31 results on '"Pal Saetrom"'
Search Results
2. Supplementary Legends from MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial
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Nagy Habib, John J. Rossi, David C. Blakey, Hans E. Huber, Pal Saetrom, Chris Wood, Robert Habib, Jenni Vasara, Steve Felstead, Peter Lloyd, Pinelopi Andrikakou, Stephanie Dorman, Jon Voutila, Vikash Reebye, Sonia Fairbairn, Helen Glenny, Robert Nutbrown, David Collin, Joanna P. Nicholls, Vineet Kwatra, Sarah Hunter, James Spicer, David J. Pinato, Rohini Sharma, Madhava Pai, Duncan R.C. Spalding, T.R. Jeff Evans, Yuk Ting Ma, Daniel H. Palmer, Kai-Wen Huang, Cheng Ean Chee, Bristi Basu, Mikael H. Sodergren, Tim Meyer, Ruth Plummer, and Debashis Sarker more...
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Supplementary Legends
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- 2023
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Catalog
3. Supplementary Figure 5 from MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial
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Nagy Habib, John J. Rossi, David C. Blakey, Hans E. Huber, Pal Saetrom, Chris Wood, Robert Habib, Jenni Vasara, Steve Felstead, Peter Lloyd, Pinelopi Andrikakou, Stephanie Dorman, Jon Voutila, Vikash Reebye, Sonia Fairbairn, Helen Glenny, Robert Nutbrown, David Collin, Joanna P. Nicholls, Vineet Kwatra, Sarah Hunter, James Spicer, David J. Pinato, Rohini Sharma, Madhava Pai, Duncan R.C. Spalding, T.R. Jeff Evans, Yuk Ting Ma, Daniel H. Palmer, Kai-Wen Huang, Cheng Ean Chee, Bristi Basu, Mikael H. Sodergren, Tim Meyer, Ruth Plummer, and Debashis Sarker more...
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Showing complete radiological response of lung metastases
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- 2023
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4. Supplementary Figure 1 from MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial
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Nagy Habib, John J. Rossi, David C. Blakey, Hans E. Huber, Pal Saetrom, Chris Wood, Robert Habib, Jenni Vasara, Steve Felstead, Peter Lloyd, Pinelopi Andrikakou, Stephanie Dorman, Jon Voutila, Vikash Reebye, Sonia Fairbairn, Helen Glenny, Robert Nutbrown, David Collin, Joanna P. Nicholls, Vineet Kwatra, Sarah Hunter, James Spicer, David J. Pinato, Rohini Sharma, Madhava Pai, Duncan R.C. Spalding, T.R. Jeff Evans, Yuk Ting Ma, Daniel H. Palmer, Kai-Wen Huang, Cheng Ean Chee, Bristi Basu, Mikael H. Sodergren, Tim Meyer, Ruth Plummer, and Debashis Sarker more...
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Dose escalation flow chart. DLT - dose limiting toxicity, MTD - maximum tolerated dose
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- 2023
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5. Appendix A from MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial
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Nagy Habib, John J. Rossi, David C. Blakey, Hans E. Huber, Pal Saetrom, Chris Wood, Robert Habib, Jenni Vasara, Steve Felstead, Peter Lloyd, Pinelopi Andrikakou, Stephanie Dorman, Jon Voutila, Vikash Reebye, Sonia Fairbairn, Helen Glenny, Robert Nutbrown, David Collin, Joanna P. Nicholls, Vineet Kwatra, Sarah Hunter, James Spicer, David J. Pinato, Rohini Sharma, Madhava Pai, Duncan R.C. Spalding, T.R. Jeff Evans, Yuk Ting Ma, Daniel H. Palmer, Kai-Wen Huang, Cheng Ean Chee, Bristi Basu, Mikael H. Sodergren, Tim Meyer, Ruth Plummer, and Debashis Sarker more...
- Abstract
Trial Protocol
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- 2023
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6. Supplementary Tables from MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial
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Nagy Habib, John J. Rossi, David C. Blakey, Hans E. Huber, Pal Saetrom, Chris Wood, Robert Habib, Jenni Vasara, Steve Felstead, Peter Lloyd, Pinelopi Andrikakou, Stephanie Dorman, Jon Voutila, Vikash Reebye, Sonia Fairbairn, Helen Glenny, Robert Nutbrown, David Collin, Joanna P. Nicholls, Vineet Kwatra, Sarah Hunter, James Spicer, David J. Pinato, Rohini Sharma, Madhava Pai, Duncan R.C. Spalding, T.R. Jeff Evans, Yuk Ting Ma, Daniel H. Palmer, Kai-Wen Huang, Cheng Ean Chee, Bristi Basu, Mikael H. Sodergren, Tim Meyer, Ruth Plummer, and Debashis Sarker more...
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Supplementary Table 1 CEBPA-51 PK parameters Supplementary Table 2 RECIST 1.1 response observed overall and per cohorts in HCC patients at cut-off (12 Sep 2018) presented as n (%)
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- 2023
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7. Data from MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial
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Nagy Habib, John J. Rossi, David C. Blakey, Hans E. Huber, Pal Saetrom, Chris Wood, Robert Habib, Jenni Vasara, Steve Felstead, Peter Lloyd, Pinelopi Andrikakou, Stephanie Dorman, Jon Voutila, Vikash Reebye, Sonia Fairbairn, Helen Glenny, Robert Nutbrown, David Collin, Joanna P. Nicholls, Vineet Kwatra, Sarah Hunter, James Spicer, David J. Pinato, Rohini Sharma, Madhava Pai, Duncan R.C. Spalding, T.R. Jeff Evans, Yuk Ting Ma, Daniel H. Palmer, Kai-Wen Huang, Cheng Ean Chee, Bristi Basu, Mikael H. Sodergren, Tim Meyer, Ruth Plummer, and Debashis Sarker more...
