@article{pmid38783413,

title = {Maternal serum unmetabolized folic acid concentration following multivitamin and mineral supplementation with or without folic acid after 12 weeks gestation: A randomized controlled trial},

author = {Dian C Sulistyoningrum and Thomas R Sullivan and Monika Skubisz and Debra J Palmer and Simon Wood and Per Magne Ueland and Adrian McCann and Maria Makrides and Timothy J Green and Karen P Best},

doi = {10.1111/mcn.13668},

issn = {1740-8709},

year  = {2024},

date = {2024-10-01},

journal = {Matern Child Nutr},

volume = {20},

number = {4},

pages = {e13668},

abstract = {Pregnant women are advised to take folic acid (FA) supplements before conception and during the first trimester of pregnancy. Many women continue FA supplementation throughout pregnancy, and concerns have been raised about associations between excessive FA intake and adverse maternal and child health outcomes. Unmetabolized folic acid (UMFA) is found in serum after high FA intakes and is proposed as a biomarker for excessive FA intake. We aimed to determine if removing FA from prenatal micronutrient supplements after 12 weeks of pregnancy reduces serum UMFA concentrations at 36 weeks gestation. In this double-blind, randomized controlled trial conducted in South Australia, 103 women with a singleton pregnancy were randomly assigned at 12-16 weeks gestation to take a micronutrient supplement containing no FA or 800 µg/day FA from enrollment until 36 weeks gestation. Ninety women (0 µg/day FA n = 46; 800 µg/day FA n = 44) completed the study. Mean, UMFA concentration was lower in the women randomized to the 0 µg/day group compared to the 800 µg/day FA group, 0.6 ± 0.7 and 1.4 ± 2.7 nmol/L, respectively. The adjusted mean difference (95% CI) in UMFA between the groups was [-0.85 (-1.62, -0.08) nmol/L, p = 0.03]. Maternal serum and red blood cell folate concentrations were lower in the 0 µg/day FA group than in the 800 µg/day group (median 23.2 vs. 49.3 and 1335 vs. 1914 nmol/L, respectively; p < 0.001). Removing FA at 12-16 weeks gestation from prenatal micronutrient supplements reduced the concentration of UMFA at 36 weeks gestation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39399688,

title = {Parkinson's disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction},

author = {Edward Wilson and Jacob Umans and Michelle Swarovski and Paras Minhas and Øivind Midttun and Arve Arve Ulvik and Marian Shahid-Besanti and Patricia Linortner and Siddhita Mhatre and Qian Wang and Divya Channappa and Nicole Corso and Lu Tian and Carolyn Fredericks and Geoffrey Kerchner and Edward Plowey and Brenna Cholerton and Per Ueland and Cyrus Zabetian and Nora Gray and Joseph Quinn and Thomas Montine and Sharon Sha and Frank Longo and David Wolk and Alice Chen-Plotkin and Victor Henderson and Tony Wyss-Coray and Anthony Wagner and Elizabeth Mormino and Nima Aghaeepour and Kathleen Poston and Katrin Andreasson},

doi = {10.21203/rs.3.rs-4980210/v1},

issn = {2693-5015},

year  = {2024},

date = {2024-09-01},

journal = {Res Sq},

abstract = {Parkinson's disease (PD) is a complex multisystem disorder clinically characterized by motor, non-motor, and premotor manifestations. Pathologically, PD involves neuronal loss in the substantia nigra, striatal dopamine deficiency, and accumulation of intracellular inclusions containing aggregates of α-synuclein. Recent studies demonstrate that PD is associated with dysregulated metabolic flux through the kynurenine pathway (KP), in which tryptophan is converted to kynurenine (KYN), and KYN is subsequently metabolized to neuroactive compounds quinolinic acid (QA) and kynurenic acid (KA). This multicenter study used highly sensitive liquid chromatography-tandem mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. Results indicate that increased neuroexcitatory QA/KA ratio in both plasma and CSF of PD participants associated with peripheral and cerebral inflammation and vitamin B6 deficiency. Furthermore, increased QA tracked with CSF tau and severity of both motor and non-motor PD clinical dysfunction. Importantly, plasma and CSF kynurenine metabolites classified PD participants with a high degree of accuracy (AUC = 0.897). Finally, analysis of metabolite data revealed subgroups with distinct KP profiles, and these were subsequently found to display distinct PD clinical features. Together, these data further support the hypothesis that the KP serves as a site of brain and periphery crosstalk, integrating B-vitamin status, inflammation and metabolism to ultimately influence PD clinical manifestation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38749786,

title = {Influence of cardiorespiratory fitness on obesity-associated inflammation in women and men: The FATCOR study},

author = {Helga Midtbø and Arve Ulvik and Dana Cramariuc and Klaus Meyer and Per M Ueland and Hilde Halland and Eva Gerdts},

