OncoDB.HCC: an integrated oncogenomic database of hepatocellular carcinoma revealed aberrant cancer target genes and loci

The OncoDB.HCC () is based on physical maps of rodent and human genomes containing quantitative trait loci of rodent HCC models and various human HCC somatic aberrations including chromosomal data from loss of heterozygosity and comparative genome hybridization analyses, altered expression of genes from microarray and proteomic studies, and finally experimental data of published HCC genes. Comprehensive integration of HCC genomic aberration data avoids potential pitfalls of data inconsistency from single genomic approach and provides lines of evidence to reveal somatic aberrations from levels of DNA, RNA to protein. Twenty-nine of 30 (96.7%) novel HCC genes with significant altered expressions in compared between tumor and adjacent normal tissues were validated by RT–PCR in 45 pairs of HCC tissues and by matching expression profiles in 57 HCC patients of re-analyzed Stanford HCC microarray data. Comparative mapping of HCC loci in between human aberrant chromosomal regions and QTLs of rodent HCC models revealed 12 syntenic HCC regions with 2 loci effectively narrowed down to 2 Mb. Together, OncoDB.HCC graphically presents comprehensive HCC data integration, reveals important HCC genes and loci for positional cloning and functional studies, and discloses potential molecular targets for improving HCC diagnosis and therapy

Re-evaluation of the carcinogenic significance of hepatitis B virus integration in hepatocarcinogenesis

To examine the role of hepatitis B virus (HBV) integration in hepatocarcinogenesis, a systematic comparative study of both tumor and their corresponding non-tumor derived tissue has been conducted in a cohort of 60 HBV associated hepatocellular carcinoma (HCC) patients. By using Alu-polymerase chain reaction (PCR) and ligation-mediated PCR, 233 viral-host junctions mapped across all human chromosomes at random, no difference between tumor and non-tumor tissue was observed, with the exception of fragile sites (P = 0.0070). HBV insertions in close proximity to cancer related genes such as hTERT were found in this study, however overall they were rare events. No direct correlation between chromosome aberrations and the number of HBV integration events was found using a sensitive array-based comparative genomic hybridization (aCGH) assay. However, a positive correlation was observed between the status of several tumor suppressor genes (TP53, RB1, CDNK2A and TP73) and the number of chromosome aberrations (r = 0.6625, P = 0.0003). Examination of the viral genome revealed that 43% of inserts were in the preC/C region and 57% were in the HBV X gene. Strikingly, approximately 24% of the integrations examined had a breakpoint in a short 15 nt viral genome region (1820-1834 nt). As a consequence, all of the confirmed X gene insertions were C-terminal truncated, losing their growth-suppressive domain. However, the same pattern of X gene C-terminal truncation was found in both tumor and non-tumor derived samples. Furthermore, the integrated viral sequences in both groups had a similar low frequency of C1653T, T1753V and A1762T/G1764A mutations. The frequency and patterns of HBV insertions were similar between tumor and their adjacent non-tumor samples indicating that the majority of HBV DNA integration events are not associated with hepatocarcinogenesis

Ocimum gratissimum Aqueous Extract Induces Apoptotic Signalling in Lung Adenocarcinoma Cell A549

Ocimum gratissimum (OG) is widely used as a traditional herb for its antibacterial activity in Taiwan. Recently, antitumor effect of OG on breast cancer cell is also reported; however, the effects of OG on human pulmonary adenocarcinoma cell A549 remain unclear. Therefore, we aimed to investigate whether aqueous OG extract (OGE) affects viability of A549 cells and the signals induced by OGE in A549 cells. Cell viability assays revealed that OGE significantly and dose-dependently decreased the viability of A549 cell but not that of BEAS-2B cell. Morphological examination and DAPI staining indicated that OGE induced cell shrinkage and DNA condensation for A549 cells. Further investigation showed that OGE enhanced activation of caspase-3, caspase-9 and caspase-8 and increased protein level of Apaf-1 and Bak, but diminished the level of Bcl-2. Additionally, OGE inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) yet enhanced the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAP kinase (p38). In conclusion, our findings indicate that OGE suppressed the cell viability of A549 cells, which may result from the activation of apoptotic signaling and the inhibition of anti-apoptotic signaling, suggesting that OGE might be beneficial to lung carcinoma treatment

Associations Between Hepatitis B Virus Genotype and Mutants and the Risk of Hepatocellular Carcinoma

