Neonatal gonocytes are precursors of spermatogonial stem cells. Preserving their integrity by elimination of damaged germ cells may be crucial to avoid the transmission of genetic alterations to progeny. Using 7-irrad...Neonatal gonocytes are precursors of spermatogonial stem cells. Preserving their integrity by elimination of damaged germ cells may be crucial to avoid the transmission of genetic alterations to progeny. Using 7-irradiation, we investigated by immunohistochemistry, flow cytometry and real-time PCR components of the death machinery in neonatal gonocytes. Their death was correlated with caspase 3 activation but not with AIF translocation into the nu- cleus. The in vivo contribution of both the extrinsic and the intrinsic pathways was then investigated. We focused on the roles of TRAIL/Death Receptor 5 （DR5） and PUMA. Our results were validated using knockout mice. Whereas DR5 expression was upregulated at the cell surface after radiation, caspase 8 was not activated. However, we detected caspase 9 cleavage associated with cytochrome c release. In mice deficient for PUMA, radiation-induced gonocyte apoptosis was reduced, whereas invalidation of TRAIL had no effect. Overall, our results show that genotoxic stressinduced apoptosis of gonocytes is caspase-dependent and involves almost exclusively the intrinsic pathway. Furthermore, PUMA plays a critical role in the maintenance of genomic integrity of spermatogonial stem cell precursors.展开更多
Colorectal cancer(CRC) is one of the most common human cancers and the cause of about 700000 deaths per year worldwide. Deregulation of the WNT/β-catenin pathway is a key event in CRC initiation. This pathway interac...Colorectal cancer(CRC) is one of the most common human cancers and the cause of about 700000 deaths per year worldwide. Deregulation of the WNT/β-catenin pathway is a key event in CRC initiation. This pathway interacts with other nuclear signaling pathways, including members of the nuclear receptor superfamily and their transcription coregulators. In this review, we provide an overview of the literature dealing with the main coactivators(NCo A-1 to 3, NCo A-6, PGC1-α, p300, CREBBP and MED1) and corepressors(N-Co R1 and 2, NRIP1 and MTA1) of nuclear receptors and summarize their links with the WNT/β-catenin signaling cascade, their expression in CRC and their role in intestinal physiopathology.展开更多
Diethylstilbestrol （DES） has a direct cellular mechanism inhibition on prostate cancer. Its action is independent from the oestrogen receptors and is preserved after a first-line hormonal therapy. We aimed to identi...Diethylstilbestrol （DES） has a direct cellular mechanism inhibition on prostate cancer. Its action is independent from the oestrogen receptors and is preserved after a first-line hormonal therapy. We aimed to identify proteins involved in the direct cellular inhibition effects of DES on prostate cancer. We used a clonogenic assay to establish the median lethal concentration of DES on 22RV1 cells. 22RV1 cells were exposed to standard and DES-enriched medium. After extraction, protein expression levels were obtained by two-dimensional differential in-gel electrophoresis （2D-DIGE） and isotope labelling tags for relative and absolute quantification （iTRAQ）. Proteins of interest were analysed by quantitative RT-PCR and western blotting. The differentially regulated proteins （P〈0.01） were interrogated against a global molecular network based on the ingenuity knowledge base. The 2D-DIGE analyses revealed DES-induced expression changes for 14 proteins （〉 1.3 fold; P〈0.05）. The iTRAQ analyses allowed the identification of 895 proteins. Among these proteins, 65 had a modified expression due to DES exposure （i.e., 23 overexpressed and 42 underexpressed）. Most of these proteins were implicated in apoptosis and redox processes and had a predicted mitochondrial expression. Additionally, ingenuity pathway analysis placed the OAT and HSBP1 genes at the centre of a highly significant network. RT-PCR confirmed the overexpression of OAT （P=0.006） and HSPB1 （P=0.046）.展开更多
While the incidence of gastric cancer(GC)in general has decreased worldwide in recent decades,the incidence of diffuse cancer historically comprising poorly cohesive cells-GC(PCC-GC)and including signet ring cell canc...While the incidence of gastric cancer(GC)in general has decreased worldwide in recent decades,the incidence of diffuse cancer historically comprising poorly cohesive cells-GC(PCC-GC)and including signet ring cell cancer is rising.Literature concerning PCC-GC is scarce and unclear,mostly due to a large variety of historically used definitions and classifications.Compared to other histological subtypes of GC,PCC-GC is nevertheless characterized by a distinct set of epidemiological,histological and clinical features which require a specific diagnostic and therapeutic approach.The aim of this review was to provide an update on the definition,classification and therapeutic strategies of PCC-GC.We focus on the updated histological definition of PCC-GC,along with its implications on future treatment strategies and study design.Also,specific considerations in the diagnostic management are discussed.Finally,the impact of some recent developments in the therapeutic management of GC in general such as the recently validated taxane-based regimens(5-Fluorouracil,leucovorin,oxaliplatin and docetaxel),the use of hyperthermic intraperitoneal chemotherapy as well as pressurized intraperitoneal aerosol chemotherapy and targeted therapy have been reviewed in depth for their relative importance for PCC-GC in particular.展开更多
Estrogen receptors and E2F transcription factors are the key players of two nuclear signaling pathways which exert a major role in oncogenesis, particularly in the mammary gland. Different levels of dialogue between t...Estrogen receptors and E2F transcription factors are the key players of two nuclear signaling pathways which exert a major role in oncogenesis, particularly in the mammary gland. Different levels of dialogue between these two pathways have been deciphered and deregulation of the E2F pathway has been shown to impact the response of breast cancer cells to endocrine therapies. The present review focuses on the transcriptional coregulator RIP140/NRIP1 which is involved in several regulatory feed-back loops and inhibitory cross-talks between different nuclear signaling pathways. RIP140 regulates the transactivation potential of estrogen receptors and E2Fs and is also a direct transcriptional target of these transcription factors. Published data highlight the complex regulation of RIP140 expression at the transcriptional level and its potential role in transcription cross-talks. Indeed, a subtle regulation of RIP140 expression levels has important consequences on other transcription networks targeted by this coregulator. Another level of regulation implies titration mechanisms by which activation of a pathway leads to sequestration of the RIP140 protein and thus impinges other gene regulatory circuitries. Altogether, RIP140 occupies a place of choice in the dialogue between nuclear receptors and E2Fs, which could be highly relevant in various human pathologies such as cancer or metabolic diseases.展开更多
