A M Di Bisceglie

Saint Louis University, Saint Louis, Michigan, United States

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Publications (383)3416.87 Total impact

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    ABSTRACT: To investigate in this phase 2a study (ZENITH) the safety, tolerability, and antiviral activity of VX-222, a selective, non-nucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase, combined with various telaprevir-based regimens for treatment of genotype 1 HCV.
    European journal of gastroenterology & hepatology. 07/2014; 26(7):761-773.
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    ABSTRACT: Background Effective treatment for hepatitis C virus (HCV) genotype 1 infection in patients who have not had a sustained virologic response to prior interferon-based therapy represents an unmet medical need. Methods We conducted a phase 3, randomized, open-label study involving patients infected with HCV genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin, with or without a protease inhibitor. Patients were randomly assigned to receive the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir in a once-daily, fixed-dose combination tablet for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. Results Among the 440 patients who underwent randomization and were treated, 20% had cirrhosis and 79% had HCV genotype 1a infection. The rates of sustained virologic response were high in all treatment groups: 94% (95% confidence interval [CI], 87 to 97) in the group that received 12 weeks of ledipasvir-sofosbuvir; 96% (95% CI, 91 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir and ribavirin; 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir and ribavirin. No patient discontinued treatment owing to an adverse event. The most common adverse events were fatigue, headache, and nausea. Conclusions Treatment with a once-daily, single-tablet regimen of ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a sustained virologic response to prior interferon-based treatment. (Funded by Gilead Sciences; ION-2 ClinicalTrials.gov number, NCT01768286 .).
    New England Journal of Medicine 04/2014; · 51.66 Impact Factor
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    ABSTRACT: Background High rates of sustained virologic response were observed among patients with hepatitis C virus (HCV) infection who received 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor ledipasvir. This study examined 8 weeks of treatment with this regimen. Methods In this phase 3, open-label study, we randomly assigned 647 previously untreated patients with HCV genotype 1 infection without cirrhosis to receive ledipasvir and sofosbuvir (ledipasvir-sofosbuvir) for 8 weeks, ledipasvir-sofosbuvir plus ribavirin for 8 weeks, or ledipasvir-sofosbuvir for 12 weeks. The primary end point was sustained virologic response at 12 weeks after the end of therapy. Results The rate of sustained virologic response was 94% (95% confidence interval [CI], 90 to 97) with 8 weeks of ledipasvir-sofosbuvir, 93% (95% CI, 89 to 96) with 8 weeks of ledipasvir-sofosbuvir plus ribavirin, and 95% (95% CI, 92 to 98) with 12 weeks of ledipasvir-sofosbuvir. As compared with the rate of sustained virologic response in the group that received 8 weeks of ledipasvir-sofosbuvir, the rate in the 12-week group was 1 percentage point higher (97.5% CI, -4 to 6) and the rate in the group that received 8 weeks of ledipasvir-sofosbuvir with ribavirin was 1 percentage point lower (95% CI, -6 to 4); these results indicated noninferiority of the 8-week ledipasvir-sofosbuvir regimen, on the basis of a noninferiority margin of 12 percentage points. Adverse events were more common in the group that received ribavirin than in the other two groups. No patient who received 8 weeks of only ledipasvir-sofosbuvir discontinued treatment owing to adverse events. Conclusions Ledipasvir-sofosbuvir for 8 weeks was associated with a high rate of sustained virologic response among previously untreated patients with HCV genotype 1 infection without cirrhosis. No additional benefit was associated with the inclusion of ribavirin in the regimen or with extension of the duration of treatment to 12 weeks. (Funded by Gilead Sciences; ION-3 ClinicalTrials.gov number, NCT01851330 .).
