AIM: To investigate the efficacy(survival) and safety of treatments for recurrent hepatocellular carcinoma(HCC) in liver transplantation(LT) patients.METHODS: Literature search was performed on available online databa...AIM: To investigate the efficacy(survival) and safety of treatments for recurrent hepatocellular carcinoma(HCC) in liver transplantation(LT) patients.METHODS: Literature search was performed on available online databases without a time limit until January 2015. Clinical studies describing survival after HCC recurrence in LT patients were retrieved for a fulltext evaluation. A total of 61 studies were selected: 13 case reports, 41 retrospective case series, and 7 retrospective comparative studies.RESULTS: Based on all included studies, the mean HCC recurrence rate was 16% of all LTs for HCC. A total of 1021 LT patients experienced HCC recurrence. The median time from LT to HCC recurrence was 13 mo(range 2-132 mo). The majority of patients(67%) presented with HCC extra-hepatic recurrences, involving lung, bone, adrenal gland, peritoneal lymph nodes, and rarely the brain. Overall survival after HCC recurrence was 12.97 mo. Surgical resection of localized HCC recurrence and Sorafenib for controlling systemic spread of HCC recurrence were associated with the higher survival rates(42 and 18 mo, res-pectively). However, Sorafenib, especially when combined with m TOR, was frequently associated with severe side effects that required dose reduction or discontinuation CONCLUSION: Management of recurrent HCC in LT patients is challenging and associated with poor prognosis independently of the type of treatment.展开更多
There has been a growing interest over the past few years in the impact of male nutrition on fertility. Infertility has been linked to male overweight or obesity, and conventional semen parameter values seem to be alt...There has been a growing interest over the past few years in the impact of male nutrition on fertility. Infertility has been linked to male overweight or obesity, and conventional semen parameter values seem to be altered in case of high body mass index （BMI）. A few studies assessing the impact of BMI on sperm DNA integrity have been published, but they did not lead to a strong consensus. Our objective was to explore further the relationship between sperm DNA integrity and BMI, through a 3-year multicentre study. Three hundred and thirty male partners in subfertile couples were included. Using the terminal uridine nick-end labelling （TUNEL） assay, we observed an increased rate of sDerm DNA damage in obese men （odds ratio （95% confidence interval）： 2.5 （1.2-5.1））.展开更多
In recent years , a second pathway for colonic carcinogenesis , distinct from the adenomatous pathway, has been explored. This is referred to as serrated pathway and includes three types of polyp,characterised by a se...In recent years , a second pathway for colonic carcinogenesis , distinct from the adenomatous pathway, has been explored. This is referred to as serrated pathway and includes three types of polyp,characterised by a serrated appearance of the crypts:hyperplastic polyps(HP),sessile serrated adenomas(SSA)or lesions,and traditional serrated adenomas.Each lesion has its own genetic,as well as macroscopic and microscopic morphological features.Because of their flat aspect,their detection is easier with chromoendoscopy(carmin indigo or narrow-band imaging).However,as we show in this review,the distinction between SSA and HP is quite difficult.It is now recommended to resect in one piece as it is possible the serrated polyps with a control in a delay depending on the presence or not of dysplasia.These different types of lesion are described in detail in the present review in general population,in polyposis and in inflammatory bowel diseases patients.This review highlights the need to improve characterization and understanding of this way of colorectal cancerogenesis.展开更多
According to epidemiological studies,twice as many women as men are affected by irritable bowel syndrome(IBS)in western countries,suggesting a role for sex hormones in IBS pathophysiology.Despite growing evidence abou...According to epidemiological studies,twice as many women as men are affected by irritable bowel syndrome(IBS)in western countries,suggesting a role for sex hormones in IBS pathophysiology.Despite growing evidence about the implications of sex hormones in IBS symptom modulation,data on mechanisms by which they influence disease development are sparse.This review aims to determine the state of knowledge about the role of sex hormones in sensorimotor dysfunctions and to address the possible interplay of sex hormones with common risk factors associated with IBS.The scientific bibliography was searched using the following keywords:irritable bowel syndrome,sex,gender,ovarian hormone,estradiol,progesterone,testosterone,symptoms,pain,sensitivity,motility,permeability,stress,immune system,brain activity,spinal,supraspinal,imaging.Ovarian hormones variations along themenstrual cycle affect sensorimotor gastrointestinal function in both healthy and IBS populations.They can modulate pain processing by interacting with neuromodulator systems and the emotional system responsible for visceral pain perception.These hormones can also modulate the susceptibility to stress,which is a pivotal factor in IBS occurrence and symptom severity.For instance,estrogen-dependent hyper-responsiveness to stress can promote immune activation or impairments of gut barrier function.In conclusion,whereas it is important to keep in mind that ovarian hormones cannot be considered as a causal factor of IBS,they arguably modulate IBS onset and symptomatology.However,our understanding of the underlying mechanisms remains limited and studies assessing the link between IBS symptoms and ovarian hormone levels are needed to improve our knowledge of the disease evolution with regard to gender.Further studies assessing the role of male hormones are also needed to understand fully the role of sex hormones in IBS.Finally,investigation of brain-gut interactions is critical to decipher how stress,ovarian hormones,and female brain processing of pain can translate 展开更多
TREM-1(triggering receptor expressed on myeloid cells-1)is a transmembrane receptor expressed by innate immune cells,including endothelial cells and platelets.TREM-1 is a crucial mediator of septic shock that acts by ...TREM-1(triggering receptor expressed on myeloid cells-1)is a transmembrane receptor expressed by innate immune cells,including endothelial cells and platelets.TREM-1 is a crucial mediator of septic shock that acts by synergizing with Toll-like receptors(TLRs)to amplify the inflammatory responses to pathogens,thus promoting sepsis-induced immune dysregulation and organ dysfunction[1,2,3].展开更多
Hepatocellular carcinoma(HCC)is the sixth most common cancer worldwide,with an increasing diffusion in Europe and the United States.The management of such a cancer is continuously progressing and the objective of this...Hepatocellular carcinoma(HCC)is the sixth most common cancer worldwide,with an increasing diffusion in Europe and the United States.The management of such a cancer is continuously progressing and the objective of this paper is to evaluate innovation in the surgical treatment of HCC.In this review,we will analyze the modern concept of preoperative management,the role of laparoscopic and robotic surgery,the intraoperative use of three dimensional models and augmented reality,as well as the potential application of fluorescence.展开更多
Recently the Chinese Ministry of Health declared that 93 million people wer.e chronically infected with hepatitis B virus （HBV） in China. Four nucleotide analogues （NAs） are currently approved for the treatment of...Recently the Chinese Ministry of Health declared that 93 million people wer.e chronically infected with hepatitis B virus （HBV） in China. Four nucleotide analogues （NAs） are currently approved for the treatment of HBV infection, i.e., lamivudine （LAM）, adefovir （ADV）, entecavir （ETV）, and telbivudine （L-dT）. In contrast to therapeutic benefits, prolonged use of NAs increases the emergence of drug-resistant mutations in the HBV reverse transcriptase （RT） domain, leading to a progressive accumulation of NAs-resistant patients. Especially, LAM-refractory patients are prone to develop cross-resistance to other NAs. Novel anti-HBV drugs that are able to deal with the cross-resistance are needed in the clinic. Tenofovir （TDF）, which was recently approved in Europe and United States of America, has potential to be such a drug. Clinical trials have proven its high potency for inhibiting HBV replication in HBV-infected patients,展开更多