- Abstract
Purpose:Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α.Patients and Methods:We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design).Results:Thirty-eight participants have been treated across six dose levels (28–160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment–related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD.Conclusions:MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC. more...
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- 2023
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8. Supplementary Figure 3 from MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial
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Nagy Habib, John J. Rossi, David C. Blakey, Hans E. Huber, Pal Saetrom, Chris Wood, Robert Habib, Jenni Vasara, Steve Felstead, Peter Lloyd, Pinelopi Andrikakou, Stephanie Dorman, Jon Voutila, Vikash Reebye, Sonia Fairbairn, Helen Glenny, Robert Nutbrown, David Collin, Joanna P. Nicholls, Vineet Kwatra, Sarah Hunter, James Spicer, David J. Pinato, Rohini Sharma, Madhava Pai, Duncan R.C. Spalding, T.R. Jeff Evans, Yuk Ting Ma, Daniel H. Palmer, Kai-Wen Huang, Cheng Ean Chee, Bristi Basu, Mikael H. Sodergren, Tim Meyer, Ruth Plummer, and Debashis Sarker more...
- Abstract
Longitudinal changes in WBC mRNA expression of CEBPA, adenosine, PD-1 & CXCR4 at screening, day2, 8 and 15 of a single patient treated in the 130mg/m2 cohort
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- 2023
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9. Supplementary Figure 2 from MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial
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Nagy Habib, John J. Rossi, David C. Blakey, Hans E. Huber, Pal Saetrom, Chris Wood, Robert Habib, Jenni Vasara, Steve Felstead, Peter Lloyd, Pinelopi Andrikakou, Stephanie Dorman, Jon Voutila, Vikash Reebye, Sonia Fairbairn, Helen Glenny, Robert Nutbrown, David Collin, Joanna P. Nicholls, Vineet Kwatra, Sarah Hunter, James Spicer, David J. Pinato, Rohini Sharma, Madhava Pai, Duncan R.C. Spalding, T.R. Jeff Evans, Yuk Ting Ma, Daniel H. Palmer, Kai-Wen Huang, Cheng Ean Chee, Bristi Basu, Mikael H. Sodergren, Tim Meyer, Ruth Plummer, and Debashis Sarker more...
- Abstract
qPCR of CEBPA mRNA levels at days 2, 8 and 15 following treatment
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- 2023
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10. Increased expression of individual genes in whole blood is associated with late-stage lung cancer at and close to diagnosis
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Ilona Urbarova, Anne Heidi Skogholt, Yi-Qian Sun, Xiao-Mei Mai, Bjørn Henning Grønberg, Torkjel Manning Sandanger, Pål Sætrom, and Therese Haugdahl Nøst
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Medicine ,Science - Abstract
Abstract Lung cancer (LC) mortality rates are still increasing globally. As survival is linked to stage, there is a need to identify markers for earlier LC diagnosis and individualized treatment. The whole blood transcriptome of LC patients represents a source of potential LC biomarkers. We compared expression of > 60,000 genes in whole blood specimens taken from LC cases at diagnosis (n = 128) and controls (n = 62) using genome-wide RNA sequencing, and identified 14 candidate genes associated with LC. High expression of ANXA3, ARG1 and HP was strongly associated with lower survival in late-stage LC cases (hazard ratios (HRs) = 2.81, 2.16 and 2.54, respectively). We validated these markers in two independent population-based studies with pre-diagnostic whole blood specimens taken up to eight years prior to LC diagnosis (n = 163 cases, 184 matched controls). ANXA3 and ARG1 expression was strongly associated with LC in these specimens, especially with late-stage LC within two years of diagnosis (odds ratios (ORs) = 3.47 and 5.00, respectively). Additionally, blood CD4 T cells, NK cells and neutrophils were associated with LC at diagnosis and improved LC discriminative ability beyond candidate genes. Our results indicate that in whole blood, increased expression levels of ANXA3, ARG1 and HP are diagnostic and prognostic markers of late-stage LC. more...
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- 2023
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11. Generation of an enhancer-driven gene expression viral tool specific to dentate granule cell-types through direct hippocampal injection
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Maria Letizia Potenza, Stefan Blankvoort, Miguel M. Carvalho, Joachim S. Grimstvedt, Valentina Di Maria, Kristian Moan, Rajeevkumar Raveendran Nair, Marcus S. Flatset, Qiangwei Zhang, Laurent F. Thomas, Francois P. Pauzin, Rodolfo Da Silva Mazzarini Baldinotti, Giulia Quattrocolo, Clive R. Bramham, Pål Sætrom, Menno P. Witter, and Clifford G. Kentros more...
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rAAVs ,dentate gyrus ,genetic tool ,chromatin immunoprecipitation ,stereotaxic injection ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Accurate investigations of neural circuitry require specific genetic access to individual circuit elements, i.e., the myriad neuronal cell-types in the brain. However, native promoters cannot achieve this because while most genes are expressed in the brain, few are expressed in a single neuronal cell-type. We recently used enhancers, the subcomponents of the transcriptional apparatus which tell promoters when and where to express, combined with heterologous minimal promoters to increase specificity of transgene expression, an approach we call Enhancer-Driven Gene Expression (EDGE). As we discuss, EDGE is a marked improvement in specificity over native promoters, but still requires careful anatomical analysis to avoid off-target effects. In this study we present a more complete set of genomic markers from the mouse brain and characterize a novel EDGE viral vector capable of specifically driving expression in distinct subtypes of hippocampal neurons, even though it can express in other cell-types elsewhere. The advent of cell-type specific viral tools in wild-type animals provides a powerful strategy for neural circuit investigation and holds promise for studies using animal models for which transgenic tools are not available. more...
