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Öling, S., Struck, E., Noreen-Thorsen, M., Zwahlen, M., von Feilitzen, K., Odeberg, J., . . . Butler, L. M. (2024). A human stomach cell type transcriptome atlas. BMC Biology, 22(1), Article ID 36.
Open this publication in new window or tab >>A human stomach cell type transcriptome atlas
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2024 (English)In: BMC Biology, E-ISSN 1741-7007, Vol. 22, no 1, article id 36Article in journal (Refereed) Published
Abstract [en]

Background

The identification of cell type-specific genes and their modification under different conditions is central to our understanding of human health and disease. The stomach, a hollow organ in the upper gastrointestinal tract, provides an acidic environment that contributes to microbial defence and facilitates the activity of secreted digestive enzymes to process food and nutrients into chyme. In contrast to other sections of the gastrointestinal tract, detailed descriptions of cell type gene enrichment profiles in the stomach are absent from the major single-cell sequencing-based atlases.

Results

Here, we use an integrative correlation analysis method to predict human stomach cell type transcriptome signatures using unfractionated stomach RNAseq data from 359 individuals. We profile parietal, chief, gastric mucous, gastric enteroendocrine, mitotic, endothelial, fibroblast, macrophage, neutrophil, T-cell, and plasma cells, identifying over 1600 cell type-enriched genes.

Conclusions

We uncover the cell type expression profile of several non-coding genes strongly associated with the progression of gastric cancer and, using a sex-based subset analysis, uncover a panel of male-only chief cell-enriched genes. This study provides a roadmap to further understand human stomach biology.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2024
Keywords
Cell profiling, Gene enrichment, Bulk RNAseq, Stomach
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-524333 (URN)10.1186/s12915-024-01812-5 (DOI)001162444800002 ()38355543 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Heart Lung Foundation, 20170759Swedish Heart Lung Foundation, 20170537Swedish Heart Lung Foundation, 20200544Swedish Research Council, 2019-01493Region Stockholm, 2017–0842
Available from: 2024-03-01 Created: 2024-03-01 Last updated: 2024-03-01Bibliographically approved
Omenn, G. S., Lane, L., Overall, C. M., Lindskog, C., Pineau, C., Packer, N. H., . . . Deutsch, E. W. (2024). The 2023 Report on the Proteome from the HUPO Human Proteome Project. Journal of Proteome Research, 23(2), 532-549
Open this publication in new window or tab >>The 2023 Report on the Proteome from the HUPO Human Proteome Project
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2024 (English)In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 23, no 2, p. 532-549Article, review/survey (Refereed) Published
Abstract [en]

