After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact...After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.展开更多
Gain-of-function mutations in fibroblast growth factor receptor(FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, ...Gain-of-function mutations in fibroblast growth factor receptor(FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, we analyzed the impact of Fgfr2- and Fgfr3- activating mutations on mandibular bone formation and endochondral bone repair after non-stabilized mandibular fractures in mouse models of Crouzon syndrome(Crz) and hypochondroplasia(Hch).展开更多
In 1993,the World Bank released a global report on the efficacy of health promotion,introducing the disability-adjusted life years(DALY)as a novel indicator.The DALY,a composite metric incorporating temporal and quali...In 1993,the World Bank released a global report on the efficacy of health promotion,introducing the disability-adjusted life years(DALY)as a novel indicator.The DALY,a composite metric incorporating temporal and qualitative data,is grounded in preferences regarding disability status.This review delineates the algorithm used to calculate the value of the proposed DALY synthetic indicator and elucidates key methodological challenges associated with its application.In contrast to the quality-adjusted life years approach,derived from multi-attribute utility theory,the DALY stands as an independent synthetic indicator that adopts the assumptions of the Time Trade Off utility technique to define Disability Weights.Claiming to rely on no mathematical or economic theory,DALY users appear to have exempted themselves from verifying whether this indicator meets the classical properties required of all indicators,notably content validity,reliability,specificity,and sensitivity.The DALY concept emerged primarily to facilitate comparisons of the health impacts of various diseases globally within the framework of the Global Burden of Disease initiative,leading to numerous publications in international literature.Despite widespread adoption,the DALY synthetic indicator has prompted significant methodological concerns since its inception,manifesting in inconsistent and non-reproducible results.Given the substantial diffusion of the DALY indicator and its critical role in health impact assessments,a reassessment is warranted.This reconsideration is imperative for enhancing the robustness and reliability of public health decisionmaking processes.展开更多
Inflammatory bowel diseases （IBDs） are complex and chronic disabling conditions resulting from a dysregulated dialogue between intestinal microbiota and components of both the innate and adaptive immune systems. Cyt...Inflammatory bowel diseases （IBDs） are complex and chronic disabling conditions resulting from a dysregulated dialogue between intestinal microbiota and components of both the innate and adaptive immune systems. Cytokines are essential mediators between activated immune and non-immune cells, including epithelial and mes- enchymal cells. They are immunomodulatory peptides released by numerous cells and these have significant effects on immune function leading to the differentiation and survival of T cells. The physiology of IBD is becom- ing a very attractive field of research for development of new therapeutic agents. These include cytokines involved in intestinal immune inflammation. This review will focus on mechanisms of action of oytokines involved in IBD and new therapeutic opportunities for these diseases.展开更多
AIM: To evaluate the performance of elastography by ultrasound with acoustic radiation force impulse(ARFI) in determining fibrosis stage in patients with alcoholic liver disease(ALD) undergoing alcoholic detoxificatio...AIM: To evaluate the performance of elastography by ultrasound with acoustic radiation force impulse(ARFI) in determining fibrosis stage in patients with alcoholic liver disease(ALD) undergoing alcoholic detoxification in relation to biopsy.METHODS: Eighty-three patients with ALD undergoing detoxification were prospectively enrolled. Each patient underwent ARFI imaging and a liver biopsy onthe same day. Fibrosis was staged according to the METAVIR scoring system. The median of 10 valid ARFI measurements was calculated for each patient.RESULTS: Sixty-nine males and thirteen females(one patient excluded due to insufficient biopsy size) were assessed with a mean alcohol consumption of 132.4 ± 128.8 standard drinks per week and mean cumulative year duration of 17.6 ± 9.5 years. Sensitivity and specificity were respectively 82.4%(0.70-0.95) and 83.3%(0.73-0.94)(AUROC = 0.87) for F ≥ 2 with a cut-off value of 1.63m/s; 82.4%(0.64-1.00) and 78.5%(0.69-0.89)(AUROC = 0.86) for F ≥ 3 with a cut-off value of 1.84m/s; and 92.3%(0.78-1.00] and 81.6%(0.72-0.90)(AUROC = 0.89) for F = 4 with a cut-off value of 1.94 m/s.CONCLUSION: ARFI is an accurate, non-invasive and easy method for assessing liver fibrosis in patients with ALD undergoing alcoholic detoxification.展开更多
AIM： To analyse αv integrin expression induced by gas- trin in pancreatic cancer models.METHODS： αv integrin mRNA expression in human pan- creatic cancer cells was analysed using a ＂cancer genes＂ array and confi...AIM： To analyse αv integrin expression induced by gas- trin in pancreatic cancer models.METHODS： αv integrin mRNA expression in human pan- creatic cancer cells was analysed using a ＂cancer genes＂ array and confirmed by real-time reverse transcription- polymerase chain reaction （PCR）. Western blotting and semi-quantitative immunohistochemistry were used to examine protein levels in human pancreatic cancer cell lines and pancreatic tissues, respectively, The role of αv integrin on gastrin-induced cell adhesion was examined using blocking anti-αv integrin monoclonal antibodies. Adherent cells were quantified by staining with crystal violet.RESULTS： Using a ＂cancer genes＂ array we identi- fied c^v integrin as a new gastrin target gene in human pancreatic cancer cells. A quantitative real-time PCR approach was used to confirm αv integrin gene expression. We also demonstrate that Src family kinases and the PI 3-kinase, two signalling pathways specifically activated by the CCK-2 receptor （CCK2R）, are involved in gastrin-mediated αv integrin expression. In contrast, inhibition of the ERK pathway was without any effect on αv integrin expression induced by gastrin. Our results also show that gastrin modulates cell adhesion via αv integrins. Indeed, in vitro adhesion assays performed on fibronectin show that gastrin significantly increases adhesion of pancreatic cancer cells. The use of blocking anti-αv integrin monoclonal antibodies completely reversed the increase in cell-substrate adhesion induced by gastrin. In addition, we showed in vivo that the targeted CCK2R expression in the pancreas of Elas-CCK2 mice, leads to the overexpression of αv integrin. This process may contribute to pancreatic turnout development observed in these transgenic animals.CONCLUSION： αv integrin is a new gastrin target in pancreatic cancer models and contributes to gastrin effects on cell adhesion.展开更多