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- 2024
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12. DNA hydroxymethylation differences underlie phenotypic divergence of somatic growth in Nile tilapia reared in common garden
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Ioannis Konstantinidis, Pål Sætrom, Marine S. O. Brieuc, Kjetill S. Jakobsen, Hannes Liedtke, Caroline Pohlmann, Thomais Tsoulia, and Jorge M. O. Fernandes
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Epigenetics ,DNA hydroxymethylation ,domestication ,somatic growth ,teleosts ,phenotypic plasticity ,Genetics ,QH426-470 - Abstract
ABSTRACTPhenotypic plasticity of metabolism and growth are essential for adaptation to new environmental conditions, such as those experienced during domestication. Epigenetic regulation plays a key role in this process but the underlying mechanisms are poorly understood, especially in the case of hydroxymethylation. Using reduced representation 5-hydroxymethylcytosine profiling, we compared the liver hydroxymethylomes in full-sib Nile tilapia with distinct growth rates (3.8-fold difference) and demonstrated that DNA hydroxymethylation is strongly associated with phenotypic divergence of somatic growth during the early stages of domestication. The 2677 differentially hydroxymethylated cytosines between fast- and slow-growing fish were enriched within gene bodies (79%), indicating a pertinent role in transcriptional regulation. Moreover, they were found in genes involved in biological processes related to skeletal system and muscle structure development, and there was a positive association between somatic growth and 5hmC levels in genes coding for growth factors, kinases and receptors linked to myogenesis. Single nucleotide polymorphism analysis revealed no genetic differentiation between fast- and slow-growing fish. In addition to unveiling a new link between DNA hydroxymethylation and epigenetic regulation of growth in fish during the initial stages of domestication, this study suggests that epimarkers may be applied in selective breeding programmes for superior phenotypes. more...
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- 2023
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13. Randomised controlled trial of exercise training during lactation on breast milk composition in breastfeeding people with overweight/obesity: a study protocol for the MILKSHAKE trial
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Trine Moholdt, Ann-Charlotte Iversen, Melanie Rae Simpson, Emily Rose Ashby, Karina Hammer Tømmerdal, Maëliss Cynthia Chloé Lemoine, Rebecca Lyng Holm, Pål Sætrom, Anuradha Ravi, and Guro F Giskeødegård more...
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Medicine (General) ,R5-920 - Abstract
Breast milk from people with overweight/obesity may differ in composition compared with that from normal-weight people. Exercise training can modify breast milk composition in rodent models, with a beneficial impact demonstrated on the offspring’s metabolism, but whether these findings translate to humans is unclear. This trial aims to determine the effect of an exercise intervention on breast milk composition and whether an exercise-induced modification of breast milk impacts the infants’ growth and body composition. Effect of Exercise Training on Breastmilk Composition is a randomised, controlled trial with two parallel groups, one exercise group and one control group, with a 1:1 allocation. We will include a minimum of 62 exclusively breastfeeding participants, 6 weeks postpartum. The exercise intervention lasts 8 weeks and comprises 25 supervised endurance exercise sessions with moderate or high intensity. The primary outcome measure is the change in the relative concentration of the human milk oligosaccharide 3′sialyllactose in breast milk from baseline at 6 weeks postpartum to the end of the intervention period. Secondary outcomes include breast milk concentrations of other metabolites, cytokines, hormones and microRNA, maternal health outcomes, infant growth, infant gut microbiome and infant circulating microRNA. Maternal and infant outcomes will be measured before, during and after the intervention period, with a follow-up of the infants until they are 24 months old. Trial registration number NCT05488964. more...
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- 2023
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14. Genome-wide hydroxymethylation profiles in liver of female Nile tilapia with distinct growth performance
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Ioannis Konstantinidis, Pål Sætrom, and Jorge M. O. Fernandes
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Science - Abstract
Abstract The mechanisms underlying the fast genome evolution that occurs during animal domestication are poorly understood. Here, we present a genome-wide epigenetic dataset that quantifies DNA hydroxymethylation at single nucleotide resolution among full-sib Nile tilapia (Oreochromis niloticus) with distinct growth performance. In total, we obtained 355 million, 75 bp reads from 5 large- and 5 small-sized fish on an Illumina NextSeq500 platform. We identified several growth-related genes to be differentially hydroxymethylated, especially within gene bodies and promoters. Previously, we proposed that DNA hydroxymethylation greatly affects the earliest responses to adaptation and potentially drives genome evolution through its targeted enrichment and elevated nucleotide transversion rates. This dataset can be analysed in various contexts (e.g., epigenetics, evolution and growth) and compared to other epigenomic datasets in the future, namely DNA methylation and histone modifications. With forthcoming advancements in genome research, this hydroxymethylation dataset will also contribute to better understand the epigenetic regulation of key genomic features, such as cis-regulatory and transposable elements. more...
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- 2023
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15. Increased levels of microRNA‐320 in blood serum and plasma is associated with imminent and advanced lung cancer
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Therese Haugdahl Nøst, Anne Heidi Skogholt, Ilona Urbarova, Robin Mjelle, Erna‐Elise Paulsen, Tom Dønnem, Sigve Andersen, Maria Markaki, Oluf Dimitri Røe, Mikael Johansson, Mattias Johansson, Bjørn Henning Grønberg, Torkjel Manning Sandanger, and Pål Sætrom more...