Since 2010, the Human Proteome Project (HPP), the flagship initiative of the Human Proteome Organization (HUPO), has pursued two goals: (1) to credibly identify the protein parts list and (2) to make proteomics an integral part of multiomics studies of human health and disease. The HPP relies on international collaboration, data sharing, standardized reanalysis of MS data sets by PeptideAtlas and MassIVE-KB using HPP Guidelines for quality assurance, integration and curation of MS and non-MS protein data by neXtProt, plus extensive use of antibody profiling carried out by the Human Protein Atlas. According to the neXtProt release 2023-04-18, protein expression has now been credibly detected (PE1) for 18,397 of the 19,778 neXtProt predicted proteins coded in the human genome (93%). Of these PE1 proteins, 17,453 were detected with mass spectrometry (MS) in accordance with HPP Guidelines and 944 by a variety of non-MS methods. The number of neXtProt PE2, PE3, and PE4 missing proteins now stands at 1381. Achieving the unambiguous identification of 93% of predicted proteins encoded from across all chromosomes represents remarkable experimental progress on the Human Proteome parts list. Meanwhile, there are several categories of predicted proteins that have proved resistant to detection regardless of protein-based methods used. Additionally there are some PE1–4 proteins that probably should be reclassified to PE5, specifically 21 LINC entries and ∼30 HERV entries; these are being addressed in the present year. Applying proteomics in a wide array of biological and clinical studies ensures integration with other omics platforms as reported by the Biology and Disease-driven HPP teams and the antibody and pathology resource pillars. Current progress has positioned the HPP to transition to its Grand Challenge Project focused on determining the primary function(s) of every protein itself and in networks and pathways within the context of human health and disease.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2024
Keywords
Human Proteome Organization (HUPO), Human Proteome Project (HPP), neXtProt protein existence (PE) metrics, missing proteins (MP), non-MS PE1 proteins, uncharacterizedprotein existence 1 (uPE1), Chromosome-centric HPP (C-HPP), Biology and Disease-HPP (B/D-HPP), PeptideAtlas, Mass Spectrometry Interactive Virtual Environment Knowledge Base (MassIVE-KB), Human Protein Atlas, Grand Challenge Project
National Category
Biochemistry and Molecular Biology Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:uu:diva-523979 (URN)10.1021/acs.jproteome.3c00591 (DOI)001157566300001 ()38232391 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationNIH (National Institutes of Health), P30ES017885-11-S1NIH (National Institutes of Health), U24CA271037NIH (National Institutes of Health), R01GM087221NIH (National Institutes of Health), R24GM127667NIH (National Institutes of Health), U19AG023122NIH (National Institutes of Health), S10OD026936NIH (National Institutes of Health), R01LM013115NIH (National Institutes of Health), R21CA263262NIH (National Institutes of Health), U01CA253217NIH (National Institutes of Health), R21CA251992NIH (National Institutes of Health), P30CA008748NIH (National Institutes of Health), U01CA263986
Available from: 2024-02-27 Created: 2024-02-27 Last updated: 2024-02-27Bibliographically approved
Méar, L., Hao, X., Hikmet Noraddin, F., Damdimopoulou, P., Rodriguez-Wallberg, K. A. & Lindskog, C. (2024). Transcriptomics and Spatial Proteomics for Discovery and Validation of Missing Proteins in the Human Ovary. Journal of Proteome Research, 23(1), 238-248
Open this publication in new window or tab >>Transcriptomics and Spatial Proteomics for Discovery and Validation of Missing Proteins in the Human Ovary
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2024 (English)In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 23, no 1, p. 238-248Article in journal (Refereed) Published
Abstract [en]

Efforts to understand the complexities of human biology encompass multidimensional aspects, with proteins emerging as crucial components. However, studying the human ovary introduces unique challenges due to its complex dynamics and changes over a lifetime, varied cellular composition, and limited sample access. Here, four new RNA-seq samples of ovarian cortex spanning ages of 7 to 32 were sequenced and added to the existing data in the Human Protein Atlas (HPA) database www.proteinatlas.org, opening the doors to unique possibilities for exploration of oocyte-specific proteins. Based on transcriptomics analysis of the four new tissue samples representing both prepubertal girls and women of fertile age, we selected 20 protein candidates that lacked previous evidence at the protein level, so-called "missing proteins" (MPs). The proteins were validated using high-resolution antibody-based profiling and single-cell transcriptomics. Fourteen proteins exhibited consistent single-cell expression patterns in oocytes and granulosa cells, confirming their presence in the ovary and suggesting that these proteins play important roles in ovarian function, thus proposing that these 14 proteins should no longer be classified as MPs. This research significantly advances the understanding of MPs, unearthing fresh avenues for prospective exploration. By integrating innovative methodologies and leveraging the wealth of data in the HPA database, these insights contribute to refining our understanding of protein roles within the human ovary and opening the doors for further investigations into missing proteins and human reproduction.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2024
Keywords
missing proteins, ovary, oocyte, ovarianfollicle, fertility, antibody-based proteomics, immunohistochemistry, bulk RNA, multiplexedimmunofluorescence, HPA
National Category
Obstetrics, Gynecology and Reproductive Medicine Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-521183 (URN)10.1021/acs.jproteome.3c00545 (DOI)001137612400001 ()38085962 (PubMedID)
Funder
EU, Horizon 2020, EU952516Knut and Alice Wallenberg FoundationSwedish Research Council, 2020-02132Swedish Research Council, 2022-02742Swedish Research Council, 2021-06116Swedish Cancer Society, 190249PjSwedish Cancer Society, 20 0170FSwedish Childhood Cancer Foundation, PR2022-0081The Cancer Research Funds of Radiumhemmet, 201313The Karolinska Institutet's Research Foundation, 2020-00339
Available from: 2024-01-22 Created: 2024-01-22 Last updated: 2024-01-22Bibliographically approved
Naguib, M., Eriksson, P., Jax, E., Wille, M., Lindskog, C., Bröjer, C., . . . Ellström, P. (2023). A Comparison of Host Responses to Infection with Wild-Type Avian Influenza Viruses in Chickens and Tufted Ducks. Microbiology Spectrum, 11(4)
Open this publication in new window or tab >>A Comparison of Host Responses to Infection with Wild-Type Avian Influenza Viruses in Chickens and Tufted Ducks
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2023 (English)In: Microbiology Spectrum, E-ISSN 2165-0497, Vol. 11, no 4Article in journal (Refereed) Published
Abstract [en]

