The analysis used data and stored samples from a prospective cohort inQidong, Jiangsu Province, China. The enrollment ofthe study cohort has been described previously [17–19]. Briefly, a total of 2387 males living in 17 townships ofQidong who were seropositive for hepatitisB surface antigen (HBsAg) and free of HCC at recruitment were followed up from 1996 to October 2006. Study participants were scheduled to undergo ultrasonog- raphy measurements, serum alpha-fetoprotein (AFP) level and conventional liver function tests every 6–12 months. The diagnosis of HCC was based on the following criteria: a histopathological examination; 1 imaging technique and a serum AFP level $ 400 ng/mL; or a positive lesion detected by at least 2 different imaging techniques (US, CT, MRI, and hepatic angiography). Several cases qualified based on more than 1 criterion. For this case-control study, we recruited 100 HCC patients and 100 chronic hepatitis (CH) patients as controls from the cohort of HBsAg carriers who were alive and had not been diagnosed with HCC throughout the follow-up period. All these 200 participants were positive for HBsAg and HBV DNA. The controls were individually matched to the cases by age (within 2 years). Subjects were excluded if they had poor sequence data (2 cases and 1 control) or a history of antiviral therapy (2 cases and 2 controls). Consequently, a total of 96 cases and 97 controls were included inthe analysis. At recruitment, each study participant provided informed written consent and a structured questionnaire on sociodemographic characteristics, habits of alcohol and tobacco consumption. Serum samples collected at interview were stored at 270uC before analysis. This study was approved by the research ethics committee at Zhongshan Hospital, Fudan University, Shanghai, China.
It is biologically reasonable that pre-S deletion and BCP mutations could contribute to the risk of HCC. The HBV envelope is composed of 3 forms of HBV surface antigen: large (coded for by thepre-S1/pre-S2/S gene), middle (the preS2/S gene), and small (theS gene) protein. Thepre-S regions play an essential role inthe interaction withthe immune responses because they contain several epitopes for T or B cells [25,26]. In persistent HBV infection, immune epitope deletion mutants occur, escape the host immune surveillance, and lose important functional sites. The deletion over thepre-S gene may affect the expression of middle and small surface proteins, resulting in intracellular accumulation of large surface protein and viral particles, formation of ground glass hepatocytes. These deletion mutations accumulate inthe endoplasmic reticulum and cause endoplasmic reticulum stress signals. Through endoplasmic reticulum stress signaling pathways, thepre-S mutant large HBV surface antigens can induce oxidative stress and lead to oxidative DNA damage of HBV infected hepatocytes. Presence ofthe oxidative DNA lesions stimulates DNA repair activity; the induced mutagenesis occurs inthe genome [27,28]. It has been proposed that BCP mutations may diminish the production of HBeAg and increase viral replication, which theoretically results in increased host immune responses against thevirus, therefore increasing hepatocyte apoptosis and degeneration, which leads to liver injury [29,30]. In addition, this mutation in BCP may alter the binding ability of trans-regulating nuclear factors (such as CCAAT/enhancer- binding protein-a, the ubiquitous transcription factor Sp1, and hepatocyte nuclear factor 4) and may also lead to amino acid alterations of X protein, affect the function ofthe X protein, interfere with cell growth control and DNA repair and may contribute to the process of multiple steps in hepatocarcinogenesis [31,32].
The a-fetoprotein fraction L3 (AFP-L3), which is synthesized by malignant cells and incorporates a fucosylated oligosaccharide, has been investigated as a diagnostic and prognostic marker for hepatocellularcarcinoma (HCC). Quantification of AFP-L3 by conventional enzyme-linked immunosorbent assay (ELISA) has not always produced reliable results for serum samples with low AFP, and thus we evaluated the clinical utility of quantifying AFP-L3 using a new and highly sensitive glycan microarray assay. Sera from 9 patients with chronic hepatitisB and 32 patients withhepatitisBvirus (HBV)-related HCC were tested for AFP-L3 level using the glycan microarray. Additionally, we compared receiver operator characteristic curves for the ELISA and glycan microarray methods for determination ofthe AFP-L3: AFP-L1 ratio in patient samples. This ratio was calculated for 8 HCC patients who underwent transarterial embolization therapy pre- or post- treatment with AFP-L3. Glycan microarrays showed that the AFP-L3 ratio of HBV-related HCC patients was significantly higher than that measured for chronic hepatitisB patients. Overall parameters for estimating AFP-L3% in HCC samples were as follows: sensitivity, 53.13%; specificity, 88.89%; and area under the curve, 0.75. The elevated AFP-L3% inthe 8 patients with HBV-related HCC was strongly associated with HCC progression. Following one month of transarterial embolization therapy, the relative mean AFP-L3% decreased significantly. In addition, we compared Fut8 gene expression between paired tumor and non-tumor tissues from 24 patients with HBV-related HCC. The Fut8 mRNA expression was significantly increased in tumorous tissues in these patients than that in non-tumor tissue controls. Higher expression of Fut8 mRNA in tumorous tissues in these patients was associated with poor differentiation than well and moderate differentiation. Our results describe a new glycan microarray for the sensitive and rapid quantification of fucosylated AFP; this method is potentially applicable to screening changes in AFP-L3 level for assessment of HCC progression.
