This is the first of a three-part study designed to demonstrate dynamic entanglements among gaseous organic compounds (VOC), particulate matter (PM), and their subsequent potential biological effects. We study these entanglements in increasingly complex VOC and PM mixtures in urban-like conditions in a large outdoor chamber. To the traditional chemical and physical characterizations of gas and PM, we added new measurements of gas-only- and PM-only-biological effects, using cultured human lung cells as model indicators. These biological effects are assessed here as increases in cellular damage or expressed irritation (i.e., cellular toxic effects) from cells exposed to chamber air relative to cells exposed to clean air. The exposure systems permit gas-only- or PM-only-exposures from the same air stream containing both gases and PM in equilibria, i.e., there are no extractive operations prior to cell exposure.

Our simple experiments in this part of the study were designed to eliminate many competing atmospheric processes to reduce ambiguity in our results. Simple volatile and semi-volatile organic gases that have inherent cellular toxic properties were tested individually for biological effect in the dark (at constant humidity). Airborne mixtures were then created with each compound and PM that has no inherent cellular toxic properties for another cellular exposure. Acrolein and p-tolualdehyde were used as model VOCs and mineral oil aerosol (MOA) was selected as a surrogate for organic-containing PM. MOA is appropriately complex in composition to represent ambient PM, and it exhibits no inherent cellular toxic effects and thus did not contribute any biological detrimental effects on its own.

Chemical measurements, combined with the responses of our biological exposures, clearly demonstrate that gas-phase pollutants can modify the composition of PM (and its resulting detrimental effects on lung cells) – even if the gas-phase pollutants are not considered likely to partition to the condensed phase: the VOC-modified-PM showed significantly more damage and inflammation to lung cells than did the original PM. Because gases and PM are transported and deposited differently within the atmosphere and the lungs, these results have significant consequences. For example, current US policies for research and regulation of PM do not recognize this “effect modification” phenomena (NAS, 2004).

These results present an unambiguous demonstration that – even in these simple mixtures – physical and thermal interactions alone can cause a modification of the distribution of species among the phases of airborne pollution mixtures and can result in a non-toxic phase becoming toxic due to atmospheric thermal processes only. Subsequent work extends the simple results reported here to systems with photochemical transformations of complex urban mixtures and to systems with diesel exhaust produced by different fuels.

In 2006, the Canadian National Advisory Committee on Blood and Blood Products (NAC) developed a transfusion policy framework for the use of off-label recombinant factor VIIa (rFVIIa) in massive bleeding. Because the number of randomised controlled trials has doubled, the NAC undertook a review of the policy framework in 2011. On the basis of the review of 29 randomised controlled trials, there remains little evidence to support the routine use of rFVIIa in massive bleeding. Mortality benefits have not been demonstrated. Contrarily, an increase in arterial thromboembolic events has been observed with the use of off-label rFVIIa. Given the absence of evidence of benefit and with evidence of the risk of harm, the NAC recommends that recombinant VIIa no longer be used for the off-label indications of prevention and treatment of bleeding in patients without haemophilia.

Bisphenol A (BPA) is widely used in plastic products, through which humans are exposed to it. Accumulating evidence suggests that BPA exposure is associated with β-cell dysfunction. Mitochondrial defects can cause impairment and failure of β cells, but there is little information about the effects of BPA on the mitochondrial function of β cells. In this study, we assessed the role of mitochondria-mediated mechanisms underlying BPA-induced β-cell dysfunction and resulting β-cell apoptosis. INS-1 cells were cultured with 0, 0.0020, 0.020, 0.20, or 2.0 μM BPA. Cell viability, glucose-stimulated insulin secretion (GSIS), and mitochondrial function were examined. The mitochondrial apoptotic pathway was also analyzed at molecular level. We found that BPA suppressed cell viability and disturbed GSIS in a dose-dependent manner. Positive Annexin- propidium iodide (PI) staining and altered expression of Bcl-2 family members and caspases in INS-1 cells indicated that the cells progressively became apoptotic after BPA exposure. Additionally, BPA-induced apoptosis was associated with mitochondrial defects in β cells, as evidenced by depletion of ATP, release of cytochrome c, loss of mitochondrial mass and membrane potential, and alterations in expression of genes involved in mitochondrial function and metabolism. Taken together, these findings provide strong evidence that BPA triggers INS-1 cells dysfunction and apoptosis may be meditated via the mitochondrial pathway.