BACKGROUND: Chronic pancreatitis (CP) is a risk factor of pancreatic adenocarcinoma (PA). The discovery of a pancreatic head lesion in CP frequently leads to a pancreaticoduo denectomy (PD) which preceded by a multidi...BACKGROUND: Chronic pancreatitis (CP) is a risk factor of pancreatic adenocarcinoma (PA). The discovery of a pancreatic head lesion in CP frequently leads to a pancreaticoduo denectomy (PD) which preceded by a multidisciplinary meeting(MM). The aim of this study was to evaluate the relevance between this indication of PD and the definitive pathological results.METHODS: Between 2000 and 2010, all patients with CP who underwent PD for suspicion of PA without any histological proof were retrospectively analyzed. The operative decision has always been made at an MM. The definitive pathological finding was retrospectively confronted with the decision made at an MM, and patients were classified in two groups according to this concordance (group 1) or not (group 2). Clinical and biological parameters were analyzed, preoperative imaging were reread and confronted to pathological findings in order to identify predictive factors of malignant degeneration.RESULTS: During the study period, five of 18 (group 1) patients with CP had PD were histologically confirmed to have PA, and the other 13 (group 2) did not have PA. The median age was52.5 ±8.2 years (gender ratio 3.5). The main symptoms were pain (94.4%) and weight loss (72.2%). There was no patient’s death. Six (33.3%) patients had a major complication (ClavienDindo classification ≥3). There was no statistical difference in clinical and biological parameters between the two groups. The rereading of imaging data could not detect efficiently all patients with PA.CONCLUSIONS: Our results confirmed the difficulty in detecting malignant transformation in patients with CP before surgery and therefore an elevated rate of unnecessary PD was found. A uniform imaging protocol is necessary to avoid PD as a less invasive treatment could be proposed.展开更多
Pancreatic ductal adenocarcinoma remains one of the most deadly types of tumor. Endoscopic ultrasoundguided fine-needle aspiration(EUS-FNA) is a safe, cost-effective, and accurate technique for evaluating and staging ...Pancreatic ductal adenocarcinoma remains one of the most deadly types of tumor. Endoscopic ultrasoundguided fine-needle aspiration(EUS-FNA) is a safe, cost-effective, and accurate technique for evaluating and staging pancreatic tumors. However, EUS-FNA may be inconclusive or doubtful in up to 20% of cases. This review underlines the clinical interest of the molecular analysis of samples obtained by EUS-FNA in assessing diagnosis or prognosis of pancreatic cancer, especially in locally advanced tumors. On EUS-FNA materials DNA, mRNA and miRNA can be extracted, amplified, quantified and subjected to methylation assay. Kras mutation assay, improves diagnosis of pancreatic cancer. When facing to clinical and radiological presentations of pseudo-tumorous chronic pancreatitis, wildtype Kras is evocative of benignity. Conversely, in front of a pancreatic mass suspected of malignancy, a mutated Kras is highly evocative of pancreatic adenocarci-noma. This strategy can reduce false-negative diagnoses, avoids the delay of making decisions and reduces loss of surgical resectability. Similar approaches are conducted using analysis of miRNA expression as well as Mucin or markers of invasion(S100P, S100A6, PLAT or PLAU). Beyond the diagnosis approach, the prediction of response to treatment can be also investigated form biomarkers expression within EUS-FNA materials.展开更多
Hypothalamic neuropeptides named hypocretin/orexins which were identified in 1998 regulate critical functions such as wakefulness in the central nervous system.These past 20 years had revealed that orexins/receptors s...Hypothalamic neuropeptides named hypocretin/orexins which were identified in 1998 regulate critical functions such as wakefulness in the central nervous system.These past 20 years had revealed that orexins/receptors system was also present in the peripheral nervous system where they participated to the regulation of multiple functions including blood pressure regulation,intestinal motility,hormone secretion,lipolyze and reproduction functions.Associated to these peripheral functions,it was found that orexins and their receptors were involved in various diseases such as acute/chronic inflammation,metabolic syndrome and cancers.The present review suggests that orexins or the orexin neural circuitry represent potential therapeutic targets for the treatment of multiple pathologies related to inflammation including intestinal bowel disease,multiple sclerosis and septic shock,obesity and digestive cancers.展开更多
AIM: To analyse allelic frequency of NOD2 gene variantsand to assess their correlation with inflammatory bowel disease(IBD) in Algeria.METHODS: We studied 132 unrelated patients diagnosed with IBD, 86 with Crohn's...AIM: To analyse allelic frequency of NOD2 gene variantsand to assess their correlation with inflammatory bowel disease(IBD) in Algeria.METHODS: We studied 132 unrelated patients diagnosed with IBD, 86 with Crohn's disease(CD) and 46 with ulcerative colitis(UC). Data was prospectively collected between January 2011 and December 2013. The demographic and clinical characteristics were recorded for all the patients. A group of 114 healthy unrelated individuals were selected as controls. All groups studied originated from different regions of North Algeria and confirmed the Algerian origin of their parents and grandparents. Informed and written consent was obtained from each of the participants. All individuals were genotyped for the three CDassociated NOD2 variants(p.Arg702 Trp, p.Gly908 Arg and p.Leu1007 fsins C mutations) using the polymerase chain reaction-restriction fragment length polymorphism method. Allele and genotype frequencies in patients and control subjects were compared by χ2 test and Fisher's exact test where appropriate. Odds ratios(OR) and 95% confidence intervals(95%CI) were also estimated. Association analyses were performed to study the influence of these variants on IBD and on clinical phenotypes.RESULTS: The p.Arg702 Trp mutation showed the highest frequency in CD patients(8%) compared to UC patients(2%)(P = 0.09, OR = 3.67, 95%CI: 0.48-4.87) and controls(5%)(P = 0.4, OR = 1.47, 95%CI: 0.65-3.31). In CD patients allelic frequencies of p.Gly908 Arg and p.Leu1007 fsins C variants compared to HC were 3% vs 2%(P = 0.5, OR = 1.67, 95%CI: 0.44-6.34); 2% vs 1%(P = 0.4 OR = 2.69 95%CI: 0.48-14.87 respectively). In UC patients, allelic frequencies of p.Gly908 Arg and p.Leu1007 fsins C variants compared to HC were 1% vs 2%(P = 1, OR = 1.62, 95%CI: 0.17-4.74) and 2% vs 1%(P = 0.32, OR = 0.39, 95%CI: 0.05-2.87). The total frequency of the mutated NOD2 chromosomes was higher in CD(13%), than in HC(8%) and UC(5%). In addition, NOD2 variants were linked to a particular clinical sub-phenotype in CD in this Algerian cohort. As expected, the three NOD2 variants showed a significant association with CD but did not reach statistical significance, despite the fact that the allele frequency of NOD2 variants was in the range found in most of the European populations. This might be due to the non-exposure of the NOD2 carriers to environmental factors, required for the expression of the disease.CONCLUSION: Further analyses are necessary to study genetic and environmental factors in IBD in the Algerian population, using larger patient groups.展开更多
