Chirurgie pédiatrique | EPFL Graph Search

La chirurgie pédiatrique est une branche de la chirurgie qui se limite à une tranche d'âge s'étendant de la période prénatale à l'adolescence. La chirurgie pédiatrique peut également s'intituler chirurgie infantile. Comme de nombreuses disciplines médicales, la chirurgie pédiatrique prend son essor à la fin du . L’hôpital Necker-Enfants malades se trouve en tête des efforts menés dans ce domaine grâce aux travaux de Paul Guersant, et Louis-Alexandre de Saint Germain. En 1881 se déroule la première intervention de chirurgie esthétique pédiatrique qui est une otoplastie. En 1893, le premier titulaire d'une chaire de chirurgie infantile en France est le professeur Timothée Piéchaud, à Bordeaux. Édouard Kirmisson, premier titulaire de la chaire de clinique chirurgicale des maladies de l’enfant en 1899 publie un manuel de chirurgie pédiatrique en 1906. Ce manuel couvre la radiologie, les malformations congénitales et l'ostéomyélite. Marie Nageotte-Wilbouchewitch, première chirurgienne en France, se forme en chirurgie pédiatrique auprès de Georges Félizet et Louis-Alexandre de Saint Germain au début du siècle. L’occurrence de deux guerres mondiales freine les efforts pour moderniser la chirurgie pédiatrique. La Société française de chirurgie pédiatrique est créée en 1959 sous le nom de Société française de chirurgie infantile. La première professeure de chirurgie pédiatrique est Claire Nihoul-Feketé en 1971. La plupart des pathologies chirurgicales pédiatriques sont très spécifiques et différentes de celles de l'adulte. Les malformations congénitales sont généralement décelées et traitées pendant l'enfance. Bon nombre de pathologies, telle la sténose hypertrophique du pylore, se présentent à des âges spécifiques. L'anamnèse d'un enfant (infant en latin : « qui ne parle pas ») provient d'un tiers, le plus souvent de la mère. Chirurgie néonatale (nouveau-nés) : malformations digestives, urinaires et pulmonaires Chirurgie thoracique Chirurgie urologique (troubles urinaires) Orthopédie infantile, chirurgie des mains et traumatologie Traitement des maladies osseuses et des malformations infantiles Chirurgie lié aux handicaps et scolioses Chirurgie post brûlures La charge affective et émotive est très élevée.

Roles of Epigenetic Dysregulation in Cancer Progression and Metastasis

Mohammad Sadegh Saghafinia

Nearly all the cells of an organism share the same DNA sequence or genome, and yet they show different phenotypes and carry out different functions. This diversity is made possible by a verity of molecular modifications acting on the DNA sequence that collectively define the cell's epigenome. Failure in the proper regulation of epigenome can lead to abnormal activation or inhibition of vital signaling pathways, which contributes to the initiation and progression of multiple diseases, including cancer. In this thesis, I used a combination of in silico, in vitro, and in vivo techniques to explore the roles of epigenetic dysregulation in tumor progression and metastasis. In the first part, I performed a systematic and unbiased investigation of cancer-associated DNA methylation and gene expression changes across human cancers. I designed a novel algorithmic approach (RESET) to identify aberrant DNA methylation and associated gene expression changes across >6,000 human tumors. We identified a DNA Methylation Instability (DMI) phenotype in tumors acquiring numerous hyper and hypomethylated transcription start sites, which is associated with mutations of chromatin remodeling factors and Wnt-signaling. We showed that silenced genes coalesced in specific pathways including apoptosis, transcriptional regulation, and cell metabolism. The majority of the enhanced genes belonged to cancer-germline antigens (CG), whose expression correlated with response to anti-PD-1 in melanoma patients. Finally, we demonstrated the potential of RESET to explore aberrant DNA methylation in pediatric tumors; pediatric Wilms tumors with diffuse anaplasia exhibit DMI, and specific silencing events predict a worse outcome in cases with favorable histology. These results established a new approach to explore pan-cancer epigenetic modifications and provided a resource of candidate oncogenic events for future functional and therapeutic studies. In the second part, I studied the dynamics of cancer progression and metastasis in Pancreatic Neuroendocrine Tumors (PanNET). This rare tumor is the second most common form of pancreatic cancer. Two principal subtypes of PanNET has been identified: insulinomas (IT) and metastasis-like primaries (MLP), corresponding to the low and high grade of human PanNETs, respectively. From the mouse model of PanNET (RT2), we profiled the single-cell, bulk mRNA and miRNA transcriptomes, and the proteomes of primary and metastasis specimens. We demonstrated that the tumor progression from IT to MLP follows the reverse embryonic and postnatal developmental path. Transcriptomic data from human patients showed that aggressive human PanNETs also follow the same reverse developmental trajectory of dedifferentiation. We established one possible mechanism underlying IT-to-MLP transition. Over-expression of the miR-181cd cluster in IT-like cancer cell-lines resulted in acquisition of the MLP phenotypes. miR-181cd mediated its effect through suppressing the expression of Meis2 and, indirectly, inducing the expression of Hmgb3 and Mycn transcription factors. Inhibiting the expression of Hmgb3 in MLP-like cancer cell-lines resulted in a significant growth decrease both in vitro and in vivo, demonstrating the importance of Hmgb3 in the maintenance of MLP-like cell state. These data presented dedifferentiation as a mechanism by which malignant neuroendocrine cancer cells acquire progenitor-like features, enabling them to become more aggressive and metastatic.

EPFL2020

Roles of Epigenetic Dysregulation in Cancer Progression and Metastasis

Mohammad Sadegh Saghafinia

EPFL2020