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Neuroblastoma is a common childhood tumor originating from neural crest progenitors with variable clinical behavior. Despite improved overall survival, factors such as stage, histoprognosis, MYCN status, and age still influence outcome. MCM6 regulates DNA replication and contributes to cancer progression. PRAME, first identified in melanoma, also acts on cell replication, epithelial-mesenchymal transition, and cell migration and has been associated with poor outcomes in several cancers, including neuroblastoma, using molecular biology techniques. The study aims to investigate MCM6 and PRAME expression and prognostic roles in neuroblastoma. A retrospective study was conducted, which included data of 84 patients with neuroblastoma diagnosed between 2000 and 2022, sourced from the pediatric tumor registry. Patient's characteristics and prognostic tumor factors were collected. Expression of MCM6 and PRAME proteins was evaluated using digital image analysis techniques. Univariate and multivariate analyses were performed using Cox regression to assess the impact of protein expression on survival and their associations with these prognostic factors. A total of 84 children diagnosed with neuroblastoma were included. MCM6 and PRAME were associated with unfavorable histologies (p = 0.03). PRAME was associated with bone marrow metastases (p < 0.01), high mitotic-karyorrhectic index (p = 0.04), and poor histoprognosis (p < 0.01). PRAME and MCM6 expression was correlated with several neuroblastoma prognostic factors. PRAME was significantly (p = 0.05) associated with poor event-free survival (EFS) and not significantly (p = 0.08) associated with overall survival (OS). Although statistical significance was not reached in multivariate analysis, the trends strongly suggested that the overexpression of MCM6 and PRAME was correlated with decreased survival., Competing Interests: Declaration of competing interest The authors declare that they have no financial or intellectual conflicts of interest pertaining to the contents of this manuscript., (Copyright © 2025 Elsevier Inc. All rights reserved.)

The realms of natural products and synthetic compounds exhibit distinct chemical spaces that not only differ but also complement each other. While the convergence of these two domains has been explored through semisynthesis and conventional pharmacomodulation endeavours applied to natural frameworks, a recent and innovative approach has emerged that involves the combinatorial generation of libraries of 'natural product-like compounds' (NPLCs) through the direct synthetic derivatization of natural extracts. This has led to the production of numerous NPLCs that incorporate structural elements from both their natural (multiple saturated rings, oxygen content, chiral centres) and synthetic (aromatic rings, nitrogen and halogen content, drug-like properties) precursors. Through careful selection of extracts and reagents, specific bioactivities have been achieved, and this strategy has been deployed in various ways, showing great promise without reaching its full potential to date. This review seeks to provide an overview of reported examples involving the chemical engineering of extracts, showcasing a spectrum of natural product alterations spanning from simple substitutions to complete scaffold remodelling. It also includes an analysis of the accomplishments, perspectives and technical challenges within this field., (© 2024 Wiley-VCH GmbH.)

Bacterial resistance is undoubtedly one of the main public health concerns especially with the emergence of metallo-β-lactamases (MBLs) able to hydrolytically inactivate β-lactam antibiotics. Currently, there are no inhibitors of MBLs in clinical use to rescue antibiotic action and the New Delhi metallo-β-lactamase-1 (NDM-1) is still considered as one of the most relevant targets for inhibitor development. Following a fragment-based strategy to find new NDM-1 inhibitors, we identified aurone as a promising scaffold. A series of 60 derivatives were then evaluated and two of them were identified as promising inhibitors with K i values as low as 1.7 and 2.5 µM. Moreover, these two most active compounds were able to potentiate meropenem in in vitro antimicrobial susceptibility assays. The molecular modelling provided insights about their likely interactions with the active site of NDM-1, thus enabling further improvement in the structure of this new inhibitor family., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Although uncommon, Epstein-Barr virus-related neurological disorders represent the seventh most frequent cause of infectious encephalitis in adults. The limited number of publications on EBV encephalitis mainly document isolated clinical cases. This study aimed to summarize published data on EBV encephalitis. A systematic literature search identified 97 EBV encephalitis cases. In the selected cases, EBV-related neurological disorders manifested as lymphocytic pleocytosis in the cerebrospinal fluid (CSF) with moderate hyperproteinorachia. The EBV PCR test was positive in 87% of the CSF samples, with wide-ranging viral loads. When encephalitis occurred in the context of past EBV infections, all of the EBV PCR tests on CSF samples were positive. On the contrary, negative EBV PCR tests on CSF samples occurred only in the context of primary infections. EBV PCR was rarely carried out on blood samples, contributing minimally to the diagnosis. For the treatment of EBV encephalitis, Aciclovir was used alone in 29% of cases, and in association with other drugs in 40% of cases. Ganciclovir (30%), corticoids (52%), and immunoglobulins (15%) were mainly used in association with other drugs. Cerebral imaging was abnormal in 69% of cases, mostly in the cerebellum and basal ganglia. This work highlights that the EBV PCR test on CSF samples is currently the main laboratory diagnostic test to diagnose EBV encephalitis. This diagnostic test is useful; however, it is imperfect. New complementary diagnostic tools, approved treatments, and standardized practices could improve patient management.

Introduction: The study of tumor extension in knee osteosarcomas is an essential diagnostic tool that helps determine the surgical approach. Magnetic resonance imaging (MRI) is the key component in this decision-making process, but the interpretation of signals can be difficult because peritumoral edema and inflammation may be mistaken for the tumor., Hypothesis: There is a discrepancy between MRI and histopathology findings in the assessment of joint involvement in pediatric osteosarcomas of the knee., Materials and Methods: All children who underwent an extra-articular resection for an osteosarcoma of the knee between 2007 and 2016 were included. This was indicated if there was at least one of the following MRI signs: presence of articular effusion, involvement of either the peripheral capsuloligamentous structures, central pivot or patella, or lesion abutting the articular cartilage., Results: Nine patients were operated on with a mean age of 13±2.7 years. There were at least two of the described signs, mainly the involvement of the peripheral capsuloligamentous structures (78%) and central pivot (56%). The histopathology confirmed that the resection margins were healthy in all cases, but the indication for extra-articular resection could have been avoided in 89% of them., Discussion: MRI is the current gold standard for assessing tumor extension, but the signs contraindicating the transarticular approach remain poorly defined. Joint effusion detected by clinical or radiological assessment is the least reliable one. It seems that the tumor's proximity to the articular cartilage, as long as there is no loss of continuity in the latter, or its extension into the central pivot should no longer be considered as relevant signs. The involvement of the peripheral capsuloligamentous structure remains an indication criterion because oncologic resection is otherwise impossible, and the risk of false-negative histopathologic diagnoses is higher. Other MRI sequences could better assess the true extension into the joint space., Level of Evidence: IV, retrospective study., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Despite several studies on the Ajuga L. genus, the chemical composition of Ajuga pyramidalis , an alpine endemic species, is still largely unknown. The purpose of this study was to therefore deeper describe it, particularly from the phytochemistry and bioactivity perspectives. In that respect, A. pyramidalis was investigated and 95% of the extracted mass of the plant was characterized by chromatography and mass spectrometry. Apart from the already determined chemical compounds, namely, harpagide and 8- O -acetylharpagide, two iridoids, and neoajugapyrin A, a neo-clerodane diterpene, and three polyphenols (echinacoside, verbascoside and teupoloside) were identified for the first time in A. pyramidalis . Incidentally, the first RX structure of a harpagoside derivative is also described in this paper. The extracts and isolated compounds were then evaluated for various biochemical or biological activities; notably a targeted action on the renewal of the epidermis was highlighted with potential applications in the cosmetic field for anti-aging.

