Strong evidence supports the concept of immunosurveillance and immunoediting in colorectal cancer. In particular, the density of T CD8<sup>+</sup> and CD45<sup>+</sup> lymphocyte infiltration w...Strong evidence supports the concept of immunosurveillance and immunoediting in colorectal cancer. In particular, the density of T CD8<sup>+</sup> and CD45<sup>+</sup> lymphocyte infiltration was recently shown to have a better prognostic value than the classic tumor node metastasis classification factor. Other immune subsets, as macrophages, natural killer cells or unconventionnal lymphocytes, seem to play an important role. Induction of regulatory T cells (Tregs) or immunosuppressive molecules such as PD-1 or CTLA-4 and downregulation of antigen-presenting molecules are major escape mechanisms to antitumor immune response. The development of these mechanisms is a major obstacle to the establishment of an effective immune response, but also to the use of immunotherapy. Although immunotherapy is not yet routinely used in colorectal cancer, we now know that most treatments used (chemotherapy and biotherapy) have immunomodulatory effects, such as induction of immunogenic cell death by chemotherapy, inhibition of immunosuppression by antiangiogenic agents, and antibody-dependent cytotoxicity induced by cetuximab. Finally, many immunotherapy strategies are being developed and tested in phase I to III clinical trials. The most promising strategies are boosting the immune system with cytokines, inhibition of immunoregulatory checkpoints, vaccination with vectorized antigens, and adoptive cell therapy. Comprehension of antitumor immune response and combination of the different approaches of immunotherapy may allow the use of effective immunotherapy for treatment of colorectal cancer in the near future.展开更多
The features of JAK-STAT signaling in liver cells are discussed in the current review. The role of this signaling cascade in carcinogenesis is accentuated. The possible involvement of this pathway and alteration of it...The features of JAK-STAT signaling in liver cells are discussed in the current review. The role of this signaling cascade in carcinogenesis is accentuated. The possible involvement of this pathway and alteration of its elements are compared for normal cholangiocytes, cholangiocarcinoma predisposition and development. Prolactin and interleukin-6 are described in detail as the best studied examples. In addition, the non-classical nuclear translocation of cytokine receptors is discussed in terms of its possible implication to cholangiocarcinoma development.展开更多
Hepatitis C virus （HCV） is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma （HCC）. In man, the pathobiological changes associated with HCV infection have been attributed to both the i...Hepatitis C virus （HCV） is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma （HCC）. In man, the pathobiological changes associated with HCV infection have been attributed to both the immune system and direct viral cytopathic effects. Until now, the lack of simple culture systems to infect and propagate the virus has hampered progress in understanding the viral life cycle and pathogenesis of HCV infection, including the molecular mechanisms implicated in HCV-induced HCC. This clearly demonstrates the need to develop small animal models for the study of HCV-associated pathogenesis. This review describes and discusses the development of new HCV animal models to study viral infection and investigate the direct effects of viral protein expression on liver disease.展开更多
AIM:To achieve an evidence-based conclusion regarding the safety and efficacy of telbivudine during pregnancy.METHODS:A pooled analysis of data from a literature search reported 1739 pregnancy outcomes(1673 live birth...AIM:To achieve an evidence-based conclusion regarding the safety and efficacy of telbivudine during pregnancy.METHODS:A pooled analysis of data from a literature search reported 1739 pregnancy outcomes(1673 live births)from 1725 non-overlapping pregnant women treated with telbivudine.The prevalence of live birth defects(3.6/1000)was similar to that of the nonantiviral controls(3.0/1000)and not increased as compared with overall prevalence(14.5 to 60/1000).No target organ toxicity was identified.The prevalence of spontaneous abortion in pregnant women treated with telbivudine(4.2/1000)was not increased compared with the overall prevalence(16/1000).The mother-to-child transmission rate was significantly reduced in pregnant women treated with telbivudine(0.70%)compared to those treated with the non-antiviral controls(11.9%;P<0.0001)or compared to the historical rates of hepatitis B virus(HBV)-infected population without antiviral treatment(10%-15%).RESULTS:Cumulatively 489 pregnancy cases have been reported in the telbivudine pharmacovigilance database(with a cut-off date 31 August 2014),of those,308 had known pregnancy outcomes with 249 cases of live births(239 cases of live birth without congenital anomaly and 10 cases of live birth with congenital anomaly).In the latest antiretroviral pregnancy registry report(1 January 1989 through 31 January 2015)of27 patients exposed to telbivudine during pregnancy(18,6 and 3 during first,second and third trimester,respectively)19 live births were reported and there were no cases of birth defects reported.CONCLUSION:Telbivudine treatment during pregnancy presents a favorable safety profile without increased rates of live birth defects,spontaneous abortion or elective termination,or fetal/neonatal toxicity.Exposure to telbivudine in the first,second and third trimester of pregnancy has been shown to significantly reduce the risk of HBV transmission from mother to child on the basis of standard immune prophylaxis procedure.展开更多
Hepatitis B and human immunodeficiency virus(HBV and HIV)infection share transmission patterns and risk factors,which explains high prevalence of chronic HBV infection in HIV infected patients.The natural course of HB...Hepatitis B and human immunodeficiency virus(HBV and HIV)infection share transmission patterns and risk factors,which explains high prevalence of chronic HBV infection in HIV infected patients.The natural course of HBV disease is altered by the HIV infection with less chance to clear acute HBV infection,faster progression to cirrhosis and higher risk of liver-related death in HIVHBV co-infected patients than in HBV mono-infected ones.HIV infected patients with chronic hepatitis B should be counseled for liver damage and surveillance of chronic hepatitis B should be performed to screen early hepatocellular carcinoma.Noninvasive tools are now available to evaluate liver fibrosis.Isolated hepatitis B core antibodies(anti-HBc)are a good predictive marker of occult HBV infection.Still the prevalence and significance of occult HBV infection is controversial,but its screening may be important in the management of antiretroviral therapy.Vaccination against HBV infection is recommended in non-immune HIV patients.The optimal treatment for almost all HIV-HBV co-infectedpatients should contain tenofovir plus lamivudine or emtricitabine and treatment should not be stopped to avoid HBV reactivation.Long term tenofovir therapy may lead to significant decline in hepatitis B surface Antigen.The emergence of resistant HBV strains may compromise the HBV therapy and vaccine therapy.展开更多
