195 results on '"Almstrup K"'
Search Results
2. Possible involvement of the glucocorticoid receptor (NR3C1) and selected NR3C1 gene variants in regulation of human testicular function
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Nordkap, L., Almstrup, K., Nielsen, J. E., Bang, A. K., Priskorn, L., Krause, M., Holmboe, S. A., Winge, S. B., Egeberg Palme, D. L., Mørup, N., Petersen, J. H., Juul, A., Skakkebæk, N. E., Rajpert‐De Meyts, E., and Jørgensen, N.
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- 2017
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3. The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans
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Wyrwoll, MJ, Gaasbeek, CM, Golubickaite, I, Stakaitis, R, Oud, MS, Nagirnaja, L, Dion, C, Sindi, EB, Leitch, HG, Jayasena, CN, Sironen, A, Dicke, A-K, Rotte, N, Stallmeyer, B, Kliesch, S, Grangeiro, CHP, Araujo, TF, Lasko, P, Genetics of Male Infertility Initiative (GEMINI) consortium, D'Hauwers, K, Smits, RM, Ramos, L, Xavier, MJ, Conrad, DF, Almstrup, K, Veltman, JA, Tüttelmann, F, Van der Heijden, GW, and National Institute for Health Research
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Male ,male infertility ,Tacrolimus Binding Proteins ,LINE-1 ,Mice ,Semen ,Testis ,meiosis ,Animals ,Humans ,genetics ,RNA, Small Interfering ,Spermatogenesis ,Genetics (clinical) ,11 Medical and Health Sciences ,Infertility, Male ,Azoospermia ,Genetics & Heredity ,Genetics of Male Infertility Initiative (GEMINI) consortium ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Other Research Radboud Institute for Health Sciences [Radboudumc 0] ,06 Biological Sciences ,oligozoospermia ,Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10] ,FKBP6 ,Long Interspersed Nucleotide Elements ,round spermatid arrest ,piRNA-pathway - Abstract
Contains fulltext : 282942.pdf (Publisher’s version ) (Open Access) Infertility affects around 7% of the male population and can be due to severe spermatogenic failure (SPGF), resulting in no or very few sperm in the ejaculate. We initially identified a homozygous frameshift variant in FKBP6 in a man with extreme oligozoospermia. Subsequently, we screened a total of 2,699 men with SPGF and detected rare bi-allelic loss-of-function variants in FKBP6 in five additional persons. All six individuals had no or extremely few sperm in the ejaculate, which were not suitable for medically assisted reproduction. Evaluation of testicular tissue revealed an arrest at the stage of round spermatids. Lack of FKBP6 expression in the testis was confirmed by RT-qPCR and immunofluorescence staining. In mice, Fkbp6 is essential for spermatogenesis and has been described as being involved in piRNA biogenesis and formation of the synaptonemal complex (SC). We did not detect FKBP6 as part of the SC in normal human spermatocytes, but small RNA sequencing revealed that loss of FKBP6 severely impacted piRNA levels, supporting a role for FKBP6 in piRNA biogenesis in humans. In contrast to findings in piRNA-pathway mouse models, we did not detect an increase in LINE-1 expression in men with pathogenic FKBP6 variants. Based on our findings, FKBP6 reaches a "strong" level of evidence for being associated with male infertility according to the ClinGen criteria, making it directly applicable for clinical diagnostics. This will improve patient care by providing a causal diagnosis and will help to predict chances for successful surgical sperm retrieval.
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- 2022
4. A de novo paradigm for male infertility
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Oud M.S., Smits R.M., Smith H.E., Mastrorosa F.K., Holt G.S., Houston B.J., de Vries P.F., Alobaidi B.K.S., Batty L.E., Ismail H., Greenwood J., Sheth H., Mikulasova A., Astuti G.D.N., Gilissen C., McEleny K., Turner H., Coxhead J., Cockell S., Braat D.D.M., Fleischer K., D’Hauwers K.W.M., Schaafsma E., Carrell D.T., Hotaling J.M., Jenkins T.G., McLachlan R., Schlegel P.N., Eisenberg M.L., Sandlow J.I., Jungheim E.S., Omurtag K.R., Lopes A.M., Seixas S., Carvalho F., Fernandes S., Barros A., Gonçalves J., Caetano I., Pinto G., Correia S., Laan M., Punab M., Meyts E.R.-D., Jørgensen N., Almstrup K., Krausz C.G., Jarvi K.A., Nagirnaja L., Conrad D.F., Friedrich C., Kliesch S., Aston K.I., Riera-Escamilla A., Krausz C., Gonzaga-Jauregui C., Santibanez-Koref M., Elliott D.J., Vissers L.E.L.M., Tüttelmann F., O’Bryan M.K., Ramos L., Xavier M.J., van der Heijden G.W., Veltman J.A., and Genetics of Male Infertility Initiative (GEMINI) consortium
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Adult ,Male ,phenotype ,Mutation, Missense ,Gene Expression ,Cell Cycle Proteins ,Whole Exome Sequencing ,loss of function mutation ,cell cycle protein ,gene expression profiling ,Humans ,genetics ,Exome ,Genetic Predisposition to Disease ,human ,tumor suppressor protein ,oligospermia ,Azoospermia ,missense mutation ,Tumor Suppressor Proteins ,RNA-Binding Proteins ,case control study ,RNA binding protein ,DNA binding protein ,RBM5 protein, human ,DNA-Binding Proteins ,Case-Control Studies ,RNA ,pathology ,mutation ,infertility ,genetic predisposition - Abstract
De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10-5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10-4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility. © 2022, The Author(s).
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- 2022
5. Syncytin-1 and its receptor is present in human gametes
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Bjerregaard, B., Lemmen, J. G., Petersen, M. R., Østrup, E., Iversen, L. H., Almstrup, K., Larsson, L.-I., and Ziebe, S.
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- 2014
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6. O-228 The SSRI antidepressant Sertraline inhibits CatSper calcium channels in human sperm
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Rahban, R, primary, Rehfeld, A, additional, Schiffer, C, additional, Brenker, C, additional, Palme, D. Louise Egeberg, additional, Wang, T, additional, Lorenz, J, additional, Almstrup, K, additional, Skakkebaek, N E, additional, Strünker, T, additional, and Nef, S, additional
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- 2021
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7. Screening for carcinoma in situ in the contralateral testicle in patients with testicular cancer: a population-based study
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Kier, M. G. G., Lauritsen, J., Almstrup, K., Mortensen, M. S., Toft, B. G., Rajpert-De Meyts, E., Skakkebaek, N. E., Rørth, M., von der Maase, H., Agerbaek, M., Holm, N. V., Andersen, K. K., Dalton, S. O., Johansen, C., and Daugaard, G.
