Faculty Bibliography

BACKGROUND AND AIMS/OBJECTIVE:The aim was to externally validate the capability of a simplified Barcelona Clinic Liver Cancer (s-BCLC) staging system in allocating patients to hepatic resection (HR) and the effect on survival: S-BCLC was defined by only 2 groups: AA included BCLC A1 + A2 classes with alpha-fetoprotein (AFP) ≤ 20 ng/ml and AB included A1 + A2 with AFP > 20 ng/ml plus A3 + A4 subgroups. METHODS:This study compared a training group (TG) with hepatocellular carcinoma (HCC) submitted to hepatic resection (HR) in Milan with another group of patients, the validation group (VG) in Creteil. All patients underwent ultrasound-guided anatomical resection (<3 segments). RESULTS:Overall survival got worse from A1 to A4 (p = 0.0271) in TG (n = 132), as well as in VG (n = 100) (p = 0.0044) with a more important overlapping of each curves. According s-BCLC classification, the survival curves of TG (p = 0.0001) and VG (p = 0.0250) showed a definitive separation in two different staging groups. The s-BCLC provided the best predictive accuracy and it also presented the highest separability index and C-statistics in both TG and VG. On the other hand, in the evaluation of discriminatory ability for death, measured by ROC curve areas, the s-BCLC system gave better results than the others. CONCLUSION/CONCLUSIONS:This experience stressed the high value of BCLC system in staging of HCC, but the s-BCLC system seems to be more useful for therapeutic decision making.

Abstract DNA methylation plays an intricate role in the regulation of gene expression and events that compromise the integrity of the methylome may potentially contribute to disease development. DNA methylation is a reversible and regulatory modification that elicits a cascade of events leading to chromatin condensation and gene silencing. In general, normal cells are characterized by gene-specific hypomethylation and global hypermethylation, while cancer cells portray a reverse profile to this norm. The unique methylome displayed in cancer cells is induced after exposure to carcinogenic metals such as nickel, arsenic, cadmium, and chromium (VI). These metals alter the DNA methylation profile by provoking both hyper- and hypo-methylation events. The metal-stimulated deviations to the methylome are possible mechanisms for metal-induced carcinogenesis and may provide potential biomarkers for cancer detection. Development of therapies based on the cancer methylome requires further research including human studies that supply results with larger impact and higher human relevance.

Occupational and/or environmental exposure to nickel has been implicated in various types of cancer, and in vitro exposure to nickel compounds results in the accumulation of Ni(II) ions in cells. One group of major targets of Ni(II) ions inside the cell consists of Fe(II)- and alphaKG-dependent dioxygenases. Using JMJD2A and JMJD2C as examples, we show that the JMJD2 family of histone demethylases, which are products of putative oncogenes as well as Fe(II)- and alphaKG-dependent dioxygenases, are highly sensitive to inhibition by Ni(II) ions. In this work, X-ray absorption spectroscopy (XAS) has been used to investigate the Fe(II) active site of truncated JMJD2A and JMJD2C (1-350 amino acids) in the presence and absence of alphaKG and/or substrate to obtain mechanistic details of the early steps in catalysis that precede O2 binding in histone demethylation by the JMJD2 family of histone demethylases. Zinc K-edge XAS has been performed on the resting JMJD2A (with iron in the active site) to confirm the presence of the expected structural zinc site. XAS of the Ni(II)-substituted enzymes has also been performed to investigate the inhibition of these enzymes by Ni(II) ions. Our XAS results indicate that the five-coordinate Fe(II) center in the resting enzyme is retained in the binary and ternary complexes. In contrast, the Ni(II) center is six-coordinate in the resting enzyme and binary and ternary complexes. XAS results indicate that both Fe(II) and Ni(II) bind alphaKG in the binary and ternary complexes. The electron density buildup that is observed at the Fe(II) center in the presence of alphaKG and substrate is not observed at the Ni(II) center. Thus, both electronic and steric factors are responsible for Ni-induced inhibition of the JMJD2 family of histone demethylases. Ni-induced inhibition of these enzymes may explain the alteration of the epigenetic mechanism of gene expression that is responsible for Ni-induced carcinogenesis.

PURPOSE: Taurine (2-aminoethanesulfonic acid), a molecule obtained from diet, is involved in bile acid conjugation, blood pressure regulation, anti-oxidation and anti-inflammation. We performed the first prospective study of taurine and CHD risk. METHODS: We conducted a case-control study nested in the New York University Women's Health Study to evaluate the association between circulating taurine levels and risk of coronary heart disease (CHD). Taurine was measured in two yearly pre-diagnostic serum samples of 223 CHD cases and 223 matched controls and averaged for a more reliable measurement of long-term taurine levels. RESULTS: Mean serum taurine was positively related to age and dietary intake of poultry, niacin, vitamin B1, fiber and iron, and negatively related to dietary intake of saturated fat (all p values 250 mg/dL) (adjusted OR = 0.39 (0.19-0.83) for the third versus first tertile; p for trend = 0.02) but not among those with low total serum cholesterol (p for interaction = 0.01). The data suggest a possible inverse association of serum taurine with diabetes and hypertension risk. CONCLUSIONS: The findings suggest that high levels of taurine may be protective against CHD among individuals with high serum cholesterol levels.

