Bjørn Steen Skålhegg

Proteome analysis of pancreatic tumors implicates extracellular matrix in patient outcome.Laxmi Silwal-Pandit, et al and Bjørn S. Skålhegg, Janne Lehtiö, Elin H. Kure. Cancer Research Communications, 2022, DOI: 10.1158/2767-9764. (IF: 11.5)

Endogenous glutamine is rate limiting for anti-CD3 and anti-CD28 induced CD4+ T cell proliferation and glycolytic activity under hypoxia and normoxia. Wik, J., Chowdhury, A.I., Bastani, N.E, Kolan S., Sener, Z, Alam, Kazi, and Skålhegg, B.S. Biochem J 2022, DOI: 10.1042/BCJ20220144. (IF 4.7)

Identification of SNPs associated with methotrexate treatment outcomes in patients with earlyrheumatoid arthritis. Kolan SS, Li G, Grimolizzi F, Sexton J, Goll G, Kvien TK, Sundlisæter NP, Zucknick M, Lillegraven S, Haavardsholm EA, Skålhegg BS. Front Pharmacol. 2022 doi: 10.3389/fphar.2022.1075603. eCollection 2022. (IF: 6)

Antibody blockade of Jagged1 attenuates choroidal neovascularization. Gjølberg TT, Wik JA,Johannessen H, Krüger S, Bassi N, Christopoulos PF, Bern M, Foss S, Petrovski G, Moe MC, Haraldsen G, Fosse JH, Skålhegg BS, Andersen JT, Sundlisæter E. Nature Comm., 2023 May 30;14(1):3109. doi: 10.1038/s41467-023-38563-w. (IF: 14.6)

Systemic Adaptions to Extreme Caloric Restrictions of Different Durations in Humans". M.Pietzner, B. Uluvar, K. J. Kolnes, P. B. Jeppesen, S.V Frivold, Ø. Skattebo, E.I. Johansen, B.S. Skålhegg, J.F. P. Wojtaszewski, A.J. Kolnes, G.S.H. Yeo, S.O’Rahilly, J.Jensen, C. Langenberg. Nature Metabol. 2024 ;6(4):764-777. doi: 10.1038/s42255-024-01008-9. (IF: 21)

Preoperative profiles of plasma amino acids and derivatives distinguish periampullary cancer andbenign disease. Stålberg SM, Silwal-Pandit L, Bastani NE, Nebdal DJH, Lingjærde OC, Skålhegg BS, Kure EH. BMC Cancer. 2024 3;24(1):555. doi: 10.1186/s12885-024-12320-8. (IF: 5.8)

Reduced EO771-induced tumour growth and increased overall-survival of mice ablated for immune cell specific catalytic subunit Cβ2 of protein kinase A. Shuai Guo, Shrikant Kolan, Gaoyang Li, ClaraLouise Hammarström, Franco Grimolizzi, Linda Elin Birkhaug Stuhr, Bjørn Steen Skålhegg. Immunol Lett. 2024 Aug:268:106884. doi: 10.1016/j.imlet.2024.106884. (IF: 4.4)

Effects of Seven Days Fasting on Physical Performance and Metabolic Adaptation during Exercise in Young and Healthy Individuals. Kristoffer J. Kolnes, Emelie F. Nilsen, Steffen Brufladt, Allison M. Meadows, Per B. Jeppesen, Øyvind Skattebo, Egil I. Johansen, Jesper B. Birk, Kurt Højlund, Janne Hingst, Bjørn S. Skålhegg, Rasmus Købsted, Julian L. Griffin, Anders J. Kolnes, Stephen O’Rahilly, Jørgen F.P. Wojtaszewski, Jørgen Jensen. Nature Comm., 2025. doi: 10.1038/s41467-024-55418-0. (IF: 14.6)

Development of machine learning models for predicting non-remission in early RA highlights the robust predictive importance of the RAID score-evidence from the ARCTIC study. Kolan SS, Li G, Grimolizzi F, Sexton J, Goll G, Kvien TK, Sundlisæter NP, Zucknick M, Lillegraven S, Haavardsholm EA, Skålhegg BS. Front Med 2025, doi.org/10.3389/fmed.2025.1526708 (IF: 6.0)

Multiple signaling events are required for NAADP synthesis by DUOX2 and formation of Ca2+ microdomains to initiate T cell activation. Winterberg KJ, Schwentner V, Gu F, Möckl F, Li G, Bauche A, Etzold S, Rosche A, Weiß M, Thuille N, Förster F, Woelk L, Werner R, Kovacevic D, Fehse B, Kurelic R, Nawrocki M, Huber S, Mittrücker HW, Meier C, Müller CE, Baier G, Skålhegg BS, de Deken X, Wahl-Schott C, Mair T, Siebels B, Cugota Canals R, Odoardi F, Lodygin D, Flügel A, Nikolaev VO, Diercks BP, Guse AH. Sci Signal. 2026 Jan 13;19(920):eadp4326. doi: 10.1126/scisignal.adp4326. (IF 6.6)

• Nothnagel, Patrizia Maria Christiane; Meslin, Paul-Arthur Richard; Wik, Jonas Aakre; Dufour, Damien; Strøm, Yunna Erika & Bjørås, Magnar [Show all 11 contributors for this article] (2026). Transient SUMOylation inhibition in human pre-adipocytes stably imprints a transcriptional beiging fate. Nucleic Acids Research (NAR). ISSN 0305-1048. 54(6), p. 1–22. doi: 10.1093/nar/gkag232. Full text in Research Archive Show summary

  SUMOylation regulates chromatin states and transcriptional programs that preserve cellular identity, yet how perturbation of the SUMOylation pathway impacts adipocyte plasticity remains unclear. Here, we show that brief pharmacologic inhibition of SUMOylation in human pre-adipocytes using TAK-981 primes stable de novo beige differentiation in the presence of the PPARG agonist rosiglitazone. Transient TAK-981 exposure produces changes in the transcriptome and metabolism of mature adipocytes, including robust induction of canonical beiging markers like UCP1 and increased mitochondrial respiration. Mechanistically, ATAC-seq and RNA-sequencing revealed immediate chromatin remodeling and early mobilization of CEBP family members, followed by stable activation of CEBPA and PPARG regulatory networks. ChIP experiments demonstrated loss of H3K27me3 and gain of H3K27ac at PPAR response elements at thermogenic enhancers, and increased PPARG occupancy across the UCP1 regulatory unit. This mechanism is enforced by enhanced cAMP-PKA-p38 signaling and stabilization of beiging transcription activators. We propose that transient relief of SUMO-mediated repression unlocks dominant regulatory units, notably the UCP1 enhancer cluster, producing a monomorphic reprogramming toward adaptive thermogenesis. These findings identify SUMOylation as a reversible epigenetic barrier to adipocyte beiging and suggest that temporally controlled SUMO pathway inhibition combined with PPARG activation could be exploited to modulate adipose tissue thermogenic capacity.

• Yadav, Ajay; Richartz, Nina; Bhagwat, Sampada; Burman, Marta Maria; Munthe-Kaas, Monica Cheng & Skålhegg, Bjørn Steen [Show all 9 contributors for this article] (2026). Starvation of leukemic cells enhances DNA damage-induced apoptosis in vitro via ROS/p38 MAPK and prevents leukemia progression in fasting xenograft mice. Journal of Biological Chemistry. ISSN 0021-9258. 302(3). doi: 10.1016/j.jbc.2026.111143. Full text in Research Archive Show summary

  Most children with acute lymphoblastic leukemia (ALL) achieve long-term survival due to intensive multimodal chemotherapy. However, the use of cytotoxic DNA-damaging agents is frequently associated with severe long-term side effects, prompting continued efforts to improve treatment strategies. This study explores the potential of starving the leukemic cells to enhance the efficacy of DNA-damaging therapy in ALL. Previous work demonstrated that cAMP signaling attenuates DNA damage-induced apoptosis in ALL cells, both in vitro and in a xenograft model. The current findings show that glucose and serum deprivation reverse the effect of cAMP, converting it from a survival factor to a promoter of DNA damage-induced apoptosis in ALL-derived cell lines and patient-derived leukemic cells in vitro. The starvation-induced sensitization was independent of p53 but was shown to require increased levels of reactive oxygen species (ROS). In turn, the elevated ROS levels enhanced the activation of the mitogen-activated protein kinase p38 (p38 MAPK). The resulting augmented cell death was inhibited both by the ROS scavenger N-acetyl cysteine and the p38 MAPK inhibitor SB 202190. The translational potential of increasing the efficacy of DNA damaging agents in starving ALL cells was supported by in vivo data showing that intermittent fasting, combined with subtherapeutic doses of irradiation, significantly inhibits the leukemia progression in a xenograft model of severe combined immunodeficiency mice.

• Park, Johan & Skålhegg, Bjørn Steen (2025). Combination of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment of cancer – a brief update. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1680838. Full text in Research Archive Show summary

  The introduction of immune checkpoint inhibitors (ICIs) has revolutionized cancer therapy, offering durable responses in multiple malignancies by targeting regulatory pathways such as programmed cell death protein 1 (PD-1), its ligand (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). These pathways, which normally maintain immune tolerance and homeostasis, can be exploited by tumors to evade immune surveillance. Dual blockade using monoclonal antibodies (mAbs) targeting PD-1/PD-L1 and CTLA-4 has shown synergistic effects, improving response rates, overall survival, and progression-free survival in several cancer types. The U.S. Food and Drug Administration (FDA) has approved two such combinations: nivolumab plus ipilimumab and durvalumab plus tremelimumab, based on demonstrated clinical benefit in melanoma, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer, pleural mesothelioma, and esophageal squamous cell carcinoma. However, clinical benefit has not been consistent across all tumor types, with limited efficacy observed in cancers such as glioblastoma, head and neck squamous cell carcinoma, and Merkel cell carcinoma. Additionally, combination therapy is associated with a higher incidence of immune-related adverse events, affecting multiple organ systems and necessitating careful dosing strategies to balance efficacy and toxicity. This review summarizes the current landscape of FDA-approved PD-1/PD-L1 and CTLA-4 combinations, their therapeutic achievements, clinical limitations, and supports future research in combination immunotherapy.

• Wik, Jonas Aakre; Berge, Emma Riiser; Strømsnes, Kristine Bakklund & Skålhegg, Bjørn Steen (2025). Metabolism in the tumor microenvironment: implications for pathogenesis and therapeutics. Frontiers in Immunology. 16, p. 1–20. doi: 10.3389/fimmu.2025.1610255. Full text in Research Archive Show summary

  The immune system protects the body against dangers that include pathogens, damage and cancer. Modern cancer therapies have sought to bolster immune responses against cancer using immunotherapy, which may include various forms of immune checkpoint therapy (ICT) in addition to methods of adoptive cell transfer (ACT), which is often associated with transfer of chimeric antigen receptor (CAR) T cells. Despite favorable outcomes in some patients and some cancers, as many as 60-80% of patients fail to benefit from ICT due to primary or adaptive resistance. This highlights the need for deeper understanding of how cancers suppress the immune system. Solid tumors, which make up approximately 90% of all cancers, are characterized by an immunosuppressive tumor microenvironment (TME). A hallmark of the TME is dysfunctional vascularization and impaired perfusion, which hinder effective drug delivery and promote hypoxia-induced metabolic reprograming in both cancer and immune cells. As the TME imposes intense metabolic stress through nutrient competition and lactate-driven acidification – both of which activates immunosuppressive pathways, targeting the TME itself may be beneficial in enhancing the efficacy of immunotherapy. Here we will briefly discuss the potential of targeting the metabolism of the TME as a means to promote normalized tumor vascularization and/or enhance anti-tumor immune responses.

• Doncheva, Atanaska; Higa, Ryoko; Khanal, Prabhat; Ingebrigtsen, Martine Villemo Øksenvåg; Li, Yuchuan & Kolan, Shrikant [Show all 16 contributors for this article] (2025). Elevated adipose inflammation, but reduced hepatic triacylglycerol storage in diet-induced obese Plin4/mice. Journal of Biological Chemistry. ISSN 0021-9258. 302(2). doi: 10.1016/j.jbc.2025.111043. Full text in Research Archive
• Nothnagel, Patrizia Maria Christiane; Meslin, Paul-Arthur Richard; Wik, Jonas Aakre; Strøm, Yunna Erika; Bjørås, Magnar & Enserink, Jorrit [Show all 10 contributors for this article] (2025). Transient SUMOylation Inhibition In Human Pre-adipocytes Stably Imprints a Transcriptional Beiging Fate. bioRxiv (preprint article). 54(6). doi: 10.1101/2025.03.07.642034. Full text in Research Archive Show summary

  Abstract SUMOylation regulates chromatin states and transcriptional programs that preserve cellular identity, yet how transient perturbation of the SUMO pathway impacts adipocyte plasticity remains unclear. Here we show that brief pharmacologic inhibition of SUMO conjugation in human pre-adipocytes using TAK-981 primes stable de novo beige differentiation in the presence of the PPARG agonist rosiglitazone. Transient TAK-981 exposure before adipogenic induction produces long-lasting changes in the transcriptome and metabolism of mature adipocytes, including robust induction of canonical beiging markers like UCP1 and increased mitochondrial respiration. Mechanistically, ATAC-seq and transcription factor footprinting revealed immediate and durable chromatin remodeling and early mobilization of CEBP family members, followed by stable activation of CEBPA and PPARG regulatory networks. ChIP experiments demonstrated loss of H3K27me3 and gain of H3K27ac at PPAR response elements within key thermogenic enhancers, with increased PPARG occupancy across the UCP1 regulatory unit. This mechanism is enforced by enhanced cAMP-PKA-p38 signaling, and stabilization of beiging transcriptional activators. Our data support a model in which transient relief of SUMO-mediated repression unlocks dominant regulatory units, notably the UCP1 enhancer cluster, producing a monomorphic, cell type specific reprogramming toward adaptive thermogenesis. These findings identify SUMOylation as a reversible epigenetic barrier to adipocyte beiging and suggest that temporally controlled SUMO pathway inhibition combined with PPARG activation could be exploited to modulate adipose tissue thermogenic capacity. Graphical abstract SUMOylation restricts de novo differentiation of pre-adipocytes into beige adipocytes by repressing cAMP signaling and preventing epigenetic and transcriptional reprogramming of white adipocytes.