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- 2015
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8. A survey of etiologic hypotheses among testicular cancer researchers
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Stang, A., Trabert, B., Rusner, C., Poole, C., Almstrup, K., Meyts, E. Rajpert-De, and McGlynn, K. A.
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- 2015
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9. Increasing international efforts to understand and conquer testicular germ cell cancer
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Meyts, E. Rajpert-De, Daugaard, G., Almstrup, K., Jrgensen, A., Rrth, M., Jrgensen, N., von der Maase, H., and Skakkebaek, N. E.
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- 2015
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10. Carcinoma in situ testis displays permissive chromatin modifications similar to immature foetal germ cells
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Almstrup, K, Nielsen, J E, Mlynarska, O, Jansen, M T, Jørgensen, A, Skakkebæk, N E, and Rajpert-De Meyts, E
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- 2010
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11. Image cytometer method for automated assessment of human spermatozoa concentration
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Egeberg, D. L., Kjærulff, S., Hansen, C., Petersen, J. H., Glensbjerg, M., Skakkebæk, N. E., Jrgensen, N., and Almstrup, K.
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- 2013
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12. A novel double staining strategy for improved detection of testicular carcinoma in situ cells in human semen samples
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Nielsen, J. E., Kristensen, D. M., Almstrup, K., Jrgensen, A., Olesen, I. A., Jacobsen, G. K., Horn, T., Skakkebæk, N. E., Leffers, H., and Rajpert-De Meyts, E.
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- 2012
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13. Screening of subfertile men for testicular carcinoma in situ by an automated image analysis-based cytological test of the ejaculate
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Almstrup, K., Lippert, M., Mogensen, H. O., Nielsen, J. E., Hansen, J. D., Daugaard, G., Jrgensen, N., Foged, N. T., Skakkebæk, N. E., and Rajpert-De Meyts, E.
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- 2011
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14. Lipoprotein lipase and endothelial lipase in human testis and in germ cell neoplasms
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Nielsen, J. E., Lindegaard, M. L., Friis-Hansen, L., Almstrup, K., Leffers, H., Nielsen, L. B., and Rajpert-De Meyts, E.
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- 2010
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15. Stem cell pluripotency factor NANOG is expressed in human fetal gonocytes, testicular carcinoma in situ and germ cell tumours
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Hoei-Hansen, C E, Almstrup, K, Nielsen, J E, Sonne, S Brask, Graem, N, Skakkebaek, N E, Leffers, H, and De Meyts, E Rajpert
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- 2005
16. A subfertile patient diagnosed with testicular carcinoma in situ by immunocytological staining for AP-2γ in semen samples: Case report
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Hoei-Hansen, C.E., Rajpert-De Meyts, E., Carlsen, E., Almstrup, K., Leffers, H., and Skakkebaek, N.E.
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- 2005
17. Identification of genes differentially expressed in testes containing carcinoma in situ
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Hoei-Hansen, C.E., Nielsen, J.E., Almstrup, K., Hansen, M.A., Skakkebaek, N.E., Rajpert-DeMeyts, E., and Leffers, H.
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- 2004
18. Developmental origins of testicular germ cell tumours (TGCT)
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Rajpert-De Meyts, E., primary, Jørgensen, A., additional, Jørgensen, N., additional, Almstrup, K., additional, and Skakkebaek, N.E., additional
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- 2019
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19. Decrease in semen quality and Leydig cell function in infertile men: a longitudinal study
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Olesen, I A, primary, Joensen, U N, additional, Petersen, J H, additional, Almstrup, K, additional, Rajpert-De Meyts, E, additional, Carlsen, E, additional, McLachlan, R, additional, Juul, A, additional, and Jørgensen, N, additional
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- 2018
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20. EDC IMPACT: Chemical UV filters can affect human sperm function in a progesterone-like manner
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Rehfeld, A, primary, Egeberg, D L, additional, Almstrup, K, additional, Petersen, J H, additional, Dissing, S, additional, and Skakkebæk, N E, additional
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- 2018
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21. Is the FSHR 2039A>G variant associated with susceptibility to testicular germ cell cancer?
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Bang, A. K., primary, Busch, A. S., additional, Almstrup, K., additional, Gromoll, J., additional, Kliesch, S., additional, Rajpert-De Meyts, E., additional, Skakkebaek, N. E., additional, Juul, A., additional, Tüttelmann, F., additional, and Jørgensen, N., additional
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- 2017
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22. A survey of etiologic hypotheses among testicular cancer researchers
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Rajpert-De Meyts, E., Almstrup, K., and McGlynn, K. A.
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Basic research results can provide new ideas and hypotheses to be examined in epidemiological studies. We conducted a survey among testicular cancer researchers on hypotheses concerning the etiology of this malignancy. All researchers on the mailing list of Copenhagen Testis Cancer Workshops and corresponding authors of PubMed-indexed articles identified by the search term “testicular cancer” and published within 10 years (in total 2750 recipients) were invited to respond to an e-mail based survey. Participants of the 8th Copenhagen Testis Cancer Workshop in May 2014 were subsequently asked to rate the plausibility of the suggested etiologic hypotheses on a scale of 1 (very implausible) to 10 (very plausible). This report describes the methodology of the survey, the score distributions by individual hypotheses, hypothesis group and the participants’ major research fields, and discuss the hypotheses that scored as most plausible. We also present plans for improving the survey that may be repeated at a next international meeting of experts in testicular cancer.
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- 2015
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23. GCT-17 - Developmental origins of testicular germ cell tumours (TGCT)
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Rajpert-De Meyts, E., Jørgensen, A., Jørgensen, N., Almstrup, K., and Skakkebaek, N.E.