Hydrolysis of β-lactam drugs, a major class of antibiotics, by serine or metallo-β-lactamases (SBL or MBL) is one of the main mechanisms for antibiotic resistance. New Delhi Metallo-β-lactamase-1 (NDM-1), an acquired metallo-carbapenemase first reported in 2009, is currently considered one of the most clinically relevant targets for the development of β-lactam-β-lactamase inhibitor combinations active on NDM-producing clinical isolates. Identification of scaffolds that could be further rationally pharmacomodulated to design new and efficient NDM-1 inhibitors is thus urgently needed. Fragment-based drug discovery (FBDD) has become of great interest for the development of new drugs for the past few years and combination of several FBDD strategies, such as virtual and NMR screening, can reduce the drawbacks of each of them independently. Our methodology starting from a high throughput virtual screening on NDM-1 of a large library (more than 700,000 compounds) allowed, after slicing the hit molecules into fragments, to build a targeted library. These hit fragments were included in an in-house untargeted library fragments that was screened by Saturation Transfer Difference (STD) Nuclear Magnetic Resonance (NMR). 37 fragments were finally identified and used to establish a pharmacophore. 10 molecules based on these hit fragments were synthesized to validate our strategy. Indenone 89 that combined two identified fragments shows an inhibitory activity on NDM-1 with a K i value of 4 μM., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Tauopathies, such as Alzheimer's disease, have been the subject of several hypotheses regarding the way to treat them. Hyperphosphorylation of tau protein leading to its aggregation is widely recognized as a key step in the development of these diseases resulting in neuronal dysfunction. The AcPHF6 model of tau that includes the shorter critical fragment involved in the protein aggregation was used in vitro to identify new potential inhibitors. Following a previous study on aurone derivatives, we herein compare this polyphenol family to a very close one, the benzylidene-2,3-dihydro-1H-inden-1-one (also named indanone). The structure activity relationship studies bring to light the importance of the hydroxylation pattern in both series: the more hydroxylated, the more active. In addition, the three-dimensional shape of the molecules is involved in their interaction mode with their target, thus defining their role either as inhibitors of fiber elongation or as fiber-binding molecules. Indanone 13a was identified as a promising inhibitor: its activity was confirmed by circular dichroism and atomic force microscopy studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Childhood IgA nephropathy (IgAN) includes a wide spectrum of clinical presentations, from isolated hematuria to acute nephritis with rapid loss of kidney function. In adults, IgAN is an autoimmune disease and its pathogenesis involves galactose deficient (Gd) IgA1, IgG anti-Gd-IgA1 autoantibodies and the soluble IgA Fc receptor (CD89). However, implication of such factors, notably soluble CD89, in childhood IgAN pathogenesis remains unclear. Here, we studied these biomarkers in a cohort of 67 patients with childhood IgAN and 42 pediatric controls. While Gd-IgA1 was only moderately increased in patient plasma, levels of circulating IgA complexes (soluble CD89-IgA and IgG-IgA) and free soluble CD89 were markedly increased in childhood IgAN. Soluble CD89-IgA1 complexes and free soluble CD89 correlated with proteinuria, as well as histological markers of disease activity: mesangial, endocapillary hypercellularity and cellular crescents. Soluble CD89 was found in patient's urine but not in urine from pediatric controls. Mesangial deposits of soluble CD89 were detected in biopsies from patients with childhood IgAN. Serum chromatographic fractions containing covalently linked soluble CD89-IgA1 complexes or free soluble CD89 from patients induced mesangial cell proliferation in vitro in a soluble CD89-dependent manner. Recombinant soluble CD89 induced mesangial cell proliferation in vitro which was inhibited by free soluble recombinant CD71 (also a mesangial IgA receptor) or mTOR blockers. Interestingly, injection of recombinant soluble CD89 induced marked glomerular proliferation and proteinuria in mice expressing human IgA1. Thus, free and IgA1-complexed soluble CD89 are key players in mesangial proliferation. Hence, our findings suggest that soluble CD89 plays an essential role in childhood IgAN pathogenesis making it a potential biomarker and therapeutic target., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Multidrug ABC transporters translocate drugs across membranes by a mechanism for which the molecular features of drug release are so far unknown. Here, we resolved three ATP-Mg 2+ -bound outward-facing conformations of the Bacillus subtilis (homodimeric) BmrA by x-ray crystallography and single-particle cryo-electron microscopy (EM) in detergent solution, one of them with rhodamine 6G (R6G), a substrate exported by BmrA when overexpressed in B. subtilis . Two R6G molecules bind to the drug-binding cavity at the level of the outer leaflet, between transmembrane (TM) helices 1-2 of one monomer and TM5'-6' of the other. They induce a rearrangement of TM1-2, highlighting a local flexibility that we confirmed by hydrogen/deuterium exchange and molecular dynamics simulations. In the absence of R6G, simulations show a fast postrelease occlusion of the cavity driven by hydrophobicity, while when present, R6G can move within the cavity, maintaining it open.

Objective: Adrenal ganglioneuromas are rare, differentiated, neuroblastic tumors that originate from the peripheral sympathetic nervous system. Because of their rarity, information is limited, derived from small cases series. Our objective was to characterize this tumor and provide help for its management., Methods: A retrospective multicenter analysis of adrenal ganglioneuromas from 20 French centers belonging to the COMETE network and one Belgian center., Results: Among the 104 cases identified, 59.6% were women (n = 62/104), median age at diagnosis was 29 years, with 24 pediatric cases. 60.6% (n = 63/104) were incidentalomas. Ganglioneuromas were non-secreting tumors in 90.8% of cases (n = 89/98), whereas the preoperative hormonal evaluation was indeterminate for 9.2% of patients (n = 9/98). CT imaging, performed on 96 patients, revealed large tumors (median diameter of 50 mm) with a non-contrast density > 10 Hounsfield units in 98.1% (n = 52/53) and calcifications in 64.6% of cases (n = 31/48). Increased uptake on 123I-MIBG scintigraphy and 18F-FDG-PET/CT was observed in 26.7% (n = 8/30) and 42.2% (n = 19/45) of the tumors, respectively. All 104 patients underwent surgery. No recurrence was observed among the 42 patients who had an imaging follow-up (mean 29.6 months, median 18 months (4-156))., Conclusion: Adrenal ganglioneuromas are large tumors, mostly nonfunctioning, without benign imaging features. Although the duration of follow-up was limited in our series, no recurrence was identified. A review of the literature confirms the absence of postoperative recurrence. Based on all available data, in the absence of special circumstances (genetic form, uncertain histological diagnosis), long-term follow-up is not necessary after complete surgery for patients with an adrenal ganglioneuroma.