Human cell types affected by retinal diseases(such as age-related macular degeneration or retinitis pimentosa) are limited in cell number and of reduced accessibility. As a consequence, their isolation for in vitro st...Human cell types affected by retinal diseases(such as age-related macular degeneration or retinitis pimentosa) are limited in cell number and of reduced accessibility. As a consequence, their isolation for in vitro studies of disease mechanisms or for drug screening efforts is fastidious. Human pluripotent stem cells(h PSCs), either of embryonic origin or through reprogramming of adult somatic cells,represent a new promising way to generate models of human retinopathies, explore the physiopathological mechanisms and develop novel therapeutic strategies. Disease-specific human embryonic stem cells were the first source of material to be used to study certain disease states. The recent demonstration that human somatic cells, such as fibroblasts or blood cells, can be genetically converted to induce pluripotent stem cells together with the continuous improvement of methods to differentiate these cells into disease-affected cellular subtypes opens new perspectives to model and understand a large number of human pathologies, including retinopathies. This review focuses on the added value of h PSCs for the disease modeling of human retinopathies and the study of their molecular pathological mechanisms. We also discuss the recent use of these cells for establishing the validation studies for therapeutic intervention and for the screening of large compound libraries to identify candidate drugs.展开更多
BACKGROUND Benzylamine and methylamine activate glucose uptake in adipocytes.For tyramine,this effect has even been extended to cardiomyocytes.AIM To investigate the effects of catecholamines and other amines on gluco...BACKGROUND Benzylamine and methylamine activate glucose uptake in adipocytes.For tyramine,this effect has even been extended to cardiomyocytes.AIM To investigate the effects of catecholamines and other amines on glucose uptake.METHODS A screening compared 25 biogenic amines on 2-deoxyglucose(2-DG)uptake activation in rat adipocytes.Pharmacological approaches and transgenic mouse models were then used to decipher the mode of action of several hits.RESULTS In rat adipocytes,insulin stimulation of 2-DG uptake was reproduced with catecholamines.100μmol/L or 1 mmol/L adrenaline,noradrenaline,dopamine and deoxyepinephrine,maximally activated hexose transport only when sodium orthovanadate was added at 100μmol/L.Such activation was similar to that already reported for benzylamine,methylamine and tyramine,well-recognized substrates of semicarbazide-sensitive amine oxidase(SSAO)and monoamine oxidase(MAO).Several,but not all,tested agonists ofβ-adrenoreceptors(β-ARs)also activated glucose transport whileα-AR agonists were inactive.Lack of blockade byα-andβ-AR antagonists indicated that catecholamine-induced 2-DG uptake was not mediated by AR stimulation.Adipocytes from mice lackingβ1-,β2-andβ3-ARs(triple KO)also responded to millimolar doses of adrenaline or noradrenaline by activating hexose transport in the presence of 100μmol/L vanadate.The MAO blocker pargyline,and SSAO inhibitors did not block the effects of adrenaline or noradrenaline plus vanadate,which were blunted by antioxidants.CONCLUSION Catecholamines exert unexpected insulin-like actions in adipocytes when combined with vanadium.For limiting insulin resistance by activating glucose consumption at least in fat stores,we propose that catecholamine derivatives combined with vanadium can generate novel complexes that may have low toxicity and promising anti-diabetic properties.展开更多
AIM:To assess the effects and safety of Lactobacillus casei rhamnosus LCR35 complete freeze-dried culture(LCR35) in patients suffering from irritable bowel syndrome(IBS).METHODS:A randomized,double-blind pilot study w...AIM:To assess the effects and safety of Lactobacillus casei rhamnosus LCR35 complete freeze-dried culture(LCR35) in patients suffering from irritable bowel syndrome(IBS).METHODS:A randomized,double-blind pilot study was performed in 50 patients complaining of IBS symptoms complying with RomeⅢcriteria.Patients were allocated to receive either LCR35(n = 25) at a minimum daily dose of 6 × 108 colony forming units or placebo(n = 25) for 4 wk.At inclusion,after treatment and 2 wk later,patients completed the IBS severity scale.Change from baseline in the IBS severity score at the end of treatment was the primary efficacy criterion.Changes were compared between groups in the whole population and in IBS subtypes(IBS with predominance of constipation,IBS with predominance of diarrhoea,mixed IBS,unsubtyped IBS).The presence of lactobacillus casei rhamnosus in stools was investigated at inclusion and at the end of treatment.The gastrointestinal quality of life questionnaire and the hospital anxiety and depression(HAD) scale were also completed.RESULTS:Both groups were balanced for baseline characteristics.In 85% of patients,stool analyses showed that lactobacillus casei rhamnosus able to survive in the digestive tract.In the whole population,improvements in the IBS severity score did not differ significantly between treatments with a 25% decrease after 4-wk treatment,and a 15% decrease from baseline 2 wk later in both groups.In IBS subgroups,statistical analysis could not be performed due to small sample size,but a clinical response in favour of LCR35 was observed in IBS patients with predominance of diarrhoea:no change in the symptom severity score was seen with the placebo after 4 wk treatment,whereas a clinically relevant decrease occurred with LCR35(-37% vs-3%).Furthermore,in spite of an increase in symptom intensity,the IBS severity score was maintained below the baseline value 2 wk later with LCR35(-19% from baseline),whilst a slight 5% increase from baseline was observed with placebo.In the IBS subgroup with predominance of diarrhoea only,a clinically relevant decrease in abdominal pain severity score(-36%)was observed with LCR35,whereas no change occurred with placebo.In mixed IBS patients,the 20% and 30% decreases in the IBS severity score observed after treatment with LCR35 and placebo,respectively,were maintained 2 wk later in both groups.A clinical response slightly in favour of placebo was observed at the end of the treatment period in IBS patients with predominance of constipation(-41% vs-20%) and unsubtyped IBS patients(-47% vs-17%),with the same value maintained 2 wk later.In both groups,no clinically relevant changes were observed either for the gastrointestinal quality of life index or HAD score.Thus,these results suggest that sub-grouping of IBS patients may be important for optimizing treatment responses by the physician.CONCLUSION:This pilot study suggests that LCR35 could have some efficacy in IBS patients complaining of diarrhoea.These preliminary results need to be conf irmed in larger studies.展开更多
Precision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genet...Precision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer(CRC). Besides for these well-known mutations, the purpose of performing larger genetic testing in this pathology is unknown. Recent reports have shown that using the poly ADP ribose polymerase(PARP) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast, ovarian and prostate cancers. We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses. The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients(Check2 for the first patient and RAD51 C for the second one). Both patients were treated with off-label usage of olaparib. While the first patient showed clinical benefit, reduction of carcinoembryonic antigen tumor marker and radiologic response, the second patient quickly presented a progression of the tumor. Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed. Interestingly, deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models. Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency.展开更多
