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1.  Translational Phase I Trial of Vorinostat (Suberoylanilide Hydroxamic Acid) Combined with Cytarabine and Etoposide in Patients with Relapsed, Refractory, or High-Risk Acute Myeloid Leukemia 
To determine the maximum-tolerated dose (MTD) of the histone deacetylase inhibitor vorinostat combined with fixed doses of cytarabine (ara-C or cytosine arabinoside) and etoposide in patients with poor-risk or advanced acute leukemia, to obtain preliminary efficacy data, describe pharmacokinetics, and in vivo pharmacodynamic effects of vorinostat in leukemia blasts.
Experimental Design
In this open-label phase I study, vorinostat was given orally on days one to seven at three escalating dose levels: 200 mg twice a day, 200 mg three times a day, and 300 mg twice a day. On days 11 to 14, etoposide (100 mg/m2) and cytarabine (1 or 2 g/m2 twice a day if ≥65 or <65 years old, respectively) were given. The study used a standard 3+3 dose escalation design.
Eighteen of 21 patients with acute myelogenous leukemia (AML) treated on study completed planned therapy. Dose-limiting toxicities [hyperbilirubinemia/septic death (1) and anorexia/fatigue (1)] were encountered at the 200 mg three times a day level; thus, the MTD was established to be vorinostat 200 mg twice a day. Of 21 patients enrolled, seven attained a complete remission (CR) or CR with incomplete platelet recovery, including six of 13 patients treated at the MTD. The median remission duration was seven months. No differences in percentage S-phase cells or multidrug resistance transporter (MDR1 or BCRP) expression or function were observed in vivo in leukemia blasts upon vorinostat treatment.
Vorinostat 200 mg twice a day can be given safely for seven days before treatment with cytarabine and etoposide. The relatively high CR rate seen at the MTD in this poor-risk group of patients with AML warrants further studies to confirm these findings.
PMCID: PMC4332848  PMID: 23403629
2.  A Dual Vaccine Candidate against Norovirus and Hepatitis E Virus 
Vaccine  2013;32(4):445-452.
Norovirus (NoV) and hepatitis E virus (HEV) are both enterically-transmitted viruses causing gastroenteritis and hepatitis, respectively, in humans. While a vaccine against HEVs recently became available in China, there is no prophylactic or therapeutic approach against NoVs. Both NoV and HEV have surface protrusions formed by dimers of the protruding (P) domains of the viral capsids, which is responsible for virus-host interactions and eliciting viral neutralizing antibody. We developed in this study a bivalent vaccine against the two viruses through a recently developed polyvalent complex platform. The dimeric P domains of NoV and HEV were fused together, designated as NoV P−-HEV P, which was then linked with the dimeric glutathione-s-transferase (GST). After expression and purification in E. coli, the GST-NoV P−-HEV P fusion protein assembled into polyvalent complexes with a mean size of 1.8 μm, while the NoV P−-HEV P formed oligomers ranging from 100 to 420 kDa. Mouse immunization study demonstrated that both GST-NoV P−-HEV P and NoV P−-HEV P complexes induced significantly higher antibody titers to NoV P− and HEV P, respectively, than those induced by a mixture of the NoV P− and HEV P dimers. Furthermore, the complex-induced antisera exhibited significantly higher neutralizing activity against HEV infection in HepG2/3A cells and higher blocking activity on NoV P particles binding to HBGA receptors than those of the dimer-induced antisera. Thus, GST-NoV P−-HEV P and NoV P−-HEV P complexes are promising dual vaccine candidates against both NoV and HEV.
PMCID: PMC3898346  PMID: 24291540
Polyvalent complex; immune response; vaccine development; bivalent vaccine; vaccine platform; norovirus; hepatitis E virus (HEV)
3.  Comparative antigen-induced gene expression profiles unveil novel aspects of susceptibility/resistance to adjuvant arthritis in rats 
Molecular immunology  2013;56(4):531-539.
Lewis (LEW) and Wistar Kyoto (WKY) rats of the same major histocompatibility complex (MHC) haplotype (RT.1l) display differential susceptibility to adjuvant-induced arthritis (AIA). LEW are susceptible while WKY are resistant to AIA. To gain insights into the mechanistic basis of these disparate outcomes, we compared the gene expression profiles of the draining lymph node cells (LNC) of these two rat strains early (day 7) following a potentially arthritogenic challenge. LNC were tested both ex vivo and after restimulation with the disease-related antigen, mycobacterial heat-shock protein 65. Biotin-labeled fragment cRNA was generated from RNA of LNC and then hybridized with an oligonucleotide-based DNA microarray chip. The differentially expressed genes (DEG) were compared by limiting the false discovery rate to <5% and fold change ≥2.0, and their association with quantitative trait loci (QTL) was analyzed. This analysis revealed a more active immune response overall in WKY than LEW rats. Important differences were observed in the association of DEG with QTL in LEW vs. WKY rats. Both the number of upregulated DEG associated with rat arthritis-QTL and their level of expression were relatively higher in LEW when compared to WKY rat; however, the number of downregulated DEG-associated with rat arthritis-QTL as well as AIA-QTL were found to be higher in WKY than in LEW rats. In conclusion, distinct gene expression profiles define arthritis-susceptible versus resistant phenotype of MHC-compatible inbred rats. These results would advance our understanding of the pathogenesis of autoimmune arthritis and might also offer potential novel targets for therapeutic purposes.