Viral protein U （Vpu） is an accessory protein associated with two main functions important in human immu-nodeficiency virus type 1 （HIV-1） replication and dis-semination; these are down-regulation of CD4 receptor ...Viral protein U （Vpu） is an accessory protein associated with two main functions important in human immu-nodeficiency virus type 1 （HIV-1） replication and dis-semination; these are down-regulation of CD4 receptor through mediating its proteasomal degradation and en-hancement of virion release by antagonizing tetherin/BST2. It is also well established that Vpu is one of the most highly variable proteins in the HIV-1 proteome. However it is still unclear what drives Vpu sequence variability, whether Vpu acquires polymorphisms as a means of immune escape, functional advantage, or otherwise. It is assumed that the host-pathogen inter-action is a cause of polymorphic phenotype of Vpu and that the resulting functional heterogeneity of Vpu may have critical significance in vivo . In order to compre-hensively understand Vpu variability, it is important to integrate at the population level the genetic association approaches to identify specifc amino acid residues and the immune escape kinetics which may impose Vpu functional constraints in vivo . This review will focus on HIV-1 accessory protein Vpu in the context of its sequence variability at population level and also bring forward evidence on the role of the host immune re-sponses in driving Vpu sequence variability; we will also highlight the recent findings that illustrate Vpu func-tional implication in HIV-1 pathogenesis.展开更多
Objective: To investigate if an exaggerated peak exercise systolic blood pressure (peak ESBP) is associated with alteration of cardiometabolic risk factors and predict future resting hypertension in middle aged women....Objective: To investigate if an exaggerated peak exercise systolic blood pressure (peak ESBP) is associated with alteration of cardiometabolic risk factors and predict future resting hypertension in middle aged women. Methods: Data analysis was performed in 95 healthy normotensive premeno-pausal women at baseline and 84 after 5-year follow-up (age, 49.9 ± 1.9 years;BMI, 23.3 ± 2.2 kg/m2;resting BP, 117/73 ± 11.8/7.6 mmHg). Blood pressure was measured at rest and during a progressive exercise test on treadmill. Women were divided into two groups according to their peak ESBP <190 mmHg vs. ≥190 mmHg. Other outcome measures were: cardiorespiratory fitness (VO2 peak), body composition, body fat distribution and fasting plasma lipids, glucose and insulin levels. Results: 15% and 27% of women presented an exaggerated peak ESBP response (≥190 mmHg) at baseline and year 5 respectively. Linear mixed model repeated measures analysis revealed higher values of fasting glucose, resting systolic and diastolic BP in women with an exaggerated peak ESBP (≥190 mmHg) compared to women with a peak ESBP (<190 mmHg). No significant difference was observed between the two groups for VO2 peak, body composition and body fat distribution indices and other cardiometabolic risk factors. Finally, baseline peak ESBP was not a significant risk factor for future resting hypertension (OR: 2.96, 95%CI [0.48 - 18.12];P = 0.24). Conclusion: Our results, despite being non significant, are of great interest because in healthy and active premenopausal women, exaggerated peak ESBP is not predictive of future hypertension after 5-year follow-up throughout menopause transition.展开更多
In the present review, we first summarize the main benefits, limitations and pitfalls of conventional in vivo approaches to assessing male reproductive structures and functions in rodents in cases of endocrine active ...In the present review, we first summarize the main benefits, limitations and pitfalls of conventional in vivo approaches to assessing male reproductive structures and functions in rodents in cases of endocrine active substance （EAS） exposure from the postulate that they may provide data that can be extrapolated to humans. Then, we briefly present some integrated approaches in rodents we have recently developed at the organism level. We particularly focus on the possible effects and modes of action （MOA） of these substances at low doses and in mixtures, real-life conditions and at the organ level, deciphering the precise effects and MOA on the fetal testis. It can be considered that the in vivo experimental EAS exposure of rodents remains the first choice for studies and is a necessary tool （together with the epidemiological approach） for understanding the reproductive effects and MOA of EASs, provided the pitfalls and limitations of the rodent models are known and considered. We also provide some evidence that classical rodent models may be refined for studying the multiple consequences of EAS exposure, not only on the reproductive axis but also on various hormonally regulated organs and tissues, among which several are implicated in the complex process of mammalian reproduction. Such models constitute an interesting way of approaching human exposure conditions. Finally, we show that organotypic culture models are powerful complementary tools, especially when focusing on the MOA. All these approaches have contributed in a combinatorial manner to a better understanding of the impact of EAS exposure on human reproduction.展开更多