outcomes of HBV disease , . The most clinically relevant mutations intheS region arise inthe immunologic ‘‘a de- terminant’’ domain and neutralizing antibodies (anti-HBs) are targeted against this epitope . The basic core promoter (BCP, nt 1742–1849) and its adjacent precore (preC) region are crucial for replication of HBV. BCP binds various liver factors and preC forms e structure in pregenomic RNA (pgRNA) as the encapsida- tion signal . Changes in viral replication may influence the progression of liver diseases, particularly in fulminant hepatitis and acute exacerbation of chronic hepatitis , . Mounting evidence has emerged to demonstrate that BCP and preC mutants are predisposed to severe and progressive liver diseases after HBV infection, causing an increased risk for hepatocellularcarcinoma (HCC) , , . For instance, mutations T1762/A1764 and A1899 have been reported to be independent risk factors for HCC , and T1653 and/or V1753 mutations are believed to promote the process of liver degradation . However, theassociationof these mutations with severe symptoms is manifested in certain populations but not in others , , .
HCC cases can be attributable to chronic infection with HBV in hyper-endemic regions, suggesting CHB was a major risk factor for developmentof HCC . The enormous variation in clinical outcome of HBV infection highlights the importance of identification of mechanism underlying the progression of HBV exposure to CHB for prevention against HBV-induced fatal liver disease. Although the environmental factors such as alcohol abuse, infection age, and co-infection with other hepatitisvirus unveiled as risk factors of HBV-induced liver disease, genetic factors may also influence clinical progression after HBV exposure, which is indicated by familial studies . In fact, multiple candidate genes, such as IFNG, TNF, VDR, and HLA loci, have been extensively investigated inthe progression to CHB, but results were inclusive [10–13]. A recent genome- wide association study (GWAS) by Kamatani et al. in Japanese population has suggested two SNPs of rs3077 and rs9277535 in
The clinical picture of CHC without HCC was low symptomatic, and clinical signs were absent in 36% of patients. Withthedevelopmentof HCC in CHC patients, clinical manifestations were absent only in 2.2% of patients. In some patients, the disease was diagnosed in connection withthe “accidental” discovery of elevated levels of serum transaminases and/or detection of anti-HCV. Often, especially in women, the irst clinical signs ofthe disease were extrahepatic signs. Determining factors in HCC development are male sex, mature age, the maintained HCV replication, moderate and severe ibrosis, disease duration of more than 10 years, and the lack of effect of AVT.