AIM:To investigate the mucosal morphology in Barrett's oesophagus by chromo and magnifying endoscopy.METHODS:A prospective pilot study at a tertiary medical centre was conducted to evaluate the use of acetic acid ...AIM:To investigate the mucosal morphology in Barrett's oesophagus by chromo and magnifying endoscopy.METHODS:A prospective pilot study at a tertiary medical centre was conducted to evaluate the use of acetic acid pulverisation combined with virtual chromoendoscopy using Fujinon intelligent chromoendoscopy(FICE) for semiological characterization of the mucosal morphology in Barrett's oesophagus and its neoplastic complications.Upper endoscopy using high definition whitelight,2% acid acetic pulverisation and FICE with high definition videoendoscopy were performed in 20 patients including 18 patients who presented with aspects of Barrett's oesophagus at endoscopy examination.Two patients used as controls had normal endoscopy and histological results.Prospectively,videos were watched blind from histological results by three trained FICE technique endoscopists.RESULTS:The videos of patients with high-grade dysplasia showed an irregular mucosal pattern in 14% using high definition white light endoscopy and in 100% using acid acetic-FICE combined.Videos did not identify irregular vascular patterns using high definition white light endoscopy,while acid acetic-FICE combined visualised one in 86% of cases.CONCLUSION:Combined acetic acid and FICE is a promising method for screening high-grade dysplasia and early cancer in Barrett's oesophagus.展开更多
Hepatocellular carcinoma （HCC） is the ffth most com-mon cancer and the second cause of cancer-related death worldwide. The incidence of HCC is constantly increasing in correlation with the rise in diabetes and obesi...Hepatocellular carcinoma （HCC） is the ffth most com-mon cancer and the second cause of cancer-related death worldwide. The incidence of HCC is constantly increasing in correlation with the rise in diabetes and obesity, arguing for an urgent need for new develo-pments in the treatment of this lethal cancer. Exoso-mes are small double-membrane vesicles loaded with distinct cargos, particularly small non-coding RNAs called microRNAs, representative of each donor cell and secreted to affect the features of neighboring cells or recipient cells located further away, like in the case of metastasis. A better understanding of the role of exosomes with a microRNA signature in cancer path-ogenesis gave rise to the concept of their use as a non-invasive diagnostic biomarker and in the treatment of cancer, including HCC. In this communication, we review recent works that demonstrate that hepatic stellate cells establish an epigenetic communication with liver cancer cells, which affects their pro-malignant features. If naturally secreted patient-derived exosomes show major limitations concerning their clinical use, bio-engin-eered exosome mimetics that incorporate controlled components and exhibit no protumoral properties could be promising carriers for the treatment of liver cancers, which is the organ preferentially targeted by systemic injection of exosomes.展开更多
In healthy people,balance between glucose production and its utilization is precisely controlled.When circulating glucose reaches a critical threshold level,pancreaticβcells secrete insulin that has two major actions...In healthy people,balance between glucose production and its utilization is precisely controlled.When circulating glucose reaches a critical threshold level,pancreaticβcells secrete insulin that has two major actions:to lower circulating glucose levels by facilitating its uptake mainly into skeletal muscle while inhibiting its production by the liver.Interestingly,dietary triglycerides are the main source of fatty acids to fulfill energy needs of oxidative tissues.Normally,the unconsumed fraction of excess of fatty acids is stored in lipid droplets that are localized in adipocytes to provide energy during fasting periods.Thus,adipose tissue acts as a trap for fatty acid excess liberated from plasma triglycerides.When the buffering action of adipose tissue to store fatty acids is impaired,fatty acids that build up in othertissues are metabolized as sphingolipid derivatives such as ceramides.Several studies suggest that ceramides are among the most active lipid second messengers to inhibit the insulin signaling pathway and this review describes the major role played by ceramide accumulation in the development of insulin resistance of peripherals tissues through the targeting of specific proteins of the insulin signaling pathway.展开更多
AIM: To investigate the role of host and bacterial arginases in the colonization of mice by Helicobacter pylori (H.pylori).METHODS: H.pylori produces a very powerful urease that hydrolyzes urea to carbon dioxide and a...AIM: To investigate the role of host and bacterial arginases in the colonization of mice by Helicobacter pylori (H.pylori).METHODS: H.pylori produces a very powerful urease that hydrolyzes urea to carbon dioxide and ammonium,which neutralizes acid.Urease is absolutely essential to H.pylori pathogenesis;therefore,the urea substrate must be in ample supply for urease to work efficiently.The urea substrate is most likely provided by arginase activity,which hydrolyzes L-arginine to L-ornithine and urea.Previous work has demonstrated that H.pylori arginase is surprisingly not required for colonization of wild-type mice.Hence,another in vivo source of the critical urea substrate must exist.We hypothesized that the urea source was provided by host arginase Ⅱ,since this enzyme is expressed in the stomach,and H.pylori has previously been shown to induce the expression of murine gastric arginase Ⅱ.To test this hypothesis,wild-type and arginase (rocF) mutant H.pylori strain SS1 were inoculated into arginase Ⅱ knockout mice.RESULTS: Surprisingly,both the wild-type and rocF mutant bacteria still colonized arginase Ⅱ knockout mice.Moreover,feeding arginase Ⅱ knockout mice the host arginase inhibitor S-(2-boronoethyl)L-cysteine (BEC),while inhibiting > 50% of the host arginase Ⅰ?activity in several tissues,did not block the ability of the rocF mutant H.pylori to colonize.In contrast,BEC poorly inhibited H.pylori arginase activity.CONCLUSION: The in vivo source for the essential urea utilized by H.pylori urease is neither bacterial arginase nor host arginase Ⅱ;instead,either residual host arginase Ⅰ?or agmatinase is probably responsible.展开更多