• Stålberg, Stina Margrethe; Silwal-Pandit, Laxmi; Hamfjord, Julian; Nebdal, Daniel Johan Hammer; Lehtiö, J. & Lingjærde, Ole Christian [Show all 8 contributors for this article] (2025). Elevated KRAS protein level is associated with better survival in pancreatic cancer. BMC Cancer. 25. doi: 10.1186/s12885-025-14461-w. Full text in Research Archive Show summary

  Background Activating somatic KRAS mutations in hotspot loci occur almost universally (> 95%) in pancreatic ductal adenocarcinoma (PDAC). Both the presence of a KRAS mutation and high mRNA expression levels of KRAS in tumor tissue have been associated with worse outcome. Less is known about the expression of KRAS at the protein level and its association with clinical and molecular parameters. In the present study, we investigated the prognostic significance of the KRAS protein level and its relation to KRAS mutation status and the mRNA expression level. Methods A total of 41 PDAC tumors were screened for seven KRAS mutations (p.G12D, p.G12V, p.G12R, p.G12C, p.G12S, p.G13D, p.G12A) by the Wobble-enhanced ARMS method. Whole transcriptome and proteome profiles were obtained using mRNA microarrays (Agilent) and quantitative mass spectrometry-based proteomics (HiRIEF LC–MS/MS), respectively. The clinical outcome was overall survival (OS). Results KRAS mutations were identified in 88% of the tumors with p.G12D and p.G12V mutations being the most frequent. Tumors with p.G12V mutation had significantly higher KRAS mRNA expression than tumors with p.G12D, p.G12C, p.G12R or no mutation identified (P < 0.01). KRAS protein levels did not associate significantly to neither KRAS mRNA levels (Spearman’s rho = 0.18, P = 0.28) nor type of KRAS mutation. High KRAS protein level and mutation p.G12V were found to be significantly associated with better (P < 0.01) and worse OS (P < 0.05), respectively. Conclusions The KRAS protein level correlated poorly with KRAS mRNA expression level and was not significantly associated with the type of mutation present. Interestingly, we found that patients with high KRAS protein level in their tumors had a better clinical outcome.

• Aune, Dagfinn; Nordsletten, Marie Wiborg; Myklebust, Tor Åge; Robsahm, Trude Eid; Skålhegg, Bjørn Steen & Mala, Tom [Show all 8 contributors for this article] (2025). Body mass index and risk of Hodgkin's lymphoma: Insights from a Norwegian cohort study. European Journal of Cancer. ISSN 0959-8049. 221. doi: 10.1016/j.ejca.2025.115400. Full text in Research Archive Show summary

  Background Several studies have reported positive associations between higher body mass index (BMI) and risk of Hodgkin's lymphoma. However, the evidence is not entirely consistent. We investigated the association between BMI and Hodgkin's lymphoma in a large Norwegian cohort with up to 50 years follow-up. Methods The analytical dataset included 1723,692 men and women aged 16–75 years at baseline in 1963–1975. Multivariable Cox regression analyses were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for the associations between BMI and Hodgkin's lymphoma incidence. Results During 56.1 million person-years of follow-up, 1608 incident Hodgkin's lymphoma cases occurred. Compared to individuals with BMI 18.5-< 25, the HRs (95 % CIs) for those with a BMI of 15-< 18.5, 25-< 30, and ≥ 30 were 0.87 (0.59–1.27), 1.05 (0.94–1.18), and 1.61 (1.35–1.91), respectively, and 1.57 (1.30–1.90) and 1.80 (1.24–2.62) for obesity grade 1 and grade 2, respectively. A positive association was also observed per 5 kg/m2 increment with a HR (95 % CI) of 1.16 (1.08–1.24) overall, 1.20 (1.09–1.31) in women, and 1.08 (0.96–1.20) in men. Positive associations were also observed between obesity vs. normal weight in early adulthood (age 16–29 years) and Hodgkin's lymphoma (HR, 95 % CIs: 1.89, 1.10–3.22, ptrend<0.0001, n = 489 cases) and between obesity and early-onset (age <50 years at diagnosis) disease (HR, 95 % CIs: 1.67, 1.01–2.78, ptrend<0.0001, n = 393 cases). Conclusion The positive associations observed between higher BMI overall and in young adulthood and Hodgkin's lymphoma and between BMI and early-onset disease emphasize the potential role of adiposity in development of this malignancy.

• Kolnes, Kristoffer Jensen; Nilsen, Emelie; Brufladt, Steffen Johnsen; Meadows, Allison; Jeppesen, Per Bendix & Skattebo, Øyvind [Show all 17 contributors for this article] (2025). Effects of seven days’ fasting on physical performance and metabolic adaptation during exercise in humans. Nature Communications. 16(1). doi: 10.1038/s41467-024-55418-0. Full text in Research Archive Show summary

  Humans have, throughout history, faced periods of starvation necessitating increased physical effort to gather food. To explore adaptations in muscle function, 13 participants (7 males and 6 females) fasted for seven days. They lost 4.6 ± 0.3 kg lean and 1.4 ± 0.1 kg fat mass. Maximal isometric and isokinetic strength remained unchanged, while peak oxygen uptake decreased by 13%. Muscle glycogen was halved, while expression of electron transport chain proteins was unchanged. Pyruvate dehydrogenase kinase 4 (PDK4) expression increased 13-fold, accompanied by inhibitory pyruvate dehydrogenase phosphorylation, reduced carbohydrate oxidation and decreased exercise endurance capacity. Fasting had no impact on 5’ AMP-activated protein kinase (AMPK) activity, challenging its proposed role in muscle protein degradation. The participants maintained muscle strength and oxidative enzymes in skeletal muscle during fasting but carbohydrate oxidation and high-intensity endurance capacity were reduced.

• Aune, Dagfinn; Nordsletten, Marie Wiborg; Myklebust, Tor Åge; Robsahm, Trude Eid; Skålhegg, Bjørn Steen & Mala, Tom [Show all 8 contributors for this article] (2025). Body mass index and risk of connective and soft tissue cancer: results from a large cohort of 1.7 million individuals in Norway. BMC Cancer. 25. doi: 10.1186/s12885-025-13637-8. Full text in Research Archive Show summary

  Background Few studies have investigated the association between adiposity and connective and soft tissue cancer, a rare and understudied cancer entity. We investigated this association in a large cohort of more than 1.7 million individuals in Norway. Methods The study cohort included 1,723,692 men and women aged 16–75 years at baseline in 1963–1975. Data on weight and height measurements from the Norwegian Tuberculosis Screening Programme were linked to the Cancer Registry. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between body mass index (BMI) and risk of connective and soft tissue cancer, adjusting for age and sex. Results In total 1758 connective and soft tissue cancer cases were registered during 56.1 million person-years of follow-up. The HRs (95% CIs) for the BMI categories of 15-<18.5, 18.5-<25.0 (reference), 25.0-<30.0, 30.0-<35.0, ≥ 35.0 were 0.77 (0.50–1.20), 1.00 (reference), 1.15 (1.03–1.27), 1.28 (1.06–1.54), and 1.69 (1.21–2.37, ptrend<0.0001). The HR per 5 kg/m2 increment in BMI was 1.14 (1.07–1.22) overall, 1.10 (0.99–1.23) in men and 1.17 (1.08–1.27) in women. Obesity in early adulthood (age 16–29 years) showed a suggestive positive association with connective and soft tissue cancer risk with HR (95%CIs) of 1.73 (0.95–3.16), ptrend=0.09) when compared to normal weight. No clear association was observed between BMI and early-onset (age < 50 years at diagnosis) connective and soft tissue cancer. Positive associations were observed between BMI and soft tissue sarcoma, fibrosarcoma, dermatofibroma, and lipoleiomyoma, but no clear associations were observed with fibrous histiocytoma and liposarcoma. Conclusion These results suggest that higher BMI overall and in early adulthood may be associated with increased risk of connective and soft tissue cancer, but BMI seems not to influence early-onset disease. Large cohort studies with more detailed information on confounding factors and BMI trajectories over time are needed for further verification before firm conclusions can be made.

• Aune, Dagfinn; Nordsletten, Marie Wiborg; Myklebust, Tor Åge; Robsahm, Trude Eid; Skålhegg, Bjørn Steen & Mala, Tom [Show all 8 contributors for this article] (2025). Body mass index and ampulla of Vater cancer incidence and survival: a cohort study of 1.7 million Norwegians. Hepatobiliary surgery and nutrition. ISSN 2304-3881. p. 1–8. doi: 10.21037/hbsn-2024-636. Full text in Research Archive Show summary

  Background: Although higher body mass index (BMI) has been associated with increased risk of hepatobiliary cancers in previous studies, the association with risk of ampulla of Vater cancer has rarely been reported. We therefore investigated the association between BMI and ampulla of Vater cancer incidence in a large Norwegian cohort. Methods: The analytical dataset included 1,723,692 men and women aged 16–75 years at baseline in 1963– 1975. Multivariable Cox regression analyses were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between BMI and ampulla of Vater cancer incidence and survival. Results: During 56.1 million person-years of follow-up, a total of 814 cases with ampulla of Vater cancer were identified. Compared to participants with a BMI of 18.5–<25 kg/m2, the HRs (95% CIs) of those with a BMI of 15–<18.5, 25–<30, and ≥30 kg/m2 were 0.19 (0.05–0.77), 1.02 (0.88–1.19), and 1.03 (0.80–1.32), respectively, and 1.02 (0.92–1.12) per 5 kg/m2 increment. No association was observed in men and women, when analysed separately. The HRs (95% CIs) for BMI in young adulthood were 0.39 (0.10–1.57), 1.00, 1.26 (0.80–1.99), and 3.62 (1.76–7.48, Ptrend=0.004) for a BMI of 15–<18.5, 18.5–<25.0, 25–<30, and ≥30 kg/m2, and 1.61 (1.25–2.06) per 5 kg/m2 increment (n=130), and for early-onset ampulla of Vater cancer (n=19) was 1.00, 2.10 (0.75–5.88), and 5.45 (1.16–25.70, Ptrend=0.01), and 1.91 (1.10–3.32) per 5 kg/m2 increment. Higher BMI was not clearly associated with cancer-specific survival among ampulla of Vater cancer patients (HR 1.19, 95% CI: 0.89–1.61 for BMI ≥30 vs. 18.5–<25.0 kg/m2). Conclusions: Overall, the results show no clear association between higher BMI and ampulla of Vater cancer incidence or survival. However, strong positive associations were observed between BMI in young adulthood and risk of ampulla of Vater cancer and between BMI and early-onset diagnosis. Further studies are needed to verify these findings.

• Li, Gaoyang; Kolan, Shrikant; Grimolizzi, Franco; Sexton, Joseph; Malachin, Giulia & Goll, Guro Løvik [Show all 12 contributors for this article] (2025). Development of machine learning models for predicting non-remission in early RA highlights the robust predictive importance of the RAID score-evidence from the ARCTIC study. Frontiers of Medicine. ISSN 2095-0217. 12. doi: 10.3389/fmed.2025.1526708. Full text in Research Archive Show summary

  Introduction: Achieving remission is a critical therapeutic goal in the management of rheumatoid arthritis (RA). Despite methotrexate being the cornerstone of early RA treatment, a significant proportion of patients fail to achieve remission. This study aims to predict 6-month non-remission in 222 disease-modifying antirheumatic drug (DMARD)-naïve RA patients initiating methotrexate monotherapy, using baseline patient characteristics from the ARCTIC trial. Methods: Machine learning models were developed utilizing twenty-one baseline demographic, clinical and laboratory features to predict non-remission according to ACR/EULAR Boolean, SDAI and CDAI criteria. The model employed a super learner algorithm that combine three base algorithms of elastic net, random forest and support vector machine. The model performance was evaluated through five independent unseen tests with nested 5-fold cross-validation. The predictive power of each feature was assessed using a composite measure derived from individual algorithm estimates. Results: The model demonstrated a mean AUC-ROC of 0.75-0.76, with mean sensitivity of 0.77-0.81, precision (also referred to as Positive Predictive Value) of 0.77-0.79 and specificity of 0.63-0.66 across the criteria. Predictive power analysis of each feature identified the baseline Rheumatoid Arthritis Impact of Disease (RAID) score as the strongest predictor of non-remission. A simplified model using RAID score alone demonstrated comparable performance to the full-feature model. Conclusion: These findings highlight the potential utility of baseline RAID scorebased model as an effective tool for early identification of patients at risk of nonremission in clinical practise.

• Saeed, Usman; Myklebust, Tor Åge; Robsahm, Trude Eid; Aune, Dagfinn; Møller, Bjørn & Skålhegg, Bjørn Steen [Show all 8 contributors for this article] (2025). Associations between body mass index and gastroesophageal cancer incidence and mortality: novel insights from a nationwide registry-based cohort study. Diseases of the esophagus. ISSN 1120-8694. 38(2). doi: 10.1093/dote/doaf018. Full text in Research Archive Show summary

  The association between body mass index (BMI) and cancers of the esophagus and the stomach remains complex and requires further exploration. This study aimed to investigate this association, including early-onset (< 50 years) cancer and cancer related mortality. A nationwide registry-based cohort study was performed by linking data from multiple national registries in Norway. The cohort included 1,723,692 individuals, with 22,473 gastroesophageal cancer cases identified over 55,701,169 person-years of follow-up. In men, a 5 kg/m2 increase in BMI was associated with an increased risk of esophageal (HR 1.34, 95%CI 1.22–1.48) and cardia adenocarcinoma (HR 1.36, 95% CI, 1.22–1.50). This finding extended to individuals with high BMI in early life (16–29 years) for esophageal adenocarcinoma. The highest risk per 5 kg/m2 increase in BMI was observed for early-onset esophageal (HR 2.49, 95%CI 1.23–5.02) and cardia adenocarcinoma (HR 2.26, 95%CI 1.19–4.27). Among women, increased BMI was associated with a higher risk of both esophageal (HR 1.28, 95%CI 1.13–1.44) and gastric adenocarcinoma (HR 1.04, 95%CI 1.01–1.07). Women with elevated BMI in early life also demonstrated increased risk for these cancers. In both sexes, a 5 kg/m2 increase in BMI was inversely associated with squamous cell carcinoma of the esophagus. No association was observed between BMI and risk of cancer-related mortality. This study highlights an elevated risk of gastroesophageal adenocarcinomas with increasing BMI, with notable sex, age, and site-specific variations. The findings also point to a heightened risk of early-onset esophageal and cardia adenocarcinoma in men with high BMI.

