The role of genetic polymorphisms in endolysosomal ion channels TPC2 and P2RX4 in cancer pathogenesis, prognosis, and diagnosis: a genetic association in the UK Biobank

AbstractRecent studies have implicated important roles for endolysosomal ion channels in cancer biology. We used UK Biobank data to characterise the relationships between genetic variants in two genes coding for endolysosomal ion channels—i.e. TPCN2 and P2RX4—and cancer in terms of the definition of tumour types, susceptibility, and prognosis. We investigated these relationships at both global and local levels with regard to specific types of cancer, including malignant neoplasms of the brain, breast, bronchus, lung, colon, lymphoid and haematopoietic systems, skin, ovary, prostate, rectum, thyroid gland, lip, oral cavity, pharynx, and urinary tract. Apart from rs3829241 (p value < 0.05), all the genetic variants were in Hardy–Weinberg equilibrium. We included 468,436 subjects in the analysis and stratified them into two major cohorts: cancer-free controls (385,253) and cancer cases (83,183). For the first time, we report novel associations between genetic variants of TPCN2 and P2RX4 and cancer/cancer subtypes in the UK Biobank’s population. Genotype GG in TPCN2 rs3750965 was significantly associated with a decreased risk of cancer and an increased risk of lip, oral cavity, and pharynx cancer and cancer recurrence in patients with prostate cancer, and genotypes GA/GG were associated with a significantly lower risk of developing various malignant neoplasms (involving melanoma, prostate, mesothelial, and soft tissues). rs35264875:TA was associated with a high risk of cancer at the global level, with subtypes of cancer at the local level (including breast, colon, prostate, and stated or presumed primary cancer of lymphoid, haematopoietic, and related tissue), and with a significantly low risk of cancer metastasis. rs72932540:GA was associated with a higher incidence of cancer/cancer subtypes (including breast, melanoma, and rectal cancer), and genotypes GA/GG were associated with an increased risk of prostate cancer. The P2RX4 rs25644 allele GG was associated with a high risk of prostate cancer, whereas it was associated with a low risk of cancer recurrence in patients with prostate cancer. Genotypes GA/GG in rs28360472 were associated with an increased risk of breast, mesothelial, and soft tissue cancers but with a decreased risk of colon cancer. We also provide insights into the pathophysiological contributions made by these significant polymorphisms to cancer/cancer subtypes and their effects on expression or channel activity. Further investigations of these genetic variants could help identify novel cancer biomarkers and facilitate the development of new diagnostic and therapeutic strategies. This would constitute a further step towards personalised cancer care.

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Rapidly Shifting Concepts Regarding Androgens and Prostate Cancer

The Scientific World JOURNAL ◽

10.1100/tsw.2009.80 ◽

2009 ◽

Vol 9 ◽

pp. 685-690 ◽

Cited By ~ 8

Author(s):

Abraham Morgentaler

Keyword(s):

Prostate Cancer ◽

Cancer Recurrence ◽

Serum Testosterone ◽

High Serum ◽

Prior History ◽

Minimal Risk ◽

Increased Risk ◽

History Of ◽

Dramatic Shift ◽

Risk Of Cancer

There has been a recent dramatic shift in our understanding of the relationship between androgens and prostate cancer (PCa). Whereas for several decades it had been assumed that higher serum testosterone (T) concentrations would lead to ever-greater PCa growth, current literature indicates that PCa growth is unaffected by changes in serum T throughout most of the naturally occurring range. A Saturation Model has been proposed to explain how prostate tissue can be exquisitely sensitive to changes in serum T at the very low end of the concentration range, but appears indifferent to such changes above the near-castrate range. This has special applicability to T-deficient men, since this means that T therapy may not be nearly as risky as once assumed. Indeed, one of the more interesting changes over the last several years has been the growing acceptance of the use of T therapy in men with a prior history of PCa, with early data indicating minimal risk of cancer recurrence or progression. Provocative new evidence suggests that it is not high serum T that is problematic for PCa, butlowserum T that is associated with worrisome cancer features and outcomes, such as high Gleason score, advanced stage of presentation, and increased risk of biochemical recurrence after surgery. It will be interesting to see what changes will occur in this rapidly changing field over the next several years.

