Probiotic intervention has strain-specific anti-inflammatory effects in healthy adults

AIM: To evaluate the effects of three potentially anti- inflammatory probiotic bacteria from three different genera on immune variables in healthy adults in a clinical setting based on previous in vitro characterization of cytokine responses. METHODS: A total of 62 volunteers participated in this randomized, double-blind and placebo-controlled parallel group intervention study. The volunteers were randomized to receive a milk-based drink containing either Lactobacillus rhamnosus GG (LGG), Bifidobacterium animalis ssp. lactis Bb12 (Bb12), or Propionibacterium freudenreichii ssp. shermanii JS (PJS) or a placebo drink for 3 wk. Venous blood and saliva samples were taken at baseline and on d 1, 7 and 21. Fecal samples were collected at baseline and at the end of intervention. RESULTS: The serum hsCRP expressed as the median AUC0-21 (minus baseline) was 0.018 mg/L in the placebo group, -0.240 mg/L in the LGG group, 0.090 mg/L in the Bb12 group and -0.085 mg/L in the PJS group (P = 0.014). In vitro production of TNF-α from in vitro cultured peripheral blood mononuclear cells (PBMC) was significantly lower in subjects receiving LGG vs placebo. IL-2 production from PBMC in the Bb12 group was significantly lower compared with the other groups. CONCLUSION: In conclusion, probiotic bacteria have strain-specific anti-inflammatory effects in healthy adults.

Effect of probiotic Lactobacillus rhamnosus GG intervention on global serum lipidomic profiles in healthy adults

AIM: To investigate the effect of three weeks’ intervention with a probiotic Lactobacillus rhamnosus GG (LGG) bacteria on global serum lipidomic profiles and evaluate whether the changes in inflammatory variables (CRP, TNF-α and IL-6) are reflected in the global lipidomic profiles of healthy adults. METHODS: We performed UPLC/MS-based global lipidomic platform analysis of serum samples (n = 26) in a substudy of a randomised, double-blind, placebo- controlled 3-wk clinical intervention trial investigating the immunomodulatory effects of probiotics in healthy adults. RESULTS: A total of 407 lipids were identified, corresponding to 13 different lipid classes. Serum samples showed decreases in the levels of lysophosphatidylcholines (LysoGPCho), sphingomyelins (SM) and several glycerophosphatidylcholines (GPCho), while triacylglycerols (TAG) were mainly increased in the probiotic LGG group during the intervention. Among the inflammatory variables, IL-6 was moderatelyassociated by changes in global lipidomic profiles, with the top-ranked lipid associated with IL-6 being the proinflammatory LysoGPCho (20:4). There was a weak association between the lipidomic profiles and the two other inflammatory markers, TNF-α and CRP. CONCLUSION: This was the first study to investigate the effects of probiotic intervention on global lipidomic profiles in humans. There are indications that probiotic LGG intervention may lead to changes in serum global lipid profiles, as reflected in decreased GPCho, LysoGPCho and SM as well as mainly increased TAG.

The Role of Health Inequality in the Maternal Health Services Provided by Public Institutions in Mexico

This work aims to determine the role of inequality in the provision of maternal health services among five regions in Mexico (northwest, northeast, central, the Mexico City-State of Mexico region and the south). We consider the most important service providers corresponding to the main health institutions in Mexico (IMSS, ISSSTE, SESAS, IMSS-Oportunidades). Therefore, a cross-sectional prospective study was conducted to analyze eight intervention packages (Prenatal Care, Syphilis, Influenza, Obstetric Urgent Care, HIV in pregnancy, delivery care, neonatal care and accessibility) offered by the Maternal and Perinatal Health (MPH) program. A quantitative analysis demonstrates low to marginal performance of the MPH program in three regions (South, Mexico City-State of Mexico and the Northwest) and marginal in two other regions (Central and Northeast). Furthermore, four of the intervention packages presented the lowest performance in the South (Prenatal Care, Syphilis, Influenza and Obstetric Urgent Care), as did the average of the total of the MPH packages. The performance of HIV in Pregnancy package was marginal in the Southern and Mexico City-State of Mexico regions and Neonatal Care was low in the Northwest. The assessment of the MPH intervention packages allows us to identify their strengths and weaknesses. This information allows us to identify similarities and differences among the geographical regions in order to describe and analyze the strengths, weaknesses, opportunities and threats in the current system and hence to improve the decision making regarding the Maternal and Perinatal Health Programs in Mexico. The results suggest that a homogenization has taken place in terms of the low quality of the services.