• Aune, Dagfinn; Mala, Tom; Myklebust, Tor Åge; Nordsletten, Marie Wiborg; Robsahm, Trude Eid & Saeed, Usman [Show all 8 contributors for this article] (2024). The association between body mass index and vulvar and vaginal cancer incidence: findings from a large Norwegian cohort study | Cancer Causes & Control. Cancer Causes and Control. ISSN 0957-5243. 36(2), p. 191–198. doi: 10.1007/s10552-024-01930-z. Full text in Research Archive Show summary

  There is limited evidence of potential associations between body mass index (BMI) and risk of vulvar and vaginal cancer. We explored these associations in a large cohort of Norwegian women. The analytical dataset included 889,441 women aged 16–75&nbsp;years at baseline in 1963–1975. Multivariable Cox regression analyses were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between BMI and vulvar and vaginal cancer incidence. During 30.1 million person-years of follow-up, 1748 incident vulvar and 408 incident vaginal cancer cases occurred. The HRs (95% CIs) for vulvar cancer for a BMI of 15- &lt; 18.5, 18.5- &lt; 25, 25- &lt; 30, 30- &lt; 35, ≥ 35 were 0.62 (0.38–1.01), 1.00 (reference), 1.23 (1.10–1.40), 1.43 (1.23–1.66) and 1.72 (1.35–2.20, ptrend &lt; 0.001), and per 5&nbsp;kg/m2 increment was 1.20 (1.13–1.26). The corresponding HRs (95% CIs) for vaginal cancer were 1.05 (0.52–2.15), 1.00, 0.89 (0.71–1.12), 0.95 (0.68–1.34), and 2.01 (1.29–3.13, ptrend &lt; 0.001), respectively, and per 5&nbsp;kg/m2 was 1.11 (0.99–1.25). The HR (95% CI) per 5&nbsp;kg/m2 increase in BMI at ages 16–29 was 1.28 (1.07–1.54, n = 250 cases) for vulvar and 1.53 (1.11–2.11, n = 66 cases) for vaginal cancers. The HR (95% CI) per 5&nbsp;kg/m2 for early-onset (&lt; 50&nbsp;years age at diagnosis) vulvar cancer was 0.92 (0.66–1.28, n = 87 cases) and 1.70 (1.05–2.76, n = 21 cases) for vaginal cancer. These results further support the associations between higher BMI and increased risk of vulvar and vaginal cancers, with suggestive stronger associations between BMI in early adulthood for both cancers and for early-onset vaginal cancer. Further studies are needed to elucidate these findings and investigate the underlying mechanisms.

• Stålberg, Stina Margrethe; Silwal-Pandit, Laxmi; Bastani, Nasser Ezzatkhah; Nebdal, Daniel J.H.; Lingjærde, Ole Christian & Skålhegg, Bjørn Steen [Show all 7 contributors for this article] (2024). Preoperative profiles of plasma amino acids and derivatives distinguish periampullary cancer and benign disease. BMC Cancer. 24(1). doi: 10.1186/s12885-024-12320-8. Full text in Research Archive Show summary

  Periampullary cancers, including pancreatic ductal adenocarcinoma, ampullary-, cholangio-, and duodenal carcinoma, are frequently diagnosed in an advanced stage and are associated with poor overall survival. They are difficult to differentiate from each other and challenging to distinguish from benign periampullary disease preoperatively. To improve the preoperative diagnostics of periampullary neoplasms, clinical or biological markers are warranted. In this study, 28 blood plasma amino acids and derivatives from preoperative patients with benign (N = 45) and malignant (N = 72) periampullary disease were analyzed by LC-MS/MS. Principal component analysis and consensus clustering both separated the patients with cancer and the patients with benign disease. Glutamic acid had significantly higher plasma expression and 15 other metabolites significantly lower plasma expression in patients with malignant disease compared with patients having benign disease. Phenylalanine was the only metabolite associated with improved overall survival (HR = 0.50, CI 0.30–0.83, P < 0.01). Taken together, plasma metabolite profiles from patients with malignant and benign periampullary disease were significantly different and have the potential to distinguish malignant from benign disease preoperatively.

• Pietzner, Maik; Uluvar, Burulca; Kolnes, Kristoffer Jensen; Jeppesen, Per Bendix; Frivold, Victoria & Skattebo, Øyvind [Show all 14 contributors for this article] (2024). Systemic proteome adaptions to 7-day complete caloric restriction in humans. Nature Metabolism. 6, p. 764–777. doi: 10.1038/s42255-024-01008-9. Full text in Research Archive Show summary

  Surviving long periods without food has shaped human evolution. In ancient and modern societies, prolonged fasting was/is practiced by billions of people globally for religious purposes, used to treat diseases such as epilepsy, and recently gained popularity as weight loss intervention, but we still have a very limited understanding of the systemic adaptions in humans to extreme caloric restriction of different durations. Here we show that a 7-day water-only fast leads to an average weight loss of 5.7 kg (±0.8 kg) among 12 volunteers (5 women, 7 men). We demonstrate nine distinct proteomic response profiles, with systemic changes evident only after 3 days of complete calorie restriction based on in-depth characterization of the temporal trajectories of ~3,000 plasma proteins measured before, daily during, and after fasting. The multi-organ response to complete caloric restriction shows distinct effects of fasting duration and weight loss and is remarkably conserved across volunteers with >1,000 significantly responding proteins. The fasting signature is strongly enriched for extracellular matrix proteins from various body sites, demonstrating profound non-metabolic adaptions, including extreme changes in the brain-specific extracellular matrix protein tenascin-R. Using proteogenomic approaches, we estimate the health consequences for 212 proteins that change during fasting across ~500 outcomes and identified putative beneficial (SWAP70 and rheumatoid arthritis or HYOU1 and heart disease), as well as adverse effects. Our results advance our understanding of prolonged fasting in humans beyond a merely energy-centric adaptions towards a systemic response that can inform targeted therapeutic modulation.

• Guo, Shuai; Kolan, Shrikant; Li, Gaoyang; Hammarström, Clara Louise; Grimolizzi, Franco & Stuhr, Linda Elin Birkhaug [Show all 7 contributors for this article] (2024). Reduced EO771-induced tumour growth and increased overall-survival of mice ablated for immune cell-specific catalytic subunit Cβ2 of protein kinase A. Immunology Letters. ISSN 0165-2478. 268. doi: 10.1016/j.imlet.2024.106884. Full text in Research Archive Show summary

  Ablation of the immune-specific catalytic subunit Cβ2 of protein kinase A is associated with a proinflammatory phenotype and increased sensitivity to autoimmunity in mice. Here we show that tumour growth of the adenocarcinoma cell line EO771 in the breast and in the lung after injection into the mammary fat pad and tail vein, respectively, was significantly reduced in mice ablated for Cβ2 compared to wild-type mice. In both cases, the breast and lung tumours showed increased infiltration of immune cells in the mice lacking Cβ2 compared to wild-type mice. Despite this, it appeared that solid tissue- versus intravenously injected EO771 cells evoked different immune responses. This was reflected by significantly increased levels of splenic proinflammatory immune cells and circulating cytokines in Cβ2 ablated mice carrying breast- but not the lung tumours. Moreover, Cβ2 ablated mice injected with EO771 cells showed increased overall survival compared to wild-type mice. Taken together, our results suggest for a role for immune cell-specific Cβ2 in protecting against tumour growth induced by EO771 cells in mice that is reflected in improved overall survival.

• Aune, Dagfinn; Nordsletten, Marie Wiborg; Myklebust, Tor Åge; Robsahm, Trude Eid; Skålhegg, Bjørn Steen & Mala, Tom [Show all 8 contributors for this article] (2024). The association between body mass index and vulvar and vaginal cancer incidence: findings from a large Norwegian cohort study. Cancer Causes and Control. ISSN 0957-5243. 36, p. 191–198. doi: 10.1007/s10552-024-01930-z. Full text in Research Archive Show summary

  Background There is limited evidence of potential associations between body mass index (BMI) and risk of vulvar and vaginal cancer. We explored these associations in a large cohort of Norwegian women. Methods The analytical dataset included 889,441 women aged 16–75 years at baseline in 1963–1975. Multivariable Cox regression analyses were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between BMI and vulvar and vaginal cancer incidence. Results During 30.1 million person-years of follow-up, 1748 incident vulvar and 408 incident vaginal cancer cases occurred. The HRs (95% CIs) for vulvar cancer for a BMI of 15- < 18.5, 18.5- < 25, 25- < 30, 30- < 35, ≥ 35 were 0.62 (0.38–1.01), 1.00 (reference), 1.23 (1.10–1.40), 1.43 (1.23–1.66) and 1.72 (1.35–2.20, ptrend < 0.001), and per 5 kg/m2 increment was 1.20 (1.13–1.26). The corresponding HRs (95% CIs) for vaginal cancer were 1.05 (0.52–2.15), 1.00, 0.89 (0.71–1.12), 0.95 (0.68–1.34), and 2.01 (1.29–3.13, ptrend < 0.001), respectively, and per 5 kg/m2 was 1.11 (0.99–1.25). The HR (95% CI) per 5 kg/m2 increase in BMI at ages 16–29 was 1.28 (1.07–1.54, n = 250 cases) for vulvar and 1.53 (1.11–2.11, n = 66 cases) for vaginal cancers. The HR (95% CI) per 5 kg/m2 for early-onset (< 50 years age at diagnosis) vulvar cancer was 0.92 (0.66–1.28, n = 87 cases) and 1.70 (1.05–2.76, n = 21 cases) for vaginal cancer. Conclusion These results further support the associations between higher BMI and increased risk of vulvar and vaginal cancers, with suggestive stronger associations between BMI in early adulthood for both cancers and for early-onset vaginal cancer. Further studies are needed to elucidate these findings and investigate the underlying mechanisms.

• Aune, Dagfinn; Nordsletten, Marie Wiborg; Myklebust, Tor Åge; Robsahm, Trude Eid; Skålhegg, Bjørn Steen & Mala, Tom [Show all 8 contributors for this article] (2024). Body mass index and penile cancer incidence: results from a Norwegian cohort study of 829,081 men. BMC Urology. 24(1), p. 1–6. doi: 10.1186/s12894-024-01636-z. Full text in Research Archive Show summary

  Background A few previous studies have suggested a possible association between adiposity and increased risk of penile cancer, however, the evidence is to date limited for this rare cancer. We investigated the association between body mass index (BMI) and penile cancer risk in a large Norwegian cohort. Methods The analyses included 829,081 men aged 16–75 years at baseline in 1963–1975. Multivariable Cox regression analyses were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between BMI and penile cancer incidence. Results A total of 725 incident penile cancer cases occurred during 25.6 million person-years of follow-up. Compared to men with BMI 18.5-<25, the HRs (95% CIs) of those with a BMI of 15-<18.5, 25-<30, and ≥ 30 were 0.45 (0.15–1.41), 1.14 (0.97–1.33) and 1.63 (1.20–2.22), respectively, and the HR was 1.26 (1.12–1.42) per 5 kg/m2 increase in BMI. When the obese category was further subdivided in grade 1 (BMI 30-<35) and grade 2 obesity (≥ 35), the respe

• Nilsen, Lotte LK; Lambert, Max Norman Tandrup; Haubek, Dorte; Bastani, Nasser Ezzatkhah; Skålhegg, Bjørn Steen & Overgaard, Kristian [Show all 8 contributors for this article] (2024). The Effect of Alginate Encapsulated Plant-Based Carbohydrate and Protein Supplementation on Recovery and Subsequent Performance in Athletes. Nutrients. 16(3). doi: 10.3390/nu16030413. Full text in Research Archive Show summary

  The main purpose of this study was to investigate the effect of a novel alginate-encapsulated carbohydrate–protein (CHO–PRO ratio 2:1) supplement (ALG) on cycling performance. The ALG, designed to control the release of nutrients, was compared to an isocaloric carbohydrate-only control (CON). Alginate encapsulation of CHOs has the potential to reduce the risk of carious lesions. Methods: In a randomised cross-over clinical trial, 14 men completed a preliminary test over 2 experimental days separated by ~6 days. An experimental day consisted of an exercise bout (EX1) of cycling until exhaustion at W~73%, followed by 5 h of recovery and a subsequent time-to-exhaustion (TTE) performance test at W~65%. Subjects ingested either ALG (0.8 g CHO/kg/hr + 0.4 g PRO/kg/hr) or CON (1.2 g CHO/kg/hr) during the first 2 h of recovery. Results: Participants cycled on average 75.2 ± 5.9 min during EX1. Levels of plasma branched-chain amino acids decreased significantly after EX1, and increased significantly with the intake of ALG during the recovery period. During recovery, a significantly higher plasma insulin and glucose response was observed after intake of CON compared to ALG. Intake of ALG increased plasma glucagon, free fatty acids, and glycerol significantly. No differences were found in the TTE between the supplements (p = 0.13) nor in the pH of the subjects’ saliva. Conclusions: During the ALG supplement, plasma amino acids remained elevated during the recovery. Despite the 1/3 less CHO intake with ALG compared to CON, the TTE performance was similar after intake of either supplement.

• Clauss, Matthieu; Bukhardt, Meike; Wøber, Sophie; Skålhegg, Bjørn Steen & Jensen, Jørgen (2024). Effect of five hours of mixed exercise on urinary nitrogen excretion in healthy moderate-to-well-trained young adults. Frontiers in Nutrition. 11. doi: 10.3389/fnut.2024.1345922. Full text in Research Archive Show summary

  Introduction: Carbohydrates and fats are the primary energy substrates during exercise, but proteins can also contribute. When proteins are degraded in the body, the amino groups are mainly converted to urea and excreted. Therefore, nitrogen excretion has been used as a marker of protein degradation, but a clear conclusion has yet to be reached on the effect of exercise on nitrogen excretion. Thus, we tested whether exercise increases nitrogen excretion. Methods: Fifteen young, healthy, moderate-to-well-trained participants (4 females, 11 males, VO2max 54.4 ± 1.7 mL·kg−1·min−1; mean ± SEM) participated in a randomized, balanced cross-over design investigation consisting of 1 day with 5 h of exercise (exercise day, EX) and 1 day with no exercise (control day, CON). The participants recorded their dietary intake the day before from 16:00 and throughout the intervention day. They then repeated these dietary intakes on the second trial day. A standardized lunch was provided on both days. In addition, participants were allowed to consume almost protein-free snacks in EX to ensure the same energy balance during both trial days. Urine was collected throughout the whole testing period, and urinary 3-methylhistidine (3-MH) excretion was measured to examine muscular catabolism. The sweat rate was calculated during the exercise period. Results and discussion: The urinary nitrogen and 3-MH excretions did not differ significantly between EX and CON (p = 0.764 and p = 0.953). The sweat rate was 2.55 ± 0.25 L in EX and 0.14 ± 0.15 L in CON (p 

• Saeed, Usman; Nordsletten, Marie Wiborg; Myklebust, Tor Åge; Robsahm, Trude Eid; Møller, Bjørn & Skålhegg, Bjørn Steen [Show all 8 contributors for this article] (2023). Cancer risk and survival according to body mass index in hepatobiliary malignancies: a nationwide registry-based cohort study. HPB. ISSN 1365-182X. 25(11), p. 1382–1392. doi: 10.1016/j.hpb.2023.07.882. Full text in Research Archive Show summary

  Background The aim of this study was to explore the associations between BMI and cancer of the liver, bile ducts, and gallbladder. Methods A registry-based cohort study was performed by linking data from several national registries in Norway. Results The cohort comprised 1 723 692 individuals including 4768 hepatobiliary cancer cases during 55 743 509 person-years of follow-up. In men, we found increased risk of cancer per 5 kg/m2 BMI increase for hepatocellular carcinoma and extrahepatic cholangiocarcinoma. In women there was increased risk of extrahepatic cholangiocarcinoma and gallbladder cancer. Women with high BMI in early adulthood had increased risk of intrahepatic cholangiocarcinoma. Reduced cancer-specific survival was found for all hepatobiliary malignancies in women with overweight and obesity. In men, reduced survival was observed in individuals with obesity for all hepatobiliary cancers, except gallbladder cancer. Increased risk of cancer-death per 5 kg/m2 BMI increase was found for hepatocellular carcinoma, intra-, and extrahepatic cholangiocarcinoma in women. For men, 5 kg/m2 BMI increase was positively associated with cancer-death from intrahepatic cholangiocarcinoma. Discussion This study supports the notion of an increased risk of hepatobiliary cancers with increasing BMI, with sex and age variations. The findings also suggest a higher risk of cancer-death with increasing BMI.

