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Background: Lung cancer is a public health problem, and squamous cell carcinoma (SCC) is the second most prevalent subtype of this neoplasm. Compared to other subtypes, including adenocarcinoma, SCC is less well understood in terms of molecular pathogenesis, limiting therapeutic options among targeted agents approved for other disease subgroups. In this study, we sought to characterize the SCC genomic profile using a validated Next Generation Sequencing (NGS) platform., Methods: The comprehensive NGS assay ( TruSight Tumor 170 ) was used in order to target the full coding regions of 170 cancer-related genes on SCC samples. PD-L1 expression in tumor cells (TCs) was assessed using clone 22C3 (Dako). Clinical outcomes were correlated with molecular profile, including progression free survival (PFS), overall response rate (ORR), and overall survival (OS)., Results: A total of 26 samples were included, median age was 67 years (r, 33-83) and 53.8% were men. Tobacco consumption was identified in all subjects (mean 34-year package). For first-line treatment 80.8% of patients received cisplatin or carboplatin plus gemcitabine. In terms of molecular profile, we identified a high prevalence of inactivating mutations in TP53 (61.5%), PIK3CA (34.6%), MLL2 (34.6%), KEAP1 (38.4%), and NOTCH1 (26.9%). PD-L1 expression ranged from negative, 1, 2-49, and ≥50% in 23.1, 38.5, 26.9, and 11.5%, respectively. Interestingly, the genetic alterations did not have an effect in PFS, OS or ORR in this study. However, PDL1 expression was higher among those who had mutations in TP53 (p = 0.037) and greater expression of PDL1 was related to PIK3CA alterations (p = 0.05)., Conclusions: The genomic profile of SCC encompasses important genes including TP53, PIK3CA and KEAP1. TP53 mutations could be associated with PDL1 expression, generating hypothesis regarding specific treatment options., 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. The reviewer AA declared a past co-authorship with one of the authors CR to the handling editor., (Copyright © 2020 Cardona, Ruiz-Patiño, Arrieta, Ricaurte, Zatarain-Barrón, Rodriguez, Avila, Rojas, Recondo, Barron, Archila, Sotelo, Bravo, Zamudio, Corrales, Martín, Rolfo, Viola, Carranza, Vargas, Otero, Bermudez, Gamez, Pino and Rosell.)

Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function 1 . Among the genes coding for the MYST family of KATs (KAT5-KAT8) are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF) 2,3 . KAT6A has essential roles in normal haematopoietic stem cells 4-6 and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia 7,8 . Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers 8 . KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus 9,10 , a function that requires its KAT activity 10 . Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days 11 . These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.

DNA methylation is prevalent in mammalian genomes and plays a central role in the epigenetic control of development. The mammalian DNA methylation machinery is thought to be composed of three DNA methyltransferase enzymes (DNMT1, DNMT3A, and DNMT3B) and one cofactor (DNMT3L). Here, we describe the discovery of Dnmt3C, a de novo DNA methyltransferase gene that evolved via a duplication of Dnmt3B in rodent genomes and was previously annotated as a pseudogene. We show that DNMT3C is the enzyme responsible for methylating the promoters of evolutionarily young retrotransposons in the male germ line and that this specialized activity is required for mouse fertility. DNMT3C reveals the plasticity of the mammalian DNA methylation system and expands the scope of the mechanisms involved in the epigenetic control of retrotransposons., (Copyright © 2016, American Association for the Advancement of Science.)

DNA methylation is essential for protecting the mammalian germline against transposons. When DNA methylation-based transposon control is defective, meiotic chromosome pairing is consistently impaired during spermatogenesis: How and why meiosis is vulnerable to transposon activity is unknown. Using two DNA methylation-deficient backgrounds, the Dnmt3L and Miwi2 mutant mice, we reveal that DNA methylation is largely dispensable for silencing transposons before meiosis onset. After this, it becomes crucial to back up to a developmentally programmed H3K9me2 loss. Massive retrotransposition does not occur following transposon derepression, but the meiotic chromatin landscape is profoundly affected. Indeed, H3K4me3 marks gained over transcriptionally active transposons correlate with formation of SPO11-dependent double-strand breaks and recruitment of the DMC1 repair enzyme in Dnmt3L(-/-) meiotic cells, whereas these features are normally exclusive to meiotic recombination hot spots. Here, we demonstrate that DNA methylation restrains transposons from adopting chromatin characteristics amenable to meiotic recombination, which we propose prevents the occurrence of erratic chromosomal events., (© 2015 Zamudio et al.; Published by Cold Spring Harbor Laboratory Press.)

