants and baseline information about eGFR and urine albumin concentrations. Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality associated with eGFR and albuminuria, adjusted for potential confounders. Findings The analysis included 105 872 participants (730 577 person-years) from 14 studies with urine albumin-to-creatinine ratio (ACR) measurements and 1128 310 participants (4 732110 person-years) from seven studies with urine protein dipstick measurements. In studies with ACR measurements, risk of mortality was unrelated to eGFR between 75 mL/min/1.73 m(2) and 105 mL/min/1.73 m(2) and increased at lower eGFRs. Compared with eGFR 95 mL/min/1.73 m(2), adjusted HRs for all-cause mortality were 1.18 (95% CI 1.05-1.32) for eGFR 60 mL/min/1.73 m(2), 1.57 (1.39-1.78) for 45 mL/min/1.73 m(2), and 3.14 (2.39-4.13) for 15 mL/min/1. 73 m(2). ACR was associated with risk of mortality linearly on the log-log scale without threshold effects. Compared with ACR 0.6 mg/mmol, adjusted HRs for all-cause mortality were 1.20 (1.15-1.26) for ACR 1.1 mg/mmol, 1.63 (1.50-1.77) for 3.4 mg/mmol, and 2.22 (1.97-2.51) for 33.9 mg/mmol. eGFR and ACR were multiplicatively associated with risk of mortality without evidence of interaction. Similar findings were recorded for cardiovascular mortality and in studies with dipstick measurements. Interpretation eGFR less than 60 mi./min/1.73 m(2) and ACR 1.1 mg/mmol (10 mg/g) or more are independent predictors of mortality risk in the general population. This study provides quantitative data for use of both kidney measures for risk assessment and definition and staging of chronic kidney disease.

Keywords: chronic kidney-disease, risk-factor, cystatin-c, serum creatinine, pooled analysis, renal-disease, older-adults, prevalence, equation, outcomes

*Times Cited: 391

PMID: 20483451


3. Common SNPs explain a large proportion of the heritability for human height

J. A. Yang, B. Benyamin, B. P. McEvoy, S. Gordon, A. K. Henders, D. R. Nyholt, P. A. Madden, A. C. Heath, N. G. Martin, G. W. Montgomery, M. E. Goddard and P. M. Visscher

Nature Genetics.2010 Jul;42(7):565-U131.

Abstract: SNPs discovered by genome-wide association studies (GWASs) account for only a small fraction of the genetic variation of complex traits in human populations. Where is the remaining heritability? We estimated the proportion of variance for human height explained by 294,831 SNPs genotyped on 3,925 unrelated individuals using a linear model analysis, and validated the estimation method with simulations based on the observed genotype data. We show that 45% of variance can be explained by considering all SNPs simultaneously. Thus, most of the heritability is not missing but has not previously been detected because the individual effects are too small to pass stringent significance tests. We provide evidence that the remaining heritability is due to incomplete linkage disequilibrium between causal variants and genotyped SNPs, exacerbated by causal variants having lower minor allele frequency than the SNPs explored to date.

Keywords: genome-wide association, missing heritability, artificial selection, complex diseases, traits, loci, populations, prediction

*Times Cited: 389

PMID: 20562875


4. Early Palliative Care for Patients with Metastatic Non-Small-Cell Lung Cancer

J. S. Temel, J. A. Greer, A. Muzikansky, E. R. Gallagher, S. Admane, V. A. Jackson, C. M. Dahlin, C. D. Blinderman, J. Jacobsen, W. F. Pirl, J. A. Billings and T. J. Lynch

N Engl J Med.2010 Aug;363(8):733-742.

Abstract: BACKGROUND Patients with metastatic non-small-cell lung cancer have a substantial symptom burden and may receive aggressive care at the end of life. We examined the effect of introducing palliative care early after diagnosis on patient-reported outcomes and end-of-life care among ambulatory patients with newly diagnosed disease. METHODS We randomly assigned patients with newly diagnosed metastatic non-small-cell lung cancer to receive either early palliative care integrated with standard oncologic care or standard oncologic care alone. Quality of life and mood were assessed at baseline and at 12 weeks with the use of the Functional Assessment of Cancer Therapy-Lung (FACT-L) scale and the Hospital Anxiety and Depression Scale, respectively. The primary outcome was the change in the quality of life at 12 weeks. Data on end-of-life care were collected from electronic medical records. RESULTS Of the 151 patients who underwent randomization, 27 died by 12 weeks and 107 (86% of the remaining patients) completed assessments. Patients assigned to early palliative care had a better quality of life than did patients assigned to standard care (mean score on the FACT-L scale [in which scores range from 0 to 136, with higher scores indicating better quality of life], 98.0 vs. 91.5; P = 0.03). In addition, fewer patients in the palliative care group than in the standard care group had depressive symptoms (16% vs. 38%, P = 0.01). Despite the fact that fewer patients in the early palliative care group than in the standard care group received aggressive end-of-life care (33% vs. 54%, P = 0.05), median survival was longer among patients receiving early palliative care (11.6 months vs. 8.9 months, P = 0.02). CONCLUSIONS Among patients with metastatic non-small-cell lung cancer, early palliative care led to significant improvements in both quality of life and mood. As compared with patients receiving standard care, patients receiving early palliative care had less aggressive care at the end of life but longer survival. (Funded by an American Society of Clinical Oncology Career Development Award and philanthropic gifts; number, NCT01038271.)