PMCID: PMC3783567  PMID: 23911410
4.  Crystal structures of GI.8 Boxer virus P dimers in complex with HBGAs, a novel evolutionary path selected by the Lewis epitope 
Protein & Cell  2014;6(2):101-116.
Human noroviruses (huNoVs) recognize histo-blood group antigens (HBGAs) as attachment factors, in which genogroup (G) I and GII huNoVs use distinct binding interfaces. The genetic and evolutionary relationships of GII huNoVs under selection by the host HBGAs have been well elucidated via a number of structural studies; however, such relationships among GI NoVs remain less clear due to the fact that the structures of HBGA-binding interfaces of only three GI NoVs with similar binding profiles are known. In this study the crystal structures of the P dimers of a Lewis-binding strain, the GI.8 Boxer virus (BV) that does not bind the A and H antigens, in complex with the Lewis b (Leb) and Ley antigens, respectively, were determined and compared with those of the three previously known GI huNoVs, i.e. GI.1 Norwalk virus (NV), GI.2 FUV258 (FUV) and GI.7 TCH060 (TCH) that bind the A/H/Le antigens. The HBGA binding interface of BV is composed of a conserved central binding pocket (CBP) that interacts with the β-galactose of the precursor, and a well-developed Le epitope-binding site formed by five amino acids, including three consecutive residues from the long P-loop and one from the S-loop of the P1 subdomain, a feature that was not seen in the other GI NoVs. On the other hand, the H epitope/acetamido binding site observed in the other GI NoVs is greatly degenerated in BV. These data explain the evolutionary path of GI NoVs selected by the polymorphic human HBGAs. While the CBP is conserved, the regions surrounding the CBP are flexible, providing freedom for changes. The loss or degeneration of the H epitope/acetamido binding site and the reinforcement of the Le binding site of the GI.8 BV is a typical example of such change selected by the host Lewis epitope.
PMCID: PMC4312760  PMID: 25547362
norovirus; P domain; histo-blood group antigens (HBGAs); crystal structure; norovirus-host interaction
5.  Crystal structures of GI.8 Boxer virus P dimers in complex with HBGAs, a novel evolutionary path selected by the Lewis epitope 
Protein & Cell  2014;6(2):101-116.
Human noroviruses (huNoVs) recognize histo-blood group antigens (HBGAs) as attachment factors, in which genogroup (G) I and GII huNoVs use distinct binding interfaces. The genetic and evolutionary relationships of GII huNoVs under selection by the host HBGAs have been well elucidated via a number of structural studies; however, such relationships among GI NoVs remain less clear due to the fact that the structures of HBGA-binding interfaces of only three GI NoVs with similar binding profiles are known. In this study the crystal structures of the P dimers of a Lewis-binding strain, the GI.8 Boxer virus (BV) that does not bind the A and H antigens, in complex with the Lewis b (Leb) and Ley antigens, respectively, were determined and compared with those of the three previously known GI huNoVs, i.e. GI.1 Norwalk virus (NV), GI.2 FUV258 (FUV) and GI.7 TCH060 (TCH) that bind the A/H/Le antigens. The HBGA binding interface of BV is composed of a conserved central binding pocket (CBP) that interacts with the β-galactose of the precursor, and a well-developed Le epitope-binding site formed by five amino acids, including three consecutive residues from the long P-loop and one from the S-loop of the P1 subdomain, a feature that was not seen in the other GI NoVs. On the other hand, the H epitope/acetamido binding site observed in the other GI NoVs is greatly degenerated in BV. These data explain the evolutionary path of GI NoVs selected by the polymorphic human HBGAs. While the CBP is conserved, the regions surrounding the CBP are flexible, providing freedom for changes. The loss or degeneration of the H epitope/acetamido binding site and the reinforcement of the Le binding site of the GI.8 BV is a typical example of such change selected by the host Lewis epitope.
