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1.  HCC surveillance results in earlier HCC detection: results from an Indian cohort 
SpringerPlus  2014;3:610.
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide, with an increased incidence in South Asia. In order to describe the effect of surveillance for HCC with biannual ultrasound and alpha-fetoprotein (AFP) on diagnosis and survival in an Indian population a retrospective cohort-control study was performed at two liver clinics in India. The medical records of 3,258 patients with cirrhosis who received surveillance for HCC were reviewed, and 100 patients who developed HCC identified. Sixty-four cirrhotic patients diagnosed with HCC during the same time period without a history of surveillance were included and survival, BCLC stage at diagnosis, and treatment were compared.
Patients who underwent surveillance were more likely to be diagnosed with potentially curable or treatable BCLC Stage 0/A disease and Stage B/C disease respectively, than late Stage D disease (χ2 = 0.0007). Patients diagnosed at an earlier stage of HCC lived significantly longer after diagnosis than patients diagnosed at a later stage (Stage 0/A: 15.6 ± 14.2 months vs. Stage B/C: 9.43 ± 19.7 months vs. Stage D: 5.59 ± 11.9 months; p = 0.0006). While treatment for HCC improved overall survival, only 28% of eligible patients received treatment, explaining the lack of survival benefit noted in the surveillance group. Surveillance for HCC led to detection of HCC at earlier stages. The impact of surveillance on improved mortality could not be evaluated given the limited number of patients who received treatment. HCC surveillance has the potential to improve survival in South Asian patients with cirrhosis only if improvements in access to appropriate treatment are made.
PMCID: PMC4209002  PMID: 25392781
Hepatocellular carcinoma; Surveillance; Ultrasounds; Survival; Treatment; India
2.  A Whole Recombinant Yeast-Based Therapeutic Vaccine Elicits HBV X, S and Core Specific T Cells in Mice and Activates Human T Cells Recognizing Epitopes Linked to Viral Clearance 
PLoS ONE  2014;9(7):e101904.
Chronic hepatitis B infection (CHB) is characterized by sub-optimal T cell responses to viral antigens. A therapeutic vaccine capable of restoring these immune responses could potentially improve HBsAg seroconversion rates in the setting of direct acting antiviral therapies. A yeast-based immunotherapy (Tarmogen) platform was used to make a vaccine candidate expressing hepatitis B virus (HBV) X, surface (S), and Core antigens (X-S-Core). Murine and human immunogenicity models were used to evaluate the type and magnitude of HBV-Ag specific T cell responses elicited by the vaccine. C57BL/6J, BALB/c, and HLA-A*0201 transgenic mice immunized with yeast expressing X-S-Core showed T cell responses to X, S and Core when evaluated by lymphocyte proliferation assay, ELISpot, intracellular cytokine staining (ICS), or tumor challenge assays. Both CD4+ and CD8+ T cell responses were observed. Human T cells transduced with HBc18–27 and HBs183–91 specific T cell receptors (TCRs) produced interferon gamma (IFNγ following incubation with X-S-Core-pulsed dendritic cells (DCs). Furthermore, stimulation of peripheral blood mononuclear cells (PBMCs) isolated from CHB patients or from HBV vaccine recipients with autologous DCs pulsed with X-S-Core or a related product (S-Core) resulted in pronounced expansions of HBV Ag-specific T cells possessing a cytolytic phenotype. These data indicate that X-S-Core-expressing yeast elicit functional adaptive immune responses and supports the ongoing evaluation of this therapeutic vaccine in patients with CHB to enhance the induction of HBV-specific T cell responses.
PMCID: PMC4106793  PMID: 25051027
3.  Genome sequence of the human malaria parasite Plasmodium falciparum 
Nature  2002;419(6906):10.1038/nature01097.
