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Children born small for gestational age (SGA) may present advanced bone maturation in childhood and reduced final height. The objectives of the study were to evaluate adrenarche, pubertal development, age at menarche and final height in full-term born-SGA girls. Twenty-four girls (12 born-SGA and 12 matched controls) were evaluated at 6-7.5 years of age for clinical signs of puberty and dehydroepiandrosterone sulfate (DHEAS) levels, as a marker of adrenarche. Thirty-eight girls (19 born-SGA and 19 matched controls) were evaluated at 17.5-18.5 years of age to assess final height, sexual maturation and age at menarche. SGA girls had a mean final height (160.1 cm vs 165.8 cm, p0.01) and mean weight (52.1 kg vs 56.5 kg, p0.05) significantly lower than controls. Controls had a mean final height significantly higher than their mean target height. Sexual maturation was at stage 5 of Tanner's staging in SGA girls and control subjects. SGA girls had a slightly anticipated puberty (9.9 vs 10.4 years for initial breast development) and a lower age at menarche (11.9 vs 12.3 years). At 6-7.5 years of age, SGA females and controls did not show any difference for clinical signs of puberty; however, DHEAS levels (0.75 + 0.18 microgram/ml vs 0.57 + 0.22 microgram/ml, p0.05) were significantly higher in SGA girls than in control subjects. We concluded that full-term born-SGA females have impaired final height and weight in adolescence but substantially normal sexual maturation and age at menarche. Increased DHEAS levels before puberty in born-SGA girls may predispose to increased bone maturation in childhood with a reduced final height. In our population a progressive increment in final stature is evident.

During development the vertebrate skeleton is the product of deriving cells from distinct embryonic lineages. The craniofacial skeleton is formed by migrating cranial neural crest cells, whereas the axial and limb skeletons are derived from mesodermal cells. The Vascular Endothelial Growth Factors (VEGFs) / receptors (VEGFRs) system plays an important role in angiogenesis, as well as osteogenesis, during bone development, growth, and remodeling, attracting endothelial cells and osteoclasts and stimulating osteoblast differentiation. Recent evidence has shown that during development VEGFR-3 is also expressed in neural and glial precursors of forebrain and cerebellum, as well as in the eye. In this study, we found that VEGFR-1, VEGFR-2 and VEGFR-3 are expressed in human bone both in fetal and adult life. The gene expression levels were significantly higher in fetal samples especially in mandibles. In addition, higher levels of VEGFR-3 in orofacial district were confirmed by western blotting analysis. We also observed that in fetal mandibular samples VEGFRs colocalized in several osteoblasts, osteoclasts and osteoprogenitor cells. Furthermore, some cells coexpressed VEGFR-3 and ET-1, a marker of neural crest cells. The results demonstrated different expression of VEGFRs in human mandibular and femoral bones which could be correlated to their different structure, function and development during organogenesis. VEGFR-3 might represent a specific signal for ectomesenchymal lineage differentiation during early human development.

Of the 10,730 neonates born in the period 1978-1997 and examined for cryptorchidism (C) at birth, 1387 were pre-term (gestational age37 wk), and 9343 were full-term. At birth, a total of 737 neonates (6.9%) were cryptorchid, 487 had bilateral C and 250 unilateral C. The C rate of pre-terms was 10 times higher than that of the full-terms (30.1 and 3.4%, respectively). Comparing the two studied decades, a significant decrease of C rate was found in the second decade in full-term neonates. The rates of C at birth were significantly elevated for low birth weight, babies born from mothers with an age20 or35 yr, newborns from mothers with A Rh positive and B Rh positive blood group. Of the 737 cryptorchid newborns at birth, 613 (83%) were re-examined after 12 months from the expected date of delivery, and those born in the period 1988-1997 were also re-evaluated at 6 months of life. Late spontaneous descent occurred in 464 cases (75.7%), while 149 (24.3%) were still cryptorchid. The incidence of C at 12 months from the expected date of delivery, after survival curve calculation, in term and pre-term infants, was 1.53 and 7.31%, respectively, in the period 1978-1987, and 1.22 and 3.13% respectively, in the 2nd decade (1988-1997). In the groups also examined at 6 months of life, spontaneous descent occurred almost completely within the first 6 months of life in term infants, but not in pre-terms. No evidence of seasonal cyclicity was found. Medical and/or surgical treatment was generally started within 2-4 yr of age earlier in the second decade of the study. In conclusion, the main risk factor for C at birth and at 12 months of life seems to be pre-term birth and low birth weight. If this is associated itself to a higher risk of infertility too, it remains to be defined.

