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Article ; Online: Expression profiles of small non-coding RNAs in breast cancer tumors characterize clinicopathological features and show prognostic and predictive potential.

Kärkkäinen, Emmi / Heikkinen, Sami / Tengström, Maria / Kosma, Veli-Matti / Mannermaa, Arto / Hartikainen, Jaana M

2022 Volume 12, Issue 1, Page(s) 22614

Abstract: Precision medicine approaches are required for more effective therapies for cancer. As small non-coding RNAs (sncRNAs) have recently been suggested as intriguing candidates for cancer biomarkers and have shown potential also as novel therapeutic targets, ...

Abstract	Precision medicine approaches are required for more effective therapies for cancer. As small non-coding RNAs (sncRNAs) have recently been suggested as intriguing candidates for cancer biomarkers and have shown potential also as novel therapeutic targets, we aimed at profiling the non-miRNA sncRNAs in a large sample set to evaluate their role in invasive breast cancer (BC). We used small RNA sequencing and 195 fresh-frozen invasive BC and 22 benign breast tissue samples to identify significant associations of small nucleolar RNAs, small nuclear RNAs, and miscellaneous RNAs with the clinicopathological features and patient outcome of BC. Ninety-six and five sncRNAs significantly distinguished (Padj < 0.01) invasive local BC from benign breast tissue and metastasized BC from invasive local BC, respectively. Furthermore, 69 sncRNAs significantly associated (Padj < 0.01) with the tumor grade, hormone receptor status, subtype, and/or tumor histology. Additionally, 42 sncRNAs were observed as candidates for prognostic markers and 29 for predictive markers for radiotherapy and/or tamoxifen response (P < 0.05). We discovered the clinical relevance of sncRNAs from each studied RNA type. By introducing new sncRNA biomarker candidates for invasive BC and validating the potential of previously described ones, we have guided the way for further research that is warranted for providing novel insights into BC biology.
MeSH term(s)	Humans ; Animals ; Female ; RNA, Small Untranslated/genetics ; RNA, Small Untranslated/metabolism ; Breast Neoplasms/genetics ; Prognosis ; Sequence Analysis, RNA ; Mammary Neoplasms, Animal
Chemical Substances	RNA, Small Untranslated
Language	English
Publishing date	2022-12-30
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-26954-w
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Article ; Online: Genetic variation is a key determinant of chromatin accessibility and drives differences in the regulatory landscape of C57BL/6J and 129S1/SvImJ mice.

Mononen, Juho / Taipale, Mari / Malinen, Marjo / Velidendla, Bharadwaja / Niskanen, Einari / Levonen, Anna-Liisa / Ruotsalainen, Anna-Kaisa / Heikkinen, Sami

Nucleic acids research

2023 Volume 52, Issue 6, Page(s) 2904–2923

Abstract: Most common genetic variants associated with disease are located in non-coding regions of the genome. One mechanism by which they function is through altering transcription factor (TF) binding. In this study, we explore how genetic variation is connected ...

Abstract	Most common genetic variants associated with disease are located in non-coding regions of the genome. One mechanism by which they function is through altering transcription factor (TF) binding. In this study, we explore how genetic variation is connected to differences in the regulatory landscape of livers from C57BL/6J and 129S1/SvImJ mice fed either chow or a high-fat diet. To identify sites where regulatory variation affects TF binding and nearby gene expression, we employed an integrative analysis of H3K27ac ChIP-seq (active enhancers), ATAC-seq (chromatin accessibility) and RNA-seq (gene expression). We show that, across all these assays, the genetically driven (i.e. strain-specific) differences in the regulatory landscape are more pronounced than those modified by diet. Most notably, our analysis revealed that differentially accessible regions (DARs, N = 29635, FDR < 0.01 and fold change > 50%) are almost always strain-specific and enriched with genetic variation. Moreover, proximal DARs are highly correlated with differentially expressed genes. We also show that TF binding is affected by genetic variation, which we validate experimentally using ChIP-seq for TCF7L2 and CTCF. This study provides detailed insights into how non-coding genetic variation alters the gene regulatory landscape, and demonstrates how this can be used to study the regulatory variation influencing TF binding.
MeSH term(s)	Mice ; Animals ; Chromatin/genetics ; Mice, Inbred C57BL ; Mice, Inbred Strains ; Gene Expression Regulation ; Genetic Variation
Chemical Substances	Chromatin
Language	English
Publishing date	2023-12-28
Publishing country	England
Document type	Journal Article
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkad1225
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Article ; Online: Vitamin D Treatment Sequence Is Critical for Transcriptome Modulation of Immune Challenged Primary Human Cells.