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diagnostic markers ,lung cancer ,MiRNA ,peripheral blood ,pre‐diagnostic markers ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Lung cancer (LC) incidence is increasing globally and altered levels of microRNAs (miRNAs) in blood may contribute to identification of individuals with LC. We identified miRNAs differentially expressed in peripheral blood at LC diagnosis and evaluated, in pre‐diagnostic blood specimens, how long before diagnosis expression changes in such candidate miRNAs could be detected. We identified upregulated candidate miRNAs in plasma specimens from a hospital‐based study sample of 128 patients with confirmed LC and 62 individuals with suspected but confirmed negative LC (FalsePos). We then evaluated the expression of candidate miRNAs in pre‐diagnostic plasma or serum specimens of 360 future LC cases and 375 matched controls. There were 1663 miRNAs detected in diagnostic specimens, nine of which met our criteria for candidate miRNAs. Higher expression of three candidates, miR‐320b, 320c, and 320d, was associated with poor survival, independent of LC stage and subtype. Moreover, miR‐320c and miR‐320d expression was higher in pre‐diagnostic specimens collected within 2 years of LC diagnosis. Our results indicated that elevated levels of miR‐320c and miR‐320d may be early indications of imminent and advanced LC. more...
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- 2023
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16. The Salmon Oil OmeGo Reduces Viability of Colorectal Cancer Cells and Potentiates the Anti-Cancer Effect of 5-FU
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Caroline H. H. Pettersen, Helle Samdal, Pål Sætrom, Arne Wibe, Erland Hermansen, and Svanhild A. Schønberg
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colorectal cancer ,CRC ,fish oil ,omega-3 fatty acids ,salmon oil ,OmeGo ,Biology (General) ,QH301-705.5 - Abstract
Colorectal cancer (CRC) is one of the most common cancer types worldwide. Chemotherapy is toxic to normal cells, and combinatory treatment with natural well-tolerated products is being explored. Some omega-3 polyunsaturated fatty acids (n-3 PUFAs) and marine fish oils have anti-cancer effects on CRC cells. The salmon oil OmeGo (Hofseth BioCare) contains a spectrum of fatty acids, including the n-3 PUFAs docosahexaenoic acid (DHA) and eicosahexaenoic acid (EPA). We explored a potential anti-cancer effect of OmeGo on the four CRC cell lines DLD-1, HCT-8, LS411N, and LS513, alone and in combination with the chemotherapeutic agent 5-Fluorouracil (5-FU). Screening indicated a time- and dose-dependent effect of OmeGo on the viability of the DLD-1 and LS513 CRC cell lines. Treatment with 5-FU and OmeGo (IC20–IC30) alone indicated a significant reduction in viability. A combinatory treatment with OmeGo and 5-FU resulted in a further reduction in viability in DLD-1 and LS513 cells. Treatment of CRC cells with DHA + EPA in a concentration corresponding to the content in OmeGo alone or combined with 5-FU significantly reduced viability of all four CRC cell lines tested. The lowest concentration of OmeGo reduced viability to a higher degree both alone and in combination with 5-FU compared to the corresponding concentrations of DHA + EPA in three of the cell lines. Results suggest that a combination of OmeGo and 5-FU could have a potential as an alternative anti-cancer therapy for patients with CRC. more...
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- 2023
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17. NEIL1 and NEIL2 DNA glycosylases modulate anxiety and learning in a cooperative manner in mice
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Gunn A. Hildrestrand, Veslemøy Rolseth, Nicolas Kunath, Rajikala Suganthan, Vidar Jensen, Anna M. Bugaj, Marion S. Fernandez-Berrocal, Sunniva B. Sikko, Susanne Vetlesen, Anna Kuśnierczyk, Ann-Karin Olsen, Kristine B. Gützkow, Alexander D. Rowe, Wei Wang, Olve Moldestad, Monica D. Syrstad, Geir Slupphaug, Lars Eide, Arne Klungland, Pål Sætrom, Luisa Luna, Jing Ye, Katja Scheffler, and Magnar Bjørås more...
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Biology (General) ,QH301-705.5 - Abstract
Gunn Hildrestrand, Veslemøy Rolseth, and Nicolas Kunath et al. examine mice lacking the NEIL1 and NEIL2 DNA glycosylases involved in base excision repair. Their results suggest that loss of both NEIL1 and NEIL2 dysregulates genes relevant to synaptic function and modulates behavior in mice. more...
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- 2021
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18. Joint changes in RNA, RNA polymerase II, and promoter activity through the cell cycle identify non-coding RNAs involved in proliferation
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Siv Anita Hegre, Helle Samdal, Antonin Klima, Endre B. Stovner, Kristin G. Nørsett, Nina Beate Liabakk, Lene Christin Olsen, Konika Chawla, Per Arne Aas, and Pål Sætrom
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Medicine ,Science - Abstract
Abstract Proper regulation of the cell cycle is necessary for normal growth and development of all organisms. Conversely, altered cell cycle regulation often underlies proliferative diseases such as cancer. Long non-coding RNAs (lncRNAs) are recognized as important regulators of gene expression and are often found dysregulated in diseases, including cancers. However, identifying lncRNAs with cell cycle functions is challenging due to their often low and cell-type specific expression. We present a highly effective method that analyses changes in promoter activity, transcription, and RNA levels for identifying genes enriched for cell cycle functions. Specifically, by combining RNA sequencing with ChIP sequencing through the cell cycle of synchronized human keratinocytes, we identified 1009 genes with cell cycle-dependent expression and correlated changes in RNA polymerase II occupancy or promoter activity as measured by histone 3 lysine 4 trimethylation (H3K4me3). These genes were highly enriched for genes with known cell cycle functions and included 57 lncRNAs. We selected four of these lncRNAs—SNHG26, EMSLR, ZFAS1, and EPB41L4A-AS1—for further experimental validation and found that knockdown of each of the four lncRNAs affected cell cycle phase distributions and reduced proliferation in multiple cell lines. These results show that many genes with cell cycle functions have concomitant cell-cycle dependent changes in promoter activity, transcription, and RNA levels and support that our multi-omics method is well suited for identifying lncRNAs involved in the cell cycle. more...