    New England Journal of Medicine 04/2014; · 51.66 Impact Factor
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    ABSTRACT: Background In this phase 3 trial we evaluated the efficacy and safety of the interferon-free combination of ABT-450 with ritonavir (ABT-450/r), ombitasvir (also known as ABT-267), dasabuvir (also known as ABT-333), and ribavirin for the retreatment of HCV in patients who were previously treated with peginterferon-ribavirin. Methods We enrolled patients with HCV genotype 1 infection and no cirrhosis who had previously been treated with peginterferon-ribavirin and had a relapse, a partial response, or a null response. Patients were randomly assigned in a 3:1 ratio to receive coformulated ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir) and dasabuvir (250 mg twice daily) with ribavirin (1000 or 1200 mg daily) or matching placebos during the 12-week double-blind period. The primary end point was the rate of sustained virologic response 12 weeks after the end of study treatment. The primary efficacy analysis compared this rate among patients assigned to the active regimen with a historical response rate (65%) among previously treated patients with HCV genotype 1 infection and no cirrhosis who had received retreatment with telaprevir and peginterferon-ribavirin. Results A total of 394 patients received at least one study-drug dose. In the active-regimen group, 286 of 297 patients had a sustained virologic response at post-treatment week 12, for an overall rate of 96.3% (95% confidence interval, 94.2 to 98.4). This rate was noninferior and superior to the historical control rate. Rates were 95.3% among patients with a prior relapse (82 of 86 patients), 100% among patients with a prior partial response (65 of 65 patients), and 95.2% among patients with a prior null response (139 of 146 patients). Pruritus occurred more frequently with the active regimen (in 13.8% of patients) than with placebo (5.2%, P=0.03). Three patients in the active-regimen group (1.0%) discontinued the study drugs owing to adverse events. Hemoglobin values of grade 2 (8.0 to <10.0 g per deciliter) and grade 3 (6.5 to <8.0 g per deciliter) occurred in 4.7% and 0.3% of patients in the active-regimen group, respectively. Conclusions Rates of response to a 12-week interferon-free combination regimen were more than 95% among previously treated patients with HCV genotype 1 infection, including patients with a prior null response. (Funded by AbbVie; SAPPHIRE-II ClinicalTrials.gov number, NCT01715415 .).
    New England Journal of Medicine 04/2014; · 51.66 Impact Factor
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    Hangeun Kim, Keith Meyer, Adrian M Di Bisceglie, Ranjit Ray
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    ABSTRACT: We have previously reported that in vitro HCV infection of cells of hepatocyte origin attenuates complement system at multiple steps, and attenuation also occurs in chronically HCV infected liver, irrespective of the disease stage. However, none of these regulations alone completely impaired complement pathways. Modulation of the upstream proteins involved in proteolytic processing of the complement cascade prior to convertase formation is critical in promoting the function of the complement system in response to infection. Here, we examined the regulation of C2 complement expression in hepatoma cells infected in vitro with cell culture grown virus, and validated our observations using randomly selected chronically HCV infected patient liver biopsy specimens. C2 mRNA expression was significantly inhibited, and classical C3 convertase (C4b2a) decreased. In separate experiments for C3 convertase function, C3b deposition onto bacterial membrane was reduced using HCV infected patient sera as compared to uninfected control, suggesting impaired C3 convertase. Further, iC3b level, a proteolytically inactive form of C3b, was lower in HCV infected patient sera, reflecting impairment of both C3 convertase and Factor I activity. The expression level of Factor I was significantly reduced in HCV infected liver biopsy specimens, while Factor H level remained unchanged or enhanced. Together, these results suggested that inhibition of C3 convertase activity is an additional cumulative effect for attenuation of complement system adopted by HCV for weakening innate immune response.
    PLoS ONE 01/2014; 9(7):e101422. · 3.73 Impact Factor
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    ABSTRACT: Background & Aims Chronic hepatitis B virus (HBV) infection is an important cause of cirrhosis and hepatocellular carcinoma worldwide; populations that migrate to the US and Canada might be disproportionately affected. The Hepatitis B Research Network (HBRN) is a cooperative network of investigators from the United States and Canada, created to facilitate clinical, therapeutic, and translational research in adults and children with hepatitis B. We describe the structure of the network and baseline characteristics of adults with hepatitis B enrolled in the network. Methods The HBRN collected data on clinical characteristics of 1625 adults with chronic HBV infection who are not receiving antiviral therapy from 21 clinical centers in North America. Results Half of the subjects in the HBRN are male, and the mean age is 42 years; 72% are Asian, 15% are Black, and 11% are White, with 82% born outside of North America. The most common HBV genotype was B (39%); 745 of subjects were negative for the hepatitis B e antigen. The median serum level of HBV DNA when the study began was 3.6 log10 IU/mL; 68% of male subjects and 67% of female subjects had levels of alanine aminotransferase above the normal range. Conclusions The HBRN cohort will be used to address important clinical and therapeutic questions for North Americans infected with chronic HBV and to guide health policies on HBV prevention and management in North America.