The Microrchidia (Morc) family of GHKL ATPases are present in a wide variety of prokaryotic and eukaryotic organisms but are of largely unknown function. Genetic screens in Arabidopsis thaliana have identified Morc genes as important repressors of transposons and other DNA-methylated and silent genes. MORC1-deficient mice were previously found to display male-specific germ cell loss and infertility. Here we show that MORC1 is responsible for transposon repression in the male germline in a pattern that is similar to that observed for germ cells deficient for the DNA methyltransferase homologue DNMT3L. Morc1 mutants show highly localized defects in the establishment of DNA methylation at specific classes of transposons, and this is associated with failed transposon silencing at these sites. Our results identify MORC1 as an important new regulator of the epigenetic landscape of male germ cells during the period of global de novo methylation.

Many loci maintain parent-of-origin DNA methylation only briefly after fertilization during mammalian development: Whether this form of transient genomic imprinting can impact the early embryonic transcriptome or even have life-long consequences on genome regulation and possibly phenotypes is currently unknown. Here, we report a maternal germline differentially methylated region (DMR) at the mouse Gpr1/Zdbf2 (DBF-type zinc finger-containing protein 2) locus, which controls the paternal-specific expression of long isoforms of Zdbf2 (Liz) in the early embryo. This DMR loses parental specificity by gain of DNA methylation at implantation in the embryo but is maintained in extraembryonic tissues. As a consequence of this transient, tissue-specific maternal imprinting, Liz expression is restricted to the pluripotent embryo, extraembryonic tissues, and pluripotent male germ cells. We found that Liz potentially functions as both Zdbf2-coding RNA and cis-regulatory RNA. Importantly, Liz-mediated events allow a switch from maternal to paternal imprinted DNA methylation and from Liz to canonical Zdbf2 promoter use during embryonic differentiation, which are stably maintained through somatic life and conserved in humans. The Gpr1/Zdbf2 locus lacks classical imprinting histone modifications, but analysis of mutant embryonic stem cells reveals fine-tuned regulation of Zdbf2 dosage through DNA and H3K27 methylation interplay. Together, our work underlines the developmental and evolutionary need to ensure proper Liz/Zdbf2 dosage as a driving force for dynamic genomic imprinting at the Gpr1/Zdbf2 locus.

Study Question: What is the consequence of Tex19.1 gene deletion in mice?, Summary Answer: The Tex19.1 gene is important in spermatogenesis and placenta-supported development., What Is Known Already: Tex19.1 is expressed in embryonic stem (ES) cells, primordial germ cells (PGCs), placenta and adult gonads. Its invalidation in mice leads to a variable impairment in spermatogenesis and reduction of perinatal survival., Study Design, Size, Duration: We generated knock-out mice and ES cells and compared them with wild-type counterparts. The phenotype of the Tex19.1 knock-out mouse line was investigated during embryogenesis, fetal development and placentation as well as during adulthood., Participants/materials, Setting, Methods: We used a mouse model system to generate a mutant mouse line in which the Tex19.1 gene was deleted in the germline. We performed an extensive analysis of Tex19.1-deficient ES cells and assessed their in vivo differentiation potential by generating chimeric mice after injection of the ES cells into wild-type blastocysts. For mutant animals, a morphological characterization was performed for testes and ovaries and placenta. Finally, we characterized semen parameters of mutant animals and performed real-time RT-PCR for expression levels of retrotransposons in mutant testes and ES cells., Main Results and the Role of Chance: While Tex19.1 is not essential in ES cells, our study points out that it is important for spermatogenesis and for placenta-supported development. Furthermore, we observed an overexpression of the class II LTR-retrotransposon MMERVK10C in Tex19.1-deficient ES cells and testes., Limitations, Reasons for Caution: The Tex19.1 knock-out phenotype is variable with testis morphology ranging from severely altered (in sterile males) to almost indistinguishable compared with the control counterparts (in fertile males). This variability in the testis phenotype subsequently hampered the molecular analysis of mutant testes. Furthermore, these results were obtained in the mouse, which has a second isoform (i.e. Tex19.2), while other mammals possess only one Tex19 (e.g. in humans)., Wider Implications of the Findings: The fact that one gene has a role in both placentation and spermatogenesis might open new ways of studying human pathologies that might link male fertility impairment and placenta-related pregnancy disorders., Study Funding/competing Interest(s): This work was supported by the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM) (Grant Avenir), the Ministère de l'Education Nationale, de l'Enseignement Supérieur et de la Recherche, the Université de Strasbourg, the Association Française contre les Myopathies (AFM) and the Fondation pour la Recherche Médicale (FRM) and Hôpitaux Universitaires de Strasbourg.The authors have nothing to disclose.