Cross-species transmission of influenza A virus (IAV) from wild waterfowl to poultry is the first step in a chain of events that can ultimately lead to exposure and infection of humans. Herein, we study the outcome of infection with eight different mallard-origin IAV subtypes in two different avian hosts: tufted ducks and chickens. We found that infection and shedding patterns as well as innate immune responses were highly dependent on viral subtypes, host species, and inoculation routes. For example, intraoesophageal inoculation, commonly used in mallard infection experiments, resulted in no infections in contrast to oculonasal inoculation, suggesting a difference in transmission routes. Despite H9N2 being endemic in chickens, inoculation of mallard-origin H9N2 failed to cause viable infection beyond 1 day postinfection in our study design. The innate immune responses were markedly different in chickens and tufted ducks, and despite the presence of retinoic acid-inducible gene-I (RIG-I) in tufted duck transcriptomes, it was neither up nor downregulated in response to infection. Overall, we have revealed the heterogeneity of infection patterns and responses in two markedly different avian hosts following a challenge with mallard-origin IAV. These virus-host interactions provide new insights into important aspects of interspecies transmission of IAV.IMPORTANCE Our current findings highlight important aspects of IAV infection in birds that have implications for our understanding of its zoonotic ecology. In contrast to mallards where the intestinal tract is the main site of IAV replication, chickens and tufted ducks show limited or no signs of intestinal infection suggesting that the fecal-oral transmission route might not apply to all bird IAV host species. Our results indicate that mallard-origin IAVs undergo genetic changes upon introduction into new hosts, suggesting rapid adaptation to a new environment. However, similar to the mallard, chickens and tufted ducks show a limited immune response to infection with low pathogenic avian influenza viruses. These findings and future studies in different IAV hosts are important for our understanding of barriers to IAV transmission between species and ultimately from the wild reservoir to humans.

Place, publisher, year, edition, pages
American Society for Microbiology, 2023
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-519125 (URN)10.1128/spectrum.02586-22 (DOI)001016283300001 ()37358408 (PubMedID)
Funder
Swedish Research Council, 2015-03877Swedish Research Council, 2016-02606Swedish Research Council, 2016-02606Swedish Research Council, 2017-00955
Available from: 2024-01-03 Created: 2024-01-03 Last updated: 2024-01-12Bibliographically approved
Lesage, A., Lorenzini, M., Burel, S., Sarlandie, M., Bibault, F., Lindskog, C., . . . Marionneau, C. (2023). Determinants of iFGF13-mediated regulation of myocardial voltage-gated sodium (NaV) channels in mouse. The Journal of General Physiology, 155(9), Article ID e202213293.
Open this publication in new window or tab >>Determinants of iFGF13-mediated regulation of myocardial voltage-gated sodium (NaV) channels in mouse
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2023 (English)In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 155, no 9, article id e202213293Article in journal (Refereed) Published
Abstract [en]

