Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes.

Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging and tumor treatment by selective activation of the prodrug ganciclovir at tumor sites. Translation of this AAVP system is expected simultaneously to image, monitor, and treat the IBC phenotype and possibly other aggressive (e.g., invasive and/or metastatic) subtypes of breast cancer, based on the inducible cell-surface expression of the stress-response chaperone GRP78, and possibily other cell-surface receptors in human tumors.

Different associations of albuminuria with total and cardiovascular mortality by concentrations of persistent organic pollutants in the elderly.

Epidemiologic studies have indicated that albuminuria is associated with mortality from all causes and cardiovascular disease (CVD), with substantial heterogeneity. We evaluated if the associations of urine albumin creatinine ratio (ACR) with all-cause and CVD mortality differed depending on serum concentrations of persistent organic pollutants (POPs), strong lipophilic chemical mixtures with very long half-lives, which are recently linked to many degenerative diseases. Study subjects were participants of the National Health and Nutrition Examination Survey 1999-2004 who were 60 years or older at baseline (n=1215 and 1067 for organochlorine pesticides (OCPs) and other POPs, respectively). They were followed-up through 2011 (mean follow-up periods: 8.1 and 8.0 years for OCPs and other POPs, respectively). The associations between the ACR and all-cause mortality significantly differed by the serum levels of POPs, especially organochlorine pesticides (OCPs; Pinteraction<0.01). Stratified analyses indicated that the associations between ACR and all-cause mortality became stronger as the serum levels of OCPs increased. Among the elderly with the highest tertile of OCPs, the adjusted hazard ratios were 1.0, 1.1, and 2.9 (Ptrend<0.01) across the categories of ACR (<10, 10-<30, and ≥30mg/g); however, ACR was not clearly related to mortality among the elderly with the lowest tertile of OCPs. CVD mortality showed similar interactions, as noted for all-cause mortality (Pinteraction<0.01). The different associations between albuminuria and mortality by the serum OCP levels and the little association among the elderly with low serum OCPs levels suggest that OCPs play an important role in albuminuria-related death risk. However, these findings need to be replicated in other cohort studies.

Persistent organic pollutants and promoter hypermethylation of the O(6)-methylguanine-DNA methyltransferase gene.

Promoter hypermethylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) DNA repair gene is important during carcinogenesis. We explored whether organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs), were associated with hypermethylation of the MGMT gene promoter in peripheral leukocytes among 368 Koreans without cancer. Hypermethylation decreased as OCPs increased (Ptrend = 0.02), while PCB concentrations showed an inverted U-shaped association (Pquadratic < 0.01). The prevalence of MGMT promoter hypermethylation was highest within the 2nd quintile of the PCB summary score (28.4%), while it was only 2.7% in the upper 10% score. Chronic exposure to these chemicals may affect methylation of the MGMT promoter, with possibly non-monotonic dose response relationships.

Associations of organochlorine pesticides and polychlorinated biphenyls with total, cardiovascular, and cancer mortality in elders with differing fat mass.

BACKGROUND: We investigated if certain persistent organic pollutants (POPs), namely polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides, predicted total, cardiovascular disease (CVD), and cancer mortality among the elderly, with the hypothesis that associations differ by the amount of fat mass. METHODS: We studied serum concentrations of 11 PCBs in 633 elders (age≥70 years) and of 5 OC pesticides in 675 elders within the National Health and Nutrition Examination Survey (NHANES) 1999-2004. Mean follow-up was 4.1-years. RESULTS: Neither PCBs nor OC pesticides were associated with total mortality when fat mass was not considered in analyses. However, associations of PCBs and OC pesticides with total mortality depended on fat mass (Pinteraction<0.01 and 0.06, respectively). PCBs associated inversely with total mortality for high fat mass, but not for lower fat mass. On the contrary, OC pesticides associated positively with total mortality for low fat mass and this association weakened at higher fat mass. The interaction was also observed with CVD mortality. In elders with low fat mass, higher PCBs associated with 2-3 fold higher risk of CVD mortality, while this association was absent in elders with more fat mass (Pinteraction=0.03). The positive association between OC pesticides and CVD mortality was also observed only among elderly with low fat mass (Pinteraction=0.03). CONCLUSIONS: The possibility of interaction between POPs and the amount of fat mass on risk of mortality from chronic diseases is clinically important in modern societies with an obesity epidemic and requires confirmation in other studies with larger sample size.

Different associations between obesity and impaired fasting glucose depending on serum gamma-glutamyltransferase levels within normal range: a cross-sectional study.

BACKGROUND: Despite the consistent relationship between serum γ-glutamyltransferase (GGT) and type 2 diabetes (T2D), one unsolved issue is the role of serum GGT in the well-known association between obesity and T2D. This study was performed to investigate whether the association between body mass index (BMI) and impaired fasting glucose (IFG) differed depending on serum GGT levels within the normal range. METHODS: Study subjects were 2,424 men and 3,652 women aged ≥ 40, participating in the Fifth Korean National Health and Nutrition Examination Survey. Serum GGT levels within the normal range were classified into gender-specific tertiles. RESULTS: Among men and women belonging to the lowest tertile of serum GGT, BMI showed statistically non-significant weak associations with the risk of IFG. However, among persons in the highest tertile of serum GGT, the risk of IFG was 3 - 4 times higher among persons with BMI ≥ 25 kg/m2 than those with BMI < 23 kg/m2 (Pinteraction = 0.032 in men and 0.059 in women). CONCLUSIONS: The well-known strong association between BMI and IFG was observed mainly among persons with elevation of serum GGT to certain physiological levels, suggesting a critical role of serum GGT in the pathogenesis of IFG. This finding has an important clinical implication because serum GGT can be used to detect high-risk obese persons.