doi = {10.1016/j.numecd.2024.04.002},

issn = {1590-3729},

year  = {2024},

date = {2024-08-01},

journal = {Nutr Metab Cardiovasc Dis},

volume = {34},

number = {8},

pages = {1942--1949},

abstract = {BACKGROUND AND AIMS: Cardiorespiratory fitness has been postulated to lower chronic inflammation in obesity. We assessed sex-specific associations of inflammation with cardiorespiratory fitness in overweight and obese persons.nnMETHODS AND RESULTS: Peak oxygen uptake (VO) was measured by treadmill in 566 participants (age 48 ± 9 years, 60% women) with body mass index >27.0 kg/m in the FAT associated CardiOvasculaR dysfunction (FATCOR) study. Fitness was identified from age- and sex specific reference levels of VO. The inflammatory markers C-reactive protein (CRP), serum amyloid A (SAA), kynurenine:tryptophan ratio (KTR) and pyriodoxic acid ratio (PAr) were measured by mass spectrometry. In the total study population 63% had obesity and 74% were cardiorespiratory unfit. Unfit women had the highest fat percentage and the highest serum levels of CRP and SAA (p < 0.05). In multivariable linear regression analyses in women, higher CRP (β -0.15, p = 0.001), SAA (β -0.10, p = 0.03) and PAr (β -0.09, p = 0.03) were associated with lower VO after adjusting for confounders. In multivariable analyses in men, higher PAr (β -0.14, p = 0.02) was associated with lower VO. In multivariable analyses in obese women, higher CRP and PAr remained associated with lower VO (p < 0.05), while in obese men there was no significant association. When normalizing VO for fat-free mass (VO) higher CRP, SAA and PAr index were associated with lower VO in women, while only higher PAr index was associated with lower VO in men.nnCONCLUSION: The association of inflammation with lower cardiorespiratory fitness was more pronounced in women than men, in particular when obesity was present.nnCLINICAL TRIAL REGISTRATION: URL: http://www.nnCLINICALTRIALS: gov NCT02805478.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37918674,

title = {The Effect of Vitamin B Supplementation on Leukocyte Telomere Length in Mildly Stunted Nepalese Children: A Secondary Outcome of a Randomized Controlled Trial},

author = {Manjeswori Ulak and Ingrid Kvestad and Ram K Chandyo and Catherine Schwinger and Sudha Basnet and Merina Shrestha and Suman Ranjitkar and Linda Vy Nguyen and Diana Corona-Pérez and Immaculata De Vivo and Per M Ueland and Adrian McCann and Tor A Strand},

doi = {10.1016/j.tjnut.2023.10.015},

issn = {1541-6100},

year  = {2024},

date = {2024-08-01},

journal = {J Nutr},

volume = {154},

number = {8},

pages = {2543--2550},

abstract = {BACKGROUND: Vitamin B is essential for deoxyribonucleic acid synthesis and genome stability. A deficiency of vitamin B is associated with telomere shortening, genomic aging, and increased risk of chronic disease and mortality.nnOBJECTIVES: The study aims to determine the effect of vitamin B supplementation on leukocyte telomere length (LTL) in infants at risk of vitamin B deficiency.nnMETHODS: The study was a predefined secondary analysis of a randomized controlled trial enrolling 600 Nepalese infants aged 6 -11 mo, who were supplemented with 2 μg (2-3 recommended daily allowances) vitamin B or placebo daily for 1 y. At the end of the study, LTL was measured in 497 participants. Mean LTL was compared between the treatment arms in the full sample and predefined subgroups based on markers of vitamin B status, hemoglobin, sex, and growth indices.nnRESULTS: LTL at end-study did not differ between the vitamin B and placebo arm with a standardized mean difference (95% confidence interval) of 0.04 (-0.14, 0.21). There was no effect of vitamin B on LTL in any of the subgroups.nnCONCLUSIONS: Providing daily vitamin B for 1 y during infancy in a population at risk of vitamin B deficiency does not affect LTL. This trial was registered at clinicaltrials.gov as NCT02272842.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39068471,

title = {Sex-specific associations of kynurenic acid with neopterin in Alzheimer's disease},

author = {Anne-Brita Knapskog and Trine Holt Edwin and Per Magne Ueland and Arve Ulvik and Evandro Fei Fang and Rannveig Sakshaug Eldholm and Nathalie Bodd Halaas and Lasse M Giil and Ingvild Saltvedt and Leiv Otto Watne and Mari Aksnes},

doi = {10.1186/s13195-024-01531-7},

issn = {1758-9193},

year  = {2024},

date = {2024-07-01},

journal = {Alzheimers Res Ther},

volume = {16},

number = {1},

pages = {167},

abstract = {BACKGROUND: Sex differences in neuroinflammation could contribute to women's increased risk of Alzheimer's disease (AD), providing rationale for exploring sex-specific AD biomarkers. In AD, dysregulation of the kynurenine pathway (KP) contributes to neuroinflammation and there is some evidence of sex differences in KP metabolism. However, the sex-specific associations between KP metabolism and biomarkers of AD and neuroinflammation need to be explored further.nnMETHODS: Here we investigate sex differences in cerebrospinal fluid concentrations of seven KP metabolites and sex-specific associations with established AD biomarkers and neopterin, an indicator of neuroinflammation. This study included 311 patients with symptomatic AD and 105 age-matched cognitively unimpaired (CU) controls, followed for up to 5 years.nnRESULTS: We found sex differences in KP metabolites in the AD group, with higher levels of most metabolites in men, while there were no sex differences in the CU group. In line with this, more KP metabolites were significantly altered in AD men compared to CU men, and there was a trend in the same direction in AD women. Furthermore, we found sex-specific associations between kynurenic acid and the kynurenic acid/quinolinic acid ratio with neopterin, but no sex differences in the associations between KP metabolites and clinical progression.nnDISCUSSION: In our cohort, sex differences in KP metabolites were restricted to AD patients. Our results suggest that dysregulation of the KP due to increased inflammation could contribute to higher AD risk in women.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38924428,