Posttranslational regulation of cardiac Na(V)1.5 channels is critical in modulating channel expression and function, yet their regulation by phosphorylation of accessory proteins has gone largely unexplored. Using phosphoproteomic analysis of Na-V channel complexes from adult mouse left ventricles, we identified nine phosphorylation sites on intracellular fibroblast growth factor 13 (iFGF13). To explore the potential roles of these phosphosites in regulating cardiac NaV currents, we abolished expression of iFGF13 in neonatal and adult mouse ventricular myocytes and rescued it with wild-type (WT), phosphosilent, or phosphomimetic iFGF13-VY. While the increased rate of closed-state inactivation of NaV channels induced by Fgf13 knockout in adult cardiomyocytes was completely restored by adenoviral-mediated expression of WT iFGF13-VY, only partial rescue was observed in neonatal cardiomyocytes after knockdown. The knockdown of iFGF13 in neonatal ventricular myocytes also shifted the voltage dependence of channel activation toward hyperpolarized potentials, a shift that was not reversed by WT iFGF13-VY expression. Additionally, we found that iFGF13-VY is the predominant isoform in adult ventricular myocytes, whereas both iFGF13-VY and iFGF13-S are expressed comparably in neonatal ventricular myocytes. Similar to WT iFGF13-VY, each of the iFGF13-VY phosphomutants studied restored NaV channel inactivation properties in both models. Lastly, Fgf13 knockout also increased the late Na+ current in adult cardiomyocytes, and this effect was restored with expression of WT and phosphosilent iFGF13-VY. Together, our results demonstrate that iFGF13 is highly phosphorylated and displays differential isoform expression in neonatal and adult ventricular myocytes. While we found no roles for iFGF13 phosphorylation, our results demonstrate differential effects of iFGF13 on neonatal and adult mouse ventricular NaV channels.

Place, publisher, year, edition, pages
Rockefeller University Press, 2023
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-514922 (URN)10.1085/jgp.202213293 (DOI)001075625000001 ()37516919 (PubMedID)
Available from: 2023-10-26 Created: 2023-10-26 Last updated: 2023-10-26Bibliographically approved
Hikmet Noraddin, F., Rassy, M., Backman, M., Méar, L., Mattsson, J. S., Djureinovic, D., . . . Lindskog, C. (2023). Expression of cancer-testis antigens in the immune microenvironment of non-small cell lung cancer. Molecular Oncology, 17(12), 2603-2617
Open this publication in new window or tab >>Expression of cancer-testis antigens in the immune microenvironment of non-small cell lung cancer
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2023 (English)In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 17, no 12, p. 2603-2617Article in journal (Refereed) Published
Abstract [en]

The antigenic repertoire of tumors is critical for successful anti-cancer immune response and the efficacy of immunotherapy. Cancer-testis antigens (CTAs) are targets of humoral and cellular immune reactions. We aimed to characterize CTA expression in non-small cell lung cancer (NSCLC) in the context of the immune microenvironment. Of 90 CTAs validated by RNA sequencing, eight CTAs (DPEP3, EZHIP, MAGEA4, MAGEB2, MAGEC2, PAGE1, PRAME, and TKTL1) were selected for immunohistochemical profiling in cancer tissues from 328 NSCLC patients. CTA expression was compared with immune cell densities in the tumor environment and with genomic, transcriptomic, and clinical data. Most NSCLC cases (79%) expressed at least one of the analyzed CTAs, and CTA protein expression correlated generally with RNA expression. CTA profiles were associated with immune profiles: high MAGEA4 expression was related to M2 macrophages (CD163) and regulatory T cells (FOXP3), low MAGEA4 was associated with T cells (CD3), and high EZHIP was associated with plasma cell infiltration (adj. P-value < 0.05). None of the CTAs correlated with clinical outcomes. The current study provides a comprehensive evaluation of CTAs and suggests that their association with immune cells may indicate in situ immunogenic effects. The findings support the rationale to harness CTAs as targets for immunotherapy.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
cancer-testis antigens, immune phenotype, immune-oncology, non-small cell lung cancer
National Category
Cancer and Oncology Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-522496 (URN)10.1002/1878-0261.13474 (DOI)001020469000001 ()37341056 (PubMedID)
Funder
Swedish Cancer Society, 21 1790Knut and Alice Wallenberg Foundation, 2015.0344Sjöberg Foundation
Available from: 2024-02-07 Created: 2024-02-07 Last updated: 2024-02-07Bibliographically approved
Abdulla, M., Sundström, C., Lindskog, C. & Hollander, P. (2023). Expression of IDO1 and PD-L2 in Patients with Benign Lymphadenopathies and Association with Autoimmune Diseases. Biomolecules, 13(2), Article ID 240.
Open this publication in new window or tab >>Expression of IDO1 and PD-L2 in Patients with Benign Lymphadenopathies and Association with Autoimmune Diseases
2023 (English)In: Biomolecules, E-ISSN 2218-273X, Vol. 13, no 2, article id 240Article in journal (Refereed) Published
Abstract [en]