Prevalence of Ventilatory Function Abnormalities in Residents of Attecoube Lagune, Abidjan (Côte d’Ivoire)

Introduction: Studies of abnormal ventilatory function in Côte d’Ivoire have been carried out in the workplace and in schools. The objective of this study was to determine the prevalence of respiratory symptoms and ventilatory function abnormalities in the population of the lagoon district of Attécoubé in Abidjan. Material and Methods: A cross-sectional study was carried out on 170 people in the municipality of Attécoubé Lagune. A questionnaire was used to collect information on sociodemographic, clinical, and environmental characteristics. A basic spirometry and a beta mimetic test were carried out on all the subjects surveyed. Data analysis was done with the stata 15.1 software. Results: The study population was composed of 103 women and 67 men with a sex ratio (M/F) of 0.65. The average age was 35.92 ± 15.28 years. The most frequent respiratory symptoms were chest tightness (29.41%), dyspnea (28.82%), sneezing (22.94%) and cough (22.35%). The prevalence of ventilatory function abnormalities was 43.24% among residents of Attécoubé Lagune and the most frequent abnormality was ventilatory restriction (35.15%) followed by obstruction (4.85%). The risk factor for ventilatory function abnormalities was heavy pollution [OR = 2.66;IC: 1.053 - 6.743;P = 0.038]. Conclusion: Residents of the Attécoubé Lagune district had many respiratory symptoms and a high prevalence of ventilatory function abnormalities. Improving air quality is urgently needed in this municipality.

Cerebral ischemia and neuroregeneration

Cerebral ischemia is one of the leading causes of morbidity and mortality worldwide. Although stroke （a form of cerebral ischemia）-related costs are expected to reach 240.67 billion dollars by 2030, options for treatment against cerebral ischemia/stroke are limited. All therapies except anti-thrombolytics （i.e., tissue plasminogen activator） and hypothermia have failed to reduce neuronal injury, neurological deficits, and mortality rates following cerebral ischemia, which suggests that development of novel therapies again st stroke/cerebral ischemia are urgently needed. Here, we discuss the possible mechanism（s） underlying cerebral ischemia-induced brain injury, as well as current and future novel therapies （i.e., growth factors, nicotinamide adenine dinucleotide, melatonin, resveratrol, protein kinase C isozymes, pifithrin, hypothermia, fatty acids, sympathoplegic drugs, and stem cells） as it relates to cerebral ischemia.

HNF-4α determines hepatic differentiation of human mesenchymal stem cells from bone marrow

AIM: To investigate the differentiation status and key factors to facilitate hepatic differentiation of human bone-marrow-derived mesenchymal stem cells (MSCs). METHODS: Human MSCs derived from bone marrow were induced into hepatocyte-like cells following a previously published protocol. The differentiation status of the hepatocyte-like cells was compared with various human hepatoma cell lines. Overexpression of hepatocyte nuclear factor (HNF)-4α was mediated by adenovirus infection of these hepatocyte-like cells. The expression of interesting genes was then examined by either re-verse transcription-polymerase chain reaction (RT-PCR) or real-time RT-PCR methods. RESULTS: Our results demonstrated that the differentiation status of hepatocyte-like cells induced from human MSCs was relatively similar to poorly differentiated human hepatoma cell lines. Interestingly, the HNF-4 isoform in induced MSCs and poorly differentiated human hepatoma cell lines was identified as HNF4γ instead of HNF-4α. Overexpression of HNF-4α in induced MSCs significantly enhanced the expression level of hepatic-specific genes, liver-enriched transcription factors, and cytochrome P450 (P450) genes. CONCLUSION: Overexpression of HNF-4α improves the hepatic differentiation of human MSCs from bone marrow and is a simple way of providing better cell sources for clinical applications.