Malmberg, Henna-Riikka / Hanel, Andrea / Taipale, Mari / Heikkinen, Sami / Carlberg, Carsten

Frontiers in immunology

2021 Volume 12, Page(s) 754056

Abstract: Microbe-associated molecular patterns, such as lipopolysaccharide (LPS) and β-glucan (BG), are surrogates of immune challenges like bacterial and fungal infections, respectively. The biologically active form of vitamin D, 1α,25-dihydroxyvitamin ... ...

Abstract	Microbe-associated molecular patterns, such as lipopolysaccharide (LPS) and β-glucan (BG), are surrogates of immune challenges like bacterial and fungal infections, respectively. The biologically active form of vitamin D, 1α,25-dihydroxyvitamin D
MeSH term(s)	Cells, Cultured ; Drug Administration Schedule ; Gene Expression Regulation/drug effects ; Humans ; Leukocytes, Mononuclear/drug effects ; Leukocytes, Mononuclear/immunology ; Leukocytes, Mononuclear/metabolism ; Lipopolysaccharides/pharmacology ; Male ; Middle Aged ; Models, Immunological ; Primary Cell Culture ; Transcriptome/drug effects ; Vitamin D/analogs & derivatives ; Vitamin D/pharmacology ; beta-Glucans/pharmacology
Chemical Substances	Lipopolysaccharides ; beta-Glucans ; dihydroxy-vitamin D3 ; Vitamin D (1406-16-2)
Language	English
Publishing date	2021-12-10
Publishing country	Switzerland
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.754056
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Article ; Online: The debatable presence of PIWI-interacting RNAs in invasive breast cancer.

Kärkkäinen, Emmi / Heikkinen, Sami / Tengström, Maria / Kosma, Veli-Matti / Mannermaa, Arto / Hartikainen, Jaana M

Cancer medicine

2021 Volume 10, Issue 11, Page(s) 3593–3603

Abstract: Numerous factors influence breast cancer (BC) prognosis, thus complicating the prediction of outcome. By identifying biomarkers that would distinguish the cases with poorer response to therapy already at the time of diagnosis, the rate of survival could ... ...

Abstract	Numerous factors influence breast cancer (BC) prognosis, thus complicating the prediction of outcome. By identifying biomarkers that would distinguish the cases with poorer response to therapy already at the time of diagnosis, the rate of survival could be improved. Lately, Piwi-interacting RNAs (piRNAs) have been introduced as potential cancer biomarkers, however, due to the recently raised challenges in piRNA annotations, further evaluation of piRNAs' involvement in cancer is required. We performed small RNA sequencing in 227 fresh-frozen breast tissue samples from the Eastern Finnish Kuopio Breast Cancer Project material to study the presence of piRNAs in BC and their associations with the clinicopathological features and outcome of BC patients. We observed the presence of three small RNAs annotated as piRNA database entries (DQ596932, DQ570994, and DQ571955) in our samples. The actual species of these RNAs however remain uncertain. All three small RNAs were upregulated in grade III tumors and DQ596932 additionally in estrogen receptor negative tumors. Furthermore, patients with estrogen receptor positive BC and higher DQ571955 had shorter relapse-free survival and poorer BC-specific survival, thus indicating DQ571955 as a candidate predictive marker for radiotherapy response in estrogen receptor positive BC. DQ596932 showed possible prognostic value in BC, whereas DQ570994 was identified as a candidate predictive marker for tamoxifen and chemotherapy response. These three small RNAs appear as candidate biomarkers for BC, which could after further investigation provide novel approaches for the treatment of therapy resistant BC. Overall, our results indicate that the prevalence of piRNAs in cancer is most likely not as comprehensive as has been previously thought.
MeSH term(s)	Antineoplastic Agents/therapeutic use ; Biomarkers, Tumor/analysis ; Breast/chemistry ; Breast Neoplasms/chemistry ; Breast Neoplasms/mortality ; Breast Neoplasms/pathology ; Breast Neoplasms/therapy ; Disease-Free Survival ; Female ; Humans ; Neoplasm Grading ; Prognosis ; RNA, Small Interfering/analysis ; Radiotherapy ; Receptors, Estrogen/analysis ; Sequence Analysis, RNA ; Tamoxifen/therapeutic use ; Treatment Outcome ; Up-Regulation
Chemical Substances	Antineoplastic Agents ; Biomarkers, Tumor ; RNA, Small Interfering ; Receptors, Estrogen ; Tamoxifen (094ZI81Y45)
Language	English
Publishing date	2021-05-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2659751-2
ISSN	2045-7634 ; 2045-7634
ISSN (online)	2045-7634
ISSN	2045-7634
DOI	10.1002/cam4.3915
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Article ; Online: Brainstem atrophy is linked to extrapyramidal symptoms in frontotemporal dementia.

