Cochlear-optimized treatment planning in photon and proton radiosurgery for vestibular schwannoma patients

ObjectiveTo investigate the potential to reduce the cochlear dose with robotic photon radiosurgery or intensity-modulated proton therapy planning for vestibular schwannomas.Materials and MethodsClinically delivered photon radiosurgery treatment plans were compared to five cochlear-optimized plans: one photon and four proton plans (total of 120). A 1x12 Gy dose was prescribed. Photon plans were generated with Precision (Cyberknife, Accuray) with no PTV margin for set-up errors. Proton plans were generated using an in-house automated multi-criterial planning system with three or nine-beam arrangements, and applying 0 or 3 mm robustness for set-up errors during plan optimization and evaluation (and 3 % range robustness). The sample size was calculated based on a reduction of cochlear Dmean > 1.5 Gy(RBE) from the clinical plans, and resulted in 24 patients.ResultsCompared to the clinical photon plans, a reduction of cochlear Dmean > 1.5 Gy(RBE) could be achieved in 11/24 cochlear-optimized photon plans, 4/24 and 6/24 cochlear-optimized proton plans without set-up robustness for three and nine-beam arrangement, respectively, and in 0/24 proton plans with set-up robustness. The cochlea could best be spared in cases with a distance between tumor and cochlea. Using nine proton beams resulted in a reduced dose to most organs at risk.ConclusionCochlear dose reduction is possible in vestibular schwannoma radiosurgery while maintaining tumor coverage, especially when the tumor is not adjacent to the cochlea. With current set-up robustness, proton therapy is capable of providing lower dose to organs at risk located distant to the tumor, but not for organs adjacent to it. Consequently, photon plans provided better cochlear sparing than proton plans.Otorhinolaryngolog

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

Disease gene discovery in male infertility: past, present and future

Contains fulltext : 231663.pdf (Publisher’s version ) (Open Access)Identifying the genes causing male infertility is important to increase our biological understanding as well as the diagnostic yield and clinical relevance of genetic testing in this disorder. While significant progress has been made in some areas, mainly in our knowledge of the genes underlying rare qualitative sperm defects, the same cannot be said for the genetics of quantitative sperm defects. Technological advances and approaches in genomics are critical for the process of disease gene identification. In this review we highlight the impact of various technological developments on male infertility gene discovery as well as functional validation, going from the past to the present and the future. In particular, we draw attention to the use of unbiased genomics approaches, the development of increasingly relevant functional assays and the importance of large-scale international collaboration to advance disease gene identification in male infertility

Improved detection of CFTR variants by targeted next-generation sequencing in male infertility: a case series

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Shaping the future of male reproductive health: fostering talent at the 14th Network of Young Researchers in Andrology meeting.

The 14th Network of Young Researchers in Andrology (NYRA) meeting was a 2-day conference held at the University of East Anglia in Norwich, UK, organized by the NYRA. The meeting brought together researchers and experts to discuss and exchange ideas on male infertility and spermatogenesis. The meeting covered a wide range of topics related to male germline research, including the impact of mutations in the male germline on future generations, the use of innovative sequencing tools for the study of male infertility, and the intricate germline epigenome. The impact of aging on spermatogenesis was also discussed, with a focus on the increased DNA fragmentation rates, changes in DNA methylation patterns, and longer telomeres associated with aging sperm. Additionally, progress on fertility preservation options for children undergoing gonadotoxic cancer treatments was presented. The meeting also featured workshops on leadership and career development strategies in science, providing a valuable opportunity for young researchers to learn from experts in the field and exchange ideas with their peers. Overall, the meeting provided a platform for researchers to discuss the latest developments in male germline research, highlighting the importance of empowering young researchers to tackle male reproductive health

Phasing of de novo mutations using a scaled-up multiple amplicon long-read sequencing approach

De novo mutations (DNMs) play an important role in severe genetic disorders that reduce fitness. To better understand their role in disease, it is important to determine the parent-of-origin and timing of mutational events that give rise to these mutations, especially in sex-specific developmental disorders such as male infertility. However, currently available short-read sequencing approaches are not ideally suited for phasing, as this requires long continuous DNA strands that span both the DNM and one or more informative single-nucleotide polymorphisms. To overcome these challenges, we optimized and implemented a multiplexed long-read sequencing approach using Oxford Nanopore technologies MinION platform. We focused on improving target amplification, integrating long-read sequenced data with high-quality short-read sequence data, and developing an anchored phasing computational method. This approach handled the inherent phasing challenges of long-range target amplification and the normal accumulation of sequencing error associated with long-read sequencing. In total, 77 of 109 DNMs (71%) were successfully phased and parent-of-origin identified. The majority of phased DNMs were prezygotic (90%), the accuracy of which is highlighted by an average mutant allele frequency of 49.6% and standard error of 0.84%. This study demonstrates the benefits of employing an integrated short-read and long-read sequencing approach for large-scale DNM phasing

TRIM71 Deficiency Causes Germ Cell Loss During Mouse Embryogenesis and Is Associated With Human Male Infertility

Contains fulltext : 233989.pdf (Publisher’s version ) (Open Access