Neurofibromatosis type 1(NF1)is a genetic disorder affecting 1 in 3000 people due to heterozygous mutations in the NF1 gene.Patients with NF1 can develop multiple symptoms,such as neurofibromas,skin hyperpigmentation,...Neurofibromatosis type 1(NF1)is a genetic disorder affecting 1 in 3000 people due to heterozygous mutations in the NF1 gene.Patients with NF1 can develop multiple symptoms,such as neurofibromas,skin hyperpigmentation,and bone abnormalities,including tibial pseudarthrosis and spine deformity.Here,we aimed to elucidate the cellular origin and pathogenic mechanism of NF1 spine deformity.We explored the Prss56-Nf1 knockout(KO)mouse model that recapitulates neurofibromas and pseudarthrosis by carrying Nf1 gene inactivation in Prss56-expressing boundary cap cells,a neural crest subset,and their derivatives.Micro-CT analyses showed that Prss56-Nf1 KO mice exhibit spine deformity from 12 months of age,associated with vertebral anomalies reminiscent of patients with NF1.Fate mapping revealed a significant increase in OSX^(+)osteoblasts of the Prss56 lineage in vertebrae of Prss56-Nf1 KO mice.Increased traced Nf1-deficient cells correlated with increased vertebral bone volume and kyphosis spine curvature.Finally,we showed that treating Prss56-Nf1 KO mice with RAS-MAPK pathway inhibitors prevented spine deformity.Overall,the Prss56-Nf1 KO mouse model unravels the role of osteoblasts from the Prss56 lineage as the cellular origin of NF1 spine deformity and highlights RAS-MAPK pathway inhibition as a promising therapeutic strategy for preventing NF1 spine deformity.展开更多
The homeoprotein encoded by the intestinal-specific Cdx2 gene is a major regulator of gut development and homeostasis,also involved in colon cancer as well as in intestinal-type metaplasias when it is abnormally expre...The homeoprotein encoded by the intestinal-specific Cdx2 gene is a major regulator of gut development and homeostasis,also involved in colon cancer as well as in intestinal-type metaplasias when it is abnormally expressed outside the gut.At the molecular level,structure/function studies have demonstrated that the Cdx2 protein is a transcription factor containing a conserved homeotic DNA-binding domain made ofthree alpha helixes arranged in a helix-turn-helix motif,preceded by a transcriptional domain and followed by a regulatory domain.The protein interacts with several thousand sites on the chromatin and widely regulates intestinal functions in stem/progenitor cells as well as in mature differentiated cells.Yet,this transcription factor also acts trough original nontranscriptional mechanisms.Indeed,the identification of novel protein partners of Cdx2 and also of a splicing variant revealed unexpected functions in the control of signaling pathways like the Wnt and NF-k B pathways,in double-strand break DNA repair and in premessenger RNA splicing.These novel functions of Cdx2 must be considered to fully understand the complexity of the role of Cdx2 in the healthy intestine and in diseases.展开更多
AIM To determine whether hepatitis B virus(HBV)-testing could serve as a gateway to vaccinate non-immunized individuals in a low-prevalent country.METHODS Non-immunized subjects participating in a multi-center, HBV-te...AIM To determine whether hepatitis B virus(HBV)-testing could serve as a gateway to vaccinate non-immunized individuals in a low-prevalent country.METHODS Non-immunized subjects participating in a multi-center, HBV-testing campaign in Paris, France were identified and contacted via telephone 3-9 mo after testing in order to determine vaccination status. Vaccination coverage was evaluated in per-protocol(for all respondents) and intent-to-treat analysis(assuming all non-responders did not vaccinate).RESULTS In total, 1215/4924(24.7%) enrolled subjects with complete HBV serology were identified as nonimmunized and eligible for analysis. There were 99/902 successfully contacted subjects who had initiated HBV vaccination after screening: per-protocol, 11.0%(95%CI: 9.0-13.2); intent-to-treat, 8.2%(95%CI: 6.7-9.8). In multivariable analysis, vaccination was more likely to be initiated in individuals originating from moderate or high HBV-endemic countries(P < 0.001), patients with limited healthcare coverage(P = 0.01) and men who have sex with men(P = 0.02). When asked about the reasons for not initiating HBV vaccination, the most frequent response was "will be vaccinated later"(33.4%), followed by "did not want to vaccinate"(29.8%), and "vaccination was not proposed by the physician"(21.5%). Sub-group analysis indicated a stark contrast in vaccination coverage across centers, ranging from 0%-56%.CONCLUSION HBV-vaccination after HBV screening was very low in this study, which appeared largely attributed to physician-patient motivation towards vaccination. Increased vaccination coverage might be achieved by emphasizing its need at the organizational level.展开更多
Progeria is a rare genetic disease that causes accelerated aging and death in children at a mean age of 13.5 years. An?aminobisphosphonate-statin combination has been shown to reduce the toxicity of the mutated protei...Progeria is a rare genetic disease that causes accelerated aging and death in children at a mean age of 13.5 years. An?aminobisphosphonate-statin combination has been shown to reduce the toxicity of the mutated protein, progerin, in progeria patient cell cultures and in a mouse model of the disease. This combination is currently being tested in a European Therapeutic Trial for progeria in Marseille (ClinicalTrials.gov identifier NCT00731016). Progerin has been shown to be produced by skin cells during physiological aging. The objective of this study was to assess the efficiency of a new and original cosmetic formulation containing alendronate and pravastatin sodium salts, reduce crow’s feet wrinkles, and cheek hollow in a double blind, randomized and placebo controlled comparative study. Three cosmetic preparations were evaluated using Fast Optical in vivo Topometry of human Skin (FOITS): one containing sodium alendronate and sodium pravastatin, a placebo, and a commercial anti-aging product. Fifty-seven female and twenty-five male volunteers between 51 and 71-year-old were selected. Each subject tested two of the three products once a day, in the evening, by spreading each selected product on one side of the face. Skin micro-relief was analyzed at 0, 28, 56 and 84 days. Statistical analysis of 7 clinical qualitative (left or right side of face, gender, and 3 skin types) and 6 quantitative parameters (age, weight at each test time, wrinkle clinical grade at inclusion time) showed no statistical differences between the three tested products. In contrast, most of the 8 quantitative FOITS parameters describing skin micro-relief were statistically improved by the alendronate-pravastatin combination compared to the placebo or to the commercial anti-aging product. A cosmetic preparation containing alendronate and pravastatin sodium salts exhibited anti-aging effects by reducing crow’s feet wrinkles and restoring cheek volume.展开更多