Cytokine and apoptosis gene polymorphisms influence the outcome of hepatitis C virus infection

BACKGROUND:Hepatitis C virus (HCV) infection is thought to be chronic and the factors leading to viral clearance or persistence are poorly understood.This study was undertaken to investigate the possibility of a significant relationship between the spontaneous clearance or the persistence of hepatitis C virus (HCV) infection and cytokine and apoptosis gene polymorphisms in Tunisian patients on hemodialysis.METHODS:Polymorphisms of the genes IL-1 (-889 IL-1α,-511 and +3954 IL-1β,IL-1Ra),IL-18 (-137 and-607),IL-12 (-1188) and Apo1/Fas (-670) were determined by PCR-RFLP,PCR-SSP and PCR-VNTR in 100 healthy blood donors and 100 patients infected with HCV and undergoing hemodialysis.The patients were classified into two groups:G1 consisted of 76 active chronic hepatitis patients (positive for HCV RNA) and G2 consisted of 24 hemodialysed patients who spontaneously eliminated the virus (negative for HCV RNA).RESULTS:The frequency of genotype association [-137GC/-607CA] IL-18 was higher in G2 (41.7%) than in G1 (15.8%) (P=0.008;OR=0.26;95% CI,0.10-0.73).We also found a higher frequency of the AA genotype of the Apo1/Fas gene in G2 (41.6%) than in G1 (17.5%) (P=0.026;OR=3.49;95% CI,1.13-10.69).Adjustment for known covariate factors (age,gender and genotype) confirmed these univariate findings and revealed that the genotype association GC-CA of the (-137 and-607) IL-18 gene and the AA genotype of the Apo1/Fas gene were associated with the clearance of HCV (P=0.041 and 0.017,respectively).CONCLUSION:The two genotypes GC-CA of the (-137 and-607) IL-18 polymorphism and the AA genotype of the Apo1/Fas gene influence the outcome of HCV infection in Tunisian patients on hemodialysis.

Optimal combination of antiangiogenic therapy for hepatocellular carcinoma

The success of sorafenib in prolonging survival of patients with hepatocellular carcinoma(HCC) makes therapeutic inhibition of angiogenesis a component of treatment for HCC. To enhance therapeutic efficacy, overcomedrug resistance and reduce toxicity, combination of antiangiogenic agents with chemotherapy, radiotherapy or other targeted agents were evaluated. Nevertheless, the use of antiangiogenic therapy remains suboptimal regarding dosage, schedule and duration of therapy. The issue is further complicated by combination antiangiogenesis to other cytotoxic or biologic agents. There is no way to determine which patients are most likely respond to a given form of antiangiogenic therapy. Activation of alternative pathways associated with disease progression in patients undergoing antiangiogenic therapy has also been recognized. There is increasing importance in identifying, validating and standardizing potential response biomarkers for antiangiogenesis therapy for HCC patients. In this review, biomarkers for antiangiogenesis therapy including systemic, circulating, tissue and imaging ones are summarized. The strength and deficit of circulating and imaging biomarkers were further demonstrated by a series of studies in HCC patients receiving radiotherapy with or without thalidomide.