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Genetically determined risk of keratinocyte carcinoma and risk of other cancers

International Journal of Epidemiology ◽

10.1093/ije/dyaa265 ◽

2020 ◽

Author(s):

Jean Claude Dusingize ◽

Catherine M Olsen ◽

Jiyuan An ◽

Nirmala Pandeya ◽

Upekha E Liyanage ◽

...

Keyword(s):

Genetic Variants ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Epidemiological Studies ◽

Risk Scores ◽

Cancer Site ◽

Uk Biobank ◽

Individual Level ◽

Increased Risk ◽

The Uk

Abstract Background Epidemiological studies have consistently documented an increased risk of developing primary non-cutaneous malignancies among people with a history of keratinocyte carcinoma (KC). However, the mechanisms underlying this association remain unclear. We conducted two separate analyses to test whether genetically predicted KC is related to the risk of developing cancers at other sites. Methods In the first approach (one-sample), we calculated the polygenic risk scores (PRS) for KC using individual-level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 16 896). The association between the KC PRS and each cancer site was assessed using logistic regression. In the secondary (two-sample) approach, we used genome-wide association study (GWAS) summary statistics identified from the most recent GWAS meta-analysis of KC and obtained GWAS data for each cancer site from the UK-Biobank participants only. We used inverse-variance-weighted methods to estimate risks across all genetic variants. Results Using the one-sample approach, we found that the risks of cancer at other sites increased monotonically with KC PRS quartiles, with an odds ratio (OR) of 1.16, 95% confidence interval (CI): 1.13–1.19 for those in KC PRS quartile 4 compared with those in quartile 1. In the two-sample approach, the pooled risk of developing other cancers was statistically significantly elevated, with an OR of 1.05, 95% CI: 1.03–1.07 per doubling in the odds of KC. We observed similar trends of increasing cancer risk with increasing KC PRS in the QSkin cohort. Conclusion Two different genetic approaches provide compelling evidence that an instrumental variable for KC constructed from genetic variants predicts the risk of cancers at other sites.

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Alcohol causes an increased risk of head and neck but not breast cancer in individuals from the UK Biobank study: A Mendelian randomisation analysis

10.1101/19002832 ◽

2019 ◽

Author(s):

Nathan Ingold ◽

Hasnat A Amin ◽

Fotios Drenos

Keyword(s):

Breast Cancer ◽

Alcohol Consumption ◽

Head And Neck ◽

Causal Effect ◽

Head And Neck Cancers ◽

Mendelian Randomisation ◽

Uk Biobank ◽

Increased Risk ◽

The Uk ◽

Risk Of Cancer

ABSTACTAlcohol intake and the risk of various types of cancers have been previously correlated. Correlation though does not always mean that a causal relationship between the two is present. Excessive alcohol consumption is also correlated with other lifestyle factors and behaviours, such as smoking and increased adiposity, that also affect the risk of cancer and make the identification and estimation of the causal effect of alcohol on cancer difficult. Here, using individual level data for 322,193 individuals from the UK Biobank, we report the observational and causal effects of alcohol consumption on types of cancer previously suggested as correlated to alcohol. Alcohol was observationally associated with cancers of the lower digestive system, head and neck and breast cancer. No associations were observed when we considered those keeping alcohol consumption below the recommended threshold of 14 units/week. When Mendelian randomisation was used to assess the causal effect of alcohol on cancer, we found that increasing alcohol consumption, especially above the recommended level, was causal to head and neck cancers but not breast cancer. Our results where replicated using a two sample MR method and data from the much larger COGS genome wide analysis of breast cancer. We conclude that alcohol is causally related to head and neck cancers, especially cancer of larynx, but the observed association with breast cancer are likely due to confounding. The suggested threshold of 14 units/week appears suitable to manage the risk of cancer due to alcohol.