In obesity, persistent low-grade inflammation is considered as a major contributor towards the progression to insulin resistance and type 2 diabetes while in lean subjects the immune environment is non-inflammatory. M...In obesity, persistent low-grade inflammation is considered as a major contributor towards the progression to insulin resistance and type 2 diabetes while in lean subjects the immune environment is non-inflammatory. Massive adipose tissue(AT) infiltration by pro-inflammatory M1 macrophages and several T cell subsets as obesity develops leads to the accumulation-both in the AT and systemically-of numerous pro-inflammatory cytokines, including interleukin-1β(IL-1β), tumor necrosis factor a, IL-17 and IL-6 which are strongly associated with the progression of the obese phenotype towards the metabolic syndrome. At the same time, anti-inflammatory M2 macrophages and Th subsets producing the antiinflammatory cytokines IL-10, IL-5 and interferon-γ, including Th2 and T-reg cells are correlated to the maintenance of AT homeostasis in lean individuals. Here, we discuss the basic principles in the control of the interaction between the AT and infiltrating immune cells both in the lean and the obese condition with a special emphasis on the contribution of pro-and antiinflammatory cytokines to the establishment of the insulinresistant state. In this context, we will discuss the current knowledge about alterations in the levels on pro-and antiinflammatory cytokines in obesity, insulin resistance and type 2 diabetes mellitus, in humans and animal models. Finally, we also briefly survey the recent novel therapeutic strategies that attempt to alleviate or reverse insulin resistance and type 2 diabetes via the administration of recombinant inhibitory antibodies directed towards some pro-inflammatory cytokines.展开更多
Background Despite advances in asthma treatments,severe asthma exacerbation(SAE)remains a life-threatening condition in adults,and there is a lack of data derived from adult patients admitted to intensive care units(I...Background Despite advances in asthma treatments,severe asthma exacerbation(SAE)remains a life-threatening condition in adults,and there is a lack of data derived from adult patients admitted to intensive care units(ICUs)for SAE.The current study investigated changes in adult patient characteristics,management,and outcomes of SAE over a 20-year period in 40 ICUs in the greater Paris area.Methods In this retrospective observational study,admissions to 40 ICUs in the greater Paris area for SAE from January 1,1997,to December 31,2016 were analyzed.The primary outcome was the proportion of ICU admissions for SAE during 5-year periods.Secondary outcomes were ICU and hospital mortality,and the use of mechanical ventilation and catecholamine.Multivariate analysis was performed to assess factors associated with ICU mortality.Results A total of 7049 admissions for SAE were recorded.For each 5-year period,the proportion decreased over time,with SAE accounting for 2.84%of total ICU admissions(n=2841)between 1997 and 2001,1.76%(n=1717)between 2002 and 2006,1.05%(n=965)between 2007 and 2011,and 1.05%(n=1526)between 2012 and 2016.The median age was 46 years(interquartile range[IQR]:32–59 years),55.41%were female,the median Simplified Acute Physiology Score II was 20(IQR:13–28),and 19.76%had mechanical ventilation.The use of mechanical ventilation remained infrequent throughout the 20-year period,whereas the use of catecholamine decreased.ICU and hospital mortality rates decreased.Factors associated with ICU mortality were renal replacement therapy,catecholamine,cardiac arrest,pneumothorax,acute respiratory distress syndrome,sepsis,and invasive mechanical ventilation(IMV).Non-survivors were older,had more severe symptoms,and were more likely to have received IMV.Conclusion ICU admission for SAE remains uncommon,and the proportion of cases decreased over time.Despite a slight increase in symptom severity during a 20-year period,ICU and hospital mortality decreased.Patients requiring IMV had a higher mortality rate.展开更多
Background:Liver biopsy for the diagnosis of non-alcoholic steatohepatitis(NASH)is limited by its inherent invasiveness and possible sampling errors.Some studies have shown that cytokeratin-18(CK-18)concentrations may...Background:Liver biopsy for the diagnosis of non-alcoholic steatohepatitis(NASH)is limited by its inherent invasiveness and possible sampling errors.Some studies have shown that cytokeratin-18(CK-18)concentrations may be useful in diagnosing NASH,but results across studies have been inconsistent.We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH.Methods:Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease(NAFLD),and in all patients,circulating CK-18 M30 levels were measured.Individuals with a NAFLD activity score(NAS)≥5 with a score of≥1 for each of steatosis,ballooning,and lobular inflammation were diagnosed as having definite NASH;individuals with a NAS≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver(NAFL).Results:A total of 2571 participants were screened,and 1008(153 with NAFL and 855 with NASH)were finally enrolled.Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL(mean difference 177 U/L;standardized mean difference[SMD]:0.87[0.69–1.04]).There was an interaction between CK-18 M30 levels and serum alanine aminotransferase,body mass index(BMI),and hypertension(P<0.001,P=0.026 and P=0.049,respectively).CK-18 M30 levels were positively associated with histological NAS in most centers.The area under the receiver operating characteristics(AUROC)for NASH was 0.750(95%confidence intervals:0.714–0.787),and CK-18 M30 at Youden’s index maximum was 275.7 U/L.Both sensitivity(55%[52%–59%])and positive predictive value(59%)were not ideal.Conclusion:This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.展开更多
Background Severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)is responsible for an important mortality rate worldwide.We aimed to evaluate the actual imputability of SARS-CoV-2 on the mortality rate associate...Background Severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)is responsible for an important mortality rate worldwide.We aimed to evaluate the actual imputability of SARS-CoV-2 on the mortality rate associated with SARS-CoV-2-related illnesses in the pediatric intensive care unit(PICU).Secondary objectives were to identify risk factors for death.Methods This national multicenter comparative study comprised all patients under 18 years old with positive SARS-CoV-2 polymerase chain reactions(PCRs)[acute corona virus disease 2019(COVID-19)or incidental SARS-CoV-2 infection]and/or pediatric inflammatory multisystem syndrome(PIMS)recorded in the French PICU registry(PICURe)between September 1,2021,and August 31,2022.Included patients were classified and compared according to their living status at the end of their PICU stay.Deceased patients were evaluated by four experts in the field of pediatric infectiology and/or pediatric intensive care.The imputability of SARS-CoV-2 as the cause of death was classified into four categories:certain,very probable,possible,or unlikely,and was defined by any of the first three categories.Results There were 948 patients included of which 43 died(4.5%).From this,26 deaths(67%)could be attributed to SARS-CoV-2 infection,with an overall mortality rate of 2.8%.The imputability of death to SARS-CoV-2 was considered certain in only one case(O.1%).Deceased patients suffered more often from comorbidities,especially heart disease,neurological disorders,hematological disease,cancer,and obesity.None of the deceased patients were admitted for pediatric inflam-matory multisystem syndrome(PIMS).Mortality risk factors were male gender,cardiac comorbidities,cancer,and acute respiratorydistress syndrome.Conclusions SARS-CoV-2 mortality in the French pediatric population was low.Even though the imputability of SARS-Cov-2 on mortality was considered in almost two-thirds of cases,this imputability was considered certain in only one case.展开更多