• gjølberg, torleif; Wik, Jonas Aakre; Johannessen, Hanna; Krüger, Stig; Bassi, Nicola & Christopoulos, Panagiotis [Show all 15 contributors for this article] (2023). Antibody blockade of Jagged1 attenuates choroidal neovascularization. Nature Communications. 14(1). doi: 10.1038/s41467-023-38563-w. Full text in Research Archive Show summary

  Antibody-based blocking of vascular endothelial growth factor (VEGF) reduces choroidal neovascularization (CNV) and retinal edema, rescuing vision in patients with neovascular age-related macular degeneration (nAMD). However, poor response and resistance to anti-VEGF treatment occurs. We report that targeting the Notch ligand Jagged1 by a monoclonal antibody reduces neovascular lesion size, number of activated phagocytes and inflammatory markers and vascular leakage in an experimental CNV mouse model. Additionally, we demonstrate that Jagged1 is expressed in mouse and human eyes, and that Jagged1 expression is independent of VEGF signaling in human endothelial cells. When anti-Jagged1 was combined with anti-VEGF in mice, the decrease in lesion size exceeded that of either antibody alone. The therapeutic effect was solely dependent on blocking, as engineering antibodies to abolish effector functions did not impair the therapeutic effect. Targeting of Jagged1 alone or in combination with anti-VEGF may thus be an attractive strategy to attenuate CNV-bearing diseases.

• Pfabigan, Daniela M.; Frogner, Erik Rimestad; Schéle, Erik; Thorsby, Per Medbøe; Skålhegg, Bjørn Steen & Dickson, Suzanne L. [Show all 7 contributors for this article] (2023). Ghrelin is related to lower brain reward activation during touch. Psychophysiology. ISSN 0048-5772. 61(2). doi: 10.1111/psyp.14443. Full text in Research Archive Show summary

  The gut hormone ghrelin drives food motivation and increases food intake, but it is also involved in the anticipation of and response to rewards other than food. This pre-registered study investigated how naturally varying ghrelin concentrations affect the processing of touch as a social reward in humans. Sixty-seven volunteers received slow caressing touch (so-called CT-targeted touch) as a social reward and control touch on their shins during 3T functional imaging on two test days. On one occasion, participants were fasted, and on another, they received a meal. On each occasion, plasma ghrelin was measured at three time points. All touch was rated as more pleasant after the meal, but there was no association between ghrelin concentrations and pleasantness. CT-targeted touch was rated as the most pleasant and activated somatosensory and reward networks (whole brain). A region-of-interest in the right medial orbitofrontal cortex (mOFC) showed lower activation during all touches, the higher the ghrelin concentrations were. During CT-targeted touch, a larger satiety response (ghrelin decrease after the meal) was associated with higher mOFC activation, and this mOFC activation was associated with higher experienced pleasantness. Overall, higher ghrelin concentrations appear to be related to a lower reward value for touch. Ghrelin may reduce the value of social stimuli, such as touch, to promote food search and intake in a state of low energy. This suggests that the role of ghrelin goes beyond assigning value to food reward.

• Clauss, Matthieu; Skattebo, Øyvind; Dæhli, Malin Rasen; Valsdottir, Thorhildur Ditta; Bastani, Nasser Ezzatkhah & Johansen, Egil Ivar [Show all 9 contributors for this article] (2023). Carbohydrate Ingestion during Prolonged Cycling Improves Next-Day Time Trial Performance and Alters Amino Acid Concentrations. Medicine & Science in Sports & Exercise. ISSN 0195-9131. 55(12), p. 2228–2240. doi: 10.1249/MSS.0000000000003264. Full text in Research Archive
• Sollie, Ove; Clauss, Matthieu; Jeppesen, Per Bendix; Tangen, Daniel S.; Johansen, Egil Ivar & Skålhegg, Bjørn Steen [Show all 8 contributors for this article] (2023). Similar performance after intake of carbohydrate plus whey protein and carbohydrate only in the early phase after non-exhaustive cycling. Scandinavian Journal of Medicine & Science in Sports. ISSN 0905-7188. 33(7), p. 1091–1103. doi: 10.1111/sms.14364. Full text in Research Archive Show summary

  Aim: The aim of the present study was to compare performance 5 h after a 90-min endurance training session when either carbohydrate only or carbohydrate with added whey hydrolysate or whey isolate was ingested during the first 2 h of the recovery period. Methods: Thirteen highly trained competitive male cyclists completed three exercise and diet interventions (double-blinded, randomized, crossover design) separated by 1 week. The 90-min morning session (EX1) included a 60 min time-trial (TT60). Immediately and 1 h after exercise, participants ingested either (1) 1.2 g carbohydrate∙kg−1∙h−1 (CHO), (2) 0.8 g carbohydrate∙kg−1∙h−1 + 0.4 g isolate whey protein∙kg−1∙h−1 (ISO) or (3) 0.8 g carbohydrate∙kg−1∙h−1 + 0.4 g hydrolysate whey protein∙kg−1∙h−1 (HYD). Additional intakes were identical between interventions. After 5 h of recovery, participants completed a time-trial performance (TTP) during which a specific amount of work was performed. Blood and urine were collected throughout the day. Results: TTP did not differ significantly between dietary interventions (CHO: 43:54 ± 1:36, ISO: 46:55 ± 2:32, HYD: 44:31 ± 2:01 min). Nitrogen balance during CHO was lower than ISO (p < 0.0001) and HYD (p < 0.0001), with no difference between ISO and HYD (p = 0.317). In recovery, the area under the curve for blood glucose was higher in CHO compared to ISO and HYD. HR, VO2, RER, glucose, and lactate during EX2 were similar between interventions. Conclusion: Performance did not differ after 5 h of recovery whether carbohydrate only or isocaloric carbohydrate plus protein was ingested during the first 2 h. Correspondingly, participants were not in negative nitrogen balance in any dietary intervention.

• Nordsletten, Marie Wiborg; Saeed, Usman; Myklebust, Tor Åge; Robsahm, Trude Eid; Møller, Bjørn & Skålhegg, Bjørn Steen [Show all 8 contributors for this article] (2023). Body mass index and its association with 22 cancer types: a Norwegian cohort study of 481 202 cancer cases. Acta Oncologica. ISSN 0284-186X. 62(10), p. 1273–1278. doi: 10.1080/0284186X.2023.2258443. Full text in Research Archive
• Silwal-Pandit, Laxmi; Stålberg, Stina Margrethe; Johansson, Henrik J.; Mermelekas, Georgios; Lothe, Inger Marie Bowitz & Skrede, Martina Landschoof [Show all 14 contributors for this article] (2022). Proteome Analysis of Pancreatic Tumors Implicates Extracellular Matrix in Patient Outcome. Cancer Research Communications. 2(6), p. 434–446. doi: 10.1158/2767-9764.CRC-21-0100. Full text in Research Archive Show summary

  Pancreatic cancer remains a disease with unmet clinical needs and inadequate diagnostic, prognostic, and predictive biomarkers. In-depth characterization of the disease proteome is limited. This study thus aims to define and describe protein networks underlying pancreatic cancer and identify protein centric subtypes with clinical relevance. Mass spectrometry–based proteomics was used to identify and quantify the proteome in tumor tissue, tumor-adjacent tissue, and patient-derived xenografts (PDX)-derived cell lines from patients with pancreatic cancer, and tissues from patients with chronic pancreatitis. We identified, quantified, and characterized 11,634 proteins from 72 pancreatic tissue samples. Network focused analysis of the proteomics data led to identification of a tumor epithelium–specific module and an extracellular matrix (ECM)-associated module that discriminated pancreatic tumor tissue from both tumor adjacent tissue and pancreatitis tissue. On the basis of the ECM module, we defined an ECM-high and an ECM-low subgroup, where the ECM-high subgroup was associated with poor prognosis (median survival months: 15.3 vs. 22.9 months; log-rank test, P = 0.02). The ECM-high tumors were characterized by elevated epithelial–mesenchymal transition and glycolytic activities, and low oxidative phosphorylation, E2F, and DNA repair pathway activities. This study offers novel insights into the protein network underlying pancreatic cancer opening up for proteome precision medicine development. Significance: Pancreatic cancer lacks reliable biomarkers for prognostication and treatment of patients. We analyzed the proteome of pancreatic tumors, nonmalignant tissues of the pancreas and PDX-derived cell lines, and identified proteins that discriminate between patients with good and poor survival. The proteomics data also unraveled potential novel drug targets.

• Wik, Jonas Aakre; Chowdhury, Azazul Islam; Kolan, Shrikant; Bastani, Nasser Ezzatkhah; Li, Gaoyang & Alam, Kazi [Show all 8 contributors for this article] (2022). Endogenous glutamine is rate-limiting for anti-CD3 and anti-CD28 induced CD4+ T-cell proliferation and glycolytic activity under hypoxia and normoxia. Biochemical Journal. ISSN 0264-6021. 479(11), p. 1221–1235. doi: 10.1042/BCJ20220144. Full text in Research Archive Show summary

  To meet the demand for energy and biomass, T lymphocytes (T cells) activated to proliferation and clonal expansion, require uptake and metabolism of glucose (Gluc) and the amino acid (AA) glutamine (Gln). Whereas exogenous Gln is converted to glutamate (Glu) by glutaminase (GLS), Gln is also synthesized from the endogenous pool of AA through Glu and activity of glutamine synthase (GS). Most of this knowledge comes from studies on cell cultures under ambient oxygen conditions (normoxia, 21% O2). However, in vivo, antigen induced T-cell activation often occurs under moderately hypoxic (1–4% O2) conditions and at various levels of exogenous nutrients. Here, CD4+ T cells were stimulated for 72 h with antibodies targeting the CD3 and CD28 markers at normoxia and hypoxia (1% O2). This was done in the presence and absence of the GLS and GS inhibitors, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and methionine sulfoximine (MSO) and at various combinations of exogenous Gluc, Gln and pyruvate (Pyr) for the last 12 h of stimulation. We found that T-cell proliferation, viability and levels of endogenous AA were significantly influenced by the availability of exogenous Gln, Gluc and Pyr as well as inhibition of GLS and GS. Moreover, inhibition of GLS and GS and levels of oxygen differentially influenced oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Finally, BPTES-dependent down-regulation of ECAR was associated with reduced hexokinase (HK) activity at both normoxia and hypoxia. Our results demonstrate that Gln availability and metabolism is rate-limiting for CD4+ T-cell activity.

• Saaed, Usman; Myklebust, Tor Åge; Robsahm, Trude Eid; Møller, Bjørn; Mala, Tom & Skålhegg, Bjørn Steen [Show all 7 contributors for this article] (2022). Body mass index and pancreatic adenocarcinoma: A nationwide registry-based cohort study. Scandinavian Journal of Surgery. ISSN 1457-4969. 112(1), p. 11–21. doi: 10.1177/14574969221127530. Full text in Research Archive Show summary

  Background and objective:An association between body mass index (BMI) and pancreatic cancer is suggested in observational studies. However, further studies are required to substantiate available evidence. The aim of this study was to explore the association between BMI and pancreatic ductal adenocarcinoma (PDAC) risk, treatment, and mortality. Methods:A registry-based cohort study was performed by combining data from four registries in Norway. Baseline data were collected between 1963 and 1975 with follow-up data collected until 2018. Kaplan–Meier curves and multivariable Cox regressions were estimated. Chi-square tests were used to analyze differences between groups. Results:The study cohort consisted of 1,723,692 individuals. A total of 8973 PDAC cases were identified during 55,744,749 person-years of follow-up. A 5 kg/m2 increase in BMI was associated with an increased risk of PDAC if high BMI at young age (16–29 years) (hazard ratio (HR): 1.21, 95% confidence interval (CI): 1.13–1.31), both for men (HR: 1.30, 95% CI: 1.15–1.46) and women (HR: 1.16, 95% CI: 1.05–1.28). In men, there was a 52% increase in risk of early-onset PDAC (<age 50) (HR: 1.52, 95% CI: 1.13-2.03) with 5 kg/m2 increase in BMI. A total of 2645 individuals were diagnosed with stage 1–3 disease, of whom 1131 underwent curative surgery. In all, 49% of normal weight, 38% overweight, and 30% obese individuals with stage 1–3 PDAC underwent surgery with curative intent (p < 0.001). Cancer survival was lower in overweight and obese individuals for both sexes. Analysis adjusted for sex, age, and period of diagnosis confirmed increased risk of cancer death in obese individuals. Conclusion:This study suggests that increased BMI in young adults may increase the risk of PDAC, and higher BMI in men is associated with an increased risk of early onset PDAC (<age 50). Overweight and obese individuals were less likely to undergo curative surgery and obese individuals had a higher risk of cancer-related death.