PMCID: PMC4312760  PMID: 25547362
norovirus; P domain; histo-blood group antigens (HBGAs); crystal structure; norovirus-host interaction
6.  Intervention of transforming pulmonary fibrosis with NF-κB p65 antisense oligonucleotide 
Objective: NF-κB, especially p65 subunit, plays important role in the process of pulmonary fibrosis. In this study, we transformed fibroblast into myofibroblast induced by bleomycin, and then studied the effects of NF-κB p65 antisense oligonucleotide on pulmonary fibrosis in mouse model. Methods: Pulmonary fibrosis was induced by bleomycin in C57BL/6 mouse (modeling group). The NF-κB antisense oligonucleotide was injected intravenously into mouse 6 hours before inducing (test group), we performed broncho-alveolar lavage and blood collecting through cardiac puncture. Bronchoalveolar Lavage Fluid (BALF) and serum from normal C57BL/6 mouse (control group) were collected for comparison. Immunohistochemistry staining of the NF-κB and α-SMA on lung tissues and cultured cells were carried out in each group, respectively. Results: The expression level of NF-κB and α-SMA were both consistently higher in modeling group when compared with control group (P < 0.05). Meanwhile, they were reduced significantly through the intervention of NF-κB p65 antisense oligonucleotide in the test group (P < 0.05). More importantly, the expression of NF-κB was positively correlated with α-SMA. Conclusion: our study suggests the potential in prevention of bleomycin-induced pulmonary fibrosis with NF-κB p65 antisense oligonucleotide.
PMCID: PMC4307475  PMID: 25664028
Fibroblast; myofibroblast; NF-κB; α-SMA; antisense oligonucleotide
7.  LOC401317, a p53-Regulated Long Non-Coding RNA, Inhibits Cell Proliferation and Induces Apoptosis in the Nasopharyngeal Carcinoma Cell Line HNE2 
PLoS ONE  2014;9(11):e110674.
Recent studies have revealed that long non-coding RNAs participate in all steps of cancer initiation and progression by regulating protein-coding genes at the epigenetic, transcriptional, and post-transcriptional levels. Long non-coding RNAs are in turn regulated by other genes, forming a complex regulatory network. The regulation networks between the p53 tumor suppressor and these RNAs in nasopharyngeal carcinoma remains unclear. The aims of this study were to investigate the regulatory roles of the TP53 gene in regulating long non-coding RNA expression profiles and to study the function of a TP53-regulated long non-coding RNA (LOC401317) in the nasopharyngeal carcinoma cell line HNE2. Long non-coding RNA expression profiling indicated that 133 long non-coding RNAs were upregulated in the human NPC cell line HNE2 cells following TP53 overexpression, while 1057 were downregulated. Among these aberrantly expressed long non-coding RNAs, LOC401317 was the most significantly upregulated one. Further studies indicated that LOC401317 is directly regulated by p53 and that ectopic expression of LOC401317 inhibits HNE2 cell proliferation in vitro and in vivo by inducing cell cycle arrest and apoptosis. LOC401317 inhibited cell cycle progression by increasing p21 expression and decreasing cyclin D1 and cyclin E1 expression and promoted apoptosis through the induction of poly(ADP-ribose) polymerase and caspase-3 cleavage. Collectively, these results suggest that LOC401317 is directly regulated by p53 and exerts antitumor effects in HNE2 nasopharyngeal carcinoma cells.
PMCID: PMC4244030  PMID: 25422887
8.  Median infectious dose of human norovirus GII.4 in gnotobiotic pigs is decreased by simvastatin treatment and increased by age 
The Journal of General Virology  2013;94(Pt 9):2005-2016.
Human noroviruses (NoVs), a major cause of viral gastroenteritis, are difficult to study due to the lack of a cell-culture and a small-animal model. Pigs share with humans the types A and H histo-blood group antigens on the intestinal epithelium and have been suggested as a potential model for studies of NoV pathogenesis, immunity and vaccines. In this study, the effects of age and a cholesterol-lowering drug, simvastatin, on the susceptibility of pigs to NoV infection were evaluated. The median infectious dose (ID50) of a genogroup II, genotype 4 (GII.4) 2006b variant was determined. The ID50 in neonatal (4–5 days of age) pigs was ≤2.74×103 viral RNA copies. In older pigs (33–34 days of age), the ID50 was 6.43×104 but decreased to <2.74×103 in simvastatin-fed older pigs. Evidence of NoV infection was obtained by increased virus load in the intestinal contents, cytopathological changes in the small intestine, including irregular microvilli, necrosis and apoptosis, and detection of viral antigen in the tip of villi in duodenum. This GII.4 variant was isolated in 2008 from a patient from whom a large volume of stool was collected. GII.4 NoVs are continuously subjected to selective pressure by human immunity, and antigenically different GII.4 NoV variants emerge every 1–2 years. The determination of the ID50 of this challenge virus is valuable for evaluation of protection against different GII.4 variants conferred by NoV vaccines in concurrence with other GII.4 variants in the gnotobiotic pig model.
PMCID: PMC3749057  PMID: 23804568
9.  Tissue-specific isoform switch and DNA hypomethylation of the pyruvate kinase PKM gene in human cancers 
Oncotarget  2013;5(18):8202-8210.