Objective: To determine the effects of 8 weeks of therapy with amlodipine, ramipril or telmisartan on the autonomic system over 24 h in hypertensives. Methods: After a placebo run-in, 57 patients were included in a pr...Objective: To determine the effects of 8 weeks of therapy with amlodipine, ramipril or telmisartan on the autonomic system over 24 h in hypertensives. Methods: After a placebo run-in, 57 patients were included in a prospective randomized open-label design protocol for therapy with amlodipine(5 mg for 4 weeks followed by 10 mg for 4 weeks, n=22), or ramipril(2.5 mg for 1 week, 5.0 mg for 3 weeks and 10 mg for 4 weeks, n=17) or telmisartan(80 mg for 8 weeks, n=18). Autonomic functions were assessed by norepinephrine(NE) and epinephrine(E), as well as by the spectral analysis of heart rate variability(HRV). Results: The 24-h ambulatory blood pressure, plasma NE and HRV demonstrated the characteristic day-night circadian rhythm in hypertensives. Higher values for SBP and DBP and for NE levels, as well as for spectral analysis components-low frequency band(LF) and low frequency/high frequency(LF/HF) ratio-were found during the day, whereas the HF was higher during the night. In patients treated with amlodipine, the HF decreased significantly during the night, while the LF and the LF/HF ratio increased during the day in association with the rise in NE. The therapy with telmisartan did increase the HF during the night and the day, while ramipril did not influence all HRV components during the night but significantly increased the HF, and decreased the LF/HF ratio during the day. No changes were observed in plasma NE with telmisartan or ramipril, but a 50%increase in NE levels throughout the 24-h period was found in amlodipine-treated patients. Conclusion: These data suggest a sympathetic activation during the day and a decrease in parasympathetic activity during the night after therapy with amlodipine, correlated with increases in plasma NE. In contrast, the therapy with telmisartan significantly increased parasympathetic activity without changes in NE during the night and day. The therapy with ramipril increased the parasympathetic activity only during the day.展开更多
Background:Rods and cones are critical for light detection.Although there has been considerable work done in elucidating the molecular mechanisms involved in rod development,not much is known about how the cone cell f...Background:Rods and cones are critical for light detection.Although there has been considerable work done in elucidating the molecular mechanisms involved in rod development,not much is known about how the cone cell fate decision is made by the multipotent retinal progenitor cells during development.Analysis of the promoter regions of Nrl and trβ2,rod and cone differentiation factors respectively,revealed DNA binding motifs of two POU-domain containing transcription factors,Pou2f1 and Pou2f2.Preliminary experiments showed that Pou2f1/2 are expressed during the peak of cone genesis in the embryonic retina.Therefore,we hypothesize that Pou2f1/2 specify cone cell fate in the developing retina.Methods:We used immunofluorescence and in situ hybridization to establish the spatiotemporal expression of Pou2f1/2 during retinogenesis.We performed in vivo electroporation in post-natal mice to misexpress Pou2f1/2 and used antibodies specific to proteins expressed in cones such as Rxrγand S-opsin to count cones.Using ex vivo electroporation of embryonic retinal explants,we knocked out Pou2f1 and Pou2f2 using CRISPR/Cas9 gRNAs at the peak of cone production window.Finally,we transfected post-natal retinal explants with a combination of regulatory elements of Nrl or thrb with control backbone vector,Pou2f1 or Pou2f2 using electroporation.Results:We found that Pou2f1/2 are expressed in retinal progenitor cells in the developing retina and subsequently in the differentiated cones.Pou2f1/2 misexpression outside the cone genesis window led to an increase in cones at the expense of rods.Pou2f1/2 indel knockouts generated by CRISPR/Cas9 gRNAs led to a decrease in cones and a converse increase in rods.Finally,we found that Pou2f1/2 activate the cis-regulatory module(CRM)of the thrb gene and repress the activity of the CRM of Nrl.Conclusions:These results uncover novel players that establish the complex gene regulatory network for cone photoreceptor fate specification in the retinal progenitor cells.We anticipate that this work should help us devise improved replacement therapies in the future utilizing stem cells for retinal degenerative diseases such as aged-related macular degeneration(AMD)and Stargardt’s disease.展开更多
The Vision Health Research Network(VHRN)was established in 1995 to increase research capacity,productivity,and visibility of vision science carried out in Quebec,Canada.The VHRN is funded by the Fonds de la recherche ...The Vision Health Research Network(VHRN)was established in 1995 to increase research capacity,productivity,and visibility of vision science carried out in Quebec,Canada.The VHRN is funded by the Fonds de la recherche du Québec en santé(FRQS),a Quebec government agency,and the Foundation Antoine-Turmel,a private charity organization.In the past decades,the VHRN has fostered productive collaborations and helped improve access to specialized infrastructure and tissue banks,thereby enhancing competitivity of Quebec vision research on the international stage.The VHRN also supports vision research directly by providing seed funding for national and international collaborative projects.The VHRN is also dedicated to support the training of the next generation of vision researchers by funding scholarships and awards for the best trainees,which not only help them carry out their projects but also make them more competitive to apply for funding at national and international granting agencies.The VHRN strongly believe that these research building initiatives will help us achieve our ultimate goal,which is to improve care and develop treatments for patients living with various vision impairments.展开更多