AIM: To investigate if correction of hypovitaminosis D before initiation of Peg-interferon-alpha/ribavirin(Peg IFN/RBV) therapy could improve the efficacy of Peg IFN/RBV in previously null-responder patients with chro...AIM: To investigate if correction of hypovitaminosis D before initiation of Peg-interferon-alpha/ribavirin(Peg IFN/RBV) therapy could improve the efficacy of Peg IFN/RBV in previously null-responder patients with chronic genotype 1 or 4 hepatitis C virus(HCV) infection.METHODS:Genotype 1 or 4 HCV-infected patients with null response to previous Peg IFN/RBV treatment and with hypovitaminosis D(<30 ng/m L)prospectively received cholecalciferol 100000 IU per week for 4 wk[from week-4(W-4)to W0],followed by 100000 IUper month in combination with Peg IFN/RBV for 12 mo(from W0 to W48).The primary outcome was the rate of early virological response defined by an HCV RNA<12 IU/m L after 12 wk Peg IFN/RBV treatment.RESULTS:A total of 32 patients were included,19(59%)and 13(41%)patients were HCV genotype1 and 4,respectively.The median baseline vitamin D level was 15 ng/m L(range:7-28).In modified intention-to-treat analysis,29 patients who received at least one dose of Peg IFN/RBV were included in the analysis.All patients except one normalized their vitamin D serum levels.The rate of early virologic response was 0/29(0%).The rate of HCV RNA<12IU/m L after 24 wk of Peg IFN/RBV was 1/27(4%).The safety profile was favorable.CONCLUSION:Addition of vitamin D to Peg IFN/RBV does not improve the rate of early virologic response in previously null-responders with chronic genotype 1or 4 HCV infection.展开更多
Diaphragm repair after congenital diaphragmatic hernia is associated with hernia recurrence due to prosthesis failure. Expanded polytetrafluoroethylene (e-PTFE), a synthetic non-degradable biomaterial, is currently us...Diaphragm repair after congenital diaphragmatic hernia is associated with hernia recurrence due to prosthesis failure. Expanded polytetrafluoroethylene (e-PTFE), a synthetic non-degradable biomaterial, is currently used for those diaphragmatic defect repairs. The drawback of e-PTFE is its poor wettability that leads to coating difficulties, bonding that could favor implant integration. However, polydopamine (PDA) can be deposited as well on organic as on inorganic substrates. Therefore, we assessed the biological responses of a clinically used e-PTFE biomaterial treated with PDA in two different manners: one impregnated with PDA and the other coated with a one side PDA film. Mechanical properties of the raw e-PTFE, the PDA soaked biomaterial and the PDA coated surface were characterized by colloidal probe atomic force microscopy. Behaviors of primary human fibroblasts and Wharton’s jelly stem cells were investigated by electron microscopy. Findings reveal that the mechanical properties at the microscopic scale are not modified by the PDA treatments. Cells spread onto both PDA functionalized substrates. In addition, microscopic observations disclose numerous focal cell contacts, evidencing cell attachment, and cytoplasmic projections particularly with the nanoscale PDA coating. Results clearly suggest that PDA in general but above all the PDA coating enhance cellular colonization of the implant material.展开更多
The synthesis of new 4-imino-4H-chromeno[2,3-d]pyrimidin-3(5H)-amine in four steps including one step under microwave dielectric heating is reported. The structural identity of the synthesized compounds was establishe...The synthesis of new 4-imino-4H-chromeno[2,3-d]pyrimidin-3(5H)-amine in four steps including one step under microwave dielectric heating is reported. The structural identity of the synthesized compounds was established according to their spectroscopic analysis, such as FT-IR, NMR and mass spectroscopy. These new compounds were tested for their antiproliferative activities on seven representative human tumoral cell lines (Huh7 D12, Caco2, MDA-MB231, MDA-MB468, HCT116, PC3 and MCF7) and also on fibroblasts. Among them, only the compounds 6c showed micromolar cytotoxic activity on tumor cell lines (1.8 50 50 > 25 μM). Finally, in silico ADMET studies ware performed to investigate the possibility of using of the identified compound 6c as potential anti-tumor compound.展开更多
In fifty years, laser technology has made great progress, and its many applications make it essential in everyday life. However, this technology is still open to numerous developments. Across multiple applications, th...In fifty years, laser technology has made great progress, and its many applications make it essential in everyday life. However, this technology is still open to numerous developments. Across multiple applications, there is particular focus in the field of medicine, for diagnosis for tailored therapies, and as a research tool in biology. Whereas its use is now well-demonstrated in ophthalmologic and dermatologic treatments, and surgery, one of the most fascinating aspects of laser technology in the field of biology emerged in the late 1990s with the development of devices able to perform fine dissections of biological tissues using a laser beam. The so-called laser-associated microdissection offers a rapid, precise method of isolating and removing targeted cells or groups of cells from complex biological tissues. It represents the missing link between clinical observations and the intrinsic physiological mechanisms of biological tissues. The molecular examination of pathologically altered cells and tissues for DNA, RNA, and protein expression has revolutionized research and diagnosis in pathology, enabling assessment of the role of the cell type in the normal physiological or disease process. Alongside conventional diagnostic and therapeutic approaches, another field of application contribute to the development of targeted treatments at the nanoscale level of laser technology, mainly in the field of cancer, leading to design new and innovative strategies in drug delivery and image-guided surgery. Most of these approaches, but although not exhaustively, will be presented here.展开更多
Ruthenium and osmium complexes have been shown to bypass several resistance mechanisms of platinum anticancer drugs,suggesting that they might represent therapeutic alternatives.However,the resistance mechanisms that ...Ruthenium and osmium complexes have been shown to bypass several resistance mechanisms of platinum anticancer drugs,suggesting that they might represent therapeutic alternatives.However,the resistance mechanisms that may alter the cytotoxicity of ruthenium and osmium complexes have not been identified yet.展开更多
Objective Impaired hepatic expression of protein tyrosine phosphatase delta(PTPRD)is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic...Objective Impaired hepatic expression of protein tyrosine phosphatase delta(PTPRD)is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic hepatitis C virus infection.However,the PTPRD-expressing hepatic cell types,signalling pathways responsive to PTPRD and their role in non-viral liver disease are largely unknown.Methods We studied PTPRD expression in single-cell and bulk liver transcriptomic data from mice and humans,and established a Ptprd-deficient mouse model for metabolic dysfunction-associated steatohepatitis(MASH).Identified pathways were validated by perturbation studies in human hepatocytes and PTPRD substrates by pull-down assays.The clinical relevance was further explored in a cohort with metabolic disease by ranking patients according to PTPRD expression and analysing its association with metabolic disease markers.Results The analysis of individuals ranked according to PTPRD expression and Ptprd-deficient mice,showed that PTPRD levels were associated with hepatic glucose/lipid signalling and peroxisome function.Hepatic PTPRD expression is impaired in aetiologies of chronic liver diseases that are associated with metabolic disease.We further validated PTPRD as a STAT3 phosphatase in the liver,acting as a regulator of peroxisomal fatty acid metabolism.During MASH,low PTPRD led to increased liver steatosis in Ptprd+/−mice and a pronounced unfolded protein response,which impacts insulin signalling.Accordingly,silencing of PTPRD blunted insulin-induced AKT phosphorylation.Patients with obesity and low hepatic PTPRD expression exhibit increased levels of metabolic risk factors.Conclusion Our data revealed an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis,which is recapitulated in clinical manifestations of metabolic liver disease.展开更多