Idiopathic nephrotic syndrome (INS) is characterized by proteinuria and renal sodium retention leading to edema. This sodium retention is usually attributed to epithelial sodium channel (ENaC) activation after plasma aldosterone increase. However, most nephrotic patients show normal aldosterone levels. Using a corticosteroid-clamped (CC) rat model of INS (CC-PAN), we showed that the observed electrogenic and amiloride-sensitive Na retention could not be attributed to ENaC. We then identified a truncated variant of acid-sensing ion channel 2b (ASIC2b) that induced sustained acid-stimulated sodium currents when coexpressed with ASIC2a. Interestingly, CC-PAN nephrotic ASIC2b-null rats did not develop sodium retention. We finally showed that the expression of the truncated ASIC2b in the kidney was dependent on the presence of albumin in the tubule lumen and activation of ERK in renal cells. Finally, the presence of ASIC2 mRNA was also detected in kidney biopsies from patients with INS but not in any of the patients with other renal diseases. We have therefore identified a variant of ASIC2b responsible for the renal Na retention in the pathological context of INS.

Objective: SRY-negative 46,XX testicular and ovotesticular disorders/differences of sex development (T/OTDSD) represent a very rare and unique DSD condition where testicular tissue develops in the absence of a Y chromosome. To date, very few studies have described the phenotype, clinical and surgical management and long-term outcomes of these patients. Particularly, early blockade of the gonadotropic axis in patients raised in the female gender to minimize postnatal androgenization has never been reported., Design: Retrospective description of sixteen 46,XX T/OTDSD patients., Results: Sixteen 46,XX SRY-negative T/OTDSD were included. Most (12/16) were diagnosed in the neonatal period. Sex of rearing was male for six patients and female for ten, while the clinical presentation varied, with an external masculinization score from 1 to 10. Five patients raised as girl were successfully treated with GnRH analog to avoid virilization during minipuberty. Ovotestes/testes were found bilaterally for 54% of the patients and unilaterally for the others (with a contralateral ovary). Gonadal surgery preserved appropriate tissue in the majority of cases. Spontaneous puberty occurred in two girls and one boy, while two boys required hormonal induction of puberty. One of the girls conceived spontaneously and had an uneventful pregnancy. DNA analyses (SNP-array, next-generation sequencing and whole-exome sequencing) were performed. A heterozygous frameshit mutation in the NR2F2 gene was identified in one patient., Conclusions: This study presents a population of patients with 46,XX SRY-negative T/OTDSD. Early blockade of gonadotropic axis appears efficient to reduce and avoid further androgenization in patients raised as girls., (© 2020 John Wiley & Sons Ltd.)

Introduction: Childhood IgA nephropathy (cIgAN) is a primary glomerulonephritis clinically characterized by microscopic hematuria and proteinuria, the presence of which may potentially overlap with Alport syndrome. Interestingly, earlier studies suggested that familial IgAN could be linked to the chromosome 2q36 region, also the coding region for collagen type 4 alpha 3/4 (COL4A3/A4)., Methods: To investigate a possible relationship or phenocopy between Alport syndrome and cIgAN, COL4A3, COL4A4, and COL4A5 exons were sequenced in 36 cIgAN patients. Clinical data and treatment were collected retrospectively. COL4A3/A4/A5 variants were classified according to American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) guidelines., Results: Four of 36 cIgAN patients were affected by ACMG class 4/5 COL4A3 heterozygous variants (COL4A3-cIgAN). We found no COL4A4 or COL4A5 variant. Despite having rare and deleterious COL4A3 variants, 3 of 4 COL4A3-cIgAN children developed clinical and biologic features of active IgAN rather than Alport syndrome. Response to intensive immunosuppressive treatment was favorable, leading to a reduction of endocapillary and extracapillary proliferation lesions. High levels of immune immunoglobulin G and A (IgG/IgA) complexes, reduction of proteinuria, and gradual stabilization of estimated glomerular filtration rate (eGFR) argued against Alport syndrome. Nevertheless, COL4A3-cIgAN patients seemed predisposed to a more serious IgAN presentation compared with the non‒COL4A3-cIgAN group, with more glomerulosclerosis and a lower eGFR over time. One of the 4 patients underwent kidney transplant with subsequent IgAN recurrence., Conclusions: Predisposition factors for developing serious cIgAN flare-up should be considered for cIgAN with COL4A3 pathologic heterozygous variants. COL4A3 variants, usually responsible for Alport syndrome in adults, should not automatically exclude an immunosuppressive regimen in cIgAN. Moreover, evidence of an ACMG class 4/5 COL4A3 variant in early-stage cIgAN could be a helpful tool for stratifying severity of cIgAN beyond the Oxford classification., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

The natural β-carboline alkaloids display similarities with neurotransmitters that can be favorably exploited to design bioactive and bioavailable drugs for Alzheimer's disease (AD) therapy. Several AD targets are currently and intensively being investigated, divided in different hypotheses: mainly the cholinergic, the amyloid β (Aβ), and the Tau hypotheses. To date, only symptomatic treatments are available involving acetylcholinesterase and NMDA inhibitors. On the basis of plethoric single-target structure-activity relationship studies, the β-carboline scaffold was identified as a powerful tool for fostering activity and molecular interactions with a wide range of AD-related targets. This knowledge can undoubtedly be used to design multitarget-directed ligands, a highly relevant strategy preferred in the context of multifactorial pathology with intricate etiology such as AD. In this review, we first individually discuss the AD targets of the β-carbolines, and then we focus on the multitarget strategies dedicated to the deliberate design of new efficient scaffolds.

