The detection of a strong episignature for Chung–Jansen syndrome, partially overlapping with Börjeson–Forssman–Lehmann and White–Kernohan syndromes

Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung–Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung–Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White–Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson–Forssman–Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung–Jansen, Börjeson–Forssman–Lehmann and White–Kernohan syndromes.</p

In silico molecular target prediction unveils mebendazole as a potent MAPK14 inhibitor

International audienceThe concept of polypharmacology involves the interaction of drug mole- cules with multiple molecular targets. It provides a unique opportunity for the repurposing of already-approved drugs to target key factors involved in human diseases. Herein, we used an in silico target prediction algorithm to investigate the mechanism of action of mebendazole, an antihelminthic drug, currently repurposed in the treatment of brain tumors. First, we con- firmed that mebendazole decreased the viability of glioblastoma cells in vitro (IC50 values ranging from 288 nM to 2.1 μM). Our in silico approach unveiled 21 putative molecular targets for mebendazole, includ- ing 12 proteins significantly upregulated at the gene level in glioblastoma as compared to normal brain tissue (fold change > 1.5; P < 0.0001). Vali- dation experiments were performed on three major kinases involved in can- cer biology: ABL1, MAPK1/ERK2, and MAPK14/p38a. Mebendazole could inhibit the activity of these kinases in vitro in a dose-dependent man- ner, with a high potency against MAPK14 (IC50 = 104 +/- 46 nM). Its direct binding to MAPK14 was further validated in vitro, and inhibition of MAPK14 kinase activity was confirmed in live glioblastoma cells. Consis- tent with biophysical data, molecular modeling suggested that mebendazole was able to bind to the catalytic site of MAPK14. Finally, gene silencing demonstrated that MAPK14 is involved in glioblastoma tumor spheroid growth and response to mebendazole treatment. This study thus high- lighted the role of MAPK14 in the anticancer mechanism of action of mebendazole and provides further rationale for the pharmacological target- ing of MAPK14 in brain tumors. It also opens new avenues for the devel- opment of novel MAPK14/p38a inhibitors to treat human diseases

Overlapping microdeletions involving 15q22.2 narrow the critical region for intellectual disability to NARG2 and RORA

Microdeletions in the 15q22 region have not been well documented. We collected genotype and phenotype data from five patients with microdeletions involving 15q22.2, which were between 0.7 Mb and 6.5 Mb in size; two were of de novo origin and one was of familial origin. Intellectual disability and epilepsy are frequently observed in patients with 15q22.2 deletions. Genotype-phenotype correlation analysis narrowed the critical region for such neurologic symptoms to a genomic region of 654 Kb including the NMDA receptor-regulated 2 gene (NARG2) and the PAR-related orphan receptor A gene (RORA), either of which may be responsible for neurological symptoms commonly observed in patients with deletions in this region. The neighboring regions, including the forkhead box B1 gene (FOXB1), may also be related to the additional neurological features observed in the patients with larger deletions

Partial pancreatoduodenectomy versus duodenum-preserving pancreatic head resection in chronic pancreatitis: the multicentre, randomised, controlled, double-blind ChroPac trial

Background There is substantial uncertainty regarding the optimal surgical treatment for chronic pancreatitis. Short-term outcomes have been found to be better after duodenum-preserving pancreatic head resection (DPPHR) than after partial pancreatoduodenectomy. Therefore, we designed the multicentre ChroPac trial to investigate the long-term outcomes of patients with chronic pancreatitis within 24 months after surgery. Methods This randomised, controlled, double-blind, parallel-group, superiority trial was done in 18 hospitals across Europe. Patients with chronic pancreatitis who were planned for elective surgical treatment were randomly assigned to DPPHR or partial pancreatoduodenectomy with a central web-based randomisation tool. The primary endpoint was mean quality of life within 24 months after surgery, measured with the physical functioning scale of the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. Primary analysis included all patients who underwent one of the assigned procedures; safety analysis included all patients who underwent surgical intervention (categorised into groups as treated). Patients and outcome assessors were masked to group assignment. The trial was registered, ISRCTN38973832. Recruitment was completed on Sept 3, 2013. Findings Between Sept 10, 2009, and Sept 3, 2013, 250 patients were randomly assigned to DPPHR (n=125) or partial pancreatoduodenectomy (n=125), of whom 226 patients (115 in the DPPHR group and 111 in the partial pancreatoduodenectomy group) were analysed. No difference in quality of life was seen between the groups within 24 months after surgery (75.3 [SD 16.4] for partial pancreatoduodenectomy vs 73.0 [16.4] for DPPHR; mean difference -2.3, 95% CI -6.6 to 2.0; p=0.284). The incidence and severity of serious adverse events did not differ between the groups. 70 (64%) of 109 patients in the DPPHR group and 61 (52%) of 117 patients in the partial pancreatoduodenectomy group had at least one serious adverse event, with the most common being reoperations (for reasons other than chronic pancreatitis), gastrointestinal problems, and other surgical morbidity. Interpretation No differences in quality of life after surgery for chronic pancreatitis were seen between the interventions. Results from single-centre trials showing superiority for DPPHR were not confirmed in the multicentre setting