Macrozoospermia,characterized by the presence of largeheaded spermatozoa usually carrying several flagella,is one of the most severe phenotypes of male infertility.As in most cases,the gametes are chromosomally abnorm...Macrozoospermia,characterized by the presence of largeheaded spermatozoa usually carrying several flagella,is one of the most severe phenotypes of male infertility.As in most cases,the gametes are chromosomally abnormal and cannot be used for assisted reproductive technologies(ART)(Ray et al.,2017).In 2007,subjects from consanguineous families were shown to carry the same homozygous deleterious AURKC variant(NM_001015878.2:c.144delC,later renamed c.145delC,p.Leu49TrpfsTer23),establishing AURKC as the first and main gene associated with macrozoospermia(Dieterich et al.,2007).Using flow cytometry,all spermatozoa from patients homozygous for the c.145delC variant were shown to be tetraploid,highlighting a cytokinesis blockage of the first meiotic divisions thus confirming that ART cannot be successful for these patients(Dieterich et al.,2009).展开更多
We suggest that during severe acute pancreatitis(SAP)with intra-abdominal hypertension,practitioners should consider decompressive laparotomy,even with intra-abdominal pressure(IAP)below 25 mmHg.Indeed,in this setting...We suggest that during severe acute pancreatitis(SAP)with intra-abdominal hypertension,practitioners should consider decompressive laparotomy,even with intra-abdominal pressure(IAP)below 25 mmHg.Indeed,in this setting,non-occlusive mesenteric ischemia(NOMI)may occur even with IAP below this cutoff and lead to transmural necrosis if abdominal perfusion pressure is not promptly restored.We report our experience of 18 critically ill patients with SAP having undergone decompressive laparotomy of which one third had NOMI while IAP was mostly below 25 mmHg.展开更多
Background:The AbSeS-classification defines specific phenotypes of patients with intra-abdominal infection based on the(1)setting of infection onset(community-acquired,early onset,or late-onset hospital-acquired),(2)p...Background:The AbSeS-classification defines specific phenotypes of patients with intra-abdominal infection based on the(1)setting of infection onset(community-acquired,early onset,or late-onset hospital-acquired),(2)presence or absence of either localized or diffuse peritonitis,and(3)severity of disease expression(infection,sepsis,or septic shock).This classification system demonstrated reliable risk stratification in intensive care unit(ICU)patients with intra-abdominal infection.This study aimed to describe the epidemiology of ICU patients with pancreatic infection and assess the relationship between the components of the AbSeS-classification and mortality.Methods:This was a secondary analysis of an international observational study(“AbSeS”)investigating ICU patients with intra-abdominal infection.Only patients with pancreatic infection were included in this analysis(n=165).Mortality was defined as ICU mortality within 28 days of observation for patients discharged earlier from the ICU.Relationships with mortality were assessed using logistic regression analysis and reported as odds ratio(OR)and 95%confidence interval(CI).Results:The overall mortality was 35.2%(n=58).The independent risk factors for mortality included older age(OR=1.03,95%CI:1.0 to 1.1 P=0.023),localized peritonitis(OR=4.4,95%CI:1.4 to 13.9 P=0.011),and persistent signs of inflammation at day 7(OR=9.5,95%CI:3.8 to 23.9,P<0.001)or after the implementation of additional source control interventions within the first week(OR=4.0,95%CI:1.3 to 12.2,P=0.013).Gramnegative bacteria were most frequently isolated(n=58,49.2%)without clinically relevant differences in microbial etiology between survivors and non-survivors.Conclusions:In pancreatic infection,a challenging source/damage control and ongoing pancreatic inflammation appear to be the strongest contributors to an unfavorable short-term outcome.In this limited series,essentials of the AbSeS-classification,such as the setting of infection onset,diffuse peritonitis,and severity of disease express展开更多
Background:Populations of French Polynesia(FP),where France performed atmospheric tests between 1966 and 1974,experience a high incidence of differentiated thyroid cancer(DTC).However,up to now,no sufficiently large s...Background:Populations of French Polynesia(FP),where France performed atmospheric tests between 1966 and 1974,experience a high incidence of differentiated thyroid cancer(DTC).However,up to now,no sufficiently large study of DTC genetic factors in this population has been performed to reach definitive conclusion.This research aimed to analyze the genetic factors of DTC risk among the native FP populations.Methods:We analyzed more than 300000 single nucleotide polymorphisms(SNPs)genotyped in 283 DTC cases and 418 matched controls born in FP,most being younger than 15 years old at the time of the first nuclear tests.We analyzed the genetic profile of our cohort to identify population subgroups.We then completed a genome-wide analysis study on the whole population.Results:We identified a specific genetic structure in the FP population reflecting admixture from Asian and European populations.We identified three regions associated with increased DTC risk at 6q24.3,10p12.2,and 17q21.32.The lead SNPs at these loci showed respective p-values of 1.66×10^(−7),2.39×10^(−7),and 7.19×10^(−7) and corresponding odds ratios of 2.02,1.89,and 2.37.Conclusion:Our study results suggest a role of the loci 6q24.3,10p12.2 and 17q21.32 in DTC risk.However,a whole genome sequencing approach would be better suited to characterize these factors than genotyping with microarray chip designed for the Caucasian population.Moreover,the functional impact of these three new loci needs to be further explored and validated.展开更多
AIM: To compare Institut Georges Lopez(IGL-1) and Celsior preservation solutions for hepatic endothelium relaxation and liver cold ischemia reperfusion injury(IRI).METHODS: Two experimental models were used.In the fir...AIM: To compare Institut Georges Lopez(IGL-1) and Celsior preservation solutions for hepatic endothelium relaxation and liver cold ischemia reperfusion injury(IRI).METHODS: Two experimental models were used.In the first one, acetylcholine-induced endotheliumdependent relaxation(EDR) was measured in isolated ring preparations of rat hepatic arteries preserved or not in IGL-1 or Celsior solutions(24 h at 4 ℃).To determine nitric oxide(NO) and cyclooxygenase EDR, hepatic arteries were incubated with L-NG-nitroarginine methyl ester(L-NAME), an inhibitor of endothelium nitric oxide synthase(e NOS), or with L-NAME plus indomethacin, an inhibitor of cyclooxygenase.In the second experiment, rat livers were cold-stored in IGL-1 or Celsior solutions for 24 h at 4 ℃ and then perfused "ex vivo " for 2 h at 37 ℃.Liver injury was assessed by transaminase measurements, liver function by bile production and bromosulfophthalein clearance, oxidative stress by malondialdehyde levels and catalase activity and alterations in cell signaling pathways by pA kt, pA MPK, eN OS and MAPKs proteins level.RESULTS: After cold storage for 24 h with either Celsior or IGL-1, EDR was only slightly altered.Infreshly isolated arteries, EDR was exclusively mediated by NO.However, cold-stored arteries showed NOand COX-dependent relaxation.The decrease in NO-dependent relaxation after cold storage was significantly more marked with Celsior.The second study indicated that IGL-1 solution obtained better liver preservation and protection against IRI than Celsior.Liver injury was reduced, function was improved and there was less oxidative stress.IGL-1 solution activated Akt and AMPK, which was concomitant with increased eN OS expression and nitrite/nitrate levels.Furthermore, MAPKs kinases were regulated in livers preserved with IGL-1 solution since reductions in p-p38, p-ERK and p-JNK protein levels were observed.CONCLUSION: IGL-1 solution preserved NO-dependent relaxation better than Celsior storage solution and enhanced liver graft preservation.展开更多