    Clinical Gastroenterology and Hepatology. 01/2014;
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    ABSTRACT: Background & Aims TG4040 is a Modified Vaccinia Ankara (MVA) virus that expresses the hepatitis C virus (HCV) proteins NS3, NS4, and NS5B. We performed a phase II open-label study to determine the efficacy, safety, and immunotherapeutic properties of TG4040 in combination with pegylated interferon α-2a and ribavirin (PEG-IFNα /RBV) in patients with chronic HCV infection. Methods Treatment-naive patients with HCV genotype 1 infection were randomly assigned to 1 of the following groups: PEG-IFNα/RBV for 48 weeks (group A, n=31), PEG-IFNα/RBV for 4 weeks followed by PEG-IFNα/RBV for 44 weeks with 6 injections of TG4040 (group B, n=63), or TG4040 for 12 weeks (7 injections) followed by PEG-IFNα/RBV for 48 weeks with 6 injections of TG4040 (group C, n=59). The primary endpoint was complete early virologic response (cEVR), defined as HCV RNA<10 IU/mL after 12 weeks of PEG-IFNα/RBV treatment. Results In group C, 64.2% of evaluable patients achieved cEVR, compared to 30.0% in group A and 45.9% in group B (P=.0003 for group C vs A). A higher percentage of patients achieved a sustained virologic response 24 weeks after therapy ended in group C (58.2%) than in groups A (48.4%) or B (50.8%). HCV- and MVA-specific T-cell responses were predominantly observed in group C. As expected, most patients given injections of TG4040 developed anti-MVA antibodies. The combination of TG4040 and PEG-IFNα/RBV was reasonably well tolerated. However, PEG-IFNα-associated thrombocytopenia developed in 3 patients who carried the class II HLA allele DRB01*04. Conclusions A higher percentage of patients with chronic HCV infection who received immunotherapy with TG4040 followed by TG4040 and PEG-IFNα/RBV achieved a cEVR compared to patients who received only PEG-IFNα/RBV therapy. These findings show that immunotherapies that activate T cells are effective in patients with chronic HCV infection. ClinicalTrials.gov number, NCT01055821.
    Gastroenterology 01/2014; · 12.82 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) is a highly mutable RNA virus and circulates as a heterogeneous population in individual patients. The magnitude of such population heterogeneity has long been proposed to be linked with diverse clinical phenotypes, including antiviral therapy. Yet data accumulated thus far are fairly inconclusive. By the integration of long RT-PCR with 454 sequencing, we have built a pipeline optimized for the quantification of HCV genome-wide mutation load at 1% resolution of mutation frequency, followed by a retrospective study to examine the role of HCV mutation load in peginterferon-alpha2a and ribavirin combination antiviral therapy. Genome-wide HCV mutation load varied widely with a range from 92 to 1639 mutations and presented a Poisson distribution among 56 patients (Kolmogorov-Smirnov statistic = 0.078, p = 0.25). Patients achieving sustained virological response (n = 26) had significantly lower mutation loads than that in null responders (n = 30) (mean and standard derivation: 524±279 vs. 805±271, p = 0.00035). All 36,818 mutations detected in 56 patients displayed a power-law distribution in terms of mutation frequency in viral population. The low-frequency mutation load, but not the high-frequency load, was proportional firmly to the total mutation load. In-depth analyses revealed that intra-patient HCV population structure was shaped by multiple factors, including immune pressure, strain difference and genetic drift. These findings explain previous conflicting reports using low-resolution methods and highlight a dominant role of natural selection in response to therapeutic intervention. By attaining its signatures from complex interaction between host and virus, the high-resolution quantification of HCV mutation load predicts outcomes from interferon-based antiviral therapy and could also be a potential biomarker in other clinical settings.