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Genetic variants related to antihypertensive targets inform drug efficacy and side effects

10.1101/460543 ◽

2018 ◽

Cited By ~ 2

Author(s):

Dipender Gill ◽

Marios K. Georgakis ◽

Fotios Koskeridis ◽

Lan Jiang ◽

Qiping Feng ◽

...

Keyword(s):

Side Effects ◽

Genetic Variants ◽

Stroke Risk ◽

Drug Effects ◽

Consistent Estimate ◽

Uk Biobank ◽

Observational Analysis ◽

Increased Risk ◽

The Uk ◽

Genetic Instruments

AbstractBackgroundDrug effects can be investigated through natural variation in the genes for their protein targets. We aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are amongst the most commonly used medications worldwide.MethodsWe identified genetic instruments for antihypertensive drug classes as variants in the gene for the corresponding target that associated with systolic blood pressure at genome-wide significance. To validate the instruments, we compared Mendelian randomisation (MR) estimates for drug effects on coronary heart disease (CHD) and stroke risk to randomised controlled trial (RCT) results. Phenome-wide association study (PheWAS) in the UK Biobank was performed to identify potential side effects and repurposing opportunities, with findings investigated in the Vanderbilt University Biobank (BioVU) and in observational analysis of the UK Biobank.FindingsWe identified suitable genetic instruments for beta-blockers (BBs) and calcium channel blockers (CCBs). MR estimates for their effect on CHD and stroke risk respectively were comparable to results from RCTs against placebo. PheWAS in the UK Biobank identified an association of the CCB genetic risk score (scaled to drug effect) with increased risk of diverticulosis (odds ratio [OR] 1.23, 95%CI 1.10-1.38), with a consistent estimate found in BioVU (OR 1.16, 95%CI 0.94-1.44). Association with diverticulosis was further supported in observational analysis of CCB use in the UK Biobank (OR 1.08, 95%CI 1.02-1.15).InterpretationWe identified valid genetic instruments for BBs and CCBs. Using genetic and observational approaches, we highlighted a previously unreported potential detrimental effect of CCBs on risk of diverticulosis. This work serves as a proof of concept that investigation of genetic variants can offer a complementary approach to exploring the efficacy and side effects of anti-hypertensive medications.FundingWellcome Trust.

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Prostate brachytherapy: the impact of smoking on recurrence and overall survival of localized prostate cancer

American Journal of BioMedicine ◽

10.18081/ajbm/2333-5106-013-12/58-72 ◽

2013 ◽

Vol 2 (1) ◽

pp. 58-72

Author(s):

Edwin Cohen ◽

Justin Robinson ◽

Paul Margolis ◽

Marcia Gaut ◽

Amie Alperson ◽

...

Keyword(s):

Prostate Cancer ◽

Locally Advanced ◽

Cancer Recurrence ◽

Localized Prostate Cancer ◽

Smoking History ◽

Prostate Brachytherapy ◽

Cost Effective Treatment ◽

Increased Risk ◽

Risk Of Cancer ◽

The Impact

Brachytherapy has been shown to be an efficacious and cost-effective treatment among patients with localized prostate cancer. In this study, we examined the effects of smoking on prostate cancer recurrence and mortality in patients undergoing brachytherapy for locally advanced prostate cancer. The study population consisted of 405 patients with an average age of 73.4 years. Smoking history included 88 (21.7%) patients with no history of smoking, 108(26.6%) patients with one to twenty pack-years, and 209 (51.7%) patients with twenty-one or more pack-years. The impact of smoking history on OS relative to nonsmokers was hazards ratio 1.39 (CI: 0.81-2.64; P<0.05). In conclusion, the era of brachytherapy dose and treatment intensification strategies to improve upon prostate cancer outcomes, our study showed that smoking increases the risk of cancer recurrence and mortality. Patients who have smoked a higher number of pack-years are at increased risk of recurrence and mortality compared to those who smoked less.