• Saaed, Usman; Myklebust, Tor Åge; Robsahm, Trude Eid; Kielland, Marlene Fritsch; Møller, Bjørn & Skålhegg, Bjørn Steen [Show all 8 contributors for this article] (2022). Risk and survival in colorectal cancer with increasing body mass index: A nationwide population-based cohort study. Colorectal Disease. ISSN 1462-8910. p. 1–11. doi: 10.1111/codi.16367. Full text in Research Archive Show summary

  Aim: The aim was to explore potential associations between the body mass index (BMI) and the risk of colorectal cancer (CRC), including subsites of the colon, and cancer-specific death. Methods: A registry-based cohort study was conducted with baseline data gathered from the Norwegian Tuberculosis Screening Programme, collected between 1963 and 1975, and linked to follow-up data from the Cancer Registry of Norway and the Norwegian Cause of Death Registry. Cox regression models were used to explore associations between BMI and CRC risk and cancer-specific death. Results: Of 1 723 692 included individuals, 76 616 developed CRC during 55 370 707 person-years of follow-up. In men, a 5 kg/m2 increase in BMI was associated with an increased risk of colon cancer, including both right and left subsites, and rectal cancer. Allowing for nonlinearities, we found a U-shaped association for the right colon and an inverse U-shape for the left colon and rectum cancer. In women, a 5 kg/m2 increase in BMI in early adulthood was associated with increased risk of colon cancer, including both subsites. In women, an increased risk of CRC death with increasing BMI was found for colon cancer. Conclusions: Men of all ages have an increased risk of CRC with increasing BMI, with the highest risk for right-sided colon cancer. An increased risk for colon cancer was also found in women with high BMI in early adulthood. Furthermore, women of all age groups appeared to have an increased risk of CRC death with higher BMI.

• Kolan, Shrikant; Li, Gaoyang; Grimolizzi, Franco; Sexton, Joseph; Kvien, Tore Kristian & Goll, Guro Løvik [Show all 11 contributors for this article] (2022). Identification of SNPs associated with methotrexate treatment outcomes in patients with early rheumatoid arthritis. Frontiers in Pharmacology. 13. doi: 10.3389/fphar.2022.1075603. Full text in Research Archive Show summary

  Methotrexate is one of the cornerstones of rheumatoid arthritis (RA) therapy. Genetic factors or single nucleotide polymorphisms (SNPs) are responsible for 15%–30% of the variation in drug response. Identification of clinically effective SNP biomarkers for predicting methotrexate (MTX) sensitivity has been a challenge. The aim of this study was to explore the association between the disease related outcome of MTX treatment and 23 SNPs in 8 genes of the MTX pathway, as well as one pro-inflammatory related gene in RA patients naïve to MTX. Categorical outcomes such as Disease Activity Score (DAS)-based European Alliance of Associations for Rheumatology (EULAR) non-response at 4 months, The American College of Rheumatology and EULAR (ACR/EULAR) non-remission at 6 months, and failure to sustain MTX monotherapy from 12 to 24 months were assessed, together with continuous outcomes of disease activity, joint pain and fatigue. We found that the SNPs rs1801394 in the MTRR gene, rs408626 in DHFR gene, and rs2259571 in AIF-1 gene were significantly associated with disease activity relevant continuous outcomes. Additionally, SNP rs1801133 in the MTHFR gene was identified to be associated with improved fatigue. Moreover, associations with p values at uncorrected significance level were found in SNPs and different categorical outcomes: 1) rs1476413 in the MTHFR gene and rs3784864 in ABCC1 gene are associated with ACR/EULAR non-remission; 2) rs1801133 in the MTHFR gene is associated with EULAR response; 3) rs246240 in the ABCC1 gene, rs2259571 in the AIF-1 gene, rs2274808 in the SLC19A1 gene and rs1476413 in the MTHFR gene are associated with failure to MTX monotherapy after 12–24 months. The results suggest that SNPs in genes associated with MTX activity may be used to predict MTX relevant-clinical outcomes in patients with RA.

• Wik, Jonas Aakre & Skålhegg, Bjørn Steen (2022). T Cell Metabolism in Infection. Frontiers in Immunology. 13, p. 1–17. doi: 10.3389/fimmu.2022.840610. Full text in Research Archive Show summary

  T lymphocytes (T cells) are divided into two functionally different subgroups the CD4+ T helper cells (Th) and the CD8+ cytotoxic T lymphocytes (CTL). Adequate CD4 and CD8 T cell activation to proliferation, clonal expansion and effector function is crucial for efficient clearance of infection by pathogens. Failure to do so may lead to T cell exhaustion. Upon activation by antigen presenting cells, T cells undergo metabolic reprograming that support effector functions. In this review we will discuss how metabolic reprograming dictates functionality during viral infections using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human immunodeficiency virus (HIV) as examples. Moreover, we will briefly discuss T cell metabolic programs during bacterial infections exemplified by Mycobacterium tuberculosis (MT) infection.

• Pfabigan, Daniela Melitta; Frogner, Erik Rimestad; Erik, Schéle; Thorsby, Per Medbøe; Skålhegg, Bjørn Steen & Dickson, Suzanne L. [Show all 7 contributors for this article] (2022). The “hunger” hormone ghrelin is associated with neural activation during touch, but not its affective experience. BioRxiv. ISSN 0362-4331. doi: 10.1101/2022.05.10.491384. Full text in Research Archive
• Taylor, Susan S.; Wallbott, Maximillian; Machal, Erik F; Søberg, Kristoffer; Ahmed, Faihaa & Bruystens, Jessica [Show all 13 contributors for this article] (2021). PKA Cβ: a forgotten catalytic subunit of cAMP-dependent protein kinase opens new windows for PKA signaling and disease pathologies. Biochemical Journal. ISSN 0264-6021. 478, p. 2101–2119. doi: 10.1042/BCJ20200867. Full text in Research Archive Show summary

  3',5'-cyclic adenosine monophosphate (cAMP) dependent protein kinase or protein kinase A (PKA) has served as a prototype for the large family of protein kinases that are crucially important for signal transduction in eukaryotic cells. The PKA catalytic subunits are encoded by the two major genes PRKACA and PRKACB, respectively. The PRKACA gene encodes two known splice variants, the ubiquitously expressed Cα1 and the sperm-specifically expressed Cα2. In contrast, the PRKACB gene encodes several splice variants expressed in a highly cell and tissue-specific manner. The Cβ proteins are called Cβ1, Cβ2, Cβ3, Cβ4 and so-called abc variants of Cβ3 and Cβ4. Whereas Cβ1 is ubiquitously expressed, Cβ2 is enriched in immune cells and the Cβ3, Cβ4 and their abc variants are solely expressed in neuronal cells. All Cα and Cβ splice variants share a kinase-conserved catalytic core and a C-terminal tail encoded by exons 2 through 10 in the PRKACA and PRKACB genes, respectively. All Cα and Cβ splice variants with the exception of Cα1 and Cβ1 are hyper-variable at the N-terminus. Here, we will discuss how the PRKACA and PRKACB genes have developed as paralogs that encode distinct and functionally non-redundant proteins. The fact that Cα and Cβ splice variant mutations are associated with numerous diseases further opens new windows for PKA-induced disease pathologies.

• Wik, Jonas Aakre; Phung, Danh; Kolan, Shrikant; Haraldsen, Guttorm; Skålhegg, Bjørn Steen & Fosse, Johanna Hol (2021). Inflammatory activation of endothelial cells increases glycolysis and oxygen consumption despite inhibiting cell proliferation. FEBS Open Bio. 11(6), p. 1719–1730. doi: 10.1002/2211-5463.13174. Full text in Research Archive Show summary

  Endothelial cell function and metabolism are closely linked to differential use of energy substrate sources and combustion. While endothelial cell migration is promoted by 2-phosphofructokinase-6/fructose-2,6-bisphosphatase (PFKFB3)-driven glycolysis, proliferation also depends on fatty acid oxidation for dNTP synthesis. We show that inflammatory activation of human umbilical vein endothelial cells (HUVECs) by interleukin-1β (IL-1β), despite inhibiting proliferation, promotes a shift toward more metabolically active phenotype. This was reflected in increased cellular glucose uptake and consumption, which was preceded by an increase in PFKFB3 mRNA and protein expression. However, despite a modest increase in extracellular acidification rates, the increase in glycolysis did not correlate with extracellular lactate accumulation. Accordingly, IL-1β stimulation also increased oxygen consumption rate, but without a concomitant rise in fatty acid oxidation. Together, this suggests that the IL-1β-stimulated energy shift is driven by shunting of glucose-derived pyruvate into mitochondria to maintain elevated oxygen consumption in HUVECs. We also revealed a marked donor-dependent variation in the amplitude of the metabolic response to IL-1β and postulate that the donor-specific response should be taken into account when considering targeting dysregulated endothelial cell metabolism.

• Wendel, Kristina; Pfeiffer, Helle Cecilie; Fugelseth, Drude; Nestaas, Eirik; Domellöf, Magnus & Skålhegg, Bjørn Steen [Show all 42 contributors for this article] (2021). Effects of nutrition therapy on growth, inflammation and metabolism in immature infants: a study protocol of a double-blind randomized controlled trial (ImNuT). BMC Pediatrics. 21. doi: 10.1186/s12887-020-02425-x. Full text in Research Archive Show summary

  Background: Current nutritional management of infants born very preterm results in significant deficiency of the essential fatty acids (FAs) arachidonic acid (ARA) and docosahexaenoic acid (DHA). The impact of this deficit on brain maturation and inflammation mediated neonatal morbidities are unknown. The aim of this study is to determine whether early supply of ARA and DHA improves brain maturation and neonatal outcomes in infants born before 29 weeks of gestation. Methods: Infants born at Oslo University Hospital are eligible to participate in this double-blind randomized controlled trial. Study participants are randomized to receive an enteral FA supplement of either 0.4 ml/kg MCT-oil™ (medium chain triglycerides) or 0.4 ml/kg Formulaid™ (100 mg/kg of ARA and 50 mg/kg of DHA). The FA supplement is given from the second day of life to 36 weeks' postmenstrual age (PMA). The primary outcome is brain maturation assessed by Magnetic Resonance Imaging (MRI) at term equivalent age. Secondary outcomes include quality of growth, incidence of neonatal morbidities, cardiovascular health and neuro-development. Target sample size is 120 infants (60 per group), this will provide 80% power to detect a 0.04 difference in mean diffusivity (MD, mm2/sec) in major white matter tracts on MRI. Discussion: Supplementation of ARA and DHA has the potential to improve brain maturation and reduce inflammation related diseases. This study is expected to provide valuable information for future nutritional guidelines for preterm infants. Trial registration: Clinicaltrials.gov ID: NCT03555019 . Registered 4 October 2018- Retrospectively registered.

• Richartz, Nina; Pietka, Wojciech; Gilljam, Karin Margaretha; Skah, Seham; Skålhegg, Bjørn Steen & Bhagwat, Sampada [Show all 9 contributors for this article] (2021). cAMP-Mediated Autophagy Promotes Cell Survival via ROS-Induced Activation of PARP1: Implications for Treatment of Acute Lymphoblastic Leukemia. Molecular Cancer Research. ISSN 1541-7786. doi: 10.1158/1541-7786.MCR-21-0652. Full text in Research Archive
• Taylor, Susan S.; Søberg, Kristoffer; Kobori, Evan; Wu, Jian; Pautz, Sabine & Herberg, Friedrich W. [Show all 7 contributors for this article] (2021). The tails of PKA. Molecular Pharmacology. ISSN 0026-895X. 101(4), p. 219–225. doi: 10.1124/molpharm.121.000315. Full text in Research Archive
• Cederkvist, Fritjof Henning; Kolan, Shrikant; Wik, Jonas Aakre; Sener, Zeynep & Skålhegg, Bjørn Steen (2021). Identification and characterization of a novel glutaminase inhibitor. FEBS Open Bio. 12(1), p. 163–174. doi: 10.1002/2211-5463.13319. Full text in Research Archive Show summary

  In humans, there are two forms of glutaminase (GLS), designated GLS1 and GLS2. These enzymes catalyse the conversion of glutamine to glutamate. GLS1 exists as two isozymes: kidney glutaminase (KGA) and glutaminase C (GAC). Several GLS inhibitors have been identified, of which DON (6-diazo-5-oxonorleucine), BPTES (bis-2-(5-phenylacetamido-1, 3, 4-thiadiazol-2-yl) ethyl sulphide), 968 (5-(3-Bromo-4-(dimethylamino)phenyl)-2,2-dimethyl-2,3,5,6-tetrahydrobenzo[a]phenanthridin-4(1H)-one) and CB839 (Telaglenastat) are the most widely used. However, these inhibitors have variable efficacy, specificity and bioavailability in research and clinical settings, implying the need for novel and improved GLS inhibitors. Based on this need, a diverse library of 28,000 compounds from Enamine was screened for inhibition of recombinant, purified GAC. From this library, one inhibitor designated compound 19 (C19) was identified with kinetic features revealing allosteric inhibition of GAC in the µm range. Moreover, C19 inhibits anti-CD3/CD28-induced CD4+ T-cell proliferation and cytokine production with similar or greater potency as compared to BPTES. Taken together, our data suggest that C19 has the potential to modulate GLS1 activity and alter metabolic activity of T cells.

• Li, Gaoyang; Kolan, Shrikant; Guo, Shuai; Marciniak, Katarzyna; Kolan, Pratibha Shrikant & Malachin, Giulia [Show all 9 contributors for this article] (2021). Activated, Pro-Inflammatory Th1, Th17, and Memory CD4+ T Cells and B Cells Are Involved in Delayed-Type Hypersensitivity Arthritis (DTHA) Inflammation and Paw Swelling in Mice. Frontiers in Immunology. 12, p. 1–15. doi: 10.3389/fimmu.2021.689057. Full text in Research Archive Show summary

  Delayed-type hypersensitivity arthritis (DTHA) is a recently established experimental model of rheumatoid arthritis (RA) in mice with pharmacological values. Despite an indispensable role of CD4+ T cells in inducing DTHA, a potential role for CD4+ T cell subsets is lacking. Here we have quantified CD4+ subsets during DTHA development and found that levels of activated, pro-inflammatory Th1, Th17, and memory CD4+ T cells in draining lymph nodes were increased with differential dynamic patterns after DTHA induction. Moreover, according to B-cell depletion experiments, it has been suggested that this cell type is not involved in DTHA. We show that DTHA is associated with increased levels of B cells in draining lymph nodes accompanied by increased levels of circulating IgG. Finally, using the anti-rheumatoid agents, methotrexate (MTX) and the anti-inflammatory drug dexamethasone (DEX), we show that MTX and DEX differentially suppressed DTHA-induced paw swelling and inflammation. The effects of MTX and DEX coincided with differential regulation of levels of Th1, Th17, and memory T cells as well as B cells. Our results implicate Th1, Th17, and memory T cells, together with activated B cells, to be involved and required for DTHA-induced paw swelling and inflammation.