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- 2021
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19. Gene expression in blood reflects smoking exposure among cancer-free women in the Norwegian Women and Cancer (NOWAC) postgenome cohort
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Nikita Baiju, Torkjel M. Sandanger, Pål Sætrom, and Therese H. Nøst
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Medicine ,Science - Abstract
Abstract Active smoking has been linked to modulated gene expression in blood. However, there is a need for a more thorough understanding of how quantitative measures of smoking exposure relate to differentially expressed genes (DEGs) in whole-blood among ever smokers. This study analysed microarray-based gene expression profiles from whole-blood samples according to smoking status and quantitative measures of smoking exposure among cancer-free women (n = 1708) in the Norwegian Women and Cancer postgenome cohort. When compared with never smokers and former smokers, current smokers had 911 and 1082 DEGs, respectively and their biological functions could indicate systemic impacts of smoking. LRRN3 was associated with smoking status with the lowest FDR-adjusted p-value. When never smokers and all former smokers were compared, no DEGs were observed, but LRRN3 was differentially expressed when never smokers were compared with former smokers who quit smoking ≤ 10 years ago. Further, LRRN3 was positively associated with smoking intensity, pack-years, and comprehensive smoking index score among current smokers; and negatively associated with time since cessation among former smokers. Consequently, LRRN3 expression in whole-blood is a molecular signal of smoking exposure that could supplant self-reported smoking data in further research targeting blood-based markers related to the health effects of smoking. more...
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- 2021
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20. Major gene expression changes and epigenetic remodelling in Nile tilapia muscle after just one generation of domestication
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Ioannis Konstantinidis, Pål Sætrom, Robin Mjelle, Artem V. Nedoluzhko, Diego Robledo, and Jorge M. O. Fernandes
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domestication ,epigenetics ,dna hydroxymethylation ,muscle growth ,oreochromis niloticus ,Genetics ,QH426-470 - Abstract
The historically recent domestication of fishes has been essential to meet the protein demands of a growing human population. Selection for traits of interest during domestication is a complex process whose epigenetic basis is poorly understood. Cytosine hydroxymethylation is increasingly recognized as an important DNA modification involved in epigenetic regulation. In the present study, we investigated if hydroxymethylation plays a role in fish domestication and demonstrated for the first time at a genome-wide level and single nucleotide resolution that the muscle hydroxymethylome changes after a single generation of Nile tilapia (Oreochromis niloticus, Linnaeus) domestication. The overall decrease in hydroxymethylcytosine levels was accompanied by the downregulation of 2015 genes in fish reared in captivity compared to their wild progenitors. In contrast, several myogenic and metabolic genes that can affect growth potential were upregulated. There were 126 differentially hydroxymethylated cytosines between groups, which were not due to genetic variation; they were associated with genes involved in immune-, growth- and neuronal-related pathways. Taken together, our data unveil a new role for DNA hydroxymethylation in epigenetic regulation of fish domestication with impact in aquaculture and implications in artificial selection, environmental adaptation and genome evolution. more...
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- 2020
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21. Non-Coding RNAs in Human Breast Milk: A Systematic Review
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Lina Tingö, Emelie Ahlberg, Lovisa Johansson, Sindre Andre Pedersen, Konika Chawla, Pål Sætrom, Erika Cione, and Melanie Rae Simpson
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microRNA ,non-coding RNA ,breast milk ,miRNA ,ncRNA ,extracellular vesicles ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Breast milk is the primary source of nutrition and hydration for the newborn infant but also plays an important role in the child’s first immune defense. Additionally, several breast milk factors have been implicated in immune-related health outcomes later in life, including immunoglobulins, cytokines, chemokines, growth factors and, more recently, non-coding RNA (ncRNA) species. In this systematic review, we provide a comprehensive summary of the current literature on endogenous ncRNAs found in human breast milk. Thirty (30) relevant studies were identified and, whilst the majority studies focused on microRNAs (miRNAs), there is evidence that breast milk contains high quantities of RNA which also include long-coding RNAs, circular RNAs, as well as other short RNAs and fragmented tRNA and rRNAs. Among studies investigating miRNAs, miR-148a-3p, miR-30a/d-5p, miR-22-3p, miR-146b-5p, miR-200a/c-3p, and the 5p end of the let-7 miRNAs were commonly reported among the top 10 miRNAs in the cell, lipid, and skim milk fractions of breast milk. Methodological difference and small sample sizes limit the possibility of conclusively identifying which maternal and infant characteristics affect the miRNA profile. The highly expressed miRNAs were generally reported to be similar across lactational stage, milk fraction, maternal and infant characteristics, or infant growth and health. All the same, individual studies identify potential differences in miRNA expression levels which should be confirmed by future studies. Stability, uptake, and physiological functions of miRNAs were also considered in several studies. Breast milk miRNAs are relatively resistant to a range of harsh conditions and uptake experiments suggest that extracellular vesicles containing miRNAs and circular RNAs can be taken up by intestinal epithelial cells. Although the evidence regarding the functional effect of breast milk miRNAs is limited, the predicted functions range from metabolic and biosynthetic processes to signaling pathways, cellular adhesion, communication, growth, and differentiation. Finally, this systematic review highlights some of the methodological challenges and knowledge gaps which can help direct future research in this field. In particular, it is important to further investigate the bioavailability of miRNAs in different milk fractions, and to characterize other ncRNAs which are largely unstudied.Systematic Review RegistrationPROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=138989, identifier CRD42020138989. more...
