| 1. |
- Abdellah, Tebani, et al.
(författare)
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Annotation of pituitary neuroendocrine tumors with genome-wide expression analysis
- 2021
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Ingår i: Acta neuropathologica communications. - : BioMed Central (BMC). - 2051-5960. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Pituitary neuroendocrine tumors (PitNETs) are common, generally benign tumors with complex clinical characteristics related to hormone hypersecretion and/or growing sellar tumor mass. PitNETs can be classified based on the expression pattern of anterior pituitary hormones and three main transcriptions factors (TF), SF1, PIT1 and TPIT that regulate differentiation of adenohypophysial cells. Here, we have extended this classification based on the global transcriptomics landscape using tumor tissue from a well-defined cohort comprising 51 PitNETs of different clinical and histological types. The molecular profiles were compared with current classification schemes based on immunohistochemistry. Our results identified three main clusters of PitNETs that were aligned with the main pituitary TFs expression patterns. Our analyses enabled further identification of specific genes and expression patterns, including both known and unknown genes, that could distinguish the three different classes of PitNETs. We conclude that the current classification of PitNETs based on the expression of SF1, PIT1 and TPIT reflects three distinct subtypes of PitNETs with different underlying biology and partly independent from the expression of corresponding hormones. The transcriptomic analysis reveals several potentially targetable tumor-driving genes with previously unknown role in pituitary tumorigenesis.
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| 2. |
- Abdellah, Tebani, et al.
(författare)
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Integration of molecular profiles in a longitudinal wellness profiling cohort.
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies andimmune cell profiling, complementedwith gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine.
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| 3. |
- Arif, Muhammad, et al.
(författare)
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INetModels 2.0: An interactive visualization and database of multi-omics data
- 2021
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 49:W1, s. W271-W276
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Tidskriftsartikel (refereegranskat)abstract
- It is essential to reveal the associations between various omics data for a comprehensive understanding of the altered biological process in human wellness and disease. To date, very few studies have focused on collecting and exhibiting multi-omics associations in a single database. Here, we present iNetModels, an interactive database and visualization platform of Multi-Omics Biological Networks (MOBNs). This platform describes the associations between the clinical chemistry, anthropometric parameters, plasma proteomics, plasma metabolomics, as well as metagenomics for oral and gut microbiome obtained from the same individuals. Moreover, iNetModels includes tissue- and cancer-specific Gene Co-expression Networks (GCNs) for exploring the connections between the specific genes. This platform allows the user to interactively explore a single feature's association with other omics data and customize its particular context (e.g. male/female specific). The users can also register their data for sharing and visualization of the MOBNs and GCNs. Moreover, iNetModels allows users who do not have a bioinformatics background to facilitate human wellness and disease research. iNetModels can be accessed freely at https://inetmodels.com without any limitation.
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| 4. |
- Danielsson, H., et al.
(författare)
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Blood protein profiles related to preterm birth and retinopathy of prematurity
- 2022
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Ingår i: Pediatric Research. - : Springer Science and Business Media LLC. - 0031-3998 .- 1530-0447. ; 91:4, s. 937-946
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Tidskriftsartikel (refereegranskat)abstract
- Background Nearly one in ten children is born preterm. The degree of immaturity is a determinant of the infant's health. Extremely preterm infants have higher morbidity and mortality than term infants. One disease affecting extremely preterm infants is retinopathy of prematurity (ROP), a multifactorial neurovascular disease that can lead to retinal detachment and blindness. The advances in omics technology have opened up possibilities to study protein expressions thoroughly with clinical accuracy, here used to increase the understanding of protein expression in relation to immaturity and ROP. Methods Longitudinal serum protein profiles the first months after birth in 14 extremely preterm infants were integrated with perinatal and ROP data. In total, 448 unique protein targets were analyzed using Proximity Extension Assays. Results We found 20 serum proteins associated with gestational age and/or ROP functioning within mainly angiogenesis, hematopoiesis, bone regulation, immune function, and lipid metabolism. Infants with severe ROP had persistent lower levels of several identified proteins during the first postnatal months. Conclusions The study contributes to the understanding of the relationship between longitudinal serum protein levels and immaturity and abnormal retinal neurovascular development. This is essential for understanding pathophysiological mechanisms and to optimize diagnosis, treatment and prevention for ROP. Impact Longitudinal protein profiles of 14 extremely preterm infants were analyzed using a novel multiplex protein analysis platform combined with perinatal data. Proteins associated with gestational age at birth and the neurovascular disease ROP were identified. Among infants with ROP, longitudinal levels of the identified proteins remained largely unchanged during the first postnatal months. The main functions of the proteins identified were angiogenesis, hematopoiesis, immune function, bone regulation, lipid metabolism, and central nervous system development. The study contributes to the understanding of longitudinal serum protein patterns related to gestational age and their association with abnormal retinal neuro-vascular development.
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| 5. |
- Gummesson, Anders, 1973, et al.