Keywords: quality-of-life, cooperative-oncology-group, randomized, controlled-trial, functional assessment, elderly-patients, supportive, care, therapy-lung, depression, survival, chemotherapy

*Times Cited: 421

PMID: 20818875


5. Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus

H. N. Ginsberg, M. B. Elam, L. C. Lovato, J. R. Crouse, L. A. Leiter, P. Linz, W. T. Friedewald, J. B. Buse, H. C. Gerstein, J. Probstfield, R. H. Grimm, F. Ismail-Beigi, J. T. Bigger, D. C. Goff, W. C. Cushman, D. G. Simons-Morton, R. P. Byington and A. S. Grp

N Engl J Med.2010 Apr;362(17):1563-1574.

Abstract: BACKGROUND We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease. METHODS We randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P = 0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P = 0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P = 0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol (P = 0.057 for interaction). CONCLUSIONS The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. ( number, NCT00000620.)

Keywords: coronary-heart-disease, placebo-controlled trial, treatment panel-iii, cardiovascular-disease, artery-disease, risk-factors, myocardial-infarction, secondary prevention, intervention trial, ldl, cholesterol

*Times Cited: 396

PMID: 20228404


6. Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus

W. C. Cushman, G. W. Evans, R. P. Byington, D. C. Goff, R. H. Grimm, J. A. Cutler, D. G. Simons-Morton, J. N. Basile, M. A. Corson, J. L. Probstfield, L. Katz, K. A. Peterson, W. T. Friedewald, J. B. Buse, J. T. Bigger, H. C. Gerstein and F. Ismail-Beigi

N Engl J Med.2010 Apr;362(17):1575-1585.

Abstract: BACKGROUND There is no evidence from randomized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus. We investigated whether therapy targeting normal systolic pressure (i.e., < 120 mm Hg) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events. METHODS A total of 4733 participants with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic pressure of less than 120 mm Hg, or standard therapy, targeting a systolic pressure of less than 140 mm Hg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS After 1 year, the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% confidence interval [CI], 0.73 to 1.06; P = 0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (hazard ratio, 1.07; 95% CI, 0.85 to 1.35; P = 0.55). The annual rates of stroke, a prespecified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P = 0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P<0.001). CONCLUSIONS In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. ( number, NCT00000620.)

Keywords: microvascular complications, risk, disease, trial, prevention, hot

*Times Cited: 463

PMID: 20228401


7. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study

K. K. Kumarasamy, M. A. Toleman, T. R. Walsh, J. Bagaria, F. Butt, R. Balakrishnan, U. Chaudhary, M. Doumith, C. G. Giske, S. Irfan, P. Krishnan, A. V. Kumar, S. Maharjan, S. Mushtaq, T. Noorie, D. L. Paterson, A. Pearson, C. Perry, R. Pike, B. Rao, U. Ray, J. B. Sarma, M. Sharma, E. Sheridan, M. A. Thirunarayan, J. Turton, S. Upadhyay, M. Warner, W. Welfare, D. M. Livermore and N. Woodford

Lancet Infect Dis.2010 Sep;10(9):597-602.