The parasite Plasmodium falciparum is responsible for hundreds of millions of cases of malaria, and kills more than one million African children annually. Here we report an analysis of the genome sequence of P. falciparum clone 3D7. The 23-megabase nuclear genome consists of 14 chromosomes, encodes about 5,300 genes, and is the most (A + T)-rich genome sequenced to date. Genes involved in antigenic variation are concentrated in the subtelomeric regions of the chromosomes. Compared to the genomes of free-living eukaryotic microbes, the genome of this intracellular parasite encodes fewer enzymes and transporters, but a large proportion of genes are devoted to immune evasion and host–parasite interactions. Many nuclear-encoded proteins are targeted to the apicoplast, an organelle involved in fatty-acid and isoprenoid metabolism. The genome sequence provides the foundation for future studies of this organism, and is being exploited in the search for new drugs and vaccines to fight malaria.
PMCID: PMC3836256  PMID: 12368864
4.  Viral clearance is associated with improved insulin resistance in genotype 1 chronic hepatitis C but not genotype 2/3 
Gut  2011;61(1):128-134.
Genotype-specific associations between hepatitis C virus (HCV) and insulin resistance (IR) have been described, but a causal relationship remains unclear. This study investigated the association between a sustained virological response (SVR) and IR after chronic HCV therapy.
2255 treatment-naive patients with chronic HCV genotype 1 or 2/3 were enrolled in two phase 3 trials of albinterferon alpha-2b versus pegylated interferon alpha-2a for 48 or 24 weeks, respectively. IR was measured before treatment and 12 weeks after treatment using homeostasis model assessment (HOMA)-IR.
Paired HOMA-IR measurements were available in 1038 non-diabetic patients (497 with genotype 1; 541 with genotype 2/3). At baseline the prevalence of HOMA-IR >3 was greater in patients with genotype 1 than 2/3 (33% vs 27%; p=0.048). There was a significant reduction in the prevalence of IR in patients with genotype 1 achieving SVR (δ 10%; p<0.001), but not in genotype 1 non-responders or those with genotype 2/3. Multivariate analysis indicated that SVR was associated with a significant reduction in mean HOMA-IR in patients with genotype 1 (p=0.004), but not in those with genotype 2/3, which was independent of body mass index, alanine transaminase, γ-glutamyl transpeptidase and lipid level changes.
SVR is associated with a reduction in HOMA-IR in patients with HCV genotype 1 but not in those with genotype 2/3. Genotype 1 may have a direct effect on the development of IR, independent of host metabolic factors, and may be partially reversed by viral eradication.
PMCID: PMC3766841  PMID: 21873466
5.  Use of Triplex PCR for Rapid Detection of PVL and Differentiation of MRSA from Methicillin Resistant Coagulase Negative Staphylococci 
Introduction: Methicillin-Resistant Staphylococcus aureus (MRSA) has become a major public health problem in both hospitals and communities. Panton – Valentine Leucocidin (PVL) has been reported to be an important marker for the highly pathogenic community acquired S. aureus infections. A rapid detection of these MRSA is very important for its treatment. The specific detection of MRSA is always a problem due to the prevalence of methicillin resistance among the coagulase negative Staphylococci. Hence, this study was done to develop a rapid triplex PCR for the detection of PVL positive MRSA and for the simultaneous differentiation of MRSA from Coagulase Negative Staphylococci (CoNS).
Materials and Methods: We developed a triplex PCR for the specific detection of PVL positive Community Acquired (CA) – MRSA and for its simultaneous differentiation from the coagulase negative Staphylococci. We used PCR for targeting the fem A gene which is specific for S. aureus, mecA which is specific for methicillin-resistance and luk - PV which is specific for the PVL toxin. The method was evaluated with a total of 100 clinical isolates of Staphylococcus spp.
Results: The triplex PCR was successfully standardized by using the reference strains and it was evaluated by using clinical strains. The method was found to be rapid, highly sensitive (100%), specific (99%) and cost effective.
Conclusion: Triplex PCR can be used as a diagnostic tool for the detection of the highly pathogenic strains of CA-MRSA.
PMCID: PMC3592277  PMID: 23542876
PVL MRSA; MRCoNS; Triplex PCR; femA; mecA
6.  Protective Antigen Antibody Augments Hemodynamic Support in Anthrax Lethal Toxin Shock in Canines 
The Journal of Infectious Diseases  2012;205(5):818-829.