The M2 isoform of pyruvate kinase (PKM2) plays an important role in aerobic glycolysis and is a mediator of the Warburg effect in tumors. It was previously thought that tumor cells switch expression of PKM from normal tissue-expressed PKM1 to tumor-specific PKM2 via an alternative splicing mechanism. This view was challenged by a recent report demonstrating that PKM2 is already the major PKM isoform expressed in many differentiated normal tissues. Here, through analyses on sixteen tumor types using the cancer genome atlas RNA-Seq and exon array datasets, we confirmed that isoform switch from PKM1 to PKM2 occurred in glioblastomas but not in other tumor types examined. Despite lacking of isoform switches, PKM2 expression was found to be increased in all cancer types examined, and correlated strongly to poor prognosis in head and neck cancers. We further demonstrated that elevated PKM2 expression correlated well with the hypomethylation status of intron 1 of the PKM gene in multiple cancer types, suggesting epigenetic regulation by DNA methylation as a major mechanism in controlling PKM transcription in tumors. Our study suggests that isoform switch of PKM1 to PKM2 in cancers is tissue-specific and targeting PKM2 activity in tumors remains a promising approach for clinical intervention of multiple cancer types.
PMCID: PMC4226677  PMID: 24077665
PKM2; alternative splicing; DNA methylation
10.  OMIT: Dynamic, Semi-Automated Ontology Development for the microRNA Domain 
PLoS ONE  2014;9(7):e100855.
As a special class of short non-coding RNAs, microRNAs (a.k.a. miRNAs or miRs) have been reported to perform important roles in various biological processes by regulating respective target genes. However, significant barriers exist during biologists' conventional miR knowledge discovery. Emerging semantic technologies, which are based upon domain ontologies, can render critical assistance to this problem. Our previous research has investigated the construction of a miR ontology, named Ontology for MIcroRNA Target Prediction (OMIT), the very first of its kind that formally encodes miR domain knowledge. Although it is unavoidable to have a manual component contributed by domain experts when building ontologies, many challenges have been identified for a completely manual development process. The most significant issue is that a manual development process is very labor-intensive and thus extremely expensive. Therefore, we propose in this paper an innovative ontology development methodology. Our contributions can be summarized as: (i) We have continued the development and critical improvement of OMIT, solidly based on our previous research outcomes. (ii) We have explored effective and efficient algorithms with which the ontology development can be seamlessly combined with machine intelligence and be accomplished in a semi-automated manner, thus significantly reducing large amounts of human efforts. A set of experiments have been conducted to thoroughly evaluate our proposed methodology.
PMCID: PMC4099014  PMID: 25025130
11.  Effectiveness of moxibustion treatment as adjunctive therapy in osteoarthritis of the knee: a randomized, double-blinded, placebo-controlled clinical trial 
Arthritis Research & Therapy  2014;16(3):R133.
Our objective was to compare the effectiveness and safety of traditional Chinese moxibustion to that of sham moxibustion in patients with chronic knee osteoarthritis (KOA) pain.
We conducted a randomized placebo-controlled trial involving 110 patients with KOA who met the inclusion criteria. These patients randomly received either active moxibustion (n = 55) or sham moxibustion control (n = 55) at acupoints Dubi (ST 35), extra-point Neixiyan (EX-LE 4), and an Ashi (tender) point three times a week for 6 weeks. Effects were evaluated with Western Ontario and McMaster Universities’ Osteoarthritis Index (WOMAC VA 3.1) criteria at the end of the course of treatment and 3, 12, and 24 weeks after the initial treatment.
The WOMAC pain scores showed greater improvement in the active treatment group than in control at weeks 3 (P = 0.012), 6 (P <0.001), 12 (P = 0.002), and 24 (P = 0.002) as did WOMAC physical function scores of the active treatment group at week 3 (P = 0.002), 6 (P = 0.015), and 12 (P <0.001) but not 24 (P = 0.058). Patients and practitioners were blinded successfully, and no significant adverse effects were found during the trial.
A 6-week course of moxibustion seems to relieve pain effectively and improve function in patients with KOA for up to 18 weeks after the end of treatment. Moxibustion treatment appears to be safe, and the usefulness of the novel moxa device was validated.
Trial registration
Current controlled trial: ISRCTN68475405. Registered 4 April 2014.
PMCID: PMC4095686  PMID: 24962039
12.  Panepoxydone Targets NF-kB and FOXM1 to Inhibit Proliferation, Induce Apoptosis and Reverse Epithelial to Mesenchymal Transition in Breast Cancer 
PLoS ONE  2014;9(6):e98370.
Triple-negative breast cancer (TNBC) is a highly diverse group that is associated with an aggressive phenotype. Its treatment has been challenging due to its heterogeneity and absence of well-defined molecular targets. Thus, there is an urgent need to identify novel agents with therapeutic application. NF-κB is over-expressed in many breast cancers; thus, inactivation of the NF-κB pathway could serve as a therapeutic target. Here we report for the first time the anti-tumor activity of panepoxydone (PP), a NF-κB inhibitor isolated from an edible mushroom, in several breast cancer cell lines.
We investigated the effects of PP on cell growth, migration-invasion, apoptosis and EMT-related proteins expression in MCF-7 and TNBC cell lines MDA-MB-231, MDA-MB-468 and MDA-MB-453.