Long-term hepatic consequences of chemotherapy-related HBV reactivation in lymphoma patients

AIM: To investigate the long-term consequences of chemotherapy-related HBV reactivation in patients with lymphoma.METHODS: This study was based on the database of published prospective study evaluating HBV reactivation in HBV lymphoma patients during chemotherapy.Deteriorated liver reserve (DLR) was defined as development of either one of the following conditions during follow-up: (1) newly onset parenchyma liver disease, splenomegaly or ascites without evidence of lymphoma involvement; (2) decrease of the ratio (albumin/globulin ratio) to less than 0.8 or increase of the ratio of INR of prothrombin time to larger than 1.2 without evidence of malnutrition or infection. Liver cirrhosis was diagnosed by imaging studies.RESULTS: A total of 49 patients were included. The median follow-up was 6.2 years (range, 3.9-8.1 years).There were 31 patients with and 18 patients without HBV reactivation. Although there was no difference of overall survival (OS) and chemotherapy response rate between the two groups, DLR developed more frequently in patients with HBV reactivation (48.4% vs 16.7%; P= 0.0342). Among the HBV reactivators, HBV genotype C was associated with a higher risk of developing DLR (P = 0.0768) and liver cirrhosis (P = 0.003). Four of five patients with sustained high titer of HBV DNA and two of three patients with multiple HBV reactivation developed DLR. Further, patients with a sustained high titer of HBV DNA had the shortest OS among the HBV reactivators (P= 0.0000). No patients in the non-HBV reactivation group developed hepatic failure or liver cirrhosis.CONCLUSION: Chemotherapy-related HBV reactivation is associated with the long-term effect of deterioration of hepatic function.

Spider angiomas in patients with liver cirrhosis: Role of vascular endothelial growth factor and basic fibroblast growth factor

AIM: To investigate whether vascular endothelial growth factor (VEGF) and basic fibroblastic growth factor (bFGF) are associated wibh spider angiomas in patients wibh liver cirrhosis. METHODS: Eighty-six patients with liver cirrhosis were enrolled and the number and size of the spider angiomas were recorded. Fifty-three healthy subjects were selected as controls. Plasma levels of VEGF and bFGF were measured in both the cirrhotics and the controls. RESULTS: Plasma VEGF and bFGF were increased in cirrhotics compared with controls (122±13 vs. 71±11 pg/mL, P=0.003 for VEGF; 5.1±0.5 vs. 3.4±0.5 pg/mL, P=0.022 for bFGF). In cirrhotics, plasma VEGF and bFGF were also higher in patients with spider angiomas compared with patients without spider angiomas (185±28 vs. 90±10 pg/mL, P=-0.003 for VEGF; 6.8±1.0 vs. 4.1±0.5 pg/mL, P=0.017 for bFGF). Multivariate logistic regression showed that young age and increased plasma levels of VEGF and bFGF were the most significant predictors for the presence of spider angiomas in cirrhotic patients (odds ratio [OR]=6.64, 95% confidence interval[CI]=2.02-21.79, P=0.002; OR=4.35, 95% CI=1.35-14.01,P=0.014; OR=5.66, 95% CI=1.72-18.63, P=0.004, respectively). CONCLUSION: Plasma VEGF and bFGF are elevated inpatients with liver cirrhosis. Age as well as plasma levels of VEGF and bFGF are significant predictors for spider angiomas in cirrhotic patients.

Potentially probiotic bacteria induce efficient maturation but differential cytokine production in human monocyte-derived dendritic cells

AIM: To analyze the ability of nine different potentially probiotic bacteria to induce maturation and cytokine production in human monocyte-derived dendritic cells (moDCs). METHODS: Cytokine production and maturation of moDCs in response to bacterial stimulation was analyzed with enzyme-linked immunosorbent assay (ELISA) and flow cytometric analysis (FACS), respectively. The kinetics of mRNA expression of cytokine genes was determined by Northern blotting. The involvement of different signaling pathways in cytokine gene expression was studied using specific pharmacological signaling inhibitors. RESULTS: All studied bacteria induced the maturation of moDCs in a dose-dependent manner. More detailed analysis with S. thermophilus THS, B. breve Bb99, and L. lactis subsp. cremoris ARH74 indicated that these bacteria induced the expression of moDC maturationmarkers HLA class Ⅱ and CD86 as efficiently as pathogenic bacteria. However, these bacteria differed in their ability to induce moDC cytokine gene expression. S. thermophilus induced the expression of pro-inflammatory (TNF-α, IL-12, IL-6, and CCL20) and Th1 type (IL-12 and IFN-γ) cytokines, while B. breve and L. lactis were also potent inducers of anti- inflammatory IL-10. Mitogen-activated protein kinase (MAPK) p38, phosphatidylinositol 3 (PI3) kinase, and nuclear factor-kappa B (NF-κB) signaling pathways were shown to be involved in bacteria-induced cytokine production. CONCLUSION: Our results indicate that potentially probiotic bacteria are able to induce moDC maturation, but their ability to induce cytokine gene expression varies significantly from one bacterial strain to another.