Background:The loss of cell polarity plays a key part in retinal dystrophies such as retinitis pigmentosa(RP)and Leber congenital amaurosis(LCA),resulting in photoreceptor(PR)degeneration and vision loss.Despite not k...Background:The loss of cell polarity plays a key part in retinal dystrophies such as retinitis pigmentosa(RP)and Leber congenital amaurosis(LCA),resulting in photoreceptor(PR)degeneration and vision loss.Despite not knowing the direct genotype-to-phenotype correlation,many disease-causing mutations in the polarity determinant Crumbs(Crb1),have been identified.Indeed,the loss of Crb1 in mice was shown to cause PR death,due to the loss of adhesions between PR and Müller cells at the apical surface of the retina.Unfortunately,although the role of Crb1 in neuron polarity and survival is well established,little is known about how its intracellular trafficking is regulated.With future treatments for retinal degenerative diseases in mind,the goal of this project is to understand the mechanism by which Crb1 is regulated and how it maintains retinal integrity.Previous work in our laboratory showed that Numb,an endocytic adaptor protein,is an important regulator of protein trafficking in retinal cells.We therefore hypothesized that Numb might function as regulator of Crb1 in Müller glia.Methods:To study Numb function in Müller cells,we generated a conditional knockout(cKO)mouse line to inactivate Numb specifically in Müller cells by crossing a Glast-CreERT2 mouse line with a Numb-floxed line.At 30 days,mice were administered tamoxifen to trigger inactivation of Numb and retinas were then collected at time points varying from 2 weeks to 17 months for analysis.Firstly,we studied the retinal morphology and outer limiting membrane integrity by histology and immunohistochemistry.Using electron microscopy(EM),adhesions between Müller glia and photoreceptors were analysed and retinal function was assayed in live mice by electroretinography(ERG).To detect protein expression levels,protein extracts were prepared from cKO and control retinas for immunoblotting.To test for the presence of a biochemical interaction,Hek-293 cells were transfected with Numb and Crb1 vectors,and protein extracts were processed for co-immunoprecipitation.Results:When Numb was deleted in Müller cells,we observed a similar retinal phenotype than what was reported in the Crb1 KO.In 3-month-old animals,we found a disruption of the outer limiting membrane and an ingression of photoreceptor cells in the inner layers of the retina.In older animals(17 months),we observed a clear thinning of the photoreceptor layer and reduced ERG responses.Immunoblotting of retinal lysates revealed that Numb cKO retinas had significantly lower expression of Crb1,suggesting that Numb function in Müller cells is critical to maintain Crb1 levels and thereby outer limiting membrane integrity.Interestingly,we found that Numb can interact with Crb1 both in vitro and in vivo,suggesting that Numb might function as an adaptor protein regulating Crb1 trafficking.Conclusions:Based on these results,we suggest that,in the absence of Numb,Crb1 cannot be trafficked to the apical membrane of Müller cells,and is instead degraded.This ruptures the adhesion between Müller and photoreceptor cells,leading to photoreceptor degeneration.We anticipate that understanding the mechanisms by which Crb1 maintains the structural integrity of the retina will lead to new possibilities for target-based therapies against retinal dystrophies.展开更多
Background:We previously showed that embolization of portal inflow and hepatic vein(HV)outflow(liver venous deprivation,LVD)promotes future liver remnant(FLR)volume(FLR-V)and function(FLR-F)gain.Here,we compared FLR-V...Background:We previously showed that embolization of portal inflow and hepatic vein(HV)outflow(liver venous deprivation,LVD)promotes future liver remnant(FLR)volume(FLR-V)and function(FLR-F)gain.Here,we compared FLR-V and FLR-F changes after portal vein embolization(PVE)and LVD.Methods:This study included all patients referred for liver preparation before major hepatectomy over 26 months.Exclusion criteria were:unavailable baseline/follow-up imaging,cirrhosis,Klatskin tumor,two-stage hepatectomy.99mTc-mebrofenin SPECT-CT was performed at baseline and at day 7,14 and 21 after PVE or LVD.FLR-V and FLR-F variations were compared using multivariate generalized linear mixed models(joint modelling)with/without missing data imputation.Results:Baseline FLR-F was lower in the LVD(n=29)than PVE group(n=22)(P<0.001).Technical success was 100%in both groups without any major complication.Changes in FLR-V at day 14 and 21(+14.2%vs.+50%,P=0.002;and+18.6%vs.+52.6%,P=0.001),and in FLR-F at day 7,14 and 21(+23.1%vs.+54.3%,P=0.02;+17.6%vs.+56.1%,P=0.006;and+29.8%vs.+63.9%,P<0.001)differed between PVE and LVD group.LVD(P=0.009),age(P=0.027)and baseline FLR-V(P=0.001)independently predicted FLR-V variations,whereas only LVD(P=0.01)predicted FLR-F changes.After missing data handling,LVD remained an independent predictor of FLR-V and FLR-F variations.Conclusions:LVD is safe and provides greater FLR-V and FLR-F increase than PVE.These results are now evaluated in the HYPERLIV-01 multicenter randomized trial.展开更多
If the current rate of infection are to be better managed,and future waves of infection kept at bay,it is absolutely necessary that the conditions and mechanisms of exposure to Severe Acute Respiratory Syndrome-Corona...If the current rate of infection are to be better managed,and future waves of infection kept at bay,it is absolutely necessary that the conditions and mechanisms of exposure to Severe Acute Respiratory Syndrome-Coronavirus 2(SARS-CoV-2)be better understood,as well as the downstream severe or lethal clinical complications.While the identification of notable comorbidities has now helped to define broad risk groups,the idiosyncratic responses of individual patients can generate unexpected clinical deterioration that is difficult to predict from initial clinical features.Thus,physicians caring for patients with COVID-19 face clinical dilemmas on a daily basis.The ability to decipher individual predispositions to SARS-CoV-2 infection or severe illness,in light of variations in host immunological and inflammatory responses,in particular as a result of genetic variations,would be of great benefit in infection management.To this end,this work associates the description of COVID-19 clinical complications,comorbidities,sequelae,and environmental and genetic factors.We also give examples of underlying genomic susceptibility to COVID-19,especially with regard to the newly reported link between the disease and the unbalanced formation of neutrophil extracellular traps.As a consequence,we propose that the host/genetic factors associated with COVID-19 call for precision medicine in its treatment.This is to our knowledge the first article describing elements towards precision medicine for patients with COVID-19.展开更多