(författare)
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Longitudinal plasma protein profiling of newly diagnosed type 2 diabetes
- 2021
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Ingår i: EBioMedicine. - : Elsevier B.V.. - 2352-3964. ; 63
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Tidskriftsartikel (refereegranskat)abstract
- Background: Comprehensive proteomics profiling may offer new insights into the dysregulated metabolic milieu of type 2 diabetes, and in the future, serve as a useful tool for personalized medicine. This calls for a better understanding of circulating protein patterns at the early stage of type 2 diabetes as well as the dynamics of protein patterns during changes in metabolic status. Methods: To elucidate the systemic alterations in early-stage diabetes and to investigate the effects on the proteome during metabolic improvement, we measured 974 circulating proteins in 52 newly diagnosed, treatment-naïve type 2 diabetes subjects at baseline and after 1 and 3 months of guideline-based diabetes treatment, while comparing their protein profiles to that of 94 subjects without diabetes. Findings: Early stage type 2 diabetes was associated with distinct protein patterns, reflecting key metabolic syndrome features including insulin resistance, adiposity, hyperglycemia and liver steatosis. The protein profiles at baseline were attenuated during guideline-based diabetes treatment and several plasma proteins associated with metformin medication independently of metabolic variables, such as circulating EPCAM. Interpretation: The results advance our knowledge about the biochemical manifestations of type 2 diabetes and suggest that comprehensive protein profiling may serve as a useful tool for metabolic phenotyping and for elucidating the biological effects of diabetes treatments. Funding: This work was supported by the Swedish Heart and Lung Foundation, the Swedish Research Council, the Erling Persson Foundation, the Knut and Alice Wallenberg Foundation, and the Swedish state under the agreement between the Swedish government and the county councils (ALF-agreement).
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| 6. |
- Jotanovic, Jelena, et al.
(författare)
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Transcriptome Analysis Reveals Distinct Patterns Between the Invasive and Noninvasive Pituitary Neuroendocrine Tumors
- 2024
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Ingår i: Journal of the Endocrine Society. - : Oxford University Press. - 2472-1972. ; 8:5
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Tidskriftsartikel (refereegranskat)abstract
- Although most pituitary neuroendocrine tumors (PitNETs)/pituitary adenomas remain intrasellar, a significant proportion of tumors show parasellar invasive growth and 6% to 8% infiltrate the bone structures, thus affecting the prognosis. There is an unmet need to identify novel markers that can predict the parasellar growth of PitNETs. Furthermore, mechanisms that regulate bone invasiveness of PitNETs and factors related to tumor vascularization are largely unknown.We used genome-wide mRNA analysis in a cohort of 77 patients with PitNETs of different types to explore the differences in gene expression patterns between invasive and noninvasive tumors with respect to the parasellar growth and regarding the rare phenomenon of bone invasiveness. Additionally, we studied the genes correlated to the contrast enhancement quotient, a novel radiological parameter of tumor vascularization.Most of the genes differentially expressed related to the parasellar growth were genes involved in tumor invasiveness. Differentially expressed genes associated with bone invasiveness are involved in NF-κB pathway and antitumoral immune response. Lack of clear clustering regarding the parasellar and bone invasiveness may be explained by the influence of the cell lineage-related genes in this heterogeneous cohort of PitNETs.Our transcriptomics analysis revealed differences in the molecular fingerprints between invasive, including bone invasive, and noninvasive PitNETs, although without clear clustering. The contrast enhancement quotient emerged as a radiological parameter of tumor vascularization, correlating with several angiogenesis-related genes. Several of the top genes related to the PitNET invasiveness and vascularization have potential prognostic and therapeutic application requiring further research.
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| 7. |
- Jotanovic, Jelena, et al.
(författare)
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Transcriptome Analysis Reveals Distinct Patterns Between the Invasive and Noninvasive Pituitary Neuroendocrine Tumors
- 2024
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Ingår i: Journal of the Endocrine Society. - : The Endocrine Society. - 2472-1972. ; 8:5
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Tidskriftsartikel (refereegranskat)abstract
- Although most pituitary neuroendocrine tumors (PitNETs)/pituitary adenomas remain intrasellar, a significant proportion of tumors show parasellar invasive growth and 6% to 8% infiltrate the bone structures, thus affecting the prognosis. There is an unmet need to identify novel markers that can predict the parasellar growth of PitNETs. Furthermore, mechanisms that regulate bone invasiveness of PitNETs and factors related to tumor vascularization are largely unknown.We used genome-wide mRNA analysis in a cohort of 77 patients with PitNETs of different types to explore the differences in gene expression patterns between invasive and noninvasive tumors with respect to the parasellar growth and regarding the rare phenomenon of bone invasiveness. Additionally, we studied the genes correlated to the contrast enhancement quotient, a novel radiological parameter of tumor vascularization.Most of the genes differentially expressed related to the parasellar growth were genes involved in tumor invasiveness. Differentially expressed genes associated with bone invasiveness are involved in NF-kappa B pathway and antitumoral immune response. Lack of clear clustering regarding the parasellar and bone invasiveness may be explained by the influence of the cell lineage-related genes in this heterogeneous cohort of PitNETs.Our transcriptomics analysis revealed differences in the molecular fingerprints between invasive, including bone invasive, and noninvasive PitNETs, although without clear clustering. The contrast enhancement quotient emerged as a radiological parameter of tumor vascularization, correlating with several angiogenesis-related genes. Several of the top genes related to the PitNET invasiveness and vascularization have potential prognostic and therapeutic application requiring further research.