Jun activation domain-binding protein 1 (JAB1) is a multifunctional protein that participates in the control cell proliferation and the stability of multiple proteins. JAB1 overexpression has been implicated in the pathogenesis of human cancer. JAB1 regulates several key proteins and thereby produces varied effects on cell cycle progression, genome stability, and cell survival. However, the biological significance of JAB1 activity in these cellular signaling pathways is unclear. Therefore, we developed mice that were deficient in Jab1 and analyzed the null embryos and heterozygous cells. This disruption of Jab1 in mice resulted in early embryonic lethality due to accelerated apoptosis. Loss of Jab1 expression sensitized both mouse primary embryonic fibroblasts and osteosarcoma cells to gamma radiation–induced apoptosis, with an increase in spontaneous DNA damage and homologous recombination (HR) defects, both of which correlated with reduced levels of the DNA repair protein Rad51 and elevated levels of p53. Furthermore, the accumulated p53 directly binds to Rad51 promoter, inhibited its activity, and represent a major mechanism underlying the HR repair defect in Jab1-deficient cells. These results indicate that Jab1 is essential for efficient DNA repair and mechanistically link Jab1 to the maintenance of genome integrity and to cell survival.

Background:

Amplification of aurora kinase A (AK-A) overrides the mitotic spindle assembly checkpoint, inducing resistance to taxanes. RNA interference targeting AK-A in human pancreatic cancer cell lines enhanced taxane chemosensitivity. In this study, a novel AK-A inhibitor, CYC3, was investigated in pancreatic cancer cell lines, in combination with paclitaxel.

Methods:

Western blot, flow cytometry and immunostaining were used to investigate the specificity of CYC3. Sulforhodamine B staining, time-lapse microscopy and colony-formation assays were employed to evaluate the cytotoxic effect of CYC3 and paclitaxel. Human colony-forming unit of granulocyte and macrophage (CFU-GM) cells were used to compare the effect in tumour and normal tissue.

Results:

CYC3 was shown to be a specific AK-A inhibitor. Three nanomolar paclitaxel (growth inhibition 50% (GI50) 3 nℳ in PANC-1, 5.1 nℳ in MIA PaCa-2) in combination with 1 μℳ CYC3 (GI50 1.1 μℳ in MIA PaCa2 and 2 μℳ in PANC-1) was synergistic in inhibiting pancreatic cell growth and causing mitotic arrest, achieving similar effects to 10-fold higher concentrations of paclitaxel (30 nℳ). In CFU-GM cells, the effect of the combination was simply additive, displaying significantly less myelotoxicity compared with high concentrations of paclitaxel (30 nℳ; 60–70% vs 100% inhibition).

Conclusion:

The combination of lower doses of paclitaxel and CYC3 merits further investigation with the potential for an improved therapeutic index in vivo.

Engineering design often involves the determination of design variable settings to optimize competing performance requirements. In the early design stages we propose narrowing down the domain of design solutions using metamodels of principal components of the multiple performance levels that have been scaled by a multivariate quadratic loss function. The multivariate quadratic loss function is often used as the objective function in reaching optimal solutions because it utilizes the correlation structure of the design’s performance metrics and penalizes off-target performance in a symmetrical manner. We also compare the computational performance of these loss-scaled principal components when used to solve for the design with minimal expected multivariate quadratic loss under three modeling approaches: response surface methodology, multivariate adaptive regression splines, and spatial point modeling. We demonstrate the technique on the design of the mechanical frame of an electric vehicle with six desired performance levels determined simultaneously by the dimensions of eight mechanical design elements. The method is the focus in this work.

We have previously demonstrated that interrupting the protein–protein interaction (PPI) of β-tubulin:chaperonin-containing TCP-1β (CCT-β) induces the selective killing of multidrug-resistant cancer cells due to CCT-β overexpression. However, the molecular mechanism has not yet been identified. In this study, we found that CCT-β interacts with a myriad of intracellular proteins involved in the cellular functions of the endoplasmic reticulum (ER), mitochondria, cytoskeleton, proteasome and apoptosome. Our data show that the targeted cells activate both the heat-shock protein 90 (Hsp90)-associated protein ubiquitination/degradation pathway to eliminate misfolded proteins in the cytoplasm and the valosin-containing protein (VCP)-centered ER-associated protein degradation pathway to reduce the excessive levels of unfolded polypeptides from the ER, thereby mitigating ER stress, at the onset of β-tubulin:CCT-β complex disruption. Once ER stress is expanded, ER stress-associated apoptotic signaling is enforced, as exhibited by cellular vacuolization and intracellular Ca2+ release. Furthermore, the elevated intracellular Ca2+ levels resulting from capacitative Ca2+ entry augments apoptotic signaling by provoking mitochondrial perturbation and caspase overactivation in the targeted cells. These findings not only provide a detailed picture of the apoptotic signaling cascades evoked by targeting the β-tubulin:CCT-β complex but also demonstrate a strategy to combat malignancies with chemoresistance to Hsp90- and VCP-related anticancer agents.