title = {Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency},

author = {John V Pluvinage and Thomas Ngo and Camille Fouassier and Maura McDonagh and Brandon B Holmes and Christopher M Bartley and Sravani Kondapavulur and Charlotte Hurabielle and Aaron Bodansky and Vincent Pai and Sam Hinman and Ava Aslanpour and Bonny D Alvarenga and Kelsey C Zorn and Colin Zamecnik and Adrian McCann and Andoni I Asencor and Trung Huynh and Weston Browne and Asritha Tubati and Michael S Haney and Vanja C Douglas and Martineau Louine and Bruce A C Cree and Stephen L Hauser and William Seeley and Sergio E Baranzini and James A Wells and Serena Spudich and Shelli Farhadian and Prashanth S Ramachandran and Leslie Gillum and Chadwick M Hales and Julie Zikherman and Mark S Anderson and Jinoos Yazdany and Bryan Smith and Avindra Nath and Gina Suh and Eoin P Flanagan and Ari J Green and Ralph Green and Jeffrey M Gelfand and Joseph L DeRisi and Samuel J Pleasure and Michael R Wilson},

doi = {10.1126/scitranslmed.adl3758},

issn = {1946-6242},

year  = {2024},

date = {2024-06-01},

journal = {Sci Transl Med},

volume = {16},

number = {753},

pages = {eadl3758},

abstract = {Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38361451,

title = {Association between dietary macronutrient composition and plasma one-carbon metabolites and B-vitamin cofactors in patients with stable angina pectoris},

author = {Marianne Bråtveit and Anthea Van Parys and Thomas Olsen and Elin Strand and Ingvild Marienborg and Johnny Laupsa-Borge and Teresa Risan Haugsgjerd and Adrian McCann and Indu Dhar and Per Magne Ueland and Jutta Dierkes and Simon Nitter Dankel and Ottar Kjell Nygård and Vegard Lysne},

doi = {10.1017/S0007114524000473},

issn = {1475-2662},

year  = {2024},

date = {2024-05-01},

journal = {Br J Nutr},

volume = {131},

number = {10},

pages = {1678--1690},

abstract = {Elevated plasma concentrations of several one-carbon metabolites are associated with increased CVD risk. Both diet-induced regulation and dietary content of one-carbon metabolites can influence circulating concentrations of these markers. We cross-sectionally analysed 1928 patients with suspected stable angina pectoris (geometric mean age 61), representing elevated CVD risk, to assess associations between dietary macronutrient composition (FFQ) and plasma one-carbon metabolites and related B-vitamin status markers (GC-MS/MS, LC-MS/MS or microbiological assay). Diet-metabolite associations were modelled on the continuous scale, adjusted for age, sex, BMI, smoking, alcohol and total energy intake. Average (geometric mean (95 % prediction interval)) intake was forty-nine (38, 63) energy percent (E%) from carbohydrate, thirty-one (22, 45) E% from fat and seventeen (12, 22) E% from protein. The strongest associations were seen for higher protein intake, i.e. with higher plasma pyridoxal 5'-phosphate (PLP) (% change (95 % CI) 3·1 (2·1, 4·1)), cobalamin (2·9 (2·1, 3·7)), riboflavin (2·4 (1·1, 3·7)) and folate (2·1 (1·2, 3·1)) and lower total homocysteine (tHcy) (-1·4 (-1·9, -0·9)) and methylmalonic acid (MMA) (-1·4 (-2·0, -0·8)). Substitution analyses replacing MUFA or PUFA with SFA demonstrated higher plasma concentrations of riboflavin (5·0 (0·9, 9·3) and 3·3 (1·1, 5·6)), tHcy (2·3 (0·7, 3·8) and 1·3 (0·5, 2·2)) and MMA (2·0 (0·2, 3·9) and 1·7 (0·7, 2·7)) and lower PLP (-2·5 (-5·3, 0·3) and -2·7 (-4·2, -1·2)). In conclusion, a higher protein intake and replacing saturated with MUFA and PUFA were associated with a more favourable metabolic phenotype regarding metabolites associated with CVD risk.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38335827,

title = {Longitudinal associations of plasma kynurenines and ratios with anxiety and depression scores in colorectal cancer survivors up to 12 months post-treatment},

author = {Daniëlle D B Holthuijsen and Eline H van Roekel and Martijn J L Bours and Per M Ueland and Stéphanie O Breukink and Maryska L G Janssen-Heijnen and Eric T P Keulen and Biljana Gigic and Andrea Gsur and Klaus Meyer and Jennifer Ose and Arve Ulvik and Matty P Weijenberg and Simone J P M Eussen},