Heikkinen, Sami / Cajanus, Antti / Katisko, Kasper / Hartikainen, Päivi / Vanninen, Ritva / Haapasalo, Annakaisa / Krüger, Johanna / Remes, Anne M / Solje, Eino

Journal of neurology

2022 Volume 269, Issue 8, Page(s) 4488–4497

Abstract: Extrapyramidal (EP) symptoms are a known feature in a subpopulation of patients with behavioral variant frontotemporal dementia (bvFTD). Concomitant EP symptoms with FTD-like neuropsychiatric symptoms are also core features in progressive supranuclear ... ...

Abstract	Extrapyramidal (EP) symptoms are a known feature in a subpopulation of patients with behavioral variant frontotemporal dementia (bvFTD). Concomitant EP symptoms with FTD-like neuropsychiatric symptoms are also core features in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). This complicates the early diagnosis of these disorders. Our retrospective register study aimed to discover imaging (MRI and FDG-PET) biomarkers to differentiate PSP, CBD, and bvFTD patients with extrapyramidal symptoms (EP +) from bvFTD patients without EP symptoms (EP-). The records of 2751 patients were screened for the diagnoses and presence of EP symptoms. A total of 222 patients were submitted to imaging analysis and applicable imaging data were recovered from 139 patients. Neuroimaging data were analyzed using Freesurfer software. In the whole cohort, EP + patients showed lower volumes of gray matter compared to EP- patients in the putamen (p = 0.002), bilateral globus pallidum (p = 0.002, p = 0.042), ventral diencephalon (p = 0.002) and brain stem (p < 0.001). In the bvFTD subgroup, there was volumetric difference between EP + and EP- patients in the brain stem. FDG-PET scans in the bvFTD patient subgroup showed that EP + patients had comparative hypometabolism of the superior cerebellar peduncle (SCP) and the frontal lobes. We discovered that EP symptoms are linked to brainstem atrophy in bvFTD patients and the whole cohort. Also, evident hypometabolism in the SCP of bvFTD EP + patients was detected as compared to bvFTD EP- patients. This could indicate that the EP symptoms in these diseases have a more caudal origin in the brainstem than in Parkinson's disease.
MeSH term(s)	Atrophy ; Basal Ganglia Diseases/diagnostic imaging ; Brain Stem ; Fluorodeoxyglucose F18 ; Frontotemporal Dementia/complications ; Frontotemporal Dementia/diagnostic imaging ; Humans ; Magnetic Resonance Imaging ; Retrospective Studies
Chemical Substances	Fluorodeoxyglucose F18 (0Z5B2CJX4D)
Language	English
Publishing date	2022-04-04
Publishing country	Germany
Document type	Journal Article
ZDB-ID	187050-6
ISSN	1432-1459 ; 0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
ISSN (online)	1432-1459
ISSN	0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
DOI	10.1007/s00415-022-11095-x
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Article: Toxicological transcriptome of human airway constructs after exposure to indoor air particulate matter: In search of relevant pathways of moisture damage-associated health effects

Nordberg, Maria-Elisa / Täubel, Martin / Heikkinen, Sami / Jalkanen, Kaisa / Köliö, Arto / Stranger, Marianne / Leppänen, Hanna / Hyvärinen, Anne / Huttunen, Kati

Environment international. 2022 Jan., v. 158

2022

Abstract: Multiple health effects are associated with moisture damage in buildings. Studies explaining these associations and cell-level mechanisms behind the observed health effects are urgently called for. We focused on characterizing gene expression in human ... ...