The expression patterns of IDO1 and PD-L2 have not been thoroughly investigated in benign lymphadenopathies. The aim with this study was to elucidate how IDO1 and PD-L2 are expressed in benign lymphadenopathies in patients with autoimmune diseases (AD) compared to patients without AD. Formalin-fixed paraffin-embedded lymph nodes from 22 patients with AD and 57 patients without AD were immunohistochemically stained to detect IDO1 and PD-L2. The material was previously stained with EBER in situ hybridization to detect cells harboring the Epstein-Barr virus (EBV). IDO1 and PD-L2 were generally expressed by leukocytes to low degrees, while follicular IDO1+ cells were very rare. IDO1+ cells in single germinal centers were detected in five patients, and there was a high co-occurrence of follicular EBV+ cells in these cases (three of five patients). There were also significant correlations between interfollicular EBV+ cells and interfollicular IDO1+ cells (Spearman rho = 0.32, p = 0.004) and follicular IDO1+ cells (Spearman rho = 0.34, p = 0.004). High or low amounts of IDO1+ or PD-L2+ cells were not statistically significantly associated with patients with AD. However, the lymphadenopathy with the highest amount of interfollicular IDO1+ cells, which was also the only lymphadenopathy in which endothelial cells expressed IDO1, was in a patient with sarcoidosis. This study further supports that the EBV induces the expression of IDO1 and our findings should be recognized by future studies on IDO1 and PD-L2 in inflammatory and malignant conditions.

Place, publisher, year, edition, pages
MDPI, 2023
Keywords
IDO1, PD-L2, lymphadenopathy, immunohistochemistry, histopathology
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-498546 (URN)10.3390/biom13020240 (DOI)000938382500001 ()36830609 (PubMedID)
Available from: 2023-03-22 Created: 2023-03-22 Last updated: 2023-03-22Bibliographically approved
Keller, M., Rohlf, K., Glotzbach, A., Leonhardt, G., Lueke, S., Derksen, K., . . . Marchan, R. (2023). Inhibiting the glycerophosphodiesterase EDI3 in ER-HER2+breast cancer cells resistant to HER2-targeted therapy reduces viability and tumour growth. Journal of Experimental & Clinical Cancer Research, 42, Article ID 25.
Open this publication in new window or tab >>Inhibiting the glycerophosphodiesterase EDI3 in ER-HER2+breast cancer cells resistant to HER2-targeted therapy reduces viability and tumour growth
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2023 (English)In: Journal of Experimental & Clinical Cancer Research, E-ISSN 1756-9966, Vol. 42, article id 25Article in journal (Refereed) Published
Abstract [en]

Background: Intrinsic or acquired resistance to HER2-targeted therapy is often a problem when small molecule tyrosine kinase inhibitors or antibodies are used to treat patients with HER2 positive breast cancer. Therefore, the identification of new targets and therapies for this patient group is warranted. Activated choline metabolism, characterized by elevated levels of choline-containing compounds, has been previously reported in breast cancer. The glycerophosphodiesterase EDI3 (GPCPD1), which hydrolyses glycerophosphocholine to choline and glycerol-3-phosphate, directly influences choline and phospholipid metabolism, and has been linked to cancer-relevant phenotypes in vitro. While the importance of choline metabolism has been addressed in breast cancer, the role of EDI3 in this cancer type has not been explored.