doi = {10.1016/j.psyneuen.2024.106981},

issn = {1873-3360},

year  = {2024},

date = {2024-05-01},

journal = {Psychoneuroendocrinology},

volume = {163},

pages = {106981},

abstract = {INTRODUCTION: Colorectal cancer (CRC) survivors often experience neuropsychological symptoms, including anxiety and depression. Mounting evidence suggests a role for the kynurenine pathway in these symptoms due to potential neuroprotective and neurotoxic roles of involved metabolites. However, evidence remains inconclusive and insufficient in cancer survivors. Thus, we aimed to explore longitudinal associations of plasma tryptophan, kynurenines, and their established ratios with anxiety and depression in CRC survivors up to 12 months post-treatment.nnMETHODS: In 249 stage I-III CRC survivors, blood samples were collected at 6 weeks, 6 months, and 12 months post-treatment to analyze plasma concentrations of tryptophan and kynurenines using liquid-chromatography tandem-mass spectrometry (LC/MS-MS). At the same timepoints, anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS). Confounder-adjusted linear mixed models were used to analyze longitudinal associations. Sensitivity analyses with false discovery rate (FDR) correction were conducted to adjust for multiple testing.nnRESULTS: Higher plasma tryptophan concentrations were associated with lower depression scores (β as change in depression score per 1 SD increase in the ln-transformed kynurenine concentration: -0.31; 95%CI: -0.56,-0.05), and higher plasma 3-hydroxyanthranilic acid concentrations with lower anxiety scores (-0.26; -0.52,-0.01). A higher 3-hydroxykynurenine ratio (HKr; the ratio of 3-hydroxykynurenine to the sum of kynurenic acid, xanthurenic acid, anthranilic acid, and 3-hydroxyanthranilic acid) was associated with higher depression scores (0.34; 0.04,0.63) and higher total anxiety and depression scores (0.53; 0.02,1.04). Overall associations appeared to be mainly driven by inter-individual associations, which were statistically significant for tryptophan with depression (-0.60; -1.12,-0.09), xanthurenic acid with total anxiety and depression (-1.04; -1.99,-0.10), anxiety (-0.51; -1.01,-0.01), and depression (-0.56; -1.08,-0.05), and kynurenic-acid-to-quinolinic-acid ratio with depression (-0.47; -0.93,-0.01). In sensitivity analyses, associations did not remain statistically significant after FDR adjustment.nnCONCLUSION: We observed that plasma concentrations of tryptophan, 3-hydroxyanthranilic acid, xanthurenic acid, 3-hydroxykynurenine ratio, and kynurenic-acid-to-quinolinic-acid ratio tended to be longitudinally associated with anxiety and depression in CRC survivors up to 12 months post-treatment. Future studies are warranted to further elucidate the association of plasma kynurenines with anxiety and depression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38428649,

title = {Neopterin, kynurenine metabolites, and indexes related to vitamin B6 are associated with post-stroke cognitive impairment: The Nor-COAST study},

author = {Heidi Vihovde Sandvig and Stina Aam and Katinka N Alme and Stian Lydersen and Per Magne Ueland and Arve Ulvik and Torgeir Wethal and Ingvild Saltvedt and Anne-Brita Knapskog},

doi = {10.1016/j.bbi.2024.02.030},

issn = {1090-2139},

year  = {2024},

date = {2024-05-01},

journal = {Brain Behav Immun},

volume = {118},

pages = {167--177},

abstract = {BACKGROUND AND AIMS: We have previously shown that systemic inflammation was associated with post-stroke cognitive impairment (PSCI). Because neopterin, kynurenine pathway (KP) metabolites, and B6 vitamers are linked to inflammation, in our study we investigated whether those biomarkers were associated with PSCI.nnMATERIAL AND METHODS: The Norwegian Cognitive Impairment After Stroke study is a prospective multicenter cohort study of patients with acute stroke recruited from May 2015 through March 2017. Plasma samples of 422 participants (59 % male) with ischemic stroke from the index hospital stay and 3 months post-stroke were available for analyses of neopterin, KP metabolites, and B6 vitamers using liquid chromatography-tandem mass spectrometry. Mixed linear regression analyses adjusted for age, sex, and creatinine, were used to assess whether there were associations between those biomarkers and cognitive outcomes, measured by the Montreal Cognitive Assessment scale (MoCA) at 3-, 18-, and 36-month follow-up.nnRESULTS: Participants had a mean (SD) age of 72 (12) years, with a mean (SD) National Institutes of HealthStroke Scale score of 2.7 (3.6) at Day 1. Higher baseline values of quinolinic acid, PAr (i.e., an inflammatory marker based on vitamin B6 metabolites), and HKr (i.e., a marker of functional vitamin B6 status based on selected KP metabolites) were associated with lower MoCA score at 3, 18, and 36 months post-stroke (p < 0.01). Higher baseline concentrations of neopterin and 3-hydroxykynurenine were associated with lower MoCA scores at 18 and 36 months, and higher concentrations of xanthurenic acid were associated with higher MoCA score at 36 months (p < 0.01). At 3 months post-stroke, higher concentrations of neopterin and lower values of pyridoxal 5́-phosphate were associated with lower MoCA scores at 18- and 36-month follow-up, while lower concentrations of picolinic acid were associated with a lower MoCA score at 36 months (p < 0.01).nnCONCLUSION: Biomarkers and metabolites of systemic inflammation, including biomarkers of cellular immune activation, indexes of vitamin B6 homeostasis, and several neuroactive metabolites of the KP pathway, were associated with PSCI.nnTRIAL REGISTRATION: ClinicalTrials.gov: NCT02650531.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38693263,