Background. Anthrax-associated shock is closely linked to lethal toxin (LT) release and is highly lethal despite conventional hemodynamic support. We investigated whether protective antigen–directed monoclonal antibody (PA-mAb) treatment further augments titrated hemodynamic support.
Methods and Results. Forty sedated, mechanically ventilated, instrumented canines challenged with anthrax LT were assigned to no treatment (controls), hemodynamic support alone (protocol-titrated fluids and norepinephrine), PA-mAb alone (administered at start of LT infusion [0 hours] or 9 or 12 hours later), or both, and observed for 96 hours. Although all 8 controls died, 2 of 8 animals receiving hemodynamic support alone survived (median survival times 65 vs 85 hours, respectively; P = .03). PA-mAb alone at 0 hour improved survival (5 of 5 animals survived), but efficacy decreased progressively with delayed treatment (9 hours, 2 of 3 survived; 12 hours, 0 of 4 survived) (P = .004 comparing survival across treatment times). However, combined treatment increased survival irrespective of PA-mAb administration time (0 hours, 4 of 5 animals; 9 hours, 3 of 3 animals; and 12 hours, 4 of 5 animals survived) (P = .95 comparing treatment times). Compared to hemodynamic support alone, when combined over PA-mAb treatment times (0, 9, and 12 hours), combination therapy produced higher survival (P = .008), central venous pressures, and left ventricular ejection fractions, and lower heart rates, norepinephrine requirements and fluid retention (P ≤ .03).
Conclusions. PA-mAb may augment conventional hemodynamic support during anthrax LT-associated shock.
PMCID: PMC3274375  PMID: 22223857
8.  Steatosis Is an Independent Predictor of Relapse Following Rapid Virologic Response in Patients With HCV Genotype 3 
Background & Aims
It is recommended that patients with chronic hepatitis C virus (HCV) genotype 3 infections receive 24 weeks of treatment. A rapid virologic response (RVR, at week 4) predicts a sustained virologic response (SVR), although not all patients with an RVR achieve an SVR. We explored the relationships among hepatic steatosis, level of HCV RNA, relapse, and RVR in a phase 3 randomized controlled trial of 932 patients infected with HCV genotype 2 (n = 427) or 3 (n = 505) who received 24 weeks of therapy with interferon-α.
In patients with an RVR (HCV RNA <43 IU/mL), the presence of an SVR was modeled using multivariate logistic regression as a function of age, sex, weight, body-mass index, insulin resistance, steatosis, and levels of γ-glutamyl transpeptidase, alanine transaminase, liver fibrosis, and baseline HCV RNA.
RVR, SVR, and relapse rates among patients with HCV genotype 3 were 79.6%, 79.2%, and 15.6%, respectively; corresponding rates among patients with HCV genotype 2 were 86.7%, 84.3%, and 10.1%. An RVR had high predictive value for an SVR in patients with HCV genotypes 2 (88.9%) and 3 (88.1%). The strongest independent predictors of relapse in patients with genotype 3 and an RVR were steatosis (odds ratio 3.0; P=.003) and HCV RNA ≥400,000 IU/mL (2.5; P=.04). Relapse rates in patients with steatosis were 17.4% and 20.9% for low and high baseline levels of HCV RNA, respectively; corresponding rates in those without steatosis were 2.5% and 8.8%.
Steatosis was associated with significantly higher rates of relapse, irrespective of viral load, in patients infected with HCV genotype 3 who had an RVR. Further studies are needed to determine if longer treatment durations are effective in patients with an RVR and these risk factors.
PMCID: PMC3155986  PMID: 21640198
Liver disease; response to therapy; prognosis; recurrence
9.  Anthrax Lethal and Edema Toxins Produce Different Patterns of Cardiovascular and Renal Dysfunction and Synergistically Decrease Survival in Canines 
The Journal of infectious diseases  2010;202(12):1885-1896.
High mortality in the 2001 US and recent European anthrax outbreaks suggests that better understanding of the effects of this bacteria’s toxins is needed to improve treatment.