Significant antitumor activity was seen in all cell lines, with differential responses noted in cell-line specific manner. Treatment with PP resulted in significant cytotoxicity, decreased invasion, migration and increased apoptosis in all cell lines tested. Up-regulation of Bax and cleaved PARP and down-regulation of Bcl-2, survivin, cyclin D1 and caspase 3 were noted in PP-treated breast cancer cells. The antitumor effect of PP appeared related to its ability to inhibit the phosphorylation of inhibitor of NF-κB (IκBα) with cytoplasmic accumulation. PP treatment also down-regulated FOXM1 which resulted in a reversal of EMT. Similar results were obtained after silencing of NF-kB and FOXM1.
Altogether, these studies show, for the first time the antitumor activity of PP against breast cancer cells, in particular TNBC cells. Furthermore, it highlights the concept that optimal treatment of TNBC warrants attention to the differential sensitivity of various TNBC subtypes to therapeutic agents. These results suggest that the PP may be a potentially effective chemopreventive or therapeutic agent against breast cancer. However, additional studies are required to more fully elucidate the mechanism of antitumor effect of PP.
PMCID: PMC4045585  PMID: 24896091
13.  Polyvalent complexes for vaccine development 
Biomaterials  2013;34(18):4480-4492.
Homotypic interaction is a common phenomenon of many proteins, through which they form dimers. We developed a simple approach to turn small dimeric proteins into large polyvalent complexes for increased immunogenicity and functionality. This was achieved via a fusion of two or more dimeric proteins together to induce polyvalent complex formation through intermolecular dimerizations. Two types of polyvalent complexes, linear and network, assembled spontaneously when a dimeric glutathione S-transferase (GST) was fused with one or two protruding (P) domains of norovirus (NoV). Additionally, a monomeric antigen, the peptide epiope M2e of the influenza virus (IV) or the VP8* antigen of rotavirus (RV), can be inserted to the polyvalent complexes. Mouse immunization demonstrated that the polyvalent complexes induced significantly higher antibody and CD4+ T cell responses to the complex components than those induced by the free epitope and antigens. Further evaluations indicated that the polyvalent complex vaccines exhibited significantly higher neutralization activity against NoV and RV and stronger protection against IV challenges in a mouse model than those of the monomeric or dimeric vaccines. The binding of NoV P proteins to their HBGA ligands was also significantly increased through the polyvalent complex formation. Therefore, our polyvalent complex system provides a new strategy for novel vaccine development and may find various applications throughout biomedicine.
PMCID: PMC3635153  PMID: 23498893
14.  Stalling the engine of resistance: targeting cancer metabolism to overcome therapeutic resistance 
Cancer research  2013;73(9):2709-2717.
Cancer cells are markedly different from normal cells with regards to how their metabolic pathways are utilized to fuel cellular growth and survival. Two basic metabolites that exemplify these differences through increased uptake and altered metabolic usage are glucose and glutamine. These molecules can be catabolized to manufacture many of the building blocks required for active cell growth and proliferation. The alterations in the metabolic pathways necessary to sustain this growth have been linked to therapeutic resistance, a trait that is correlated with poor patient outcomes. By targeting the metabolic pathways that import, catabolize, and synthesize essential cellular components, drug resistant cancer cells can often be resensitized to anti-cancer treatments. The specificity and efficacy of agents directed at the unique aspects of cancer metabolism is expected to be high; and may, when in utilized in combination with more traditional therapeutics, present a pathway to surmount resistance within tumors that no longer respond to current forms of treatment.
PMCID: PMC3644012  PMID: 23610447
cancer; metabolism; resistance; chemotherapy
15.  A Dual Chicken IgY Against Rotavirus and Norovirus 
Antiviral research  2012;97(3):293-300.
Rotavirus (RV) and norovirus (NoV) are the two most important causes of viral gastroenteritis. While vaccine remains an effective prophylactic strategy, development of other approaches, such as passive immunization to control and treat clinical infection and illness of the two pathogens, is necessary. Previously we demonstrated that high titers of NoV-specific IgY were readily developed by immunization of chickens with the NoV P particles. In this study, we developed a dual IgY against both RV and NoV through immunization of chickens with a divalent vaccine comprising neutralizing antigens of both RV and NoV. This divalent vaccine, named P-VP8* particle, is made of the NoV P particle as a carrier with the RV spike protein VP8* as a surface insertion. Approximately 45 mg of IgY were readily obtained from each yolk with high titers of anti-P particle and anti-VP8* antibodies detected by ELISA, Western blot, HBGA blocking (NoV and RV) and neutralization (RV) assays. Reductions of RV replication were observed with viruses treated with the IgY before and after inoculation into cells, suggesting an application of the IgY as both prophylactic and a therapeutic treatment. Collectively, our data suggested that the P-VP8* based IgY could serve as a practical approach against both NoV and RV.