title = {Geographic variation of mutagenic exposures in kidney cancer genomes},

author = {Sergey Senkin and Sarah Moody and Marcos Díaz-Gay and Behnoush Abedi-Ardekani and Thomas Cattiaux and Aida Ferreiro-Iglesias and Jingwei Wang and Stephen Fitzgerald and Mariya Kazachkova and Raviteja Vangara and Anh Phuong Le and Erik N Bergstrom and Azhar Khandekar and Burçak Otlu and Saamin Cheema and Calli Latimer and Emily Thomas and Joshua Ronald Atkins and Karl Smith-Byrne and Ricardo Cortez Cardoso Penha and Christine Carreira and Priscilia Chopard and Valérie Gaborieau and Pekka Keski-Rahkonen and David Jones and Jon W Teague and Sophie Ferlicot and Mojgan Asgari and Surasak Sangkhathat and Worapat Attawettayanon and Beata Świątkowska and Sonata Jarmalaite and Rasa Sabaliauskaite and Tatsuhiro Shibata and Akihiko Fukagawa and Dana Mates and Viorel Jinga and Stefan Rascu and Mirjana Mijuskovic and Slavisa Savic and Sasa Milosavljevic and John M S Bartlett and Monique Albert and Larry Phouthavongsy and Patricia Ashton-Prolla and Mariana R Botton and Brasil Silva Neto and Stephania Martins Bezerra and Maria Paula Curado and Stênio de Cássio Zequi and Rui Manuel Reis and Eliney Ferreira Faria and Nei Soares de Menezes and Renata Spagnoli Ferrari and Rosamonde E Banks and Naveen S Vasudev and David Zaridze and Anush Mukeriya and Oxana Shangina and Vsevolod Matveev and Lenka Foretova and Marie Navratilova and Ivana Holcatova and Anna Hornakova and Vladimir Janout and Mark P Purdue and Nathaniel Rothman and Stephen J Chanock and Per Magne Ueland and Mattias Johansson and James McKay and Ghislaine Scelo and Estelle Chanudet and Laura Humphreys and Ana Carolina de Carvalho and Sandra Perdomo and Ludmil B Alexandrov and Michael R Stratton and Paul Brennan},

doi = {10.1038/s41586-024-07368-2},

issn = {1476-4687},

year  = {2024},

date = {2024-05-01},

journal = {Nature},

volume = {629},

number = {8013},

pages = {910--918},

abstract = {International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence. Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37886826,

title = {Time-resolved concentrations of serum amino acids, one-carbon metabolites and B-vitamin biomarkers during the postprandial and fasting state: the Postprandial Metabolism in Healthy Young Adults (PoMet) Study},

author = {Åslaug Matre Anfinsen and Christina Osland Johannesen and Vilde Haugen Myklebust and Hanne Rosendahl-Riise and Adrian McCann and Ottar Kjell Nygård and Jutta Dierkes and Vegard Lysne},

doi = {10.1017/S0007114523002490},

issn = {1475-2662},

year  = {2024},

date = {2024-03-01},

journal = {Br J Nutr},

volume = {131},

number = {5},

pages = {786--800},

abstract = {Metabolomics has been utilised in epidemiological studies to investigate biomarkers of nutritional status and metabolism in relation to non-communicable diseases. However, little is known about the effect of prandial status on several biomarker concentrations. Therefore, the aim of this intervention study was to investigate the effect of a standardised breakfast meal followed by food abstinence for 24 h on serum concentrations of amino acids, one-carbon metabolites and B-vitamin biomarkers. Thirty-four healthy subjects (eighteen males and sixteen females) aged 20-30 years were served a breakfast meal (∼500 kcal) after which they consumed only water for 24 h. Blood samples were drawn before and at thirteen standardised timepoints after the meal. Circulating concentrations of most amino acids and metabolites linked to one-carbon metabolism peaked within the first 3 h after the meal. The branched-chain amino acids steadily increased from 6 or 8 hours after the meal, while proline decreased in the same period. Homocysteine and cysteine concentrations immediately decreased after the meal but steadily increased from 3 and 4 hours until 24 h. FMN and riboflavin fluctuated immediately after the meal but increased from 6 h, while folate increased immediately after the meal and remained elevated during the 24 h. Our findings indicate that accurate reporting of time since last meal is crucial when investigating concentrations of certain amino acids and one-carbon metabolites. Our results suggest a need for caution when interpretating studies, which utilise such biomarkers, but do not strictly control for time since the last meal.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38430452,

title = {Inflammation, the kynurenines, and mucosal injury during human experimental enterotoxigenic Escherichia coli infection},

author = {Sehee Rim and Oda Barth Vedøy and Ingeborg Brønstad and Adrian McCann and Klaus Meyer and Hans Steinsland and Kurt Hanevik},

doi = {10.1007/s00430-024-00786-z},

issn = {1432-1831},

year  = {2024},

date = {2024-03-01},

journal = {Med Microbiol Immunol},

volume = {213},

number = {1},

pages = {2},

abstract = {Enterotoxigenic Escherichia coli (ETEC) is an important cause of diarrhea in children and travelers, especially in low- and middle-income countries. ETEC is a non-invasive gut pathogen colonizing the small intestinal wall before secreting diarrhea-inducing enterotoxins. We sought to investigate the impact of ETEC infection on local and systemic host defenses by examining plasma markers of inflammation and mucosal injury as well as kynurenine pathway metabolites. Plasma samples from 21 volunteers experimentally infected with ETEC were collected before and 1, 2, 3, and 7 days after ingesting the ETEC dose, and grouped based on the level of intestinal ETEC proliferation: 14 volunteers experienced substantial proliferation (SP) and 7 had low proliferation (LP). Plasma markers of inflammation, kynurenine pathway metabolites, and related cofactors (vitamins B2 and B6) were quantified using targeted mass spectrometry, whereas ELISA was used to quantify the mucosal injury markers, regenerating islet-derived protein 3A (Reg3a), and intestinal fatty acid-binding protein 2 (iFABP). We observed increased concentrations of plasma C-reactive protein (CRP), serum amyloid A (SAA), neopterin, kynurenine/tryptophan ratio (KTR), and Reg3a in the SP group following dose ingestion. Vitamin B6 forms, pyridoxal 5'-phosphate and pyridoxal, decreased over time in the SP group. CRP, SAA, and pyridoxic acid ratio correlated with ETEC proliferation levels. The changes following experimental ETEC infection indicate that ETEC, despite causing a non-invasive infection, induces systemic inflammation and mucosal injury when proliferating substantially, even in cases without diarrhea. It is conceivable that ETEC infections, especially when repeated, contribute to negative health impacts on children in ETEC endemic areas.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38195204,