AIM: To assess the predictive value of the insulinlike growth factor 2 (Igf2) methylation profile for the occurrence of Hepatocellular Carcinoma (HCC) in hepatitis C (HCV) cirrhosis. METHODS: Patients with: (1) biopsy...AIM: To assess the predictive value of the insulinlike growth factor 2 (Igf2) methylation profile for the occurrence of Hepatocellular Carcinoma (HCC) in hepatitis C (HCV) cirrhosis. METHODS: Patients with: (1) biopsy-proven compensated HCV cirrhosis; (2) available baseline frozen liver sample; (3) absence of detectable HCC; (4) regular screening for HCC; (5) informed consent for genetic analysis were studied. After DNA extraction from liver samples and bisulfite treatment, unbiased PCR and DHPLC analysis were performed for methylation analysis at the Igf2 locus. The predictive value of the Igf2 methylation profile for HCC wasassessed by Kaplan-Meier and Cox methods. RESULTS: Among 94 included patients, 20 developed an HCC during follow-up (6.9 ± 3.2 years). The methylation profile was hypomethylated, intermediate and hypermethylated in 13, 64 and 17 cases, respectively. In univariate analysis, two baseline parameters were associated with the occurrence of HCC: age (P = 0.01) and prothrombin (P = 0.04). The test of linear tendency between the three ordered levels of Igf2 methylation and probability of HCC occurrence was significant (Log Rank, P = 0.043; Breslow, P = 0.037; Tarone-Ware, P = 0.039). CONCLUSION: These results suggest that hypomethylation at the Igf2 locus in the liver could be predictive for HCC occurrence in HCV cirrhosis.展开更多
BACKGROUND The association between the intestinal microbiota and psychiatric disorders is becoming increasingly apparent.The gut microbiota contributes to colorectal carcinogenesis(CRC),as demonstrated with colibactin...BACKGROUND The association between the intestinal microbiota and psychiatric disorders is becoming increasingly apparent.The gut microbiota contributes to colorectal carcinogenesis(CRC),as demonstrated with colibactin-producing Escherichia coli(CoPEC).AIM To evaluate the association between CoPEC prevalence and anxiety-and depressive-like behaviors with both preclinical and clinical approaches.METHODS Patients followed after a CRC surgery and for whom the prevalence of CoPEC has been investigated underwent a psychiatric interview.Results were compared according to the CoPEC colonization.In parallel C57BL6/J wild type mice and mice with a CRC susceptibility were chronically infected with a CoPEC strain.Their behavior was assessed using the Elevated Plus Maze test,the Forced Swimming Test and the Behavior recognition system PhenoTyper®.RESULTS In a limited cohort,all patients with CoPEC colonization presented with psychiatric disorders several years before cancer diagnosis,whereas only one patient(17%)without CoPEC did.This result was confirmed in C57BL6/J wildtype mice and in a CRC susceptibility mouse model(adenomatous polyposis colimultiple intestinal neoplasia/+).Mice exhibited a significant increase in anxiety-and depressive-like behaviors after chronic infection with a CoPEC strain.CONCLUSION This finding provides the first evidence that CoPEC infection can induce microbiota-gut-brain axis disturbances in addition to its procarcinogenic properties.展开更多
Patients with hormone receptor(HR)-positive tumors breast cancer usually experience a relatively low pathological complete response(p CR)to neoadjuvant chemotherapy(NAC).Here,we derived a 10-micro RNA risk score(10-mi...Patients with hormone receptor(HR)-positive tumors breast cancer usually experience a relatively low pathological complete response(p CR)to neoadjuvant chemotherapy(NAC).Here,we derived a 10-micro RNA risk score(10-mi RNA RS)-based model with better performance in the prediction of p CR and validated its relation with the disease-free survival(DFS)in 755 HRpositive breast cancer patients(273,265,and 217 in the training,internal,and external validation sets,respectively).This model,presented as a nomogram,included four parameters:the 10-mi RNA RS found in our previous study,progesterone receptor(PR),human epidermal growth factor receptor 2(HER2)status,and volume transfer constant(K).Favorable calibration and discrimination of 10-mi RNA RS-based model with areas under the curve(AUC)of 0.865,0.811,and 0.804 were shown in the training,internal,and external validation sets,respectively.Patients who have higher nomogram score(>92.2)with NAC treatment would have longer DFS(hazard ratio=0.57;95%CI:0.39–0.83;P=0.004).In summary,our data showed the 10-mi RNA RS-based model could precisely identify more patients who can attain p CR to NAC,which may help clinicians formulate the personalized initial treatment strategy and consequently achieves better clinical prognosis for patients with HRpositive breast cancer.展开更多
Background It remains unclear if intensive antiplatelet and statin treatments begun within 24-72 hours of cerebral ischaemic events from intracranial or extracranial atherosclerosis is effective or safe.Methods The In...Background It remains unclear if intensive antiplatelet and statin treatments begun within 24-72 hours of cerebral ischaemic events from intracranial or extracranial atherosclerosis is effective or safe.Methods The Intensive Statin and Antiplatelet Therapy for High-risk Intracranial or Extracranial Atherosclerosis(INSPIRES)trial is a randomised,double-blind,placebo-controlled,multicentre and 2×2 factorial trial.6100 individuals between the ages of 35 and 80 who have experienced a mild ischaemic stroke or high-risk transient ischaemic attack(TIA)within the previous 72 hours that is attributed to≥50%atherosclerotic stenosis of a major intracranial or extracranial artery or multiple infarctions of atherosclerotic origin will be enrolled in the trial.Eligible subjects will be randomised 1:1:1:1 to one of four groups:(1)intensive antiplatelet therapy(combined clopidogrel and aspirin for days 1-21,then aspirin placebo and clopidogrel for days 22-90)plus immediate intensive statin therapy(atorvastatin at a dose of 80 mg daily for the first 21 days,then 40 mg daily for days 22-90);(2)intensive antiplatelet therapy plus delayed intensive statin therapy(atorvastatin placebo for days 1-3,followed by 40 mg per day of atorvastatin for days 4-90);(3)standard antiplatelet therapy(combination of clopidogrel placebo with aspirin for 90 days)plus immediate intensive statin therapy and(4)standard antiplatelet therapy plus delayed intensive statin therapy.The primary efficacy endpoint is any new stroke(ischaemic or haemorrhagic)within 90 days after randomisation.The primary safety endpoint is moderate to severe bleeding at 90 days.Conclusion The INSPIRES trial will assess the efficacy and safety of intensive antiplatelet therapy and immediate intensive statin therapy begun within 72 hours of onset in decreasing the recurrent stroke at 90 days in patients with acute mild ischaemic stroke or high-risk TIA of intracranial or extracranial atherosclerosis origin.展开更多
文摘AIM: To investigate the efficacy(survival) and safety of treatments for recurrent hepatocellular carcinoma(HCC) in liver transplantation(LT) patients.METHODS: Literature search was performed on available online databases without a time limit until January 2015. Clinical studies describing survival after HCC recurrence in LT patients were retrieved for a fulltext evaluation. A total of 61 studies were selected: 13 case reports, 41 retrospective case series, and 7 retrospective comparative studies.RESULTS: Based on all included studies, the mean HCC recurrence rate was 16% of all LTs for HCC. A total of 1021 LT patients experienced HCC recurrence. The median time from LT to HCC recurrence was 13 mo(range 2-132 mo). The majority of patients(67%) presented with HCC extra-hepatic recurrences, involving lung, bone, adrenal gland, peritoneal lymph nodes, and rarely the brain. Overall survival after HCC recurrence was 12.97 mo. Surgical resection of localized HCC recurrence and Sorafenib for controlling systemic spread of HCC recurrence were associated with the higher survival rates(42 and 18 mo, res-pectively). However, Sorafenib, especially when combined with m TOR, was frequently associated with severe side effects that required dose reduction or discontinuation CONCLUSION: Management of recurrent HCC in LT patients is challenging and associated with poor prognosis independently of the type of treatment.