A lock solution composed of gentamicin sulfate(5 mg/mL) and ethylenediaminetetraacetic acid disodium salt(EDTA-Na2, 30 mg/mL) could fully eradicate in vivo bacterial biofilms in totally implantable venous access ports...A lock solution composed of gentamicin sulfate(5 mg/mL) and ethylenediaminetetraacetic acid disodium salt(EDTA-Na2, 30 mg/mL) could fully eradicate in vivo bacterial biofilms in totally implantable venous access ports(TIVAP). In this study, fabrication, conditioning and sterilization processes of antimicrobial lock solution(ALS) were detailed and completed by a stability study. Stability of ALS was conducted for12 months in vial(25 °C 7 2 °C, 60% 7 5% relative humidity(RH), and at 40 °C 7 2 °C, RH 75% 7 5%)and for 24 h and 72 h in TIVAP(40 °C 7 2 °C, RH 75% 7 5%). A stability indicating HPLC assay with UV detection for simultaneous quantification of gentamicin sulfate and EDTA-Na2 was developed. ALS was assayed by ion-pairing high performance liquid chromatography(HPLC) needing gentamicin derivatization, EDTA-Na2 metallocomplexation of samples and gradient mobile phase. HPLC methods to separate four gentamicin components and EDTA-Na2 were validated. Efficiency of sterility procedure and conditioning of ALS was confirmed by bacterial endotoxins and sterility tests. Physicochemical stability of ALS was determined by visual inspection, osmolality, pH, and sub-visible particle counting. Results confirmed that the stability of ALS in vials was maintained for 12 months and 24 h and 72 h in TIVAP.展开更多
AIM: To investigate genetics of two cases of colorectal tumor local recurrence and throw some light on the etiopathogenesis of anastomotic recurrence. METHODS: Two cases are presented: a 65-year-old female receiving t...AIM: To investigate genetics of two cases of colorectal tumor local recurrence and throw some light on the etiopathogenesis of anastomotic recurrence. METHODS: Two cases are presented: a 65-year-old female receiving two colonic resections for primary anastomotic recurrences within 21 mo, and a 57-year-old female undergoing two local excisions of recurrent anastomotic adenomas within 26 mo. A loss of heterozygosity (LOH) study of 25 microsatellite markers and a mutational analysis of genes BRAF , K-RAS and APC were performed in samples of neoplastic and normal colonic mucosa collected over the years. RESULTS: A diffuse genetic instability was present in all samples, including neoplastic and normal colonic mucosa. Two different patterns of genetic alterations (LOH at 5q21 and 18p11.23 in the first case, and LOH at 1p34 and 3p14 in the second) were found to be associated with carcinogenesis over the years. A role for the genes MYC-L (mapping at 1p34) and FIHT (mapping at 3p14.2) is suggested, whereas a role for APC (mapping at 5q21) is not shown. CONCLUSION: The study challenges the most credited intraluminal implantation and metachronous carcinogenesis theories, and suggests a persistent, patient-specific alteration as the trigger of colorectal cancer anastomotic recurrence.展开更多
AIM： To analyze the modulation of gene expression profile associated with inhibition of liver regeneration in hepatitis B X （HBx）-expressing transgenic mice. METHODS： Microarray technology was performed on liver t...AIM： To analyze the modulation of gene expression profile associated with inhibition of liver regeneration in hepatitis B X （HBx）-expressing transgenic mice. METHODS： Microarray technology was performed on liver tissue obtained from 4 control （LacZ） and 4 transgenic mice （HBx-LacZ）, 48 h after partial hepatectomy. The significance of the normalized logratios was assessed for each gene, using robust t-tests under an empirical Bayes approach. Microarray hybridization data was verified on selected genes by quantitative PCR. RESULTS： The comparison of gene expression patterns showed a consistent modulation of the expression of 26 genes, most of which are implicated in liver regeneration. Up-regulated genes included DNA repair proteins （Rad-52, MSH6） and transmembrane proteins （syndecan 4, tetraspanin）, while down-regulated genes were connected to the regulation of transcription （histone deacetylase, Zfp90, MyoDl） and were involved in the cholesterol metabolic pathway and isoprenoidbiosynthesis （farnesyl diphosphate synthase, Cyp7b1, geranylgeranyl diphosphate synthase, SAA3）. CONCLUSION： Our results provide a novel insight into the biological activities of HBx, implicated in the inhibition of liver regeneration,展开更多
Despite the development of information and communication technologies, mobility still remains an important factor in the development of the social capital, by promoting social interactions. However, rural African popu...Despite the development of information and communication technologies, mobility still remains an important factor in the development of the social capital, by promoting social interactions. However, rural African populations face more difficulties getting around than city dwellers. In addition, studies on mobility in Africa are relatively weak. In rural African areas, this ignorance of mobility is even more important. It is necessary to identify the characteristics and the spatial structure of mobility flows before starting any reflection on solutions, particularly in terms of spatial allocation of transport resources. Our main objective is to map the current movement flows in the Niakhar area. We chose to use the cartographic approach to analyze mobility flows. The data come from a survey carried out in 2018, as part of the French Institute of Research for Development (IRD) Niakhar Atlas project. For the data analysis, we used 4 methods: dominant flux method, net flux calculation method, directional mean statistics and areal interpolation. The results revealed differences in mobility behavior depending on the season and in space, and the existence of three dominant centers: Ngayokhème, Diohine and Toucar. They also made it possible to highlight the main directions of the flows and the scalar fields of mobility.展开更多
Hepatocellular carcinoma（HCC）is one of the leading causes of cancer related death in Asia and Africa（1）.It reflects the high burden of hepatitis B virus（HBV）infection in these areas.Curative treatments of HCC as...Hepatocellular carcinoma（HCC）is one of the leading causes of cancer related death in Asia and Africa（1）.It reflects the high burden of hepatitis B virus（HBV）infection in these areas.Curative treatments of HCC as radiofrequency ablation and resection are impaired by a high rate of tumor recurrence.However,most of the time,HCC is frequently diagnosed at advanced stages where only展开更多