Useful biomarkers for assessment of hepatitis C virus infection-associated autoimmune disorders

During the course of chronic hepatitis C virus(HCV)infection,various extrahepatic manifestations of autoimmune disorders may occur,including arthralgia/arthritis,sicca complex,purpura,cutaneous ulcer,and thyroid dysfunction.In addition,the prevalence of circulating autoantibodies is high among patients with HCV infection.Commonly detected autoantibodies in HCVinfected patients include rheumatoid factor,antinuclear antibody,anti-SSA/anti-SSB antibody,cryoglobulin,antineutrophil cytoplasmic antibody,anti-smooth muscle antibody,anti-liver and anti-thyroid autoantibodies.These autoantibodies may be associated with underlying autoimmune disorders or liver inflammation in HCV infection.A possible reason for antibody production is overactivation and proliferation of B lymphocytes,via the interaction with the surface protein of HCV.Because immunotherapy can cause HCV flare-up or liver damage,overdiagnosis of HCV-related autoimmune symptoms as primary autoimmune disorders should be avoided.This review describes biomarkers that are useful in clinically evaluating autoimmune manifestations and disorders associated with HCV infection.

Association of Helicobacter pylori IgA antibodies with the risk of peptic ulcer disease and gastric cancer

AIM: To compare the prevalence of Helicobacter pylori (Hpylori) IgG and IgA antibodies between adult subjects,with defined gastric diseases, nondefined gastric disorders and those representing the population.METHODS: Data on H pylori IgG and IgA antibodies,determined by enzyme immunoassay, were analyzed in 3 252 subjects with DGD including 482 patients with gastric ulcer, 882 patients with duodenal ulcer, 1 525patients with chronic gastritis only and 363 subjects with subsequent gastric cancer, 19 145 patients with NoDg and4 854 POPUL subjects. The age-adjusted prevalences were calculated for 1- and 20-year age cohorts.RESULTS: The prevalences of IgG antibodies were equally high (89-96%) in all 20-year age cohorts of the DGD groups, whereas the prevalences of IgG antibodies were lower and increased by age in the POPUL and NoDg groups. The prevalences of IgA antibodies were also higher in the DGD groups; among them CA (84-89%) and GU groups (78-91%) showed significantly higher prevalences than DU (68-77%) and CG patients (59-74%) (OR 2.49, 95%CI 1.86-3.34 between the GU and DU groups). In the CA, GU, and DU groups, the IgA prevalences showed only minor variation according to age, while they increased by age in the CG, POPUL, and NoDg groups (P≤0.0001). The IgA response, but not the IgG response, was associated with an increased risk of CA (OR 2.41, 95%CI 1.79-3.53) and GU (OR 2.57,95%CI 1.95-3.39) in comparison with CG patients.CONCLUSION: An IgA antibody response during H pylori infection is significantly more common in CA and GU patients as compared with CG patients.

Probiotic Leuconostoc mesenteroides ssp. cremoris and Streptococcus thermophilus induce IL-12 and IFN-γ production

