ESF-EMBO symposium "molecular biology and innovative therapies in sarcomas of childhood and adolescence" Sept 29–Oct 4, Polonia Castle Pultusk, Poland

Rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) are among the most common pediatric sarcomas (Arndt et al., 2012). Despite sarcomas representing a highly heterogeneous group of tumors, ES and alveolar RMS (ARMS) typically share one common genetic characteristic, namely a specific chromosomal translocation (Helman and Meltzer, 2003; Lessnick and Ladanyi, 2012). These translocations generate fusion proteins, which are composed of two transcription factors (TF). Typically, one TF is a developmentally regulated factor that is essential for proper specification of a given lineage and provides the DNA-binding domain, while the partner TF contributes a transactivation domain that drives aberrant expression of target genes. Based on these common genetic characteristics, the first ESF-EMBO research conference entitled “Molecular Biology and Innovative Therapies in Sarcomas of Childhood and Adolescence” with special focus on RMS and ES was held at the Polonia Castle in Pultusk, Poland. The conference gathered 70 participants from more than 15 countries and several continents representing most research groups that are active in this field

Die Tibiavalgisationsosteotomie mittels Kallusdistraktion

Zusammenfassung: Operationsziel: Korrektur einer varischen Tibiaachse und Entlastung des medialen Kniekompartiments durch mediale Osteotomie im Tibiakopfbereich und Kallusdistraktion zur Valgisation. Indikationen: Symptomatisches Varusknie bei —medialem Postmeniskektomie-Syndrom, —medialer Gonarthrose, —Knorpelläsionen des medialen Kompartiments, —avaskulärer Osteonekrose des medialen Femurkondylus (Morbus Ahlbäck), —Osteochondrosis dissecans des medialen Femurkondylus, —posterolateraler und/oder anteromedialer Rotationsinstabilität des Kniegelenks. Kontraindikationen: Fortgeschrittene Pathologie der Kniegelenkflächen des lateralen Kompartiments. Fortgeschrittene Begleitarthrose des femoropatellaren Gelenks. Extensionsdefizit > 10°. Wenig aktive > 60-jährige Patienten. Operationstechnik: Anlegen eines Fixateur externe unter Bildwandlerkontrolle möglichst nahe zur Gelenklinie. Hautinzision medial der Tuberositas tibiae. Tibiaosteotomie zwischen den proximalen Schrauben des Fixateurs und der Tuberositas tibiae unter Schonung der lateralen Kortikalis. Intraoperative Kontrolle der Distraktion unter dem Bildwandler bis zur gewünschten Korrektur. Zuklappen der Distraktion. Weiterbehandlung: Distraktionsphase ab dem 5. postoperativen Tag mit 1 mm Distraktion pro Tag. Röntgenkontrollen am 5.-7. Tag, nach 6 Wochen und nach 8-10 Wochen nach Beginn der Distraktion, je nach Heilungsverlauf. Bei radiologisch erreichter Korrektur Beendigung der Distraktion und bei genügender Kallusformation Entfernung des Fixateurs unter Belassen der Schrauben. Bei unveränderter Korrektur nach Vollbelastung Entfernung der Schrauben. Ergebnisse: Zwischen 1998 und 2000 wurden bei 24 Patienten (sechs weiblich, 18 männlich, Alter 21-64 Jahre) 34 Kallusdistraktionen durchgeführt, bei zehn Patienten bilateral. 21 Patienten wurden nach 6-36 Monaten (Durchschnitt 23 Monate) nachuntersucht; eine Patientin wurde nach Implantation einer Totalendoprothese ausgeschlossen. Die femorotibiale Achse betrug präoperativ 179° (172-183°) und postoperativ 185° (179-191°). Die mediane Korrektur belief sich somit auf 6° (3-12°). 20 Patienten würden die Operation nochmals durchführen lassen. Der von den Autoren entwickelte Score verbesserte sich von präoperativ 15 auf postoperativ 10 Punkte, entsprechend einem guten Ergebnis. Komplikationen traten bei 15 Korrekturen (48%) auf, wovon acht (26%) eine operative Revision benötigte

Teachers involved in school improvement: Analyzing mediating mechanisms of teachers’ boundary-crossing activities between leadership perception and teacher involvement

Teachers are drivers for change in school improvement. However, not all teachers participate in further developing schools' educational practice. This study aimed to understand conditional factors in teachers' involvement. To this end, we analyzed teachers' leadership perception and boundary-crossing activities aimed at increasing professional capital. Structural equation modeling analyses based on a sample of N = 1232 teachers at N = 59 schools indicated partial mediations of cognitive and social boundary-crossing activities on the relationship between leadership perception and involvement. This study contributes to the literature by illuminating the potential of teachers’ activities to enhance professional capital for school improvement

Junctional adhesion molecule (JAM)-C deficient C57BL/6 mice develop a severe hydrocephalus