AIM: To investigate if correction of hypovitaminosis D before initiation of Peg-interferon-alpha/ribavirin(Peg IFN/RBV) therapy could improve the efficacy of Peg IFN/RBV in previously null-responder patients with chro...AIM: To investigate if correction of hypovitaminosis D before initiation of Peg-interferon-alpha/ribavirin(Peg IFN/RBV) therapy could improve the efficacy of Peg IFN/RBV in previously null-responder patients with chronic genotype 1 or 4 hepatitis C virus(HCV) infection.METHODS:Genotype 1 or 4 HCV-infected patients with null response to previous Peg IFN/RBV treatment and with hypovitaminosis D(<30 ng/m L)prospectively received cholecalciferol 100000 IU per week for 4 wk[from week-4(W-4)to W0],followed by 100000 IUper month in combination with Peg IFN/RBV for 12 mo(from W0 to W48).The primary outcome was the rate of early virological response defined by an HCV RNA<12 IU/m L after 12 wk Peg IFN/RBV treatment.RESULTS:A total of 32 patients were included,19(59%)and 13(41%)patients were HCV genotype1 and 4,respectively.The median baseline vitamin D level was 15 ng/m L(range:7-28).In modified intention-to-treat analysis,29 patients who received at least one dose of Peg IFN/RBV were included in the analysis.All patients except one normalized their vitamin D serum levels.The rate of early virologic response was 0/29(0%).The rate of HCV RNA<12IU/m L after 24 wk of Peg IFN/RBV was 1/27(4%).The safety profile was favorable.CONCLUSION:Addition of vitamin D to Peg IFN/RBV does not improve the rate of early virologic response in previously null-responders with chronic genotype 1or 4 HCV infection.展开更多
Amyotrophic lateral sclerosis （ALS） is a lethal disorder char- acterized by the gradual degeneration of brainstem and spinal motoneurons as well as lateral cortico-spinal tracts. The onset generally occurs during th...Amyotrophic lateral sclerosis （ALS） is a lethal disorder char- acterized by the gradual degeneration of brainstem and spinal motoneurons as well as lateral cortico-spinal tracts. The onset generally occurs during the adult age except for some juvenile aggressive forms. Until recently, the vast majority of the cases （90%） were deemed sporadic. Mutations in the SOD1 gene have been for a long time the only ones reported in familiar forms of ALS. However, the recent implication of new genes of little known function cast a new view on this disease. C9ORF72, for example, is now recognized to account for 30% of the familial cases. Overall, ALS has been linked to 20 different genes, many also associated with other degenerative diseases （frontotemporal dementia, Alzheimer or ataxia）. Some of these genes are in- volved in RNA maturation （FUS, TARBD）. Clinical observation of human patients and mouse models suggests that all motor pools and motoneurons are not equally affected （see Kanning et al., 2010）. The disease usually starts in motor pools controlling the limbs or in the bulbar area before expanding to other motor pools, with the exception of a few resistant ones （Onuf＇s and oculomotor nuclei）. Within a vulnerable motor pool, motoneu- tons subtypes also exhibit differential vulnerability and follow an orderly degeneration; starting with the motoneurons innervating fast-contracting fatigable motor units （IZF motoneurons） and followed by the ones innervating fast-contractile fatigue-resistant motor units （FR motoneurons）. The motoneurons in- nervating slow motor units （S motoneurons） appear resistant to the disease. Although the mechanisms leading to the orderly degeneration are not known, many hypotheses have been raised （Ilieva et al., 2009）.展开更多
AIMTo describe factors associated with treatment failure and frequency of resistance-associated substitutions （RAS）.METHODSHuman immunodefciency virus （HIV）/hepatitis C virus （HCV） coinfected patients starting a...AIMTo describe factors associated with treatment failure and frequency of resistance-associated substitutions （RAS）.METHODSHuman immunodefciency virus （HIV）/hepatitis C virus （HCV） coinfected patients starting a first direct-acting antiviral （DAA） regimen before February 2016 and included in the French ANRS CO13 HEPAVIH cohort were eligible. Failure was defned as： （1） non-response [HCV-RNA remained detectable during treatment, at end of treatment （EOT）]; and （2） relapse （HCV-RNA suppressed at EOT but detectable thereafter）. Sequencing analysis was performed to describe prevalence of drug class-specifc RAS. Factors associated with failure were determined using logistic regression models.RESULTSAmong 559 patients, 77% had suppressed plasmaHIV-RNA 〈 50 copies/mL at DAA treatment initiation41% were cirrhotic, and 68% were HCV treatmentexperienced. Virological treatment failures occurred in22 patients and were mainly relapses （17, 77%） thenundefined failures （3, 14%） and non-responses （29%）. Mean treatment duration was 16 wk overall. Posttreatment NS3, NS5A or NS5B RAS were detected in10/14 patients with samples available for sequencinganalysis. After adjustment for age, sex, ribavirin useHCV genotype and treatment duration, low platelecount was the only factor signifcantly associated with ahigher risk of failure （OR： 6.5; 95%CI： 1.8-22.6）. CONCLUSIONOnly 3.9% HIV-HCV coinfected patients failed DAAregimens and RAS were found in 70% of those failingLow platelet count was independently associated withvirological failure.展开更多
Introduction: Pelvic exenteration can cure recurrent gynecological malignancies. However, treatment morbidity is over 50% in radiated pelves. We evaluated the outcome, the morbidity and the quality of life after exent...Introduction: Pelvic exenteration can cure recurrent gynecological malignancies. However, treatment morbidity is over 50% in radiated pelves. We evaluated the outcome, the morbidity and the quality of life after exenteration. Methods: Patients who underwent an exenteration for recurrent cervical or endometrial cancer in our institution between 1999 and 2011 were retrieved. Survival rates were calculated according to Kaplan-Meier method and compared using the logrank test. The EORTC QLQ-C30 and QLQ-CX24 questionnaires were sent to patients alive in January 2012. Results: We identified 25 patients: 17 (68%) had cervical cancer and 8 (32%) endometrial cancer. 92% of them had received radiotherapy previously. All patients had a central pelvic recurrence, within a median time of 30 months [4 - 384] from initial treatment. Early complications requiring a re-laparotomy occurred in 9 patients (36%). Late complications included 2 (8%) fistulas, 2 (8%) occlusion and 1 (4%) ureteral stenosis. Complete resection was obtained in 92% of patients. Disease Free and Overall survival rates were better in cervical rather than in endometrial cancer (median DFS in months 17 [2 - 145] vs 9.5 [3 - 21], p = 0.064, median OS in months 20 [2 - 145] vs 13 [4 - 42], p = 0.019). 69% of patients answered the quality of life questionnaires. Mean global quality of life score was 45 on a scale of 0 - 100, none of the patients had a sexual activity. Conclusions: Morbidity of exenteration remains high and quality of life is altered. Endometrial cancer is associated with a poorer prognosis. In those patients, exenteration should be put in balance with best supportive care.展开更多