    PLoS ONE 01/2014; 9(6):e100131. · 3.73 Impact Factor
  • Adrian M Di Bisceglie
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 12/2013; · 5.64 Impact Factor
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    ABSTRACT: There is a close relationship between chronic hepatitis B virus (HBV) infection and chronic renal disease. We analyzed changes in renal function using different markers of glomerular filtration rate (GFR) in multiple studies of telbivudine treatment of patients with chronic HBV infection. We used serum creatinine-based equations (Cockcroft-Gault, modification of diet in renal disease [MDRD], and chronic kidney disease epidemiology collaboration [CKP-EPI]) to estimate GFR (eGFRs) in adults with chronic HBV infection and compensated liver disease who participated in a phase III randomized double-blind study comparing the efficacy and safety of telbivudine (600 mg/day) and lamivudine (100 mg/day) for 2 y (the GLOBE study) and in long-term extension studies (4-6 years), as well as in patients with decompensated cirrhosis (2 y). eGFRs calculated using the Cockcroft-Gault, MDRD, and CKP-EPI equations were concordant, indicating improved renal function in telbivudine-treated patients during the 2 y GLOBE study (there was an 8.5% increase in mean eGFR, based on the MDRD equation). Improved renal function was maintained for 4-6 y. Increased eGFR with telbivudine treatment was also observed in patients at increased risk for renal impairment: patients with baseline eGFRs of 60-89 mL/min/1.73 m(2) (+17.2%), older than 50 y (+11.4%), and with liver fibrosis/cirrhosis, (+7.2% for patients with Ishak fibrosis score at 5-6). In decompensated patients with high renal risk, eGFR was also improved on telbivudine (+2.0%). In global trials of patients with compensated and decompensated cirrhosis, long-term telbivudine therapy was associated with a sustained improvement of renal function-particularly among patients with increased risk of renal impairment. The mechanisms of this renal protective effect remain to be determined.
    Gastroenterology 09/2013; · 12.82 Impact Factor
  • Weihua Wang, Xiaoan Zhang, Yanjuan Xu, Adrian M Di Bisceglie, Xiaofeng Fan
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    ABSTRACT: Serum is the most common and easily accessible patient specimen in a minimally invasive manner. As a biological resource, RNA in serum has been less explored for its clinical utilization due to prevailing concerns regarding its high degradable nature. In the current study, however, we have documented the use of human serum RNA for viral categorization and discovery through transcriptome sequencing and analysis using well-curated databases and advanced bioinformatic tools. Such an integrated approach may have an immediate application in any clinical situations concerning with viral etiology.
    Biochemical and Biophysical Research Communications 06/2013; · 2.41 Impact Factor
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    ABSTRACT: CD55 limits excessive complement activation on the host cell surface by accelerating the decay of C3 convertases. In this study, we observed that hepatitis C virus (HCV) infection of hepatocytes or HCV core protein expression in transfected hepatocytes upregulated CD55 expression at the mRNA and protein levels. Further analysis suggested that HCV core or full-length (FL) genome enhanced CD55 promoter activity in a luciferase based assay, which is further augmented in the presence of IL-6. Mutation of the CREB or SP-1 binding site on the CD55 promoter impaired HCV core mediated upregulation of CD55. HCV infected or core transfected Huh7.5 cells displayed greater cell viability in the presence of CD81 and CD55 antibodies and complement. Biochemical analysis revealed that CD55 was associated with cell culture grown HCV after purification by sucrose density gradient ultracentrifugation. Consistent with this, a polyclonal antibody to CD55 captured cell culture grown HCV. Blocking antibodies against CD55 or virus envelope glycoproteins in the presence of normal human serum as a source of complement inhibited HCV infection. The inhibition was enhanced in the presence of both the antibodies and serum complement. Collectively, these results suggest that HCV induces and associates with a negative regulator of the complement pathway, a likely mechanism for immune evasion.
    Journal of Virology 05/2013; · 5.08 Impact Factor
  • Yang Lu, Yanjuan Xu, Adrian M Di Bisceglie, Xiaofeng Fan
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    ABSTRACT: The instability of recombinant clones accommodating large or full-length viral genomes is frequently a technical challenge in RNA virus research. In an attempt to establish a rapid plasmid-based reverse genetics system that utilizes long RT-PCR technique (LRP), similar difficulty was encountered in the cloning of 9022-bp LRP amplicon. All HCV genotype 1a strains used for LRP cloning showed a remarkable difference in terms of cloning stability. Subsequent analysis revealed the predictive value of phylogenetic positions in determining the cloning stability. Putative E. coli promoters on the HCV genome might be responsible for such cloning difference. An exhaustive exploration, testing nearly one hundred cloning protocols, did not reveal a general approach that can achieve stable cloning for all HCV 1a strains. The selection of appropriate strains, guided by phylogenetic analysis, appears to be necessary prior to the construction of infectious HCV 1a clones. These observations are not only valuable for potentially establishing an HCV 1a cell culture model but also have general implications for other RNA viruses due to concern about cloning instability.