One of the hallmarks of live cells is the asymmetric distribution of lipids across their plasma membrane.Changes in this asymmetry due to lipid"scrambling"result in phosphatidylserine exposure at the cell su...One of the hallmarks of live cells is the asymmetric distribution of lipids across their plasma membrane.Changes in this asymmetry due to lipid"scrambling"result in phosphatidylserine exposure at the cell surface that is detected by annexin V staining.This alteration is observed during cell death processes such as apoptosis,and during physiological responses such as platelet degranulation and membrane repair.Previous studies have shown that activation of NK cells is accompanied by exposure of phosphatidylserine at the cell surface.While this response was thought to be indicative of ongoing NK cell death,it may also reflect the regulation of NK cell activation in the absence of cell death.Herein,we found that NK cell activation was accompanied by rapid phosphatidylserine exposure to an extent proportional to the degree of NK cell activation.Through enforced expression of a lipid scramblase,we provided evidence that activation-induced lipid scrambling in NK cells is reversible and does not lead to cell death.In contrast,lipid scrambling attenuates NKcell activation.This response was accompanied by reduced cell surface expression of activating receptors such as 2B4,and by loss of binding of Src family protein tyrosine kinases Fyn and Lck to the inner leaflet of the plasma membrane.Hence,lipid scrambling during NK cell activation is,at least in part,a physiological response that reduces the NK cell activation level.This effect is due to the ability of lipid scrambling to alter the distribution of membrane-associated receptors and kinases required for NK cell activation.展开更多
文摘Neonatal gonocytes are precursors of spermatogonial stem cells. Preserving their integrity by elimination of damaged germ cells may be crucial to avoid the transmission of genetic alterations to progeny. Using 7-irradiation, we investigated by immunohistochemistry, flow cytometry and real-time PCR components of the death machinery in neonatal gonocytes. Their death was correlated with caspase 3 activation but not with AIF translocation into the nu- cleus. The in vivo contribution of both the extrinsic and the intrinsic pathways was then investigated. We focused on the roles of TRAIL/Death Receptor 5 （DR5） and PUMA. Our results were validated using knockout mice. Whereas DR5 expression was upregulated at the cell surface after radiation, caspase 8 was not activated. However, we detected caspase 9 cleavage associated with cytochrome c release. In mice deficient for PUMA, radiation-induced gonocyte apoptosis was reduced, whereas invalidation of TRAIL had no effect. Overall, our results show that genotoxic stressinduced apoptosis of gonocytes is caspase-dependent and involves almost exclusively the intrinsic pathway. Furthermore, PUMA plays a critical role in the maintenance of genomic integrity of spermatogonial stem cell precursors.
基金Supported by SIRIC and the PHC-UTIQUE program,No.16G 0805PHC-UTIQUE program,No.16G 0805+1 种基金Tunisian government(Bourse d’alternance)INSERM,Universitéde Montpellier,INCa,SIRIC Montpellier,the Institut régional du Cancer de Montpellier
文摘Colorectal cancer(CRC) is one of the most common human cancers and the cause of about 700000 deaths per year worldwide. Deregulation of the WNT/β-catenin pathway is a key event in CRC initiation. This pathway interacts with other nuclear signaling pathways, including members of the nuclear receptor superfamily and their transcription coregulators. In this review, we provide an overview of the literature dealing with the main coactivators(NCo A-1 to 3, NCo A-6, PGC1-α, p300, CREBBP and MED1) and corepressors(N-Co R1 and 2, NRIP1 and MTA1) of nuclear receptors and summarize their links with the WNT/β-catenin signaling cascade, their expression in CRC and their role in intestinal physiopathology.
文摘Diethylstilbestrol （DES） has a direct cellular mechanism inhibition on prostate cancer. Its action is independent from the oestrogen receptors and is preserved after a first-line hormonal therapy. We aimed to identify proteins involved in the direct cellular inhibition effects of DES on prostate cancer. We used a clonogenic assay to establish the median lethal concentration of DES on 22RV1 cells. 22RV1 cells were exposed to standard and DES-enriched medium. After extraction, protein expression levels were obtained by two-dimensional differential in-gel electrophoresis （2D-DIGE） and isotope labelling tags for relative and absolute quantification （iTRAQ）. Proteins of interest were analysed by quantitative RT-PCR and western blotting. The differentially regulated proteins （P〈0.01） were interrogated against a global molecular network based on the ingenuity knowledge base. The 2D-DIGE analyses revealed DES-induced expression changes for 14 proteins （〉 1.3 fold; P〈0.05）. The iTRAQ analyses allowed the identification of 895 proteins. Among these proteins, 65 had a modified expression due to DES exposure （i.e., 23 overexpressed and 42 underexpressed）. Most of these proteins were implicated in apoptosis and redox processes and had a predicted mitochondrial expression. Additionally, ingenuity pathway analysis placed the OAT and HSBP1 genes at the centre of a highly significant network. RT-PCR confirmed the overexpression of OAT （P=0.006） and HSPB1 （P=0.046）.
文摘While the incidence of gastric cancer(GC)in general has decreased worldwide in recent decades,the incidence of diffuse cancer historically comprising poorly cohesive cells-GC(PCC-GC)and including signet ring cell cancer is rising.Literature concerning PCC-GC is scarce and unclear,mostly due to a large variety of historically used definitions and classifications.Compared to other histological subtypes of GC,PCC-GC is nevertheless characterized by a distinct set of epidemiological,histological and clinical features which require a specific diagnostic and therapeutic approach.The aim of this review was to provide an update on the definition,classification and therapeutic strategies of PCC-GC.We focus on the updated histological definition of PCC-GC,along with its implications on future treatment strategies and study design.Also,specific considerations in the diagnostic management are discussed.Finally,the impact of some recent developments in the therapeutic management of GC in general such as the recently validated taxane-based regimens(5-Fluorouracil,leucovorin,oxaliplatin and docetaxel),the use of hyperthermic intraperitoneal chemotherapy as well as pressurized intraperitoneal aerosol chemotherapy and targeted therapy have been reviewed in depth for their relative importance for PCC-GC in particular.