A study examining affective information processing in persons with Multiple Sclerosis and healthy adults was carried out. It was hypothesized that individual characteristics could modulate participants’ emotional cat...A study examining affective information processing in persons with Multiple Sclerosis and healthy adults was carried out. It was hypothesized that individual characteristics could modulate participants’ emotional categorization and reaction times for categorization decisions. For example, individuals with negative valenced emotional profile (e.g. anxious) should choose negative emotional alternatives faster and more frequently. Participants consisted of two different populations: 80 right-handed healthy French-speakers, and 40 right-handed French- speakers with multiple sclerosis. The results showed a positive correlation between high- level of negative emotional sensibility and emotional categorization (decision and decision speed) for affective information presented on the right-side of the screen. For all participants there were more frequent emotional choices and faster decisions for left-side presented emotional alternatives. It seems individuals’ emotional differences in general and in MS populations modulate hemispheric asymmetry of processing emotional judgments.展开更多
文摘Strong evidence supports the concept of immunosurveillance and immunoediting in colorectal cancer. In particular, the density of T CD8<sup>+</sup> and CD45<sup>+</sup> lymphocyte infiltration was recently shown to have a better prognostic value than the classic tumor node metastasis classification factor. Other immune subsets, as macrophages, natural killer cells or unconventionnal lymphocytes, seem to play an important role. Induction of regulatory T cells (Tregs) or immunosuppressive molecules such as PD-1 or CTLA-4 and downregulation of antigen-presenting molecules are major escape mechanisms to antitumor immune response. The development of these mechanisms is a major obstacle to the establishment of an effective immune response, but also to the use of immunotherapy. Although immunotherapy is not yet routinely used in colorectal cancer, we now know that most treatments used (chemotherapy and biotherapy) have immunomodulatory effects, such as induction of immunogenic cell death by chemotherapy, inhibition of immunosuppression by antiangiogenic agents, and antibody-dependent cytotoxicity induced by cetuximab. Finally, many immunotherapy strategies are being developed and tested in phase I to III clinical trials. The most promising strategies are boosting the immune system with cytokines, inhibition of immunoregulatory checkpoints, vaccination with vectorized antigens, and adoptive cell therapy. Comprehension of antitumor immune response and combination of the different approaches of immunotherapy may allow the use of effective immunotherapy for treatment of colorectal cancer in the near future.
文摘The features of JAK-STAT signaling in liver cells are discussed in the current review. The role of this signaling cascade in carcinogenesis is accentuated. The possible involvement of this pathway and alteration of its elements are compared for normal cholangiocytes, cholangiocarcinoma predisposition and development. Prolactin and interleukin-6 are described in detail as the best studied examples. In addition, the non-classical nuclear translocation of cytokine receptors is discussed in terms of its possible implication to cholangiocarcinoma development.
文摘Hepatitis C virus （HCV） is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma （HCC）. In man, the pathobiological changes associated with HCV infection have been attributed to both the immune system and direct viral cytopathic effects. Until now, the lack of simple culture systems to infect and propagate the virus has hampered progress in understanding the viral life cycle and pathogenesis of HCV infection, including the molecular mechanisms implicated in HCV-induced HCC. This clearly demonstrates the need to develop small animal models for the study of HCV-associated pathogenesis. This review describes and discusses the development of new HCV animal models to study viral infection and investigate the direct effects of viral protein expression on liver disease.
文摘AIM:To achieve an evidence-based conclusion regarding the safety and efficacy of telbivudine during pregnancy.METHODS:A pooled analysis of data from a literature search reported 1739 pregnancy outcomes(1673 live births)from 1725 non-overlapping pregnant women treated with telbivudine.The prevalence of live birth defects(3.6/1000)was similar to that of the nonantiviral controls(3.0/1000)and not increased as compared with overall prevalence(14.5 to 60/1000).No target organ toxicity was identified.The prevalence of spontaneous abortion in pregnant women treated with telbivudine(4.2/1000)was not increased compared with the overall prevalence(16/1000).The mother-to-child transmission rate was significantly reduced in pregnant women treated with telbivudine(0.70%)compared to those treated with the non-antiviral controls(11.9%;P<0.0001)or compared to the historical rates of hepatitis B virus(HBV)-infected population without antiviral treatment(10%-15%).RESULTS:Cumulatively 489 pregnancy cases have been reported in the telbivudine pharmacovigilance database(with a cut-off date 31 August 2014),of those,308 had known pregnancy outcomes with 249 cases of live births(239 cases of live birth without congenital anomaly and 10 cases of live birth with congenital anomaly).In the latest antiretroviral pregnancy registry report(1 January 1989 through 31 January 2015)of27 patients exposed to telbivudine during pregnancy(18,6 and 3 during first,second and third trimester,respectively)19 live births were reported and there were no cases of birth defects reported.CONCLUSION:Telbivudine treatment during pregnancy presents a favorable safety profile without increased rates of live birth defects,spontaneous abortion or elective termination,or fetal/neonatal toxicity.Exposure to telbivudine in the first,second and third trimester of pregnancy has been shown to significantly reduce the risk of HBV transmission from mother to child on the basis of standard immune prophylaxis procedure.
文摘Hepatitis B and human immunodeficiency virus(HBV and HIV)infection share transmission patterns and risk factors,which explains high prevalence of chronic HBV infection in HIV infected patients.The natural course of HBV disease is altered by the HIV infection with less chance to clear acute HBV infection,faster progression to cirrhosis and higher risk of liver-related death in HIVHBV co-infected patients than in HBV mono-infected ones.HIV infected patients with chronic hepatitis B should be counseled for liver damage and surveillance of chronic hepatitis B should be performed to screen early hepatocellular carcinoma.Noninvasive tools are now available to evaluate liver fibrosis.Isolated hepatitis B core antibodies(anti-HBc)are a good predictive marker of occult HBV infection.Still the prevalence and significance of occult HBV infection is controversial,but its screening may be important in the management of antiretroviral therapy.Vaccination against HBV infection is recommended in non-immune HIV patients.The optimal treatment for almost all HIV-HBV co-infectedpatients should contain tenofovir plus lamivudine or emtricitabine and treatment should not be stopped to avoid HBV reactivation.Long term tenofovir therapy may lead to significant decline in hepatitis B surface Antigen.The emergence of resistant HBV strains may compromise the HBV therapy and vaccine therapy.