Methods and results
Here, 24h edema (ETx) and lethal (LeTx) toxin infusions were investigated for 96h in sedated and mechanically ventilated canines. Initial study compared similarly lethal doses of ETx (n=8) or LeTx (n=15) alone. ETx was 24 times less lethal than LeTx, while median time to death in non-survivors (n=6 and 9 respectively) was shorter with ETx (42 vs. 67h, p=0.04). Compared to controls (n=9), both toxins decreased arterial and central venous pressures (CVP) and systemic vascular resistance (SVRI) and increased heart rate (HR), cardiac index, blood urea nitrogen (BUN), creatinine (Cr), BUN:Cr ratio, and hepatic transaminases (p≤0.05, toxin effect or time interaction). However, ETx stimulated early diuresis, reduced serum sodium and had more pronounced vasodilatory effects than LeTx as reflected by greater or earlier CVP, SVRI, and BUN:Cr changes (p≤0.01). LeTx progressively decreased left ventricular ejection fraction (p≤0.002). In subsequent study, lethal dose LeTx with an equimolar nonlethal ETx dose (n=8) increased mortality versus LeTx alone (n=8) (p=0.05).
Shock with ETx or LeTx may require differing supportive therapies while toxin antagonists should likely target both toxins.
PMCID: PMC3061475  PMID: 21067373
Anthrax; edema and lethal toxins; shock; organ injury
10.  Anthrax Lethal and Edema Toxins Produce Different Patterns of Cardiovascular and Renal Dysfunction and Synergistically Decrease Survival in Canines 
The Journal of Infectious Diseases  2010;202(12):1885-1896.
Background. High mortality in the 2001 US and recent European anthrax outbreaks suggests that better understanding of the effects of the toxins produced by this bacterium is needed to improve treatment.
Methods and results. Here, 24-h edema (ETx) and lethal (LeTx) toxin infusions were investigated for 96 h in sedated canines receiving mechanical ventilation. The initial study compared similarly lethal doses of ETx (n=8) or LeTx (n=15) alone. ETx was 24 times less lethal than LeTx, and the median time to death in nonsurvivors (n=6 and n=9, respectively) was shorter with ETx (42 vs 67 h; P=.04). Compared with controls (n=9), both toxins decreased arterial and central venous pressures and systemic vascular resistance and increased heart rate, cardiac index, blood urea nitrogen (BUN) level, creatinine (Cr) concentration, BUN:Cr ratio, and hepatic transaminase levels (P ⩽ .05 for toxin effect or time interaction). However, ETx stimulated early diuresis, reduced serum sodium levels, and had more pronounced vasodilatory effects, compared with LeTx, as reflected by greater or earlier central venous pressures, systemic vascular resistance, and changes in the BUN:Cr ratio (P ⩽ .01). LeTx progressively decreased the left ventricular ejection fraction (P ⩽ .002). In a subsequent study, a lethal dose of LeTx with an equimolar nonlethal ETx dose (n=8) increased mortality, compared with LeTx alone (n=8;P=.05).
Conclusion. Shock with ETx or LeTx may require differing supportive therapies, whereas toxin antagonists should likely target both toxins.
PMCID: PMC3061475  PMID: 21067373
11.  FibroSURE™ and FibroScan® in relation to treatment response in chronic hepatitis C virus 
AIM: To compare histological endpoint assessment using noninvasive alternatives to biopsy during treatment in a chronic hepatitis C virus (HCV) cohort.
METHODS: Patients with chronic HCV were randomized to receive interferon-based therapy for 24 (genotypes 2/3) or 48 (genotype 1) wk. FibroSURE™ (FS) was assessed at baseline and at week-12 post-treatment follow-up. Baseline biopsy for METAVIR was assessed by a single pathologist. FibroScan® transient elastography (TE) was performed during treatment in a patient subset.
RESULTS: Two thousand and sixty patients (n = 253 in Asia) were classified as METAVIR F0-1 (n = 1682) or F2-4 (n = 378). For F2-4, FS (n = 2055) had sensitivity and specificity of 0.87 and 0.61, respectively, with area under the receiver-operating curve of 0.82; corresponding values for TE (n = 214) and combined FS/TE (n = 209) were 0.77, 0.88 and 0.88, and 0.93, 0.68 and 0.88. Overall FS/TE agreement for F2-4 was 71% (κ = 0.41) and higher in Asians vs non-Asians (κ = 0.86 vs 0.35; P < 0.001). Combined FS/TE had 97% accuracy in Asians (n = 33). Baseline FS (0.38 vs 0.51, P < 0.001) and TE (8.0 kPa vs 11.9 kPa, P = 0.006) scores were lower in patients with sustained virological response than in nonresponders, and were maintained through follow-up.
