Dakeun Lee

Association between serum concentrations of persistent organic pollutants and prevalence of newly diagnosed hypertension: results from the National Health and Nutrition Examination Survey 1999–2002

Epidemiological studies have suggested a link between exposure to persistent organic pollutants (POPs) and hypertension. Cross-sectional associations of serum POP concentrations with the prevalence of newly diagnosed hypertension were investigated in 524 adult participants aged ⩾40 years in the National Health and Nutrition Examination Survey 1999–2002. Twenty-one POPs (three polychlorinated dibenzo-p-dioxins (PCDDs), three polychlorinated dibenzofurans (PCDFs), five dioxin-like polychlorinated biphenyls (PCBs), six dioxin-unlike PCBs and four organochlorine (OC) pesticides) were selected because they were detectable in ⩾60% of participants. Serum concentrations of PCDDs and PCDFs were associated with prevalent but newly diagnosed hypertension among women, but not among men. Across quartiles of the sum of category numbers of the three PCDDs and the three PCDFs, adjusted odds ratios in women were 1.0, 4.2 (95% confidence interval (CI): 1.0–17.1), 4.5 (1.0–19.9) and 5.0 (1.2–21.5) (P for trend=0.08) and 1.0, 2.6 (0.8–9.0), 5.9 (1.7–20.0) and 4.2 (1.3–14.3) (P for trend=0.01), respectively. On the other hand, PCBs tended toward positive association with hypertension only among men. Adjusted odds ratios in men in the highest quartiles of the sum of category numbers of the dioxin-like and non-dioxin-like PCBs were 2.3 (0.8–6.6) and 2.8 (0.9–8.5) (P for trend=0.11 or 0.04), respectively. OC pesticides were not clearly associated with hypertension in either gender. Hypertension had gender-specific associations with serum concentrations of some POPs. Considering the common presence of exposure to POPs in the general population, these findings need to be clarified in prospective studies.

The association between obesity and mortality in the elderly differs by serum concentrations of persistent organic pollutants: a possible explanation for the obesity paradox

Objective:Numerous studies have documented an obesity paradox in which the overweight and obese elderly have a better prognosis than those with ideal body weight. Good prognosis among the overweight or obese elderly may reflect the relative safety of storing the harmful lipophilic chemicals, known as persistent organic pollutants (POPs), in adipose tissue rather than in other critical organs. Therefore, we hypothesized lower mortality among the obese elderly with a higher body burden of POPs, but this pattern may not exist among the obese elderly with a lower body burden of POPs.Participants:Using the National Health and Nutrition Examination Survey (NHANES) 1999–2004 study with a mean 4.2-year follow-up, we tested whether the association between fat mass and total mortality in 635 (652 for organochlorine pesticides) elderly participants aged ⩾70 years differed depending on serum concentrations of 23 POPs.Results:There were statistically significant interactions between fat mass and POPs in predicting total mortality. In those with low POP concentrations, there was no obesity paradox; mortality increased with fat mass (hazard ratios about 2–3 in the highest vs lowest quintile of fat mass). However, consistent with an obesity paradox, these patterns completely disappeared in those with high POP concentrations. Compared with the lowest quintile of fat mass, statistically significantly lower mortality was observed in the elderly in the third to fifth quintiles of fat mass. In the case of polychlorinated biphenyls, the mortality in the highest quintile of fat mass was only one-fifth of that in the lowest quintile.Conclusion:These findings are consistent with our hypothesis that adipose tissue provides relatively safe storage of toxic lipophilic chemicals, a phenomenon that could explain the obesity paradox. Although weight loss may be beneficial among the obese elderly with low POP concentrations, weight loss in the obese elderly with higher serum concentrations of POPs may carry some risk.

Gamma-glutamyltransferase: an effect modifier in the association between age and hypertension in a 4-year follow-up study.

We performed a prospective study to assess whether the relationship of age with hypertension was stronger in men with high normal serum gamma glutamyltransferase (GGT) than in those with lower GGT levels. The study population included 8170 healthy male workers in a steel manufacturing company who had undergone health examinations in both 1994 and 1998. The higher the baseline GGT level, the effect of age on the development of hypertension was stronger. The incidence of hypertension among those aged 25–34, 35–44 and 45–50 years was 0.9, 2.2, 3.8% in those with GGT<20 U/l; 1.0, 4.1, 12.5% in those with GGT between 20 and 39 U/l; and 1.9, 6.3, 17.2% in those with GGT⩾40 U/l, respectively. All relationships persisted after adjusting for baseline values of body mass index, alcohol intake, smoking, exercise, family history of hypertension, systolic and diastolic blood pressure, and changes of body mass index during 4 years (P for interaction=0.03). Our data supported the hypothesis that the effect of age on the development of hypertension differed by baseline GGT level, although the underlying mechanism for this interaction is unclear.