    Journal of virological methods 04/2013; · 2.13 Impact Factor
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    Hangeun Kim, Keith Meyer, Adrian M Di Bisceglie, Ranjit Ray
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    ABSTRACT: Hepatitis C virus (HCV) proteins inhibit complement component expression, which may attenuate immunity against infection. In this study, we examined whether HCV regulates membrane attack complex (MAC) via complement component C9. MAC is composed of C5b- 9, and mediates cell lysis of invaded pathogens. Liver biopsy specimens from chronically HCV infected patients exhibited a lower level of C9 mRNA expression as compared to liver biopsy specimens from unrelated disease, or healthy control human liver RNA. Hepatocytes infected with cell culture grown HCV or expressing HCV core protein also displayed significant repression of C9 mRNA and protein levels. Promoter analysis suggested TCF-4E transcription factor is responsible for HCV core mediated C9 promoter regulation. Sera from chronically HCV infected patients displayed a lower C5b-9 level and a reduced antimicrobial effect on model organisms, as compared to unrelated patient sera or sera from healthy volunteers. Together, these results on C9 regulation by HCV core protein coupled with functional impairment of membrane attack complex underscore HCV mediated attenuation of immune mechanisms.
    Journal of Virology 03/2013; · 5.08 Impact Factor
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    ABSTRACT: GOALS:: To evaluate the predictive value of complete early virological response (cEVR) on sustained virological response (SVR) following retreatment with peginterferon alpha-2a (40 kDa) plus ribavirin in previous nonresponders to peginterferon alpha-2b (12 kDa). BACKGROUND:: In the randomized multinational retreatment with Pegasys in patients not responding to PegIntron therapy study, a 72-week regimen of peginterferon alpha-2a (40 kDa) plus ribavirin improved SVR rates over a standard 48-week regimen in previous nonresponders to peginterferon alpha-2b (12 kDa). cEVR, defined as hepatitis C virus RNA <50 IU/mL at treatment week 12, was an important predictor of SVR. STUDY:: We conducted an exploratory analysis of the retreatment with Pegasys in patients not responding to PegIntron therapy study data to better define the predictive value of cEVR for SVR in this patient population. RESULTS:: In total, 157 of the 942 patients achieved a cEVR (16.7%). SVR rates were higher with 72 versus 48 weeks of retreatment in patients with a cEVR (57% vs. 35%), whereas SVR rates were <5% in patients without cEVR in both groups. The relative adverse event (AE) burden was lower with 72 weeks of treatment (8.1 vs. 10.1 AEs/y of treatment) as was the estimated number of AEs per SVR achieved (55 vs. 100). Cumulative treatment duration required to achieve 1 SVR was lower with 72 weeks of treatment (6.7 vs. 10.0 y/SVR) and lower still assuming that treatment was stopped at week 12 for non-cEVR patients (3.6 vs. 7.1 y/SVR). CONCLUSIONS:: cEVR is a reliable predictor of SVR in patients retreated with peginterferon alpha-2a (40 kDa) plus ribavirin. Seventy-two-week retreatment has a more favorable benefit-risk ratio than 48 weeks, especially when cEVR is used to identify patients most likely to be cured.
    Journal of clinical gastroenterology 02/2013; · 2.21 Impact Factor
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    ABSTRACT: Chronic hepatitis C Virus (HCV) infection is one of the major causes of liver fibrosis and liver transplantation in the United States. Circulating microRNA (miRNA) in the blood are emerging as biomarkers for pathological conditions. In the present study, we performed a systematic screening approach to identify upregulated miRNAs in the plasma/serum of HCV infected patients with different stages of hepatic histological disease severity. We initially screened serum samples of HCV infected patientswith fibrosisand compared with sera of healthy volunteers using serum miRNA array profiling, and identified a group of modulated miRNAs. Subsequent study demonstrated that miR-20aand miR-92a in HCV infected fibrosispatients sera were significantly upregulated when compared with that of healthy volunteers or non-HCV associated liver disease. We have also observed anincrease of plasma miR-20a and miR-92a in acute and chronic HCV infected patients as compared to that of healthy volunteers. However, there was no correlation between the plasma/serum levels of any of these miRNAs with HCV viral loads.We next investigated longitudinal plasma samples from HCV infected patients. Our results suggested that miR-20a and miR-92a remained unaltered in HCV infected patients who progressed from acute to chronic infection. On the other hand, miR-92a expression was reduced in acute to resolved individuals. These data provide evidence that plasma/serumlevels of miR-20a and miR-92a have potential as sensitive and cost effective biomarkers for early detectionof HCV infection. Conclusion: The circulating miR-20a may serve as a potential for predictive biomarker in HCV mediated fibrosis. (HEPATOLOGY 2013.).