Introduction Intrathoracic accessory spleen is an exceptionally rare finding that is usually discovered incidentally and is rarely symptomatic[1-3].This case is unique because the ectopic splenic tissue caused severe ...Introduction Intrathoracic accessory spleen is an exceptionally rare finding that is usually discovered incidentally and is rarely symptomatic[1-3].This case is unique because the ectopic splenic tissue caused severe dysphagia through extrinsic esophageal compression-a presentation almost never reported(Figure 1).It highlights the importance of considering non-gastrointestinal causes of dysphagia and the value of multimodal imaging and multidisciplinary evaluation in atypical clinical scenarios.展开更多
In 2014,the Joint United Nations Programme on HIV/AIDS(UNAIDS)first proposed the vision of“ending AIDS by 2030”,aiming to reduce new HIV infections and AIDS-related deaths to minimal levels while eliminating all for...In 2014,the Joint United Nations Programme on HIV/AIDS(UNAIDS)first proposed the vision of“ending AIDS by 2030”,aiming to reduce new HIV infections and AIDS-related deaths to minimal levels while eliminating all forms of HIVrelated stigma and discrimination(Kirby,2018).In 2021,the United Nations General Assembly adopted a new global political declaration on AIDS,which committed countries to achieving the“95-95-95”target by 2030.展开更多
Background:Gout,which manifests as severe inflammation caused by excessive serum urate levels and monosodium urate deposits in the joints,is associated with multiple genomic loci in Europeans.In this exploratory work,...Background:Gout,which manifests as severe inflammation caused by excessive serum urate levels and monosodium urate deposits in the joints,is associated with multiple genomic loci in Europeans.In this exploratory work,we aimed to identify additional gene variants in Melanesian families from New Caledonia,a population in which the disease is highly prevalent.Methods:Two families from Lifou Island(New Caledonia)in which multiple members were diagnosed with gout were selected.Whole exome sequencing and/or targeted sequencing of a panel of genes involved in immunity was performed in patients and their healthy relatives.Rare variants in Melanesian populations were selected using an autosomal dominant segregation model.Results:Several variants were identified in genes not previously involved in immune diseases or hyperuricemia,several of which were not observed in control individuals from Remote Oceania.Conclusion:This work highlights new candidate susceptibility loci for gout in New Caledonians,an underrepresented population in genomic studies,and suggests that novel pathways are likely involved in gout pathogenesis.展开更多
Prior research indicated low genotypic resistance testing(GRT)for human immunodeficiency virus(HIV)utilization in China due to partial cost coverage under national antiretroviral therapy policies,limited testing acces...Prior research indicated low genotypic resistance testing(GRT)for human immunodeficiency virus(HIV)utilization in China due to partial cost coverage under national antiretroviral therapy policies,limited testing accessibility,and financial barriers.Temporal and spatial data on GRT trends were also scarce.We analyzed GRT patterns among 6,895 untreated individuals at a tertiary hospital using Joinpoint regression,multivariable logistic modeling,and spatial analysis(GeoDa/SatScan).GRT rates showed a significant two-phase upward trend,increasing from 5.36%in 2014 to 74.17%in 2023,with an average annual percentage change of 31.30%(P<0.001).Beijing residency(adjusted odds ratio[aOR]=2.596,95%confidence interval[CI]:2.307-2.921)and older age were associated with higher GRT uptake.Specifically,ages 35-44 years(aOR=1.207,95%CI:1.026-1.420),45-54 years(aOR=1.335,95%CI:1.104-1.613),and≥55 years(aOR=1.424,95%CI:1.126-1.802)had significantly higher odds of testing.Lower testing rates were observed in individuals with lower education attainment(high school or technical secondary:aOR=0.827;junior high school:aOR=0.835;primary school:aOR=0.695),unknown sexually transmitted diseases(STDs)history(aOR=0.415),and non-heterosexual transmission routes(homosexual:aOR=0.834).Spatial analysis identified GRT clustering across Beijing until 2021,with two space-time clusters identified in 2019-2023 and 2018-2022.This study demonstrates substantial increase in GRT uptake achieving more balanced district-level distribution since 2021.Age,educational attainment,STDs history,and transmission route influence GRT utilization.Improving access,reducing costs,and implementing targeted interventions are critical for optimizing testing and guiding antiretroviral therapy decisions.展开更多
Human pluripotent stem cells(hPSCs)can in theory give rise to any hematopoietic lineages,thereby offering opportunities for disease modeling,drug screening and cell therapies.However,gaps in our knowledge of the signa...Human pluripotent stem cells(hPSCs)can in theory give rise to any hematopoietic lineages,thereby offering opportunities for disease modeling,drug screening and cell therapies.However,gaps in our knowledge of the signaling requirements for the specification of human hematopoietic stem/progenitor cells(HSPCs),which lie at the apex of all hematopoietic lineages,greatly limit the potential of hPSC in hematological research and application.Transcriptomic analysis reveals aberrant regulation of WNT signaling during maturation of hPSC-derived hematopoietic progenitor cells(hPSC-HPCs),which results in higher mitochondria activity,misregulation of HOX genes,loss of self-renewal and precocious differentiation.These defects are partly due to the activation of the WNT target gene CDX2.Late-stage WNT inhibition improves the yield,self-renewal,multilineage differentiation,and transcriptional and metabolic profiles of hPSC-HPCs.Genome-wide mapping of transcription factor(TF)accessible chromatin reveals a significant overrepresentation of myeloid TF binding motifs in hPSC-HPCs,which could underlie their myeloid-biased lineage potential.Together our findings uncover a previously unappreciated dynamic requirement of the WNT signaling pathway during the specification of human HSPCs.Modulating the WNT pathway with small molecules normalizes the molecular differences between hPSC-HPCs and endogenous hematopoietic stem cells(HSCs),thereby representing a promising approach to improve the differentiation and function of hPSC-HPCs.展开更多
