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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, with overall long-term survival rates of about 65-70%. Thus, additional molecular insights and representative models are critical for further identifying and evaluating new treatment modalities. Using MyoD-Cre mediated introduction of mutant K-RasG12D and perturbations in p53 we have developed a novel genetically engineered mouse model (GEMM) for RMS. Specifically, we directly crossed mice expressing MyoD promoter-regulated Cre-recombinase with germline p53Flox or Lox-Stop-Lox (LSL) knock-in alleles expressing oncogenic p53R172H and/or K-RasG12D mutants. The anatomic sites of primary RMS development observed in these mice recapitulated human disease, with the most frequent sites of tumor growth seen in the head, neck, extremities, and abdomen.We have confirmed RMS histology and diagnosis through hematoxylin and eosin (H&E) staining, as well as positive immunohistochemistry (IHC) staining for desmin, myogenin, and phosphotungstic acid hematoxylin (PTAH). We established cell lines from several of the GEMM tumors with the ability to engraft and develop tumors in immunocompetent mice with similar histological and staining features as the primary tumors. Furthermore, injection of syngeneic RMS lines via tail vein had high metastatic potential to the lungs. Transcriptomic analyses of p53R172H/K-RasG12D GEMM-derived tumors showed evidence of high molecular homology with human RMS. Specifically, we noted alterations in gene ontologies including immune response, metabolism and mRNA processing. Finally, pre-clinical use of these murine RMS lines demonstrated similar therapeutic responsiveness to relevant chemotherapy and targeted therapies as human cell line models.Summary StatementWe have developed a new conditional genetically engineered mouse model of rhabdomyosarcoma (RMS) with homologous molecular signature to human RMS that provides valuable pre-clinical models for evaluating novel therapies.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, with overall long-term survival rates of ∼65-70%. Thus, additional molecular insights and representative models are critical for identifying and evaluating new treatment modalities. Using MyoD-Cre-mediated introduction of mutant K-RasG12D and perturbations in p53, we developed a novel genetically engineered mouse model (GEMM) for RMS. The anatomic sites of primary RMS development recapitulated human disease, including tumors in the head, neck, extremities and abdomen. We confirmed RMS histology and diagnosis through Hematoxylin and Eosin staining, and positive immunohistochemical staining for desmin, myogenin, and phosphotungstic acid-Hematoxylin. Cell lines from GEMM tumors were established with the ability to engraft in immunocompetent mice with comparable histological and staining features as the primary tumors. Tail vein injection of cell lines had high metastatic potential to the lungs. Transcriptomic analyses of p53R172H/K-RasG12D GEMM-derived tumors showed evidence of high molecular homology with human RMS. Finally, pre-clinical use of these murine RMS lines showed similar therapeutic responsiveness to chemotherapy and targeted therapies as human RMS cell lines. ispartof: DISEASE MODELS & MECHANISMS vol:15 issue:2 ispartof: location:England status: published

The main objective of this book is to present a thorough update on stem cell research and the potential therapeutic applications of stem cells. The text is structured following a path that starts from the molecular basics and the biological properties of pluripotent, embryonic or reprogrammed stem cells, and it compares the different degrees of stemness, while describing the adult stem populations residing in the various tissues and organs of the human body. Starting from basic research, the book discusses examples of regenerative medicine that translate the experimental findings into clinical applications of cell therapy. Finally, the book reviews how stem cells represent a model to understand not only the physiological mechanisms that control their fate, but also the pathological mechanisms involved in the aberrant biology of cancer stem cells. Each chapter has been conceived by distinguished researchers in the field who provide detailed and updated contributions that distill knowledge in a very readable text. Laura Bonsi is Associate Professor of Histology at the Department of Experimental, Diagnostic and Specialty Medicine of the University of Bologna. Francesco Alviano is Assistant Professor of Histology at the Department of Experimental, Diagnostic and Specialty Medicine of the University of Bologna. Prof. Bonsi and Dr. Alviano are authors of numerous scientific papers published in international journals. They coordinate the Biotechnology Laboratory of Human Stem Cells at the University of Bologna, that is focused on the study of stem cells isolated from different sources, above all from extraembryonic tissues such as the placenta, the umbilical cord, and the fetal membranes. They are longterm members of the International Placenta Stem Cell Society (IPLASS).

Cardiac development in the human embryo is characterized by the interactions of several transcription and growth factors leading the heart from a primordial linear tube into a synchronous contractile four-chamber organ. Studies on cardiogenesis showed that cell proliferation, differentiation, fate specification and morphogenesis are spatiotemporally coordinated by cell-cell interactions and intracellular signalling cross-talks. In recent years, research has focused on a class of inter- and intra-cellular modulators called non-coding RNAs (ncRNAs), transcribed from the noncoding portion of the DNA and involved in the proper formation of the heart. In this chapter, we will summarize the current state of the art on the roles of three major forms of ncRNAs [microRNAs (miRNAs), long ncRNAs (lncRNAs) and circular RNAs (circRNAs)] in orchestrating the four sequential phases of cardiac organogenesis.