Abstract: Background Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-beta-lactamase 1 (NDM-1) are potentially a major global health problem. We investigated the prevalence of NDM-1, in multidrug-resistant Enterobacteriaceae in India, Pakistan, and the UK. Methods Enterobacteriaceae isolates were studied from two major centres in India-Chennai (south India), Haryana (north India)-and those referred to the UK’s national reference laboratory. Antibiotic susceptibilities were assessed, and the presence of the carbapenem resistance gene bla(NDM 1) was established by PCR. Isolates were typed by pulsed-field gel electrophoresis of XbaI-restricted genomic DNA. Plasmids were analysed by Si nuclease digestion and PCR typing. Case data for UK patients were reviewed for evidence of travel and recent admission to hospitals in India or Pakistan Findings We identified 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the UK, and 73 in other sites in India and Pakistan. NDM-1 was mostly found among Escherichia coli (36) and Klebsiella pneumoniae (111), which were highly resistant to all antibiotics except to tigecycline and colistin. K pneumoniae isolates from Haryana were clonal but NDM-1 producers from the UK and Chennai were clonally diverse. Most isolates carried the NDM-1 gene on plasmids: those from UK and Chennai were readily transferable whereas those from Haryana were not conjugative. Many of the UK NDM-1 positive patients had travelled to India or Pakistan within the past year, or had links with these countries. Interpretation The potential of NDM-1 to be a worldwide public health problem is great, and co-ordinated international surveillance is needed.

Keywords: klebsiella-pneumoniae carbapenemase, ctx-m, beta-lactamases, enterobacteriaceae, infections, prevalence, hospitals, threat

*Times Cited: 482

PMID: 20705517


8. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008

J. Ferlay, H. R. Shin, F. Bray, D. Forman, C. Mathers and D. M. Parkin

Int J Cancer.2010 Dec;127(12):2893-2917.

Abstract: Estimates of the worldwide incidence and mortality from 27 cancers in 2008 have been prepared for 182 countries as part of the GLOBOCAN series published by the International Agency for Research on Cancer. In this article, we present the results for 20 world regions, summarizing the global patterns for the eight most common cancers. Overall, an estimated 12.7 million new cancer cases and 7.6 million cancer deaths occur in 2008, with 56% of new cancer cases and 63% of the cancer deaths occurring in the less developed regions of the world. The most commonly diagnosed cancers worldwide are lung (1.61 million, 12.7% of the total), breast (1.38 million, 10.9%) and colorectal cancers (1.23 million, 9.7%). The most common causes of cancer death are lung cancer (1.38 million, 18.2% of the total), stomach cancer (738,000 deaths, 9.7%) and liver cancer (696,000 deaths, 9.2%). Cancer is neither rare anywhere in the world, nor mainly confined to high-resource countries. Striking differences in the patterns of cancer from region to region are observed.

Keywords: incidence, mortality, cancer, global estimates, 18 major cancers, mortality, population, prediction, frequency, survival

*Times Cited: 1185

PMID: 21351269


9. Exome sequencing identifies the cause of a mendelian disorder

S. B. Ng, K. J. Buckingham, C. Lee, A. W. Bigham, H. K. Tabor, K. M. Dent, C. D. Huff, P. T. Shannon, E. W. Jabs, D. A. Nickerson, J. Shendure and M. J. Bamshad

Nature Genetics.2010 Jan;42(1):30-U41.

Abstract: We demonstrate the first successful application of exome sequencing to discover the gene for a rare mendelian disorder of unknown cause, Miller syndrome (MIM%263750). For four affected individuals in three independent kindreds, we captured and sequenced coding regions to a mean coverage of 40x and sufficient depth to call variants at similar to 97% of each targeted exome. Filtering against public SNP databases and eight HapMap exomes for genes with two previously unknown variants in each of the four individuals identified a single candidate gene, DHODH, which encodes a key enzyme in the pyrimidine de novo biosynthesis pathway. Sanger sequencing confirmed the presence of DHODH mutations in three additional families with Miller syndrome. Exome sequencing of a small number of unrelated affected individuals is a powerful, efficient strategy for identifying the genes underlying rare mendelian disorders and will likely transform the genetic analysis of monogenic traits.

Keywords: postaxial acrofacial dysostosis, ultraconserved elements, drosophila-melanogaster, rheumatoid-arthritis, kappa-b, leflunomide, mice, inhibition, mutations, capture

*Times Cited: 466

PMID: 19915526


10. Gefitinib or Chemotherapy for Non-Small-Cell Lung Cancer with Mutated EGFR

M. Maemondo, A. Inoue, K. Kobayashi, S. Sugawara, S. Oizumi, H. Isobe, A. Gemma, M. Harada, H. Yoshizawa, I. Kinoshita, Y. Fujita, S. Okinaga, H. Hirano, K. Yoshimori, T. Harada, T. Ogura, M. Ando, H. Miyazawa, T. Tanaka, Y. Saijo, K. Hagiwara, S. Morita, T. Nukiwa and N. E. J. S. Grp

N Engl J Med.2010 Jun;362(25):2380-2388.