Background The risk of hepatocellular carcinoma (HCC) increases with increasing level of hepatitis B virus (HBV) in serum (viral load). However , it is unclear whether genetic characteristics of HBV, including HBV genotype and specific genetic mutations, contribute to the risk of HCC. We examined the HCC risk associated with HBV genotypes and common variants in the precore and basal core promoter (BCP) regions. Methods From January 5, 1991, to December 21, 1992 , baseline blood samples were collected from 2762 Taiwanese men and women who were seropositive for HBV surface antigen but had not been diagnosed with HCC; the samples were tested for HBV viral load by real-time polymerase chain reaction and genotyped by melting curve analysis. Participants who had a baseline serum HBV DNA level greater than 101 copies/ mL (n = 1526) were tested for the precore G 1896A and BCP A 1762T/G1764A mutants by direct sequencing. Incident cases of HCC were ascertained through follow-up examinations and computerized linkage to the National Cancer Registry and death certification profiles. A Cox proportional hazards model was used to estimate the risk of HCC associated with HBV genotype and precore and BCP mutants after adjustment for other risk factors. All statistical tests were two-sided . Results A total of 153 HCC cases occurred during 33847 person-years of follow-up. The HCC incidence rates per 100000 person-years for participants infected with HBV genotype B or C were 305.6 (95% confidence interval [CI] = 236.9 to 388.1) and 785.8 (95% CI = 626.8 to 972.9), respectively. Among participants with a baseline HBV DNA level of at least 10(4) copies/mL, HCC incidence per 100000 person-years was higher for those with the precore G1896 ( wild-type) variant than for those with the G1896A variant ( 955.5 [95% CI = 749.0 to 1201.4] vs 269.4 [95% CI = 172.6 to 400.9]) and for those with the BCP A1762T/G1764A double mutant than for those with BCP A1762/G1764 (wild-type) variant (1149.2 [95% CI = 872.6 to 1485.6] vs 358.7 [95% Cl = 255.1 to 490.4]). The multivariable-adjusted hazard ratio of developing HCC was 1.76 (95% CI = 1.19 to 2.61) for genotype C vs genotype B, 0.34 (95% CI = 0.21 to 0.57) for precore G1896A vs wild type, and 1.73 (95% CI = 1.13 to 2.67 ) for BCP A1762T/G1764A vs wild type. Risk was highest among participants infected with genotype C HBV and wild type for the precore 1896 variant and mutant for the BCP 1762/1764 variant ( adjusted hazard ratio = 2.99, 95% CI = 1.57 to 5.70 , P<.001). Conclusions HBV genotype C and specific alleles of BCP and precore were associated with risk of HCC. These associations were independent of serum HBV DNA level

SARS Exposure and Emergency Department Workers

Of 193 emergency department workers exposed to severe acute respiratory syndrome (SARS), 9 (4.7%) were infected. Pneumonia developed in six workers, and assays showed anti-SARS immunoglobulin (Ig) M and IgG. The other three workers were IgM-positive and had lower IgG titers; in two, mild illness developed, and one remained asymptomatic

Establishment of a Knock-In Mouse Model with the SLC26A4 c.919-2A>G Mutation and Characterization of Its Pathology

Recessive mutations in the SLC26A4 gene are a common cause of hereditary hearing impairment worldwide. Previous studies have demonstrated that different SLC26A4 mutations may have different pathogenetic mechanisms. In the present study, we established a knock-in mouse model (i.e., Slc26a4tm1Dontuh/tm1Dontuh mice) homozygous for the c.919-2A>G mutation, which is a common mutation in East Asians. Mice were then subjected to audiologic assessment, a battery of vestibular evaluations, and inner ear morphological studies. All Slc26a4tm1Dontuh/tm1Dontuh mice revealed profound hearing loss, whereas 46% mice demonstrated pronounced head tilting and circling behaviors. There was a significant difference in the vestibular performance between wild-type and Slc26a4tm1Dontuh/tm1Dontuh mice, especially those exhibiting circling behavior. Inner ear morphological examination of Slc26a4tm1Dontuh/tm1Dontuh mice revealed an enlarged endolymphatic duct, vestibular aqueduct and sac, atrophy of stria vascularis, deformity of otoconia in the vestibular organs, consistent degeneration of cochlear hair cells, and variable degeneration of vestibular hair cells. Audiologic and inner ear morphological features of Slc26a4tm1Dontuh/tm1Dontuh mice were reminiscent of those observed in humans. These features were also similar to those previously reported in both knock-out Slc26a4−/− mice and Slc26a4loop/loop mice with the Slc26a4 p.S408F mutation, albeit the severity of vestibular hair cell degeneration appeared different among the three mouse strains

Infection Control and SARS Transmission among Healthcare Workers, Taiwan

This study found infrequent transmission of severe acute respiratory syndrome (SARS) coronavirus to healthcare workers involved in the care of the first five case-patients in Taiwan, despite a substantial number of unprotected exposures. Nonetheless, given that SARS has been highly transmissible on some occasions, we still recommend strict precautions

Liposome-based polymer complex as a novel adjuvant: enhancement of specific antibody production and isotype switch

The aim of vaccination is to induce appropriate immunity against pathogens. Antibody-mediated immunity is critical for protection against many virus diseases, although it is becoming more evident that coordinated, multifunctional immune responses lead to the most effective defense. Specific antibody (Ab) isotypes are more efficient at protecting against pathogen invasion in different locations in the body. For example, compared to other Ab isotypes, immunoglobulin (Ig) A provides more protection at mucosal areas. In this study, we developed a cationic lipopolymer (liposome-polyethylene glycol-polyethyleneimine complex [LPPC]) adjuvant that strongly adsorbs antigens or immunomodulators onto its surface to enhance or switch immune responses. The results demonstrate that LPPC enhances uptake ability, surface marker expression, proinflammatory cytokine release, and antigen presentation in mouse phagocytes. In contrast to Freund’s adjuvant, LPPC preferentially activates Th1- immunity against antigens in vivo. With lipopolysaccharides or CpG oligodeoxynucleotides, LPPC dramatically enhances the IgA or IgG2A proportion of total Ig, even in hosts that have developed Th2 immunities and high IgG1 serum titers. Taken together, the results demonstrate that the LPPC adjuvant not only increases the immunogenicity of antigens but also modulates host immunity to produce an appropriate Ab isotype by combining with immunomodulators

Microbiologic Characteristics, Serologic Responses, and Clinical Manifestations in Severe Acute Respiratory Syndrome, Taiwan1

The genome of one Taiwanese severe acute respiratory syndrome-associated coronavirus (SARS-CoV) strain (TW1) was 29,729 nt in length. Viral RNA may persist for some time in patients who seroconvert, and some patients may lack an antibody response (immunoglobulin G) to SARS-CoV >21 days after illness onset. An upsurge of antibody response was associated with the aggravation of respiratory failure