The active component extraction from plants is the first crucial step in natural product research. For non-targeted extraction with an objective to isolate and characterize as many compounds as possible, the most classical technique, and the simplest to implement, is the Soxhlet extraction; however, it does not allow retrieving all the compounds from the plant (when it does not additionally cause artifacts during long heating process). The second most used technique is the extraction by successive macerations using solvents of increasing polarity. While this method is frequently used, few studies are available to rationalize and optimize it. Furthermore, this extraction technique requires some enhancement mainly for efficiency, environmental and time constraint reasons. Here, we present an innovative method of successive macerations using a mixture of solvents with the aim of simultaneously improving the yield, the partition of the compounds between the different phases and reducing the volume of extraction solvents. Triphasic systems were prepared by mixing five solvents (n-heptane, ethyl acetate, acetonitrile, butan-1-ol, water) in various proportions. To validate this method, the most efficient triphasic system was subsequently used to perform three successive macerations with a polarity gradient on a model plant before being extended to several alpine plants. Our results showed an overall good yield compared to conventional maceration techniques, while improving phase partition and reducing extraction time and volume of solvents., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Previous reports suggest initial presentation of IgA nephropathy (IgAN) in children is different from adults. No systematic comparison of clinical, biological, and histological childhood- and adult-onset IgAN is currently available., Methods: We compared pediatric and adult clinical and histological characteristics at IgAN diagnosis. Data on 211 consecutive patients from two different centers in Paris (82 children, 129 adults) were reviewed. Kidney biopsies were scored for Oxford classification and podocytopathic (P1) features., Results: We report higher eGFR at diagnosis in children compared to adults (89.5 vs. 64 ml/min/1.73 m 2 ; p = 0.0001) but no difference in proteinuria. Histological analysis of kidney biopsy found higher proportions of mesangial (M1) and endocapillary (E1) hypercellularity in children compared with adults (M1 [80.7% vs. 27.9%, p = 0.0001]; E1 [71.3% vs. 30%, p = 0.0001]). Focal glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis ≥ 25% (T1), and P1 were more frequent in adults (S1 [81.5% vs. 61.3%, p = 0.0012], T1 [49.5% vs. 1.35%, p = 0.0001], P1 [33.8% vs. 16.4%, p = 0.008). Proteinuria associated with M1, E1, and C1 in children (M1, p = 0.0001; E1, p = 0.0005; C1, p = 0.0014) but S1, P1, and T1 in adults (S1, p = 0.0001; P1, p = 0.0001; T1, p = 0.001). After steroid treatment (41 children and 28 adults), proteinuria decreased in children (p < 0.001, follow-up 38 months) and adults (p < 0.001, follow-up 76.9 months), whereas eGFR remained stable in adults but increased significantly in children (90.6 to 110 ml/min/1.73m 2 )., Conclusion: Proteinuria in children with IgAN is a marker of glomerular proliferative lesions whereas its presence in adults often reflects the presence of chronic lesions. This suggests the need for histological assessment.

Hirschsprung disease (HD) is a congenital disorder of the enteric nervous system that occurs in ∼1 in 5000 live births. It is characterized by the absence of ganglionic cells (GCs) in the distal intestine. The diagnosis relies on the thorough analysis of a rectal suction biopsy (RSB), which must show a complete absence of GCs after careful examination of at least 100 serial sections. Such a negative characteristic explains the difficulty of this diagnosis. Moreover, GCs may be immature in very young or preterm born children, making them hard to recognize. Therefore, ancillary techniques have been developed as diagnostic help, such as acetylcholinesterase histochemistry and calretinin immunostaining. These techniques reveal only indirect clues, focusing mainly on the changes in nerve fibers, but not on GCs themselves. As PHOX2B has been shown to be a very specific transcription factor in GCs and in progenitor enteric nerve cells, we have assessed (i) PHOX2B immunostaining in immature enteric ganglia and (ii) the use of PHOX2B immunostaining for the recognition of GCs on RSBs for suspicion of HD. We have observed PHOX2B expression in all GCs, both mature and immature, and its complete absence in Hirschsprung cases. We suggest that the use of PHOX2B immunostaining is of great help (i) in the recognition of GCs on RSBs regardless of their differentiation and therefore (ii) in the diagnosis of HD.

Background: High-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 is an aggressive mature B-cell neoplasm, whereas B-lymphoblastic lymphoma is immature cell proliferation, with a frequent positivity for terminal deoxynucleotidyl transferase. The transformation of a low-grade follicular lymphoma into a lymphoblastic neoplasm expressing terminal deoxynucleotidyl transferase is a very rare event., Case Presentation: A 55-year-old Caucasian man was followed for a grade 1-2 follicular lymphoma carrying a t(14;18) IGH/BCL2+ and was initially treated with R-CHOP. The follicular lymphoma presented two relapses. In the third relapse, the patient had multiple lymphadenopathy and ascites, which motivated a retroperitoneal biopsy and an ascitic tap. These samples were analyzed by histological, cytological, flow cytometric, cytogenetic, and molecular assessments. The patient died of a multiple organ dysfunction syndrome 2 weeks after his third relapse. The biopsy revealed a diffuse proliferation made up of two types of tumor cells: centroblasts (Bcl-6-positive) and immature cells (terminal deoxynucleotidyl transferase-positive). Flow cytometric analysis confirmed the immature phenotype, with an expression of terminal deoxynucleotidyl transferase, combined with a loss of membrane immunoglobulins. The cytogenetic analysis performed on the ascites revealed a clonal evolution characterized by a t(8;22)(q24;q11) MYC+ translocation not previously detected in follicular lymphoma. Fluorescence in situ hybridization confirmed the double rearrangement of the BCL2 and MYC genes. Polymerase chain reactions and sequencing were used to study the clonal relationship between follicular lymphoma and the secondary tumors. The IGVH gene rearrangement revealed a unique clonal rearrangement involving an IGVH4-59 subset in all three specimens., Conclusion: These findings suggest a clonal relationship between the two types of lymphoma cells. Furthermore, they support the transformation of an acute follicular lymphoma into a composite lymphoma combining a high-grade B-cell lymphoma and a lymphoblastic neoplasm expressing terminal deoxynucleotidyl transferase. This case report highlights the possible transformation of follicular lymphoma into a highly aggressive and immature proliferation.

Background: The management of IgA vasculitis with nephritis (IgAVN) remains controversial because of the difficulty to identify prognostic factors. This study reports the prognosis of children with IgAVN in relation to histological parameters., Methods: All children with IgAVN diagnosed between 2000 and 2015 in three pediatric nephrology centers were included. The following histological parameters were analyzed: mesangial proliferation (MP), endocapillary proliferation (EP), crescents, active, or chronic tubular and interstitial lesions (TIa lesions/TIc lesions), and segmental glomerulosclerosis (GS). Clinical and biological data were collected at the time of renal biopsy. The primary endpoint was IgAVN remission defined as a proteinuria < 200 mg/l without renal failure., Results: One hundred fifty-nine children were included with a median age of 7.6 years. Acute glomerular or TI lesions including MP, EP, crescents, and TIa lesions were observed, respectively, in 81%, 86%, 49%, and 21% of patients. Chronic glomerular lesions including GS and TIc lesions were observed in 6 and 7% of patients. Median initial proteinuria was 330 mg/mmol, albuminemia 32 g/l, and eGFR 110 ml/min/1.73 m 2 . One hundred twelve (70%) patients were in remission at the end of a median follow-up of 37.4 months. Chronic lesions were significantly associated with the absence of remission in multivariate analysis, whereas EP, crescents and TIa were not associated with a poor prognosis., Conclusions: Of children with IgAVN, 30% present a persistent renal disease at the end of a 3-year follow-up. Chronic histological lesions, but not EP or crescents, are associated with a bad prognosis and must be evaluated in IgAVN histological classification.