AIM: To investigate the capacity of potentially probiotic strains from six bacterial genera to induce cytokine production alone or in combinations in order to identify potential enhancing or synergistic effects in order to select probiotic bacteria for in vivo purposes. METHODS: Cytokine production in human peripheral blood mononuclear cells (PBMC) in response to stimulation with eleven different potentially probiotic bacterial strains from Streptococcus , Lactobacillus , Bifidobacterium , Lactococcus , Leuconostoc and Propionibacterium genera was analysed. Production and mRNA expression of TNF-α, IL-12, IFN-γ and IL-10 were determined by ELISA and Northern blotting, respectively. RESULTS: All tested bacteria induced TNF-α production. The best inducers of Th1 type cytokines IL-12 and IFN-γ were Streptococcus and Leuconostoc strains. All Bifidobacterium and Propionibacterium strains induced higher IL-10 production than other studied bacteria. Stimulation of PBMC with any bacterial combinations did not result in enhanced cytokine production suggesting that different bacteria whether gram-positive or gram- negative compete with each other during host cell interactions.CONCLUSION: The probiotic S. thermophilus and Leuconostoc strains are more potent inducers of Th1 type cytokines IL-12 and IFN-γ than the probiotic Lactobacillus strains. Bacterial combinations did not result in enhanced cytokine production.

遗传、环境和青少年的吸烟饮酒行为:芬兰双生子研究的回溯与前瞻(英文)

本文介绍的两个"芬兰双生子(Finn Twin)"研究是对10个出生组的青少年双生子及其家庭的长期跟踪研究。本文概述了这两个项目对遗传与环境的关联和互动对吸烟饮酒行为影响的研究。这些研究的结果提示个体差异对吸烟饮酒行为的长期变动的影响受到兄弟姐妹互动、同伴互动以及父母教养方式的调节。环境对吸烟饮酒的影响主要表现在学校、居住社区与家庭环境的差异上。环境与遗传影响的程度和持久度有城乡差异。遗传的影响受居住社区的制约。多阶段模型的分析揭示了遗传与环境的互动对这些行为的演变(从试吸试饮到发展到滥用)的动态的影响,遗传似乎对吸烟饮酒的共同轨迹更有影响。这些结果对今后本项目对这约1万对芬兰成年双生子的分子遗传学研究提供了有益的线索。

Chromatin-binding in vivo of the erythroid kruppel-like factor,EKLF,in the murine globin loci

EKLF 是一 erythroid 特定，锌为在在权威的系的 erythroid 房间的基因的哺乳动物的贝它滴的激活的包含手指的抄写因素必需品。我们准备了对西方的弄污和免疫降水(IP ) 质量合适的 polyclonal 反老鼠 EKLF 抗体，并且使用了它在老鼠 erythroid 开发期间定义 EKLF 蛋白质的表示模式。我们也为 chromatin-immunoprecipitation (薄片) 使用了这抗体试金。EKLF 被发现以一种 DMSO 可诱导的方式在老鼠 erythroleukemia 房间(MEL ) 在老鼠 beta-major-globin 倡导者和 beta-LCR 的 HS2 地点在 vivo 绑。象三另外的蛋白质一样的 EKLF 的 导致DMSO 的绑定，也就是 RNA 聚合酶 II ，乙酰 ated 嘘一 H3 ，和 methylated 嘘一 H3 ，没在 CB3 被废除，但是显著地降低了，一根 导出MEL 的房间线与 p45/NF-E2 空表示，在 loci 为哺乳动物的滴的激活需要的一个 充实erythroid 的因素。有趣地，在 vivo 的 EKLF 的绑定也在地点在鼠标象 alpha 一样滴被检测，在成年高山哈在倡导者和它的远在上游的规章的元素 alpha-MRE (HS26 ) 的滴。这研究提供直接证据为在在在基因的像贝它的滴聚类的老鼠的主要规章的元素的 vivo EKLF 有约束力数据也在基因规定在哺乳动物的滴关于 EKLF 染色质相互作用的角色有有趣的含意。

Incidence, clinical features and para-clinical findings of achalasia in Algeria: Experience of 25 years