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- 2021
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22. Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression
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Nicola P. Montaldo, Diana L. Bordin, Alessandro Brambilla, Marcel Rösinger, Sarah L. Fordyce Martin, Karine Øian Bjørås, Stefano Bradamante, Per Arne Aas, Antonia Furrer, Lene C. Olsen, Nicolas Kunath, Marit Otterlei, Pål Sætrom, Magnar Bjørås, Leona D. Samson, and Barbara van Loon more...
- Subjects
Science - Abstract
How genome stability is maintained at regions of active transcription is currently not entirely clear. Here, the authors reveal an association between base excision repair factors and transcription elongation to modulate DNA repair. more...
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- 2019
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23. Comprehensive transcriptomic analyses of tissue, serum, and serum exosomes from hepatocellular carcinoma patients
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Robin Mjelle, Simona O. Dima, Nicolae Bacalbasa, Konika Chawla, Andrei Sorop, Dana Cucu, Vlad Herlea, Pål Sætrom, and Irinel Popescu
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HCC ,microRNA ,Gene expression ,Exosomes ,Serum ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The expression of microRNAs (miRNAs) is a promising prognostic and diagnostic tool in hepatocellular carcinoma (HCC). Here we performed small RNA sequencing (sRNA-seq) of tissue, serum and serum exosomes to investigate changes in miRNA expression between the different sample types and correlated the expression with clinical parameters. We also performed gene expression arrays on tumor and normal tissue. Results Paired tissue, serum and serum exosomes sequencing revealed consistent positive correlation of miR-21 between serum exosomes and tumor tissue, indicating that miR-21 could be exported from tissue to circulation via exosomes. We found that let-7 miRNAs are generally upregulated in serum exosomes compared to whole serum, indicating that these miRNAs could be preferentially loaded into exosomes. Comparing serum from HCC patients with serum from healthy individuals revealed a global increase of miRNAs in serum from HCC patients, including an almost 4-fold increase of several miRNAs, including the liver-specific miR-122. When correlating miRNA expression with clinical parameters we detected significant association between hepatitis B virus (HBV) infection and miR-122 in serum as well as several serum and tissue-miRNAs that correlated with surgery type. We found that miR-141 and miR-146 correlated with cirrhosis in tumor tissue and normal tissue, respectively. Finally, high expression of miR-21 in tumors were associated with poor survival. Focusing on gene expression we found several significant messenger RNAs (mRNAs) between tumor and normal tissue and a Gene Ontology (GO) analysis revealed that these changes were mainly related to cell cycle and metabolism. Further, we detected mRNAs that correlated with cirrhosis and HBV infection in tissue. Finally, GO analysis of predicted targets for miRNAs down-regulated in tumor found that these were enriched for functions related to collagen synthesis. Conclusions Our combined data point to altered miRNA and mRNA expression contributing to both generally impaired lipid metabolism and increased cell proliferation and a miRNA-driven increase in collagen synthesis in HCC. Our results further indicate a correlation in miRNA expression between exosomes, serum, and tissue samples suggesting export from tumors via exosomes. This correlation could provide a basis for a more tumor-specific miRNA profile in serum. more...
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- 2019
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24. Small RNA expression from viruses, bacteria and human miRNAs in colon cancer tissue and its association with microsatellite instability and tumor location
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Robin Mjelle, Wenche Sjursen, Liv Thommesen, Pål Sætrom, and Eva Hofsli
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miRNA ,isomiR ,ncRNA ,sRNA ,Epstein-Barr virus ,Fusobacterium nucleatum ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background MicroRNAs (miRNA) and other small RNAs are frequently dysregulated in cancer and are promising biomarkers for colon cancer. Here we profile human, virus and bacteria small RNAs in normal and tumor tissue from early stage colon cancer and correlate the expression with clinical parameters. Methods Small RNAs from colon cancer tissue and adjacent normal mucosa of 48 patients were sequenced using Illumina high-throughput sequencing. Clinical parameters were correlated with the small RNA expression data using linear models. We performed a meta-analysis by comparing publicly available small RNA sequencing datasets with our original sequencing data to confirm the main findings. Results We identified 331 differentially expressed miRNAs between tumor and normal samples. We found that the major changes in miRNA expression between left and right colon are due to miRNAs located within the Hox-developmental genes, including miR-10b, miR-196b and miR-615. Further, we identified new miRNAs associated with microsatellite instability (MSI), including miR-335, miR-26 and miR-625. We performed a meta-analysis on all publicly available miRNA-seq datasets and identified 117 common miRNAs that were differentially expressed between tumor and normal tissue. The miRNAs miR-135b and miR-31 were the most significant upregulated miRNA in tumor across all datasets. The miRNA miR-133a was the most strongly downregulated miRNA in our dataset and also showed consistent downregulation in the other datasets. The miRNAs associated with MSI and tumor location in our data showed similar changes in the other datasets. Finally, we show that small RNAs from Epstein-Barr virus and Fusobacterium nucleatum are differentially expressed between tumor and normal adjacent tissue. Conclusions Small RNA profiling in colon cancer tissue revealed novel RNAs associated with MSI and tumor location. We show that Fusobacterium nucleatum are detectable at the RNA-level in colon tissue, and that both Fusobacterium nucleatum and Epstein-Barr virus separate tumor and normal tissue. more...