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- 2019
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24. Screening for carcinomain situ in the contralateral testicle in patients with testicular cancer: a population-based study
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Kier, M.G.G., primary, Lauritsen, J., additional, Almstrup, K., additional, Mortensen, M.S., additional, Toft, B.G., additional, Rajpert-De Meyts, E., additional, Skakkebaek, N.E., additional, Rørth, M., additional, von der Maase, H., additional, Agerbaek, M., additional, Holm, N.V., additional, Andersen, K.K., additional, Dalton, S.O., additional, Johansen, C., additional, and Daugaard, G., additional
- Published
- 2015
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25. Increasing international efforts to understand and conquer testicular germ cell cancer
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Rajpert‐De Meyts, E., primary, Daugaard, G., additional, Almstrup, K., additional, Jørgensen, A., additional, Rørth, M., additional, Jørgensen, N., additional, von der Maase, H., additional, and Skakkebaek, N. E., additional
- Published
- 2015
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26. A survey of etiologic hypotheses among testicular cancer researchers
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Stang, A., primary, Trabert, B., additional, Rusner, C., additional, Poole, C., additional, Almstrup, K., additional, Rajpert‐De Meyts, E., additional, and McGlynn, K. A., additional
- Published
- 2014
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27. A Tortoiseshell Male Cat: Chromosome Analysis and Histologic Examination of the Testis
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Pedersen, A.S., primary, Berg, L.C., additional, Almstrup, K., additional, and Thomsen, P.D., additional
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- 2013
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28. Evidence that active demethylation mechanisms maintain the genome of carcinoma in situ cells hypomethylated in the adult testis
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Kristensen, D G, primary, Nielsen, J E, additional, Jørgensen, A, additional, Skakkebæk, N E, additional, Rajpert-De Meyts, E, additional, and Almstrup, K, additional
- Published
- 2013
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29. A novel double staining strategy for improved detection of testicular carcinoma in situ cells in human semen samples
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Nielsen, J. E., primary, Kristensen, D. M., additional, Almstrup, K., additional, Jørgensen, A., additional, Olesen, I. A., additional, Jacobsen, G. K., additional, Horn, T., additional, Skakkebaek, N. E., additional, Leffers, H., additional, and Rajpert-De Meyts, E., additional
- Published
- 2011
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30. Genome-wide gene expression profiling of testicular carcinoma in situ progression into overt tumours
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Almstrup, K, primary, Hoei-Hansen, C E, additional, Nielsen, J E, additional, Wirkner, U, additional, Ansorge, W, additional, Skakkebæk, N E, additional, Rajpert-De Meyts, E, additional, and Leffers, H, additional
- Published
- 2005
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31. Evidence that active demethylation mechanisms maintain the genome of carcinoma in situ cells hypomethylated in the adult testis.
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Kristensen, D G, Nielsen, J E, Jørgensen, A, Skakkebæk, N E, Rajpert-De Meyts, E, and Almstrup, K
- Abstract
Background: Developmental arrest of fetal germ cells may lead to neoplastic transformation and formation of germ cell tumours via carcinoma in situ (CIS) cells. Normal fetal germ cell development requires complete erasure and re-establishment of DNA methylation. In contrast to normal spermatogonia, the genome of CIS cells remains unmethylated in the adult testis. We here investigated the possible active and passive pathways that can sustain the CIS genome hypomethylated in the adult testis.Methods: The levels of 5-methyl-cytosine (5mC) and 5-hydroxy-methyl-cytosine (5hmC) in DNA from micro-dissected CIS cells were assessed by quantitative measurements. The expression of TET1, TET2, APOBEC1, MBD4, APEX1, PARP1, DNMT1, DNMT3A, DNMT3B and DNMT3L in adult testis specimens with CIS and in human fetal testis was investigated by immunohistochemistry and immunofluorescence.Results: DNA from micro-dissected CIS cells contained very low levels of 5hmC produced by ten eleven translocation (TET) enzymes. CIS cells and fetal germ cells expressed the suggested initiator of active demethylation, APOBEC1, and the base excision repair proteins MBD4, APEX1 and PARP1, whereas TETs - the alternative initiators were absent. Both maintenance and de novo methyltransferases were detected in CIS cells.Conclusion: The data are consistent with the presence of an active DNA de-methylation pathway in CIS cells. The hypomethylated genome of CIS cells may contribute to phenotypic plasticity and invasive capabilities of this testicular cancer precursor. [ABSTRACT FROM AUTHOR]- Published
- 2014
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32. A Tortoiseshell Male Cat: Chromosome Analysis and Histologic Examination of the Testis.
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Pedersen, a.S., Berg, L.C., almstrup, K., and Thomsen, P.D.
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TORTOISESHELL cats ,CAT genetics ,CHROMOSOMES ,KLINEFELTER'S syndrome ,FIBROBLASTS - Abstract
Tortoiseshell coat color is normally restricted to female cats due to X-linkage of the gene that encodes the orange coat color. Tortoiseshell male cats do, however, occur at a low frequency among tortoiseshell cats because of chromosome aberrations similar to the Klinefelter syndrome in man: the extra X chromosome of a 39,XXY karyotype introduces the possibility of an orange and a non-orange allele which produce the mixture of orange and non-orange coat spotting known as tortoiseshell. We analyzed the chromosome complement of a fibroblast culture and did histological examinations of testicular tissue from a tortoiseshell male cat referred to us. Chromosome analysis using RBA-banding consistently revealed a 39,XXY karyotype. Histological examinations of testis biopsies from this cat showed degeneration of the tubules, hyperplasia of the interstitial tissue, and complete loss of germ cells. Immunostaining using anti-vimentin and anti-VASA (DDX4) showed that only Sertoli cells and no germ cells were observed in the testicular tubules. As no sign of spermatogenesis was detected, we conclude that this is a classic case of a sterile, male tortoiseshell cat with a 39,XXY chromosome complement. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
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- 2014
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33. Involvement of epigenetic modifiers in the pathogenesis of testicular dysgenesis and germ cell cancer
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Lawaetz Andreas C. and Almstrup Kristian
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epigenetic modifiers ,germ cell cancer ,jumonji c-domain containing ,testicular dysgenesis ,Biology (General) ,QH301-705.5 - Abstract
Testicular germ cell cancer manifests mainly in young adults as a seminoma or non-seminoma. The solid tumors are preceded by the presence of a non-invasive precursor cell, the carcinoma in situ cell (CIS), which shows great similarity to fetal germ cells. It is therefore hypothesized that the CIS cell is a fetal germ cell that has been arrested during development due to testicular dysgenesis. CIS cells retain a fetal and open chromatin structure, and recently several epigenetic modifiers have been suggested to be involved in testicular dysgenesis in mice. We here review the possible involvement of epigenetic modifiers with a focus on jumonji C enzymes in the development of testicular dysgenesis and germ cell cancer in men.