Aim: Complete or partial resistance to prednisone and calcineurin inhibitors in children with idiopathic nephrotic syndrome often leads to end-stage renal disease. The aim of the study was to report the outcome of patients with multidrug-resistant nephrotic syndrome treated with an association of immunoglobulin immunoadsorption, intravenous immunoglobulins and B-cell depletion., Methods: At treatment initiation, patients received ten sessions of immunoglobulin immunoadsorption and intravenous immunoglobulins in two weeks followed by one rituximab in case of remission., Results: A remission of proteinuria was obtained in nine out of 14 patients at the end of the initial phase and in two additional patients after an extended period. The remission was stable in three patients and after additional IgIA and heavy immunosuppression in six. Two patients that initially responded relapsed after IgIA withdrawal and remained with an uncontrolled disease at last follow-up. Three patients did not respond to the treatment including two who were found to have a genetic podocytopathy., Conclusion: Patients with multidrug-resistant idiopathic nephrotic syndrome can be successfully led into remission by IgIA prior to reaching end-stage renal disease. However, IgIA does not suppress the need for heavy additional immunosuppression to control INS in most cases., (©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Phosphatidylinositide 3-kinases (PI3Ks) are widely expressed enzymes involved in membrane signalization pathways. Attempts to administer inhibitors with broad activity against different isoforms have failed due to toxicity. Conversely the PI3Kδ isoform is much more selectively expressed, enabling therapeutic targeting of this isoform. Of particular interest PI3Kδ is expressed in human basophils and its inhibition has been shown to reduce anti-IgE induced basophil degranulation, suggesting that PI3Kδ inhibitors could be useful as anti-allergy drugs. Herein, we report for the first time the activity of compounds derived from chalcone scaffolds as inhibitors of normal human basophil degranulation and identified the most active compound with anti-PI3Kδ properties that was investigated in preclinical models. Compound 18, namely 1-[2-hydroxy-4,6-dimethoxy-3-(N-methylpiperidin-4-yl)phenyl]-3-(2,4,6-trimethoxyphenyl)-prop-2-en-1-one, was found to inhibit normal human basophil degranulation in a dose-dependent manner. In a murine model of ovalbumin-induced asthma, compound 18 was shown to reduce expiratory pressure while its impact on the inflammatory infiltrate in alveolar lavage and total lung was dependent on the route of administration. In a DNFB-induced model of atopic dermatitis compound 18 administered systemically proved to be as potent as topical betamethasone. These results support the anti-atopic and allergic properties of the title compound and warrant further clinical development., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Neuroblastoma, a malignant neoplasm of the sympathetic nervous system, is one of the most aggressive pediatric cancers. Patients with stage IV high-risk neuroblastoma receive an intensive multimodal therapy ending with an immunotherapy based on a chimeric monoclonal antibody ch14.18. Although the use of ch14.18 monoclonal antibody has significantly increased the survival rate of high-risk neuroblastoma patients, about 33% of these patients still relapse and die from their disease. Ch14.18 targets the disialoganglioside, GD2, expressed on neuroblastic tumor (NT) cells. To better understand the causes of tumor relapse following ch14.18 immunotherapy, we have analyzed the expression of GD2 in 152 tumor samples from patients with NTs using immunohistochemical stainings. We observed GD2 expression in 146 of 152 samples (96%); however, the proportion of GD2-positive cells varied among samples. Interestingly, low percentage of GD2-positive cells before immunotherapy was associated with relapse in patients receiving ch14.18 immunotherapy. In addition, we demonstrated in vitro that the sensitivity of neuroblastoma cell lines to natural killer-mediated lysis was dependent on the proportion of GD2-positive cells, in the presence of ch14.18 antibody. In conclusion, our results indicate that the proportion of tumor cells expressing GD2 in NTs should be taken in consideration, as a prognostic marker, for high-risk neuroblastoma patients receiving anti-GD2 immunotherapy.

Aim: Cisplatin resistance in ovarian cancer remains a complex problem as tumors frequently develop resistance against drugs, a mechanism sometimes mediated by ATP-Binding Cassette transporters. Our goal was to find compounds restricting their inhibition capacity to the cisplatin efflux mediated by ABCC2 pump, among previously identified inhibitors, derived from the 2- indolylmethylenebenzofuranones. Methodology & results: An original method setup allows direct quantitation of platinum by employing cyTOF mass cytometry. Among tested derivatives, some led to a full platinum accumulation and efficiently resensitized cisplatin-resistant A2780 cells to cisplatin while preserving most of the calcein efflux activity., Conclusion: CyTOF is therefore a powerful and promising method to quantify cisplatin accumulation that may be used in the clinical setting to improve and personalize cancer treatment.

Introduction: There is a need for treatment guidelines and prognostic factor identification in children with primary IgA nephropathy. We analyzed the causative effect of steroids and the applicability of the Oxford classification., Methods: A total of 82 consecutive children (mean 10.6 years; median follow-up 3.3 years) were reviewed; 21 patients (25.6%) presented with acute kidney injury, and 6 (7.3%) with nephrotic syndrome. Renal biopsies were scored for Oxford classification and podocytopathic features in 2 groups: a group treated with steroid therapy (some in association with cyclophosphamide) and supportive care (renin angiotensin system blockade) and a group treated by supportive care alone., Results: The 2 groups were not comparable because baseline clinical data were different. Estimated glomerular filtration rate (eGFR) in immunosupressive group significantly improved between M0 (at onset) and M6 (6 months after treatment) from 89.9 [61.2-114.5] to 110.5 [93.7-120] ml/min per 1.73 m 2 , P  < 0.001. Proteinuria also significantly decreased from (1.6 [1-4.3] to 0.3 [0.2-0.7] g/g, P  < 0.001). In the supportive care group, eGFR and proteinuria remained stable. Podocytopathic features were predictive of renal function decline by univariable (-4.9 ± 14.9 ml/min per 1.73 m 2 , P  = 0.0079) and multivariable analysis and of poor renal prognosis to a combined event (renal function impairment more than 10% of the eGFR baseline or chronic kidney disease stage 3 at 6 months) in univariable analysis. MEST-C score failed to prove its prognostic value., Conclusion: Immunosuppressive treatment, especially steroid therapy, seems beneficial in children with glomerular inflammation and proliferation. The Oxford classification does not appear to be entirely appropriate in predicting long-term renal prognosis for children, whereas the characteristics of podocytopathy are strongly predictive of renal prognosis.