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| 8. |
- Karlsson, Max J., et al.
(författare)
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Inflammation and Apolipoproteins Are Potential Biomarkers for Stratification of Cutaneous Melanoma Patients for Immunotherapy and Targeted Therapy
- 2021
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Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 81:9, s. 2545-2555
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Tidskriftsartikel (refereegranskat)abstract
- Malignant cutaneous melanoma is one of the most common cancers in young adults. During the last decade, targeted and immunotherapies have significantly increased the overall survival of patients with malignant cutaneous melanoma. Nevertheless, disease progression is common, and a lack of predictive biomarkers of patient response to therapy hinders individualized treatment strategies. To address this issue, we performed a longitudinal study using an unbiased proteomics approach to identify and quantify proteins in plasma both before and during treatment from 109 patients treated with either targeted or immunotherapy. Linear modeling and machine learning approaches identified 43 potential prognostic and predictive biomarkers. A reverse correlation between apolipoproteins and proteins related to inflammation was observed. In the immunotherapy group, patients with low pretreatment expression of apolipoproteins and high expression of inflammation markers had shorter progression-free survival. Similarly, increased expression of LDHB during treatment elicited a significant impact on response to immunotherapy. Overall, we identified potential common and treatment-specific biomarkers in malignant cutaneous melanoma, paving the way for clinical use of these biomarkers following validation on a larger cohort. Significance: This study identifies a potential biomarker panel that could improve the selection of therapy for patients with cutaneous melanoma.
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| 9. |
- Nilsson, Anders K., 1982, et al.
(författare)
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Longitudinal Serum Metabolomics in Extremely Premature Infants: Relationships With Gestational Age, Nutrition, and Morbidities
- 2022
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-453X .- 1662-4548. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- An increasing number of extremely premature infants survive the neonatal period and beyond. Little is known about the maturation of the preterm infant's metabolome and its relation to the development of morbidities. Using 1H-NMR, we investigated the serum metabolic profile of 87 infants born at a gestational age (GA) <28 weeks [mean GA (SD) 25.4 (1.4) weeks] in samples longitudinally collected from birth to term equivalent age. The infant metabolome was analyzed in relation to GA, postnatal age, nutrition, and preterm morbidities. At postnatal day 1, low GA correlated with high levels of 3-hydroxyisobutyrate, acetate, acetoacetate, acetone, formate, glucose, and valine. Nearly all quantified metabolites displayed postnatal concentration changes. For example, the two phospholipid-related metabolites myo-inositol and ethanolamine displayed a similar decline from birth over the first weeks of life, irrespectively of GA. The proportion of enteral/parenteral energy intake in the first 28 days significantly correlated with mean levels of 52% of the analyzed metabolites. Low enteral energy intake was associated with high serum levels of 3-hydroxyisobutyrate, creatinine, glucose, glycerol, histidine, lactate, leucine, lysine, methionine, ornithine, phenylalanine, proline, threonine, and uridine. There were also significant correlations between high enteral intake and high serum levels of isoleucine and tyrosine. Retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD) outcomes were not significantly associated with metabolite levels in the neonatal period after correcting for multiple testing. In conclusion, the serum metabolome of extremely premature infants changes substantially in the neonatal period, largely driven by the gradual transfer from total parenteral nutrition to full enteral feeding. Further studies are needed to disentangle the intricate relationships between the metabolome, nutritional management, GA, and the development of preterm morbidities.
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| 10. |
- Proffitt, Ceri, et al.
(författare)
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Genome-scale metabolic modelling of the human gut microbiome reveals changes in the glyoxylate and dicarboxylate metabolism in metabolic disorders
- 2022
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Ingår i: ISCIENCE. - : CELL PRESS. - 2589-0042. ; 25:7, s. 104513-
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Tidskriftsartikel (refereegranskat)abstract
- The human gut microbiome has been associated with metabolic disorders including obesity, type 2 diabetes, and atherosclerosis. Understanding the contri-bution of microbiome metabolic changes is important for elucidating the role of gut bacteria in regulating metabolism. We used available metagenomics data from these metabolic disorders, together with genome-scale metabolic modeling of key bacteria in the individual and community-level to investigate the mecha-nistic role of the gut microbiome in metabolic diseases. Modeling predicted increased levels of glutamate consumption along with the production of ammonia, arginine, and proline in gut bacteria common across the disorders. Abundance profiles and network-dependent analysis identified the enrichment of tartrate dehydrogenase in the disorders. Moreover, independent plasma metabolite levels showed associations between metabolites including proline and tyrosine and an increased tartrate metabolism in healthy obese individuals. We, therefore, propose that an increased tartrate metabolism could be a signifi-cant mediator of the microbiome metabolic changes in metabolic disorders.
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