AIM: To assess whether juvenile chronic ferric iron ingestion limit colitis and dysbiosis at adulthood in rats and mice. METHODS: Two sets of experiments were designed. In the first set, recently weaned mice were eith...AIM: To assess whether juvenile chronic ferric iron ingestion limit colitis and dysbiosis at adulthood in rats and mice. METHODS: Two sets of experiments were designed. In the first set, recently weaned mice were either orally administered ferrous (Fe2+) iron salt or ferric (Fe3+) microencapsulated iron for 6 wk. The last week of experiments trinitrobenzene sulfonic acid (TNBS) colitis was induced. In the second set, juvenile rats received the microencapsulated ferric iron for 6 wk and were also submitted to TNBS colitis during the last week of experiments. In both sets of experiments, animals were sacrificed 7 d after TNBS instillation. Severity of the inflammation was assessed by scoring macroscopic lesions and quantifying colonic myeloperoxidase (MPO) activity. Alteration of the microflora profile was estimated usingquantitative polymerase chain reaction (qPCR) by measuring the evolution of total caecal microflora, Bacteroidetes, Firmicutes and enterobacteria. RESULTS: Neither ferrous nor ferric iron daily exposures at the juvenile period result in any effect in control animals at adulthood although ferrous iron repeated administration in infancy limited weight gain. Ferrous iron was unable to limit the experimental colitis (1.71 ± 0.27 MPO U/mg proteinvs 2.47 ± 0.22 MPO U/mg protein in colitic mice). In contrast, ferric iron significantly prevented the increase of MPO activity (1.64 ± 0.14 MPO U/mg protein) in TNBS-induced colitis. Moreover, this positive effect was observed at both the doses of ferric iron used (75 and 150 mg/kg per day po - 6 wk). In the study we also compared, in both rats and mice, the consequences of chronic repeated low level exposure to ferric iron (75 mg/kg per day po - 6 wk) on TNBS-induced colitis and its related dysbiosis. We confirmed that ferric iron limited the TNBS-induced increase of MPO activity in both the rodent species. Furthermore, we assessed the ferric iron incidence on TNBS-induced intestinal microbiota dysbiosis. At first, we needed to optimize the isolation and quantify DNA copy numbers using standard curves to perform by qPCR this interspecies comparison. Using this approach, we determined that total microflora was similar in control rats and mice and was mainly composed of Firmicutes and Bacteroidetes at a ratio of 10/1. Ferric juvenile administration did not modify the microflora profile in control animals. Total microflora numbers remained unchanged whichever experimental conditions studied. Following TNBS-induced colitis, the Firmicutes/Bacteroidetes ratio was altered resulting in a decrease of the Firmicutes numbers and an increase of the Bacteroidetes numbers typical of a gut inflammatory reaction. In parallel, the subdominant population, the enterobacteria was also increased. However, ferric iron supplementation for the juvenile period prevented the increase of Bacteroidetes and of enterobacteria numbers consecutive to the colitis in both the studied species at adulthood.CONCLUSION: Rats and mice juvenile chronic ferric iron ingestion prevents colitis and dysbiosis at adulthood as assessed by the first interspecies comparison.展开更多
Diabetic dyslipidemia is characterized by quantitative and qualitative abnormalities in lipoproteins.In addition to glycation and oxidation,carbamylation is also a post-translational modification affecting lipoprotein...Diabetic dyslipidemia is characterized by quantitative and qualitative abnormalities in lipoproteins.In addition to glycation and oxidation,carbamylation is also a post-translational modification affecting lipoproteins in diabetes.Patients with type 2 diabetes(T2D)exhibit higher levels of carbamylated low-density lipoproteins(cLDL)and high-density lipoproteins(cHDL).Accumulating evidence suggests that cLDL plays a role in atherosclerosis in diabetes.cLDL levels have been shown to predict cardiovascular events and all-cause mortality.cLDL facilitates immune cell recruitment in the vascular wall,promotes accumulation of lipids in macrophages,and contributes to endothelial dysf-unction,endothelial nitric oxide-synthase(eNOS)inactivation and endothelial repair defects.Lastly,cLDL induces thrombus formation and platelet aggregation.On the other hand,recent data have demonstrated that cHDL serum level is independently associated with all-cause and cardiovascular-related mortality in T2D patients.This relationship may be causative since the atheroprotective properties of HDL are altered after carbamylation.Thus,cHDL loses the ability to remove cholesterol from macrophages,to inhibit monocyte adhesion and recruitment,to induce eNOS activation and to inhibit apoptosis.Taken together,it seems very likely that the abnormalities in the biological functions of LDL and HDL after carbamylation contribute to atherosclerosis and to the elevated cardiovascular risk in diabetes.展开更多
Chromophobe renal cell carcinoma(ChRCC)is the third most common renal cell carcinoma(RCC)subtype,which predominantly occurs in sporadic setting.ChRCCs are considered to originate from the intercalated cell of distal t...Chromophobe renal cell carcinoma(ChRCC)is the third most common renal cell carcinoma(RCC)subtype,which predominantly occurs in sporadic setting.ChRCCs are considered to originate from the intercalated cell of distal tubules with two main morphological variants,classic and eosinophilic.Most ChRCCs carry a favorable clinical outcome.Histology alone is limited in predicting the behavior of ChRCCs that do not have overtly aggressive morphologic findings such as necrosis and sarcomatoid features.Along with positive CD117 expression,classic ChRCCs generally express diffuse and uniform CK7,while eosinophilic variant demonstrates more heterogeneous CK7 expression(rare or patchy).Multiple losses of chromosomes 1,2,6,10,13,17,and 21 are considered to be the genetic hallmarks of classic and eosinophilic ChRCCs,while chromosomal gains are known to be associated with sarcomatoid ChRCCs.TP53 and PTEN are the two most frequently mutated genes in ChRCCs.The major challenge in the differential diagnosis of ChRCCs includes considerations around the eosinophilic variant(of ChRCCs),where it may share overlapping features with oncocytoma or other recent emergent oncocytic tumors.Most eosinophilic ChRCCs share expression of the recently described biomarkers,LINC01187 and FOXI1,with classic ChRCCs,however,a subset of eosinophilic-like ChRCCs with lower biomarker expression have been demonstrated to harbor MTOR gene mutations.Overall,the morphologic features of ChRCCs and genetic profile with combinations of chromosomal losses and gains suggest this tumor entity to represent a distinct,yet heterogeneous group of renal neoplasms.展开更多
基金supported by European Regional Development Funds RE0022527 ZEBRATOX(EU-Région Réunion-French State national counterpart,to Nicolas Diotel and Jean-Loup Bascands).