文摘AIM:To investigate the mucosal morphology in Barrett's oesophagus by chromo and magnifying endoscopy.METHODS:A prospective pilot study at a tertiary medical centre was conducted to evaluate the use of acetic acid pulverisation combined with virtual chromoendoscopy using Fujinon intelligent chromoendoscopy(FICE) for semiological characterization of the mucosal morphology in Barrett's oesophagus and its neoplastic complications.Upper endoscopy using high definition whitelight,2% acid acetic pulverisation and FICE with high definition videoendoscopy were performed in 20 patients including 18 patients who presented with aspects of Barrett's oesophagus at endoscopy examination.Two patients used as controls had normal endoscopy and histological results.Prospectively,videos were watched blind from histological results by three trained FICE technique endoscopists.RESULTS:The videos of patients with high-grade dysplasia showed an irregular mucosal pattern in 14% using high definition white light endoscopy and in 100% using acid acetic-FICE combined.Videos did not identify irregular vascular patterns using high definition white light endoscopy,while acid acetic-FICE combined visualised one in 86% of cases.CONCLUSION:Combined acetic acid and FICE is a promising method for screening high-grade dysplasia and early cancer in Barrett's oesophagus.
文摘Hepatocellular carcinoma （HCC） is the ffth most com-mon cancer and the second cause of cancer-related death worldwide. The incidence of HCC is constantly increasing in correlation with the rise in diabetes and obesity, arguing for an urgent need for new develo-pments in the treatment of this lethal cancer. Exoso-mes are small double-membrane vesicles loaded with distinct cargos, particularly small non-coding RNAs called microRNAs, representative of each donor cell and secreted to affect the features of neighboring cells or recipient cells located further away, like in the case of metastasis. A better understanding of the role of exosomes with a microRNA signature in cancer path-ogenesis gave rise to the concept of their use as a non-invasive diagnostic biomarker and in the treatment of cancer, including HCC. In this communication, we review recent works that demonstrate that hepatic stellate cells establish an epigenetic communication with liver cancer cells, which affects their pro-malignant features. If naturally secreted patient-derived exosomes show major limitations concerning their clinical use, bio-engin-eered exosome mimetics that incorporate controlled components and exhibit no protumoral properties could be promising carriers for the treatment of liver cancers, which is the organ preferentially targeted by systemic injection of exosomes.
基金Supported by INSERM,the SociétéFrancophone du Diabètean Agence Nationale de la Recherche grant project(Crisalis)
文摘In healthy people,balance between glucose production and its utilization is precisely controlled.When circulating glucose reaches a critical threshold level,pancreaticβcells secrete insulin that has two major actions:to lower circulating glucose levels by facilitating its uptake mainly into skeletal muscle while inhibiting its production by the liver.Interestingly,dietary triglycerides are the main source of fatty acids to fulfill energy needs of oxidative tissues.Normally,the unconsumed fraction of excess of fatty acids is stored in lipid droplets that are localized in adipocytes to provide energy during fasting periods.Thus,adipose tissue acts as a trap for fatty acid excess liberated from plasma triglycerides.When the buffering action of adipose tissue to store fatty acids is impaired,fatty acids that build up in othertissues are metabolized as sphingolipid derivatives such as ceramides.Several studies suggest that ceramides are among the most active lipid second messengers to inhibit the insulin signaling pathway and this review describes the major role played by ceramide accumulation in the development of insulin resistance of peripherals tissues through the targeting of specific proteins of the insulin signaling pathway.
基金Supported by Public Health Service grant R01-CA101931 (to DJM) from the National Institutes of Health
文摘AIM: To investigate the role of host and bacterial arginases in the colonization of mice by Helicobacter pylori (H.pylori).METHODS: H.pylori produces a very powerful urease that hydrolyzes urea to carbon dioxide and ammonium,which neutralizes acid.Urease is absolutely essential to H.pylori pathogenesis;therefore,the urea substrate must be in ample supply for urease to work efficiently.The urea substrate is most likely provided by arginase activity,which hydrolyzes L-arginine to L-ornithine and urea.Previous work has demonstrated that H.pylori arginase is surprisingly not required for colonization of wild-type mice.Hence,another in vivo source of the critical urea substrate must exist.We hypothesized that the urea source was provided by host arginase Ⅱ,since this enzyme is expressed in the stomach,and H.pylori has previously been shown to induce the expression of murine gastric arginase Ⅱ.To test this hypothesis,wild-type and arginase (rocF) mutant H.pylori strain SS1 were inoculated into arginase Ⅱ knockout mice.RESULTS: Surprisingly,both the wild-type and rocF mutant bacteria still colonized arginase Ⅱ knockout mice.Moreover,feeding arginase Ⅱ knockout mice the host arginase inhibitor S-(2-boronoethyl)L-cysteine (BEC),while inhibiting > 50% of the host arginase Ⅰ?activity in several tissues,did not block the ability of the rocF mutant H.pylori to colonize.In contrast,BEC poorly inhibited H.pylori arginase activity.CONCLUSION: The in vivo source for the essential urea utilized by H.pylori urease is neither bacterial arginase nor host arginase Ⅱ;instead,either residual host arginase Ⅰ?or agmatinase is probably responsible.