AIM To investigate the incidence of achalasia in Algeria and to determine its clinical and para-clinical profile. To evaluate the impact of continuing medical education(CME) on the incidence of this disease.METHODS From 1990 to 2014, 1256 patients with achalasia were enrolled in this prospective study. A campaign of CME on diagnosis involving different regions of the country was conducted between 1999 and 2003. Annual incidence and prevalence were calculated by relating the number of diagnosed cases to 105 inhabitants. Each patient completed a standardized questionnaire, and underwent upper endoscopy, barium swallow and esophageal manometry. We systematically looked for Allgrove syndrome and familial achalasia.RESULTS The mean annual incidence raised from 0.04(95%CI: 0.028-0.052) during the 1990 s to 0.27/105 inhabitants/year(95%CI: 0.215-0.321) during the 2000 s. The incidence of the disease was two and half times higher in the north and the center compared to the south of the country. One-hundred-and-twenty-nine(10%) were children and 97(7.7%) had Allgrove syndrome. Familial achalasia was noted in 18 different families. Patients had dysphagia(99%), regurgitation(83%), chest pain(51%), heartburn 24.5% and weight loss(70%). The lower esophageal sphincter was hypertensive in 53% and hypotensive in 0.6%.CONCLUSION The mean incidence of achalasia in Algeria is at least 0.27/105 inhabitants. A good impact on the incidence of CME was noted. A gradient of incidence between different regions of the country was found. This variability is probably related to genetic and environmental factors. The discovery of an infantile achalasia must lead to looking for Allgrove syndrome and similar cases in the family.

Hepatocellular carcinoma mouse models:Hepatitis B virusassociatedhepatocarcinogenesis and haploinsufficienttumor suppressor genes

The multifactorial and multistage pathogenesis of hepatocellular carcinoma(HCC)has fascinated a wide spectrum of scientists for decades.While a number of major risk factors have been identified,their mechanistic roles in hepatocarcinogenesis still need to be elucidated.Many tumor suppressor genes(TSGs)have been identified as being involved in HCC.These TSGs can be classified into two groups depending on the situation with respect to allelic mutation/loss in the tumors:the recessive TSGs with two required mutated alleles and the haploinsufficient TSGs with one required mutated allele.Hepatitis B virus(HBV)is one of the most important risk factors associated with HCC.Although mice cannot be infected with HBV due to the narrow host range of HBV and the lack of a proper receptor,one advantage of mouse models for HBV/HCC research is the numerous and powerfulgenetic tools that help investigate the phenotypic effects of viral proteins and allow the dissection of the dose-dependent action of TSGs.Here,we mainly focus on the application of mouse models in relation to HBV-associated HCC and on TSGs that act either in a recessive or in a haploinsufficient manner.Discoveries obtained using mouse models will have a great impact on HCC translational medicine.

在男吸烟者之中的白血球 DNA methylation 和 colorectal 癌症

AIM: To explore the association between methylation in leukocyte DNA and colorectal cancer (CRC) risk in male smokers using the α-tocopherol, β-carotene cancer prevention study. METHODS: About 221 incident CRC cases, and 219controls, frequency-matched on age and smoking intensity were included. DNA methylation of 1505 CpG sites selected from 807 genes were evaluated using Il-lumina GoldenGate Methylation Cancer Panel I in prediagnostic blood leukocytes of study subjects. Tertiles of methylation level classified according to the distribution in controls for each CpG site were used to analyze the association between methylation level and CRC risk with logistic regression. The time between blood draw to cancer diagnosis (classifying cases according to latency) was incorporated in further analyses using proportional odds regression. RESULTS: We found that methylation changes of 31 CpG sites were associated with CRC risk at P【0.01 level. Though none of these 31 sites remained statistically significant after Bonferroni correction, the most statistically significant CpG site associated with CRC risk achieved a Pvalue of 1.0×10-4 . The CpG site is located in DSP gene, and the risk estimate was 1.52 (95% CI: 0.91-2.53) and 2.62 (95% CI: 1.65-4.17) for the second and third tertile comparing with the lowest tertile respectively. Taking the latency information into account strengthened some associations, suggesting that the methylation levels of corresponding sites might change over time with tumor progression. CONCLUSION: The results suggest that the methylation level of some genes were associated with cancer susceptibility and some were related to tumor development over time. Further studies are warranted to confirm and refine our results.