Background. Diffuse large B-cell lymphoma (DLBCL) is the commonest lymphoma in both humans and dogs. Canine DLBCL (cDLBCL) is considered an ideal comparative model for drug development, but a complete genomic characterization of this tumor is still lacking. In this study, we report an integrated analysis to comprehensively define the molecular mechanisms of cDLBCL and possible associations with clinical outcome. Methods. Fifty cDLBCLs were analyzed by RNA-Seq, methyl-CpG-binding sequencing and array comparative genomic hybridization. Normal B-cells derived from lymph nodes of 11 healthy dogs were used as controls.Additionally, immunohistochemistry, in vitroand in vivoexperiments were performed as validation analyses. Results.Compared to normal B-cells, cDLBCL showed a marked up-regulation of genes involved in the PI3K/mTOR and NF-κB pathways, including several TLRs in association with MYD88, indicating mechanisms similar to the human activated B cell-like subtype DLBCL. Both RNA-Seq and methylation sequencing led to the identification of two groups of cDLBCLs bearing different clinical outcome. The two groups did not overlap with the human germinal center B-cell (GCB) and the activated B-cell-like (ABC) DLBCL subtypes or the human DLBCL consensus clusters. The dogs with the poorest outcome presented a signature largely defined by markers of T-cell-mediated immune responses, with a high expression of PDL-1, PD-1 and CTLA-4, also validated in an independent cohort of cDLBCL by immunohistochemistry. These data provide a strong rationale for the use of cDLBCL to study immune checkpoint modulators. The observed high expression of PI3K/mTOR pathway genes was confirmed and validated achieving a clear anti-tumor activity with the use of the PI3K-delta inhibitor idelalisib and of the novel dual PI3K/mTOR inhibitor bimiralisib in the cDLBCL cell line CLBL-1. The cDLBCLs showed an up-regulation of MYC and of its targets, sustained by recurrent gains in the chromosome 13, where the oncogene is located, in approximately half of the cases. Thus, we have exposed the cDLBCL cell line CLBL-1 to the BET inhibitor birabresib (OTX015) and to the BRD4 degrader MZ1. Both compounds caused a significant reduction in the proliferation of tumor cells, and this effect was stronger especially with the second compound. Exposure to MZ1 determined an important downregulation of MYC and also of LIN28B, the most overexpressed transcript in cDLBCL when compared to controls. While LIN28B does not seem to be a relevant gene for human DLBCL, its overexpression causes murine T-cell lymphomas (Beachy et al, Blood 2011), and there is a direct association of MYC with LIN28B promoter resulting in transcriptional transactivation (Chang et al, PNAS 2009). Here, LIN28B genetic silencing in the CLBL-1 lead to a reduction in cell growth, opening new therapeutic target perspectives in canine lymphoma. Conclusions. We have reported the first large next generation sequencing study investigating the cDLBCL transcriptome, methylome and the genome-wide CNVs. We identified deregulated pathways and individual transcripts providing therapeutic targets, including an immune-related signature affecting the outcome of a subgroup of cDLBCL. Our data sustain the use of cDLBCL as comparative models for human DLBCL but also highlight differences that must be kept in consideration. Disclosures Hillmann: PIQUR Therapeutics AG: Employment. Wymann:PIQUR Therapeutics AG: Employment, Equity Ownership, Patents & Royalties.