基金supported by Centre de Recherche Translationnelle de I'Institut Pasteur, grant Number S- PI15007-02Asupported by the French Government's Investissement d'Avenir program:Laboratoire d'Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (grant no. ANR-10-LABX62-IBEID.)+1 种基金the Fondation pour la Recherche Médicale (grant no. DEQ. 20140329508)the Center for Translational Science of the Institut Pasteur (S-PI15007-02A)
文摘A lock solution composed of gentamicin sulfate(5 mg/mL) and ethylenediaminetetraacetic acid disodium salt(EDTA-Na2, 30 mg/mL) could fully eradicate in vivo bacterial biofilms in totally implantable venous access ports(TIVAP). In this study, fabrication, conditioning and sterilization processes of antimicrobial lock solution(ALS) were detailed and completed by a stability study. Stability of ALS was conducted for12 months in vial(25 °C 7 2 °C, 60% 7 5% relative humidity(RH), and at 40 °C 7 2 °C, RH 75% 7 5%)and for 24 h and 72 h in TIVAP(40 °C 7 2 °C, RH 75% 7 5%). A stability indicating HPLC assay with UV detection for simultaneous quantification of gentamicin sulfate and EDTA-Na2 was developed. ALS was assayed by ion-pairing high performance liquid chromatography(HPLC) needing gentamicin derivatization, EDTA-Na2 metallocomplexation of samples and gradient mobile phase. HPLC methods to separate four gentamicin components and EDTA-Na2 were validated. Efficiency of sterility procedure and conditioning of ALS was confirmed by bacterial endotoxins and sterility tests. Physicochemical stability of ALS was determined by visual inspection, osmolality, pH, and sub-visible particle counting. Results confirmed that the stability of ALS in vials was maintained for 12 months and 24 h and 72 h in TIVAP.
文摘AIM: To investigate genetics of two cases of colorectal tumor local recurrence and throw some light on the etiopathogenesis of anastomotic recurrence. METHODS: Two cases are presented: a 65-year-old female receiving two colonic resections for primary anastomotic recurrences within 21 mo, and a 57-year-old female undergoing two local excisions of recurrent anastomotic adenomas within 26 mo. A loss of heterozygosity (LOH) study of 25 microsatellite markers and a mutational analysis of genes BRAF , K-RAS and APC were performed in samples of neoplastic and normal colonic mucosa collected over the years. RESULTS: A diffuse genetic instability was present in all samples, including neoplastic and normal colonic mucosa. Two different patterns of genetic alterations (LOH at 5q21 and 18p11.23 in the first case, and LOH at 1p34 and 3p14 in the second) were found to be associated with carcinogenesis over the years. A role for the genes MYC-L (mapping at 1p34) and FIHT (mapping at 3p14.2) is suggested, whereas a role for APC (mapping at 5q21) is not shown. CONCLUSION: The study challenges the most credited intraluminal implantation and metachronous carcinogenesis theories, and suggests a persistent, patient-specific alteration as the trigger of colorectal cancer anastomotic recurrence.
文摘AIM： To analyze the modulation of gene expression profile associated with inhibition of liver regeneration in hepatitis B X （HBx）-expressing transgenic mice. METHODS： Microarray technology was performed on liver tissue obtained from 4 control （LacZ） and 4 transgenic mice （HBx-LacZ）, 48 h after partial hepatectomy. The significance of the normalized logratios was assessed for each gene, using robust t-tests under an empirical Bayes approach. Microarray hybridization data was verified on selected genes by quantitative PCR. RESULTS： The comparison of gene expression patterns showed a consistent modulation of the expression of 26 genes, most of which are implicated in liver regeneration. Up-regulated genes included DNA repair proteins （Rad-52, MSH6） and transmembrane proteins （syndecan 4, tetraspanin）, while down-regulated genes were connected to the regulation of transcription （histone deacetylase, Zfp90, MyoDl） and were involved in the cholesterol metabolic pathway and isoprenoidbiosynthesis （farnesyl diphosphate synthase, Cyp7b1, geranylgeranyl diphosphate synthase, SAA3）. CONCLUSION： Our results provide a novel insight into the biological activities of HBx, implicated in the inhibition of liver regeneration,
文摘Despite the development of information and communication technologies, mobility still remains an important factor in the development of the social capital, by promoting social interactions. However, rural African populations face more difficulties getting around than city dwellers. In addition, studies on mobility in Africa are relatively weak. In rural African areas, this ignorance of mobility is even more important. It is necessary to identify the characteristics and the spatial structure of mobility flows before starting any reflection on solutions, particularly in terms of spatial allocation of transport resources. Our main objective is to map the current movement flows in the Niakhar area. We chose to use the cartographic approach to analyze mobility flows. The data come from a survey carried out in 2018, as part of the French Institute of Research for Development (IRD) Niakhar Atlas project. For the data analysis, we used 4 methods: dominant flux method, net flux calculation method, directional mean statistics and areal interpolation. The results revealed differences in mobility behavior depending on the season and in space, and the existence of three dominant centers: Ngayokhème, Diohine and Toucar. They also made it possible to highlight the main directions of the flows and the scalar fields of mobility.
基金supported by HECAM (BPI), EBCI, INCa (Wnt HCC project). J-C.N.supported by a fellowship from INCa
文摘Hepatocellular carcinoma（HCC）is one of the leading causes of cancer related death in Asia and Africa（1）.It reflects the high burden of hepatitis B virus（HBV）infection in these areas.Curative treatments of HCC as radiofrequency ablation and resection are impaired by a high rate of tumor recurrence.However,most of the time,HCC is frequently diagnosed at advanced stages where only
文摘AIM: To investigate if correction of hypovitaminosis D before initiation of Peg-interferon-alpha/ribavirin(Peg IFN/RBV) therapy could improve the efficacy of Peg IFN/RBV in previously null-responder patients with chronic genotype 1 or 4 hepatitis C virus(HCV) infection.METHODS:Genotype 1 or 4 HCV-infected patients with null response to previous Peg IFN/RBV treatment and with hypovitaminosis D(<30 ng/m L)prospectively received cholecalciferol 100000 IU per week for 4 wk[from week-4(W-4)to W0],followed by 100000 IUper month in combination with Peg IFN/RBV for 12 mo(from W0 to W48).The primary outcome was the rate of early virological response defined by an HCV RNA<12 IU/m L after 12 wk Peg IFN/RBV treatment.RESULTS:A total of 32 patients were included,19(59%)and 13(41%)patients were HCV genotype1 and 4,respectively.The median baseline vitamin D level was 15 ng/m L(range:7-28).In modified intention-to-treat analysis,29 patients who received at least one dose of Peg IFN/RBV were included in the analysis.All patients except one normalized their vitamin D serum levels.The rate of early virologic response was 0/29(0%).The rate of HCV RNA<12IU/m L after 24 wk of Peg IFN/RBV was 1/27(4%).The safety profile was favorable.CONCLUSION:Addition of vitamin D to Peg IFN/RBV does not improve the rate of early virologic response in previously null-responders with chronic genotype 1or 4 HCV infection.