The reported prevalence of dentine/root (hyper)sensitivity (DH/RS) in the published literature varies, and this may be due in part to a) the different study populations and (b) the different methodologies employed in evaluating the pain response. According to von Troil et al. (2002) there are limited data available in terms of the prevalence and intensity of DH/RS following periodontal therapy. Objectives. The aim of the present study was therefore to review the literature in order to identify all relevant studies for inclusion and to determine whether there was any evidence of DH/RS following periodontal procedures in the published literature up to 31st December 2009 using an agreed search protocol. Methods. 840 papers were identified, from searching both electronic databases (PUBMED) and hand searching of relevant written journals. Twelve papers were subsequently accepted for inclusion. Results. The results of the present study would indicate that the reported prevalence for DH/RS (following nonsurgical therapy) was between 62.5% and 90% one day after treatment decreasing to approximately 52.6% to 55% after one week. The prevalence of DH/RS following surgical therapy was between 76.8% and 80.4% one day after treatment subsequently decreasing over time to 36.8% after 1 week, 33.4% after 2 weeks, 29.6% after 4 weeks, and 21.7% after 8 weeks. Conclusions. It is evident from reviewing the included studies that patients may suffer from mild discomfort following periodontal procedures although both the prevalence and intensity of DH/RS may vary depending on the duration and the type of procedure involved. Most of the studies included in this paper would tend to suggest that DH/RS may be relatively mild/moderate in nature and transient in duration.

The field of phenomics has been investigating network structure among large arrays of phenotypes, and genome-wide association studies (GWAS) have been used to investigate the relationship between genetic variation and single diseases/outcomes. A novel approach has emerged combining both the exploration of phenotypic structure and genotypic variation, known as the phenome-wide association study (PheWAS). The Population Architecture using Genomics and Epidemiology (PAGE) network is a National Human Genome Research Institute (NHGRI)-supported collaboration of four groups accessing eight extensively characterized epidemiologic studies. The primary focus of PAGE is deep characterization of well-replicated GWAS variants and their relationships to various phenotypes and traits in diverse epidemiologic studies that include European Americans, African Americans, Mexican Americans/Hispanics, Asians/Pacific Islanders, and Native Americans. The rich phenotypic resources of PAGE studies provide a unique opportunity for PheWAS as each genotyped variant can be tested for an association with the wide array of phenotypic measurements available within the studies of PAGE, including prevalent and incident status for multiple common clinical conditions and risk factors, as well as clinical parameters and intermediate biomarkers. The results of PheWAS can be used to discover novel relationships between SNPs, phenotypes, and networks of interrelated phenotypes; identify pleiotropy; provide novel mechanistic insights; and foster hypothesis generation. The PAGE network has developed infrastructure to support and perform PheWAS in a high-throughput manner. As implementing the PheWAS approach has presented several challenges, the infrastructure and methodology, as well as insights gained in this project, are presented herein to benefit the larger scientific community.

Background

Chronic kidney disease (CKD) is associated with the incidence of cardiovascular disease. CKD may also increase the risk of atrial fibrillation (AF), but existing studies have reported inconsistent results.

Methods and Results

We estimated cystatin C-based glomerular filtration rate (eGFRcys) and measured urinary albumin-creatinine ratio (ACR) in 10,328 men and women free of AF from the Atherosclerosis Risk in Communities (ARIC) Study in 1996–98. Incidence of AF was ascertained through the end of 2007. During a median follow-up of 10.1 years, we identified 788 incident AF cases. Compared to individuals with eGFRcys ≥90 mL/min/1.73 m2, multivariable hazard ratios (HR) and 95% confidence intervals (CI) of AF were 1.3 (1.1–1.6), 1.6 (1.3–2.1), and 3.2 (2.0–5.0) (p for trend <0.0001) in those with eGFRcys of 60–89, 30–59 and 15–29 mL/min/1.73 m2, respectively. Similarly, presence of macroalbuminuria (ACR ≥300 mg/g, HR 3.2, 95% CI 2.3–4.5) and microalbuminuria (ACR 30–299 mg/g, HR 2.0, 95% CI 1.6–2.4) were associated with higher AF risk compared to those with ACR <30 mg/g. Risk of AF was particularly elevated in those with both low eGFRcys and macroalbuminuria (HR 13.1, 95% CI 6.0–28.6, comparing individuals with ACR≥300 mg/g and eGFRcys 15–29 vs. ACR<30 mg/g and eGFRcys ≥90 mL/min/1.73 m2).