Methods: EDI3 mRNA and protein expression in human breast cancer tissue were investigated using publicly-available Affymetrix gene expression microarray datasets (n = 540) and with immunohistochemistry on a tissue microarray (n = 265), respectively. A panel of breast cancer cell lines of different molecular subtypes were used to investigate expression and activity of EDI3 in vitro. To determine whether EDI3 expression is regulated by HER2 signalling, the effect of pharmacological inhibition and siRNA silencing of HER2, as well as the influence of inhibiting key components of signalling cascades downstream of HER2 were studied. Finally, the influence of silencing and pharmacologically inhibiting EDI3 on viability was investigated in vitro and on tumour growth in vivo.

Results: In the present study, we show that EDI3 expression is highest in ER-HER2 + human breast tumours, and both expression and activity were also highest in ER-HER2 + breast cancer cell lines. Silencing HER2 using siRNA, as well as inhibiting HER2 signalling with lapatinib decreased EDI3 expression. Pathways downstream of PI3K/Akt/mTOR and GSK3 beta, and transcription factors, including HIF1 alpha, CREB and STAT3 were identified as relevant in regulating EDI3 expression. Silencing EDI3 preferentially decreased cell viability in the ER-HER2 + cells. Furthermore, silencing or pharmacologically inhibiting EDI3 using dipyridamole in ER-HER2 + cells resistant to HER2-targeted therapy decreased cell viability in vitro and tumour growth in vivo.

Conclusions: Our results indicate that EDI3 may be a potential novel therapeutic target in patients with HER2-targeted therapy-resistant ER-HER2 + breast cancer that should be further explored.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Breast cancer, HER2 positive breast cancer, Choline metabolism, HER2-targeting therapy resistance, GPCPD1
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-496265 (URN)10.1186/s13046-022-02578-w (DOI)000916085700001 ()36670508 (PubMedID)
Available from: 2023-02-10 Created: 2023-02-10 Last updated: 2023-10-02Bibliographically approved
Naslunda, O., Lipatnikova, A., Denes, A., Lindskog, C., Bontell, T. O., Smits, A., . . . Corell, A. (2023). Meningioma classification by immunohistochemistry: A replicability study. BRAIN AND SPINE, 3, Article ID 101711.
Open this publication in new window or tab >>Meningioma classification by immunohistochemistry: A replicability study
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2023 (English)In: BRAIN AND SPINE, ISSN 2772-5294, Vol. 3, article id 101711Article in journal (Refereed) Published
Abstract [en]

Introduction: Meningiomas account for nearly 40% of intracranial tumors. Recently, the immunohistochemistry (IHC) markers S100B, SCGN, ACADL and MCM2 have been shown to be associated with underlying biological subtypes of meningioma (MG1-MG4). We aimed to evaluate these IHC markers in a clinical setting.

Research question: Are the new proposed IHC markers clinically useful?

Methods: In total, 244 patients with meningiomas with tissue in TMAs were included and the IHC markers S100B, SCGN, ACADL and MCM2 were analyzed. Two sets of analyses were performed; the first included all samples with any staining considered positive, the second only samples with >10% immunopositivity. PFS and OS were analyzed in correlation to immunopositivity in the second analysis set.

Results: In the first set of analyses only 26.2% of samples could be to allocate to one group. No further analyses were performed with this selection. In the second set of analyses 52.0% could be allocated to a group. There was an enrichment of WHO grade 2 and 3 tumors in MG3 and MG4 as compared to MG1 (24.1% and 25.7% vs. 12.1%). Both the molecular group (p 1/4 0.032) and WHO grade (p 1/4 0.005) had significant impact on PFS, but only WHO grade predicted OS (p 1/4 0.033).