文摘There has been a growing interest over the past few years in the impact of male nutrition on fertility. Infertility has been linked to male overweight or obesity, and conventional semen parameter values seem to be altered in case of high body mass index （BMI）. A few studies assessing the impact of BMI on sperm DNA integrity have been published, but they did not lead to a strong consensus. Our objective was to explore further the relationship between sperm DNA integrity and BMI, through a 3-year multicentre study. Three hundred and thirty male partners in subfertile couples were included. Using the terminal uridine nick-end labelling （TUNEL） assay, we observed an increased rate of sDerm DNA damage in obese men （odds ratio （95% confidence interval）： 2.5 （1.2-5.1））.
文摘In recent years , a second pathway for colonic carcinogenesis , distinct from the adenomatous pathway, has been explored. This is referred to as serrated pathway and includes three types of polyp,characterised by a serrated appearance of the crypts:hyperplastic polyps(HP),sessile serrated adenomas(SSA)or lesions,and traditional serrated adenomas.Each lesion has its own genetic,as well as macroscopic and microscopic morphological features.Because of their flat aspect,their detection is easier with chromoendoscopy(carmin indigo or narrow-band imaging).However,as we show in this review,the distinction between SSA and HP is quite difficult.It is now recommended to resect in one piece as it is possible the serrated polyps with a control in a delay depending on the presence or not of dysplasia.These different types of lesion are described in detail in the present review in general population,in polyposis and in inflammatory bowel diseases patients.This review highlights the need to improve characterization and understanding of this way of colorectal cancerogenesis.
文摘According to epidemiological studies,twice as many women as men are affected by irritable bowel syndrome(IBS)in western countries,suggesting a role for sex hormones in IBS pathophysiology.Despite growing evidence about the implications of sex hormones in IBS symptom modulation,data on mechanisms by which they influence disease development are sparse.This review aims to determine the state of knowledge about the role of sex hormones in sensorimotor dysfunctions and to address the possible interplay of sex hormones with common risk factors associated with IBS.The scientific bibliography was searched using the following keywords:irritable bowel syndrome,sex,gender,ovarian hormone,estradiol,progesterone,testosterone,symptoms,pain,sensitivity,motility,permeability,stress,immune system,brain activity,spinal,supraspinal,imaging.Ovarian hormones variations along themenstrual cycle affect sensorimotor gastrointestinal function in both healthy and IBS populations.They can modulate pain processing by interacting with neuromodulator systems and the emotional system responsible for visceral pain perception.These hormones can also modulate the susceptibility to stress,which is a pivotal factor in IBS occurrence and symptom severity.For instance,estrogen-dependent hyper-responsiveness to stress can promote immune activation or impairments of gut barrier function.In conclusion,whereas it is important to keep in mind that ovarian hormones cannot be considered as a causal factor of IBS,they arguably modulate IBS onset and symptomatology.However,our understanding of the underlying mechanisms remains limited and studies assessing the link between IBS symptoms and ovarian hormone levels are needed to improve our knowledge of the disease evolution with regard to gender.Further studies assessing the role of male hormones are also needed to understand fully the role of sex hormones in IBS.Finally,investigation of brain-gut interactions is critical to decipher how stress,ovarian hormones,and female brain processing of pain can translate
基金Septic shock patient samples from the Adrenoss-1 cohort(NCT02393781)were provided by Sphingotec,and statistical analyses were conducted by Oli Hartman and Joachim Struck(Sphingotec).
文摘TREM-1(triggering receptor expressed on myeloid cells-1)is a transmembrane receptor expressed by innate immune cells,including endothelial cells and platelets.TREM-1 is a crucial mediator of septic shock that acts by synergizing with Toll-like receptors(TLRs)to amplify the inflammatory responses to pathogens,thus promoting sepsis-induced immune dysregulation and organ dysfunction[1,2,3].
文摘Hepatocellular carcinoma(HCC)is the sixth most common cancer worldwide,with an increasing diffusion in Europe and the United States.The management of such a cancer is continuously progressing and the objective of this paper is to evaluate innovation in the surgical treatment of HCC.In this review,we will analyze the modern concept of preoperative management,the role of laparoscopic and robotic surgery,the intraoperative use of three dimensional models and augmented reality,as well as the potential application of fluorescence.
基金The study was supported by the grants from the National Key Basic Research Developing Project （No. 2007CB512803）, the Beijing Science and Technology Project （No. Z07050700690702）, and partly by the Beijing Natural Science Foundation （No. 7091006）.Acknowledgement： The authors gratefully acknowledge experimental participation of technicians at Viral Hepatitis Research Laboratory as follows： DAI Jiu-zeng, LI Le, YAO Zeng-tao.
文摘Recently the Chinese Ministry of Health declared that 93 million people wer.e chronically infected with hepatitis B virus （HBV） in China. Four nucleotide analogues （NAs） are currently approved for the treatment of HBV infection, i.e., lamivudine （LAM）, adefovir （ADV）, entecavir （ETV）, and telbivudine （L-dT）. In contrast to therapeutic benefits, prolonged use of NAs increases the emergence of drug-resistant mutations in the HBV reverse transcriptase （RT） domain, leading to a progressive accumulation of NAs-resistant patients. Especially, LAM-refractory patients are prone to develop cross-resistance to other NAs. Novel anti-HBV drugs that are able to deal with the cross-resistance are needed in the clinic. Tenofovir （TDF）, which was recently approved in Europe and United States of America, has potential to be such a drug. Clinical trials have proven its high potency for inhibiting HBV replication in HBV-infected patients,
基金Supported by The Franco--Brazilian CAPES/COFECUB colla-boration program Me797-14supported by a CAPES postdoctoral fellowship
文摘In obesity, persistent low-grade inflammation is considered as a major contributor towards the progression to insulin resistance and type 2 diabetes while in lean subjects the immune environment is non-inflammatory. Massive adipose tissue(AT) infiltration by pro-inflammatory M1 macrophages and several T cell subsets as obesity develops leads to the accumulation-both in the AT and systemically-of numerous pro-inflammatory cytokines, including interleukin-1β(IL-1β), tumor necrosis factor a, IL-17 and IL-6 which are strongly associated with the progression of the obese phenotype towards the metabolic syndrome. At the same time, anti-inflammatory M2 macrophages and Th subsets producing the antiinflammatory cytokines IL-10, IL-5 and interferon-γ, including Th2 and T-reg cells are correlated to the maintenance of AT homeostasis in lean individuals. Here, we discuss the basic principles in the control of the interaction between the AT and infiltrating immune cells both in the lean and the obese condition with a special emphasis on the contribution of pro-and antiinflammatory cytokines to the establishment of the insulinresistant state. In this context, we will discuss the current knowledge about alterations in the levels on pro-and antiinflammatory cytokines in obesity, insulin resistance and type 2 diabetes mellitus, in humans and animal models. Finally, we also briefly survey the recent novel therapeutic strategies that attempt to alleviate or reverse insulin resistance and type 2 diabetes via the administration of recombinant inhibitory antibodies directed towards some pro-inflammatory cytokines.