Conclusion

In this large population-based study, reduced kidney function and presence of albuminuria were strongly associated with the incidence of AF independently of other risk factors.

WW domain-containing oxidoreductase (WWOX), a putative tumour suppressor, is suggested to be involved in the hyperphosphorylation of Alzheimer's Tau. Tau is a microtubule-associated protein that has an important role in microtubule assembly and stability. Glycogen synthase kinase 3β (GSK3β) has a vital role in Tau hyperphosphorylation at its microtubule-binding domains. Hyperphosphorylated Tau has a low affinity for microtubules, thus disrupting microtubule stability. Bioinformatics analysis indicated that WWOX contains two potential GSK3β-binding FXXXLI/VXRLE motifs. Immunofluorescence, immunoprecipitation and molecular modelling showed that WWOX interacts physically with GSK3β. We demonstrated biochemically that WWOX can bind directly to GSK3β through its short-chain alcohol dehydrogenase/reductase domain. Moreover, the overexpression of WWOX inhibited GSK3β-stimulated S396 and S404 phosphorylation within the microtubule domains of Tau, indicating that WWOX is involved in regulating GSK3β activity in cells. WWOX repressed GSK3β activity, restored the microtubule assembly activity of Tau and promoted neurite outgrowth in SH-SY5Y cells. Conversely, RNAi-mediated knockdown of WWOX in retinoic acid (RA)-differentiated SH-SY5Y cells inhibited neurite outgrowth. These results suggest that WWOX is likely to be involved in regulating GSK3β activity, reducing the level of phosphorylated Tau, and subsequently promoting neurite outgrowth during neuron differentiation. In summary, our data reveal a novel mechanism by which WWOX promotes neuronal differentiation in response to RA.

Cauda equina syndrome (CES) is a rare manifestation in patients with long-standing ankylosing spondylitis (AS). We report a 57-year-old male patient with a 30-year history of AS who developed CES in the past 4 years. The CT and MRI examinations showed unique appearances of dural ectasia, multiple dorsal dural diverticula, erosion of the vertebral posterior elements, tethering of the conus medullaris to the dorsal aspect of the spinal canal and adhesion of the nerve roots of the cauda equina to the wall of the dural sac. A large dural defect was found at surgery. De-adhesion of the tethered conus medullaris was performed but without significant clinical improvement. The possible aetiologies of CES and dural ectasia in patients with chronic AS are discussed and the literature is reviewed.

The spin current, orbit angular momentum current and total angular momentum current in a tensor form have been universally defined according to the quantum electrodynamics. Their conservation quantities and the continuity equations have been discussed in different cases. Non-relativistic approximation forms are deduced in order to explain their physical meanings, and to analyze some experimental results. The spin current of helical edge states in HgTe/CdTe quantum wells is calculated to demonstrate the properties of the spin current of the two dimensional quantum spin-Hall system. A generalized spin-orbit coupling term in the semiconducting media is deduced based on the theory of the electrodynamics in the moving media. It is recommended to use the effective total angular momentum current instead of the pure spin current to describe the distribution of polarization and the transport properties in spintronics.

Objective

Imaging breasts with a short chest wall to nipple distance (CWND) using a traditional mammographic X-ray unit is a technical challenge for mammographers. The purpose of this study is the development of an imaging-planning program to assist in determination of imaging parameters of screen/film (SF) and computed radiography (CR) mammography for short CWND breasts.

Methods

A traditional mammographic X-ray unit (Mammomat 3000, Siemens, Munich, Germany) was employed. The imaging-planning program was developed by combining the compressed breast thickness correction, the equivalent polymethylmethacrylate thickness assessment for breasts and the tube loading (mAs) measurement. Both phantom exposures and a total of 597 exposures were used for examining the imaging-planning program.