In order to evaluate the susceptibility to hot cracking inthe high-temperature brittleness range, we have determined the changes of temperature of individual points when the alloy was cooled down from the solidus temperature. The tests were performed on the cylindrical Ø 10 x 120 mm specimens, using the Gleeble 3800 simulator, at Iron Metallurgy Institute in Gliwice. Four S-type thermocouples were pressure welded to the specimens: inthe specimen axis and 2, 5 and 8 mm away from the axis. The specimens were fixed in copper holders, keeping a constant distance of 33 mm, and then were heated inthe argon atmosphere at the 20 0 C/s rate to the temperature of liquid phase appearance, and were afterwards freely cooled. Changes in
Zimmerman (1999) in his article titled ―Mobile Computing: Characteristics, Benefits, and the Mobile fra mework‖ defined mobile computing as ―the use of computing devices, which usually interact in some way with a centralised information system while away from the normal fixed workplace‖. He went on to say that, Mobile computing technology enables the mobile person to create, access, process, store and communicate information without being constrained to a single location. It is on the above basis that this researcher views mobile computing as embracing a host of portable technologies the can access internet using wireless fidelity (WIFI). These range from notebook computers to tablets, to smartphones and e-book readers. Such devices have brought about Mobile learning (m-Learning) in Zimbabwe Polytechnics, enabling staff and students to share academic resources, be able to research and develop applications from wherever they are. Zimmerman (1999) went on to identify mobile computing hardware, software and communications in use then. He identified hardware as palmtops, clamshells, handheld Pen Keys, pen slates, and laptops. The characteristics of such devices in terms of screen size was small, processing capability was limited and supported a few mobile applications. Over the years mobile devices have improved in such characteristics to make mobile computing easy, fast and user friendly. Great improvements also came withthe associated systems software, withthe modern devices now running on Android, Symbian and windows 8 mobile, as compared to then when MS DOS, Windows 3.1, Pen DOS were used. In communications Zimmerman talked of internet speeds in kilobytes per second (Kbps), while today’s communications devices have speeds of gigabytes per second (Gbps
he serological and virological tests were consistent with a diagnosis of chronic hepatitis caused by HBV and HDV coin- fection. A real-time polymerase chain reaction (RT-PCR) for HBV deoxyribonucleic acid (TaqMan; Roche Diagnostics AG, Rotkreuz, Switzerland) showed high viral loads (log 6.22), and HDV ribonucleic acid (RNA) was detected using the same method. Serological tests for HCV were negative, and serum ala- nine transaminase (ALT) levels were ive times higher than the normal upper limit. he patient began antiviral treatment with entecavir (1.0 gram once a day).
HBeAg is a non-structural protein encoded by gene HBV preC/C gene. It is derived from HBV core antigen (HBcAg) withthe loss of some amino acid residues. After synthesized inthe cytoplasm, it is secreted out of liver cells through endoplasmic reticulum and distribute inthe periphery blood and the whole body fluid[37, 38]. HBeAg is dispensable for the assembly and the replication of HBV, but it is demonstrated to be an indicator for rapid replication of HBV in vivo and high contagion. Serological conversion of HBeAg is a critical indicator for ef- fectiveness of anti-viral drugs. After treatment, the decrease ofvirus DNA level accompanied by sero-conversion of HBeAg always indicates a good prognosis. Biologically, it is suggested that HBeAg induces immune tolerance when it is secreted into the serum. HBeAg was re- ported to be able to induce the secretion of Th2 cytokines such as IL- 4, IL-10 in peripheral blood lymphocytes. Peripheral circulation of HBeAg in transgenic mice could eliminate HBcAg- and HBeAg-specific Th1 cells through Fas-FasL mediated mechanism. Whether the decline of HBV DNA level in HBeAg negative patients is owing to the recovery of Th1 cel- lular immune responses against HBeAg or related protein (such as HBcAg) still needs to be further investigated.
rates the literature, observing negative correlation between albumin and CTP score in both groups, creatinine and CTP in group CI, and positive correlation between the uric acid and BCLC classiication. Despite the limitation resulting from its extended half-life, interfering inthe detection of acute alterations ofthe nutritional state, and the altera- tions for several other non-nutritional reasons, the albumin serum levels are strongly related to morbidity increase and mortality in liver cirrhosis patients (21) . Moreover, albumin
HBV infection, in addition to chronic inflammation, the integration of HBV DNA into the host hepatocyte DNA and the expression of viral proteins, which transactivate human oncogenes, may play a role in hepatocarcinogenesis, while in HCV infection, chronic inflammation seems to play a main role in oncogenesis [13–15]. Thus, cirrhosis almost always accompanies HCV-related HCC , but not in HBV-related HCC [17,18]. HBV infection usually occurs inthe perinatal period in an endemic area, while the immune status ofthe host is still immature . Meanwhile, HCV infection occurs in adults with a fully matured immune system . A combination ofvirus-specific, host genetic, environmental, and immune-related factors will affect the HCC manifestations, thus these differences in hepatocarcinogenesis may affect clinical manifestations as well as patients outcome. Indeed, several previous studies have assessed the impact of viral etiology on clinical manifestation and long-term outcome [20–22]. However, still controversies exist whether different HCC surveil- lance and management strategies according to the viral etiologies are needed. This question has not been answered, in part, because most studies were performed on a single hospital base which inevitably has a selection bias, with limited sample size and limited follow-up period. The sample sizes were 205, 359 and 127 in reports by Shiratori et al.’s , Tanabe et al.’s , and Hiotis et al.’s , respectively. Therefore, in this study, we used data from population-based nationwide cancer registry which has less selection bias, with large study sample and long-term follow-up period, and assessed whether true differences exist in clinical manifestations and long-term outcomes of HCC patients between the two viral etiologies.