文摘After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.
基金National Research Agency under the Investments for the Future program (ANR-10-IAHU-01)Filière Nationale TeteCou for financial support。
文摘Gain-of-function mutations in fibroblast growth factor receptor(FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, we analyzed the impact of Fgfr2- and Fgfr3- activating mutations on mandibular bone formation and endochondral bone repair after non-stabilized mandibular fractures in mouse models of Crouzon syndrome(Crz) and hypochondroplasia(Hch).
文摘In 1993,the World Bank released a global report on the efficacy of health promotion,introducing the disability-adjusted life years(DALY)as a novel indicator.The DALY,a composite metric incorporating temporal and qualitative data,is grounded in preferences regarding disability status.This review delineates the algorithm used to calculate the value of the proposed DALY synthetic indicator and elucidates key methodological challenges associated with its application.In contrast to the quality-adjusted life years approach,derived from multi-attribute utility theory,the DALY stands as an independent synthetic indicator that adopts the assumptions of the Time Trade Off utility technique to define Disability Weights.Claiming to rely on no mathematical or economic theory,DALY users appear to have exempted themselves from verifying whether this indicator meets the classical properties required of all indicators,notably content validity,reliability,specificity,and sensitivity.The DALY concept emerged primarily to facilitate comparisons of the health impacts of various diseases globally within the framework of the Global Burden of Disease initiative,leading to numerous publications in international literature.Despite widespread adoption,the DALY synthetic indicator has prompted significant methodological concerns since its inception,manifesting in inconsistent and non-reproducible results.Given the substantial diffusion of the DALY indicator and its critical role in health impact assessments,a reassessment is warranted.This reconsideration is imperative for enhancing the robustness and reliability of public health decisionmaking processes.
文摘Inflammatory bowel diseases （IBDs） are complex and chronic disabling conditions resulting from a dysregulated dialogue between intestinal microbiota and components of both the innate and adaptive immune systems. Cytokines are essential mediators between activated immune and non-immune cells, including epithelial and mes- enchymal cells. They are immunomodulatory peptides released by numerous cells and these have significant effects on immune function leading to the differentiation and survival of T cells. The physiology of IBD is becom- ing a very attractive field of research for development of new therapeutic agents. These include cytokines involved in intestinal immune inflammation. This review will focus on mechanisms of action of oytokines involved in IBD and new therapeutic opportunities for these diseases.
基金support from the national clinical research program for public hospitals of France
文摘AIM: To evaluate the performance of elastography by ultrasound with acoustic radiation force impulse(ARFI) in determining fibrosis stage in patients with alcoholic liver disease(ALD) undergoing alcoholic detoxification in relation to biopsy.METHODS: Eighty-three patients with ALD undergoing detoxification were prospectively enrolled. Each patient underwent ARFI imaging and a liver biopsy onthe same day. Fibrosis was staged according to the METAVIR scoring system. The median of 10 valid ARFI measurements was calculated for each patient.RESULTS: Sixty-nine males and thirteen females(one patient excluded due to insufficient biopsy size) were assessed with a mean alcohol consumption of 132.4 ± 128.8 standard drinks per week and mean cumulative year duration of 17.6 ± 9.5 years. Sensitivity and specificity were respectively 82.4%(0.70-0.95) and 83.3%(0.73-0.94)(AUROC = 0.87) for F ≥ 2 with a cut-off value of 1.63m/s; 82.4%(0.64-1.00) and 78.5%(0.69-0.89)(AUROC = 0.86) for F ≥ 3 with a cut-off value of 1.84m/s; and 92.3%(0.78-1.00] and 81.6%(0.72-0.90)(AUROC = 0.89) for F = 4 with a cut-off value of 1.94 m/s.CONCLUSION: ARFI is an accurate, non-invasive and easy method for assessing liver fibrosis in patients with ALD undergoing alcoholic detoxification.
文摘AIM： To analyse αv integrin expression induced by gas- trin in pancreatic cancer models.METHODS： αv integrin mRNA expression in human pan- creatic cancer cells was analysed using a ＂cancer genes＂ array and confirmed by real-time reverse transcription- polymerase chain reaction （PCR）. Western blotting and semi-quantitative immunohistochemistry were used to examine protein levels in human pancreatic cancer cell lines and pancreatic tissues, respectively, The role of αv integrin on gastrin-induced cell adhesion was examined using blocking anti-αv integrin monoclonal antibodies. Adherent cells were quantified by staining with crystal violet.RESULTS： Using a ＂cancer genes＂ array we identi- fied c^v integrin as a new gastrin target gene in human pancreatic cancer cells. A quantitative real-time PCR approach was used to confirm αv integrin gene expression. We also demonstrate that Src family kinases and the PI 3-kinase, two signalling pathways specifically activated by the CCK-2 receptor （CCK2R）, are involved in gastrin-mediated αv integrin expression. In contrast, inhibition of the ERK pathway was without any effect on αv integrin expression induced by gastrin. Our results also show that gastrin modulates cell adhesion via αv integrins. Indeed, in vitro adhesion assays performed on fibronectin show that gastrin significantly increases adhesion of pancreatic cancer cells. The use of blocking anti-αv integrin monoclonal antibodies completely reversed the increase in cell-substrate adhesion induced by gastrin. In addition, we showed in vivo that the targeted CCK2R expression in the pancreas of Elas-CCK2 mice, leads to the overexpression of αv integrin. This process may contribute to pancreatic turnout development observed in these transgenic animals.CONCLUSION： αv integrin is a new gastrin target in pancreatic cancer models and contributes to gastrin effects on cell adhesion.