title = {Gut Microbiota Alterations and Circulating Imidazole Propionate Levels Are Associated With Obstructive Coronary Artery Disease in People With HIV},

author = {Marius Trøseid and Antonio Molinaro and Marco Gelpi and Beate Vestad and Klaus Fuglsang Kofoed and Andreas Fuchs and Lars Køber and Kristian Holm and Thomas Benfield and Per M Ueland and Johannes R Hov and Susanne Dam Nielsen and Andreas Dehlbæk Knudsen},

doi = {10.1093/infdis/jiad604},

issn = {1537-6613},

year  = {2024},

date = {2024-03-01},

journal = {J Infect Dis},

volume = {229},

number = {3},

pages = {898--907},

abstract = {BACKGROUND: The impact of gut microbiota and its metabolites on coronary artery disease (CAD) in people with human immunodeficiency virus (PWH) is unknown. Emerging evidence suggests that imidazole propionate (ImP), a microbial metabolite, is linked with cardiometabolic diseases.nnMETHODS: Fecal samples from participants of the Copenhagen Comorbidity in HIV infection (COCOMO) study were processed for 16S rRNA sequencing and ImP measured with liquid chromatography-tandem mass spectrometry. CAD severity was investigated by coronary computed tomography-angiography, and participants grouped according to obstructive CAD (n = 60), nonobstructive CAD (n = 80), or no CAD (n = 114).nnRESULTS: Participants with obstructive CAD had a gut microbiota with lower diversity and distinct compositional shift, with increased abundance of Rumiococcus gnavus and Veillonella, known producers of ImP. ImP plasma levels were associated with this dysbiosis, and significantly elevated in participants with obstructive CAD. However, gut dysbiosis but not plasma ImP was independently associated with obstructive CAD after adjustment for traditional and HIV-related risk factors (adjusted odds ratio, 2.7; 95% confidence interval, 1.1-7.2; P = .048).nnCONCLUSIONS: PWH with obstructive CAD displays a distinct gut microbiota profile and increased circulating ImP plasma levels. Future studies should determine whether gut dysbiosis and related metabolites such as ImP are predictive of incident cardiovascular events.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38070682,

title = {Intake and biomarkers of folate and folic acid as determinants of chemotherapy-induced toxicities in patients with colorectal cancer: a cohort study},

author = {Dieuwertje E Kok and Fränzel Jb van Duijnhoven and Floor Je Lubberman and Jill A McKay and Anne-Sophie van Lanen and Renate M Winkels and Evertine Wesselink and Henk K van Halteren and Johannes Hw de Wilt and Cornelia M Ulrich and Arve Ulvik and Per M Ueland and Ellen Kampman},

doi = {10.1016/j.ajcnut.2023.11.023},

issn = {1938-3207},

year  = {2024},

date = {2024-02-01},

journal = {Am J Clin Nutr},

volume = {119},

number = {2},

pages = {294--301},

abstract = {BACKGROUND: Capecitabine is an oral chemotherapeutic drug showing antitumor activity through inhibition of thymidylate synthase, an enzyme involved in folate metabolism. There are concerns about the high intake of certain vitamins, and specifically folate, during chemotherapy with capecitabine. Whether folate or folic acid, the synthetic variant of the vitamin, impact treatment toxicity remains unclear.nnOBJECTIVE: We studied associations between intake and biomarkers of folate as well as folic acid and toxicities in patients with colorectal cancer (CRC) receiving capecitabine.nnMETHODS: Within the prospective COLON (Colorectal cancer: Longitudinal, Observational study on Nutritional and lifestyle factors that influence recurrence, survival, and quality of life) cohort, 290 patients with stage II to III CRC receiving capecitabine were identified. Dietary and supplemental intake of folate and folic acid were assessed at diagnosis and during chemotherapy using questionnaires (available for 280 patients). Plasma folate and folic acid levels were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) and were available for 212 patients. Toxicities were defined as toxicity-related modifications of treatment, including dose reductions, regimen switches, and early discontinuation. Associations of intake and biomarkers of folate and folic acid with toxicities were determined using Cox proportional hazards regression adjusted for age and sex.nnRESULTS: In total, 153 (53%) patients experienced toxicities leading to modification of capecitabine treatment. Folate intake and plasma folate levels were not associated with risk of toxicities. However, use of folic acid-containing supplements during treatment (hazard ratio (HR) 1.81 and 95% confidence interval (CI) 1.15-2.85) and presence of folic acid in plasma at diagnosis (HR 2.09, 95% CI: 1.24, 3.52) and during treatment (HR 2.31, 95% CI: 1.29, 4.13) were associated with an increased risk of toxicities.nnCONCLUSIONS: This study suggests a potential association between folic acid and capecitabine-induced toxicities, providing a rationale to study diet-drug interactions and raise further awareness of the use of dietary supplements during oncological treatment.nnCLINICAL TRIAL DETAILS: This trial was registered at clinicaltrials.gov as NCT03191110.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38331891,