Introduction and Objectives: Percutaneous closure of patent ductus arteriosus (PDA) is a well-established technique. We evaluated the usefulness of the Amplatzer duct occluder for the percutaneous closure of patent ductus arteriosus in 29 children under 1 year of age., Methods: The patients' mean age was 8.9±2.8 months and their mean weight was 6.4±1.5kg. In addition, 24.1% of patients were aged 6 months or less and 17.2% weighed 5kg or less. All completed follow-up (0.5-36 months)., Results: The minimum PDA diameter was 3.16±1.24 mm. The device was implanted successfully in 26 patients (89.6%). Failures were due to either the device migrating to the descending aorta, persistent moderate leakage, or to difficulty in the advancement of the device. No deaths were associated with the procedure. Three major complications occurred in two patients (10.3%). Aortography showed initial total occlusion in 65.5% of patients. At 3-month follow-up, total occlusion was observed in 96.1% of patients. Ultimately, closure was achieved successfully in 25 of the 29 patients (86.2%). During follow-up, four patients exhibited mild left pulmonary artery stenosis and one exhibited mild stenosis of the descending aorta., Conclusions: In children under 1 year of age, percutaneous closure of patent ductus arteriosus using an Amplatzer occluder was a safe and effective procedure. It is possible that improvements in the design of the occluder could decrease the complication rate., (Copyright © 2009 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.)

Introduction and Objectives: Percutaneous closure of patent ductus arteriosus (PDA) is a well-established technique. We evaluated the usefulness of the Amplatzer duct occluder for the percutaneous closure of patent ductus arteriosus in 29 children under 1 year of age., Methods: The patients' mean age was 8.9+/-2.8 months and their mean weight was 6.4+/-1.5 kg. In addition, 24.1% of patients were aged 6 months or less and 17.2% weighed 5 kg or less. All completed follow-up (0.5-36 months)., Results: The minimum PDA diameter was 3.16+/-1.24 mm. The device was implanted successfully in 26 patients (89.6%). Failures were due to either the device migrating to the descending aorta, persistent moderate leakage, or to difficulty in the advancement of the device. No deaths were associated with the procedure. Three major complications occurred in two patients (10.3%). Aortography showed initial total occlusion in 65.5% of patients. At 3-month follow-up, total occlusion was observed in 96.1% of patients. Ultimately, closure was achieved successfully in 25 of the 29 patients (86.2%). During follow-up, four patients exhibited mild left pulmonary artery stenosis and one exhibited mild stenosis of the descending aorta., Conclusions: In children under 1 year of age, percutaneous closure of patent ductus arteriosus using an Amplatzer occluder was a safe and effective procedure. It is possible that improvements in the design of the occluder could decrease the complication rate.

There is increasing evidence that epigenetic information can be inherited across generations in mammals, despite extensive reprogramming both in the gametes and in the early developing embryo. One corollary to this is that disrupting the establishment of epigenetic state in the gametes of a parent, as a result of heterozygosity for mutations in genes involved in reprogramming, could affect the phenotype of offspring that do not inherit the mutant allele. Here we show that such effects do occur following paternal inheritance in the mouse. We detected changes to transcription and chromosome ploidy in adult animals. Paternal effects of this type have not been reported previously in mammals and suggest that the untransmitted genotype of male parents can influence the phenotype of their offspring.