Abstract	Multiple health effects are associated with moisture damage in buildings. Studies explaining these associations and cell-level mechanisms behind the observed health effects are urgently called for. We focused on characterizing gene expression in human airway epithelium after exposure to indoor air particulate matter (PM) sampled from houses with and without moisture damage, alongside determination of general toxicological markers. We performed detailed technical building inspections in 25 residential houses and categorized them based on the detection of moisture damages and the probability of occupant exposure. PM sampling was complemented by microbiological and volatile organic compound assessment. We exposed human airway constructs to three dilutions (1:16, 1:8, 1:4) of collected PM from moisture-damaged (index) and non-moisture-damaged (reference) houses and imaged selected constructs with electron microscopy. We analyzed general toxicological markers and the RNA of exposed constructs was sequenced targeting genes associated with toxicological pathways. We did groupwise comparisons between index and reference houses and pairwise comparisons in matched index/reference houses. In groupwise comparison, gene Cytochrome P450 Family 1 Subfamily A Member 1 (CYP1A1) was statistically significantly over-expressed in index houses at all dilutions of collected PM and Nuclear Factor Kappa B Subunit 1 (NFKB1) at dilution 1:4 of collected PM. In pairwise index/reference house comparison, several genes related to multiple toxicological pathways were activated, largest expression differences seen for CYP1A1. However, none of the genes was consistently expressed in all the matched pairs, and general toxicological markers did not differentiate index and reference houses. The exposure to PM from index houses activated toxicology -related genes in airway constructs. Differential expression was not consistent among all the index/reference pairs, possibly due to compositional differences of bioactive particles. Our study highlights CYP1A1 and NFKB1 as potential targets in moisture damage -associated cellular responses.
Keywords	RNA ; air ; cytochrome P-450 ; electron microscopy ; environment ; epithelium ; gene expression regulation ; genes ; humans ; particulates ; probability ; toxicology ; transcription factor NF-kappa B ; transcriptome ; volatile organic compounds
Language	English
Dates of publication	2022-01
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	554791-x
ISSN	1873-6750 ; 0160-4120
ISSN (online)	1873-6750
ISSN	0160-4120
DOI	10.1016/j.envint.2021.106997
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Article ; Online: Incorporated diffusion ordered heteronuclear multiple bond correlation spectroscopy, 3D iDOSY-HMBC. Merging of diffusion delay with long polarization transfer delay of HMBC.

Perea-Buceta, Jesus / Rico Del Cerro, Daniel / Kilpeläinen, Ilkka / Heikkinen, Sami

Journal of magnetic resonance (San Diego, Calif. : 1997)

2020 Volume 323, Page(s) 106892

Abstract: 3D iDOSY-HMBC pulse sequences allow the simplification of HMBC data of mixtures via separation in the diffusion domain. The presented methods utilize incorporated DOSY approach, iDOSY, where the existing delays of the basic pulse sequence are utilized ... ...

Abstract	3D iDOSY-HMBC pulse sequences allow the simplification of HMBC data of mixtures via separation in the diffusion domain. The presented methods utilize incorporated DOSY approach, iDOSY, where the existing delays of the basic pulse sequence are utilized for diffusion attenuation. In the simplest form of the proposed 3D iDOSY-HMBC sequences, no extra delays or RF-pulses were required, only two diffusion gradients were added within HMBC polarization transfer delay.
Language	English
Publishing date	2020-12-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	1469665-4
ISSN	1096-0856 ; 1557-8968 ; 1090-7807 ; 0022-2364
ISSN (online)	1096-0856 ; 1557-8968
ISSN	1090-7807 ; 0022-2364
DOI	10.1016/j.jmr.2020.106892
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Article ; Online: Serum Cathepsin S Levels Do Not Show Alterations in Different Clinical, Neuropathological, or Genetic Subtypes of Frontotemporal Dementia Patients nor in Comparison to Healthy Control Individuals.

Heikkinen, Sami / Huber, Nadine / Katisko, Kasper / Kokkola, Tarja / Hartikainen, Päivi / Krüger, Johanna / Leinonen, Ville / Korhonen, Ville E / Herukka, Sanna-Kaisa / Remes, Anne M / Borroni, Barbara / Alberici, Antonella / Libri, Ilenia / Solje, Eino / Haapasalo, Annakaisa

Journal of Alzheimer's disease : JAD

2023 Volume 93, Issue 2, Page(s) 395–401

Abstract: Frontotemporal dementia (FTD) can manifest as diverse clinical phenotypes and is frequently caused by mutations in different genes, complicating differential diagnosis. This underlines the urgent need for valid biomarkers. Altered lysosomal and immune ... ...