Since participants in this community-based prospective study were healthier than patients in hospital-based studies, most participants would be classified as ‘‘normal’’ for these liver-related seromarkers if current clinical cut-off points were applied. Therefore, in this study, the cut-off points of these seromarkers were set by their first or third quartiles instead ofthe normal limits routinely used in clinical practice, such as 40 U/L for ALT and 20 ng/mL for AFP. Indeed, the revised cut-off points of these seromarkers were found to be significantly associated with an increased risk of subsequent HCC. We used binary variables to reduce the influence of occasional fluctuations because the scoring was based on the dichotomous classification of ‘‘positive’’ or ‘‘negative’’ instead of exact measurements of liver-related seromarkers. In Risk Models I and III, serum HBV DNA level and HBeAg serostatus were combined to classify participants into three groups: 1) HBeAg-seronegatives with serum HBV DNA level #10,000 copies/mL, 2) HBeAg-seronegatives with serum HBV DNA level .10,000 copies/mL, and 3) HBeAg-seropositives, as almost all HBeAg-seropositives had very high serum levels of HBV DNA. The cut-off point of 10,000 copies/mL was used for serum HBV DNA levels according to our previous observation that serum HBV DNA levels seldom rebound again once they have spontaneously decreased #10,000 copies/mL.  The combina- Figure 2. Receiver operating characteristic curves (ROCs) and areas under receiver operating characteristic curves (AUROCs). ROCs and AUROCs for the prediction ofthe 6-year incidence ofhepatocellularcarcinoma using sum scores of three risk models: The classical model (Risk Model I, dotted line), the model combining liver- related seromarkers without HBV seromarkers of HBeAg serostatus and serum HBV DNA level (Risk Model II, broken line), and the model combining liver-related seromarkers with HBV seromarkers (Risk Model III, solid line).
Modern developmentof steel grades for responsible engineering castings consists mainly in systematic increase ofthe imposed requirements. This is the reason why the low-alloy structural steels of high mechanical and plastic properties are gaining importance in both technology and economy. When shaping with microadditions the properties of castings made from low-alloy steel, it is very important to extensively use the impact of heat treatment and various mechanisms of microstructure hardening at a given chemical composition. The greatest possibilities in this field lie inthe mechanisms based on microalloying (V, Nb, Ti), grain refining and dispersion hardening [1-3]. The combined effect of microadditives and properly selected heat treatment regime may lead to great changes inthe properties of ready casting [4,5]. This is specially true if we remember that dispersion hardening takes place in alloys in which the volume fraction of dispersed phases does not exceed 0.1%, and the size of respective particles is 1-100nm . The data offered by technical literature and the results of own investigations [6-8] indicate that there exist vast possibilities for the use of microadditions in cast steels, having considered the,
been widely used in investigations among men who have sex with men, illicit drug users, and sex workers because of diiculties to reach these populations using population-based sampling techniques. he RDS is a form of referral sampling, and it uses the social networks ofthe target populations by peer referral methods for recruitment. he recruitment process starts with a non-random selection of key members ofthe target population denominated as “seeds” that receive a pre-established number of recruitment coupons for distribution to members of their social network. If the persons recruited by the “seeds” are eligible, they are included inthe study, and they receive coupons for subsequent peer referral. hus, based on the Markov chain model, if the peer recruitment occurs from a suiciently large number of recruitment waves, the dependence ofthe inal sample on the initial convenience sample (“seeds”) is reduced 10,31 .
A panel of ten HBV strains of known subtype and genotype was used to develop a PCR assay for specific detection of genotype F isolates. Strains adw2 (BrA and BrL; geno- type A), adw4 (BrC and 7-1991; F), ayw2 (BrF and BrN; D), and ayw3 (BrI and BrJ; D) have been previously characterized (5,11). They represent the four subtypes and three genotypes most commonly found in Brazil. Two adr strains (genotype C) from Japan were included inthe panel because this sub- type has been shown to infect South Ameri- can populations of Asian origin (7). Sev- enty-eight HBsAg-positive samples collected inthe cities of Manaus, State of Amazonas, and Macapá, State of Amapá (Brazilian Amazon region), were studied to determine the frequency of genotype F.