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- 2015
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34. Gene expression profiles of mouse spermatogenesis during recovery from irradiation
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Skakkebæk Niels E, Kobayashi Shinichi, Iwamoto Teruaki, Nielsen John E, Tanaka Masami, Shah Fozia J, Leffers Henrik, and Almstrup Kristian
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Gynecology and obstetrics ,RG1-991 ,Reproduction ,QH471-489 - Abstract
Abstract Background Irradiation or chemotherapy that suspend normal spermatogenesis is commonly used to treat various cancers. Fortunately, spermatogenesis in many cases can be restored after such treatments but knowledge is limited about the re-initiation process. Earlier studies have described the cellular changes that happen during recovery from irradiation by means of histology. We have earlier generated gene expression profiles during induction of spermatogenesis in mouse postnatal developing testes and found a correlation between profiles and the expressing cell types. The aim of the present work was to utilize the link between expression profile and cell types to follow the cellular changes that occur during post-irradiation recovery of spermatogenesis in order to describe recovery by means of gene expression. Methods Adult mouse testes were subjected to irradiation with 1 Gy or a fractionated radiation of two times 1 Gy. Testes were sampled every third or fourth day to follow the recovery of spermatogenesis and gene expression profiles generated by means of differential display RT-PCR. In situ hybridization was in addition performed to verify cell-type specific gene expression patterns. Results Irradiation of mice testis created a gap in spermatogenesis, which was initiated by loss of A1 to B-spermatogonia and lasted for approximately 10 days. Irradiation with 2 times 1 Gy showed a more pronounced effect on germ cell elimination than with 1 Gy, but spermatogenesis was in both cases completely reconstituted 42 days after irradiation. Comparison of expression profiles indicated that the cellular reconstitution appeared equivalent to what is observed during induction of normal spermatogenesis. Conclusion The data indicates that recovery of spermatogenesis can be monitored by means of gene expression, which could aid in designing radiation treatment regimes for cancer patients leading to better restoration of spermatogenesis.
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- 2009
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35. S17-02 Exposure and effect markers during firefighting activities – Danish intervention studies.
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Andersen, M.H.G., Saber, A.T., N⊘rskov, E.-C., Frederiksen, M., Grünfeld, J., M⊘ller, P., Loft, S., Petersen, K.U., Almstrup, K., and Vogel, U.
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- *
FIREFIGHTING - Published
- 2024
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36. Variant , Defective piRNA Processing, and Azoospermia.
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Nagirnaja, L., Mørup, N., Nielsen, J. E., Stakaitis, R., Golubickaite, I., Oud, M. S., Winge, S. B., Carvalho, F., Aston, K. I., Khani, ⌈., van der Heijden, G. W., Marques, C. J., Skakkebaek, N. E., Rajpert-De Meyts, E., Schlegel, P. N., Jorgensen, N., Veltman, J. A., Lopes, A. M., Conrad, D. F., and Almstrup, K.
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MALE infertility , *MISSENSE mutation , *DNA sequencing , *CELL populations , *GERM cells , *GENE expression , *AZOOSPERMIA , *RNA metabolism , *TESTIS , *RESEARCH , *GENETIC mutation , *BIOPSY , *SEQUENCE analysis , *RESEARCH methodology , *CELL physiology , *RNA , *EVALUATION research , *INFERTILITY , *COMPARATIVE studies , *RESEARCH funding , *ESTERASES , *POLYMERASE chain reaction , *PHENOTYPES - Abstract
Background: P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are short (21 to 35 nucleotides in length) and noncoding and are found almost exclusively in germ cells, where they regulate aberrant expression of transposable elements and postmeiotic gene expression. Critical to the processing of piRNAs is the protein poly(A)-specific RNase-like domain containing 1 (PNLDC1), which trims their 3' ends and, when disrupted in mice, causes azoospermia and male infertility.Methods: We performed exome sequencing on DNA samples from 924 men who had received a diagnosis of nonobstructive azoospermia. Testicular-biopsy samples were analyzed by means of histologic and immunohistochemical tests, in situ hybridization, reverse-transcriptase-quantitative-polymerase-chain-reaction assay, and small-RNA sequencing.Results: Four unrelated men of Middle Eastern descent who had nonobstructive azoospermia were found to carry mutations in PNLDC1: the first patient had a biallelic stop-gain mutation, p.R452Ter (rs200629089; minor allele frequency, 0.00004); the second, a novel biallelic missense variant, p.P84S; the third, two compound heterozygous mutations consisting of p.M259T (rs141903829; minor allele frequency, 0.0007) and p.L35PfsTer3 (rs754159168; minor allele frequency, 0.00004); and the fourth, a novel biallelic canonical splice acceptor site variant, c.607-2A→T. Testicular histologic findings consistently showed error-prone meiosis and spermatogenic arrest with round spermatids of type Sa as the most advanced population of germ cells. Gene and protein expression of PNLDC1, as well as the piRNA-processing proteins PIWIL1, PIWIL4, MYBL1, and TDRKH, were greatly diminished in cells of the testes. Furthermore, the length distribution of piRNAs and the number of pachytene piRNAs was significantly altered in men carrying PNLDC1 mutations.Conclusions: Our results suggest a direct mechanistic effect of faulty piRNA processing on meiosis and spermatogenesis in men, ultimately leading to male infertility. (Funded by Innovation Fund Denmark and others.). [ABSTRACT FROM AUTHOR]- Published
- 2021
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37. RUBIC (ReproUnion Biobank and Infertility Cohort): A binational clinical foundation to study risk factors, life course, and treatment of infertility and infertility‐related morbidity
- Author
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Kristian Almstrup, Angel Elenkov, Yvonne Lundberg Giwercman, Nina la Cour Freiesleben, Lars Rylander, Anja Pinborg, Jorge E. Chavarro, Ann Holm Hansen, Lone Schmidt, Ilpo Huhtaniemi, Kristina Wendelboe Olsen, Stephen A. Krawetz, Nathalie F Wang, Ditte Vassard, Henriette Svarre Nielsen, Shalender Bhasin, Marie Louise Grøndahl, E. V. Bräuner, Russ Hauser, Pernille Fog Svendsen, Anders Juul, Sandra Søgaard Tøttenborg, Jorma Toppari, Jonatan Axelsson, Anne Zedeler, Emir Henic, Ellen Leth Løkkegaard, Margareta Laczna Kitlinski, György Marko-Varga, Christian H. Lindh, Anna-Maria Andersson, Niels Jørgensen, Lærke Priskorn, Johan Malm, Kajsa Uglevig Petersen, Laura Smidt Hansen, Andrea Salonia, Sacha Stormlund, Michael L. Eisenberg, Aleksander Giwercman, Selma Kloeve Landersoe, Priskorn, L., Tottenborg, S. S., Almstrup, K., Andersson, A. -M., Axelsson, J., Brauner, E. V., Elenkov, A., Freiesleben, N. L. C., Giwercman, Y. L., Grondahl, M. L., Hansen, A. H., Hansen, L. S., Henic, E., Kitlinski, M. L., Landersoe, S. K., Lindh, C., Lokkegaard, E. L., Malm, J., Olsen, K. W., Petersen, K. U., Schmidt, L., Stormlund, S., Svendsen, P. F., Vassard, D., Wang, N. F., Zedeler, A., Bhasin, S., Chavarro, J., Eisenberg, M. L., Hauser, R., Huhtaniemi, I., Krawetz, S. A., Marko-Varga, G., Salonia, A., Toppari, J., Juul, A., Jorgensen, N., Nielsen, H. S., Pinborg, A., Rylander, L., and Giwercman, A.
