Receptor Tyrosine Kinases in Osteosarcoma: 2019 Update

The primary conclusions of our 2014 contribution to this series were as follows: Multiple receptor tyrosine kinases (RTKs) likely contribute to aggressive phenotypes in osteosarcoma and, therefore, inhibition of multiple RTKs is likely necessary for successful clinical outcomes. Inhibition of multiple RTKs may also be useful to overcome resistance to inhibitors of individual RTKs as well as resistance to conventional chemotherapies. Different combinations of RTKs are likely important in individual patients. AXL, EPHB2, FGFR2, IGF1R, and RET were identified as promising therapeutic targets by our in vitro phosphoproteomic/siRNA screen of 42 RTKs in the highly metastatic LM7 and 143B human osteosarcoma cell lines. This chapter is intended to provide an update on these topics as well as the large number of osteosarcoma clinical studies of inhibitors of multiple tyrosine kinases (multi-TKIs) that were recently published

Modulation of the Osteosarcoma Expression Phenotype by MicroRNAs

Molecular tumour pathology - and tumour genetic

Deletions flanked by breakpoints 3 and 4 on 15q13 may contribute to abnormal phenotypes

Non-allelic homologous recombination (NAHR) between segmental duplications in proximal chromosome 15q breakpoint (BP) regions can lead to microdeletions and microduplications. Several individuals with deletions flanked by BP3 and BP4 on 15q13, immediately distal to, and not including the Prader–Willi/Angelman syndrome (PW/AS) critical region and proximal to the BP4–BP5 15q13.3 microdeletion syndrome region, have been reported; however, because the deletion has also been found in normal relatives, the significance of these alterations is unclear. We have identified six individuals with deletions limited to the BP3–BP4 interval and an additional four individuals with deletions of the BP3–BP5 interval from 34 046 samples submitted for clinical testing by microarray-based comparative genomic hybridization (aCGH). Of four individuals with BP3–BP4 deletions for whom parental testing was conducted, two were apparently de novo and two were maternally inherited. A comparison of clinical features, available for five individuals in our study (four with deletions within BP3–BP4 and one with a BP3-BP5 deletion), with those in the literature show common features of short stature and/or failure to thrive, microcephaly, hypotonia, and premature breast development in some individuals. Although the BP3–BP4 deletion does not yet demonstrate statistically significant enrichment in abnormal populations compared with control populations, the presence of common clinical features among probands and the presence of genes with roles in development and nervous system function in the deletion region suggest that this deletion may have a role in abnormal phenotypes in some individuals

Antenatal manifestations of inborn errors of metabolism: biological diagnosis

International audienceInborn errors of metabolism (IEMs) that present with abnormal imaging findings in the second half of pregnancy are mainly lysosomal storage disorders (LSDs), cholesterol synthesis disorders (CSDs), glycogen storage disorder type IV (GSD IV), peroxisomal disorders, mitochondrial fatty acid oxidation defects (FAODs), organic acidurias, aminoacidopathies, congenital disorders of glycosylation (CDGs), and transaldolase deficiency. Their biological investigation requires fetal material. The supernatant of amniotic fluid (AF) is useful for the analysis of mucopolysaccharides, oligosaccharides, sialic acid, lysosphingolipids and some enzyme activities for LSDs, 7- and 8-dehydrocholesterol, desmosterol and lathosterol for CSDs, acylcarnitines for FAODs, organic acids for organic acidurias, and polyols for transaldolase deficiency. Cultured AF or fetal cells allow the measurement of enzyme activities for most IEMs, whole-cell assays, or metabolite measurements. The cultured cells or tissue samples taken after fetal death can be used for metabolic profiling, enzyme activities, and DNA extraction. Fetal blood can also be helpful. The identification of vacuolated cells orients toward an LSD, and plasma is useful for diagnosing peroxisomal disorders, FAODs, CSDs, some LSDs, and possibly CDGs and aminoacidopathies. We investigated AF of 1700 pregnancies after exclusion of frequent etiologies of nonimmune hydrops fetalis and identified 108 fetuses affected with LSDs (6.3 %), 29 of them with mucopolysaccharidosis type VII (MPS VII), and six with GSD IV (0.3 %). In the AF of 873 pregnancies, investigated because of intrauterine growth restriction and/or abnormal genitalia, we diagnosed 32 fetuses affected with Smith-Lemli-Opitz syndrome (3.7 %)