文摘Estrogen receptors and E2F transcription factors are the key players of two nuclear signaling pathways which exert a major role in oncogenesis, particularly in the mammary gland. Different levels of dialogue between these two pathways have been deciphered and deregulation of the E2F pathway has been shown to impact the response of breast cancer cells to endocrine therapies. The present review focuses on the transcriptional coregulator RIP140/NRIP1 which is involved in several regulatory feed-back loops and inhibitory cross-talks between different nuclear signaling pathways. RIP140 regulates the transactivation potential of estrogen receptors and E2Fs and is also a direct transcriptional target of these transcription factors. Published data highlight the complex regulation of RIP140 expression at the transcriptional level and its potential role in transcription cross-talks. Indeed, a subtle regulation of RIP140 expression levels has important consequences on other transcription networks targeted by this coregulator. Another level of regulation implies titration mechanisms by which activation of a pathway leads to sequestration of the RIP140 protein and thus impinges other gene regulatory circuitries. Altogether, RIP140 occupies a place of choice in the dialogue between nuclear receptors and E2Fs, which could be highly relevant in various human pathologies such as cancer or metabolic diseases.
基金Supported by A Grant-in-Aid for Scientific Research from the Ministry of Education,Science,Sports,and Culture(MEXT)of JapanA Grant-in-Aid for AIDS Research from the Ministry of Health,Labor,and Welfare of Japan+1 种基金The Scholarship for the International Priority Graduate Programs,to Hasan Z and Kamori DAdvanced Graduate Courses for International Students(Doctoral Course),MEXT,Japan,to Hasan Z and Kamori D
文摘Viral protein U （Vpu） is an accessory protein associated with two main functions important in human immu-nodeficiency virus type 1 （HIV-1） replication and dis-semination; these are down-regulation of CD4 receptor through mediating its proteasomal degradation and en-hancement of virion release by antagonizing tetherin/BST2. It is also well established that Vpu is one of the most highly variable proteins in the HIV-1 proteome. However it is still unclear what drives Vpu sequence variability, whether Vpu acquires polymorphisms as a means of immune escape, functional advantage, or otherwise. It is assumed that the host-pathogen inter-action is a cause of polymorphic phenotype of Vpu and that the resulting functional heterogeneity of Vpu may have critical significance in vivo . In order to compre-hensively understand Vpu variability, it is important to integrate at the population level the genetic association approaches to identify specifc amino acid residues and the immune escape kinetics which may impose Vpu functional constraints in vivo . This review will focus on HIV-1 accessory protein Vpu in the context of its sequence variability at population level and also bring forward evidence on the role of the host immune re-sponses in driving Vpu sequence variability; we will also highlight the recent findings that illustrate Vpu func-tional implication in HIV-1 pathogenesis.
文摘Objective: To investigate if an exaggerated peak exercise systolic blood pressure (peak ESBP) is associated with alteration of cardiometabolic risk factors and predict future resting hypertension in middle aged women. Methods: Data analysis was performed in 95 healthy normotensive premeno-pausal women at baseline and 84 after 5-year follow-up (age, 49.9 ± 1.9 years;BMI, 23.3 ± 2.2 kg/m2;resting BP, 117/73 ± 11.8/7.6 mmHg). Blood pressure was measured at rest and during a progressive exercise test on treadmill. Women were divided into two groups according to their peak ESBP <190 mmHg vs. ≥190 mmHg. Other outcome measures were: cardiorespiratory fitness (VO2 peak), body composition, body fat distribution and fasting plasma lipids, glucose and insulin levels. Results: 15% and 27% of women presented an exaggerated peak ESBP response (≥190 mmHg) at baseline and year 5 respectively. Linear mixed model repeated measures analysis revealed higher values of fasting glucose, resting systolic and diastolic BP in women with an exaggerated peak ESBP (≥190 mmHg) compared to women with a peak ESBP (<190 mmHg). No significant difference was observed between the two groups for VO2 peak, body composition and body fat distribution indices and other cardiometabolic risk factors. Finally, baseline peak ESBP was not a significant risk factor for future resting hypertension (OR: 2.96, 95%CI [0.48 - 18.12];P = 0.24). Conclusion: Our results, despite being non significant, are of great interest because in healthy and active premenopausal women, exaggerated peak ESBP is not predictive of future hypertension after 5-year follow-up throughout menopause transition.
文摘In the present review, we first summarize the main benefits, limitations and pitfalls of conventional in vivo approaches to assessing male reproductive structures and functions in rodents in cases of endocrine active substance （EAS） exposure from the postulate that they may provide data that can be extrapolated to humans. Then, we briefly present some integrated approaches in rodents we have recently developed at the organism level. We particularly focus on the possible effects and modes of action （MOA） of these substances at low doses and in mixtures, real-life conditions and at the organ level, deciphering the precise effects and MOA on the fetal testis. It can be considered that the in vivo experimental EAS exposure of rodents remains the first choice for studies and is a necessary tool （together with the epidemiological approach） for understanding the reproductive effects and MOA of EASs, provided the pitfalls and limitations of the rodent models are known and considered. We also provide some evidence that classical rodent models may be refined for studying the multiple consequences of EAS exposure, not only on the reproductive axis but also on various hormonally regulated organs and tissues, among which several are implicated in the complex process of mammalian reproduction. Such models constitute an interesting way of approaching human exposure conditions. Finally, we show that organotypic culture models are powerful complementary tools, especially when focusing on the MOA. All these approaches have contributed in a combinatorial manner to a better understanding of the impact of EAS exposure on human reproduction.