- Subjects
Adult ,Male ,medically assisted reproduction ,Infertility ,medicine.medical_specialty ,Medication history ,Denmark ,Urology ,Endocrinology, Diabetes and Metabolism ,media_common.quotation_subject ,Reproductive medicine ,Fertility ,human microbiome/microbiota ,03 medical and health sciences ,Reproductive Techniques ,semen quality ,0302 clinical medicine ,Endocrinology ,Pregnancy ,Risk Factors ,medicine ,Humans ,Prospective Studies ,Biological Specimen Banks ,media_common ,Sweden ,030219 obstetrics & reproductive medicine ,epigenetics ,business.industry ,Public health ,Pregnancy Outcome ,reproductive disorders ,medicine.disease ,Biobank ,Reproductive Medicine ,Family medicine ,Cohort ,Female ,infertility ,business ,Live birth ,Biomarkers - Abstract
Background Infertility affects 15-25% of all couples during their reproductive life span. It is a significant societal and public health problem with potential psychological, social, and economic consequences. Furthermore, infertility has been linked to adverse long-term health outcomes. Despite the advanced diagnostic and therapeutic techniques available, approximately 30% of infertile couples do not obtain a live birth after fertility treatment. For these couples, there are no further options to increase their chances of a successful pregnancy and live birth. Objectives Three overall questions will be studied: 1) What are the risk factors and natural life courses of infertility, early embryonic loss, and adverse pregnancy outcomes? 2) Can we develop new diagnostic and prognostic biomarkers for fecundity and treatment success? And 3) what are the health characteristics of women and men in infertile couples at the time of fertility treatment and during long-term follow-up? Material and methods ReproUnion Biobank and Infertility Cohort (RUBIC) is established as an add-on to the routine fertility management at Copenhagen University Hospital Departments in the Capital Region of Denmark and Reproductive Medicine Centre at Skane University Hospital in Sweden. The aim is to include a total of 5000 couples equally distributed between Denmark and Sweden. The first patients were enrolled in June 2020. All eligible infertile couples are prospectively asked to participate in the project. Participants complete an extensive questionnaire and undergo a physical examination and collection of bio-specimens (blood, urine, hair, saliva, rectal swabs, feces, semen, endometrial biopsies, and vaginal swabs). After the cohort is established, the couples will be linked to the Danish and Swedish national registers to obtain information on parental, perinatal, childhood, and adult life histories, including disease and medication history. This will enable us to understand the causes of infertility and identify novel therapeutic options for this important societal problem. This article is protected by copyright. All rights reserved.
- Published
- 2021
38. Prospective reproductive outcomes according to sperm parameters, including DNA fragmentation, in recurrent pregnancy loss.
- Author
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Krog MC, Nielsen JR, Slot A, Hviid KV, Kolte AM, Westergaard D, Bliddal S, Almstrup K, and Nielsen HS
- Subjects
- Humans, Female, Male, Pregnancy, Adult, Prospective Studies, Live Birth, Semen Analysis, Pregnancy Rate, DNA Fragmentation, Abortion, Habitual, Spermatozoa, Pregnancy Outcome epidemiology
- Abstract
Research Question: Are the prospective reproductive outcomes in couples experiencing recurrent pregnancy loss (RPL) related to the sperm DNA fragmentation index (DFI), as measured by sperm chromatin structure assay, sperm morphology and sperm concentration at referral?, Design: This prospective cohort study included 95 couples seen between 1 April 2018 and 1 December 2019 at the tertiary Copenhagen RPL Unit, Copenhagen University Hospital, Rigshospitalet and Hvidovre Hospital, Denmark. The couples had experienced three or more unexplained consecutive pregnancy losses or two late pregnancy losses (>12 weeks gestation). Follow-up was 12-31 months., Results: Eighty-one of 95 (85.3%) couples achieved pregnancy after referral. In the first pregnancy after referral, 46 (56.8%) couples achieved a live birth, and 35 (43.2%) couples experienced another pregnancy loss. There was no significant difference in baseline DFI between couples that experienced pregnancy loss [median 11.7, interquartile range (IQR) 9.1-17.3] and couples that achieved a live birth (median 12.5, IQR 9.3-16.5; P = 0.971). Improving sperm morphology increased the odds of a live birth after referral (adjusted OR 1.26, 95% CI 1.05-1.52; P = 0.014). DFI and sperm concentration were not associated with the outcome of the first pregnancy after referral. Overall, 35.9% of the men had DFI ≥15 at inclusion. Couples that failed to achieve pregnancy had a higher median DFI of 17.7 (IQR 7.7-27.2) compared with the rest of the cohort (median 12.0, IQR 9.3-16.5; P = 0.041)., Conclusions: At referral, sperm DFI, morphology and concentration cannot be used to identify RPL couples at risk of another pregnancy loss. Increased baseline DFI was associated with difficulty achieving another pregnancy, and improving sperm morphology was associated with increased odds of a live birth., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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39. X‑chromosome loss rescues Sertoli cell maturation and spermatogenesis in Klinefelter syndrome.
- Author
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Winge SB, Skakkebaek NE, Aksglaede L, Saritaş G, Rajpert-De Meyts E, Goossens E, Juul A, and Almstrup K
- Subjects
- Male, Animals, Humans, Mice, Chromosomes, Human, X genetics, X Chromosome genetics, Klinefelter Syndrome genetics, Klinefelter Syndrome pathology, Klinefelter Syndrome metabolism, Sertoli Cells metabolism, Sertoli Cells pathology, Spermatogenesis genetics, RNA, Long Noncoding genetics, RNA, Long Noncoding metabolism
- Abstract
Klinefelter syndrome (47,XXY) causes infertility with a testicular histology comprising two types of Sertoli cell-only tubules, representing mature and immature-like Sertoli cells, and occasionally focal spermatogenesis. Here, we show that the immature-like Sertoli cells highly expressed XIST and had two X-chromosomes, while the mature Sertoli cells lacked XIST expression and had only one X-chromosome. Sertoli cells supporting focal spermatogenesis also lacked XIST expression and the additional X-chromosome, while the spermatogonia expressed XIST despite having only one X-chromosome. XIST was expressed in Sertoli cells until puberty, where a gradual loss was observed. Our results suggest that a micro-mosaic loss of the additional X-chromosome is needed for Sertoli cells to mature and to allow focal spermatogenesis., (© 2024. The Author(s).)