Abstract: Background: Non-small-cell lung cancer with sensitive mutations of the epidermal growth factor receptor (EGFR) is highly responsive to EGFR tyrosine kinase inhibitors such as gefitinib, but little is known about how its efficacy and safety profile compares with that of standard chemotherapy. Methods: We randomly assigned 230 patients with metastatic, non-small-cell lung cancer and EGFR mutations who had not previously received chemotherapy to receive gefitinib or carboplatin-paclitaxel. The primary end point was progression-free survival; secondary end points included overall survival, response rate, and toxic effects. Results: In the planned interim analysis of data for the first 200 patients, progression-free survival was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P<0.001), resulting in early termination of the study. The gefitinib group had a significantly longer median progression-free survival (10.8 months, vs. 5.4 months in the chemotherapy group; hazard ratio, 0.30; 95% confidence interval, 0.22 to 0.41; P<0.001), as well as a higher response rate (73.7% vs. 30.7%, P<0.001). The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P=0.31). The most common adverse events in the gefitinib group were rash (71.1%) and elevated aminotransferase levels (55.3%), and in the chemotherapy group, neutropenia (77.0%), anemia (64.6%), appetite loss (56.6%), and sensory neuropathy (54.9%). One patient receiving gefitinib died from interstitial lung disease. Conclusions: First-line gefitinib for patients with advanced non-small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy. (UMIN-CTR number, C000000376.) N Engl J Med 2010;362:2380-8.

Keywords: growth-factor-receptor, previously treated patients, randomized, phase-iii, acid pcr clamp, japanese patients, gene-mutations, survival, trial, adenocarcinoma, paclitaxel

*Times Cited: 555

PMID: 20573926


11. Genetic Variation in IL28B Is Associated With Chronic Hepatitis C and Treatment Failure: A Genome-Wide Association Study

A. Rauch, Z. Kutalik, P. Descombes, T. Cai, J. Di Iulio, T. Mueller, M. Bochud, M. Battegay, E. Bernasconi, J. Borovicka, S. Colombo, A. Cerny, J. F. Dufour, H. Furrer, H. F. Gunthard, M. Heim, B. Hirschel, R. Malinverni, D. Moradpour, B. Mullhaupt, A. Witteck, J. S. Beckmann, T. Berg, S. Bergmann, F. Negro, A. Telenti, P. Y. Bochud, C. Swiss Hepatitis and S. Hiv Cohort

Gastroenterology.2010 Apr;138(4):1338-U1173.

Abstract: BACKGROUND & AIMS: Hepatitis C virus (HCV) induces chronic infection in 50% to 80% of infected persons; approximately 50% of these do not respond to therapy. We performed a genome-wide association study to screen for host genetic determinants of HCV persistence and response to therapy. METHODS: The analysis included 1362 individuals: 1015 with chronic hepatitis C and 347 who spontaneously cleared the virus (448 were coinfected with human immunodeficiency virus [HIV]). Responses to pegylated interferon alfa and ribavirin were assessed in 465 individuals. Associations between more than 500,000 single nucleotide polymorphisms (SNPs) and outcomes were assessed by multivariate logistic regression. RESULTS: Chronic hepatitis C was associated with SNPs in the IL28B locus, which encodes the antiviral cytokine interferon lambda. The rs8099917 minor allele was associated with progression to chronic HCV infection (odds ratio [OR], 2.31; 95% confidence interval [CI], 1.74-3.06; P = 6.07 x 10(-9)). The association was observed in HCV mono-infected (OR, 2.49; 95% CI, 1.64-3.79; P = 1.96 x 10(-5)) and HCV/HIV coinfected individuals (OR, 2.16; 95% CI, 1.47-3.18; P = 8.24 x 10(-5)). rs8099917 was also associated with failure to respond to therapy (OR, 5.19; 95% CI, 2.90-9.30; P = 3.11 x 10(-8)), with the strongest effects in patients with HCV genotype 1 or 4. This risk allele was identified in 24% of individuals with spontaneous HCV clearance, 32% of chronically infected patients who responded to therapy, and 58% who did not respond (P = 3.2 x 10(-10)). Resequencing of IL28B identified distinct haplotypes that were associated with the clinical phenotype. CONCLUSIONS: The association of the IL28B locus with natural and treatment-associated control of HCV indicates the importance of innate immunity and interferon lambda in the pathogenesis of HCV infection.

Keywords: Hepatitis C, Genetics, Interferon, Interleukin-28, alpha-2a plus ribavirin, virus-infection, peginterferon alpha-2a, natural-history, interferon-lambda, immune-responses, ifn-lambda, replication, host, polymorphisms

*Times Cited: 384

PMID: 20060832


*Updated on 04/10/2013

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