PMCID: PMC3995418  PMID: 23267830
rotavirus; norovirus; diarrhea; immunoglobulin Y (IgY); passive immunization
16.  Affinities of recombinant norovirus P dimers for human blood group antigens 
Glycobiology  2012;23(3):276-285.
Noroviruses (NoVs), the major cause of viral acute gastroenteritis, recognize histo-blood group antigens (HBGAs) as receptors or attachment factors. To gain a deeper understanding of the interplay between NoVs and their hosts, the affinities of recombinant P dimers (P2's) of a GII.4 NoV (VA387) to a library of 41 soluble analogs of HBGAs were measured using the direct electrospray ionization mass spectrometry assay. The HBGAs contained the A, B, H and Lewis epitopes, with variable sizes (2–6 residues) and different types (1–6). The results reveal that the P2's exhibit a broad specificity for the HBGAs and bind to all of the oligosaccharides tested. Overall, the affinities are relatively low, ranging from 400 to 3000 M−1 and are influenced by the chain type: 3 > 1 ≈ 2 ≈ 4 ≈ 5 ≈ 6 for H antigens; 6 > 1 ≈ 3 ≈ 4 ≈ 5 > 2 for A antigens; 3 > 1 ≈ 4 ≈ 5 ≈ 6 > 2 for B antigens, but not by chain length. The highest-affinity ligands are B type 3 (3000 ± 300 M−1) and A type 6 (2350 ± 60 M−1). While the higher affinity to the type 3 H antigen was previously observed, preferential binding to the types 6 and 3 antigens with A and B epitopes, respectively, has not been previously reported. A truncated P domain dimer (lacking the C-terminal arginine cluster) exhibits similar binding. The central-binding motifs in the HBGAs were identified by molecular-docking simulations.
PMCID: PMC3555502  PMID: 23118206
affinity; electrospray ionization mass spectrometry; histo-blood group antigens; norovirus; receptor
17.  A Dual-Center Randomized Controlled Double Blind Trial Assessing the Effect of Acupuncture in Reducing Musculoskeletal Symptoms in Breast Cancer Patients Taking Aromatase Inhibitors 
Up to 50% of women receiving aromatase inhibitor (AI) complain of AI-associated musculoskeletal symptoms (AIMSS) and 15% discontinue treatment. We conducted a randomized, sham-controlled trial to evaluate whether acupuncture improves AIMSS and to explore potential mechanisms.
Patients and Methods
Postmenopausal women with early stage breast cancer, experiencing AIMSS were randomized to 8 weekly real or sham acupuncture sessions. We evaluated changes in the Health Assessment Questionnaire Disability Index (HAQ-DI) and pain visual analog scale (VAS) following the intervention compared to baseline. Serum estradiol, β-endorphin and proinflammatory cytokine concentrations were measured pre and post-intervention.
We enrolled 51 women, of whom 47 were evaluable, including 23 randomized to real and 24 to sham acupuncture. Baseline characteristics were balanced between groups with the exception of a higher HAQ-DI score in the real acupuncture group (p=0.047). We did not observe a statistically significant difference in reduction of HAQ-DI (p=0.30) or VAS (p=0.31) between the two groups. Following 8 weekly treatments, we observed a statistically significant reduction of IL-17 (p≤0.009) in both groups. No significant modulation was seen in estradiol, β-endorphin, or other proinflammatory cytokine concentrations in either group.
We did not observe a significant difference in AIMSS changes between real and sham acupuncture. As sham acupuncture used in this study may not be equivalent to placebo, further studies with a non-acupuncture arm may be required to establish whether acupuncture is beneficial for the treatment of AIMSS.
PMCID: PMC3594526  PMID: 23393007
18.  Correction: Norovirus P Particle Efficiently Elicits Innate, Humoral and Cellular Immunity 
PLoS ONE  2014;9(1):10.1371/annotation/01406b4d-7869-4e7f-b294-4330ab641e85.
PMCID: PMC3879387
19.  Transcultural Diabetes Nutrition Algorithm: A Malaysian Application 
Glycemic control among patients with prediabetes and type 2 diabetes mellitus (T2D) in Malaysia is suboptimal, especially after the continuous worsening over the past decade. Improved glycemic control may be achieved through a comprehensive management strategy that includes medical nutrition therapy (MNT). Evidence-based recommendations for diabetes-specific therapeutic diets are available internationally. However, Asian patients with T2D, including Malaysians, have unique disease characteristics and risk factors, as well as cultural and lifestyle dissimilarities, which may render international guidelines and recommendations less applicable and/or difficult to implement. With these thoughts in mind, a transcultural Diabetes Nutrition Algorithm (tDNA) was developed by an international task force of diabetes and nutrition experts through the restructuring of international guidelines for the nutritional management of prediabetes and T2D to account for cultural differences in lifestyle, diet, and genetic factors. The initial evidence-based global tDNA template was designed for simplicity, flexibility, and cultural modification. This paper reports the Malaysian adaptation of the tDNA, which takes into account the epidemiologic, physiologic, cultural, and lifestyle factors unique to Malaysia, as well as the local guidelines recommendations.