BRAF V600E mutations are frequent in dysembryoplastic neuroepithelial tumors and subependymal giant cell astrocytomas

BRAF mutation has received a great deal of attention in neuro‐oncology field, recently. This study aimed to investigate the incidence and the clinical significance of BRAFV600E in low‐grade glial tumors.

Associations of fat mass and lean mass with bone mineral density differ by levels of persistent organic pollutants: National Health and Nutrition Examination Survey 1999–2004

Persistent organic pollutants (POPs), xenobiotics that accumulate in fat tissue, may impair bone metabolism. We studied (1) the association of bone mineral density (BMD) with POPs and (2) whether associations of fat mass (FM) or lean mass (LM), two components of body composition, with BMD differed depending on levels of POPs. Participants aged ≥ 20 in the National Health and Nutrition Examination Survey 1999-2004 were included (n=2769). Eight POPs with detection rate ≥ 80% and three skeletal subregions (left arm, pelvis, and right leg) were selected. All analyses were stratified by gender and age (cutpoint 50 years or more). POPs at background concentrations were mostly unassociated with BMD. However, the associations of FM and LM with BMD depended on POPs concentrations, in particular with BMD of the left arm (usually not weight-bearing) in postmenopausal women. When POPs concentrations were low, FM showed inverse associations with BMD while LM showed positive associations. However, when POPs levels were high, FM showed positive associations with BMD while the positive associations between LM and BMD weakened. POPs may biologically modify the associations of FM and LM with BMD, especially among postmenopausal women, possibly explaining inconsistent associations between FM and BMD in previous epidemiological studies.

Prognostic Stratification by Extramural Depth of Tumor Invasion of Primary Rectal Cancer Based on the Radiological Society of North America Proposal

OBJECTIVE The purpose of this study was to investigate the diagnostic performance of MRI in stratifying tumors stage III (T3) in patients with rectal cancer by measuring the extramural depth of tumor invasion based on the Radiologic Society of North America (RSNA) proposal and to validate its role as a prognostic indicator. MATERIALS AND METHODS From January 2006 to July 2009, 146 patients with surgically and pathologically confirmed T3 rectal adenocarcinoma who underwent preoperative MRI were enrolled. Two blinded radiologists measured the maximum extramural depth of tumor invasion on T2-weighted images. To evaluate the diagnostic performance of MRI for stratifying subgroups, the study population was assigned into three subgroups (T3a, T3b, and T3c) according to extramural depth of tumor invasion (< 5, 5-10, and > 10 mm).To validate the role of extramural depth of tumor invasion as a prognostic indicator, Cox regression analysis was used for estimation of independent risk factors for postoperative recurrence. Three-year recurrence-free survival was evaluated by the Kaplan-Meier method with a log-rank test. Histopathologic reports were used as the reference standard. RESULTS The overall accuracy of MRI for stratifying subgroups was 71.2% (104/146) and 77.4% (113/146) for reviewers 1 and 2. Extramural depth of tumor invasion was an independent risk factor for 3-year recurrence-free survival (hazard ratio, 2.186; 95% CI, 1.336-3.577; p = 0.002). Kaplan-Meier curves revealed a significant difference in 3-year recurrence-free survival rates for each subgroup (86%, 69%, and 43% for T3a, T3b, and T3c; p < 0.03). CONCLUSION MRI can be used for prognostic stratification according to extramural depth of tumor invasion based on the RSNA proposal for patients with T3 rectal cancer.