Results

Results of the phantom study show that the tube loading rapidly decreased with the CWND when the automatic exposure control (AEC) detector was not fully covered by the phantom. For patient exposures with the AEC fully covered by breast tissue, the average fractional tube loadings, defined as the ratio of the predicted mAs using the imaging-planning program and mAs of the mammogram, were 1.10 and 1.07 for SF and CR mammograms, respectively. The predicted mAs values were comparable to the mAs values, as determined by the AEC.

Conclusion

By applying the imaging-planning program in clinical practice, the experiential dependence of the mammographer for determination of the imaging parameters for short CWND breasts is minimised.

The ability to use autologous dental progenitor cells (DPCs) to form organized periodontal tissues on titanium implants would be a significant improvement over current implant therapies. Based on prior experimental results, we hypothesized that rat periodontal ligament (PDL)-derived DPCs can be used to bioengineer PDL tissues on titanium implants in a novel, in vivo rat maxillary molar implant model. Analyses of recovered implants revealed organized PDL tissues surrounding titanium implant surfaces in PDL-cell-seeded, and not in unseeded control, implants. Rat PDL DPCs also exhibited differentiative potential characteristic of stem cells. These proof-of-principle findings suggest that PDL DPCs can organize periodontal tissues in the jaw, at the site of previously lost teeth, indicating that this method holds potential as an alternative approach to osseointegrated dental implants. Further refinement of this approach will facilitate the development of clinically relevant methods for autologous PDL regeneration on titanium implants in humans.

Visceral pain is the most common reason for physician visits in US. Glutamate is the major excitatory neurotransmitter and mediates visceral nociceptive neuro-transmission and hypersensitivity. Removal of extracellular glutamate is predominantly mediated by glial glutamate transporter-1 (GLT-1). The pharmacological approach to up-regulate GLT-1 by 1 week administration of ceftriaxone (CTX) has been successful to mitigate visceral nociception. The present study shows that intrathecal delivery of selective GLT-1 antagonist dihydrokainate reversed CTX-blunted visceral nociceptive response, suggesting a spinal site of action. The role of GLT-1 up-regulation in animal models of colitis was studied. CTX treatment reversed TNBS-induced visceral hypersensitivity. In addition, CTX treatment initiated one week after the onset of DSS-induced visceral inflammation also attenuated visceral hypersensitivity, revealing a potential therapeutic effect. Cephalothin, a cephalosporin antibiotic lacking GLT-1 induction activity, failed to attenuate visceral nociception. CTX-induced changes in fecal microbiota do not support a role of probiotic effects in mitigating visceral nociception/hypersensitivity. Finally, adeno-associated virus serotype 9-mediated GLT-1 over-expression was effective to mitigate visceromotor response to 60 mmHg colo-rectal distension. These studies indicate that GLT-1 over-expression is a novel and effective method to attenuate visceral nociception, and is deserving of further study as a translationally relevant approach to treat visceral pain.

To assess the clinical impact of a molecular beacon (MB) assay that detects multidrug-resistant tuberculosis (MDR TB), we retrospectively reviewed records of 127 MDR TB patients with and without MB testing between 2004 and 2007. Use of the MB assay reduced the time to detection and treatment of MDR TB.

Background:

To date, there are few reports on gene products contributing to colon cancer progression.

Methods:

We used a gene trap comprised of an enhanced retroviral mutagen (ERM) cassette that includes a tetracycline-responsive promoter upstream of a haemagglutinin (HA) tag and a splice donor site. Integration of the ERM within an endogenous gene yields a tetracycline-regulated HA-tagged transcript. We transduced RKO colon cancer cells expressing a tetracycline trans-activator-off with the ERM-encoding retrovirus and screened for enhanced migration.

Results:

One clone showed fivefold enhanced migration with tetracycline withdrawal. Rapid amplification of cDNA ends identified the trapped gene as the chloride channel 4 (CLCN4) exchanger. Stable expression of a CLCN4 cDNA enhanced motility, whereas cells knocked down or null for this transcript showed reduced migration/invasion. CLCN4-overexpressing RKO colon cancer cells were more resistant than controls to proton load-induced cytotoxicity, consistent with the H+-extruding function of this antiporter. Intra-splenic delivery of RKO-CLCN4 transfectants, but not controls, yielded liver metastases, and transcript levels were higher in colon cancer metastases to the liver when compared with primary tumours.

Conclusions:

CLCN4 is a novel driver of colon cancer progression.

Motivation:

Existing methods for estimating copy number variations in array comparative genomic hybridization (aCGH) data are limited to estimations of the gain/loss of chromosome regions for single sample analysis. We propose the linear-median method for estimating shared copy numbers in DNA sequences across multiple samples, demonstrate its operating characteristics through simulations and applications to real cancer data, and compare it to two existing methods.