Antiretroviral therapy against human immunodeficiency virus (HIV) is effective in controlling viral replication but cannot completely eliminate HIV due to the persistence of the HIV reservoir. Innate and adaptive immu...Antiretroviral therapy against human immunodeficiency virus (HIV) is effective in controlling viral replication but cannot completely eliminate HIV due to the persistence of the HIV reservoir. Innate and adaptive immune responses have been proposed to contribute to preventing HIV acquisition, controlling HIV replication and eliminating HIV-infected cells. However, the immune responses naturally induced in HIV-infected individuals rarely eradicate HIV infection, which may be caused by immune escape, an inadequate magnitude and breadth of immune responses, and immune exhaustion. Optimizing these immune responses may solve the problems of epitope escape and insufficient sustained memory responses. Moreover, immune interventions aimed at improving host immune response can reduce HIV reservoirs, which have become one focus in the development of innovative strategies to eliminate HIV reservoirs. In this review, we focus on the immune response against HIV and how antiviral immune responses affect HIV reservoirs. We also discuss the development of innovative strategies aiming to eliminate HIV reservoirs and promoting functional cure of HIV infection.展开更多
In their study“Pancreatic Enucleation Patients Share the Same Quality of Life as the General Population at Long-Term Follow-Up”,Giuliani et al.(1)assess short-and long-term outcomes including quality of life after p...In their study“Pancreatic Enucleation Patients Share the Same Quality of Life as the General Population at Long-Term Follow-Up”,Giuliani et al.(1)assess short-and long-term outcomes including quality of life after pancreatic enucleation(PE).PE aims to preserve endocrine and exocrine function while ensuring surgical ablation of a presumed benign pancreatic tumor(neuroendocrine tumors,mucinous cystadenoma,serous cystadenoma,branch duct intraductal papillary mucinous neoplasms and solid pseudopapillary tumors).展开更多
Introduction In December 2019,multiple cases of aggravated pneumonia of unidentified origin were reported inWuhan,China.These were confirmed to be caused by a novel coronavirus.The World Health Organization(WHO)named ...Introduction In December 2019,multiple cases of aggravated pneumonia of unidentified origin were reported inWuhan,China.These were confirmed to be caused by a novel coronavirus.The World Health Organization(WHO)named the disease coronavirus disease 2019(COVID-19).The International Committee on Taxonomy of Viruses officially identified the novel virus severe acute respiratory syndrome coronavirus 2(SARSCoV-2).[1]Although China is now a low endemic areawith a downward trend in the number of confirmed and suspected cases,[2]the threat of the COVID-19 pandemic remains critical.By mid-March 2022,the cumulative number of reported confirmed cases of COVID-19 worldwide exceeded 450 million,with more than 6 million deaths.[3]Since there is no specific therapeutic drug for the treatment of COVID-19,it is important to control the epidemic by actively promoting SARS-CoV-2 vaccination globally,reducing the risk of viral transmission and the incidence of severe COVID-19,thus improving prognoses.[4]展开更多
The central nervous system is characterized by a peculiar vascularization termed blood–brain barrier(BBB),which regulates the exchange of cells and molecules between the cerebral tissue and the whole body.BBB dysfunc...The central nervous system is characterized by a peculiar vascularization termed blood–brain barrier(BBB),which regulates the exchange of cells and molecules between the cerebral tissue and the whole body.BBB dysfunction is a life-threatening condition since its presence corresponds to a marker of severity in most diseases encountered in the intensive care unit(ICU).During critical illness,inflammatory response,cytokine release,and other phenomena activating the brain endothelium contribute to alterations in the BBB and increase its permeability to solutes,cells,nutrients,and xenobiotics.Moreover,patients in the ICU are often old,with underlying acute or chronic diseases,and overly medicated due to their critical condition;these factors could also contribute to the development of BBB dysfunction.An accurate diagnostic approach is critical for the identification of the mechanisms underlying BBB alterations,which should be rapidly managed by intensivists.Several methods were developed to investigate the BBB and assess its permeability.Nevertheless,in humans,exploration of the BBB requires the use of indirect methods.Imaging and biochemical methods can be used to study the abnormal passage of molecules through the BBB.In this review,we describe the structural and functional characteristics of the BBB,present tools and methods for probing this interface,and provide examples of the main diseases managed in the ICU that are related to BBB dysfunction.展开更多
Dentin is a mineralized tissue with a chemical composition similar to bone but with a higher mineralized density and rigidity.It constitutes the central structure of the tooth between the internal pulp and external en...Dentin is a mineralized tissue with a chemical composition similar to bone but with a higher mineralized density and rigidity.It constitutes the central structure of the tooth between the internal pulp and external enamel toward the oral cavity or cementum toward the underlying roots.Inherited dentin defects occur in a variety of rare genetic diseases.They can manifest as“isolated”occurrences such as in dentinogenesis imperfecta(DI)or dentin dysplasia(DD)or can be associated with other symptoms in diseases such as osteogenesis imperfecta,Goldblatt syndrome,microcephalic osteodysplastic primordial dwarfism type Ⅱ,among others.展开更多
基金Association Neurofibromatoses et Recklinghausen(C.C)Agence Nationale de la Recherche-18-CE14-0033(C.C.,P.T.)+2 种基金Agence Nationale de la Recherche-21-CE18-007-01(C.C.,P.T.)US Department of the Army NF220019(C.C.)supported by a PhD fellowship from the University Paris-Est Créteil and the Fondation pour la Recherche Médicale(FRM)(FDT202304016600 to FK and ECO202306017399 to CG)。
文摘Neurofibromatosis type 1(NF1)is a genetic disorder affecting 1 in 3000 people due to heterozygous mutations in the NF1 gene.Patients with NF1 can develop multiple symptoms,such as neurofibromas,skin hyperpigmentation,and bone abnormalities,including tibial pseudarthrosis and spine deformity.Here,we aimed to elucidate the cellular origin and pathogenic mechanism of NF1 spine deformity.We explored the Prss56-Nf1 knockout(KO)mouse model that recapitulates neurofibromas and pseudarthrosis by carrying Nf1 gene inactivation in Prss56-expressing boundary cap cells,a neural crest subset,and their derivatives.Micro-CT analyses showed that Prss56-Nf1 KO mice exhibit spine deformity from 12 months of age,associated with vertebral anomalies reminiscent of patients with NF1.Fate mapping revealed a significant increase in OSX^(+)osteoblasts of the Prss56 lineage in vertebrae of Prss56-Nf1 KO mice.Increased traced Nf1-deficient cells correlated with increased vertebral bone volume and kyphosis spine curvature.Finally,we showed that treating Prss56-Nf1 KO mice with RAS-MAPK pathway inhibitors prevented spine deformity.Overall,the Prss56-Nf1 KO mouse model unravels the role of osteoblasts from the Prss56 lineage as the cellular origin of NF1 spine deformity and highlights RAS-MAPK pathway inhibition as a promising therapeutic strategy for preventing NF1 spine deformity.