• Palencia-Campos, Adrian; Aoto, Phillip C.; Machal, Erik M.F.; Rivera-Barahona, Ana; Soto-Bielicka, Patricia & Bertinetti, Daniela [Show all 42 contributors for this article] (2020). Germline and mosaic variants in PRKACA and PRKACB cause a multiple congenital malformation syndrome. American Journal of Human Genetics. ISSN 0002-9297. 107(5), p. 977–988. doi: 10.1016/j.ajhg.2020.09.005. Full text in Research Archive
• Kolan, Shrikant Shantilal; Li, Gaoyang; Wik, Jonas Aakre; Malachin, Giulia; Guo, Shuai & Kolan, Pratibha [Show all 7 contributors for this article] (2020). Cellular metabolism dictates T cell effector function in health and disease. Scandinavian Journal of Immunology. ISSN 0300-9475. 92(5). doi: 10.1111/sji.12956. Full text in Research Archive
• Dahl, Marius; Areta, José; Jeppesen, Per Bendix; Birk, Jesper B.; Johansen, Egil Ivar & Ingemann-Hansen, Thorsten [Show all 12 contributors for this article] (2020). Coingestion of protein and carbohydrate in the early recovery phase, compared with carbohydrate only, improves endurance performance despite similar glycogen degradation and AMPK phosphorylation. Journal of applied physiology. ISSN 8750-7587. 129(2), p. 297–310. doi: 10.1152/japplphysiol.00817.2019. Full text in Research Archive Show summary

  The present study compared the effects of postexercise carbohydrate plus protein (CHO+PROT) and carbohydrate (CHO)-only supplementation on muscle glycogen metabolism, anabolic cell signaling, and subsequent exercise performance. Nine endurance-trained males cycled twice to exhaustion (muscle glycogen decreased from ~495 to ~125 mmol/kg dry wt) and received either CHO only (1.2 g·kg−1·h−1) or CHO+PROT (0.8/0.4 g·kg−1·h−1) during the first 90 min of recovery. Glycogen content was similar before the performance test after 5 h of recovery. Glycogen synthase (GS) fractional activity increased after exhaustive exercise and remained activated 5 h after, despite substantial glycogen synthesis (176.1 ± 19.1 and 204.6 ± 27.0 mmol/kg dry wt in CHO and CHO+PROT, respectively; P = 0.15). Phosphorylation of GS at site 3 and site 2+2a remained low during recovery. After the 5-h recovery, cycling time to exhaustion was improved by CHO+PROT supplementation compared with CHO supplementation (54.6 ± 11.0 vs. 46.1 ± 9.8 min; P = 0.009). After the performance test, muscle glycogen was equally reduced in CHO+PROT and CHO. Akt Ser473 and p70s6k Thr389 phosphorylation was elevated after 5 h of recovery. There were no differences in Akt Ser473, p70s6k Thr389, or TSC2 Thr1462 phosphorylation between treatments. Nitrogen balance was positive in CHO+PROT (19.6 ± 7.6 mg nitrogen/kg; P = 0.04) and higher than CHO (−10.7 ± 6.3 mg nitrogen/kg; P = 0.009). CHO+PROT supplementation during exercise recovery improved subsequent endurance performance relative to consuming CHO only. This improved performance after CHO+PROT supplementation could not be accounted for by differences in glycogen metabolism or anabolic cell signaling, but may have been related to differences in nitrogen balance.

• Wik, Jonas Aakre; Lundbäck, Peter; Poulsen, Lars La Cour; Haraldsen, Guttorm; Skålhegg, Bjørn Steen & Hol, Johanna (2020). 3PO inhibits inflammatory NFκB and stress-activated kinase signaling in primary human endothelial cells independently of its target PFKFB3. PLOS ONE. 15:e0229395(3), p. 1–18. doi: 10.1371/journal.pone.0229395. Full text in Research Archive Show summary

  Inhibition of the key glycolytic activator 6-phosphofructokinase 2/fructose-2,6-bisphosphatase-3 (PFKFB3) by 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) strongly attenuates pathological angiogenesis in cancer and inflammation. In addition to modulating endothelial proliferation and migration, 3PO also dampens proinflammatory activation of endothelial cells and experimental inflammation in vivo, suggesting a potential for 3PO in the treatment of chronic inflammation. The aim of our study was to explore if the anti-inflammatory action of 3PO in human endothelial cells was mediated by inhibition of PFKFB3 and glycolysis and assess if other means of PFKFB3 inhibition reduced inflammatory activation in a similar manner. We found that 3PO caused a rapid and transient reduction in IL-1β- and TNF-induced phosphorylation of both IKKα/β and JNK, thus inhibiting signaling through the NFκB and the stress-activated kinase pathways. However, in contrast to 3PO-treatment, neither shRNA-mediated silencing of PFKFB3 nor treatment with the alternative PFKFB3 inhibitor 7,8-dihydroxy-3-(4-hydroxy-phenyl)-chromen-4-one (YN1) prevented cytokine-induced NFκB signaling and upregulation of the adhesion molecules VCAM-1 and E-selectin, implying off target effects of 3PO. Collectively, our results suggest that the anti-inflammatory action of 3PO in human endothelial cells is not limited to inhibition of PFKFB3 and cellular glycolysis.

• Kolan, Shrikant Shantilal; Li, Gaoyang; Wik, Jonas Aakre; Malachin, Giulia; Guo, Shuai & Kolan, Pratibha [Show all 7 contributors for this article] (2020). Cellular metabolism dictates T cell effector function in health and disease. Scandinavian Journal of Immunology. ISSN 0300-9475. 92(5). doi: 10.1111/sji.12956. Full text in Research Archive Show summary

  In a healthy person, metabolically quiescent T lymphocytes (T cells) circulate between lymph nodes and peripheral tissues in search of antigens. Upon infection, some T cells will encounter cognate antigens followed by proliferation and clonal expansion in a context‐dependent manner, to become effector T cells. These events are accompanied by changes in cellular metabolism, known as metabolic reprogramming. The magnitude and variation of metabolic reprogramming are, in addition to antigens, dependent on factors such as nutrients and oxygen to ensure host survival during various diseases. Herein, we describe how metabolic programmes define T cell subset identity and effector functions. In addition, we will discuss how metabolic programs can be modulated and affect T cell activity in health and disease using cancer and autoimmunity as examples.

• Volchenkov, Roman; Matthews, Jason; Zucknick, Manuela & Skålhegg, Bjørn Steen (2019). Shared epitope is associated with the reactivity of Th17 cells to cigarette smoke extract regardless of smoking history. Cellular & Molecular Immunology. ISSN 1672-7681. 16(7), p. 674–675. doi: 10.1038/s41423-019-0230-4. Full text in Research Archive
• Søberg, Kristoffer & Skålhegg, Bjørn Steen (2018). The molecular basis for specificity at the level of the protein kinase a catalytic subunit. Frontiers in Endocrinology. 9(538), p. 1–22. doi: 10.3389/fendo.2018.00538. Full text in Research Archive Show summary

  Assembly of multi enzyme complexes at subcellular localizations by anchoring- and scaffolding proteins represents a pivotal mechanism for achieving spatiotemporal regulation of cellular signaling after hormone receptor targeting [for review, see (1)]. In the 3′ 5′-cyclic adenosine monophosphate (cAMP) dependent protein kinase (PKA) signaling pathway it is generally accepted that specificity is secured at several levels. This includes at the first level stimulation of receptors coupled to heterotrimeric G proteins which through stimulation of adenylyl cyclase (AC) forms the second messenger cAMP. Cyclic AMP has several receptors including PKA. PKA is a tetrameric holoenzyme consisting of a regulatory (R) subunit dimer and two catalytic (C) subunits. The R subunit is the receptor for cAMP and compartmentalizes cAMP signals through binding to cell and tissue-specifically expressed A kinase anchoring proteins (AKAPs). The current dogma tells that in the presence of cAMP, PKA dissociates into an R subunit dimer and two C subunits which are free to phosphorylate relevant substrates in the cytosol and nucleus. The release of the C subunit has raised the question how specificity of the cAMP and PKA signaling pathway is maintained when the C subunit no longer is attached to the R subunit-AKAP complex. An increasing body of evidence points toward a regulatory role of the cAMP and PKA signaling pathway by targeting the C subunits to various C subunit binding proteins in the cytosol and nucleus. Moreover, recent identification of isoform specific amino acid sequences, motifs and three dimensional structures have together provided new insight into how PKA at the level of the C subunit may act in a highly isoform-specific fashion. Here we discuss recent understanding of specificity of the cAMP and PKA signaling pathway based on C subunit subcellular targeting as well as evolution of the C subunit structure that may contribute to the dynamic regulation of C subunit activity.

• Skålhegg, Bjørn Steen & Holm, Halvor (2018). Kollagen som vidunderkur mot underernæring,rynker og leddplager – myte eller virkelighet? Norsk tidsskrift for ernæring (NTFE). ISSN 1503-5034. p. 22–26. Full text in Research Archive
• Sollie, Ove; Jeppesen, Per Bendix; Tangen, Daniel S.; Jernerén, Fredrik; Nellemann, Birgitte & Valsdottir, Thorhildur [Show all 12 contributors for this article] (2018). Protein intake in the early recovery period after exhaustive exercise improves performance the following day. Journal of applied physiology. ISSN 8750-7587. 125(6), p. 1731–1742. doi: 10.1152/japplphysiol.01132.2017. Full text in Research Archive Show summary

  The aim of the present study was to investigate the effect of protein and carbohydrate ingestion during early recovery from exhaustive exercise on performance after 18-h recovery. Eight elite cyclists (V̇o2max: 74.0 ± 1.6 ml·kg−1·min−1) completed two exercise and diet interventions in a double-blinded, randomized, crossover design. Participants cycled first at 73% of V̇o2max (W73%) followed by 1-min intervals at 90% of V̇o2max until exhaustion. During the first 2 h of recovery, participants ingested either 1.2 g carbohydrate·kg−1·h−1 (CHO) or 0.8 g carbohydrate + 0.4 g protein·kg−1·h−1 (CHO + PROT). The diet during the remaining recovery period was similar for both interventions and adjusted to body weight. After an 18-h recovery, cycling performance was assessed with a 10-s sprint test, 30 min of cycling at W73%, and a cycling time trial (TT). The TT was 8.5% faster (41:53 ± 1:51 vs. 45:26 ± 1:32 min; P < 0.03) after CHO + PROT compared with CHO. Mean power output during the sprints was 3.7% higher in CHO + PROT compared with CHO (1,063 ± 54 vs. 1,026 ± 53 W; P = 0.01). Nitrogen balance in the recovery period was negative in CHO and neutral in CHO + PROT (−82.4 ± 11.5 vs. 7.0 ± 15.4 mg/kg; P < 0.01). In conclusion, TT and sprint performances were improved 18 h after exhaustive cycling by CHO + PROT supplementation during the first 2 h of recovery compared with isoenergetic CHO supplementation. Our results indicate that intake of carbohydrate plus protein after exhaustive endurance exercise more rapidly converts the body from a catabolic to an anabolic state than carbohydrate alone, thus speeding recovery and improving subsequent cycling performance.

• Gjevestad, Gyrd Omholt; Ottestad, Inger; Biong, Anne Sofie; Iversen, Per Ole; Retterstøl, Kjetil & Raastad, Truls [Show all 9 contributors for this article] (2017). Consumption of protein-enriched milk has minor effects on inflammation in older adults?A 12-week double-blind randomized controlled trial. Mechanisms of Ageing and Development. ISSN 0047-6374. 162, p. 1–8. doi: 10.1016/j.mad.2017.01.011. Full text in Research Archive Show summary

  Introduction: Aging is associated with increased levels of circulating inflammatory markers and reduced muscle mass and strength. Objective: We investigated whether intake of protein-enriched milk for 12 weeks would influence markers of inflammation among adults ≥70 years of age with reduced physical strength. Methods: In a double-blind randomized controlled intervention study, subjects were randomly allocated into two groups, receiving a protein-enriched milk (2 × 20 g protein/d, n = 14, mean (±SD) age 76.9 ± 4.9 yrs) or an isocaloric carbohydrate drink (n = 17, age 77.7 ± 4.8 yrs) for 12 weeks. We measured serum and mRNA expression levels of inflammatory markers in PBMCs. Results: Significant differences in the mRNA expression of nuclear receptor subfamily, group H, member 3 (NR1H3, encoding the LXRα transcription factor) and interferon gamma (INFG) were observed between groups. The mRNA level of TNFRSF1A was significantly reduced, while the mRNA level of dipeptidyl-peptidase 4 (DPP4) was significantly increased, in the control group. The serum level of TNFα increased significantly in the control group, while sTNFRSF1A increased significantly in both groups, but with no significant differences between groups. Conclusion: Consumption of a low-fat, protein-enriched milk for 12 weeks had minor effects on inflammatory related markers in older adults compared to an isocaloric carbohydrate drink.

• Søberg, Kristoffer; Moen, Line Victoria; Skålhegg, Bjørn Steen & Lærdahl, Jon Kristen (2017). Evolution of the cAMP-dependent protein kinase (PKA) catalytic subunit isoforms. PLOS ONE. 12(7). doi: 10.1371/journal.pone.0181091. Full text in Research Archive Show summary

  The 3’,5’-cyclic adenosine monophosphate (cAMP)-dependent protein kinase, or protein kinase A (PKA), pathway is one of the most versatile and best studied signaling pathways in eukaryotic cells. The two paralogous PKA catalytic subunits Cα and Cβ, encoded by the genes PRKACA and PRKACB, respectively, are among the best understood model kinases in signal transduction research. In this work, we explore and elucidate the evolution of the alternative 5’ exons and the splicing pattern giving rise to the numerous PKA catalytic subunit isoforms. In addition to the universally conserved Cα1/Cβ1 isoforms, we find kinase variants with short N-termini in all main vertebrate classes, including the sperm-specific Cα2 isoform found to be conserved in all mammals. We also describe, for the first time, a PKA Cα isoform with a long N-terminus, paralogous to the PKA Cβ2 N-terminus. An analysis of isoform-specific variation highlights residues and motifs that are likely to be of functional importance.