    Hepatology 02/2013; · 12.00 Impact Factor
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    ABSTRACT: Currently, a surgical approach is the best curative treatment for those with hepatocellular carcinoma (HCC). However, this requires HCC detection and removal of the lesion at an early stage. Unfortunately, most cases of HCC are detected at an advanced stage because of the lack of accurate biomarkers that can be used in the surveillance of those at risk. It is believed that biomarkers that could detect HCC early will play an important role in the successful treatment of HCC. In this study, we analyzed serum levels of alpha fetoprotein, Golgi protein, fucosylated alpha-1-anti-trypsin, and fucosylated kininogen from 113 patients with cirrhosis and 164 serum samples from patients with cirrhosis plus HCC. We utilized two different methods, namely, stepwise penalized logistic regression (stepPLR) and model-based classification and regression trees (mob), along with the inclusion of clinical and demographic factors such as age and gender, to determine if these improved algorithms could be used to increase the detection of cancer. The performance of multiple biomarkers was found to be better than that of individual biomarkers. Using several statistical methods, we were able to detect HCC in the background of cirrhosis with an area under the receiver operating characteristic curve of at least 0.95. stepPLR and mob demonstrated better predictive performance relative to logistic regression (LR), penalized LR and classification and regression trees (CART) used in our prior study based on three-fold cross-validation and leave one out cross-validation. In addition, mob provided unparalleled intuitive interpretation of results and potential cut-points for biomarker levels. The inclusion of age and gender improved the overall performance of both methods among all models considered, while the stratified male-only subset provided the best overall performance among all methods and models considered. In addition to multiple biomarkers, the incorporation of age and gender into statistical models significantly improved their predictive performance in the detection of HCC.
    BMC Medical Genomics 01/2013; 6 Suppl 3:S9. · 3.47 Impact Factor
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    ABSTRACT: Using comparative glycoproteomics, we have previously identified a glycoprotein that is altered in both amount and glycosylation as a function of liver cirrhosis. The altered glycoprotein is an agalactosylated (G0) immunoglobulin G molecule (IgG) that recognizes the heterophilic alpha-gal epitope. Since the alpha gal epitope is found on gut enterobacteria, it has been hypothesized that anti-gal antibodies are generated as a result of increased bacterial exposure in patients with liver disease. The N-linked glycosylation of anti-gal IgG molecules from patients with fibrosis and cirrhosis was determined and the effector function of anti-bacterial antibodies from over 100 patients examined. In addition, markers of microbial exposure were determined. Surprisingly, the subset of agalactosylated anti-gal antibodies described here, was impaired in their ability to mediate complement mediated lysis and inhibited the complement-mediated destruction of common gut bacteria. In an analysis of serum from more than 100 patients with liver disease, we have shown that those with increased levels of this modified anti-gal antibody had increased levels of markers of bacterial exposure. Anti-gal antibodies in patients with liver cirrhosis were reduced in their ability to mediate complement mediated lysis of target cells. As bacterial infection is a major complication in patients with cirrhosis and bacterial products such as LPS are thought to play a major role in the development and progression of liver fibrosis, this finding has many clinical implications in the etiology, prognosis and treatment of liver disease.
    PLoS ONE 01/2013; 8(6):e64992. · 3.73 Impact Factor
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    ABSTRACT: We have previously identified several biomarkers of hepatocellular carcinoma (HCC). The levels of three of these biomarkers were analyzed individually and in combination with the currently used marker, alpha fetoprotein (AFP), for the ability to distinguish between a diagnosis of cirrhosis (n=113) and HCC (n=164). We have utilized several novel biostatistical tools, along with the inclusion of clinical factors such as age and gender, to determine if improved algorithms could be used to increase the probability of cancer detection. Using several of these methods, we are able to detect HCC in the background of cirrhosis with an AUC of at least 0.95. The use of clinical factors in combination with biomarker values to detect HCC is discussed.