frequencies between HCC patients and healthy controls (Table 3). Regarding the c.335T.C variants, the CC genotype was strongly associated with an increased risk of developing HCC compared to TT and TC/TT geno- types. The risk of HCC was significantly higher for the CC genotype inthe c.3073A.C polymorphism compared to the AA genotype and AC/AA carriers. Thus, the C allele of both c.335T.C and c.3073A.C variants may contribute to the risk of HCC (C vs T of c.335T.C: OR = 1.512, 95%CI = 1.208-1.893; P = 0.0003 and C vs A of c.3073A.C: OR = 1.646, 95%CI = 1.322-2.049; P , 0.0001). The results ofthe present study suggest that the c.335T.C and c.3073A.C polymorphisms ofthe MDR1 gene are associated withthe risk of occurrence of HCC inthe Chinese Han population. Several previous studies have confirmed the relationship between MDR1 poly- morphisms and risk factors for HCC (25,31,32). Wu et al. (25) analyzed theassociation between three polymorph- isms (C1236T, G2677A/T, C3435T) ofthe MDR1 gene and the risk of recurrence after liver transplantation. Theassociation between recurrence-free condition and being a 2677A carrier was significant (P = 0.019), but no significant association was observed with other poly- morphisms (25). Wu et al. suggested that polymorphism ofthe MDR1 gene may be a valuable molecular marker for HCC recurrence after liver transplantation. Chen et al. (31) investigated theassociation between G2677T/A polymorphisms ofthe MDR1 gene and the risk of HCC (31) and suggested that 2677A may be an allele protecting against HCC, while 2677T may be a risk gene for HCC (31). Chen et al. (32) detected a correlation of two polymorphisms (C1236T and C3435T) ofthe MDR1 gene withthe prognosis of HCC. The correlation between prognosis of HCC and the C3435T polymorphism was
While a reduction of serum tests for fibrosis following an SVR has already been reported in HCV patients [47,49], the present study has the merit to correlate serological tests with post- treatment stages of liver fibrosis. Indeed, identification of residual cirrhotics in SVR patients bears clinical interest, since cirrhotic patients who achieve an SVR following antiviral treat- ments are currently maintained under surveillance due to their residual risk of HCC . A few years ago, Mallet and colleagues demonstrated that patients who achieved cirrhosis regres- sion after an SVR remained free from liver-related complications inthe following 5 years  whilst HCC developed in patients with persistent cirrhosis, only. Thus, assessment of post-SVR fibrosis stage might help individualizing the surveillance algorithm in patients with a pre-treat- ment diagnosis of cirrhosis who achieved viral eradication, although this individual approach is not recommended by international societies . A point which needs clarifications is also whether serum assays of liver fibrosis predict long-term outcome and prognosis of SVR patients as they do with non-viremic patients [41,50]. By the same token, it could be of interest to identify post-SVR cut-offs of fibrosis tests predicting clinical events during surveillance. In our small study, we recorded no liver-related events over a 5-year follow-up, thus preventing the possibility to correlate post-SVR fibrosis stage with clinical outcomes, or to identify those patients at risk of complications according to their post-treatment values of serum tests. Due to the lack of robust studies assessing the accuracy of non-invasive tests in staging post-SVR fibro- sis and/or predicting clinical events after HCV eradication, international guidelines do not rec- ommend their use in tailoring the management of post-treatment follow-up .
As the multinomial model is non-linear, the marginal effect ofthe treatment in a DID model is not the marginal impact ofthe interaction between time and treatment, but the difference ofthe cross-differences, as described by Puhani (2012). The results of Table 7 (in terms of marginal effects) show that the BVJ has a significant effect on the probability studying and working at the same time, but not on the other outcome variables. The estimated marginal effects mean that the probability of a youngster studying and working increases by 4.2 percentage points withthe BVJ, compared with a baseline of 30% inthe control group in 2006. The estimated coefficients for the categories ‘studying only’ and ‘working only’ were negative but not statistically significant. It seems, therefore, that treated adolescents do not quit their jobs to study because ofthe program, but do both activities at the same time. This raises questions about the long run impacts ofthe program, since the quality ofthe night classes is notoriously low in Brazil.
Descriptive analyses and calculated population estimates with their confidence intervals were used for all the variables studied. The FSW who were only anti-HBs positive were excluded from theassociation analyses. Univariate and multivariate analyses using unconditional logistic regression were used to estimate predictors of HBV exposure. Variables with p-value < 0.20 were included inthe model. As there is no consensus on the best statistical method to use in more complex analyses such as logistic regression using RDS sampling, we used the individual weights calculated by RDSAT and exported them to modeling data using Stata 15 . The significance level used inthe tests was 5%. In a