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Genetic variants are identified to increase risk of COVID-19 related mortality from UK Biobank data

Human Genomics ◽

10.1186/s40246-021-00306-7 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Jianchang Hu ◽

Cai Li ◽

Shiying Wang ◽

Ting Li ◽

Heping Zhang

Keyword(s):

Genetic Variants ◽

Genetic Factors ◽

Genome Wide Association Study ◽

Individual Risk ◽

Uk Biobank ◽

Risk Of Death ◽

Genome Wide ◽

A Genome ◽

Increased Risk ◽

The Uk

Abstract Background The severity of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly heterogeneous. Studies have reported that males and some ethnic groups are at increased risk of death from COVID-19, which implies that individual risk of death might be influenced by host genetic factors. Methods In this project, we consider the mortality as the trait of interest and perform a genome-wide association study (GWAS) of data for 1778 infected cases (445 deaths, 25.03%) distributed by the UK Biobank. Traditional GWAS fails to identify any genome-wide significant genetic variants from this dataset. To enhance the power of GWAS and account for possible multi-loci interactions, we adopt the concept of super variant for the detection of genetic factors. A discovery-validation procedure is used for verifying the potential associations. Results We find 8 super variants that are consistently identified across multiple replications as susceptibility loci for COVID-19 mortality. The identified risk factors on chromosomes 2, 6, 7, 8, 10, 16, and 17 contain genetic variants and genes related to cilia dysfunctions (DNAH7 and CLUAP1), cardiovascular diseases (DES and SPEG), thromboembolic disease (STXBP5), mitochondrial dysfunctions (TOMM7), and innate immune system (WSB1). It is noteworthy that DNAH7 has been reported recently as the most downregulated gene after infecting human bronchial epithelial cells with SARS-CoV-2. Conclusions Eight genetic variants are identified to significantly increase the risk of COVID-19 mortality among the patients with white British ancestry. These findings may provide timely clues and potential directions for better understanding the molecular pathogenesis of COVID-19 and the genetic basis of heterogeneous susceptibility, with potential impact on new therapeutic options.

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Clinical benefits and adverse effects of genetically-elevated free testosterone levels: a Mendelian randomization analysis

10.1101/19005132 ◽

2019 ◽

Cited By ~ 4

Author(s):

Pedrum Mohammadi-Shemirani ◽

Michael Chong ◽

Marie Pigeyre ◽

Robert W. Morton ◽

Hertzel C. Gerstein ◽

...

Keyword(s):

Prostate Cancer ◽

Genetic Variants ◽

Mendelian Randomization ◽

Free Testosterone ◽

Body Fat Percentage ◽

Uk Biobank ◽

Fat Percentage ◽

Clinical Benefits ◽

The Uk

ABSTRACTBACKGROUNDTestosterone products are increasingly being prescribed to males for a variety of possible health benefits but the causal relationship between testosterone and health-related outcomes is unclear. Evidence from well-powered randomized controlled trials are difficult to obtain, particularly regarding effects on long-term or adverse outcomes. We sought to determine the effects of genetically-predicted calculated free testosterone (CFT) on 23 health outcomes.METHODSGenetic variants associated with CFT were determined from 136,531 white British males in the UK Biobank. One-sample and two-sample Mendelian randomization (MR) analyses were performed to infer the effects of genetically-predicted CFT on 23 health outcomes selected based on relevance with known or suspected effects of testosterone therapy.FINDINGSIn males from the UK Biobank, 81 independent genetic variants were associated with CFT levels at genome-wide significance (p<5×10−8). Each 0.1 nmol/L increase in genetically-predicted CFT was associated with clinical benefits on increased heel bone mineral density (0.053 SD; 95% CI = 0.038 to 0.068; p=8.77×10−12) and decreased body fat percentage (−1.86%; 95% CI = −2.35 to −1.37; p=1.56×10−13), and adverse effects on increased risk of prostate cancer (OR=1.28; 95% CI=1.11 to 1.49; p=1.0×10−3), risk of androgenic alopecia (OR=1.82; 95% CI = 1.55 to 2.14; p=3.52×10−13), risk of benign prostate hyperplasia (BPH) (OR=1.81; 95% CI = 1.34 to 2.44; p=1.05×10−4) and hematocrit percentage (1.49%; 95% CI = 1.24 to 1.74; p=3.49×10−32).CONCLUSIONSLong-term elevated free testosterone levels cause prostate cancer, BPH, and hair loss while reducing body fat percentage and increasing bone density. It also has a neutral effect on type 2 diabetes, cardiovascular and cognitive outcomes. Well powered randomized trials are needed to address the effects of shorter term use of exogenous testosterone on these outcomes.