文摘Objective: To determine the effects of 8 weeks of therapy with amlodipine, ramipril or telmisartan on the autonomic system over 24 h in hypertensives. Methods: After a placebo run-in, 57 patients were included in a prospective randomized open-label design protocol for therapy with amlodipine(5 mg for 4 weeks followed by 10 mg for 4 weeks, n=22), or ramipril(2.5 mg for 1 week, 5.0 mg for 3 weeks and 10 mg for 4 weeks, n=17) or telmisartan(80 mg for 8 weeks, n=18). Autonomic functions were assessed by norepinephrine(NE) and epinephrine(E), as well as by the spectral analysis of heart rate variability(HRV). Results: The 24-h ambulatory blood pressure, plasma NE and HRV demonstrated the characteristic day-night circadian rhythm in hypertensives. Higher values for SBP and DBP and for NE levels, as well as for spectral analysis components-low frequency band(LF) and low frequency/high frequency(LF/HF) ratio-were found during the day, whereas the HF was higher during the night. In patients treated with amlodipine, the HF decreased significantly during the night, while the LF and the LF/HF ratio increased during the day in association with the rise in NE. The therapy with telmisartan did increase the HF during the night and the day, while ramipril did not influence all HRV components during the night but significantly increased the HF, and decreased the LF/HF ratio during the day. No changes were observed in plasma NE with telmisartan or ramipril, but a 50%increase in NE levels throughout the 24-h period was found in amlodipine-treated patients. Conclusion: These data suggest a sympathetic activation during the day and a decrease in parasympathetic activity during the night after therapy with amlodipine, correlated with increases in plasma NE. In contrast, the therapy with telmisartan significantly increased parasympathetic activity without changes in NE during the night and day. The therapy with ramipril increased the parasympathetic activity only during the day.
文摘Background:Rods and cones are critical for light detection.Although there has been considerable work done in elucidating the molecular mechanisms involved in rod development,not much is known about how the cone cell fate decision is made by the multipotent retinal progenitor cells during development.Analysis of the promoter regions of Nrl and trβ2,rod and cone differentiation factors respectively,revealed DNA binding motifs of two POU-domain containing transcription factors,Pou2f1 and Pou2f2.Preliminary experiments showed that Pou2f1/2 are expressed during the peak of cone genesis in the embryonic retina.Therefore,we hypothesize that Pou2f1/2 specify cone cell fate in the developing retina.Methods:We used immunofluorescence and in situ hybridization to establish the spatiotemporal expression of Pou2f1/2 during retinogenesis.We performed in vivo electroporation in post-natal mice to misexpress Pou2f1/2 and used antibodies specific to proteins expressed in cones such as Rxrγand S-opsin to count cones.Using ex vivo electroporation of embryonic retinal explants,we knocked out Pou2f1 and Pou2f2 using CRISPR/Cas9 gRNAs at the peak of cone production window.Finally,we transfected post-natal retinal explants with a combination of regulatory elements of Nrl or thrb with control backbone vector,Pou2f1 or Pou2f2 using electroporation.Results:We found that Pou2f1/2 are expressed in retinal progenitor cells in the developing retina and subsequently in the differentiated cones.Pou2f1/2 misexpression outside the cone genesis window led to an increase in cones at the expense of rods.Pou2f1/2 indel knockouts generated by CRISPR/Cas9 gRNAs led to a decrease in cones and a converse increase in rods.Finally,we found that Pou2f1/2 activate the cis-regulatory module(CRM)of the thrb gene and repress the activity of the CRM of Nrl.Conclusions:These results uncover novel players that establish the complex gene regulatory network for cone photoreceptor fate specification in the retinal progenitor cells.We anticipate that this work should help us devise improved replacement therapies in the future utilizing stem cells for retinal degenerative diseases such as aged-related macular degeneration(AMD)and Stargardt’s disease.
文摘The Vision Health Research Network(VHRN)was established in 1995 to increase research capacity,productivity,and visibility of vision science carried out in Quebec,Canada.The VHRN is funded by the Fonds de la recherche du Québec en santé(FRQS),a Quebec government agency,and the Foundation Antoine-Turmel,a private charity organization.In the past decades,the VHRN has fostered productive collaborations and helped improve access to specialized infrastructure and tissue banks,thereby enhancing competitivity of Quebec vision research on the international stage.The VHRN also supports vision research directly by providing seed funding for national and international collaborative projects.The VHRN is also dedicated to support the training of the next generation of vision researchers by funding scholarships and awards for the best trainees,which not only help them carry out their projects but also make them more competitive to apply for funding at national and international granting agencies.The VHRN strongly believe that these research building initiatives will help us achieve our ultimate goal,which is to improve care and develop treatments for patients living with various vision impairments.
文摘Background:The loss of cell polarity plays a key part in retinal dystrophies such as retinitis pigmentosa(RP)and Leber congenital amaurosis(LCA),resulting in photoreceptor(PR)degeneration and vision loss.Despite not knowing the direct genotype-to-phenotype correlation,many disease-causing mutations in the polarity determinant Crumbs(Crb1),have been identified.Indeed,the loss of Crb1 in mice was shown to cause PR death,due to the loss of adhesions between PR and Müller cells at the apical surface of the retina.Unfortunately,although the role of Crb1 in neuron polarity and survival is well established,little is known about how its intracellular trafficking is regulated.With future treatments for retinal degenerative diseases in mind,the goal of this project is to understand the mechanism by which Crb1 is regulated and how it maintains retinal integrity.Previous work in our laboratory showed that Numb,an endocytic adaptor protein,is an important regulator of protein trafficking in retinal cells.We therefore hypothesized that Numb might function as regulator of Crb1 in Müller glia.Methods:To study Numb function in Müller cells,we generated a conditional knockout(cKO)mouse line to inactivate Numb specifically in Müller cells by crossing a Glast-CreERT2 mouse line with a Numb-floxed line.At 30 days,mice were administered tamoxifen to trigger inactivation of Numb and retinas were then collected at time points varying from 2 weeks to 17 months for analysis.Firstly,we studied the retinal morphology and outer limiting membrane integrity by histology and immunohistochemistry.Using electron microscopy(EM),adhesions between Müller glia and photoreceptors were analysed and retinal function was assayed in live mice by electroretinography(ERG).To detect protein expression levels,protein extracts were prepared from cKO and control retinas for immunoblotting.To test for the presence of a biochemical interaction,Hek-293 cells were transfected with Numb and Crb1 vectors,and protein extracts were processed for co-immunoprecipitation.Results:When Numb was deleted in Müller cells,we observed a similar retinal phenotype than what was reported in the Crb1 KO.In 3-month-old animals,we found a disruption of the outer limiting membrane and an ingression of photoreceptor cells in the inner layers of the retina.In older animals(17 months),we observed a clear thinning of the photoreceptor layer and reduced ERG responses.Immunoblotting of retinal lysates revealed that Numb cKO retinas had significantly lower expression of Crb1,suggesting that Numb function in Müller cells is critical to maintain Crb1 levels and thereby outer limiting membrane integrity.Interestingly,we found that Numb can interact with Crb1 both in vitro and in vivo,suggesting that Numb might function as an adaptor protein regulating Crb1 trafficking.Conclusions:Based on these results,we suggest that,in the absence of Numb,Crb1 cannot be trafficked to the apical membrane of Müller cells,and is instead degraded.This ruptures the adhesion between Müller and photoreceptor cells,leading to photoreceptor degeneration.We anticipate that understanding the mechanisms by which Crb1 maintains the structural integrity of the retina will lead to new possibilities for target-based therapies against retinal dystrophies.