Conclusion: We studied the proposed new method of classifying meningiomas into groups MG1, MG2, MG3 and MG4 using IHC markers, but found difficulties applying the classification system in our material mainly due to lack of exclusivity of markers. Thus, in its present form the classification method lacks clinical applicability.

Place, publisher, year, edition, pages
Elsevier BV, 2023
Keywords
Meningioma, Molecular marker, Recurrence, Immunohistochemistry
National Category
Surgery Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-512848 (URN)10.1016/j.bas.2022.101711 (DOI)001057930700001 ()36685704 (PubMedID)
Available from: 2023-10-02 Created: 2023-10-02 Last updated: 2023-10-02Bibliographically approved
Stratmann, S., Vesterlund, M., Umer, H. M., Skaftason, A., Herlin, M. K., Sundström, C., . . . Holmfeldt, L. (2023). Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children. Leukemia, 37(3), 550-559
Open this publication in new window or tab >>Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children
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2023 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 37, no 3, p. 550-559Article in journal (Refereed) Published
Abstract [en]

Despite improvement of current treatment strategies and novel targeted drugs, relapse and treatment resistance largely determine the outcome for acute myeloid leukemia (AML) patients. To identify the underlying molecular characteristics, numerous studies have been aimed to decipher the genomic- and transcriptomic landscape of AML. Nevertheless, further molecular changes allowing malignant cells to escape treatment remain to be elucidated. Mass spectrometry is a powerful tool enabling detailed insights into proteomic changes that could explain AML relapse and resistance. Here, we investigated AML samples from 47 adult and 22 pediatric patients at serial time-points during disease progression using mass spectrometry-based in-depth proteomics. We show that the proteomic profile at relapse is enriched for mitochondrial ribosomal proteins and subunits of the respiratory chain complex, indicative of reprogrammed energy metabolism from diagnosis to relapse. Further, higher levels of granzymes and lower levels of the anti-inflammatory protein CR1/CD35 suggest an inflammatory signature promoting disease progression. Finally, through a proteogenomic approach, we detected novel peptides, which present a promising repertoire in the search for biomarkers and tumor-specific druggable targets. Altogether, this study highlights the importance of proteomic studies in holistic approaches to improve treatment and survival of AML patients.

Place, publisher, year, edition, pages
Springer Nature, 2023
Keywords
Acute myeloid leukemia, proteomics, proteogenomics, relapse and resistance
National Category
Cancer and Oncology Hematology
Research subject
Biology with specialization in Molecular Biology
Identifiers
urn:nbn:se:uu:diva-427205 (URN)10.1038/s41375-022-01796-7 (DOI)000903999000001 ()36572751 (PubMedID)
Funder
Swedish Research Council, 2018-05973Swedish Research Council, 2013-03486Knut and Alice Wallenberg Foundation, 2013-03486Swedish Childhood Cancer Foundation, PR2013-0070Swedish Childhood Cancer Foundation, TJ2013-0045Swedish Cancer Society, CAN2013/489Kjell and Marta Beijer Foundation
Note

Title in the list of papers of Svea Stratmann thesis: Proteogenomic analysis of relapsed acute myeloid leukemia in adults and children

Authors in the list of papers of Svea Stramann: S. Stratmann, M. Vesterlund, H.M. Umer, A. Skaftason, M. Krogh Herlin, C. Sundström, A. Eriksson, M. Höglund, J. Palle, J. Abrahamson, K. Jahnukainen, M. Cheng Munthe-Kaas, B. Zeller, K. Pokrovskaja Tamm, L. Cavelier, J. Lehtiö, L. Holmfeld

Available from: 2020-12-03 Created: 2020-12-03 Last updated: 2023-05-12Bibliographically approved
Projects
A multi-dimensional and spatio-temporal reference map of the human reproductive system [2022-02742_VR]; Uppsala University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-5611-1015

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