基金Financial supports provided by the Agence Nationale pour la Recherche(HYPER-MND,ANR-2010-BLAN-1429-01)the NIHNINDS(R01NS077863)the Thierry Latran Fundation(OHEX Project)
文摘Amyotrophic lateral sclerosis （ALS） is a lethal disorder char- acterized by the gradual degeneration of brainstem and spinal motoneurons as well as lateral cortico-spinal tracts. The onset generally occurs during the adult age except for some juvenile aggressive forms. Until recently, the vast majority of the cases （90%） were deemed sporadic. Mutations in the SOD1 gene have been for a long time the only ones reported in familiar forms of ALS. However, the recent implication of new genes of little known function cast a new view on this disease. C9ORF72, for example, is now recognized to account for 30% of the familial cases. Overall, ALS has been linked to 20 different genes, many also associated with other degenerative diseases （frontotemporal dementia, Alzheimer or ataxia）. Some of these genes are in- volved in RNA maturation （FUS, TARBD）. Clinical observation of human patients and mouse models suggests that all motor pools and motoneurons are not equally affected （see Kanning et al., 2010）. The disease usually starts in motor pools controlling the limbs or in the bulbar area before expanding to other motor pools, with the exception of a few resistant ones （Onuf＇s and oculomotor nuclei）. Within a vulnerable motor pool, motoneu- tons subtypes also exhibit differential vulnerability and follow an orderly degeneration; starting with the motoneurons innervating fast-contracting fatigable motor units （IZF motoneurons） and followed by the ones innervating fast-contractile fatigue-resistant motor units （FR motoneurons）. The motoneurons in- nervating slow motor units （S motoneurons） appear resistant to the disease. Although the mechanisms leading to the orderly degeneration are not known, many hypotheses have been raised （Ilieva et al., 2009）.
基金Supported by Inserm-ANRS(French National Institute for Health and Medical Research-ANRS/France REcherche Nord and Sud Sida-hiv Hépatites)
文摘AIMTo describe factors associated with treatment failure and frequency of resistance-associated substitutions （RAS）.METHODSHuman immunodefciency virus （HIV）/hepatitis C virus （HCV） coinfected patients starting a first direct-acting antiviral （DAA） regimen before February 2016 and included in the French ANRS CO13 HEPAVIH cohort were eligible. Failure was defned as： （1） non-response [HCV-RNA remained detectable during treatment, at end of treatment （EOT）]; and （2） relapse （HCV-RNA suppressed at EOT but detectable thereafter）. Sequencing analysis was performed to describe prevalence of drug class-specifc RAS. Factors associated with failure were determined using logistic regression models.RESULTSAmong 559 patients, 77% had suppressed plasmaHIV-RNA 〈 50 copies/mL at DAA treatment initiation41% were cirrhotic, and 68% were HCV treatmentexperienced. Virological treatment failures occurred in22 patients and were mainly relapses （17, 77%） thenundefined failures （3, 14%） and non-responses （29%）. Mean treatment duration was 16 wk overall. Posttreatment NS3, NS5A or NS5B RAS were detected in10/14 patients with samples available for sequencinganalysis. After adjustment for age, sex, ribavirin useHCV genotype and treatment duration, low platelecount was the only factor signifcantly associated with ahigher risk of failure （OR： 6.5; 95%CI： 1.8-22.6）. CONCLUSIONOnly 3.9% HIV-HCV coinfected patients failed DAAregimens and RAS were found in 70% of those failingLow platelet count was independently associated withvirological failure.
文摘Introduction: Pelvic exenteration can cure recurrent gynecological malignancies. However, treatment morbidity is over 50% in radiated pelves. We evaluated the outcome, the morbidity and the quality of life after exenteration. Methods: Patients who underwent an exenteration for recurrent cervical or endometrial cancer in our institution between 1999 and 2011 were retrieved. Survival rates were calculated according to Kaplan-Meier method and compared using the logrank test. The EORTC QLQ-C30 and QLQ-CX24 questionnaires were sent to patients alive in January 2012. Results: We identified 25 patients: 17 (68%) had cervical cancer and 8 (32%) endometrial cancer. 92% of them had received radiotherapy previously. All patients had a central pelvic recurrence, within a median time of 30 months [4 - 384] from initial treatment. Early complications requiring a re-laparotomy occurred in 9 patients (36%). Late complications included 2 (8%) fistulas, 2 (8%) occlusion and 1 (4%) ureteral stenosis. Complete resection was obtained in 92% of patients. Disease Free and Overall survival rates were better in cervical rather than in endometrial cancer (median DFS in months 17 [2 - 145] vs 9.5 [3 - 21], p = 0.064, median OS in months 20 [2 - 145] vs 13 [4 - 42], p = 0.019). 69% of patients answered the quality of life questionnaires. Mean global quality of life score was 45 on a scale of 0 - 100, none of the patients had a sexual activity. Conclusions: Morbidity of exenteration remains high and quality of life is altered. Endometrial cancer is associated with a poorer prognosis. In those patients, exenteration should be put in balance with best supportive care.
文摘A study examining affective information processing in persons with Multiple Sclerosis and healthy adults was carried out. It was hypothesized that individual characteristics could modulate participants’ emotional categorization and reaction times for categorization decisions. For example, individuals with negative valenced emotional profile (e.g. anxious) should choose negative emotional alternatives faster and more frequently. Participants consisted of two different populations: 80 right-handed healthy French-speakers, and 40 right-handed French- speakers with multiple sclerosis. The results showed a positive correlation between high- level of negative emotional sensibility and emotional categorization (decision and decision speed) for affective information presented on the right-side of the screen. For all participants there were more frequent emotional choices and faster decisions for left-side presented emotional alternatives. It seems individuals’ emotional differences in general and in MS populations modulate hemispheric asymmetry of processing emotional judgments.