CONCLUSION: FS and TE may reliably differentiate mild from moderate-advanced disease, with a potential for high diagnostic accuracy in Asians with chronic HCV.
PMCID: PMC3225094  PMID: 22147963
Albinterferon alfa-2b; FibroScan; FibroSURE; Hepatitis C virus; Interferon; Sustained virological response; Transient elastography
12.  Albinterferon Alfa-2b Was Not Inferior to Pegylated Interferon-α in a Randomized Trial of Patients With Chronic Hepatitis C Virus Genotype 2 or 3 
Gastroenterology  2010;139(4):1267-1276.
A phase 3 active-controlled study was conducted to assess the efficacy/safety of albinterferon alfa-2b (albIFN), a novel, long-acting, genetic fusion polypeptide of recombinant human albumin and interferon alfa-2b, in patients with chronic hepatitis C virus (HCV) genotype 2/3.
In all, 933 patients were randomized to open-label subcutaneous treatment with pegylated interferon-alfa-2a (Peg-IFNalfa-2a) 180 μg/wk, or albIFN 900 or 1200 μg every 2 weeks for 24 weeks, each administered with oral ribavirin 800 mg/day. The primary end point of the study was sustained virologic response (SVR) (HCV-RNA level, <15 IU/mL at week 48). During the study, the data monitoring committee recommended dose modification for all patients receiving albIFN 1200 μgto 900 μg, impacting 38% of this treatment arm.
By intention-to-treat analysis, SVR rates were 84.8% (95% confidence interval, 80.4%–88.6%), 79.8% (95% confidence interval, 74.9%–84.1%), and 80.0% (95% confidence interval, 75.1%–84.3%) with Peg-IFNalfa-2a, and albIFN 900 and 1200 μg, respectively. The primary hypothesis of noninferiority of SVR was established for albIFN 900 μg(P = .009) and 1200 μg(P = .006). Independent positive predictors of SVR by multivariate regression analysis were pretreatment HCV-RNA level less than 400,000 IU/mL, age younger than 45 years, body mass index less than 30 kg/m2, genotype 2, normal γ-glutamyl transpeptidase and increased alanine aminotransferase levels at baseline, fibrosis stage F0–F2, no steatosis, and Asian geographic region (Peg-IFNalfa-2a only). The 3 treatment groups showed similar rates of serious (7%–8%) and severe (13%–16%) adverse events, and discontinuations owing to adverse events (3.6%–5.5%).
Albinterferon alfa-2b 900 μg every 2 weeks provides an alternative efficacious treatment option in patients with chronic HCV genotype 2 or 3.
PMCID: PMC3175757  PMID: 20600017
ACHIEVE; albIFN; Pegylated Interferon-Alfa; Sustained Virologic Response
13.  Comparative Genome Analysis of the Pathogenic Spirochetes Borrelia burgdorferi and Treponema pallidum 
Infection and Immunity  2000;68(3):1633-1648.