    Proceedings. IEEE International Conference on Bioinformatics and Biomedicine. 12/2012; 2012.
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    Sandip K Bose, Keith Meyer, Adrian M Di Bisceglie, Ratna B Ray, Ranjit Ray
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    ABSTRACT: Hepatitis C virus (HCV) mediated liver disease progression may reflect distinct molecular mechanisms for increased hepatocyte growth and hepatic stellate cell activation. In this study, we have observed that primary human hepatocytes; when infected in vitro with cell culture grown HCV genotype 1a or 2a, display viral RNA and protein expression. Infected hepatocytes displayed fibroblast like shape and extended life span. To understand the changes at the molecular level, we examined for epithelial-mesenchymal (EMT) markers. An increased mRNA and protein expression of vimentin, snail, slug and twist; and a loss of the epithelial cell marker E-cadherin, were observed. Snail and twist; when examined separately, were upregulated in chronically HCV infected liver biopsy specimens; indicating an onset of an active EMT state in infected liver. An increased expression of FSP-1 in the infected hepatocytes was also evident indicating a type 2 EMT state. Infected hepatocytes significantly increased phosphorylated β-catenin (Ser(552)) as an EMT mediator; which translocated into the nucleus, and activated Akt. Phosphorylation status of β-catenin at Thr(41)/Ser(45) moieties was specifically higher in control; as compared to HCV infected hepatocytes, implicating inactivation of β-catenin. Together, these results suggested that primary human hepatocytes infected with cell culture grown HCV, display EMT via activation of the Akt/β-catenin signaling pathway. This observation may have implications for liver disease progression and therapeutic intervention strategy using inhibitory molecules.
    Journal of Virology 10/2012; · 5.08 Impact Factor

Publication Stats

17k Citations
3,416.87 Total Impact Points

Institutions

  • 2002–2014
    • Saint Louis University
      • • Department of Internal Medicine
      • • Division of Gastroenterology & Hepatology
      Saint Louis, Michigan, United States
  • 1994–2014
    • Washington University in St. Louis
      • • Division of Gastroenterology
      • • Department of Molecular Microbiology
      San Luis, Missouri, United States
  • 2010–2013
    • Drexel University College of Medicine
      • Department of Microbiology & Immunology
      Philadelphia, PA, United States
    • Duke University Medical Center
      • Duke Clinical Research Institute
      Durham, NC, United States
  • 1995–2013
    • University of Missouri - St. Louis
      Saint Louis, Michigan, United States
    • National Cancer Institute (USA)
      Maryland, United States
    • Texas Tech University Health Sciences Center
      • Department of Internal Medicine
      Lubbock, TX, United States
  • 2010–2011
    • Massachusetts General Hospital
      • Department of Medicine
      Boston, MA, United States
  • 2005–2010
    • University of Michigan
      • Department of Internal Medicine
      Ann Arbor, MI, United States
  • 1989–2010
    • National Institutes of Health
      • • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      • • Branch of Digestive Diseases (DDB)
      Maryland, United States
  • 2004–2009
    • Virginia Commonwealth University
      • Division of Gastroenterology, Hepatology and Nutrition
      Richmond, Virginia, United States
    • St Louis University Hospital
      San Luis, Missouri, United States
    • University of Texas Southwestern Medical Center
      • Division of Digestive and Liver Diseases
      Dallas, TX, United States
    • Centers for Disease Control and Prevention
      • Division of Viral Hepatitis
      Druid Hills, GA, United States
  • 2008
    • University of the Witwatersrand
      • Clinical HIV Research Unit (CHRU)
      Johannesburg, Gauteng, South Africa
  • 2006–2007
    • UConn Health Center
      • Department of Medicine
      Farmington, CT, United States
    • University of Colorado
      • Division of Gastroenterology and Hepatology
      Denver, CO, United States
  • 2005–2006
    • University of Washington Seattle
      • Department of Laboratory Medicine
      Seattle, WA, United States
  • 1988–2006
    • The National Institute of Diabetes and Digestive and Kidney Diseases
      Maryland, United States
  • 1997
    • University of Southern California
      Los Angeles, California, United States
  • 1991
    • U.S. Food and Drug Administration
      • Laboratory of Hepatitis Viruses
      Washington, D. C., DC, United States
    • Hospital Universitario de La Princesa
      • Servicio de Aparato Digestivo
      Madrid, Madrid, Spain