文摘BACKGROUND: Chronic pancreatitis (CP) is a risk factor of pancreatic adenocarcinoma (PA). The discovery of a pancreatic head lesion in CP frequently leads to a pancreaticoduo denectomy (PD) which preceded by a multidisciplinary meeting(MM). The aim of this study was to evaluate the relevance between this indication of PD and the definitive pathological results.METHODS: Between 2000 and 2010, all patients with CP who underwent PD for suspicion of PA without any histological proof were retrospectively analyzed. The operative decision has always been made at an MM. The definitive pathological finding was retrospectively confronted with the decision made at an MM, and patients were classified in two groups according to this concordance (group 1) or not (group 2). Clinical and biological parameters were analyzed, preoperative imaging were reread and confronted to pathological findings in order to identify predictive factors of malignant degeneration.RESULTS: During the study period, five of 18 (group 1) patients with CP had PD were histologically confirmed to have PA, and the other 13 (group 2) did not have PA. The median age was52.5 ±8.2 years (gender ratio 3.5). The main symptoms were pain (94.4%) and weight loss (72.2%). There was no patient’s death. Six (33.3%) patients had a major complication (ClavienDindo classification ≥3). There was no statistical difference in clinical and biological parameters between the two groups. The rereading of imaging data could not detect efficiently all patients with PA.CONCLUSIONS: Our results confirmed the difficulty in detecting malignant transformation in patients with CP before surgery and therefore an elevated rate of unnecessary PD was found. A uniform imaging protocol is necessary to avoid PD as a less invasive treatment could be proposed.
文摘Pancreatic ductal adenocarcinoma remains one of the most deadly types of tumor. Endoscopic ultrasoundguided fine-needle aspiration(EUS-FNA) is a safe, cost-effective, and accurate technique for evaluating and staging pancreatic tumors. However, EUS-FNA may be inconclusive or doubtful in up to 20% of cases. This review underlines the clinical interest of the molecular analysis of samples obtained by EUS-FNA in assessing diagnosis or prognosis of pancreatic cancer, especially in locally advanced tumors. On EUS-FNA materials DNA, mRNA and miRNA can be extracted, amplified, quantified and subjected to methylation assay. Kras mutation assay, improves diagnosis of pancreatic cancer. When facing to clinical and radiological presentations of pseudo-tumorous chronic pancreatitis, wildtype Kras is evocative of benignity. Conversely, in front of a pancreatic mass suspected of malignancy, a mutated Kras is highly evocative of pancreatic adenocarci-noma. This strategy can reduce false-negative diagnoses, avoids the delay of making decisions and reduces loss of surgical resectability. Similar approaches are conducted using analysis of miRNA expression as well as Mucin or markers of invasion(S100P, S100A6, PLAT or PLAU). Beyond the diagnosis approach, the prediction of response to treatment can be also investigated form biomarkers expression within EUS-FNA materials.
基金INSERM U1149/The Inflammation Research Center,Inserm Transfert,The Institut National du Cancer,No.2013-213Ligue Nationale Contre le Cancer,No.R16020HH,GB/MA/CD/EP-12062and AgroParisTech(INRAE and UniversitéParis-Saclay).
文摘Hypothalamic neuropeptides named hypocretin/orexins which were identified in 1998 regulate critical functions such as wakefulness in the central nervous system.These past 20 years had revealed that orexins/receptors system was also present in the peripheral nervous system where they participated to the regulation of multiple functions including blood pressure regulation,intestinal motility,hormone secretion,lipolyze and reproduction functions.Associated to these peripheral functions,it was found that orexins and their receptors were involved in various diseases such as acute/chronic inflammation,metabolic syndrome and cancers.The present review suggests that orexins or the orexin neural circuitry represent potential therapeutic targets for the treatment of multiple pathologies related to inflammation including intestinal bowel disease,multiple sclerosis and septic shock,obesity and digestive cancers.
基金Supported by the Agence Thématique de la Recherche Scientifique en Santé,(ATRSS,ex ANDRS)(PNR N°37-ANDRS-2011)
文摘AIM: To analyse allelic frequency of NOD2 gene variantsand to assess their correlation with inflammatory bowel disease(IBD) in Algeria.METHODS: We studied 132 unrelated patients diagnosed with IBD, 86 with Crohn's disease(CD) and 46 with ulcerative colitis(UC). Data was prospectively collected between January 2011 and December 2013. The demographic and clinical characteristics were recorded for all the patients. A group of 114 healthy unrelated individuals were selected as controls. All groups studied originated from different regions of North Algeria and confirmed the Algerian origin of their parents and grandparents. Informed and written consent was obtained from each of the participants. All individuals were genotyped for the three CDassociated NOD2 variants(p.Arg702 Trp, p.Gly908 Arg and p.Leu1007 fsins C mutations) using the polymerase chain reaction-restriction fragment length polymorphism method. Allele and genotype frequencies in patients and control subjects were compared by χ2 test and Fisher's exact test where appropriate. Odds ratios(OR) and 95% confidence intervals(95%CI) were also estimated. Association analyses were performed to study the influence of these variants on IBD and on clinical phenotypes.RESULTS: The p.Arg702 Trp mutation showed the highest frequency in CD patients(8%) compared to UC patients(2%)(P = 0.09, OR = 3.67, 95%CI: 0.48-4.87) and controls(5%)(P = 0.4, OR = 1.47, 95%CI: 0.65-3.31). In CD patients allelic frequencies of p.Gly908 Arg and p.Leu1007 fsins C variants compared to HC were 3% vs 2%(P = 0.5, OR = 1.67, 95%CI: 0.44-6.34); 2% vs 1%(P = 0.4 OR = 2.69 95%CI: 0.48-14.87 respectively). In UC patients, allelic frequencies of p.Gly908 Arg and p.Leu1007 fsins C variants compared to HC were 1% vs 2%(P = 1, OR = 1.62, 95%CI: 0.17-4.74) and 2% vs 1%(P = 0.32, OR = 0.39, 95%CI: 0.05-2.87). The total frequency of the mutated NOD2 chromosomes was higher in CD(13%), than in HC(8%) and UC(5%). In addition, NOD2 variants were linked to a particular clinical sub-phenotype in CD in this Algerian cohort. As expected, the three NOD2 variants showed a significant association with CD but did not reach statistical significance, despite the fact that the allele frequency of NOD2 variants was in the range found in most of the European populations. This might be due to the non-exposure of the NOD2 carriers to environmental factors, required for the expression of the disease.CONCLUSION: Further analyses are necessary to study genetic and environmental factors in IBD in the Algerian population, using larger patient groups.