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- 2019
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25. sMETASeq: Combined Profiling of Microbiota and Host Small RNAs
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Robin Mjelle, Kristin Roseth Aass, Wenche Sjursen, Eva Hofsli, and Pål Sætrom
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Genomics ,Microbiology ,Bioinformatics ,Science - Abstract
Summary: Understanding microbial communities' roles in human health and disease requires methods that accurately characterize the microbial composition and their activity and effects within human biological samples. We present sMETASeq (small RNA Metagenomics by Sequencing), a novel method that uses sequencing of small RNAs to jointly measure host small RNA expression and create metagenomic profiles and detect small bacterial RNAs. We evaluated the performance of sMETASeq on a mock bacterial community and demonstrated its use on different human samples, including colon cancer, oral leukoplakia, cervix cancer, and a panel of human biofluids. In all datasets, the detected microbes reflected the biology of the different sample types. more...
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- 2020
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26. In utero exposure to endocrine disrupting chemicals, micro-RNA profiles, and fetal growth: a pilot study protocol
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Tricia L. Larose, Pål Sætrom, Marit P. Martinussen, Håkon Skogseth, Torkjel M. Sandanger, Ghislaine Scelo, Cliona M. McHale, Geir W. Jacobsen, and Martyn T. Smith
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environmental health ,endocrine disrupting chemicals ,fetal growth ,miRNA ,Public aspects of medicine ,RA1-1270 - Abstract
Background: The developing fetus is particularly vulnerable to the effects of endocrine disrupting chemicals (EDCs). Molecular fingerprints of EDCs can be identified via microRNA (miRNA) expression profiles and may be etiologically implicated in the developmental origin of disease (DOHaD). Methods/design: This pilot study includes pregnant women at high risk (smoking at conception), and low risk (non-smoking at conception) for SGA birth (birthweight more...
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- 2019
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27. SMUG1 Promotes Telomere Maintenance through Telomerase RNA Processing
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Penelope Kroustallaki, Lisa Lirussi, Sergio Carracedo, Panpan You, Q. Ying Esbensen, Alexandra Götz, Laure Jobert, Lene Alsøe, Pål Sætrom, Sarantis Gagos, and Hilde Nilsen
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Biology (General) ,QH301-705.5 - Abstract
Summary: Telomerase biogenesis is a complex process where several steps remain poorly understood. Single-strand-selective uracil-DNA glycosylase (SMUG1) associates with the DKC1-containing H/ACA ribonucleoprotein complex, which is essential for telomerase biogenesis. Herein, we show that SMUG1 interacts with the telomeric RNA component (hTERC) and is required for co-transcriptional processing of the nascent transcript into mature hTERC. We demonstrate that SMUG1 regulates the presence of base modifications in hTERC, in a region between the CR4/CR5 domain and the H box. Increased levels of hTERC base modifications are accompanied by reduced DKC1 binding. Loss of SMUG1 leads to an imbalance between mature hTERC and its processing intermediates, leading to the accumulation of 3′-polyadenylated and 3′-extended intermediates that are degraded in an EXOSC10-independent RNA degradation pathway. Consequently, SMUG1-deprived cells exhibit telomerase deficiency, leading to impaired bone marrow proliferation in Smug1-knockout mice. : Kroustallaki et al. show that the single-strand-selective uracil-DNA glycosylase (SMUG1) functions in telomere maintenance, by removing modified bases from telomeric DNA and also by regulating modified bases in the telomerase RNA component (hTERC). SMUG1-knockout cells accumulate hTERC containing modified bases that interfere with binding of DKC1. Consequently, SMUG1-knockout cells and mice exhibit telomere maintenance defects. Keywords: SMUG1, telomere attrition, TERC, modified bases, RNA processing more...
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- 2019
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28. Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cells
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Ben F Brian IV, Adrienne S Jolicoeur, Candace R Guerrero, Myra G Nunez, Zoi E Sychev, Siv A Hegre, Pål Sætrom, Nagy Habib, Justin M Drake, Kathryn L Schwertfeger, and Tanya S Freedman
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SFKs/Src-family kinases ,Cbl E3 ubiquitin ligase ,myeloid cell signaling ,macrophage ,mast cell ,LynA ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
The activity of Src-family kinases (SFKs), which phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs), is a critical factor regulating myeloid-cell activation. We reported previously that the SFK LynA is uniquely susceptible to rapid ubiquitin-mediated degradation in macrophages, functioning as a rheostat regulating signaling (Freedman et al., 2015). We now report the mechanism by which LynA is preferentially targeted for degradation and how cell specificity is built into the LynA rheostat. Using genetic, biochemical, and quantitative phosphopeptide analyses, we found that the E3 ubiquitin ligase c-Cbl preferentially targets LynA via a phosphorylated tyrosine (Y32) in its unique region. This distinct mode of c-Cbl recognition depresses steady-state expression of LynA in macrophages derived from mice. Mast cells, however, express little c-Cbl and have correspondingly high LynA. Upon activation, mast-cell LynA is not rapidly degraded, and SFK-mediated signaling is amplified relative to macrophages. Cell-specific c-Cbl expression thus builds cell specificity into the LynA checkpoint. more...