title = {Microbial-derived imidazole propionate links the heart failure-associated microbiome alterations to disease severity},

author = {Sajan C Raju and Antonio Molinaro and Ayodeji Awoyemi and Silje F Jørgensen and Peder R Braadland and Andraz Nendl and Ingebjørg Seljeflot and Per M Ueland and Adrian McCann and Pål Aukrust and Beate Vestad and Cristiane Mayerhofer and Kaspar Broch and Lars Gullestad and Knut T Lappegård and Bente Halvorsen and Karsten Kristiansen and Johannes R Hov and Marius Trøseid},

doi = {10.1186/s13073-024-01296-6},

issn = {1756-994X},

year  = {2024},

date = {2024-02-01},

journal = {Genome Med},

volume = {16},

number = {1},

pages = {27},

abstract = {BACKGROUND: Interactions between the gut microbiota, diet, and host metabolism contribute to the development of cardiovascular disease, but a firm link between disease-specific gut microbiota alterations and circulating metabolites is lacking.nnMETHODS: We performed shot-gun sequencing on 235 samples from 166 HF patients and 69 healthy control samples. Separate plasma samples from healthy controls (n = 53) were used for the comparison of imidazole propionate (ImP) levels. Taxonomy and functional pathways for shotgun sequencing data was assigned using MetaPhlAn3 and HUMAnN3 pipelines.nnRESULTS: Here, we show that heart failure (HF) is associated with a specific compositional and functional shift of the gut microbiota that is linked to circulating levels of the microbial histidine-derived metabolite ImP. Circulating ImP levels are elevated in chronic HF patients compared to controls and associated with HF-related gut microbiota alterations. Contrary to the microbiota composition, ImP levels provide insight into etiology and severity of HF and also associate with markers of intestinal permeability and systemic inflammation.nnCONCLUSIONS: Our findings establish a connection between changes in the gut microbiota, the presence, etiology, and severity of HF, and the gut-microbially produced metabolite ImP. While ImP appears promising as a circulating biomarker reflecting gut dysbiosis related to HF, further studies are essential to demonstrate its causal or contributing role in HF pathogenesis.nnTRIAL REGISTRATION: NCT02637167, registered December 22, 2015.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39759130,

title = {Indole 3-acetate and response to therapy in borderline resectable or locally advanced pancreatic cancer},

author = {Peder R Braadland and Ingvild Farnes and Elin H Kure and Sheraz Yaqub and Adrian McCann and Per M Ueland and Knut Jørgen Labori and Johannes R Hov},

doi = {10.3389/fonc.2024.1488749},

issn = {2234-943X},

year  = {2024},

date = {2024-01-01},

journal = {Front Oncol},

volume = {14},

pages = {1488749},

abstract = {BACKGROUND/AIMS: It was recently reported that a higher concentration of the bacterially produced metabolite indole 3-acetate (3-IAA) in blood was linked to a better response to chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to extend these observations to patients diagnosed with non-metastatic PDAC.nnMETHOD: We measured circulating 3-IAA in samples from a prospective population-based cohort of 124 patients with borderline resectable or locally advanced PDAC, collected before initiating neoadjuvant chemotherapy. The majority (61%) of the patients were treated with FOLFIRINOX. We used univariable and multivariable Cox proportional hazards regression to estimate the association between pre-treatment 3-IAA and overall survival.nnRESULTS: The median serum 3-IAA concentration before chemotherapy was 290 (interquartile range 203-417) ng/mL. The unadjusted hazard ratio (HR) for pre-treatment log(3-IAA) was 0.93, 95% confidence interval (CI) [0.74-1.16], p=0.52. When adjusting for age, ECOG, CA19-9 and tumor classification, the HR for log(3-IAA) was 0.87, 95% CI [0.68-1.12], p=0.28.nnCONCLUSION: Our findings suggest that the potentiating effect of 3-IAA observed in metastatic PDAC undergoing chemotherapy may not translate to borderline resectable or locally advanced PDAC. We recommend additional clinical validation of 3-IAA's predictive value in different categories of PDAC before implementation attempts in human studies are initiated.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37801334,

title = {The inverse association between the apolipoprotein E ε4 allele and C-reactive protein levels is stronger in persons with obesity and diabetes},

author = {Lasse Melvaer Giil and Silja Hanseth and Ognjen Bojovic and Jan Erik Nordrehaug and Per Magne Ueland and Klaus Meyer and Grethe S Tell},