A comparative analysis of the predicted protein sequences encoded in the complete genomes of Borrelia burgdorferi and Treponema pallidum provides a number of insights into evolutionary trends and adaptive strategies of the two spirochetes. A measure of orthologous relationships between gene sets, termed the orthology coefficient (OC), was developed. The overall OC value for the gene sets of the two spirochetes is about 0.43, which means that less than one-half of the genes show readily detectable orthologous relationships. This emphasizes significant divergence between the two spirochetes, apparently driven by different biological niches. Different functional categories of proteins as well as different protein families show a broad distribution of OC values, from near 1 (a perfect, one-to-one correspondence) to near 0. The proteins involved in core biological functions, such as genome replication and expression, typically show high OC values. In contrast, marked variability is seen among proteins that are involved in specific processes, such as nutrient transport, metabolism, gene-specific transcription regulation, signal transduction, and host response. Differences in the gene complements encoded in the two spirochete genomes suggest active adaptive evolution for their distinct niches. Comparative analysis of the spirochete genomes produced evidence of gene exchanges with other bacteria, archaea, and eukaryotic hosts that seem to have occurred at different points in the evolution of the spirochetes. Examples are presented of the use of sequence profile analysis to predict proteins that are likely to play a role in pathogenesis, including secreted proteins that contain specific protein-protein interaction domains, such as von Willebrand A, YWTD, TPR, and PR1, some of which hitherto have been reported only in eukaryotes. We tentatively reconstruct the likely evolutionary process that has led to the divergence of the two spirochete lineages; this reconstruction seems to point to an ancestral state resembling the symbiotic spirochetes found in insect guts.
PMCID: PMC97324  PMID: 10678983
14.  Swine testis cells contain functional heparan sulfate but are defective in entry of herpes simplex virus. 
Journal of Virology  1994;68(9):5667-5676.
Herpes simplex virus (HSV) enters and infects most cultured cells. We have found that swine testis cells (ST) produce yields of infectious HSV-1 up to four orders of magnitude lower than those of human embryonic lung (HEL) and HEp-2 cells because of a defect in virus entry. For ST cells, virus binding is reduced, DNA from input virus cannot be detected, and virus proteins are not synthesized. Polyethylene glycol treatment of ST cells after exposure to HSV allows viral entry, protein synthesis, and productive infection. Transfection of viral genomic DNA that bypasses the normal entry process produces similar yields of infectious virus from ST, HEL, and HEp-2 cells. Therefore, all three cell lines can support the HSV replicative cycle. Biochemical analyses and inhibition of sulfation by sodium chlorate treatment show that ST cells contain amounts and types of heparan sulfate (HS) similar to those of highly susceptible cells. HSV infection of sodium chlorate-treated HEL and ST cells indicates the presence of a second, non-HS receptor(s) on susceptible HEp-2 and HEL cells that is missing, or not functional, on poorly susceptible ST cells. We conclude that ST cells are defective in HSV entry, contain functional HS, but lack a functional non-HS receptor(s) required for efficient HSV-1 entry. Further, ST cells provide a novel resource that can be used to identify, isolate, and characterize an HSV non-HS receptor(s) and its role in the entry and tropism of this important human pathogen.
PMCID: PMC236968  PMID: 8057447
15.  GAL4-I kappa B alpha and GAL4-I kappa B gamma activate transcription by different mechanisms. 
Nucleic Acids Research  1993;21(9):2157-2163.
I kappa B proteins regulate Rel/NF-kappa B transcription complexes through a direct protein-protein interaction. In addition, we have previously shown that certain I kappa B proteins (I kappa B alpha and I kappa B gamma) can act as activators of transcription when fused to the DNA-binding domain of GAL4. We now show that a mutant chicken I kappa B alpha protein that cannot interact with Rel proteins in vitro did not activate transcription when fused to GAL4 in chicken embryo fibroblasts (CEF) and Saccharomyces cerevisiae, and did not inhibit growth in yeast; in contrast, an I kappa B alpha mutant that can still interact in vitro with Rel proteins activated transcription in both CEF and yeast and inhibited growth in yeast. In CEF, GAL4-I kappa B alpha mediated transcription activation was inhibited by co-transfection with an expression vector for a RelA (p65) protein that contained sequences needed for interaction with I kappa B alpha but that was deleted of its transcription activation domain. Therefore, it appears that GAL4-I kappa B alpha activates transcription by interacting with an endogenous Rel family protein in CEF. In contrast, the activation domain from I kappa B gamma behaved as a genuine acidic activator of transcription and did not inhibit growth when expressed in yeast. Since transcription activation and growth inhibition by GAL4-I kappa B alpha mutants in yeast correlated with their ability to interact with vertebrate Rel proteins, our results suggest that these activities of GAL4-I kappa B alpha are mediated through interaction with a Rel-like protein in yeast, which is important for cell growth.
PMCID: PMC309479  PMID: 8502557

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