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Body size and composition and risk of site-specific cancers in the UK Biobank and large international consortia: A mendelian randomisation study

PLoS Medicine ◽

10.1371/journal.pmed.1003706 ◽

2021 ◽

Vol 18 (7) ◽

pp. e1003706

Author(s):

Mathew Vithayathil ◽

Paul Carter ◽

Siddhartha Kar ◽

Amy M. Mason ◽

Stephen Burgess ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Risk ◽

Digestive System ◽

Uterine Cancer ◽

Mendelian Randomisation ◽

Inverse Association ◽

Uk Biobank ◽

Site Specific ◽

Increased Risk ◽

The Uk

Background Evidence for the impact of body size and composition on cancer risk is limited. This mendelian randomisation (MR) study investigates evidence supporting causal relationships of body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), and height with cancer risk. Methods and findings Single nucleotide polymorphisms (SNPs) were used as instrumental variables for BMI (312 SNPs), FMI (577 SNPs), FFMI (577 SNPs), and height (293 SNPs). Associations of the genetic variants with 22 site-specific cancers and overall cancer were estimated in 367,561 individuals from the UK Biobank (UKBB) and with lung, breast, ovarian, uterine, and prostate cancer in large international consortia. In the UKBB, genetically predicted BMI was positively associated with overall cancer (odds ratio [OR] per 1 kg/m2 increase 1.01, 95% confidence interval [CI] 1.00–1.02; p = 0.043); several digestive system cancers: stomach (OR 1.13, 95% CI 1.06–1.21; p < 0.001), esophagus (OR 1.10, 95% CI 1.03, 1.17; p = 0.003), liver (OR 1.13, 95% CI 1.03–1.25; p = 0.012), and pancreas (OR 1.06, 95% CI 1.01–1.12; p = 0.016); and lung cancer (OR 1.08, 95% CI 1.04–1.12; p < 0.001). For sex-specific cancers, genetically predicted elevated BMI was associated with an increased risk of uterine cancer (OR 1.10, 95% CI 1.05–1.15; p < 0.001) and with a lower risk of prostate cancer (OR 0.97, 95% CI 0.94–0.99; p = 0.009). When dividing cancers into digestive system versus non-digestive system, genetically predicted BMI was positively associated with digestive system cancers (OR 1.04, 95% CI 1.02–1.06; p < 0.001) but not with non-digestive system cancers (OR 1.01, 95% CI 0.99–1.02; p = 0.369). Genetically predicted FMI was positively associated with liver, pancreatic, and lung cancer and inversely associated with melanoma and prostate cancer. Genetically predicted FFMI was positively associated with non-Hodgkin lymphoma and melanoma. Genetically predicted height was associated with increased risk of overall cancer (OR per 1 standard deviation increase 1.09; 95% CI 1.05–1.12; p < 0.001) and multiple site-specific cancers. Similar results were observed in analyses using the weighted median and MR–Egger methods. Results based on consortium data confirmed the positive associations between BMI and lung and uterine cancer risk as well as the inverse association between BMI and prostate cancer, and, additionally, showed an inverse association between genetically predicted BMI and breast cancer. The main limitations are the assumption that genetic associations with cancer outcomes are mediated via the proposed risk factors and that estimates for some lower frequency cancer types are subject to low precision. Conclusions Our results show that the evidence for BMI as a causal risk factor for cancer is mixed. We find that BMI has a consistent causal role in increasing risk of digestive system cancers and a role for sex-specific cancers with inconsistent directions of effect. In contrast, increased height appears to have a consistent risk-increasing effect on overall and site-specific cancers.