PMCID: PMC3872099  PMID: 24385984
20.  Evaluation of anti-norovirus IgY from egg yolk of chickens immunized with norovirus P particles 
Journal of virological methods  2012;186(1-2):126-131.
Noroviruses (NoVs) are a leading cause of epidemic acute gastroenteritis affecting millions of people worldwide. Understanding of NoV remains limited due to the lack of a cell culture system and small animal models. Currently, there are no available vaccines or antivirals against NoVs. In this study, an approach for large-scale production of anti-NoV antibodies for use as a potential treatment for NoV disease using passive immunization was evaluated. NoV-specific immunoglobulins (IgY) were produced by immunizing chickens with NoV P particles. The birds continuously produced high titers of antibodies in their eggs for at least 3 months, in which NoV-specific antibody levels reached 4.7-9.2 mg/egg yolk. The egg yolk antibodies strongly reacted with NoV P particles by both ELISA and Western blot and blocked NoV virus-like particle (VLP) and P particle binding to the histo-blood group antigen (HBGA) receptors with a BT50 of about 1:800. The blocking activity of the chicken IgY remained after an incubation at 70°C for 30 min or treatment at pH 4 to 9 for 3 h. These data suggested that chicken IgY could be a practical strategy for large-scale production of anti-NoV antibodies for potential use as passive immunization against NoV infection, as well as for diagnostic purposes.
PMCID: PMC3496071  PMID: 22867844
Norovirus; Immunoglobulin; IgY; Chicken; Norovirus P particle; Diarrhea
21.  Poly-LacNAc as an Age-Specific Ligand for Rotavirus P[11] in Neonates and Infants 
PLoS ONE  2013;8(11):e78113.
Rotavirus (RV) P[11] is an unique genotype that infects neonates. The mechanism of such age-specific host restriction remains unknown. In this study, we explored host mucosal glycans as a potential age-specific factor for attachment of P[11] RVs. Using in vitro binding assays, we demonstrated that VP8* of a P[11] RV (N155) could bind saliva of infants (60.3%, N = 151) but not of adults (0%, N = 48), with a significantly negative correlation between binding of VP8* and ages of infants (P<0.01). Recognition to the infant saliva did not correlate with the ABO, secretor and Lewis histo-blood group antigens (HBGAs) but with the binding of the lectin Lycopersicon esculentum (LEA) that is known to recognize the oligomers of N-acetyllactosamine (LacNAc), a precursor of human HBGAs. Direct evidence of LacNAc involvement in P[11] binding was obtained from specific binding of VP8* with homopolymers of LacNAc in variable lengths through a glycan array analysis of 611 glycans. These results were confirmed by strong binding of VP8* to the Lec2 cell line that expresses LacNAc oligomers but not to the Lec8 cell line lacking the LacNAc. In addition, N155 VP8* and authentic P[11] RVs (human 116E and bovine B223) hemagglutinated human red blood cells that are known to express poly-LacNAc. The potential role of poly-LacNAc in host attachment and infection of RVs has been obtained by abrogation of 116E replication by the PAA-conjugated poly-LacNAc, human milk, and LEA positive infant saliva. Overall, our results suggested that the poly-LacNAc could serve as an age-specific receptor for P[11] RVs and well explained the epidemiology that P[11] RVs mainly infect neonates and young children.
PMCID: PMC3823915  PMID: 24244290
22.  A Critical Assessment of Epidemiology Studies Regarding Dietary/Supplemental Zinc and Prostate Cancer Risk 
The open urology & nephrology journal  2008;1:10.2174/1874303X00801010026.
Despite the prevalence of prostate cancer, the etiology and factors associated with its development and progression are largely unknown. An important relationship in prostate cancer is the role of zinc. Clinical evidence and experimental evidence have established that prostate cancer is associated with a decrease in the zinc uptake and accumulation in the malignant cells; and that the accumulation of zinc in the prostate cells prevents malignancy. In contrast to this established consistent clinical relationship, numerous epidemiology studies and reports of the effect of dietary and supplemental zinc on the incidence of prostate cancer have provided divergent, inconsistent, and inconclusive results; which range from adverse effects of zinc, protective effects of zinc, and no effect of zinc on the risk of prostate cancer. Despite these divergent and inconclusive results, a prevailing view and public warning has evolved from unsubstantiated and uncorroborated epidemiology studies that zinc consumption increases the risk of developing advanced stage prostate cancer. Such a conclusion is not well-founded and has serious, confusing and erroneous implications for the medical/scientific community and for the public-at-large. The admonition of Dimitrios Trichopoulos over a decade ago [1] that, “… (epidemiology) studies will inevitably generate false positive and false negative results with disturbing frequency. …, when (people) do take us seriously, we may unintentionally do more harm than good” can be applied to the situation that is the subject of this report.