文摘Human cell types affected by retinal diseases(such as age-related macular degeneration or retinitis pimentosa) are limited in cell number and of reduced accessibility. As a consequence, their isolation for in vitro studies of disease mechanisms or for drug screening efforts is fastidious. Human pluripotent stem cells(h PSCs), either of embryonic origin or through reprogramming of adult somatic cells,represent a new promising way to generate models of human retinopathies, explore the physiopathological mechanisms and develop novel therapeutic strategies. Disease-specific human embryonic stem cells were the first source of material to be used to study certain disease states. The recent demonstration that human somatic cells, such as fibroblasts or blood cells, can be genetically converted to induce pluripotent stem cells together with the continuous improvement of methods to differentiate these cells into disease-affected cellular subtypes opens new perspectives to model and understand a large number of human pathologies, including retinopathies. This review focuses on the added value of h PSCs for the disease modeling of human retinopathies and the study of their molecular pathological mechanisms. We also discuss the recent use of these cells for establishing the validation studies for therapeutic intervention and for the screening of large compound libraries to identify candidate drugs.
基金We thank the staff of animal unit CREFRE, currently headed by Xavier Collet, andespecially its Rangueil satellite for housing wild type and transgenic rodents, andAnne Bouloumié for helpful discussions.
文摘BACKGROUND Benzylamine and methylamine activate glucose uptake in adipocytes.For tyramine,this effect has even been extended to cardiomyocytes.AIM To investigate the effects of catecholamines and other amines on glucose uptake.METHODS A screening compared 25 biogenic amines on 2-deoxyglucose(2-DG)uptake activation in rat adipocytes.Pharmacological approaches and transgenic mouse models were then used to decipher the mode of action of several hits.RESULTS In rat adipocytes,insulin stimulation of 2-DG uptake was reproduced with catecholamines.100μmol/L or 1 mmol/L adrenaline,noradrenaline,dopamine and deoxyepinephrine,maximally activated hexose transport only when sodium orthovanadate was added at 100μmol/L.Such activation was similar to that already reported for benzylamine,methylamine and tyramine,well-recognized substrates of semicarbazide-sensitive amine oxidase(SSAO)and monoamine oxidase(MAO).Several,but not all,tested agonists ofβ-adrenoreceptors(β-ARs)also activated glucose transport whileα-AR agonists were inactive.Lack of blockade byα-andβ-AR antagonists indicated that catecholamine-induced 2-DG uptake was not mediated by AR stimulation.Adipocytes from mice lackingβ1-,β2-andβ3-ARs(triple KO)also responded to millimolar doses of adrenaline or noradrenaline by activating hexose transport in the presence of 100μmol/L vanadate.The MAO blocker pargyline,and SSAO inhibitors did not block the effects of adrenaline or noradrenaline plus vanadate,which were blunted by antioxidants.CONCLUSION Catecholamines exert unexpected insulin-like actions in adipocytes when combined with vanadium.For limiting insulin resistance by activating glucose consumption at least in fat stores,we propose that catecholamine derivatives combined with vanadium can generate novel complexes that may have low toxicity and promising anti-diabetic properties.
文摘AIM:To assess the effects and safety of Lactobacillus casei rhamnosus LCR35 complete freeze-dried culture(LCR35) in patients suffering from irritable bowel syndrome(IBS).METHODS:A randomized,double-blind pilot study was performed in 50 patients complaining of IBS symptoms complying with RomeⅢcriteria.Patients were allocated to receive either LCR35(n = 25) at a minimum daily dose of 6 × 108 colony forming units or placebo(n = 25) for 4 wk.At inclusion,after treatment and 2 wk later,patients completed the IBS severity scale.Change from baseline in the IBS severity score at the end of treatment was the primary efficacy criterion.Changes were compared between groups in the whole population and in IBS subtypes(IBS with predominance of constipation,IBS with predominance of diarrhoea,mixed IBS,unsubtyped IBS).The presence of lactobacillus casei rhamnosus in stools was investigated at inclusion and at the end of treatment.The gastrointestinal quality of life questionnaire and the hospital anxiety and depression(HAD) scale were also completed.RESULTS:Both groups were balanced for baseline characteristics.In 85% of patients,stool analyses showed that lactobacillus casei rhamnosus able to survive in the digestive tract.In the whole population,improvements in the IBS severity score did not differ significantly between treatments with a 25% decrease after 4-wk treatment,and a 15% decrease from baseline 2 wk later in both groups.In IBS subgroups,statistical analysis could not be performed due to small sample size,but a clinical response in favour of LCR35 was observed in IBS patients with predominance of diarrhoea:no change in the symptom severity score was seen with the placebo after 4 wk treatment,whereas a clinically relevant decrease occurred with LCR35(-37% vs-3%).Furthermore,in spite of an increase in symptom intensity,the IBS severity score was maintained below the baseline value 2 wk later with LCR35(-19% from baseline),whilst a slight 5% increase from baseline was observed with placebo.In the IBS subgroup with predominance of diarrhoea only,a clinically relevant decrease in abdominal pain severity score(-36%)was observed with LCR35,whereas no change occurred with placebo.In mixed IBS patients,the 20% and 30% decreases in the IBS severity score observed after treatment with LCR35 and placebo,respectively,were maintained 2 wk later in both groups.A clinical response slightly in favour of placebo was observed at the end of the treatment period in IBS patients with predominance of constipation(-41% vs-20%) and unsubtyped IBS patients(-47% vs-17%),with the same value maintained 2 wk later.In both groups,no clinically relevant changes were observed either for the gastrointestinal quality of life index or HAD score.Thus,these results suggest that sub-grouping of IBS patients may be important for optimizing treatment responses by the physician.CONCLUSION:This pilot study suggests that LCR35 could have some efficacy in IBS patients complaining of diarrhoea.These preliminary results need to be conf irmed in larger studies.