To tackle the problems associated with membrane protein (MP) instability in detergent solutions, we designed a series of glycosyl-substituted dicarboxylate detergents (DCODs) in which we optimized the polar head to clamp the membrane domain by including, on one side, two carboxyl groups that form salt bridges with basic residues abundant at the membrane-cytoplasm interface of MPs and, on the other side, a sugar to form hydrogen bonds. Upon extraction, the DCODs 8 b, 8 c, and 9 b preserved the ATPase function of BmrA, an ATP-binding cassette pump, much more efficiently than reference or recently designed detergents. The DCODs 8 a, 8 b, 8 f, 9 a, and 9 b induced thermal shifts of 20 to 29 °C for BmrA and of 13 to 21 °C for the native version of the G-protein-coupled adenosine receptor A 2A R. Compounds 8 f and 8 g improved the diffraction resolution of BmrA crystals from 6 to 4 Å. DCODs are therefore considered to be promising and powerful tools for the structural biology of MPs., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Activating mutations of the ALK receptor occur in a subset of neuroblastoma tumors. We previously demonstrated that Alk mutations cooperate with MYCN overexpression to induce neuroblastoma in mice and identified Ret as being strongly upregulated in MYCN/Alk mut tumors. By a genetic approach in vivo, we now document an oncogenic cooperation between activated Ret and MYCN overexpression in neuroblastoma formation. We show that MYCN/Ret M919T tumors exhibit histological features and expression profiles close to MYCN/Alk mut tumors. We show that RET transcript levels decrease precedes RET protein levels decrease upon ALK inhibition in neuroblastoma cell lines. Etv5 was identified as a candidate transcription factor regulating Ret expression from murine MYCN/Alk mut tumor transcriptomic data. We demonstrate that ETV5 is regulated both at the protein and mRNA levels upon ALK activation or inhibition in neuroblastoma cell lines and that this regulation precedes RET modulation. We document that ALK activation induces ETV5 protein upregulation through stabilization in a MEK/ERK-dependent manner. We show that RNAi-mediated inhibition of ETV5 decreases RET expression. Reporter assays indicate that ETV5 is able to drive RET gene transcription. ChIP-seq analysis confirmed ETV5 binding on the RET promoter and identified an enhancer upstream of the promoter. Finally, we demonstrate that combining RET and ALK inhibitors reduces tumor growth more efficiently than each single agent in MYCN and Alk F1178L -driven murine neuroblastoma. Altogether, these results define the ERK-ETV5-RET pathway as a critical axis driving neuroblastoma oncogenesis downstream of activated ALK.

Purpose: Neuroblastoma displays important clinical and genetic heterogeneity, with emergence of new mutations at tumor progression. Experimental Design: To study clonal evolution during treatment and follow-up, an innovative method based on circulating cell-free DNA (cfDNA) analysis by whole-exome sequencing (WES) paired with target sequencing was realized in sequential liquid biopsy samples of 19 neuroblastoma patients. Results: WES of the primary tumor and cfDNA at diagnosis showed overlap of single-nucleotide variants (SNV) and copy number alterations, with 41% and 93% of all detected alterations common to the primary neuroblastoma and cfDNA. CfDNA WES at a second time point indicated a mean of 22 new SNVs for patients with progressive disease. Relapse-specific alterations included genes of the MAPK pathway and targeted the protein kinase A signaling pathway. Deep coverage target sequencing of intermediate time points during treatment and follow-up identified distinct subclones. For 17 seemingly relapse-specific SNVs detected by cfDNA WES at relapse but not tumor or cfDNA WES at diagnosis, deep coverage target sequencing detected these alterations in minor subclones, with relapse-emerging SNVs targeting genes of neuritogenesis and cell cycle. Furthermore a persisting, resistant clone with concomitant disappearance of other clones was identified by a mutation in the ubiquitin protein ligase HERC2 Conclusions: Modelization of mutated allele fractions in cfDNA indicated distinct patterns of clonal evolution, with either a minor, treatment-resistant clone expanding to a major clone at relapse, or minor clones collaborating toward tumor progression. Identification of treatment-resistant clones will enable development of more efficient treatment strategies. Clin Cancer Res; 24(4); 939-49. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Ethnopharmacoalogical Relevance: The genus Nauclea in Africa comprises seven species. Among them, N. latifolia, N. diderrichii and N. pobeguinii are widely used by the local population in traditional remedies. Preparation from various parts of plants (e.g. roots, bark, leaves) are indicated by traditional healers for a wide range of diseases including malaria, pain, digestive ailments or metabolic diseases., Materials and Methods: A literature search was conducted on African species of the genus Nauclea using scientific databases such as Google Scholar, Pubmed or SciFinder. Every document of ethnopharmacological, phytochemical or pharmacological relevance and written in English or French were analyzed., Results and Discussion: The Nauclea genus is used as ethnomedicine all along sub-Saharan Africa. Several local populations consider Nauclea species as a major source of remedies for malaria. In this regard, two improved traditional medicines are currently under development using extracts from N. latifolia and N. pobeguinii. Concerning the chemical composition of the Nauclea genus, indoloquinolizidines alkaloids could be considered as the major class of compounds as they are reported in every analyzed Nauclea species, with numerous structures identified. Based on traditional indications a considerable amount of pharmacological studies were conducted to ensure activity and attempt to link them to the presence of particular compounds in plant extracts., Conclusion: Many experimental studies using plant extracts of the African species of the genus Nauclea validate traditional indications (e.g. malaria and pain). However, bioactive compounds are rarely identified and therefore, there is a clear need for further evaluations as well as for toxicity experiments. The sustainability of these plants, especially of N. diderrichii, a threatened species, should be kept in mind to adapt local uses and preparation modes of traditional remedies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Mucosal-associated invariant T (MAIT) cells are semi-invariant Vα7.2 + CD161 high CD4 - T cells that recognize microbial riboflavin precursor derivatives such as 5-OP-RU presented by MR1. Human MAIT cells are abundant in adult blood, but there are very few in cord blood. We longitudinally studied Vα7.2 + CD161 high T cell and related subset levels in infancy and after cord blood transplantation. We show that Vα7.2 + and Vα7.2 - CD161 high T cells are generated early during gestation and likely share a common prenatal developmental program. Among cord blood Vα7.2 + CD161 high T cells, the minority recognizing MR1:5-OP-RU display a TRAV/TRBV repertoire very similar to adult MAIT cells. Within a few weeks of life, only the MR1:5-OP-RU reactive Vα7.2 + CD161 high T cells acquire a memory phenotype. Only these cells expand to form the adult MAIT pool, diluting out other Vα7.2 + CD161 high and Vα7.2 - CD161 high populations, in a process requiring at least 6 years to reach adult levels. Thus, the high clonal size of adult MAIT cells is antigen-driven and likely due to the fine specificity of the TCRαβ chains recognizing MR1-restricted microbial antigens., (© 2018 Ben Youssef et al.)

Ureteropelvic junction obstruction constitutes a major cause of progressive pediatric renal disease. The biological mechanisms underlying the renal response to obstruction can be investigated using a clinically relevant mouse model of partial unilateral ureteral obstruction (pUUO). Renal function and kidney morphology data can be evaluated using renal ultrasound, scintigraphy and uro-magnetic resonance imaging (uro-MRI), but these methods are poorly linked to histological change and not all are quantitative. Here, we propose to investigate pUUO for the first time using an intravoxel incoherent motion diffusion sequence. The aim of this study was to quantitatively characterize impairment of the kidney parenchyma in the pUUO model. This quantitative MRI method was able to assess the perfusion and microstructure of the kidney without requiring the injection of a contrast agent. The results suggest that a perfusion fraction (f) reduction is associated with a decrease in the volume of the renal parenchyma, which could be related to decreased renal vascularization. The latter may occur before impairment by fibrosis and the findings are in accordance with the literature using the UUO mice model and, more specifically, on pUUO. Further investigation is required before this technique can be made available for the diagnosis and management of children with antenatal hydronephrosis and to select the optimal timing of surgery if required., (Copyright © 2017 John Wiley & Sons, Ltd.)