文摘Background Despite advances in asthma treatments,severe asthma exacerbation(SAE)remains a life-threatening condition in adults,and there is a lack of data derived from adult patients admitted to intensive care units(ICUs)for SAE.The current study investigated changes in adult patient characteristics,management,and outcomes of SAE over a 20-year period in 40 ICUs in the greater Paris area.Methods In this retrospective observational study,admissions to 40 ICUs in the greater Paris area for SAE from January 1,1997,to December 31,2016 were analyzed.The primary outcome was the proportion of ICU admissions for SAE during 5-year periods.Secondary outcomes were ICU and hospital mortality,and the use of mechanical ventilation and catecholamine.Multivariate analysis was performed to assess factors associated with ICU mortality.Results A total of 7049 admissions for SAE were recorded.For each 5-year period,the proportion decreased over time,with SAE accounting for 2.84%of total ICU admissions(n=2841)between 1997 and 2001,1.76%(n=1717)between 2002 and 2006,1.05%(n=965)between 2007 and 2011,and 1.05%(n=1526)between 2012 and 2016.The median age was 46 years(interquartile range[IQR]:32–59 years),55.41%were female,the median Simplified Acute Physiology Score II was 20(IQR:13–28),and 19.76%had mechanical ventilation.The use of mechanical ventilation remained infrequent throughout the 20-year period,whereas the use of catecholamine decreased.ICU and hospital mortality rates decreased.Factors associated with ICU mortality were renal replacement therapy,catecholamine,cardiac arrest,pneumothorax,acute respiratory distress syndrome,sepsis,and invasive mechanical ventilation(IMV).Non-survivors were older,had more severe symptoms,and were more likely to have received IMV.Conclusion ICU admission for SAE remains uncommon,and the proportion of cases decreased over time.Despite a slight increase in symptom severity during a 20-year period,ICU and hospital mortality decreased.Patients requiring IMV had a higher mortality rate.
基金supported by grants from the National Natural Science Foundation of China(No.82070588)High-Level Creative Talents from the Department of Public Health in Zhejiang Province(No.S2032102600032)+4 种基金Project of New Century 551 Talent Nurturing in Wenzhou.G.Targher is supported in part by grants from the University School of Medicine of Verona,Verona,ItalyC.D.Byrne is supported in part by the Southampton NIHR Biomedical Research Centre(No.IS-BRC-20004),UK.MEJG are supported by the Robert W.Storr Bequest to the Sydney Medical Foundation,University of Sydneya National Health and Medical Research Council of Australia(NHMRC)Program Grant(No.APP1053206)Project and ideas grants(Nos.APP2001692,APP1107178,and APP1108422).
文摘Background:Liver biopsy for the diagnosis of non-alcoholic steatohepatitis(NASH)is limited by its inherent invasiveness and possible sampling errors.Some studies have shown that cytokeratin-18(CK-18)concentrations may be useful in diagnosing NASH,but results across studies have been inconsistent.We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH.Methods:Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease(NAFLD),and in all patients,circulating CK-18 M30 levels were measured.Individuals with a NAFLD activity score(NAS)≥5 with a score of≥1 for each of steatosis,ballooning,and lobular inflammation were diagnosed as having definite NASH;individuals with a NAS≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver(NAFL).Results:A total of 2571 participants were screened,and 1008(153 with NAFL and 855 with NASH)were finally enrolled.Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL(mean difference 177 U/L;standardized mean difference[SMD]:0.87[0.69–1.04]).There was an interaction between CK-18 M30 levels and serum alanine aminotransferase,body mass index(BMI),and hypertension(P<0.001,P=0.026 and P=0.049,respectively).CK-18 M30 levels were positively associated with histological NAS in most centers.The area under the receiver operating characteristics(AUROC)for NASH was 0.750(95%confidence intervals:0.714–0.787),and CK-18 M30 at Youden’s index maximum was 275.7 U/L.Both sensitivity(55%[52%–59%])and positive predictive value(59%)were not ideal.Conclusion:This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.
文摘Background Severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)is responsible for an important mortality rate worldwide.We aimed to evaluate the actual imputability of SARS-CoV-2 on the mortality rate associated with SARS-CoV-2-related illnesses in the pediatric intensive care unit(PICU).Secondary objectives were to identify risk factors for death.Methods This national multicenter comparative study comprised all patients under 18 years old with positive SARS-CoV-2 polymerase chain reactions(PCRs)[acute corona virus disease 2019(COVID-19)or incidental SARS-CoV-2 infection]and/or pediatric inflammatory multisystem syndrome(PIMS)recorded in the French PICU registry(PICURe)between September 1,2021,and August 31,2022.Included patients were classified and compared according to their living status at the end of their PICU stay.Deceased patients were evaluated by four experts in the field of pediatric infectiology and/or pediatric intensive care.The imputability of SARS-CoV-2 as the cause of death was classified into four categories:certain,very probable,possible,or unlikely,and was defined by any of the first three categories.Results There were 948 patients included of which 43 died(4.5%).From this,26 deaths(67%)could be attributed to SARS-CoV-2 infection,with an overall mortality rate of 2.8%.The imputability of death to SARS-CoV-2 was considered certain in only one case(O.1%).Deceased patients suffered more often from comorbidities,especially heart disease,neurological disorders,hematological disease,cancer,and obesity.None of the deceased patients were admitted for pediatric inflam-matory multisystem syndrome(PIMS).Mortality risk factors were male gender,cardiac comorbidities,cancer,and acute respiratorydistress syndrome.Conclusions SARS-CoV-2 mortality in the French pediatric population was low.Even though the imputability of SARS-Cov-2 on mortality was considered in almost two-thirds of cases,this imputability was considered certain in only one case.