- Published
- 2024
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40. New analysis of atypical spermatocytic tumours reveals extensive heterogeneity and plasticity of germ cell tumours † .
- Author
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Rajpert-De Meyts E, Goriely A, and Almstrup K
- Subjects
- Male, Humans, Mutation, Neoplasms, Germ Cell and Embryonal genetics, Testicular Neoplasms metabolism, Seminoma genetics
- Abstract
Testicular germ cell tumours (TGCTs) derived from immature (type I) and pluripotent germ cell neoplasia in situ (GCNIS, type II) are characterised by remarkable phenotypic heterogeneity and plasticity. In contrast, the rare spermatocytic tumour (SpT, type III), derived from mature spermatogonia, is considered a homogenous and benign tumour but may occasionally present as an anaplastic or an aggressive sarcomatoid tumour. While various oncogenic processes had been proposed, the precise mechanism driving malignant progression remained elusive until the molecular characterisation of a series of atypical SpTs described in a recent issue of The Journal of Pathology. The emerging picture suggests the presence of two distinct trajectories for SpTs, involving either RAS/mitogen-activated protein kinase pathway mutations or a ploidy shift with secondary TP53 mutations and/or gain of chromosome 12p, the latter known as pathognomonic for type II GCNIS-derived TGCTs. Here, we discuss the implications of these findings, seen from the perspective of germ cell biology and the unique features of different TGCTs. The evolving phenotype of SpTs, induced by genomic and epigenetic changes, illustrates that the concept of plasticity applies to all germ cell tumours, making them inherently heterogenous and capable of significant transformation during progression. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)
- Published
- 2024
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41. Cohort profile: The Copenhagen Analgesic Study-The COPANA cohort.
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Fischer MB, Mola G, Scheel L, Wraae KB, Rom AL, Frederiksen H, Johannsen TH, Almstrup K, Sundberg K, Hegaard HK, Juul A, and Hagen CP
- Subjects
- Humans, Female, Pregnancy, Male, Adult, Prospective Studies, Denmark epidemiology, Endocrine Disruptors adverse effects, Pregnancy Trimester, First, Infant, Newborn, Maternal Exposure adverse effects, Prenatal Exposure Delayed Effects epidemiology, Analgesics therapeutic use, Analgesics adverse effects
- Abstract
Background: Development of the gonads during fetal life is complex and vital for adult reproductive health. Cell and animal studies have shown an alarming effect of mild analgesics on germ cells in both males and females. More than 50% of pregnant women use mild analgesics during pregnancy, which potentially could compromise the reproductive health of the next generation., Objectives: We present a research protocol designed to evaluate the effect of prenatal exposure to mild analgesics and endocrine-disrupting chemicals on gonadal function in the offspring., Population: Healthy, singleton pregnant women and their partners., Design: The COPANA cohort is a prospective, observational pregnancy and birth cohort., Methods: Participants were enrolled during the first trimester of pregnancy. Information on the use of mild analgesics was collected retrospectively 3 months prior to pregnancy and prospectively every 2 weeks throughout the study. We collected extensive data on lifestyle and reproductive health. Biospecimens were collected in the first trimester (maternal and paternal urine- and blood samples), in the third trimester in conjunction with a study-specific ultrasound scan (maternal urine sample), and approximately 3 months post-partum during the infant minipuberty period (maternal and infant urine- and blood samples). A comprehensive evaluation of reproductive function in the infants during the minipuberty phase was performed, including an ultrasound scan of the testis or ovaries and uterus., Preliminary Results: In total, 685 pregnant women and their partners were included between March 2020 and January 2022. A total of 589 infants (287 males) and their parents completed the follow-up during the minipuberty phase (December 2020-November 2022)., Conclusions: The Copenhagen Analgesic Study holds the potential to provide novel and comprehensive insights into the impact of early and late prenatal exposure to mild analgesics and other endocrine-disrupting chemicals on future reproductive function in the offspring., (© 2024 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)
- Published
- 2024
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42. Sequencing Identifies Novel Genetic Variants Associated with High-risk Testicular Cancer.
- Author
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Almstrup K and Rajpert-De Meyts E
- Subjects
- Male, Humans, Mutation, Genetic Predisposition to Disease, Testicular Neoplasms genetics
- Published
- 2024
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43. Identification and comparison of m6A modifications in glioblastoma non-coding RNAs with MeRIP-seq and Nanopore dRNA-seq.
- Author
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Krusnauskas R, Stakaitis R, Steponaitis G, Almstrup K, and Vaitkiene P
- Subjects
- Humans, Exome Sequencing, DNA Methylation, RNA, Untranslated, Adenosine, Immunoprecipitation, Glioblastoma, RNA, Long Noncoding, Nanopores, Glioma
- Abstract
The most prominent RNA modification - N6-methyladenosine (m6A) - affects gene regulation and cancer progression. The extent and effect of m6A on long non-coding RNAs (lncRNAs) is, however, still not clear. The most established method for m6A detection is methylated RNA immunoprecipitation and sequencing (MeRIP-seq). However, Oxford Nanopore Technologies recently developed direct RNA-seq (dRNA-seq) method, allowing m6A identification at higher resolution and in its native form. We performed whole transcriptome sequencing of the glioblastoma cell line U87-MG with both MeRIP-seq and dRNA-seq. For MeRIP-seq, m6A peaks were identified using nf-core/chipseq, and for dRNA-seq - EpiNano pipeline. MeRIP-seq analysis revealed 5086 lncRNAs transcripts, while dRNA-seq identified 336 lncRNAs transcripts from which 556 and 198 were found to be m6A modified, respectively. While 24 lncRNAs with m6A overlapped between two methods. Gliovis database analysis revealed that the expression of the major part of identified overlapping lncRNAs was associated with glioma grade or patient survival prognosis. We found that the frequency of m6A occurrence in lncRNAs varied more than 9-fold throughout the provided list of 24 modified lncRNAs. The highest m6A frequency was detected in MIR1915HG, THAP9-AS1, MALAT1, NORAD1 , and NEAT1 ( 49-88nt), while MIR99AHG, SNHG3, LOXL1-AS1, ILF3-DT showed the lowest m6A frequency (445-261nt). Taken together, (1) we provide a high accuracy list of 24 m6A modified lncRNAs of U87-MG cells; (2) we conclude that MeRIP-seq is more suitable for an initial m6A screening study, due to its higher lncRNA coverage, whereas dRNA-seq is most useful when more in-depth analysis of m6A quantity and precise location is of interest. Abbreviations: (dRNA-seq) direct RNA-seq, (GBM) glioblastoma, (LGG) low-grade glioma, (lncRNAs) long non-coding RNAs, (m6A) N6-methyladenosine, (MeRIP-seq) methylated RNA immunoprecipitation and sequencing, (ncRNA) non-coding RNA, (ONT) Oxford Nanopore Technologi; Lietuvos Mokslo Taryba.