文摘The homeoprotein encoded by the intestinal-specific Cdx2 gene is a major regulator of gut development and homeostasis,also involved in colon cancer as well as in intestinal-type metaplasias when it is abnormally expressed outside the gut.At the molecular level,structure/function studies have demonstrated that the Cdx2 protein is a transcription factor containing a conserved homeotic DNA-binding domain made ofthree alpha helixes arranged in a helix-turn-helix motif,preceded by a transcriptional domain and followed by a regulatory domain.The protein interacts with several thousand sites on the chromatin and widely regulates intestinal functions in stem/progenitor cells as well as in mature differentiated cells.Yet,this transcription factor also acts trough original nontranscriptional mechanisms.Indeed,the identification of novel protein partners of Cdx2 and also of a splicing variant revealed unexpected functions in the control of signaling pathways like the Wnt and NF-k B pathways,in double-strand break DNA repair and in premessenger RNA splicing.These novel functions of Cdx2 must be considered to fully understand the complexity of the role of Cdx2 in the healthy intestine and in diseases.
基金Supported by the ANRS(Agence Nationale de Recherche contre le Sida et les Hépatites)and Mairie de Paris,No.2010-334
文摘AIM To determine whether hepatitis B virus(HBV)-testing could serve as a gateway to vaccinate non-immunized individuals in a low-prevalent country.METHODS Non-immunized subjects participating in a multi-center, HBV-testing campaign in Paris, France were identified and contacted via telephone 3-9 mo after testing in order to determine vaccination status. Vaccination coverage was evaluated in per-protocol(for all respondents) and intent-to-treat analysis(assuming all non-responders did not vaccinate).RESULTS In total, 1215/4924(24.7%) enrolled subjects with complete HBV serology were identified as nonimmunized and eligible for analysis. There were 99/902 successfully contacted subjects who had initiated HBV vaccination after screening: per-protocol, 11.0%(95%CI: 9.0-13.2); intent-to-treat, 8.2%(95%CI: 6.7-9.8). In multivariable analysis, vaccination was more likely to be initiated in individuals originating from moderate or high HBV-endemic countries(P < 0.001), patients with limited healthcare coverage(P = 0.01) and men who have sex with men(P = 0.02). When asked about the reasons for not initiating HBV vaccination, the most frequent response was "will be vaccinated later"(33.4%), followed by "did not want to vaccinate"(29.8%), and "vaccination was not proposed by the physician"(21.5%). Sub-group analysis indicated a stark contrast in vaccination coverage across centers, ranging from 0%-56%.CONCLUSION HBV-vaccination after HBV screening was very low in this study, which appeared largely attributed to physician-patient motivation towards vaccination. Increased vaccination coverage might be achieved by emphasizing its need at the organizational level.
文摘Progeria is a rare genetic disease that causes accelerated aging and death in children at a mean age of 13.5 years. An?aminobisphosphonate-statin combination has been shown to reduce the toxicity of the mutated protein, progerin, in progeria patient cell cultures and in a mouse model of the disease. This combination is currently being tested in a European Therapeutic Trial for progeria in Marseille (ClinicalTrials.gov identifier NCT00731016). Progerin has been shown to be produced by skin cells during physiological aging. The objective of this study was to assess the efficiency of a new and original cosmetic formulation containing alendronate and pravastatin sodium salts, reduce crow’s feet wrinkles, and cheek hollow in a double blind, randomized and placebo controlled comparative study. Three cosmetic preparations were evaluated using Fast Optical in vivo Topometry of human Skin (FOITS): one containing sodium alendronate and sodium pravastatin, a placebo, and a commercial anti-aging product. Fifty-seven female and twenty-five male volunteers between 51 and 71-year-old were selected. Each subject tested two of the three products once a day, in the evening, by spreading each selected product on one side of the face. Skin micro-relief was analyzed at 0, 28, 56 and 84 days. Statistical analysis of 7 clinical qualitative (left or right side of face, gender, and 3 skin types) and 6 quantitative parameters (age, weight at each test time, wrinkle clinical grade at inclusion time) showed no statistical differences between the three tested products. In contrast, most of the 8 quantitative FOITS parameters describing skin micro-relief were statistically improved by the alendronate-pravastatin combination compared to the placebo or to the commercial anti-aging product. A cosmetic preparation containing alendronate and pravastatin sodium salts exhibited anti-aging effects by reducing crow’s feet wrinkles and restoring cheek volume.
文摘AIM: To investigate if correction of hypovitaminosis D before initiation of Peg-interferon-alpha/ribavirin(Peg IFN/RBV) therapy could improve the efficacy of Peg IFN/RBV in previously null-responder patients with chronic genotype 1 or 4 hepatitis C virus(HCV) infection.METHODS:Genotype 1 or 4 HCV-infected patients with null response to previous Peg IFN/RBV treatment and with hypovitaminosis D(<30 ng/m L)prospectively received cholecalciferol 100000 IU per week for 4 wk[from week-4(W-4)to W0],followed by 100000 IUper month in combination with Peg IFN/RBV for 12 mo(from W0 to W48).The primary outcome was the rate of early virological response defined by an HCV RNA<12 IU/m L after 12 wk Peg IFN/RBV treatment.RESULTS:A total of 32 patients were included,19(59%)and 13(41%)patients were HCV genotype1 and 4,respectively.The median baseline vitamin D level was 15 ng/m L(range:7-28).In modified intention-to-treat analysis,29 patients who received at least one dose of Peg IFN/RBV were included in the analysis.All patients except one normalized their vitamin D serum levels.The rate of early virologic response was 0/29(0%).The rate of HCV RNA<12IU/m L after 24 wk of Peg IFN/RBV was 1/27(4%).The safety profile was favorable.CONCLUSION:Addition of vitamin D to Peg IFN/RBV does not improve the rate of early virologic response in previously null-responders with chronic genotype 1or 4 HCV infection.