文摘Background:We previously showed that embolization of portal inflow and hepatic vein(HV)outflow(liver venous deprivation,LVD)promotes future liver remnant(FLR)volume(FLR-V)and function(FLR-F)gain.Here,we compared FLR-V and FLR-F changes after portal vein embolization(PVE)and LVD.Methods:This study included all patients referred for liver preparation before major hepatectomy over 26 months.Exclusion criteria were:unavailable baseline/follow-up imaging,cirrhosis,Klatskin tumor,two-stage hepatectomy.99mTc-mebrofenin SPECT-CT was performed at baseline and at day 7,14 and 21 after PVE or LVD.FLR-V and FLR-F variations were compared using multivariate generalized linear mixed models(joint modelling)with/without missing data imputation.Results:Baseline FLR-F was lower in the LVD(n=29)than PVE group(n=22)(P<0.001).Technical success was 100%in both groups without any major complication.Changes in FLR-V at day 14 and 21(+14.2%vs.+50%,P=0.002;and+18.6%vs.+52.6%,P=0.001),and in FLR-F at day 7,14 and 21(+23.1%vs.+54.3%,P=0.02;+17.6%vs.+56.1%,P=0.006;and+29.8%vs.+63.9%,P<0.001)differed between PVE and LVD group.LVD(P=0.009),age(P=0.027)and baseline FLR-V(P=0.001)independently predicted FLR-V variations,whereas only LVD(P=0.01)predicted FLR-F changes.After missing data handling,LVD remained an independent predictor of FLR-V and FLR-F variations.Conclusions:LVD is safe and provides greater FLR-V and FLR-F increase than PVE.These results are now evaluated in the HYPERLIV-01 multicenter randomized trial.
基金The author thanks S.Dejasse,C.McCarthy,M.Ychou,and RC Gallo.A.R.Thierry is supported by INSERM.This work was funded by the SIRIC Montpellier Cancer Grant(No.INCa Inserm DGOS 12553).
文摘If the current rate of infection are to be better managed,and future waves of infection kept at bay,it is absolutely necessary that the conditions and mechanisms of exposure to Severe Acute Respiratory Syndrome-Coronavirus 2(SARS-CoV-2)be better understood,as well as the downstream severe or lethal clinical complications.While the identification of notable comorbidities has now helped to define broad risk groups,the idiosyncratic responses of individual patients can generate unexpected clinical deterioration that is difficult to predict from initial clinical features.Thus,physicians caring for patients with COVID-19 face clinical dilemmas on a daily basis.The ability to decipher individual predispositions to SARS-CoV-2 infection or severe illness,in light of variations in host immunological and inflammatory responses,in particular as a result of genetic variations,would be of great benefit in infection management.To this end,this work associates the description of COVID-19 clinical complications,comorbidities,sequelae,and environmental and genetic factors.We also give examples of underlying genomic susceptibility to COVID-19,especially with regard to the newly reported link between the disease and the unbalanced formation of neutrophil extracellular traps.As a consequence,we propose that the host/genetic factors associated with COVID-19 call for precision medicine in its treatment.This is to our knowledge the first article describing elements towards precision medicine for patients with COVID-19.
基金supported by grants from the Canadian Institutes of Health Research(CIHR)MT-14429,MOP-82906,and FDN-143338 to A.V.NSFC-31870863 from the National Natural Science Foundation of China to N.W.supported by a Postdoctoral Fellowship from Fonds de recherche du Quebec Santr(FRQS)。
文摘One of the hallmarks of live cells is the asymmetric distribution of lipids across their plasma membrane.Changes in this asymmetry due to lipid"scrambling"result in phosphatidylserine exposure at the cell surface that is detected by annexin V staining.This alteration is observed during cell death processes such as apoptosis,and during physiological responses such as platelet degranulation and membrane repair.Previous studies have shown that activation of NK cells is accompanied by exposure of phosphatidylserine at the cell surface.While this response was thought to be indicative of ongoing NK cell death,it may also reflect the regulation of NK cell activation in the absence of cell death.Herein,we found that NK cell activation was accompanied by rapid phosphatidylserine exposure to an extent proportional to the degree of NK cell activation.Through enforced expression of a lipid scramblase,we provided evidence that activation-induced lipid scrambling in NK cells is reversible and does not lead to cell death.In contrast,lipid scrambling attenuates NKcell activation.This response was accompanied by reduced cell surface expression of activating receptors such as 2B4,and by loss of binding of Src family protein tyrosine kinases Fyn and Lck to the inner leaflet of the plasma membrane.Hence,lipid scrambling during NK cell activation is,at least in part,a physiological response that reduces the NK cell activation level.This effect is due to the ability of lipid scrambling to alter the distribution of membrane-associated receptors and kinases required for NK cell activation.