Digestive graft-versus-host disease (GVHD) is a frequent complication after bone marrow transplantation, but small bowel obstruction is an extremely rare event. We present herein the first pediatric series of 4 cases of small bowel obstruction after bone marrow transplantation with detailed gross, histological data and their genetic status of the NOD2 gene. All patients had a history of severe acute GVHD treated by immunosuppressive agents and/or infliximab (in 3 cases). Acute or progressively worsening abdominal pain accompanied by small bowel occlusion occurred 5-16 months after graft, and computed tomographic scan revealed multiple small intestinal stenoses. Failure of intensive medical treatment led to surgical resection of affected loops. Stigmata of acute (apoptosis of crypts and satellitosis) and chronic GVHD features (submucosal fibrosis and serosae sclerolipomatosis), as well as extensive ulcerations, were observed in all ileal specimens. NOD2 mutation was found in only 1 patient. The follow-up showed successful outcome after surgery., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Thoracoscopic lung resection for congenital pulmonary airway malformation (CPAM) is a safe technique for children. Our purpose was to evaluate the feasibility of a fast-track protocol in such cases., Methods: From September 2007 to May 2016, 101 patients underwent a thoracoscopic pulmonary resection of which 83 for CPAM (lobectomy, wedge resection or sequestrectomy). We retrospectively reviewed the characteristics of surgical procedure, postoperative management and complications through three time periods (September 2007-December 2009: n=14, January 2010-March 2013: n=30, April 2013-May 2016: n=39) corresponding to management protocols modifications introducing fast-track pathways., Results: Through the 3 time periods, median postoperative hospital stay decreases (4, 3, 2days successively, P=0.02). In the third time period, 4 patients underwent surgery in day-case surgery. The overall and surgical complication rates, mainly related to air leakage, remain stable through the 3 time periods (14%, P=0.41 and 10%, P=0.52 respectively). Among the 13 patients without postoperative pleural drainage, one required secondary drainage after a partial resection of an emphysema., Conclusion: Fast-track protocol for children undergoing uncomplicated thoracic surgery for CPAM seems feasible without extra morbidity. Selected patient undergoing thoracoscopic resection of the lung may benefit from the absence of pleural drainage and can be operated on in day-case surgery., Level of Evidence: Level III., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Recent years have witnessed a considerable renewed interest for the uncommon flavonoid class of aurones. The characterization of two major biosynthetic machineries involved in their biosynthesis in flowers has encouraged the revival of phytochemical studies and identification of original structures, a process started almost seventy-five years ago. This review draws up an exhaustive map of natural occurrences of aurones their biosynthetic pathways and roles, with the aim to link their original structural properties among flavonoids to their place in evolution and the selective advantages they bring to some of the most advanced taxa in the plant kingdom., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: This study investigated relationships between neuroblastomas (NBs) imaging phenotypes, tumor genomic profile and patient outcome., Patients and Methods: This IRB-approved retrospective observational study included 133 NB patients (73 M, 60 F; median age 15 months, range 0-151) treated in a single institution between 1998 and 2012. A consensus review of imaging (CT-scan, MRI) categorized tumors according to both the primarily involved compartment (i.e., neck, chest, abdomen or pelvis) and the sympathetic anatomical structure the tumors rose from (i.e., cervical, paravertebral or periarterial chains, or adrenal gland). Tumor shape, volume and image-defined surgical risk factors (IDRFs) at diagnosis were recorded. Genomic profiles were assessed using array-based comparative genomic hybridization and divided into three groups: "numerical-only chromosome alterations" (NCA), "segmental chromosome alterations" (SCA) and "MYCN amplification" (MNA). Statistical analyses included Kruskal-Wallis, Chi2 and Fisher's exact tests and the Kaplan-Meier method with log-rank tests and Cox model for univariate and multivariate survival analyses., Results: A significant association between the sympathetic structure origin of tumors and genomic profiles was demonstrated. NBs arising from cervical sympathetic chains were all NCA. Paravertebral NBs were NCA or SCA in 75% and 25%, respectively and none were MNA. Periarterial NBs were NCA, SCA or MNA in 33%, 56% and 11%, respectively. Adrenal NBs were NCA, SCA or MNA in 16%, 36% and 48%, respectively. Among MNA NBs, 92% originated from the adrenal gland. The sympathetic anatomical classification was significantly better correlated to overall survival than the compartmental classification (P < .0003). The tumor volume of MNA NBs was significantly higher than NCA or SCA NBs (P < .0001). Patients with initial volume less than 160 mL had significantly better overall survival (P < .009). A "single mass" pattern was significantly more frequent in NCA NBs (P = .0003). The number of IDRFs was significantly higher in MNA NBs (P < .0001)., Conclusion: Imaging phenotypes of neuroblastomas, including tumor origin along the sympathetic system, correlate with tumor genomic profile and patient outcome.

Obstructive nephropathy constitutes a major cause of pediatric renal progressive disease. The mechanisms leading to disease progression are still poorly understood. Kidney fibrotic lesions are reproduced using a model of partial unilateral ureteral obstruction (pUUO) in newborn mice. Based on data showing significant mast cell (MC) infiltration in patients, we investigated the role of MC and murine MCPT4, a MC-released chymase, in pUUO using MC- (W sh/sh ), MCPT4-deficient ( Mcpt4 -/- ), and wild-type (WT) mice. Measurement of kidney length and volume by magnetic resonance imaging (MRI) as well as postmortem kidney weight revealed hypotrophy of operated right kidneys (RKs) and compensatory hypertrophy of left kidneys. Differences between kidneys were major for WT, minimal for W sh/sh , and intermediate for Mcpt4 -/- mice. Fibrosis development was focal and increased only in WT-obstructed kidneys. No differences were noticed for local inflammatory responses, but serum CCL2 was significantly higher in WT versus Mcpt4 -/- and W sh/sh mice. Alpha-smooth muscle actin (αSMA) expression, a marker of epithelial-mesenchymal transition (EMT), was high in WT, minimal for W sh/sh , and intermediate for Mcpt4 -/- RK. Supernatants of activated MC induced αSMA in co-culture experiments with proximal tubular epithelial cells. Our results support a role of MC in EMT and parenchyma lesions after pUUO involving, at least partly, MCPT4 chymase. They confirm the importance of morphologic impairment evaluation by MRI in pUUO.