doi = {10.1111/sji.13323},

issn = {1365-3083},

year  = {2024},

date = {2024-01-01},

journal = {Scand J Immunol},

volume = {99},

number = {1},

pages = {e13323},

abstract = {BACKGROUND: C-reactive protein (CRP) is lower in patients who carry the apolipoprotein E epsilon 4 allele variant (APOEε4) of the APOE gene. This could however be explained by other factors observed in APOEε4 carriers, such as lower body mass index (BMI), possibly less diabetes and more use of statins, all associated with CRP concentrations.nnOBJECTIVES: To assess the association between CRP and APOEε4 stratified by BMI, statin use and diabetes.nnMETHODS: We included 2700 community-dwelling older adults from the Hordaland health study with genotyping of the APOE gene by a one-step polymerase chain reaction and CRP measured using immuno-MALDI-TOF MS. Differences in CRP concentrations by APOE (ε4 vs no ε4) were assessed using the Mann-Whitney U tests, also stratified by statin use, diabetes and BMI categories. Finally, we performed linear regression with log (CRP) as the outcome and APOEε4 together with statin use, diabetes, BMI and their respective interactions.nnRESULTS: CRP was higher in APOEε4 carriers irrespective of BMI, diabetes and statin use. In APOEε4 non-carriers, CRP was elevated with diabetes and obesity as expected. However, this was attenuated or even reversed in APOEε4 carriers. Such differences were not observed for statin use.nnCONCLUSIONS: Statin use, obesity or diabetes did not confound the known association between the APOEε4 allele and lower CRP. Our data suggest that CRP is less responsive to inflammatory cues involved in diabetes and obesity in APOEε4 carriers. Epidemiological studies should take note of these relationships, as CRP, APOEε4, diabetes and obesity are both linked to neurodegenerative and cardiovascular disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38273044,

title = {Preoperative risk factors associated with left ventricular dysfunction after bariatric surgery},

author = {Lisa M D Grymyr and Gunnar Mellgren and Adrian McCann and Eva Gerdts and Klaus Meyer and Saied Nadirpour and Johan Fernø and Bjørn G Nedrebø and Dana Cramariuc},

doi = {10.1038/s41598-024-52623-1},

issn = {2045-2322},

year  = {2024},

date = {2024-01-01},

journal = {Sci Rep},

volume = {14},

number = {1},

pages = {2173},

abstract = {A large proportion of patients with severe obesity remain with left ventricular (LV) dysfunction after bariatric surgery. We assessed whether preoperative evaluation by echocardiography and inflammatory proteins can identify this high-risk group. In the Bariatric Surgery on the West Coast of Norway study, 75 patients (44 ± 10 years, body mass index [BMI] 41.5 ± 4.7 kg/m) were prospectively evaluated by echocardiography and inflammatory proteins (high-sensitivity C-reactive protein [hsCRP], serum amyloid A [SAA] and calprotectin) before and one year after Roux-en-Y gastric bypass surgery. LV mechanics was assessed by the midwall shortening (MWS) and global longitudinal strain (GLS). Bariatric surgery improved BMI and GLS, and lowered hsCRP, calprotectin and SAA (p < 0.05). MWS remained unchanged and 35% of patients had impaired MWS at 1-year follow-up. A preoperative risk index including sex, hypertension, ejection fraction (EF) and high hsCRP (index 1) or SAA (index 2) predicted low 1-year MWS with 81% sensitivity/71% specificity (index 1), and 77% sensitivity/77% specificity (index 2) in ROC analyses (AUC 0.80 and 0.79, p < 0.001). Among individuals with severe obesity, women and patients with hypertension, increased serum levels of inflammatory proteins and reduced EF are at high risk of impaired LV midwall mechanics 1 year after bariatric surgery.ClinicalTrials.gov identifier NCT01533142 February 15, 2012.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39534856,

title = {Baseline Inflammation but not Exercise Modality Impacts Exercise-induced Kynurenine Pathway Modulation in Persons With Multiple Sclerosis: Secondary Results From a Randomized Controlled Trial},

author = {Marie Kupjetz and Nadine Patt and Niklas Joisten and Per Magne Ueland and Adrian McCann and Roman Gonzenbach and Jens Bansi and Philipp Zimmer},

doi = {10.1177/11786469241284423},

issn = {1178-6469},

year  = {2024},

date = {2024-01-01},

journal = {Int J Tryptophan Res},

volume = {17},

pages = {11786469241284423},

abstract = {BACKGROUND: The kynurenine pathway (KP) is an important hub in neuroimmune crosstalk that is dysregulated in persons with multiple sclerosis (pwMS) and modulated by exercise in a modality-specific manner.nnOBJECTIVES: To compare changes in the KP metabolite profile of pwMS (1) following combined treatments including either high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT) during a 3-week multimodal rehabilitation, (2) to evaluate exercise response in relation to baseline systemic inflammation, and (3) to investigate associations of kynurenines with physical capacity and clinical outcomes.nnMETHODS: For this secondary analysis of a randomized controlled trial, serum concentrations of kynurenines at baseline and after 3 weeks were determined using targeted metabolomics (LC-MS/MS). Exercise-induced changes in the KP metabolite profile according to treatment and baseline systemic inflammation (neutrophil-to-lymphocyte ratio (NLR) <3.12 versus ⩾3.12) were investigated using covariance analyses.nnRESULTS: Regardless of treatment, concentrations of tryptophan and most kynurenines decreased over time. Quinolinic acid concentration increased ( < .001). Participants with low and high NLR revealed differential exercise-induced changes in concentrations of kynurenines and NLR. The systemic inflammation markers neopterin ( = .015) and NLR ( < .001) decreased in the whole group and in participants with high NLR, respectively.nnCONCLUSIONS: Combined treatments including HIIT or MICT do not differentially modulate the KP metabolite profile, with both reducing concentrations of most kynurenines. Baseline systemic inflammation may impact exercise-induced changes in the KP metabolite profile and anti-inflammatory effects of exercise in pwMS.nnTRIAL REGISTRATION: clinicaltrials.gov (identifier: NCT04356248).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}