The purpose of this study was to describe the natural history of severe congenital neutropenia (SCN) in 14 patients with G6PC3 mutations and enrolled in the French SCN registry.
Among 605 patients ...included in the French SCN registry, we identified 8 pedigrees that included 14 patients with autosomal recessive G6PC3 mutations.
Median age at the last visit was 22.4 years. All patients had developed various comordibities, including prominent veins (n = 12), cardiac malformations (n = 12), intellectual disability (n = 7), and myopathic syndrome with recurrent painful cramps (n = 1). Three patients developed Crohn's disease, and five had chronic diarrhea with steatorrhea. Neutropenia was profound (<0.5 × 109/l) in almost all cases at diagnosis and could marginally fluctuate. The bone marrow smears exhibited mild late-stage granulopoeitic defects. One patient developed myelodysplasia followed by acute myelogenous leukemia with translocation (18, 21) at age 14 years, cured by chemotherapy and hematopoietic stem cell transplantation. Four deaths occurred, including one from sepsis at age 5, one from pulmonary late-stage insufficiency at age 19, and two from sudden death, both at age 30 years. A new homozygous mutation (c.249G > A /p.Trp83*) was detected in one pedigree.
Severe congenital neutropenia with autosomal recessive G6PC3 mutations is associated with considerable clinical heterogeneity. This series includes the first described case of malignancy in this neutropenia.
Severe acute malnutrition (SAM) is a multifactorial disease affecting millions of children worldwide. It is associated with changes in intestinal physiology, microbiota, and mucosal immunity, ...emphasizing the need for multidisciplinary studies to unravel its full pathogenesis. We established an experimental model in which weanling mice fed a high-deficiency diet mimic key anthropometric and physiological features of SAM in children. This diet alters the intestinal microbiota (less segmented filamentous bacteria, spatial proximity to epithelium), metabolism (decreased butyrate), and immune cell populations (depletion of LysoDC in Peyer’s patches and intestinal Th17 cells). A nutritional intervention leads to a fast zoometric and intestinal physiology recovery but to an incomplete restoration of the intestinal microbiota, metabolism, and immune system. Altogether, we provide a preclinical model of SAM and have identified key markers to target with future interventions during the education of the immune system to improve SAM whole defects.
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•Mouse model of SAM mimics childhood SAM features•SAM alters the intestinal microbiota, its spatial organization, and metabolism•SAM rises fecal sIgA and Treg/Th17 ratio, but decreases LysoDC in Peyer’s patches•Dietary intervention rescues zoometry and physiology, but not microbiota and immunity
Immunology; Gastroenterology; Microbiome
Recent studies have suggested that inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (statins) can play a role in protection against vascular risk, which is independent of cholesterol ...reduction. It could act by inhibiting the synthesis of isoprenoids (farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP)), which are respectively essential for membrane attachment and biological activity of GTPases Ras and RhoA. This study demonstrates that a statin (cerivastatin) inhibits angiogenesis. This effect was due to a decrease in endothelial cell locomotion which was reversed by GGPP. It was mainly related to delocalization of RhoA from cell membrane to cytoplasm, responsible for the disorganization of actin stress fibers. Furthermore, a decrease in MMP-2 secretion, involved in cell invasion, was also observed. This effect is rather due to Ras inhibition as it was reversed by FPP. This anti-angiogenic activity could explain the beneficial effect of statins on atherosclerosis and on cancer prevention as shown by clinical studies.