Purpose: The tumor genomic copy number profile is of prognostic significance in neuroblastoma patients. We have studied the genomic copy number profile of cell-free DNA (cfDNA) and compared this with primary tumor arrayCGH (aCGH) at diagnosis., Experimental Design: In 70 patients, cfDNA genomic copy number profiling was performed using the OncoScan platform. The profiles were classified according to the overall pattern, including numerical chromosome alterations (NCA), segmental chromosome alterations (SCA), and MYCN amplification (MNA)., Results: Interpretable and dynamic cfDNA profiles were obtained in 66 of 70 and 52 of 70 cases, respectively. An overall identical genomic profile between tumor aCGH and cfDNA was observed in 47 cases (3 NCAs, 22 SCAs, 22 MNAs). In one case, cfDNA showed an additional SCA not detected by tumor aCGH. In 4 of 8 cases with a silent tumor aCGH profile, cfDNA analysis revealed a dynamic profile (3 SCAs, 1 NCA). In 14 cases, cfDNA analysis did not reveal any copy number changes. A total of 378 breakpoints common to the primary tumor and cfDNA of any given patient were identified, 27 breakpoints were seen by tumor aCGH, and 54 breakpoints were seen in cfDNA only, including two cases with interstitial IGFR1 gains and two alterations targeting TERT CONCLUSIONS: These results demonstrate the feasibility of cfDNA copy number profiling in neuroblastoma patients, with a concordance of the overall genomic profile in aCGH and cfDNA dynamic cases of 97% and a sensitivity of 77%, respectively. Furthermore, neuroblastoma heterogeneity is highlighted, suggesting that cfDNA might reflect genetic alterations of more aggressive cell clones. Clin Cancer Res; 22(22); 5564-73. ©2016 AACRSee related commentary by Janku and Kurzrock, p. 5400., (©2016 American Association for Cancer Research.)

Based on a screening process, we targeted substituted thiosemicarbazone as potential antileishmanial agents. Our objective was to identify the key structural elements contributing to the anti-parasite activity that might be used for development of effective drugs. A series of 32 compounds was synthesized and their efficacy was evaluated against the clinically relevant intracellular amastigotes of Leishmania donovani. From these, 22 compounds showed EC50 values below 10 μM with the most active derivative (compound 14) showing an EC50 of 0.8 μM with very low toxicity on two different mammalian cell lines. The most relevant structural elements required for higher activity indicate that the presence of a fused bicyclic aromatic ring such as a naphthalene bearing an alkyl or an alkoxy group substituent are prerequisites. Owing to the easy synthesis, high activity and low toxicity, the most active compounds could be considered as a lead for further development., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Secondary hyperparathyroidism is often associated with end stage renal disease; even after renal transplantation, hyperparathyroidism may persist, and is responsible for hypercalcemia, hypophosphatemia and elevated parathyroid hormone (iPTH) levels. Parathyroid hyperplasia is frequently associated with persistent hyperparathyroidism, and may require a surgical treatment. Here, we report hyperparathyroidism along with parathyroid hyperplasia in a 7-year-old child, which persisted after renal transplant. Calcitonin and pamidronate failed to decrease serum calcium levels; clodronate was also inefficient. Cinacalcet therapy normalized serum calcium and phosphorus levels, and decreased iPTH levels in 3 months; a severe parathyroid hyperplasia was also corrected under calcimimetic therapy. In conclusion, we report in a child that hypercalcemia associated with secondary hyperparathyroidism can be corrected with cinacalcet after pediatric renal transplantation. We also show that parathyroid hyperplasia can regress under calcimimetic therapy in a transplanted child, making surgery unnecessary.

ABC-transporters play a vital role in drugs bioavailability. They prevent intracellular accumulation of toxic compounds, rendering them a major defense mechanism against harmful substances. In this large family, ABCC2 is an apical efflux pump representing about 10% of all membrane proteins in liver and small intestine, and up to 25% in colon. In these tissues, ABCC2 plays a major role in the pharmacokinetics and pharmacodynamics of endo- and xenobiotics. To gain insight in the function of this crucial protein, we have investigated and developed the first effective inhibitors of this pump. Firstly, we set up a cellular flow cytometry assay for monitoring the drug efflux carried out by ABCC2, and used it for the screening of chemical libraries derived from several chemical classes. We found that 2-indolylmethylenebenzofuranone derivatives as promising candidates. Optimization of the hits provided new compounds that inhibit ABCC2 in the micromolar range, making them the first potent ABCC2 inhibitors reported so far. Such compounds would constitute valuable tools to further investigate the role of ABCC2 in the pharmacokinetics and pharmacodynamics of drugs., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Purpose: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAF(V600E) mutation occurs frequently, but clinical significance remains to be determined., Patients and Methods: BRAF(V600E) mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae., Results: Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAF(V600E) mutation. Patients with BRAF(V600E) manifested more severe disease than did those with wild-type BRAF. Patients with BRAF(V600E) comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAF(V600E) mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAF(V600E) more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001)., Conclusion: In children with LCH, BRAF(V600E) mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy., (© 2016 by American Society of Clinical Oncology.)

The formation of tau aggregates is strongly linked to the neurodegenerative process in tauopathies such as Alzheimer's disease (AD). Yet only a few molecules have shown to efficiently prevent the in vitro formation of those aggregates, and the identification of such molecules is still an ongoing interest in a therapeutic context. Herein, we report the in vitro evaluation of a series of aurones against the fibrillation of the tau-derived hexapeptide AcPHF6 model. Using thioflavin T-based fluorescence assays, circular dichroism and atomic force microscopy, we showed that aurones are capable of efficiently interacting with the tau-derived hexapeptide. Importantly, this work reveals a significant activity observed for polyhydroxylated aurones. In particular, aurone 23 displayed an almost complete inhibition of fibers formation as shown by AFM at a peptide/inhibitor 1:1 ratio. It is similar to that observed for myricetin, a polyphenolic compound, well-known to prevent the in vitro elongation of tau fibers. Moreover, a tetrahydroxylated isomer, compound 24, was shown as a chemical probe of fibers rather than an inhibitor. Consequently, these results highlight aurones as a new promising scaffold to interfere with tau aggregation for both treatment and diagnosis of AD.

In this study, we report for the first time the presence of alkaloids belonging to β-carboline type in the pods of the endemic Albizia polyphylla from Madagascar. Three major alkaloids were isolated and structurally identified as: 1-methyl-β-carboline, (+)-(R)-1-methyl-1,2,3,4-tetrahydro-β-carboline and (-)-(S)-1,2-dimethyl-1,2,3,4-tetrahydro-β-carboline.

The NS5B RNA-dependent RNA polymerase (RdRp) is a key enzyme for Hepatitis C Virus (HCV) replication. In addition to the catalytic site, this enzyme is characterized by the presence of at least four allosteric pockets making it an interesting target for development of inhibitors as potential anti-HCV drugs. Based on a previous study showing the potential of the naturally occurring aurones as inhibitors of NS5B, we pursued our efforts to focus on pseudodimeric aurones that have never been investigated so far. Hence, 14 original compounds characterized by the presence of a spacer between the benzofuranone moieties were synthesized and investigated as HCV RdRp inhibitors by means of an in vitro assay. The most active inhibitor, pseudodimeric aurone 4, induced high inhibition activity (IC50 = 1.3 μM). Mutagenic and molecular modeling studies reveal that the binding site for the most active derivatives probably is the palm pocket I instead of the thumb pocket I as for the monomeric derivatives., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)