- Published
- 2023
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44. Characterizing the evolution and phenotypic impact of ampliconic Y chromosome regions.
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Lucotte EA, Guðmundsdóttir VB, Jensen JM, Skov L, Macià MC, Almstrup K, Schierup MH, Helgason A, and Stefansson K
- Subjects
- Humans, Male, Phylogeny, Y Chromosome, Chromosomes, Human, Y genetics, Phenotype, DNA Copy Number Variations genetics, Evolution, Molecular
- Abstract
A major part of the human Y chromosome consists of palindromes with multiple copies of genes primarily expressed in testis, many of which have been claimed to affect male fertility. Here we examine copy number variation in these palindromes based on whole genome sequence data from 11,527 Icelandic men. Using a subset of 7947 men grouped into 1449 patrilineal genealogies, we infer 57 large scale de novo copy number mutations affecting palindrome 1. This corresponds to a mutation rate of 2.34 × 10
-3 mutations per meiosis, which is 4.1 times larger than our phylogenetic estimate of the mutation rate (5.72 × 10-4 ), suggesting that de novo mutations on the Y are lost faster than expected under neutral evolution. Although simulations indicate a selection coefficient of 1.8% against non-reference copy number carriers, we do not observe differences in fertility among sequenced men associated with their copy number genotype, but we lack statistical power to detect differences resulting from weak negative selection. We also perform association testing of a diverse set of 341 traits to palindromic copy number without any significant associations. We conclude that large-scale palindrome copy number variation on the Y chromosome has little impact on human phenotype diversity., (© 2023. The Author(s).)- Published
- 2023
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45. The seminal plasma microbiome of men with testicular germ cell tumours described by small RNA sequencing.
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Mørup N, Main AM, Jørgensen N, Daugaard G, Juul A, and Almstrup K
- Subjects
- Humans, Male, Semen metabolism, Sequence Analysis, RNA, Testicular Neoplasms metabolism, Neoplasms, Germ Cell and Embryonal
- Abstract
Background: It has been estimated that microorganisms are involved in the pathogenesis of approximately 20% of all cancers. Testicular germ cell tumours (TGCTs) are the most common type of malignancy in young men and arise from the precursor cell, germ cell neoplasia in situ (GCNIS). The microbiome of seminal plasma and testicular tissue has not been thoroughly investigated in regard to TGCTs., Objectives: To investigate the differences in the seminal plasma microbiome between men with TGCT or GCNIS-only compared with controls., Materials and Methods: The study population consisted of patients with GCNIS-only (n = 5), TGCT (n = 18), and controls (n = 25) with different levels of sperm counts in the ejaculate. RNA was isolated from the seminal plasma and sequenced. Reads not mapping to the human genome were aligned against a set of 2784 bacterial/archaeal and 4336 viral genomes using the Kraken pipeline., Results: We identified reads from 2172 species and most counts were from Alteromonas mediterranea, Falconid herpesvirus 1, and Stigmatella aurantiaca. Six species (Acaryochloris marina, Halovirus HGTV-1, Thermaerobacter marianensis, Thioalkalivibrio sp. K90mix, Burkholderia sp. YI23, and Desulfurivibrio alkaliphilus) were found in significantly (q-value < 0.05) higher levels in the seminal plasma of TGCT and GCNIS-only patients compared with controls. In contrast, Streptomyces phage VWB was found at significantly higher levels among controls compared with TGCT and GCNIS-only patients combined., Discussion: Often the microbiome is analysed by shotgun or 16S ribosomal sequencing whereas our present data build on small RNA sequencing. This allowed us to identify more viruses and phages compared with previous studies but also makes the results difficult to directly compare., Conclusion: Our study is the first to report identification of the microbiome species in seminal plasma of men with TGCT and GCNIS-only, which potentially could be involved in the pathogenesis of TGCTs. Further studies are, however, needed to confirm our findings., (© 2022 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)
- Published
- 2023
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46. Small RNAs in andrology: Small messengers with large perspectives.
- Author
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Almstrup K
- Subjects
- Andrology, MicroRNAs
- Published
- 2023
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47. Circulating levels and the bioactivity of miR-30b increase during pubertal progression in boys.
- Author
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Mørup N, Stakaitis R, Main AM, Golubickaite I, Hagen CP, Juul A, and Almstrup K
- Subjects
- Male, Gonadotropin-Releasing Hormone metabolism, Hypothalamus metabolism, Humans, MicroRNAs genetics, Circulating MicroRNA genetics, Puberty
- Abstract
Background: Puberty marks the transition from childhood to adulthood and is initiated by activation of a pulsatile GnRH secretion from the hypothalamus. MKRN3 functions as a pre-pubertal break on the GnRH pulse generator and hypothalamic expression and circulating levels of MKRN3 decrease peri-pubertally. In rodents, microRNA miR-30b seems to directly target hypothalamic MKRN3 expression - and in boys, circulating levels of miR-30b-5p increase when puberty is pharmacologically induced. Similarly, miR-200b-3p and miR-155-5p have been suggested to inhibit expression of other proteins potentially involved in the regulation of GnRH secretion. Here we measure circulating levels of these three miRNAs as boys progress through puberty., Materials and Methods: Forty-six boys from the longitudinal part of the Copenhagen Puberty Study were included. All boys underwent successive clinical examinations including estimation of testis size by palpation. miR-30b-5p, miR-200b-3p, and miR-155-5p were measured in serum by RT-qPCR using a kit sensitive to the phosphorylation status of the miRNAs. Thirty-nine boys had miRNA levels measured in three consecutive samples (pre-, peri-, and post-pubertally) and seven boys had miR-30b-5p levels measured in ten consecutive samples during the pubertal transition., Results: When circulating levels of miR-30b-5p in pre- and peri-pubertal samples were compared with post-pubertal levels, we observed a significant increase of 2.3 and 2.2-fold (p-value<6.0×10
-4 ), respectively, and a larger fraction of miR-30b-5p appeared to be phosphorylated post-pubertally indicating an increase in its bioactivity. We also observed a negative correlation between circulating levels of miR-30b-5p and MKRN3. The inter-individual variation in circulating miR-30b levels was substantial and we could not define a clinical threshold for miR-30b-5p suggestive of imminent puberty. Also, miR-155-5p showed significantly increasing levels from the peri- to the post-pubertal stage (p=3.0×10-3 ), whereas miR-200b-3p did not consistently increase., Conclusion: Both circulating levels of miR-30b-5p and its bioactivity increase during the pubertal transition in boys supporting its role in the activation of the HPG axis at the onset of physiologically normal puberty., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mørup, Stakaitis, Main, Golubickaite, Hagen, Juul and Almstrup.)- Published
- 2023
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48. The molecular evolution of spermatogenesis across mammals.