Abstract	Frontotemporal dementia (FTD) can manifest as diverse clinical phenotypes and is frequently caused by mutations in different genes, complicating differential diagnosis. This underlines the urgent need for valid biomarkers. Altered lysosomal and immune functions proposedly contribute to FTD pathogenesis. Cathepsins, including cathepsin S, are enzymes preferentially expressed in brain in microglia, which influence lysosomal and immune function. Here, we examined whether alterations in serum cathepsin S levels associate with specific clinical, genetic, or neuropathological FTD subgroups, but no such alterations were observed. However, further research on other lysosomal proteins may reveal new biologically relevant biomarkers in FTD.
MeSH term(s)	Humans ; Frontotemporal Dementia/diagnosis ; tau Proteins/metabolism ; Brain/pathology ; Mutation/genetics ; Biomarkers ; Cathepsins/genetics ; Cathepsins/metabolism ; C9orf72 Protein/genetics
Chemical Substances	tau Proteins ; Biomarkers ; Cathepsins (EC 3.4.-) ; C9orf72 Protein
Language	English
Publishing date	2023-04-11
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-221060
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Article ; Online: Toxicological transcriptome of human airway constructs after exposure to indoor air particulate matter: In search of relevant pathways of moisture damage-associated health effects.

Nordberg, Maria-Elisa / Täubel, Martin / Heikkinen, Sami / Jalkanen, Kaisa / Köliö, Arto / Stranger, Marianne / Leppänen, Hanna / Hyvärinen, Anne / Huttunen, Kati

Environment international

2021 Volume 158, Page(s) 106997

Abstract: Background: Multiple health effects are associated with moisture damage in buildings. Studies explaining these associations and cell-level mechanisms behind the observed health effects are urgently called for.: Objectives: We focused on ... ...

Abstract	Background: Multiple health effects are associated with moisture damage in buildings. Studies explaining these associations and cell-level mechanisms behind the observed health effects are urgently called for. Objectives: We focused on characterizing gene expression in human airway epithelium after exposure to indoor air particulate matter (PM) sampled from houses with and without moisture damage, alongside determination of general toxicological markers. Methods: We performed detailed technical building inspections in 25 residential houses and categorized them based on the detection of moisture damages and the probability of occupant exposure. PM sampling was complemented by microbiological and volatile organic compound assessment. We exposed human airway constructs to three dilutions (1:16, 1:8, 1:4) of collected PM from moisture-damaged (index) and non-moisture-damaged (reference) houses and imaged selected constructs with electron microscopy. We analyzed general toxicological markers and the RNA of exposed constructs was sequenced targeting genes associated with toxicological pathways. We did groupwise comparisons between index and reference houses and pairwise comparisons in matched index/reference houses. Results: In groupwise comparison, gene Cytochrome P450 Family 1 Subfamily A Member 1 (CYP1A1) was statistically significantly over-expressed in index houses at all dilutions of collected PM and Nuclear Factor Kappa B Subunit 1 (NFKB1) at dilution 1:4 of collected PM. In pairwise index/reference house comparison, several genes related to multiple toxicological pathways were activated, largest expression differences seen for CYP1A1. However, none of the genes was consistently expressed in all the matched pairs, and general toxicological markers did not differentiate index and reference houses. Discussion: The exposure to PM from index houses activated toxicology -related genes in airway constructs. Differential expression was not consistent among all the index/reference pairs, possibly due to compositional differences of bioactive particles. Our study highlights CYP1A1 and NFKB1 as potential targets in moisture damage -associated cellular responses.
MeSH term(s)	Air Pollutants/analysis ; Air Pollutants/toxicity ; Air Pollution, Indoor/analysis ; Humans ; Particulate Matter/analysis ; Particulate Matter/toxicity ; Transcriptome
Chemical Substances	Air Pollutants ; Particulate Matter
Language	English
Publishing date	2021-11-26
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	554791-x
ISSN	1873-6750 ; 0160-4120
ISSN (online)	1873-6750
ISSN	0160-4120
DOI	10.1016/j.envint.2021.106997
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Article ; Online: ME-CAGEBIRD

Koskela, Harri / Kilpeläinen, Ilkka / Heikkinen, Sami

Journal of magnetic resonance (San Diego, Calif. : 1997)

2016 Volume 272, Page(s) 114–122

Abstract: ... ME- ... ...

Abstract	ME-CAGEBIRD
Language	English
Publishing date	2016-09-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	1469665-4
ISSN	1096-0856 ; 1557-8968 ; 1090-7807 ; 0022-2364
ISSN (online)	1096-0856 ; 1557-8968
ISSN	1090-7807 ; 0022-2364
DOI	10.1016/j.jmr.2016.09.012
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