• Stakkestad, Øystein; Lyngstadaas, Ståle Petter; Thiede, Bernd; Vondrasesek, Jiri; Skålhegg, Bjørn Steen & Reseland, Janne Elin (2017). Phosphorylation Modulates Ameloblastin Self-assembly and Ca2+ Binding. Frontiers in Physiology. 8. doi: 10.3389/fphys.2017.00531. Full text in Research Archive Show summary

  Ameloblastin (AMBN), an important component of the self-assembled enamel extra cellular matrix, contains several in silico predicted phosphorylation sites. However, to what extent these sites actually are phosphorylated and the possible effects of such post-translational modifications are still largely unknown. Here we report on in vitro experiments aimed at investigating what sites in AMBN are phosphorylated by casein kinase 2 (CK2) and protein kinase A (PKA) and the impact such phosphorylation has on self-assembly and calcium binding. All predicted sites in AMBN can be phosphorylated by CK2 and/or PKA. The experiments show that phosphorylation, especially in the exon 5 derived part of the molecule, is inversely correlated with AMBN self-assembly. These results support earlier findings suggesting that AMBN self-assembly is mostly dependent on the exon 5 encoded region of the AMBN gene. Phosphorylation was significantly more efficient when the AMBN molecules were in solution and not present as supramolecular assemblies, suggesting that post-translational modification of AMBN must take place before the enamel matrix molecules self-assemble inside the ameloblast cell. Moreover, phosphorylation of exon 5, and the consequent reduction in self-assembly, seem to reduce the calcium binding capacity of AMBN suggesting that post-translational modification of AMBN also can be involved in control of free Ca2+ during enamel extra cellular matrix biomineralization. Finally, it is speculated that phosphorylation can provide a functional crossroad for AMBN either to be phosphorylated and act as monomeric signal molecule during early odontogenesis and bone formation, or escape phosphorylation to be subsequently secreted as supramolecular assemblies that partake in enamel matrix structure and mineralization.

• Moen, Line Victoria; Sener, Zeynep; Volchenkov, Roman; Larsen, Anja C V; Eriksen, Aud Marit & Holen, Halvor [Show all 7 contributors for this article] (2017). Ablation of the C?2 subunit of PKA in immune cells leads to increased susceptibility to systemic inflammation in mice. European Journal of Immunology. ISSN 0014-2980. 47(11), p. 1880–1889. doi: 10.1002/eji.201646809. Full text in Research Archive
• Moen, Line Victoria; Ramberg, Håkon Andre; Zhao, Sen; Grytli, Helene Hartvedt; Sveen, Anita & Berge, Viktor [Show all 9 contributors for this article] (2017). Observed correlation between the expression levels of catalytic subunit, C?2, of cyclic adenosine monophosphate-dependent protein kinase and prostate cancer aggressiveness. Urologic Oncology. ISSN 1078-1439. 35(3), p. 111.e1–111.e8. doi: 10.1016/j.urolonc.2016.10.002. Full text in Research Archive Show summary

  Background As an intracellular human pathogen, Mycobacterium tuberculosis (Mtb) is facing multiple stressful stimuli inside the macrophage and the granuloma. Understanding Mtb responses to stress is essential to identify new virulence factors and pathways that play a role in the survival of the tubercle bacillus. The main goal of this study was to map the regulatory networks of differentially expressed (DE) transcripts in Mtb upon various forms of genotoxic stress. We exposed Mtb cells to oxidative (H2O2 or paraquat), nitrosative (DETA/NO), or alkylation (MNNG) stress or mitomycin C, inducing double-strand breaks in the DNA. Total RNA was isolated from treated and untreated cells and subjected to high-throughput deep sequencing. The data generated was analysed to identify DE genes encoding mRNAs, non-coding RNAs (ncRNAs), and the genes potentially targeted by ncRNAs. Results The most significant transcriptomic alteration with more than 700 DE genes was seen under nitrosative stress. In addition to genes that belong to the replication, recombination and repair (3R) group, mainly found under mitomycin C stress, we identified DE genes important for bacterial virulence and survival, such as genes of the type VII secretion system (T7SS) and the proline-glutamic acid/proline-proline-glutamic acid (PE/PPE) family. By predicting the structures of hypothetical proteins (HPs) encoded by DE genes, we found that some of these HPs might be involved in mycobacterial genome maintenance. We also applied a state-of-the-art method to predict potential target genes of the identified ncRNAs and found that some of these could regulate several genes that might be directly involved in the response to genotoxic stress. Conclusions Our study reflects the complexity of the response of Mtb in handling genotoxic stress. In addition to genes involved in genome maintenance, other potential key players, such as the members of the T7SS and PE/PPE gene family, were identified. This plethora of responses is detected not only at the level of DE genes encoding mRNAs but also at the level of ncRNAs and their potential targets.

• Volchenkov, Roman; Nygaard, Vegard; Sener, Zeynep & Skålhegg, Bjørn Steen (2017). Th17 polarization under hypoxia results in increased IL-10 production in a pathogen-independent manner. Frontiers in Immunology. 8. doi: 10.3389/fimmu.2017.00698. Full text in Research Archive
• Sener, Zeynep; Cederkvist, Fritjof Henning; Volchenkov, Roman; Holen, Halvor Laustad & Skålhegg, Bjørn Steen (2016). T helper cell activation and expansion is sensitive to glutaminase inhibition under both hypoxic and normoxic conditions. PLOS ONE. 11(7). doi: 10.1371/journal.pone.0160291. Full text in Research Archive
• Hereng, Tuva Holt; Elgstøen, Katja B. Prestø; Eide, Lars; Rosendal, Ken Roger & Skålhegg, Bjørn Steen (2014). Serum albumin and HCO&lt;sub&gt;3&lt;/sub&gt;&lt;sup&gt;-&lt;/sup&gt; regulate separate pools of ATP in human spermatozoa. Human Reproduction. ISSN 0268-1161. 29(5), p. 918–930. doi: 10.1093/humrep/deu028. Full text in Research Archive
• Søberg, Kristoffer; Jahnsen, Tore; Rognes, Torbjørn; Skålhegg, Bjørn Steen & Lærdahl, Jon Kristen (2013). Evolutionary Paths of the cAMP-Dependent Protein Kinase (PKA) Catalytic Subunits. PLOS ONE. 8(4). doi: 10.1371/journal.pone.0060935. Full text in Research Archive Show summary

  3',5'-cyclic adenosine monophosphate (cAMP) dependent protein kinase or protein kinase A (PKA) has served as a prototype for the large family of protein kinases that are crucially important for signal transduction in eukaryotic cells. The PKA catalytic subunits Ca and Cß, encoded by the two genes PRKACA and PRKACB, respectively, are among the best understood and characterized human kinases. Here we have studied the evolution of this gene family in chordates, arthropods, mollusks and other animals employing probabilistic methods and show that Ca and Cß arose by duplication of an ancestral PKA catalytic subunit in a common ancestor of vertebrates. The two genes have subsequently been duplicated in teleost fishes. The evolution of the PRKACG retroposon in simians was also investigated. Although the degree of sequence conservation in the PKA Ca/Cß kinase family is exceptionally high, a small set of signature residues defining Ca and Cß subfamilies were identified. These conserved residues might be important for functions that are unique to the Ca or Cß clades. This study also provides a good example of a seemingly simple phylogenetic problem which, due to a very high degree of sequence conservation and corresponding weak phylogenetic signals, combined with problematic nonphylogenetic signals, is nontrivial for state-of-the-art probabilistic phylogenetic methods. Copyright: 2013 Søberg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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• Skålhegg, Bjørn Steen (2025). Mat og Medisin. 8 utgave. Kapittel 9 B vitaminer. Cappelen Damm Akademisk. ISBN 9788202846756. 23 p. Full text in Research Archive
• Skålhegg, Bjørn Steen (2025). Mat og Medisin. 8. utgave Kapittel6, Protein. Cappelen Damm Akademisk. ISBN 9788202846756. 21 p. Full text in Research Archive
• Skålhegg, Bjørn Steen (2025). Mat og medisin 8. utgave, kapittel 4 Energi og appetittregulering. Cappelen Damm Akademisk. ISBN 9788202846756. 26 p. Full text in Research Archive

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• Skålhegg, Bjørn Steen (2025). Endokrine og nevrale sult- og metthetsmekanismer. Hvordan endres de med alderen, og hvilken rolle spiller de ved underernæring? Full text in Research Archive
• Clauss, Matthieu; Puissant, Clair; Bastani, Nasser Ezzatkhah; Nielsen, Lotte L. K.; Skålhegg, Bjørn Steen & Jeppesen, Per Bendix [Show all 7 contributors for this article] (2025). Effect of high intakes of protein-only and carbohydrate-only on plasma metabolites and hormones, in addition to nitrogen excretion. doi: 10.1007/978-1-0716-4414-0_16. Full text in Research Archive
• Skålhegg, Bjørn Steen (2025). Can profiles of plasma amino acids and derivatives in patients with PDAC be used to predict overall survival? Full text in Research Archive
• Wik, Jonas Aakre; Strømsnes, Kristine Bakklund & Skålhegg, Bjørn Steen (2025). Using Seahorse technology as an efficient way of verifying T-cell stimulation. Methods in molecular biology. ISSN 1064-3745. doi: 10.1007/978-1-0716-4414-0_16. Full text in Research Archive
• Skålhegg, Bjørn Steen (2024). NUTRITION AND IMMUNITY: INDIVIDUAL VARIATION IN RESPONSE. Full text in Research Archive
• Skålhegg, Bjørn Steen (2024). Nutrition and Pancreatic Cancer.. Food Matters. Full text in Research Archive
• Clauss, Matthieu; Burkhardt, Meike; Wöber, Sophie; Skålhegg, Bjørn Steen & Jensen, Jørgen (2024). Corrigendum: Effect of five hours of mixed exercise on urinary nitrogen excretion in healthy moderate-to-well-trained young adults, (Front. Nutr, (2024), 11, (1345922), 10.3389/fnut.2024.1345922). Frontiers in Nutrition. 11. doi: 10.3389/fnut.2024.1406641. Full text in Research Archive
• Stålberg, Stina Margrethe; Silwat-Pandit, Laxmi; Hamfjord, Julian; Nebdal, Daniel JH; Lehtiö, Janne & Skålhegg, Bjørn Steen [Show all 7 contributors for this article] (2023). Elevated protein expression levels of KRAS in Pancreatic Ductal Adenocarcinoma (PDAC) are associated with better prognosis. Full text in Research Archive
• Guo, Shuai; Kolan, Shrikant Shantilal; Li, Gaoyang; Hammarstrøm, Clara L; Aure, Miriam Ragle & Stuhr, Linda Elin Birkhaug [Show all 8 contributors for this article] (2023). Ablation of PKA-Cβ2 subunit in mice curtails progression of breast adenocarcinoma and turns "cold" tumor "hot". Full text in Research Archive
• Stålberg, Stina Margrethe; Silwat-Pandit, Laxmi; Bastani, Nasser Ezzatkhah; Nebdal, Daniel JH; Skålhegg, Bjørn Steen & Kure, Elin Wenche Hegland (2023). Metabolite profiles in plasma distinguish between patients with periampullary cancer and benign pancreatic disease. Full text in Research Archive
• Silwal-Pandit, Laxmi; Stålberg, Stina Margrethe; Mermelekas, G; Lothe, Inger Marie Bowitz; Skrede, Martina Landschoof & Dalsgaard, Astrid M. [Show all 11 contributors for this article] (2019). Proteomic Landscape of Pancreatic Ductal Adenocarcinoma. Full text in Research Archive
• Tofte, Ingrid & Skålhegg, Bjørn Steen (2018). Cancer cachexia; a risk factor for increased mortality and morbidity in patients suffering from pancreatic cancer? Celgene Newsletter. p. 10–10. Full text in Research Archive
• Volchenkov, Roman; Cao, Maria Dung; Elgstøen, Katja B. Prestø; Goll, Guro Løvik; Eikvar, Kari & Bjørneboe, Olav [Show all 10 contributors for this article] (2017). Metabolic profiling of synovial tissue shows altered glucose and choline metabolism in rheumatoid arthritis samples. Scandinavian Journal of Rheumatology. ISSN 0300-9742. 46(2), p. 160–161. doi: 10.3109/03009742.2016.1164242. Full text in Research Archive
• Gjevestad, Gyrd Omholt; Ottestad, Inger; Biong, Anne Sofie; Iversen, Per Ole; Retterstøl, Kjetil & Raastad, Truls [Show all 9 contributors for this article] (2016). Consumption of protein-enriched milk does not affect inflammation in elderly subjects - a 12 week double-blind randomized controlled trial. Full text in Research Archive
• Skålhegg, Bjørn Steen (2014). Lavkarbodiett- en usunn og ensidig avsporing i ernæringsdebatten. p. 12–18. Full text in Research Archive
• Skålhegg, Bjørn Steen (2014). Mosjonistene og proteintilskuddets fortreffelighet. Norsk tidsskrift for ernæring (NTFE). ISSN 1503-5034. p. 6–11. Full text in Research Archive
• Søberg, Kristoffer; Skålhegg, Bjørn Steen & Jahnsen, Tore (2017). On the evolution and function of the catalytic subunits of protein kinase A (PKA). Universitetet i Oslo. Full text in Research Archive
• Haugen, Margaretha; Lillegaard, Inger Therese L.; Frøyland, Livar; Henjum, Sigrun; Holvik, Kristin & Løvik, Martinus [Show all 10 contributors for this article] (2017). Assessment of vitamin B6 intake in relation to tolerable upper intake Levels. Opinion of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. Nofima. ISSN 9788282592604. Full text in Research Archive Show summary

  The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the intake of vitamin B6 (pyridoxine) in the Norwegian population in relation to tolerable upper intake levels (ULs). The existing maximum limit for vitamin B6 in food supplements is 4.2 mg/day. VKM has also conducted scenario calculations to illustrate the consequences of amending the maximum limitto 2, 6, 8, 10, 20 or 25 mg/day. Vitamin B6 is water soluble and comprises six compounds with vitamin B6 activity; pyridoxine (PN, an alcohol), pyridoxal (PL, an aldehyde) and pyridoxamine (PM, the amine) and their corresponding phosphates; pyridoxine 5’-phosphate (PNP), pyridoxal 5’ -phosphate (PLP) and pyridoaxamin 5’ –phosphate (PMP). These six forms of vitamin B6 are all present in food in addition to the glycosylated form, pyridoxine-5’-β-δ-glucoside (PNG), in some plants. In food supplements the most common vitamin B6 form is pyridoxine hydrochloride. Eighty to ninety percent of vitamin B6 in the body is found in muscles and estimated body stores in adults amount to about 170 mg with a half-life of 25-33 days. Vitamin B6 deficiency is mostly seen in combination with deficiency of other B vitamins. Symptoms of vitamin B6 deficiency are anaemia and neurological abnormalities (EFSA, 2016). Intakes of vitamin B6 from the diet alone have not been reported to cause adverse effects. Sensory neuropathy has been reported to be the most sensitive adverse health effect of vitamin B6 supplementation. VKM proposes to adopt the tolerable upper intake level (UL) set by the Scientific Committee for Food (SCF) in 2000 at 25 mg/day for vitamin B6, which was based on a lowest observed adverse effect level (LOAEL) of 100 mg/day found in one randomised controlled trial. VKM recognises that there are no well-designed dose-response studies of long-term use available. However, for adults, no adverse effects have been reported at doses with vitamin B6 up to 25 mg/day. Dietary calculations have been performed for mean intakes and in various percentiles (P5, P25, P50, P75 and P95) in children (2-, 4- and 9-year-olds), adolescents (13-year-olds) and in adults. To illustrate the consequences of amending the maximum limit for vitamin B6 in food supplements to 2, 6, 8, 10, 20 or 25 mg/day in the different age groups, VKM has used the scenarios with P95 from food and added the alternative amounts of supplements. VKM has compared these scenarios with the tolerable upper intake levels set by the Scientific Committee for Food in 2000 for adults, adolescents and children. In these scenarios, the 2- and 4-year-old children will exceed the tolerable upper intake level with use of 6 mg/day or higher vitamin B6 in supplements. The 9-year-old children will exceed the tolerable upper intake level with supplemental use of 10 mg/day. The 13-year-old adolescents will exceed the tolerable upper intake level with 20 mg/day of vitamin B6 in supplements. Adults will VKM Report 2017: 3 7 exceed the tolerable upper intake level with use of 25 mg/day of vitamin B6/pyridoxine in supplements.

