A de novo paradigm for male infertility

Genetics of Male Infertility Initiative (GEMINI) consortium: Donald F. Conrad, Liina Nagirnaja, Kenneth I. Aston, Douglas T. Carrell, James M. Hotaling, Timothy G. Jenkins, Rob McLachlan, Moira K. O’Bryan, Peter N. Schlegel, Michael L. Eisenberg, Jay I. Sandlow, Emily S. Jungheim, Kenan R. Omurtag, Alexandra M. Lopes, Susana Seixas, Filipa Carvalho, Susana Fernandes, Alberto Barros, João Gonçalves, Iris Caetano, Graça Pinto, Sónia Correia, Maris Laan, Margus Punab, Ewa Rajpert-De Meyts, Niels Jørgensen, Kristian Almstrup, Csilla G. Krausz & Keith A. Jarvi.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.This project was funded by The Netherlands Organization for Scientific Research (918-15-667) to J.A.V. as well as an Investigator Award in Science from the Wellcome Trust (209451) to J.A.V. a grant from the Catherine van Tussenbroek Foundation to M.S.O. a grant from MERCK to R.S. a UUKi Rutherford Fund Fellowship awarded to B.J.H. and the German Research Foundation Clinical Research Unit “Male Germ Cells” (DFG, CRU326) to C.F. and F.T. This project was also supported in part by funding from the Australian National Health and Medical Research Council (APP1120356) to M.K.O.B., by grants from the National Institutes of Health of the United States of America (R01HD078641 to D.F.C. and K.I.A., P50HD096723 to D.F.C.) and from the Biotechnology and Biological Sciences Research Council (BB/S008039/1) to D.J.E.info:eu-repo/semantics/publishedVersio

Cytokeratins in bladder cancer: an immunohistochemical study on features of tumor progression

Contains fulltext : mmubn000001_16143830x.pdf (publisher's version ) (Open Access)Promotores : F. Ramaekers en D. Ruiter184 p

Synchronous penile metastasis from a high-grade adenocarcinoma of the prostate

Contains fulltext : 109659.pdf (publisher's version ) (Open Access)Metastasis to the glans penis is a rare phenomenon and usually occurs in a late stage of disease. A 68-year-old man was referred to our clinic because of two indurated lesions of the glans penis and minor lower urinary tract symptoms. Digital rectal examination revealed a hard nodular prostate, and serum prostate-specific antigen (sPSA) level was 13.3 ng/mL. Biopsies of the penile lesions and transrectal ultrasound-guided prostate biopsies were taken. Immunohistochemical staining of formalin-fixed paraffin-embedded tissue exposed a synchronous penile metastasis from a high-grade adenocarcinoma of the prostate. Except a pathologically enlarged lymph node detected with MRI there was no suspicion on other metastases. Currently this patient is being treated with a Gonadoreline (GnRH) antagonist. Nevertheless, the prognosis will be poor

Comparison of P53 protein overexpression with P53 mutation in bladder cancer: clinical and biologic aspects

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Giant cell tumor of the sacrum or soft tissue giant cell tumor? A case report.

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The value of neoadjuvant therapy in localized prostate cancer

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Relative absorption and dermal loading of chemical substances: Consequences for risk assessment

Quantification of skin absorption is an essential step in reducing the uncertainty of dermal risk assessment. Data from literature indicate that the relative dermal absorption of substances is dependent on dermal loading. Therefore, an internal exposure calculated with absorption data determined at a dermal loading not comparable to the actual loading may lead to a wrong assessment of the actual health risk. To investigate the relationship between dermal loading and relative absorption in a quantitative manner, 138 dermal publicly available absorption experiments with 98 substances were evaluated (87 in vitro, 51 in vivo; molecular weight between 40 and 950, log P between -5 and 13), with dermal loading ranging mostly between 0.001 and 10 mg/cm2. In 87 experiments (63%) an inverse relationship was observed between relative dermal absorption and dermal loading, with an average decrease of factor 33 ± 69. Known skin irritating and volatile substances less frequently showed an inverse relationship between dermal loading and relative absorption. © 2009 Elsevier Inc. All rights reserved

Cytokeratin and vimentin expression in normal epithelium and benign and benign lesions of the vocal cords

Contains fulltext : 23618___.PDF (publisher's version ) (Open Access

Cytokeratin expression patterns in benign lesions of the vocal cords

Contains fulltext : 23619___.PDF (publisher's version ) (Open Access