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Socioeconomic Inequalities and Ethnicity Are Associated with a Positive COVID-19 Test among Cancer Patients in the UK Biobank Cohort

Cancers ◽

10.3390/cancers13071514 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1514

Author(s):

Shing Fung Lee ◽

Maja Nikšić ◽

Bernard Rachet ◽

Maria-Jose Sanchez ◽

Miguel Angel Luque-Fernandez

Keyword(s):

Cancer Patients ◽

Socioeconomic Inequalities ◽

Uk Biobank ◽

Incident Cancer ◽

Increased Risk ◽

Exposure Variable ◽

Independent Risk Factors ◽

The Uk ◽

Deprived Areas

We explored the role of socioeconomic inequalities in COVID-19 incidence among cancer patients during the first wave of the pandemic. We conducted a case-control study within the UK Biobank cohort linked to the COVID-19 tests results available from 16 March 2020 until 23 August 2020. The main exposure variable was socioeconomic status, assessed using the Townsend Deprivation Index. Among 18,917 participants with an incident malignancy in the UK Biobank cohort, 89 tested positive for COVID-19. The overall COVID-19 incidence was 4.7 cases per 1000 incident cancer patients (95%CI 3.8–5.8). Compared with the least deprived cancer patients, those living in the most deprived areas had an almost three times higher risk of testing positive (RR 2.6, 95%CI 1.1–5.8). Other independent risk factors were ethnic minority background, obesity, unemployment, smoking, and being diagnosed with a haematological cancer for less than five years. A consistent pattern of socioeconomic inequalities in COVID-19 among incident cancer patients in the UK highlights the need to prioritise the cancer patients living in the most deprived areas in vaccination planning. This socio-demographic profiling of vulnerable cancer patients at increased risk of infection can inform prevention strategies and policy improvements for the coming pandemic waves.

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Coffee Consumption and Cardiovascular Diseases: A Mendelian Randomization Study

Nutrients ◽

10.3390/nu13072218 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2218

Author(s):

Shuai Yuan ◽

Paul Carter ◽

Amy M. Mason ◽

Stephen Burgess ◽

Susanna C. Larsson

Keyword(s):

Cardiovascular Disease ◽

Cardiovascular Diseases ◽

Intracerebral Hemorrhage ◽

Genetic Variants ◽

Odds Ratio ◽

Observational Studies ◽

Mendelian Randomization ◽

Coffee Consumption ◽

Uk Biobank ◽

The Uk

Coffee consumption has been linked to a lower risk of cardiovascular disease in observational studies, but whether the associations are causal is not known. We conducted a Mendelian randomization investigation to assess the potential causal role of coffee consumption in cardiovascular disease. Twelve independent genetic variants were used to proxy coffee consumption. Summary-level data for the relations between the 12 genetic variants and cardiovascular diseases were taken from the UK Biobank with up to 35,979 cases and the FinnGen consortium with up to 17,325 cases. Genetic predisposition to higher coffee consumption was not associated with any of the 15 studied cardiovascular outcomes in univariable MR analysis. The odds ratio per 50% increase in genetically predicted coffee consumption ranged from 0.97 (95% confidence interval (CI), 0.63, 1.50) for intracerebral hemorrhage to 1.26 (95% CI, 1.00, 1.58) for deep vein thrombosis in the UK Biobank and from 0.86 (95% CI, 0.50, 1.49) for subarachnoid hemorrhage to 1.34 (95% CI, 0.81, 2.22) for intracerebral hemorrhage in FinnGen. The null findings remained in multivariable Mendelian randomization analyses adjusted for genetically predicted body mass index and smoking initiation, except for a suggestive positive association for intracerebral hemorrhage (odds ratio 1.91; 95% CI, 1.03, 3.54) in FinnGen. This Mendelian randomization study showed limited evidence that coffee consumption affects the risk of developing cardiovascular disease, suggesting that previous observational studies may have been confounded.

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