文摘Precision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer(CRC). Besides for these well-known mutations, the purpose of performing larger genetic testing in this pathology is unknown. Recent reports have shown that using the poly ADP ribose polymerase(PARP) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast, ovarian and prostate cancers. We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses. The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients(Check2 for the first patient and RAD51 C for the second one). Both patients were treated with off-label usage of olaparib. While the first patient showed clinical benefit, reduction of carcinoembryonic antigen tumor marker and radiologic response, the second patient quickly presented a progression of the tumor. Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed. Interestingly, deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models. Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency.
基金Supported by Institut Polytechnique LaSalle Beauvais
文摘AIM: To assess whether juvenile chronic ferric iron ingestion limit colitis and dysbiosis at adulthood in rats and mice. METHODS: Two sets of experiments were designed. In the first set, recently weaned mice were either orally administered ferrous (Fe2+) iron salt or ferric (Fe3+) microencapsulated iron for 6 wk. The last week of experiments trinitrobenzene sulfonic acid (TNBS) colitis was induced. In the second set, juvenile rats received the microencapsulated ferric iron for 6 wk and were also submitted to TNBS colitis during the last week of experiments. In both sets of experiments, animals were sacrificed 7 d after TNBS instillation. Severity of the inflammation was assessed by scoring macroscopic lesions and quantifying colonic myeloperoxidase (MPO) activity. Alteration of the microflora profile was estimated usingquantitative polymerase chain reaction (qPCR) by measuring the evolution of total caecal microflora, Bacteroidetes, Firmicutes and enterobacteria. RESULTS: Neither ferrous nor ferric iron daily exposures at the juvenile period result in any effect in control animals at adulthood although ferrous iron repeated administration in infancy limited weight gain. Ferrous iron was unable to limit the experimental colitis (1.71 ± 0.27 MPO U/mg proteinvs 2.47 ± 0.22 MPO U/mg protein in colitic mice). In contrast, ferric iron significantly prevented the increase of MPO activity (1.64 ± 0.14 MPO U/mg protein) in TNBS-induced colitis. Moreover, this positive effect was observed at both the doses of ferric iron used (75 and 150 mg/kg per day po - 6 wk). In the study we also compared, in both rats and mice, the consequences of chronic repeated low level exposure to ferric iron (75 mg/kg per day po - 6 wk) on TNBS-induced colitis and its related dysbiosis. We confirmed that ferric iron limited the TNBS-induced increase of MPO activity in both the rodent species. Furthermore, we assessed the ferric iron incidence on TNBS-induced intestinal microbiota dysbiosis. At first, we needed to optimize the isolation and quantify DNA copy numbers using standard curves to perform by qPCR this interspecies comparison. Using this approach, we determined that total microflora was similar in control rats and mice and was mainly composed of Firmicutes and Bacteroidetes at a ratio of 10/1. Ferric juvenile administration did not modify the microflora profile in control animals. Total microflora numbers remained unchanged whichever experimental conditions studied. Following TNBS-induced colitis, the Firmicutes/Bacteroidetes ratio was altered resulting in a decrease of the Firmicutes numbers and an increase of the Bacteroidetes numbers typical of a gut inflammatory reaction. In parallel, the subdominant population, the enterobacteria was also increased. However, ferric iron supplementation for the juvenile period prevented the increase of Bacteroidetes and of enterobacteria numbers consecutive to the colitis in both the studied species at adulthood.CONCLUSION: Rats and mice juvenile chronic ferric iron ingestion prevents colitis and dysbiosis at adulthood as assessed by the first interspecies comparison.
文摘Diabetic dyslipidemia is characterized by quantitative and qualitative abnormalities in lipoproteins.In addition to glycation and oxidation,carbamylation is also a post-translational modification affecting lipoproteins in diabetes.Patients with type 2 diabetes(T2D)exhibit higher levels of carbamylated low-density lipoproteins(cLDL)and high-density lipoproteins(cHDL).Accumulating evidence suggests that cLDL plays a role in atherosclerosis in diabetes.cLDL levels have been shown to predict cardiovascular events and all-cause mortality.cLDL facilitates immune cell recruitment in the vascular wall,promotes accumulation of lipids in macrophages,and contributes to endothelial dysf-unction,endothelial nitric oxide-synthase(eNOS)inactivation and endothelial repair defects.Lastly,cLDL induces thrombus formation and platelet aggregation.On the other hand,recent data have demonstrated that cHDL serum level is independently associated with all-cause and cardiovascular-related mortality in T2D patients.This relationship may be causative since the atheroprotective properties of HDL are altered after carbamylation.Thus,cHDL loses the ability to remove cholesterol from macrophages,to inhibit monocyte adhesion and recruitment,to induce eNOS activation and to inhibit apoptosis.Taken together,it seems very likely that the abnormalities in the biological functions of LDL and HDL after carbamylation contribute to atherosclerosis and to the elevated cardiovascular risk in diabetes.
文摘Chromophobe renal cell carcinoma(ChRCC)is the third most common renal cell carcinoma(RCC)subtype,which predominantly occurs in sporadic setting.ChRCCs are considered to originate from the intercalated cell of distal tubules with two main morphological variants,classic and eosinophilic.Most ChRCCs carry a favorable clinical outcome.Histology alone is limited in predicting the behavior of ChRCCs that do not have overtly aggressive morphologic findings such as necrosis and sarcomatoid features.Along with positive CD117 expression,classic ChRCCs generally express diffuse and uniform CK7,while eosinophilic variant demonstrates more heterogeneous CK7 expression(rare or patchy).Multiple losses of chromosomes 1,2,6,10,13,17,and 21 are considered to be the genetic hallmarks of classic and eosinophilic ChRCCs,while chromosomal gains are known to be associated with sarcomatoid ChRCCs.TP53 and PTEN are the two most frequently mutated genes in ChRCCs.The major challenge in the differential diagnosis of ChRCCs includes considerations around the eosinophilic variant(of ChRCCs),where it may share overlapping features with oncocytoma or other recent emergent oncocytic tumors.Most eosinophilic ChRCCs share expression of the recently described biomarkers,LINC01187 and FOXI1,with classic ChRCCs,however,a subset of eosinophilic-like ChRCCs with lower biomarker expression have been demonstrated to harbor MTOR gene mutations.Overall,the morphologic features of ChRCCs and genetic profile with combinations of chromosomal losses and gains suggest this tumor entity to represent a distinct,yet heterogeneous group of renal neoplasms.