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- 2019
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29. Establishment of a Patient-Derived Xenograft Model of Colorectal Cancer in CIEA NOG Mice and Exploring Smartfish Liquid Diet as a Source of Omega-3 Fatty Acids
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Helle Samdal, Lene C Olsen, Knut S Grøn, Elin S Røyset, Therese S Høiem, Ingunn Nervik, Pål Sætrom, Arne Wibe, Svanhild A Schønberg, and Caroline H H Pettersen
- Subjects
PDX ,patient-derived xenograft ,CRC ,colorectal cancer ,omega-3 fatty acids ,Biology (General) ,QH301-705.5 - Abstract
Cancer patient-derived xenografts (PDXs) better preserve tumor characteristics and microenvironment than traditional cancer cell line derived xenografts and are becoming a valuable model in translational cancer research and personalized medicine. We have established a PDX model for colorectal cancer (CRC) in CIEA NOG mice with a 50% engraftment rate. Tumor fragments from patients with CRC (n = 5) were engrafted in four mice per tumor (n = 20). Mice with established PDXs received a liquid diet enriched with fish oil or placebo, and fatty acid profiling was performed to measure fatty acid content in whole blood. Moreover, a biobank consisting of tissue and blood samples from patients was established. Histology, immunohistochemistry and in situ hybridization procedures were used for staining of tumor and xenograft tissue slides. Results demonstrate that key histological characteristics of the patients’ tumors were retained in the established PDXs, and the liquid diets were consumed as intended by the mice. Some of the older mice developed lymphomas that originated from human Ki67+, CD45+, and EBV+ lymphoid cells. We present a detailed description of the process and methodology, as well as possible issues that may arise, to refine the method and improve PDX engraftment rate for future studies. The established PDX model for CRC can be used for exploring different cancer treatment regimes, and liquid diets enriched with fish oil may be successfully delivered to the mice through the drinking flasks. more...
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- 2021
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30. Pathway Analysis of Skin from Psoriasis Patients after Adalimumab Treatment Reveals New Early Events in the Anti-Inflammatory Mechanism of Anti-TNF-α.
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Ane Langkilde, Lene C Olsen, Pål Sætrom, Finn Drabløs, Søren Besenbacher, Line Raaby, Claus Johansen, and Lars Iversen
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Medicine ,Science - Abstract
Psoriasis is a chronic cutaneous inflammatory disease. The immunopathogenesis is a complex interplay between T cells, dendritic cells and the epidermis in which T cells and dendritic cells maintain skin inflammation. Anti-tumour necrosis factor (anti-TNF)-α agents have been approved for therapeutic use across a range of inflammatory disorders including psoriasis, but the anti-inflammatory mechanisms of anti-TNF-α in lesional psoriatic skin are not fully understood. We investigated early events in skin from psoriasis patients after treatment with anti-TNF-α antibodies by use of bioinformatics tools. We used the Human Gene 1.0 ST Array to analyse gene expression in punch biopsies taken from psoriatic patients before and also 4 and 14 days after initiation of treatment with the anti-TNF-α agent adalimumab. The gene expression was analysed by gene set enrichment analysis using the Functional Annotation Tool from DAVID Bioinformatics Resources. The most enriched pathway was visualised by the Pathview Package on Kyoto Encyclopedia of Genes and Genomes (KEGG) graphs. The analysis revealed new very early events in psoriasis after adalimumab treatment. Some of these events have been described after longer periods of anti-TNF-α treatment when clinical and histological changes appear, suggesting that effects of anti-TNF-α treatment on gene expression appear very early before clinical and histological changes. Combining microarray data on biopsies from psoriasis patients with pathway analysis allowed us to integrate in vitro findings into the identification of mechanisms that may be important in vivo. Furthermore, these results may reflect primary effect of anti-TNF-α treatment in contrast to studies of gene expression changes following clinical and histological changes, which may reflect secondary changes correlated to the healing of the skin. more...
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- 2016
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31. Human Breast Milk miRNA, Maternal Probiotic Supplementation and Atopic Dermatitis in Offspring.
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Melanie Rae Simpson, Gaute Brede, Jostein Johansen, Roar Johnsen, Ola Storrø, Pål Sætrom, and Torbjørn Øien
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Medicine ,Science - Abstract
Perinatal probiotic ingestion has been shown to prevent atopic dermatitis (AD) in infancy in a number of randomised trials. The Probiotics in the Prevention of Allergy among Children in Trondheim (ProPACT) trial involved a probiotic supplementation regime given solely to mothers in the perinatal period and demonstrated a ~40% relative risk reduction in the cumulative incidence of AD at 2 years of age. However, the mechanisms behind this effect are incompletely understood. Micro-RNAs (miRNA) are abundant in mammalian milk and may influence the developing gastrointestinal and immune systems of newborn infants. The objectives of this study were to describe the miRNA profile of human breast milk, and to investigate breast milk miRNAs as possible mediators of the observed preventative effect of probiotics.Small RNA sequencing was conducted on samples collected 3 months postpartum from 54 women participating in the ProPACT trial. Differential expression of miRNA was assessed for the probiotic vs placebo and AD vs non-AD groups. The results were further analysed using functional prediction techniques.Human breast milk samples contain a relatively stable core group of highly expressed miRNAs, including miR-148a-3p, miR-22-3p, miR-30d-5p, let-7b-5p and miR-200a-3p. Functional analysis of these miRNAs revealed enrichment in a broad range of biological processes and molecular functions. Although several miRNAs were found to be differentially expressed on comparison of the probiotic vs placebo and AD vs non-AD groups, none had an acceptable false discovery rate and their biological significance in the development of AD is not immediately apparent from their predicted functional consequences.Whilst breast milk miRNAs have the potential to be active in a diverse range of tissues and biological process, individual miRNAs in breast milk 3 months postpartum are unlikely to play a major role in the prevention of atopic dermatitis in infancy by probiotics ingestion in the perinatal period.ClinicalTrials.gov NCT00159523. more...
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- 2015
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