文摘Diaphragm repair after congenital diaphragmatic hernia is associated with hernia recurrence due to prosthesis failure. Expanded polytetrafluoroethylene (e-PTFE), a synthetic non-degradable biomaterial, is currently used for those diaphragmatic defect repairs. The drawback of e-PTFE is its poor wettability that leads to coating difficulties, bonding that could favor implant integration. However, polydopamine (PDA) can be deposited as well on organic as on inorganic substrates. Therefore, we assessed the biological responses of a clinically used e-PTFE biomaterial treated with PDA in two different manners: one impregnated with PDA and the other coated with a one side PDA film. Mechanical properties of the raw e-PTFE, the PDA soaked biomaterial and the PDA coated surface were characterized by colloidal probe atomic force microscopy. Behaviors of primary human fibroblasts and Wharton’s jelly stem cells were investigated by electron microscopy. Findings reveal that the mechanical properties at the microscopic scale are not modified by the PDA treatments. Cells spread onto both PDA functionalized substrates. In addition, microscopic observations disclose numerous focal cell contacts, evidencing cell attachment, and cytoplasmic projections particularly with the nanoscale PDA coating. Results clearly suggest that PDA in general but above all the PDA coating enhance cellular colonization of the implant material.
文摘The synthesis of new 4-imino-4H-chromeno[2,3-d]pyrimidin-3(5H)-amine in four steps including one step under microwave dielectric heating is reported. The structural identity of the synthesized compounds was established according to their spectroscopic analysis, such as FT-IR, NMR and mass spectroscopy. These new compounds were tested for their antiproliferative activities on seven representative human tumoral cell lines (Huh7 D12, Caco2, MDA-MB231, MDA-MB468, HCT116, PC3 and MCF7) and also on fibroblasts. Among them, only the compounds 6c showed micromolar cytotoxic activity on tumor cell lines (1.8 50 50 > 25 μM). Finally, in silico ADMET studies ware performed to investigate the possibility of using of the identified compound 6c as potential anti-tumor compound.
文摘In fifty years, laser technology has made great progress, and its many applications make it essential in everyday life. However, this technology is still open to numerous developments. Across multiple applications, there is particular focus in the field of medicine, for diagnosis for tailored therapies, and as a research tool in biology. Whereas its use is now well-demonstrated in ophthalmologic and dermatologic treatments, and surgery, one of the most fascinating aspects of laser technology in the field of biology emerged in the late 1990s with the development of devices able to perform fine dissections of biological tissues using a laser beam. The so-called laser-associated microdissection offers a rapid, precise method of isolating and removing targeted cells or groups of cells from complex biological tissues. It represents the missing link between clinical observations and the intrinsic physiological mechanisms of biological tissues. The molecular examination of pathologically altered cells and tissues for DNA, RNA, and protein expression has revolutionized research and diagnosis in pathology, enabling assessment of the role of the cell type in the normal physiological or disease process. Alongside conventional diagnostic and therapeutic approaches, another field of application contribute to the development of targeted treatments at the nanoscale level of laser technology, mainly in the field of cancer, leading to design new and innovative strategies in drug delivery and image-guided surgery. Most of these approaches, but although not exhaustively, will be presented here.
文摘Ruthenium and osmium complexes have been shown to bypass several resistance mechanisms of platinum anticancer drugs,suggesting that they might represent therapeutic alternatives.However,the resistance mechanisms that may alter the cytotoxicity of ruthenium and osmium complexes have not been identified yet.
基金supported by the European Union(ERC-AdG-2014 HEPCIR ERC POC PRELICAN 755460,ERC POC HEPCAN 862551 to TFB,EU H2020 HEPCAR 667273 to TFB and JL,HORIZON-HLTH-2021-DISEASE-04-07 D-SOLVE#101057917 to TFB and JL,IP-cure-B project#847939 to FZ,ERC-AdG-2020-101021417 to YH)the French Cancer Agency(TheraHCC2.0 IHU201901299 to TFB)+9 种基金the Agence Nationale de la Recherche(ANR-21-RHUS-001 to TFB)the ANRS Maladies infectieusesémergentes(ANRS-MIE)(ECTZ103701,ECTZ131760,ECTZ160436,ECTZ171594 to JL,ECTZ104017 and ECTZ75178 to TFB,ECTZ4446 and ECTZ206376 to AARS)the Fondation de l’Universitéde Strasbourg(HEPKIN)(TBA-DON-0002),SATT Conectus,University of Strasbourg(CANCLAU)(TFB)the Inserm Plan Cancer 2019-2023the US National Institutes of Health(CA233794,CA255621,CA282178,CA288375 and CA283935 to YH)the Cancer Prevention and Research Institute of Texas(RR180016,RP200554 to YH)The AEPIC animal facility platform is financially supported by the CoRTecS network of the University of StrasbourgThis work of the Interdisciplinary Thematic Institute IMCBio,as part of the ITI 2021-2028 programme of the University of Strasbourg,CNRS and Inserm,was supported by IdEx Unistra(ANR-10-IDEX-0002)SFRI-STRAT’US project(ANR 20-SFRI-0012)EUR IMCBio(ANR-17-EURE-0023)under the framework of the French Investments for the Future Programme,as well as state funds managed within the France 2030 programme(reference ANR-21-RHUS-0001).
文摘Objective Impaired hepatic expression of protein tyrosine phosphatase delta(PTPRD)is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic hepatitis C virus infection.However,the PTPRD-expressing hepatic cell types,signalling pathways responsive to PTPRD and their role in non-viral liver disease are largely unknown.Methods We studied PTPRD expression in single-cell and bulk liver transcriptomic data from mice and humans,and established a Ptprd-deficient mouse model for metabolic dysfunction-associated steatohepatitis(MASH).Identified pathways were validated by perturbation studies in human hepatocytes and PTPRD substrates by pull-down assays.The clinical relevance was further explored in a cohort with metabolic disease by ranking patients according to PTPRD expression and analysing its association with metabolic disease markers.Results The analysis of individuals ranked according to PTPRD expression and Ptprd-deficient mice,showed that PTPRD levels were associated with hepatic glucose/lipid signalling and peroxisome function.Hepatic PTPRD expression is impaired in aetiologies of chronic liver diseases that are associated with metabolic disease.We further validated PTPRD as a STAT3 phosphatase in the liver,acting as a regulator of peroxisomal fatty acid metabolism.During MASH,low PTPRD led to increased liver steatosis in Ptprd+/−mice and a pronounced unfolded protein response,which impacts insulin signalling.Accordingly,silencing of PTPRD blunted insulin-induced AKT phosphorylation.Patients with obesity and low hepatic PTPRD expression exhibit increased levels of metabolic risk factors.Conclusion Our data revealed an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis,which is recapitulated in clinical manifestations of metabolic liver disease.
文摘Introduction Intrathoracic accessory spleen is an exceptionally rare finding that is usually discovered incidentally and is rarely symptomatic[1-3].This case is unique because the ectopic splenic tissue caused severe dysphagia through extrinsic esophageal compression-a presentation almost never reported(Figure 1).It highlights the importance of considering non-gastrointestinal causes of dysphagia and the value of multimodal imaging and multidisciplinary evaluation in atypical clinical scenarios.