The junctional adhesion molecule (JAM)-C is a widely expressed adhesion molecule regulating cell adhesion, cell polarity and inflammation. JAM-C expression and function in the central nervous system (CNS) has been poorly characterized to date. Here we show that JAM-C−/− mice backcrossed onto the C57BL/6 genetic background developed a severe hydrocephalus. An in depth immunohistochemical study revealed specific immunostaining for JAM-C in vascular endothelial cells in the CNS parenchyma, the meninges and in the choroid plexus of healthy C57BL/6 mice. Additional JAM-C immunostaining was detected on ependymal cells lining the ventricles and on choroid plexus epithelial cells. Despite the presence of hemorrhages in the brains of JAM-C−/− mice, our study demonstrates that development of the hydrocephalus was not due to a vascular function of JAM-C as endothelial re-expression of JAM-C failed to rescue the hydrocephalus phenotype of JAM-C−/− C57BL/6 mice. Evaluation of cerebrospinal fluid (CSF) circulation within the ventricular system of JAM-C−/− mice excluded occlusion of the cerebral aqueduct as the cause of hydrocephalus development but showed the acquisition of a block or reduction of CSF drainage from the lateral to the 3rd ventricle in JAM-C−/− C57BL/6 mice. Taken together, our study suggests that JAM-C−/− C57BL/6 mice model the important role for JAM-C in brain development and CSF homeostasis as recently observed in humans with a loss-of-function mutation in JAM-C

Inflammatory Myofibroblastic Tumor of the Trachea with Concomitant Granulomatous Lymph Node Lesions

We report herein the case of a 57-year-old lady who had two concomittant lesions, an inflammatory myofibroblastic tumor in the trachea, and severe granulomatous lesions in the adjacent hilar lymph nodes. While these two lesions shared histological and some immunohistochemical features lesions. They differed in terms of ALK-1 expression, which was positive in the tracheal tumor and negative in the lymph nodes. The discussion of the case circles around putative pathophysiological links between the lesions. The authors favor the idea that the lymph nodes present a sarcoid-like granulomatous reaction to the inflammatory myofibroblastic tumor in the trachea over a coexistence of two independent entities. However, no conclusive evidence for this interpretation can be presented based on the existing literature

CRISPR activation screen identifies TGFβ-associated PEG10 as a crucial tumor suppressor in Ewing sarcoma

As the second most common pediatric bone and soft tissue tumor, Ewing sarcoma (ES) is an aggressive disease with a pathognomonic chromosomal translocation t(11;22) resulting in expression of EWS-FLI1, an "undruggable" fusion protein acting as transcriptional modulator. EWS-FLI1 rewires the protein expression in cancer cells by activating and repressing a multitude of genes. The role and contribution of most repressed genes remains unknown to date. To address this, we established a CRISPR activation system in clonal SKNMC cell lines and interrogated a custom focused library covering 871 genes repressed by EWS-FLI1. Among the hits several members of the TGFβ pathway were identified, where PEG10 emerged as prime candidate due to its strong antiproliferative effect. Mechanistic investigations revealed that PEG10 overexpression caused cellular dropout via induction of cell death. Furthermore, non-canonical TGFβ pathways such as RAF/MEK/ERK, MKK/JNK, MKK/P38, known to lead to apoptosis or autophagy, were highly activated upon PEG10 overexpression. Our study sheds new light onto the contribution of TGFβ signalling pathway repression to ES tumorigenesis and suggest that its re-activation might constitute a novel therapeutic strategy

Molecular Characterization of Circulating Tumor DNA in Pediatric Rhabdomyosarcoma: A Feasibility Study

PURPOSE Rhabdomyosarcomas (RMS) are rare neoplasms affecting children and young adults. Efforts to improve patient survival have been undermined by a lack of suitable disease markers. Plasma circulating tumor DNA (ctDNA) has shown promise as a potential minimally invasive biomarker and monitoring tool in other cancers; however, it remains underexplored in RMS. We aimed to determine the feasibility of identifying and quantifying ctDNA in plasma as a marker of disease burden and/or treatment response using blood samples from RMS mouse models and patients. METHODS We established mouse models of RMS and applied quantitative polymerase chain reaction (PCR) and droplet digital PCR (ddPCR) to detect ctDNA within the mouse plasma. Potential driver mutations, copy-number alterations, and DNA breakpoints associated with PAX3/7-FOXO1 gene fusions were identified in the RMS samples collected at diagnosis. Patient-matched plasma samples collected from 28 patients with RMS before, during, and after treatment were analyzed for the presence of ctDNA via ddPCR, panel sequencing, and/or whole-exome sequencing. RESULTS Human tumor-derived DNA was detectable in plasma samples from mouse models of RMS and correlated with tumor burden. In patients, ctDNA was detected in 14/18 pretreatment plasma samples with ddPCR and 7/7 cases assessed by sequencing. Levels of ctDNA at diagnosis were significantly higher in patients with unfavorable tumor sites, positive nodal status, and metastasis. In patients with serial plasma samples (n = 18), fluctuations in ctDNA levels corresponded to treatment response. CONCLUSION Comprehensive ctDNA analysis combining high sensitivity and throughput can identify key molecular drivers in RMS models and patients, suggesting potential as a minimally invasive biomarker. Preclinical assessment of treatments using mouse models and further patient testing through prospective clinical trials are now warranted