Cardiac development in the human embryo is characterized by the interactions of several transcription and growth factors leading the heart from a primordial linear tube into a synchronous contractile four-chamber organ. Studies on cardiogenesis showed that cell proliferation, differentiation, fate specification and morphogenesis are spatiotemporally coordinated by cell-cell interactions and intracellular signalling cross-talks. In recent years, research has focused on a class of inter- and intra-cellular modulators called non-coding RNAs (ncRNAs), transcribed from the noncoding portion of the DNA and involved in the proper formation of the heart. In this chapter, we will summarize the current state of the art on the roles of three major forms of ncRNAs [microRNAs (miRNAs), long ncRNAs (lncRNAs) and circular RNAs (circRNAs)] in orchestrating the four sequential phases of cardiac organogenesis.

Non-coding RNAs (ncRNAs) are emerging players in muscle regulation. Based on their length and differences in molecular structure, ncRNAs are subdivided into several categories including small interfering RNAs, stable non-coding RNAs, microRNAs (miRs), long non-coding RNAs (lncRNAs), and circular RNAs. miRs and lncRNAs are able to post-transcriptionally regulate many genes and bring into play several traits simultaneously due to a myriad of different targets. Recent studies have emphasized their importance in cardiac regeneration and repair. As their altered expression affects cardiac function, miRs and lncRNAs could be potential targets for therapeutic intervention. In this context, miR- and lncRNA-based gene therapies are an interesting field for harnessing the complexity of ncRNA-based therapeutic approaches in cardiac diseases. In this review we will focus on lncRNA- and miR-driven regulations of cardiac development and repair. Finally, we will summarize miRs and lncRNAs as promising candidates for the treatment of heart diseases. ispartof: Pharmacological Research vol:127 pages:58-66 ispartof: location:Netherlands status: published

Myocardial infarction (MI) is caused by the occlusion of coronary arteries in the heart leading to an oxygen supply-demand imbalance in the myocardium, eventually causing ischemia of the perfused tissue that—if prolonged—leads to myocardial cell death.

Dystrophinopathies are characterized by skeletal and cardiac muscle complications because of a lack or shortened DYSTROPHIN protein. Ventilation assistance and corticosteroid treatment have positively affected life outcome but lead to an increased incidence of cardiomyopathy. Cardiomyopathy is now the leading cause of death in patients with dystrophinopathy. Thus, coherent guidelines for cardiac care have become essential and need to be communicated well. Progression of cardiac complications in patients with dystrophinopathy diverges from standard dilated cardiomyopathy development and monitoring and medical care for dystrophinopathy. This chapter summarizes current guidelines and recommendations for monitoring and clinical treatment of cardiac complications in patients with dystrophinopathy and provides a thorough survey of emerging therapies focusing on cardiac outcomes. ispartof: Cardiomyopathies - Types and Treatments pages:289-311 ispartof: pages:289-311 status: published

Abnormal cord development results in spinal cord damage responsible for myelomeningocele (MMC). Amniotic fluid-derived stem cells (AFSCs) have emerged as a potential candidate for applications in regenerative medicine. However, their differentiation potential is largely unknown as well as the molecular signaling orchestrating the accurate spinal cord development. Fetal lambs underwent surgical creation of neural tube defect and its subsequent repair. AFSCs were isolated, cultured and characterized at the 12th (induction of MMC), 16th (repair of malformation), and 20th week of gestation (delivery). After performing open hysterectomy, AF collections on fetuses with sham procedures at the same time points as the MMC creation group have been used as controls. Cytological analyses with the colony forming unit assay, XTT and alkaline-phosphatase staining, qRT-PCR gene expression analyses (normalized with aged match controls) and NMR metabolomics profiling were performed. Here we show for the first time the metabolomics and molecular signature variation in AFSCs isolated in the sheep model of MMC, which may be used as diagnostic tools for the in utero identification of the neural tube damage. Intriguingly, PAX3 gene involved in the murine model for spina bifida is modulated in AFSCs reaching the peak of expression at 16 weeks of gestation, 4 weeks after the intervention. Our data strongly suggest that AFSCs reorganize their differentiation commitment in order to generate PAX3-expressing progenitors to counteract the MMC induced in the sheep model. The gene expression signature of AFSCs highlights the plasticity of these cells reflecting possible alterations of embryonic development.