Results:

Our proposed linear-median method has the power to estimate common changes that appear at isolated single probe positions or very short regions. Such changes are hard to detect by current methods. This new method shows a higher rate of true positives and a lower rate of false positives. The linear-median method is non-parametric and hence is more robust in estimating copy number. Additionally the linear-median method is easily computable for practical aCGH data sets compared to other copy number estimation methods.

It is well established that poxviruses are subjected to genetic recombination, but attempts to map vaccinia virus genes using classical genetic crosses were historically confounded by high levels of experimental noise and a poor correlation between physical and genetic map distances. These virus-by-virus crosses also never produced the 50% recombinant progeny that should be seen in experiments involving distant markers. Poxviruses replicate in membrane-wrapped cytoplasmic structures called virosomes (or factories) and we have developed a method for tracking the development of these structures using live cell imaging and cells expressing phage lambda Cro protein fused to enhanced green fluorescent protein (EGFP). The EGFP-cro protein binds nonspecifically to DNA and permits live cell imaging of developing vaccinia virus factories. Using this method, we see virosomes first appearing about 4 to 5 h postinfection. The early virosomes exhibit a compact appearance and then, after a period of exponential growth lasting several hours, blur and start to dissipate in a process presumably linked to viral packaging. During the growth period, the virosomes migrate toward the nuclear periphery while colliding and fusing at a rate dependent upon the numbers of infecting particles. However, even at high multiplicities of infection (10 PFU/cell), we estimate ∼20% of the virosomes never fuse. We have also used fluorescence in situ hybridization (FISH) methods to study virosomes formed by the fusion of viruses carrying different gene markers. FISH showed that DNA mixes rather poorly within fused virosomes and the amount of mixing is inversely dependent on the time between virosome appearance and fusion. Our studies suggest that the intracellular movement and mixing of virosomes create constraints that reduce opportunities for forming recombinants and that these phenomena create outcomes reflected in classical poxvirus genetics.

TOC summary: Type of isoniazid resistance–conferring mutation may be a determinant of genotypic clustering.

Laboratory and epidemiologic evidence suggests that pathogen-specific factors may affect multidrug-resistant (MDR) tuberculosis (TB) transmission and pathogenesis. To identify demographic and clinical characteristics of MDR TB case clustering and to estimate the effect of specific isoniazid resistance–conferring mutations and strain lineage on genotypic clustering, we conducted a population-based cohort study of all MDR TB cases reported in California from January 1, 2004, through December 31, 2007. Of 8,899 incident culture-positive cases for which drug susceptibility information was available, 141 (2%) were MDR. Of 123 (87%) strains with genotype data, 25 (20%) were aggregated in 8 clusters; 113 (92%) of all MDR TB cases and 21 (84%) of clustered MDR TB cases occurred among foreign-born patients. In multivariate analysis, the katG S315T mutation (odds ratio 11.2, 95% confidence interval 2.2–∞; p = 0.004), but not strain lineage, was independently associated with case clustering.

Bile duct cells and hepatocytes differentiate from the same hepatic progenitor cells. To investigate the possible association of viral hepatitis B and C with intrahepatic cholangiocarcinoma (ICC), we conducted a retrospective case–control study using univariate and multivariate logistic analyses to identify risk factors for ICC. Besides hepatic lithiasis (25.6%; P<0.001), seropositivity for hepatitis B surface antigen (37.5% of all ICC patients; odds ratio (OR) =4.985, P<0.001) and seropositivity for hepatitis C antibodies (13.1%; OR=2.709; P=0.021) are the primary independent risk factors for ICC. Cirrhosis exerted synergic effects on the development of ICC. We compared the age distributions of viral-hepatitis associated ICC to that of viral hepatitis-associated hepatocellular carcinoma (HCC). The mean age of ICC patients with viral hepatitis B (56.4±11.1 years) were 9 years younger than that of ICC patients with viral hepatitis C (65.6±9.17 years), similar to that observed in HCC. The incidence ratio of HCC : ICC : CHC (combined hepatocellular cholangiocarcinoma) in our population was 233 : 17 : 1 consistent with the theoretic ratio of hepatocyte number to cholangiocyte number in the liver. Our findings indicated that both viral hepatitis-associated ICC and HCC shared common disease process for carcinogenesis and, possibly, both arose from the hepatic progenitor cells.