Therefore it is extremely important to review the epidemiology studies that have lead to the conclusion of an adverse effect of zinc, and also that have produced such inconsistent and divergent results. This critical review defines issues, problems, and shortcomings that exist in the conduct, conclusions, and dissemination of the epidemiology studies. We caution that one should be knowledgeable and understanding of these issues in assessing the validity and the conclusiveness of the outcomes from the epidemiology studies of purported associations of dietary and supplemental zinc on the risk of prostate cancer; particularly when the unsubstantiated conclusions are at odds with clinical and experimental evidence. It is in the interest of the medical, scientific and public communities that this critical review is undertaken. We hope that this review will generate an open, objective, scientific and medical discussion and assessment of this important issue.
PMCID: PMC3817961  PMID: 24204440
23.  Testing the annual nature of speleothem banding 
Scientific Reports  2013;3:2633.
Speleothem laminae have been postulated to form annually, and this lamina-chronology is widely applied to high-resolution modern and past climate reconstructions. However, this argument has not been directly supported by high resolution dating methods. Here we present contemporary single-lamina 230Th dating techniques with 2σ precision as good as ±0.5 yr on a laminated stalagmite with density couplets from Xianren Cave, China, that covers the last 300 years. We find that the layers do not always deposit annually. Annual bands can be under- or over-counted by several years during different multi-decadal intervals. The irregular formation of missing and false bands in this example indicates that the assumption of annual speleothem laminae in a climate reconstruction should be approached carefully without a robust absolute-dated chronology.
PMCID: PMC3773624  PMID: 24037594
24.  Induction of MAGE-A3 and HPV-16 immunity by Trojan vaccines in patients with head and neck carcinoma 
Head & neck  2012;34(12):1734-1746.
We performed a pilot study using Trojan vaccines in patients with advanced squamous cell carcinoma of the head and neck (SCCHN). These vaccines are composed of HLA-I and HLA-II restricted melanoma antigen E (MAGE)-A3 or human papillomavirus (HPV)-16 derived peptides, joined by furin-cleavable linkers, and linked to a “penetrin” peptide sequence derived from HIV-TAT. Thirty-one patients with SCCHN were screened for the trial and 5 were enrolled.
Enrolled patients were treated with 300 lg of Trojan peptide supplemented with Montanide and granulocyte-macrophage colony-stimulating factor (GM-CSF) at 4-week intervals for up to 4 injections.
Following vaccination, peripheral blood mononuclear cells (PBMCs) from 4 of 5 patients recognized both the full Trojan constructs and constituent HLA-II peptides, whereas responses to HLA-I restricted peptides were less pronounced.
This treatment regimen seems to have acceptable toxicity and elicits measurable systemic immune responses against HLA-II restricted epitopes in a subset of patients with advanced SCCHN.
PMCID: PMC3725741  PMID: 22287423
SCCHN; vaccine; HLA-I; HLA-II; immune response
25.  Optimum Ribavirin Exposure Overcomes Racial Disparity in Efficacy of Peginterferon and Ribavirin Treatment for Hepatitis C Genotype 1 
Peginterferon and ribavirin treatment is less effective for hepatitis C virus (HCV) genotype 1 infections in African Americans (AA) compared with Caucasian Americans (CA). Host genetic variability near the interleukin-28B (IL28B) gene locus is partly responsible. We investigated the relationship between ribavirin drug exposure and week 24 and 72 (sustained virologic response, SVR) responses (undetected serum HCV RNA) in 71 AA and 74 CA with HCV genotype 1 who received >90 % of the prescribed peginterferon and weight-based ribavirin (1,000 or 1,200 mg per day) from week 1 to 24.
Ribavirin plasma levels were measured at weeks 1, 2, 4, 8, 12 and 24; ribavirin area under the concentration vs. time curve (AUC) was calculated using the linear trapezoidal rule.
Compared with CA, AA had lower week 24 (WK24VR) (57.8 vs. 78.1; P < 0.05) and week 72 (SVR) (36.6 % vs 54.8 %; P < 0.05) response rates. AA also had significantly lower ribavirin exposure (AUC) from week 1 to 12 (P < 0.05). Ribavirin exposures ≥ 4,065 and ≥ 4,480 ng/ml/day in the first week (AUC0–7) were thresholds for WK24VR and SVR in receiver-operating characteristic curve analyses. AA were less likely to have a threshold ribavirin AUC0–7 level than CA (P < 0.05). There were no significant racial differences in WK24VR (AA: 77 vs. CA: 84 %) and SVR (AA: 52 vs. CA: 60 %) rates in patients who met the ribavirin AUC0–7 thresholds. Ribavirin AUC0–7 predicted WK24VR and SVR independently of IL28B single-nucleotide polymorphism rs12979860 genotype. Yet, achieving threshold AUC0–7 levels increased response rates primarily in AA with the less favorable non-C/C genotypes.
Standard weight-based dosing leads to suboptimal ribavirin exposure in AA and contributes to the racial disparity in peginterferon and ribavirin treatment efficacy for HCV genotype 1.
PMCID: PMC3718255  PMID: 23090351

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