基金funded by the French National Research Agency(ANR)projects MAS FLAGELLA (ANR-14-CE15-0002)+2 种基金FLAGELOME (ANR-19-CE17-0014)the INSERM (Institut National de la Sante et de la Recherche Medicale)Bettencourt Foundation
文摘Macrozoospermia,characterized by the presence of largeheaded spermatozoa usually carrying several flagella,is one of the most severe phenotypes of male infertility.As in most cases,the gametes are chromosomally abnormal and cannot be used for assisted reproductive technologies(ART)(Ray et al.,2017).In 2007,subjects from consanguineous families were shown to carry the same homozygous deleterious AURKC variant(NM_001015878.2:c.144delC,later renamed c.145delC,p.Leu49TrpfsTer23),establishing AURKC as the first and main gene associated with macrozoospermia(Dieterich et al.,2007).Using flow cytometry,all spermatozoa from patients homozygous for the c.145delC variant were shown to be tetraploid,highlighting a cytokinesis blockage of the first meiotic divisions thus confirming that ART cannot be successful for these patients(Dieterich et al.,2009).
文摘We suggest that during severe acute pancreatitis(SAP)with intra-abdominal hypertension,practitioners should consider decompressive laparotomy,even with intra-abdominal pressure(IAP)below 25 mmHg.Indeed,in this setting,non-occlusive mesenteric ischemia(NOMI)may occur even with IAP below this cutoff and lead to transmural necrosis if abdominal perfusion pressure is not promptly restored.We report our experience of 18 critically ill patients with SAP having undergone decompressive laparotomy of which one third had NOMI while IAP was mostly below 25 mmHg.
文摘Background:The AbSeS-classification defines specific phenotypes of patients with intra-abdominal infection based on the(1)setting of infection onset(community-acquired,early onset,or late-onset hospital-acquired),(2)presence or absence of either localized or diffuse peritonitis,and(3)severity of disease expression(infection,sepsis,or septic shock).This classification system demonstrated reliable risk stratification in intensive care unit(ICU)patients with intra-abdominal infection.This study aimed to describe the epidemiology of ICU patients with pancreatic infection and assess the relationship between the components of the AbSeS-classification and mortality.Methods:This was a secondary analysis of an international observational study(“AbSeS”)investigating ICU patients with intra-abdominal infection.Only patients with pancreatic infection were included in this analysis(n=165).Mortality was defined as ICU mortality within 28 days of observation for patients discharged earlier from the ICU.Relationships with mortality were assessed using logistic regression analysis and reported as odds ratio(OR)and 95%confidence interval(CI).Results:The overall mortality was 35.2%(n=58).The independent risk factors for mortality included older age(OR=1.03,95%CI:1.0 to 1.1 P=0.023),localized peritonitis(OR=4.4,95%CI:1.4 to 13.9 P=0.011),and persistent signs of inflammation at day 7(OR=9.5,95%CI:3.8 to 23.9,P<0.001)or after the implementation of additional source control interventions within the first week(OR=4.0,95%CI:1.3 to 12.2,P=0.013).Gramnegative bacteria were most frequently isolated(n=58,49.2%)without clinically relevant differences in microbial etiology between survivors and non-survivors.Conclusions:In pancreatic infection,a challenging source/damage control and ongoing pancreatic inflammation appear to be the strongest contributors to an unfavorable short-term outcome.In this limited series,essentials of the AbSeS-classification,such as the setting of infection onset,diffuse peritonitis,and severity of disease express
基金supported by Institut National du Cancer(Grant No.9533)Fondation ARC(Grant No.PGA120150202302).
文摘Background:Populations of French Polynesia(FP),where France performed atmospheric tests between 1966 and 1974,experience a high incidence of differentiated thyroid cancer(DTC).However,up to now,no sufficiently large study of DTC genetic factors in this population has been performed to reach definitive conclusion.This research aimed to analyze the genetic factors of DTC risk among the native FP populations.Methods:We analyzed more than 300000 single nucleotide polymorphisms(SNPs)genotyped in 283 DTC cases and 418 matched controls born in FP,most being younger than 15 years old at the time of the first nuclear tests.We analyzed the genetic profile of our cohort to identify population subgroups.We then completed a genome-wide analysis study on the whole population.Results:We identified a specific genetic structure in the FP population reflecting admixture from Asian and European populations.We identified three regions associated with increased DTC risk at 6q24.3,10p12.2,and 17q21.32.The lead SNPs at these loci showed respective p-values of 1.66×10^(−7),2.39×10^(−7),and 7.19×10^(−7) and corresponding odds ratios of 2.02,1.89,and 2.37.Conclusion:Our study results suggest a role of the loci 6q24.3,10p12.2 and 17q21.32 in DTC risk.However,a whole genome sequencing approach would be better suited to characterize these factors than genotyping with microarray chip designed for the Caucasian population.Moreover,the functional impact of these three new loci needs to be further explored and validated.
基金Supported by Tunisian Ministry of Higher Education and Scientific Research,No.UR12ES11
文摘AIM: To compare Institut Georges Lopez(IGL-1) and Celsior preservation solutions for hepatic endothelium relaxation and liver cold ischemia reperfusion injury(IRI).METHODS: Two experimental models were used.In the first one, acetylcholine-induced endotheliumdependent relaxation(EDR) was measured in isolated ring preparations of rat hepatic arteries preserved or not in IGL-1 or Celsior solutions(24 h at 4 ℃).To determine nitric oxide(NO) and cyclooxygenase EDR, hepatic arteries were incubated with L-NG-nitroarginine methyl ester(L-NAME), an inhibitor of endothelium nitric oxide synthase(e NOS), or with L-NAME plus indomethacin, an inhibitor of cyclooxygenase.In the second experiment, rat livers were cold-stored in IGL-1 or Celsior solutions for 24 h at 4 ℃ and then perfused "ex vivo " for 2 h at 37 ℃.Liver injury was assessed by transaminase measurements, liver function by bile production and bromosulfophthalein clearance, oxidative stress by malondialdehyde levels and catalase activity and alterations in cell signaling pathways by pA kt, pA MPK, eN OS and MAPKs proteins level.RESULTS: After cold storage for 24 h with either Celsior or IGL-1, EDR was only slightly altered.Infreshly isolated arteries, EDR was exclusively mediated by NO.However, cold-stored arteries showed NOand COX-dependent relaxation.The decrease in NO-dependent relaxation after cold storage was significantly more marked with Celsior.The second study indicated that IGL-1 solution obtained better liver preservation and protection against IRI than Celsior.Liver injury was reduced, function was improved and there was less oxidative stress.IGL-1 solution activated Akt and AMPK, which was concomitant with increased eN OS expression and nitrite/nitrate levels.Furthermore, MAPKs kinases were regulated in livers preserved with IGL-1 solution since reductions in p-p38, p-ERK and p-JNK protein levels were observed.CONCLUSION: IGL-1 solution preserved NO-dependent relaxation better than Celsior storage solution and enhanced liver graft preservation.