• Strand, Tor A; Lillegaard, Inger Therese L.; Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun & Holvik, Kristin [Show all 10 contributors for this article] (2017). Assessment of zinc intake in relation to tolerable upper intake Levels. Opinion of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. Nofima. ISSN 9788282592635. Full text in Research Archive
• Haugen, Margaretha; Lillegaard, Inger Therese L.; Frøyland, Livar; Henjum, Sigrun; Holvik, Kristin & Løvik, Martinus [Show all 9 contributors for this article] (2017). Assessment of vitamin E intake in relation to tolerable upper intake Levels. Opinion of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. Norwegian Scientific Committee for Food Safety (VKM). ISSN 9788252185263. Full text in Research Archive
• Strand, Tor A; Lillegaard, Inger Therese L.; Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun & Holvik, Kristin [Show all 10 contributors for this article] (2017). Assessment of iron intake in relation to tolerable upper intake Levels. Opinion of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. Nofima. ISSN 9788282592628. Full text in Research Archive
• Henjum, Sigrun; Frøyland, Livar; Haugen, Margaretha; Holvik, Kristin; Løvik, Martinus & Skålhegg, Bjørn Steen [Show all 9 contributors for this article] (2017). Risk assessment of "other substances" – L-aspartic acid. Opinion of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. Nofima. ISSN 9788282592680. Full text in Research Archive Show summary

  At the request of the Norwegian Food Safety Authority, the Norwegian Scientific Committee for Food Safety (VKM) has characterised the risk of specified doses of L-aspartic acid in food supplements. VKM concludes that: In adults (≥18 years), adolescents (14 to < 18 years) and children (10 to < 14 years), the specified doses 3000, 3500, 4000, 4500, 5000 and 5700 mg/day L-aspartic acid in food supplements may represent a risk of adverse health effects.

• Løvik, Martinus; Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun; Holvik, Kristin & Skålhegg, Bjørn Steen [Show all 9 contributors for this article] (2017). Risk assessment of "other substances" – L-threonine. Opinion of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. Nofima. ISSN 9788282592673. Full text in Research Archive Show summary

  At the request of the Norwegian Food Safety Authority, the Norwegian Scientific Committee for Food Safety (VKM) has characterised the risk of specified doses of L-threonine in food supplements. VKM concludes that:  In adults (≥18 years), the specified doses 1000, 1200, 1500, 2000 and 2400 mg/day L-threonine in food supplements are unlikely to cause adverse health effects.  In adolescents (14 to <18 years), the specified doses 1000, 1200, 1500, 2000 and 2400 mg/day L-threonine in food supplements are unlikely to cause adverse health effects.  In children (10 to <14 years), the specified doses 1000, 1200, 1500, 2000 and 2400 mg/day L-threonine in food supplements are unlikely to cause adverse health effects.

• Strand, Tor A; Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun; Holvik, Kristin & Skålhegg, Bjørn Steen [Show all 9 contributors for this article] (2016). Risk assessment of "other substances" – L-methionine. Statement of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. Norwegian Scientific Committee for Food Safety. ISSN 9788282592475. Full text in Research Archive
• Stea, Tonje Holte; Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun; Holvik, Kristin & Løvik, Martinus [Show all 10 contributors for this article] (2016). Risk assessment of "other substances" – L-serine. Opinion of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. Norwegian Scientific Committe for Food Safety (VKM). ISSN 9788282592499. Full text in Research Archive Show summary

  At the request of the Norwegian Food Safety Authority, the Norwegian Scientific Committee for Food Safety (VKM) has characterised the risk of daily doses of 50, 500, 1000, 1250, 1500 and 1750 mg/day L-serine in food supplements. In the absence of long-term studies in healthy individuals, VKM used a NOAEL of 3000 mg/kg bw per day from a 90-days toxicological study in rodents. • In adults (≥18 years), the specified doses 50, 500, 1000, 1250, 1500 and 1750 mg/day L-serine in food supplements are unlikely to cause adverse health effects. • In adolescents (14 to < 18 years), the specified doses 50, 500, 1000, 1250, 1500 and 1750 mg/day L-serine in food supplements are unlikely to cause adverse health effects. • In children (10 to < 14 years), the specified doses 50, 500, 1000, 1500 and 1800 mg/day L-serine in food supplements are unlikely to cause adverse health effects.

• Skålhegg, Bjørn Steen; Frøyland, Livar; Haugen, Margaretha; Holvik, Kristin; Løvik, Martinus & Stea, Tonje Holte [Show all 9 contributors for this article] (2016). Risk assessment of "other substances" – L-leucine, L-isoleucine and L-valine, the branched chain amino acids (BCAA). Opinion of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. Nofima. ISSN 9788282592239. Full text in Research Archive Show summary

  The Norwegian Scientific Committee for Food Safety (VKM) has, at the request of the Norwegian Food Safety Authority, assessed the risk of specified doses of L-leucine, Lisoleucine and L-valine in food supplements. VKM concludes that: Due to lack studies addressing adverse effects of the specified doses 2500, 3000, 4000, 5000 and 5250 mg/day L-leucine, 1500, 1750, 2000 and 2500 mg/day L-isoleucine and 1500, 1750, 2000, 2250 and 2500 mg/day L-valine in food supplements, no conclusions can be made for adults (≥ 18 years), adolescents (≥ 10 and < 18 years) or children (< 10 years)

• Iversen, Per Ole; Frøyland, Livar; Haugen, Margaretha; Holvik, Kristin; Løvik, Martinus & Skålhegg, Bjørn Steen [Show all 9 contributors for this article] (2016). Risk assessment of "other substances" - creatine. Opinion of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. Nofima. ISSN 9788282592468. Full text in Research Archive Show summary

  The Norwegian Scientific Committee for Food Safety (VKM) has, at the request of the Norwegian Food Safety Authority, assessed the risk of specified doses of L-creatine in food supplements. VKM concludes that: • In adults (> 18 years) a daily dose of 3.0 g/day creatine in food supplements is unlikely to cause adverse health effects. Doses of 5.0, 10.0 and 24.0 g/day creatine in food supplements may represent a risk of adverse health effects. • In children (10-14 years) and adolescents (14-17 years) the specified doses of 3.0, 5.0, 10.0 and 24.0 g/day creatine in food supplements may represent a risk of adverse health effects.

• Holvik, Kristin; Iversen, Per Ole; Vaktskjold, Arild; Frøyland, Livar; Haugen, Margaretha & Løvik, Martinus [Show all 10 contributors for this article] (2016). Risk assessment of "other substances" – L-histidine. Opinion of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. Nofima. ISSN 9788282592147. Full text in Research Archive Show summary

  At the request of the Norwegian Food Safety Authority, the Norwegian Scientific Committee for Food Safety (VKM) has characterised the risk of specified doses of L-histidine in food supplements. VKM concludes that: • In adults (≥18 years), the specified doses 550 and 600 mg/day L-histidine in food supplements are unlikely to cause adverse health effects. • In adolescents (14 to <18 years), the specified doses 550 and 600 mg/day L-histidine in food supplements are unlikely to cause adverse health effects. • In children (10 to <14 years), the specified doses 550 and 600 mg/day L-histidine in food supplements are unlikely to cause adverse health effects.

• Løvik, Martinus; Frøyland, Livar; Haugen, Margaretha; Holvik, Kristin; Skålhegg, Bjørn Steen & Stea, Tonje Holte [Show all 9 contributors for this article] (2016). Risk assessment of "other substances" - L-glutamine and L-glutamic acid. Opinion of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. Vitenskapskomiteen for mat og miljø. ISSN 9788282592154. Full text in Research Archive Show summary

  The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has,at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by the NFSA. These risk assessments will provide the NFSA with the scientific basis for regulating the addition of “other substances” tofood supplements and other foods. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional or physiological effect. They areadded mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of "other substances" evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is limited to the use of L-glutamine and L-glutamic acid in food supplements. Risks related to glutamine and glutamic acid added to food and drinks, protein hydrolysates or high dietary protein intake are outside the scope of the opinion. The report is based on previous risk assessments of glutamine and glutamic acid and scientific papers retrieved from a comprehensive literature search

• Holvik, Kristin; Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun; Løvik, Martinus & Skålhegg, Bjørn Steen [Show all 10 contributors for this article] (2016). Risk assessment of "other substances" – L-proline. Opinion of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. Nofima. ISSN 9788282592505. Full text in Research Archive Show summary

  At the request of the Norwegian Food Safety Authority, the Norwegian Scientific Committee for Food Safety (VKM) has characterised the risk of specified doses of L-proline in food supplements. VKM concludes that: • In adults (≥18 years), the specified doses 50, 500, 1000, 1500 and 1800 mg/day Lproline in food supplements are unlikely to cause adverse health effects. • In adolescents (14 to < 18 years), the specified doses 50, 500, 1000, 1500 and 1800 mg/day L-proline in food supplements are unlikely to cause adverse health effects. • In children (10 to < 14 years), the specified doses 50, 500, 1000, 1500 and 1800 mg/day L-proline in food supplements are unlikely to cause adverse health effects.

• Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun; Holvik, Kristin; Løvik, Martinus & Skålhegg, Bjørn Steen [Show all 10 contributors for this article] (2016). Risk assessment of "other substances" – L-tyrosine. Opinion of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. Nofima. ISSN 9788282592611. Full text in Research Archive Show summary

  The Norwegian Scientific Committee for Food Safety (VKM) has, at the request of the Norwegian Food Safety Authority, assessed the risk of specified doses of L-tyrosine in food supplements. VKM concludes that: • In adults (≥18 years), the specified doses of 1250, 1500, 1750, and 2000 mg/day Ltyrosine in food supplements may represent a risk of adverse health effects. • In adolescents (14 to<18 years), the specified doses of 1250, 1500, 1750, and 2000 mg/day L-tyrosine in food supplements may represent a risk of adverse health effects. • In children (10 to <14 years), the specified doses of 1250, 1500, 1750, and 2000 mg/day L-tyrosine in food supplements may represent a risk of adverse health effects

• Henjum, Sigrun; Frøyland, Livar; Haugen, Margaretha; Holvik, Kristin; Løvik, Martinus & Skålhegg, Bjørn Steen [Show all 10 contributors for this article] (2016). Risk assessment of "other substances" – L-lysine. Opinion of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. Nofima. ISSN 9788282592529. Full text in Research Archive Show summary

  At the request of the Norwegian Food Safety Authority, the Norwegian Scientific Committee for Food Safety (VKM) has characterised the risk of specified doses of L-lysine in food supplements. VKM concludes that: • In adults (≥18 years), the specified doses 1000, 2000, 2500, 2750 and 3000 mg/day L-lysine in food supplements are unlikely to cause adverse health effects. • In adolescents (14 to< 18 years), the specified doses 1000, 2000, 2500, 2750 and 3000 mg/day L-lysine in food supplements are unlikely to cause adverse health effects. • In children (10 to <14 years), the specified doses 1000, 2000, 2500, 2750 and 3000 mg/day L-lysine in food supplements are unlikely to cause adverse health effects.

• Tell, Grethe S.; Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun; Holvik, Kristin & Løvik, Martinus [Show all 10 contributors for this article] (2016). Risk assessment of "other substances" – glycine. Opinion of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. Norwegian Scientific Committee for Food Safety (VKM). ISSN 9788282592482. Full text in Research Archive
• Haugen, Margaretha; Halvorsen, Ragnhild; Iversen, Per Ole; Mansoor, Mohammad Azam; Meltzer, Helle Margrete & Torjusen, Hanne [Show all 25 contributors for this article] (2014). Comparison of organic and conventional food and food Production. Part III: Human health – an evaluation of human studies, animal models studies and biomarker studies. Nofima. ISSN 9788282591362. Full text in Research Archive
• Haugen, Margaretha; Dierkes, Jutta; Frølich, Wenche; Frøyland, Livar; Halvorsen, Ragnhild & Iversen, Per Ole [Show all 10 contributors for this article] (2013). Vurdering av særnorske forhold for produkter som er godkjent som ny mat i EU. Uttalelse fra faggruppen for ernæring, dietetiske produkter, ny mat og allergi i Vitenskapskomiteen for mattrygghet. Nofima. ISSN 9788282591034. Full text in Research Archive
• Haugen, Margaretha; Dierkes, Jutta; Frølich, Wenche; Frøyland, Livar; Halvorsen, Ragnhild & Iversen, Per Ole [Show all 10 contributors for this article] (2013). Assessment of vitamin A and D in food supplements. Opinion of the Panel on nutrition, dietetic products, novel food and allergy of the Norwegian Scientific Committee for Food Safety. Nofima. ISSN 9788282590679. Full text in Research Archive
• Haugen, Margaretha; Dierkes, Jutta; Frølich, Wenche; Frøyland, Livar; Halvorsen, Ragnhild & Iversen, Per Ole [Show all 10 contributors for this article] (2013). Assessment and updating of the fortification model from 2006. Opinion of the Panel on nutrition, dietetic products, novel food and allergy of the Norwegian Scientific Committee for Food Safety. Nofima. ISSN 9788282590693. Full text in Research Archive
• Haugen, Margaretha; Dierkes, Jutta; Mansoor, Mohammad Azam; Skålhegg, Bjørn Steen; Frølich, Wenche & Frøyland, Livar [Show all 9 contributors for this article] (2013). Risk assessment of histidine, methionine, S-adenosylmethionine and tryptophan. Opinion of the Panel on nutrition, dietetic products, novel food and allergy of the Norwegian Scientific Committee for Food Safety. Nofima. ISSN 9788282590792. Full text in Research Archive

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