基金supported by the National Key R&D Program of China(2023YFE0116000,2023YFC2308300,2023YFC2308302)the High-Level Public Health Specialized Talents Project of Beijing Municipal Health Commission(2022-2-018)+1 种基金the Beijing Key Laboratory for HIV/AIDS Research(BZ0089)the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales(ANRS)Investissements d’Avenir program managed by the ANR under reference ANR10-LABX-77 and EHVA(N°681032,Horizon 2020)。
文摘In 2014,the Joint United Nations Programme on HIV/AIDS(UNAIDS)first proposed the vision of“ending AIDS by 2030”,aiming to reduce new HIV infections and AIDS-related deaths to minimal levels while eliminating all forms of HIVrelated stigma and discrimination(Kirby,2018).In 2021,the United Nations General Assembly adopted a new global political declaration on AIDS,which committed countries to achieving the“95-95-95”target by 2030.
基金supported by Strasbourg's Interdisciplinary Thematic Institute(ITI)for Precision Medicine,TRANSPLANTEX NG,as part of the ITI 2021-2028 program of the University of Strasbourg,CNRS and INSERM,funded by IdEx Unistra(ANR-10-IDEX-0002)SFRI-STRAT'US(ANR-20-SFRI-0012)+2 种基金the INSERM UMR_S 1109,the University of Strasbourg(IDEX UNISTRA)the European regional development fund(European Union)INTERREG V program(project PERSONALIS)the MSD-Avenir grant AUTOGEN.RC is supported by the“Association Robert Debrépour la Recherche Médicale.”。
文摘Background:Gout,which manifests as severe inflammation caused by excessive serum urate levels and monosodium urate deposits in the joints,is associated with multiple genomic loci in Europeans.In this exploratory work,we aimed to identify additional gene variants in Melanesian families from New Caledonia,a population in which the disease is highly prevalent.Methods:Two families from Lifou Island(New Caledonia)in which multiple members were diagnosed with gout were selected.Whole exome sequencing and/or targeted sequencing of a panel of genes involved in immunity was performed in patients and their healthy relatives.Rare variants in Melanesian populations were selected using an autosomal dominant segregation model.Results:Several variants were identified in genes not previously involved in immune diseases or hyperuricemia,several of which were not observed in control individuals from Remote Oceania.Conclusion:This work highlights new candidate susceptibility loci for gout in New Caledonians,an underrepresented population in genomic studies,and suggests that novel pathways are likely involved in gout pathogenesis.
基金supported by the National Key R&D Program of China(2023YFC2308300,2023YFC2308302,2023YFE0116000,2022YFC2305200,2022YFC2305202)Beijing Research Ward Excellence Program(BRWEP,2024W042180108)+2 种基金the High-Level Public Health Specialized Talents Project of Beijing Municipal Health Commission(2022-2-018,2022-1-007)the Beijing Key Laboratory for HIV/AIDS Research(BZ0089),the Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX24_0484)the SEU Innovation Capability Enhancement Plan for Doctoral Students(CXJH_SEU 24042).
文摘Prior research indicated low genotypic resistance testing(GRT)for human immunodeficiency virus(HIV)utilization in China due to partial cost coverage under national antiretroviral therapy policies,limited testing accessibility,and financial barriers.Temporal and spatial data on GRT trends were also scarce.We analyzed GRT patterns among 6,895 untreated individuals at a tertiary hospital using Joinpoint regression,multivariable logistic modeling,and spatial analysis(GeoDa/SatScan).GRT rates showed a significant two-phase upward trend,increasing from 5.36%in 2014 to 74.17%in 2023,with an average annual percentage change of 31.30%(P<0.001).Beijing residency(adjusted odds ratio[aOR]=2.596,95%confidence interval[CI]:2.307-2.921)and older age were associated with higher GRT uptake.Specifically,ages 35-44 years(aOR=1.207,95%CI:1.026-1.420),45-54 years(aOR=1.335,95%CI:1.104-1.613),and≥55 years(aOR=1.424,95%CI:1.126-1.802)had significantly higher odds of testing.Lower testing rates were observed in individuals with lower education attainment(high school or technical secondary:aOR=0.827;junior high school:aOR=0.835;primary school:aOR=0.695),unknown sexually transmitted diseases(STDs)history(aOR=0.415),and non-heterosexual transmission routes(homosexual:aOR=0.834).Spatial analysis identified GRT clustering across Beijing until 2021,with two space-time clusters identified in 2019-2023 and 2018-2022.This study demonstrates substantial increase in GRT uptake achieving more balanced district-level distribution since 2021.Age,educational attainment,STDs history,and transmission route influence GRT utilization.Improving access,reducing costs,and implementing targeted interventions are critical for optimizing testing and guiding antiretroviral therapy decisions.
基金supported by CIRM fellowshipssupported by grants from the G.Harold and Leila Y.Mathers Charitable Foundation,The California Institute of Regenerative Medicine,Ellison Medical Foundation,and The Leona M.and Harry B.Helmsley Charitable Trust grant#2012-PG-MED002supported by the KAUST Office of Sponsored Research(OSR)under Award No.BAS/1/1080-01(ML),URF/1/4716-01(ML)and KAUST Center of Excellence for Smart Health(KCSH)award number 5932.
文摘Human pluripotent stem cells(hPSCs)can in theory give rise to any hematopoietic lineages,thereby offering opportunities for disease modeling,drug screening and cell therapies.However,gaps in our knowledge of the signaling requirements for the specification of human hematopoietic stem/progenitor cells(HSPCs),which lie at the apex of all hematopoietic lineages,greatly limit the potential of hPSC in hematological research and application.Transcriptomic analysis reveals aberrant regulation of WNT signaling during maturation of hPSC-derived hematopoietic progenitor cells(hPSC-HPCs),which results in higher mitochondria activity,misregulation of HOX genes,loss of self-renewal and precocious differentiation.These defects are partly due to the activation of the WNT target gene CDX2.Late-stage WNT inhibition improves the yield,self-renewal,multilineage differentiation,and transcriptional and metabolic profiles of hPSC-HPCs.Genome-wide mapping of transcription factor(TF)accessible chromatin reveals a significant overrepresentation of myeloid TF binding motifs in hPSC-HPCs,which could underlie their myeloid-biased lineage potential.Together our findings uncover a previously unappreciated dynamic requirement of the WNT signaling pathway during the specification of human HSPCs.Modulating the WNT pathway with small molecules normalizes the molecular differences between hPSC-HPCs and endogenous hematopoietic stem cells(HSCs),thereby representing a promising approach to improve the differentiation and function of hPSC-HPCs.