BACKGROUND: Occupational exposure to nickel (Ni) is associated with an increased risk of lung and nasal cancers. Ni compounds exhibit weak mutagenic activity, alter the cell's epigenetic homeostasis, and activate signaling pathways. However, changes in gene expression associated with Ni exposure have only been investigated in vitro. This study was conducted in a Chinese population to determine whether occupational exposure to Ni was associated with differential gene expression profiles in the peripheral blood mononuclear cells (PBMC) of Ni-refinery workers when compared with referents. METHODS: Eight Ni-refinery workers and ten referents were selected. PBMC RNA was extracted and gene expression profiling was conducted using Affymetrix exon arrays. Differentially expressed genes (DEG) between both groups were identified in a global analysis. RESULTS: There were a total of 2,756 DEGs in the Ni-refinery workers relative to the referents [false discovery rate (FDR) adjusted P < 0.05] with 770 upregulated genes and 1,986 downregulated genes. DNA repair and epigenetic genes were significantly overrepresented (P < 0.0002) among the DEGs. Of 31 DNA repair genes, 29 were repressed in the Ni-refinery workers and 2 were overexpressed. Of the 16 epigenetic genes, 12 were repressed in the Ni-refinery workers and 4 were overexpressed. CONCLUSIONS: The results of this study indicate that occupational exposure to Ni is associated with alterations in gene expression profiles in PBMCs of subjects. Impact: Gene expression may be useful in identifying patterns of deregulation that precede clinical identification of Ni-induced cancers. Cancer Epidemiol Biomarkers Prev; 22(2); 261-9. (c)2012 AACR.

There are many sources of nutritionally mediated oxidative stress that trigger inflammatory cascades along short and long time frames. These events are primarily mediated via NF kappa B. On the short-term scale postprandial inflammation is characterized by an increase in circulating levels of IL-6 and TNF- alpha and is mirrored on the long-term by proinflammatory gene expression changes in the adipocytes and peripheral blood mononuclear cells (PBMCs) of obese individuals. Specifically the upregulation of CCL2/MCP-1, CCL3/MIP-1 alpha , CCL4/MIP-1 beta , CXCL2/MIP-2 alpha , and CXCL3/MIP-2 beta is noted because these changes have been observed in both adipocytes and PBMC of obese humans. In comparing numerous human intervention studies it is clear that pro-inflammatory and anti-inflammatory consumption choices mediate gene expression in humans adipocytes and peripheral blood mononuclear cells. Arachidonic acid and saturated fatty acids (SFAs) both demonstrate an ability to increase pro-inflammatory IL-8 along with numerous other inflammatory factors including IL-6, TNF alpha , IL-1 beta , and CXCL1 for arachidonic acid and IGB2 and CTSS for SFA. Antioxidant rich foods including olive oil, fruits, and vegetables all demonstrate an ability to lower levels of IL-6 in PBMCs. Thus, dietary choices play a complex role in the mediation of unavoidable oxidative stress and can serve to exacerbate or dampen the level of inflammation.

Epidemiological studies have established a positive correlation between human mortality and increased concentration of airborne particulate matters (PM). However, the mechanisms underlying PM related human diseases, as well as the molecules and pathways mediating the cellular response to PM, are not fully understood. This study aims to investigate the global gene expression changes in human cells exposed to PM(10) and to identify genes and pathways that may contribute to PM related adverse health effects. Human bronchial epithelial cells were exposed to PM(10) collected from Saudi Arabia for 1 or 4days, and whole transcript expression was profiled using the GeneChip human gene 1.0 ST array. A total of 140 and 230 genes were identified that significantly changed more than 1.5 fold after PM(10) exposure for 1 or 4days, respectively. Ingenuity Pathway Analysis revealed that different exposure durations triggered distinct pathways. Genes involved in NRF2-mediated response to oxidative stress were up-regulated after 1day exposure. In contrast, cells exposed for 4days exhibited significant changes in genes related to cholesterol and lipid synthesis pathways. These observed changes in cellular oxidative stress and lipid synthesis might contribute to PM related respiratory and cardiovascular disease.

BACKGROUND: Exposure to arsenic (As) is associated with an increased risk of several cancers as well as cardiovascular disease, and childhood neuro-developmental deficits. Arsenic compounds are weakly mutagenic, alter gene expression and posttranslational histone modifications (PTHMs) in vitro. METHODS: Water and urinary As concentrations as well as global levels of histone 3 lysine 9 di-methylation and acetylation (H3K9me2 and H3K9ac), histone 3 lysine 27 tri-methylation and acetylation (H3K27me3 and H3K27ac), histone 3 lysine 18 acetylation (H3K18ac), and histone 3 lysine 4 trimethylation (H3K4me3) were measured in peripheral blood mononuclear cells (PBMC) from a subset of participants (N = 40) of a folate clinical trial in Bangladesh (FACT study). RESULTS: Total urinary As (uAs) was positively correlated with H3K9me2 (r = 0.36, P = 0.02) and inversely with H3K9ac (r = -0.47, P = 0.002). The associations between As and other PTHMs differed in a gender-dependent manner. Water As (wAs) was positively correlated with H3K4me3 (r = 0.45, P = 0.05) and H3K27me3 (r = 0.50, P = 0.03) among females and negatively correlated among males (H3K4me3: r = -0.44, P = 0.05; H3K27me3: r = -0.34, P = 0.14). Conversely, wAs was inversely associated with H3K27ac among females (r = -0.44, P = 0.05) and positively associated among males (r = 0.29, P = 0.21). A similar pattern was observed for H3K18ac (females: r = -0.22, P = 0.36; males: r = 0.27, P = 0.24). CONCLUSION: Exposure to As is associated with alterations of global PTHMs; gender-specific patterns of association were observed between As exposure and several histone marks. Impact: These findings contribute to the growing body of evidence linking As exposure to epigenetic dysregulation, which may play a role in the pathogenesis of As toxicity. Cancer Epidemiol Biomarkers Prev; 21(12); 2252-60. (c)2012 AACR.