Complete lung agenesis caused by complex genomic rearrangements with neo-TAD formation at the SHH locus

During human organogenesis, lung development is a timely and tightly regulated developmental process under the control of a large number of signaling molecules. Understanding how genetic variants can disturb normal lung development causing different lung malformations is a major goal for dissecting molecular mechanisms during embryogenesis. Here, through exome sequencing (ES), array CGH, genome sequencing (GS) and Hi-C, we aimed at elucidating the molecular basis of bilateral isolated lung agenesis in three fetuses born to a non-consanguineous family. We detected a complex genomic rearrangement containing duplicated, triplicated and deleted fragments involving the SHH locus in fetuses presenting complete agenesis of both lungs and near-complete agenesis of the trachea, diagnosed by ultrasound screening and confirmed at autopsy following termination. The rearrangement did not include SHH itself, but several regulatory elements for lung development, such as MACS1, a major SHH lung enhancer, and the neighboring genes MNX1 and NOM1. The rearrangement incorporated parts of two topologically associating domains (TADs) including their boundaries. Hi-C of cells from one of the affected fetuses showed the formation of two novel TADs each containing SHH enhancers and the MNX1 and NOM1 genes. Hi-C together with GS indicate that the new 3D conformation is likely causative for this condition by an inappropriate activation of MNX1 included in the neo-TADs by MACS1 enhancer, further highlighting the importance of the 3D chromatin conformation in human disease

Hepatic Stem-like Phenotype and Interplay of Wnt/β-Catenin and Myc Signaling in Aggressive Childhood Liver Cancer

SummaryHepatoblastoma, the most common pediatric liver cancer, is tightly linked to excessive Wnt/β-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of liver development and a discriminating 16-gene signature. β-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy

Dendrimers in Alzheimer’s Disease: Recent Approaches in Multi-Targeting Strategies

Nanomaterials play an increasingly important role in current medicinal practice. As one of the most significant causes of human mortality, and one that is increasing year by year, Alzheimer’s disease (AD) has been the subject of a very great body of research and is an area in which nanomedicinal approaches show great promise. Dendrimers are a class of multivalent nanomaterials which can accommodate a wide range of modifications that enable them to be used as drug delivery systems. By means of suitable design, they can incorporate multiple functionalities to enable transport across the blood–brain barrier and subsequently target the diseased areas of the brain. In addition, a number of dendrimers by themselves often display therapeutic potential for AD. In this review, the various hypotheses relating to the development of AD and the proposed therapeutic interventions involving dendrimer–base systems are outlined. Special attention is focused on more recent results and on the importance of aspects such as oxidative stress, neuroinflammation and mitochondrial dysfunction in approaches to the design of new treatments

The uterosacral complex: ligament or neurovascular pathway? Anatomical and histological study of fetuses and adults.

International audienceThe aim of this study was to define the anatomical relationships of the uterosacral ligament complex (USLC) and to analyze histologically its content. Three fetal and four adult cadavers were used. Anatomical dissections were carried out. Eight fresh biopsies (four fetal and four adult) of the USLC were analyzed histologically and immunohistochemically. Specimens were stained with hematoxylin eosin safran coloration, with anti-nervous cell antibodies (PS 100) and with anti-smooth muscle antibodies (to visualize vessel walls). By removing the visceral pelvic fascia, nervous fibers were found within the USLC forming the hypogastric plexus. Histologically, the USLC contained connective tissue, nervous fibers, sympathetic nodes, vessels, and fatty tissue. No structured ligamentous organization was identified. The uterosacral "ligament" is a "complex" integrating connective tissue as well as nervous and vascular elements. Radical excisions and USLC suspension during pelvic floor reconstructive surgery should be performed with caution in order to preserve pelvic innervation

[Anatomical and histological study of the uterosacral ligament: practical surgical consequences]

International audienceOBJECTIVE: To define the vascular and nervous relationships of the uterosacral ligament and to analyze histologically its content for a better description of this structure. MATERIALS AND METHODS: Three fresh fetal cadavers, three embalmed and one fresh adult cadavers were used. The anatomical relationships of the uterosacral ligament were studied by dissecting one fresh fetal pelvis and two embalmed adult pelves. By histological and immunohistological examinations, eight biopsies of the cervical origin of the complexe ligamentaire utérosacral (USLC) were analyzed: four from fresh fetuses, two from a fresh adult cadaver and two from an embalmed adult cadaver. The specimens were stained with haematoxylin eosin safran (HES) coloration, with antinervous cell specific antibodies (PS100) and with antismooth muscle actine antibodies (to visualize vessel walls) before examination under optical microscope. RESULTS: On anatomic examination, the uterosacral ligament was covered by the visceral pelvic fascia. By removing this fascia, the uterosacral ligament appeared to be a condensation of nervous fibers made up of hypogastric and pelvic nerves forming the hypogastric plexus. Histologically, the uterosacral ligament contained connective tissue, nervous fibers, sympathetic nodes, vessels and fatty tissue. No structured ligamentous organization was identified. CONCLUSION: The uterosacral "ligament" is in fact a "ligament complex" integrating connective tissue as well as nervous and vascular elements. Radical wide excisions of the USLC during cancer or endometriosis surgery and uterosacral suspension during pelvic floor reconstructive surgery should be performed with caution in order to preserve pelvic innervation

[Primary non-Hodgkin lymphoma of the uterine corpus. Case report and review of the literature]

International audienceWe report a case of primary nonHodgkin lymphoma (NHL) of the uterine corpus, diagnosed by endometrial biopsy, in a 60-year-old patient suffering from uterine bleeding. Pathological analysis had concluded to diffuse large B-cell lymphoma. Further staging had not revealed other nodal or extranodal localization (Ann Arbor stage IE) and there were no signs of recurrence during follow-up. Therefore, the diagnostic criteria for true primary NHL of the uterine corpus were met. This localization is extremely rare since only six cases have previously been published. The patient was successfully treated by an immunochemotherapy combining rituximab-CHOP and rituximab-VCAP. After 28 months of follow-up, she is free from the disease. A review of the literature regarding these exceptional tumors is undertaken