基金This work was supported by grants from the National Natural Science Foundation of China (Nos. NSFC, 81974303 to BS, and 82072271 to TZ)the High-Level Public Health Specialized Talents Project of Beijing Municipal Health Commission (Nos. 2022-1-007 to TZ and 2022-2-018 to BS)+4 种基金the "Climbing the peak (Dengfeng) " Talent Training Program of Beijing Hospitals Authority (No. DFL20191701 to TZ)the Beijing Health Technologies Promotion Program (No. BHTPP2020 to TZ)the Beijing Key Laboratory for HIV/AIDS Research (No. BZ0089)the ANRS (Agence Nationale de Recherches sur le SIDA et les hépatites virales)the Investissements d’Avenir program managed by the ANR under reference ANR-10-LABX-77 and EHVA (No. 681032, Horizon 2020) .
文摘Antiretroviral therapy against human immunodeficiency virus (HIV) is effective in controlling viral replication but cannot completely eliminate HIV due to the persistence of the HIV reservoir. Innate and adaptive immune responses have been proposed to contribute to preventing HIV acquisition, controlling HIV replication and eliminating HIV-infected cells. However, the immune responses naturally induced in HIV-infected individuals rarely eradicate HIV infection, which may be caused by immune escape, an inadequate magnitude and breadth of immune responses, and immune exhaustion. Optimizing these immune responses may solve the problems of epitope escape and insufficient sustained memory responses. Moreover, immune interventions aimed at improving host immune response can reduce HIV reservoirs, which have become one focus in the development of innovative strategies to eliminate HIV reservoirs. In this review, we focus on the immune response against HIV and how antiviral immune responses affect HIV reservoirs. We also discuss the development of innovative strategies aiming to eliminate HIV reservoirs and promoting functional cure of HIV infection.
文摘In their study“Pancreatic Enucleation Patients Share the Same Quality of Life as the General Population at Long-Term Follow-Up”,Giuliani et al.(1)assess short-and long-term outcomes including quality of life after pancreatic enucleation(PE).PE aims to preserve endocrine and exocrine function while ensuring surgical ablation of a presumed benign pancreatic tumor(neuroendocrine tumors,mucinous cystadenoma,serous cystadenoma,branch duct intraductal papillary mucinous neoplasms and solid pseudopapillary tumors).
基金supported by the High-Level Public Health Specialized Talents Project of Beijing Municipal Health Commission(2022-2-018)the Ministry of Science and Technology of China(CPL-1233)+3 种基金the National Natural Science Foundation of China(NSFC,81974303)the“Climbing the peak(Dengfeng)”Talent Training Program of Beijing Hospitals Authority(DFL20191701)the Beijing Health Technologies Promotion Program(BHTPP2020)the Beijing Key Laboratory for HIV/AIDS Research(BZ0089).
文摘Introduction In December 2019,multiple cases of aggravated pneumonia of unidentified origin were reported inWuhan,China.These were confirmed to be caused by a novel coronavirus.The World Health Organization(WHO)named the disease coronavirus disease 2019(COVID-19).The International Committee on Taxonomy of Viruses officially identified the novel virus severe acute respiratory syndrome coronavirus 2(SARSCoV-2).[1]Although China is now a low endemic areawith a downward trend in the number of confirmed and suspected cases,[2]the threat of the COVID-19 pandemic remains critical.By mid-March 2022,the cumulative number of reported confirmed cases of COVID-19 worldwide exceeded 450 million,with more than 6 million deaths.[3]Since there is no specific therapeutic drug for the treatment of COVID-19,it is important to control the epidemic by actively promoting SARS-CoV-2 vaccination globally,reducing the risk of viral transmission and the incidence of severe COVID-19,thus improving prognoses.[4]
文摘The central nervous system is characterized by a peculiar vascularization termed blood–brain barrier(BBB),which regulates the exchange of cells and molecules between the cerebral tissue and the whole body.BBB dysfunction is a life-threatening condition since its presence corresponds to a marker of severity in most diseases encountered in the intensive care unit(ICU).During critical illness,inflammatory response,cytokine release,and other phenomena activating the brain endothelium contribute to alterations in the BBB and increase its permeability to solutes,cells,nutrients,and xenobiotics.Moreover,patients in the ICU are often old,with underlying acute or chronic diseases,and overly medicated due to their critical condition;these factors could also contribute to the development of BBB dysfunction.An accurate diagnostic approach is critical for the identification of the mechanisms underlying BBB alterations,which should be rapidly managed by intensivists.Several methods were developed to investigate the BBB and assess its permeability.Nevertheless,in humans,exploration of the BBB requires the use of indirect methods.Imaging and biochemical methods can be used to study the abnormal passage of molecules through the BBB.In this review,we describe the structural and functional characteristics of the BBB,present tools and methods for probing this interface,and provide examples of the main diseases managed in the ICU that are related to BBB dysfunction.
基金the actions of the projects Offensives Sciences INTERREG IV A27 and“RARENET:No.1.7,a trinational network for education,research and management of complex and rare disorders in the Upper Rhine”co-financed by the European Regional Development Fund(ERDF)of the European Union in the framework of the INTERREG V Upper Rhine program as well as to the ERN(European reference network)CRANIO initiative.ABZ is a USIAS 2015 Fellow of the Institute of Advanced Studies(Institut d’Etudes Avancees)de l’Universite´de Strasbourg,France.It was also supported by the grant ANR10-LABX-0030-INRT,a French State fund managed by the Agence Nationale de la Recherche under the frame programme Investissements d’Avenir labelled ANR-10-IDEX0002-02.the Projet E-GENODENT financed by the Fonds d’Intervention Re´gionale(FIR)of the Agence Re´gionale de Sante´Grand Est(2019-2022)+1 种基金the“Impulsion Recherche”financial support of the“Filie`re de Sante´Maladies Rares TETECOU”2021 and 2022 and acknowledge the Fondation Force for supporting the DIAGNODENT project(2023-2026)the study design,data collection and analysis,decision to publish,or preparation of the manuscript.
文摘Dentin is a mineralized tissue with a chemical composition similar to bone but with a higher mineralized density and rigidity.It constitutes the central structure of the tooth between the internal pulp and external enamel toward the oral cavity or cementum toward the underlying roots.Inherited dentin defects occur in a variety of rare genetic diseases.They can manifest as“isolated”occurrences such as in dentinogenesis imperfecta(DI)or dentin dysplasia(DD)or can be associated with other symptoms in diseases such as osteogenesis imperfecta,Goldblatt syndrome,microcephalic osteodysplastic primordial dwarfism type Ⅱ,among others.