- Author
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Murat F, Mbengue N, Winge SB, Trefzer T, Leushkin E, Sepp M, Cardoso-Moreira M, Schmidt J, Schneider C, Mößinger K, Brüning T, Lamanna F, Belles MR, Conrad C, Kondova I, Bontrop R, Behr R, Khaitovich P, Pääbo S, Marques-Bonet T, Grützner F, Almstrup K, Schierup MH, and Kaessmann H
- Subjects
- Animals, Male, Chromatin genetics, Meiosis genetics, Transcriptome, Single-Cell Analysis, Birds genetics, Primates genetics, Gene Expression Regulation, Spermatogonia cytology, Sertoli Cells cytology, X Chromosome genetics, Y Chromosome genetics, Dosage Compensation, Genetic, Gene Silencing, Evolution, Molecular, Mammals genetics, Spermatogenesis genetics, Testis cytology
- Abstract
The testis produces gametes through spermatogenesis and evolves rapidly at both the morphological and molecular level in mammals
1-6 , probably owing to the evolutionary pressure on males to be reproductively successful7 . However, the molecular evolution of individual spermatogenic cell types across mammals remains largely uncharacterized. Here we report evolutionary analyses of single-nucleus transcriptome data for testes from 11 species that cover the three main mammalian lineages (eutherians, marsupials and monotremes) and birds (the evolutionary outgroup), and include seven primates. We find that the rapid evolution of the testis was driven by accelerated fixation rates of gene expression changes, amino acid substitutions and new genes in late spermatogenic stages, probably facilitated by reduced pleiotropic constraints, haploid selection and transcriptionally permissive chromatin. We identify temporal expression changes of individual genes across species and conserved expression programs controlling ancestral spermatogenic processes. Genes predominantly expressed in spermatogonia (germ cells fuelling spermatogenesis) and Sertoli (somatic support) cells accumulated on X chromosomes during evolution, presumably owing to male-beneficial selective forces. Further work identified transcriptomal differences between X- and Y-bearing spermatids and uncovered that meiotic sex-chromosome inactivation (MSCI) also occurs in monotremes and hence is common to mammalian sex-chromosome systems. Thus, the mechanism of meiotic silencing of unsynapsed chromatin, which underlies MSCI, is an ancestral mammalian feature. Our study illuminates the molecular evolution of spermatogenesis and associated selective forces, and provides a resource for investigating the biology of the testis across mammals., (© 2022. The Author(s).)- Published
- 2023
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49. Diverse monogenic subforms of human spermatogenic failure.
- Author
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Nagirnaja L, Lopes AM, Charng WL, Miller B, Stakaitis R, Golubickaite I, Stendahl A, Luan T, Friedrich C, Mahyari E, Fadial E, Kasak L, Vigh-Conrad K, Oud MS, Xavier MJ, Cheers SR, James ER, Guo J, Jenkins TG, Riera-Escamilla A, Barros A, Carvalho F, Fernandes S, Gonçalves J, Gurnett CA, Jørgensen N, Jezek D, Jungheim ES, Kliesch S, McLachlan RI, Omurtag KR, Pilatz A, Sandlow JI, Smith J, Eisenberg ML, Hotaling JM, Jarvi KA, Punab M, Rajpert-De Meyts E, Carrell DT, Krausz C, Laan M, O'Bryan MK, Schlegel PN, Tüttelmann F, Veltman JA, Almstrup K, Aston KI, and Conrad DF
- Subjects
- Humans, Male, Animals, Mice, Testis pathology, Spermatogenesis genetics, Azoospermia genetics, Azoospermia pathology, Infertility, Male genetics, Infertility, Male pathology
- Abstract
Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%. We find further support for 21 genes in a 2-stage burden test with 2072 cases and 11,587 fertile controls. The disrupted genes are primarily on the autosomes, enriched for undescribed human "knockouts", and, for the most part, have yet to be linked to a Mendelian trait. Integration with single-cell RNA sequencing data shows that azoospermia genes can be grouped into molecular subforms with synchronized expression patterns, and analogs of these subforms exist in mice. This analysis framework identifies groups of genes with known roles in spermatogenesis but also reveals unrecognized subforms, such as a set of genes expressed across mitotic divisions of differentiating spermatogonia. Our findings highlight NOA as an understudied Mendelian disorder and provide a conceptual structure for organizing the complex genetics of male infertility, which may provide a rational basis for disease classification., (© 2022. The Author(s).)
- Published
- 2022
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50. Hair cortisol, glucocorticoid gene receptor polymorphisms, stress, and testicular function.
- Author
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Nordkap L, Almstrup K, Priskorn L, Bang AK, Stalder T, Petersen JH, Hansen ÅM, Juul A, Johannsen TH, and Jørgensen N
- Abstract
Objective: Self-reported psychological stress has been associated with decreased semen quality. Cortisol levels in scalp hair (hair cortisol concentration, HCC) has emerged as a potential objective marker of psychological stress. Thus, we investigated if HCC was associated with markers of testicular function. Furthermore, we examined whether three common single nucleotide polymorphisms in the glucocorticoid-receptor gene (NR3C1, chromosome 5), potentially affecting receptor sensitivity, were associated with HCC and could influence the studied association between HCC and testicular function., Design: Cross-sectional study., Methods: We analysed HCC, serum-levels of reproductive hormones, semen parameters, and the three NR3C1-polymorphisms; BclI (rs41423247), Tth111I (rs10052957), and 9β (rs6198), in a population of 696 men from the general population., Results: HCC was not associated with testicular function, and adjustment for the three NR3C1-polymorphisms did not alter the results. However, HCC increased significantly with the number of Tth111I minor-alleles (T) and decreased significantly with the number of 9β minor-alleles (G)., Conclusion: Given previously shown associations between stress and semen quality, and that no association between HCC and self-reported stress was observed in the current study, we speculate that negative reproductive effects of stress may not be mediated directly by cortisol. This study demonstrates associations between HCC and glucocorticoid receptor gene variants indicating that these SNPs may influence systemic glucocorticoid levels, but the potential health effects of such alterations are yet unknown., Competing Interests: Declaration of Competing Interest There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
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