Cerivastatin is used in the treatment of hypercholesterolemia to inhibit 3-hydroxy 3-methylglutaryl coenzyme A reductase and thus prevent the synthesis of cholesterol precursors, such as farnesyl ...pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), responsible, respectively, for translocation of Ras and Rho to the cell membrane, a step required for their cell signaling, leading to cell proliferation and migration. Recently, it has been suggested that non lipid-related effects of statins could play a beneficial role in cancer therapy. In this study, we have investigated the mechanisms by which statins inhibit cancer and the types of cancers which could benefit from this therapy. In MDA-MB-231 cells, an aggressive breast cancer cell line with spontaneous activation of Ras and NFκB and overexpression of RhoA, cerivastatin induced inhibition of both cell proliferation and invasion through Matrigel. This anti-proliferative effect was related to G1/S arrest due to an increase in p21Waf1/Cip1. The anti-invasive effect was observed from 18 h and could be explained by RhoA delocalization from the cell membrane, resulting in disorganization of the actin fibers and disappearance of focal adhesion sites. The importance of RhoA inactivation in both these inhibitory effects was proved by their reversion by GGPP but not by FPP. Moreover, cerivastatin was also shown to induce inactivation of NFκB, in a RhoA inhibition-dependent manner, resulting in a decrease in urokinase and metalloproteinase-9 expression, two proteases involved in cell migration. The participation of Ras inactivation is considered a subsidiary mechanism for the effects of cerivastatin, as they were not rescued by FPP. Prolonged treatment of MDA-MB-231 cells with high doses of cerivastatin induced a loss of cell attachment. Interestingly, the effect of cerivastatin was considerably lower on poorly invasive MCF-7 cells. In conclusion, our results suggest that cerivastatin inhibits cell signaling pathways involved in the invasiveness and metastatic properties of highly invasive cancers.
The extracellular polysaccharide hyaluronan (HA) controls cell migration, differentiation and proliferation, and contributes to the invasiveness of human cancers. In order to investigate the ...sensitivity of cancer cells to antimitotic agents, we developed a cross-linked HA hydrogel, a three-dimensional matrix in which cells can invade and grow. We have studied three cell lines (SA87, NCI-H460 and H460M), from primary tumors and metastases, that migrated into the HA hydrogel and proliferated giving rise to clusters and colonies. Concurrently, we studied the growth of these cell lines in a usual monolayer culture system. In these two models, increasing concentrations of doxorubicin and 5-fluorouracil were evaluated for their ability to inhibit tumor cell growth and colony formation. Taken together, our data suggest that the cancer cells were more resistant in the three-dimensional model than in monolayer cell systems. The antimitotic drugs were efficient after 24
h of treatment in the monolayer cultures, whereas they were significantly efficient only after one week of incubation in the HA hydrogels. Herein, we show that this cross-linked matrix provides a three-dimensional model particularly appropriate for investigating mechanisms involved in cancer cell line sensitivity to antimitotic drugs.
The most frequent germline mutations responsible for non syndromic congenital sideroblastic anemia are identified in ALAS2 and SLC25A38 genes. Iron overload is a key issue and optimal chelation ...therapy should be used to limit its adverse effects on the development of children. Our multicentre retrospective descriptive study compared the strategies for diagnosis and management of congenital sideroblastic anemia during the follow-up of six patients with an ALAS2 mutation and seven patients with an SLC25A38 mutation. We described in depth the clinical, biological and radiological phenotype of these patients at diagnosis and during follow-up and highlighted our results with a review of available evidence and data on the management strategies for congenital sideroblastic anemia. This report confirms the considerable variability in manifestations among patients with ALAS2 or SLC25A38 mutations and draws attention to differences in the assessment and the monitoring of iron overload and its complications. The use of an international registry would certainly help defining recommendations for the management of these rare disorders to improve patient outcome.