IDH1 Mutations in Oligodendroglial Tumors: Comparative Analysis of Direct Sequencing, Pyrosequencing, Immunohistochemistry, Nested PCR and PNA-Mediated Clamping PCR

Mutations in isocitrate dehydrogenase 1 (IDH1) are found in a high proportion of glial tumors and have a significant prognostic impact. Although direct sequencing has been considered to be the gold‐standard method to detect this mutation, the sensitivity of this technique has been questioned especially because specimens from glial tumors may contain large numbers of non‐tumor cells. We screened 141 cases of oligodendroglial tumors for IDH1 mutations using peptide nucleic acid (PNA)‐mediated clamping polymerase chain reaction (PCR) and compared the results with the results of direct sequencing, pyrosequencing, and immunohistochemistry (IHC). Nested PCR was only performed in cases having mutant IDH1 only discovered by clamping PCR. Using dilution experiments mixing IDH1 wild‐type and mutant DNA samples, clamping PCR detected mutations in samples with a 1% tumor DNA composition. Using PNA clamping PCR, we detected 138 of 141 (97.9%) cases with mutant IDH1 in our series, which is significantly higher (P = 0.016; PNA clamping vs. direct sequencing) than those of direct sequencing (74.5%), pyrosequencing (75.2%) and IHC (75.9%). From our results, almost all oligodendroglial tumors have IDH1 mutations, and this suggests that IDH1 mutation is an early and common event especially in the development of oligodendroglial tumors.

Prognostic significance of tetraspanin CD151 in newly diagnosed glioblastomas

Tetraspanin CD151 is a positive effector of cancer invasion and metastasis.

Cerebral granular cell tumor

Intracerebral granular cell tumors (GCTs) are a rare finding. We report here on a case of cerebral GCT in a 47‐year‐old man who suffered with severe headache. The tumor appeared as a relatively well‐defined, enhancing mass at the periventricular white matter of the left occipital lobe of the brain. Histologically, the tumor was entirely composed of granular cells. Some of the tumor cells showed peripherally accentuated cytoplasmic granules with central clearing, which produced a unique “targetoid” appearance. The granular cells of the current case were positive for neuron‐specific enolase (NSE), S‐100 protein, GFAP, vimentin, CD 68, lysozyme, and α‐1‐antitrypsin. These wide immunoexpressions were not observed for the previously reported cerebral GCTs. Interestingly, this case showed “targetoid” or “reversed targetoid” immunoreactive patterns in NSE, CD68, GFAP, and vimentin. Despite these wide immunoexpressions and the lack of any association with astrocytoma, the histogenesis of cerebral GCTs is still suggested to be of a glial origin, based on the tumor location, the GFAP positivity and the ultrastructural findings, of which the latter showed intermediate filaments, and these are reminiscent of neoplastic astrocytes.

MicroRNA Expression Signatures Associated With BRAF-Mutated Versus KRAS-Mutated Colorectal Cancers

AbstractBRAF and KRAS genes are known to play a similar role in the activation of RAS-RAF-MEK-ERK signaling pathway in colorectal tumorigenesis. However, BRAF-mutated colorectal cancers (CRCs) have distinct clinicopathologic characteristics different from those of the KRAS mutated ones as in comparison the BRAF-mutated CRCs are associated with a much worse prognosis for the afflicted patients. This study aimed to determine the different miRNA expression signatures associated with BRAF-mutated CRCs in comparison to KRAS-mutated ones, and to identify the specific miRNAs possibly mediating the aggressive phenotype of the BRAF-mutated CRCs.We screened 535 formalin-fixed paraffin-embedded CRC tissue samples for the BRAF V600E mutation, and selected 7 BRAF-mutated and 7 KRAS-mutated CRCs that were tumor size, stage, and microsatellite status-matched. Affymetrix GeneChip® miRNA 4.0 Array was used for detection of miRNA expression differences in the selected samples. We validated the array results by quantitative reverse transcription polymerase chain reaction (qRT-PCR) for selected miRNAs.A total of 10 differentially expressed (DE) miRNAs associated with BRAF-mutated CRCs were obtained, including miR-31-5p, miR-877-5p, miR-362-5p, and miR-425-3p. miR-31-5p showed the highest fold change (8.3-fold) among all of the miRNAs analyzed. From the analyses of GO biological processes, the DE-miRNAs were functionally relevant to cellular proliferation such as positive regulation of gene expression (P = 1.26 × 10−10), transcription (P = 9.70 × 10−10), and RNA metabolic process (P = 1.97 × 10−9). Bioinformatics analysis showed that the DE-miRNAs were significantly enriched in cancer-associated pathways including neutrophin signaling (P = 6.84 × 10−5), pathways in cancer (P = 0.0016), Wnt signaling (P = 0.0027), and MAPK signaling pathway (P = 0.0036).Our results suggest that the DE-miRNAs in BRAF-mutated CRCs in comparison to KRAS-mutated CRCs are implicated in the aggressive phenotype of the BRAF-mutated CRCs. Further experimental validation is required to confirm these results.