文摘AIM: To assess the predictive value of the insulinlike growth factor 2 (Igf2) methylation profile for the occurrence of Hepatocellular Carcinoma (HCC) in hepatitis C (HCV) cirrhosis. METHODS: Patients with: (1) biopsy-proven compensated HCV cirrhosis; (2) available baseline frozen liver sample; (3) absence of detectable HCC; (4) regular screening for HCC; (5) informed consent for genetic analysis were studied. After DNA extraction from liver samples and bisulfite treatment, unbiased PCR and DHPLC analysis were performed for methylation analysis at the Igf2 locus. The predictive value of the Igf2 methylation profile for HCC wasassessed by Kaplan-Meier and Cox methods. RESULTS: Among 94 included patients, 20 developed an HCC during follow-up (6.9 ± 3.2 years). The methylation profile was hypomethylated, intermediate and hypermethylated in 13, 64 and 17 cases, respectively. In univariate analysis, two baseline parameters were associated with the occurrence of HCC: age (P = 0.01) and prothrombin (P = 0.04). The test of linear tendency between the three ordered levels of Igf2 methylation and probability of HCC occurrence was significant (Log Rank, P = 0.043; Breslow, P = 0.037; Tarone-Ware, P = 0.039). CONCLUSION: These results suggest that hypomethylation at the Igf2 locus in the liver could be predictive for HCC occurrence in HCV cirrhosis.
基金Supported by the French patient’s association against cancer(ligue contre le cancer),No.00001005238the French government IDEXISITE initiative,No.16-IDEX-0001-CAP 20-25+2 种基金CPER(Nex-N-Mob)the Auvergne-Rhône-Alpes region(“Thématiquesémergentes”),No.AV0004111the Ministère de l'Enseignement supérieur,de la Recherche et de l'Innovation,INSERM,University of Clermont Auvergne[UMR1071,UMR1107],INRAE[USC-1382].
文摘BACKGROUND The association between the intestinal microbiota and psychiatric disorders is becoming increasingly apparent.The gut microbiota contributes to colorectal carcinogenesis(CRC),as demonstrated with colibactin-producing Escherichia coli(CoPEC).AIM To evaluate the association between CoPEC prevalence and anxiety-and depressive-like behaviors with both preclinical and clinical approaches.METHODS Patients followed after a CRC surgery and for whom the prevalence of CoPEC has been investigated underwent a psychiatric interview.Results were compared according to the CoPEC colonization.In parallel C57BL6/J wild type mice and mice with a CRC susceptibility were chronically infected with a CoPEC strain.Their behavior was assessed using the Elevated Plus Maze test,the Forced Swimming Test and the Behavior recognition system PhenoTyper®.RESULTS In a limited cohort,all patients with CoPEC colonization presented with psychiatric disorders several years before cancer diagnosis,whereas only one patient(17%)without CoPEC did.This result was confirmed in C57BL6/J wildtype mice and in a CRC susceptibility mouse model(adenomatous polyposis colimultiple intestinal neoplasia/+).Mice exhibited a significant increase in anxiety-and depressive-like behaviors after chronic infection with a CoPEC strain.CONCLUSION This finding provides the first evidence that CoPEC infection can induce microbiota-gut-brain axis disturbances in addition to its procarcinogenic properties.
基金the National Natural Science Foundation of China(92159303,81621004,81720108029,81930081,91940305,81672594,81772836,81872139,82072907,and 82003311)Guangdong Science and Technology Department(2020B1212060018 and 2020B1212030004)+8 种基金Clinical Innovation Research Program of Bioland Laboratory(2018GZR0201004)Bureau of Science and Technology of Guangzhou(20212200003)Program for Guangdong Introducing Innovative and Enterpreneurial Teams(2019BT02Y198)the Project of The Beijing Xisike Clinical Oncology Research Foundation(YRoche2019/2-0078)the Technology Development Program of Guangdong province(2021A0505030082)the Project of The Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation(2020B1212060018)Sun Yat-Sen Memorial Hospital Cultivation Project for Clinical Research(SYS-C-201805 and SYS-Q-202004)Guangzhou Science and Technology Program(202102010272)Medical Science and Technology Research Fund of Guangdong Province(A2020391)。
文摘Patients with hormone receptor(HR)-positive tumors breast cancer usually experience a relatively low pathological complete response(p CR)to neoadjuvant chemotherapy(NAC).Here,we derived a 10-micro RNA risk score(10-mi RNA RS)-based model with better performance in the prediction of p CR and validated its relation with the disease-free survival(DFS)in 755 HRpositive breast cancer patients(273,265,and 217 in the training,internal,and external validation sets,respectively).This model,presented as a nomogram,included four parameters:the 10-mi RNA RS found in our previous study,progesterone receptor(PR),human epidermal growth factor receptor 2(HER2)status,and volume transfer constant(K).Favorable calibration and discrimination of 10-mi RNA RS-based model with areas under the curve(AUC)of 0.865,0.811,and 0.804 were shown in the training,internal,and external validation sets,respectively.Patients who have higher nomogram score(>92.2)with NAC treatment would have longer DFS(hazard ratio=0.57;95%CI:0.39–0.83;P=0.004).In summary,our data showed the 10-mi RNA RS-based model could precisely identify more patients who can attain p CR to NAC,which may help clinicians formulate the personalized initial treatment strategy and consequently achieves better clinical prognosis for patients with HRpositive breast cancer.
基金The study was supported by grants from the National Key R&D Program of China(No.2017YFC1307900,2017YFC1307905)The National Natural Science Foundation of China(No.81825007)+3 种基金Beijing Outstanding Young Scientist Program(No.BJJWZYJH01201910025030)Youth Beijing Scholar Program(No.010)Beijing Talent Project-Class A:Innovation and Development(No.2018A12)'National Ten-Thousand Talent Plan'-Leadership of Scientific and Technological Innovation,Sanofi,and Beijing Jialin Pharmaceutical Co.LTD.
文摘Background It remains unclear if intensive antiplatelet and statin treatments begun within 24-72 hours of cerebral ischaemic events from intracranial or extracranial atherosclerosis is effective or safe.Methods The Intensive Statin and Antiplatelet Therapy for High-risk Intracranial or Extracranial Atherosclerosis(INSPIRES)trial is a randomised,double-blind,placebo-controlled,multicentre and 2×2 factorial trial.6100 individuals between the ages of 35 and 80 who have experienced a mild ischaemic stroke or high-risk transient ischaemic attack(TIA)within the previous 72 hours that is attributed to≥50%atherosclerotic stenosis of a major intracranial or extracranial artery or multiple infarctions of atherosclerotic origin will be enrolled in the trial.Eligible subjects will be randomised 1:1:1:1 to one of four groups:(1)intensive antiplatelet therapy(combined clopidogrel and aspirin for days 1-21,then aspirin placebo and clopidogrel for days 22-90)plus immediate intensive statin therapy(atorvastatin at a dose of 80 mg daily for the first 21 days,then 40 mg daily for days 22-90);(2)intensive antiplatelet therapy plus delayed intensive statin therapy(atorvastatin placebo for days 1-3,followed by 40 mg per day of atorvastatin for days 4-90);(3)standard antiplatelet therapy(combination of clopidogrel placebo with aspirin for 90 days)plus immediate intensive statin therapy and(4)standard antiplatelet therapy plus delayed intensive statin therapy.The primary efficacy endpoint is any new stroke(ischaemic or haemorrhagic)within 90 days after randomisation.The primary safety endpoint is moderate to severe bleeding at 90 days.Conclusion The INSPIRES trial will assess the efficacy and safety of intensive antiplatelet therapy and immediate intensive statin therapy begun within 72 hours of onset in decreasing the recurrent stroke at 90 days in patients with acute mild ischaemic stroke or high-risk TIA of intracranial or extracranial atherosclerosis origin.