Abstract Aim of the study To determine whether a risk factor adapted chemotherapy would improve the outcome of non-metastatic bone Ewing’s sarcoma. Methods Standard risk tumours (SR, good ...histological response to chemotherapy or small unresected tumours) received the previous EW88 chemotherapy. Ifosfamide/etoposide (IE) were introduced after 3 courses of cyclophosphamide/doxorubicine when tumour regression was <50% or during consolidation therapy for the intermediate risk tumours (IR, intermediate histological response 5–30% residual cells or large unresected tumours >100 ml). High risk tumours (HR, histological poor response >30% residual cells or clinical poor response <50% for unresectable tumours), received IE prior high dose busulfan/melphalan with stem cell rescue. Results From 1993 to 1999, 214 patients were enrolled. 5y-EFS and OS were 60% (95% confidence interval (CI), 53–66) and 69% (95% CI, 63–75), respectively. 116 (54%), 46 (21%), 48 (22%) patients were considered as SR, IR and HR of relapse, respectively. No advantage to IE was observed in the IR group. As compared to previous study, tumour with poor histological response to induction chemotherapy seemed to benefit from the consolidation strategy including busulfan/melphalan: EFS were 45% (95% CI, 30–60) and 20% (95% CI, 7–43) for EW93 and EW88, respectively. Despite a risk-adapted strategy, histological response to chemotherapy remains the main prognostic factor in resected tumours, while initial tumour volume is the main prognostic factor for unresected tumours. Conclusion These results showing a potential benefit of a consolidation strategy including busulfan/melphalan as compared to conventional chemotherapy needed confirmation by a randomised trial and were one of the bases of the ongoing EuroEwing99.
Seeking to improve ovarian cancer therapy, we compared biological characteristics of the moderately-aggressive OVCAR-3 cell line with two highly aggressive ovarian cancer cell populations: the ...SK-OV-3 cell line, and HASCJ primary cells isolated from the ascitic fluid of a patient with FIGO stage IV ovarian cancer. Secretion of angiogenic factors was not discriminative, whereas cell invasion through Matrigel and vasculogenic mimicry were much greater in the more aggressive cells. Among 10 agents tested for their ability to decrease cancer cell aggressivity using these two models, inhibitors of Stat3, IGF-IR and Rho GTPase were found to be the most promising.
While the vast majority of pediatric Hodgkin lymphoma (HL) is curable, the prognosis of early relapses and refractory diseases remains poor. Recently, the combination of gemcitabine, vinorelbine, and ...pegylated liposomal doxorubicin (GVD) displayed encouraging results on adults with relapsed/refractory diseases. Here, we retrospectively report the results of the GVD salvage regimen on four pediatric patients of our ward with a heavily pretreated relapsed/refractory HL. Three of them had nodular sclerosis subtype. They achieved a complete remission after two, three, or four courses of GVD and received high-dose chemotherapy followed by a stem-cell transplantation (auto-auto, auto-allo, and auto). They have been in sustained remission respectively for almost 2, 4, and 5 years. The fourth patient had a lymphocyte-depleted subtype which was initially diagnosed as anaplastic large cell lymphoma. After four courses of GVD, his disease stabilized then progressed again. In total, 15 cycles of GVD were applied to the patients. The toxicity of each course of GVD was mainly hematologic. No cardiotoxicity occurred despite a prior exposure to anthracyclines and radiotherapy. Thus, the GVD combination seems to be an effective pre-transplant rescue treatment for pediatric patients.
The anti-tumour effect of ferrociphenol (FcdiOH)-loaded lipid nanocapsules (LNCs), with or without a DSPE-mPEG2000 coating, was evaluated on an orthotopic gliosarcoma model after administration by ...convection-enhanced delivery (CED) technique or by intra-carotid injection. No toxicity was observed by MRI nor by MRS in healthy rats receiving a CED injection of FcdiOH-LNCs (60
μL, 0.36
mg of FcdiOH/rat) when the pH and osmolarity had been adjusted to physiological values prior to injection. At this dose, the treatment by CED with FcdiOH-LNCs significantly increased the survival time of tumour-bearing rats in comparison with an untreated group (28.5 days vs 25 days,
P
=
0.0009) whereas DSPE-mPEG2000–FcdiOH-LNCs did not exhibit any efficacy with a median survival time of 24 days. After intra-carotid injection (400
μL, 2.4
mg of FcdiOH/rat), hyperosmolar DSPE-mPEG2000–FcdiOH-LNCs markedly increased the median survival time (up to 30 days,
P
=
0.0008) as compared to the control (20%). This was strengthened by their evidenced accumulation in the tumour zone and by the measure of the fluorescent brain surface obtained on brain slides for these DiI-labelled LNCs, being 3-fold higher than for the control. These results demonstrated that, depending upon the administration route used, the characteristics of LNC suspensions had to be carefully adapted.
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