Investigating the effect of road lighting color temperature on road visibility in night foggy conditions.

Night foggy road conditions limit visibility distance of drivers and are associated with higher accident and fatality rates than other weather conditions. Therefore, ensuring road visibility in night foggy road is critical. However, it is difficult to reproduce fog on a real road and only a few studies have researched foggy road conditions and visibility in a laboratory as a small scale. Previous studies have suggested that a color temperature of road lighting is related to visibility. However, many have only investigated the effects of relative transmittance in limited indoor experiments, and the impacts of differences in transmittance on visibility have thus far not been studied in real-scale conditions. In this study, a real-scale test involving 91 subjects was conducted to investigate how the visibility distance under night foggy conditions is affected by different lighting color temperatures. Based on the real scale experiments, the correlation between the visibility distance and lighting color temperature was derived. Road lighting with a low color temperature (i.e., yellow) was found to provide longer visibility distances than that with high color temperatures under night foggy conditions having measured visibility of approximately 102m. The impact of the differences in lighting color increased as the visibility distance decreased. In contrast, road lighting with a high color temperature (i.e., white) improved driver visibility in higher-visibility conditions. Therefore, this study confirmed the correlation between lighting color temperature and visibility distance for different visibility conditions and could serve as a foundation for the development of roadway design standards as well as future studies.

Marine Plankton-Derived Whitlockite Powder-Based 3D-Printed Porous Scaffold for Bone Tissue Engineering.

Powder-based 3D printing is an excellent technique for the fabrication of complex structural shapes. The outstanding bone remodeling capacity of calcium phosphate bioceramics is a desirable characteristic for such fabrication. Whitlockite (WH) is a calcium phosphate-based ceramic that contains Mg ions and possesses good mechanical properties, rapid resorbability, and promotes osteogenesis. The aim of this study was to fabricate 3D-printed scaffolds using marine plankton-derived WH (MP-WH) powder. The surface morphology and composition of the fabricated scaffolds were characterized by scanning electron microscopy and X-ray diffraction. The biocompatibility and osteogenic effects were evaluated using human mesenchymal stem cells. We successfully obtained a 3D porous scaffold using MP-WH. The MP-WH 3D scaffold showed improved compressive strength compared to the tricalcium phosphate (TCP) 3D scaffold. The in vitro results showed that compared with TCP 3D scaffolds, MP-WH 3D scaffolds were biocompatible and enhanced cell proliferation and adhesion. In addition, alkaline phosphatase activity and real-time polymerase chain reaction assays demonstrated that osteoblast differentiation was improved on the MP-WH scaffold. These results suggest that marine plankton-derived WH is useful for fabricating 3D-printed scaffolds for bone tissue engineering applications.

High expression of the phosphoinositide 3-kinase p11γ isoform can predict poor prognosis of non-small cell lung cancer.

The protein p110γ is an isoform of the catalytic subunit of class I phosphoinositide 3-kinases (PI3Ks). PI3Ks are involved in the regulation of cell survival, growth, proliferation, and migration and have been implicated in the oncogenesis of various cancers. In this study, p110γ expression in non-small cell lung cancer (NSCLC) and its association with clinicopathological factors and patient survival were evaluated. A total of 230 NSCLC tumors were immunohistochemically stained for p110γ. Of these, 174 (75.7%) and 56 (24.3%) were placed in the low and high expression groups, respectively. The positive rate of p110γ was significantly higher in adenocarcinoma than in squamous cell carcinoma (p⟨0.001). Advanced stage NSCLCs showed higher p110γ expression than those at an early stage (p=0.002). Irrespective of the histological tumor type, the patients with high p110γ expression had significantly worse overall survival than those with low p110γ expression (p=0.004). p110γ expression was an independent poor prognostic factor in the multivariate analysis. Our results suggest that p110γ may be involved in the development and progression of NSCLC, and that p110γ has promising potential as a prognostic factor or novel therapeutic target for NSCLC.

Controlling spatial density and size of nanocrystals by two-step atomic layer deposition.

Two-step atomic layer deposition (ALD) is proposed in order to control both the spatial density and size of nanocrystals (NCs) via modulation of the nucleation rate during deposition. In this process, two different deposition conditions are sequentially used: a high nucleation rate condition for the formation of high density NCs and a low nucleation rate condition with a slow growth rate for the subsequent growth of pre-formed NCs. To control the nucleation rate of Ru during ALD, pulsing time and carrier flow rate of the Ru precursor are varied. By controlling those factors, both the film growth rate and a nucleation rate of Ru are decreased considerably. Two-step ALD of Ru NCs using the surface-saturated condition followed by the reduced condition allows for variation of the spatial density from 7.9 × 10(11) to 3.2 × 10(12) cm(-2) and variation of the average diameter from 1.9 to 3.3 nm.

A Novel T Cell-Engaging Bispecific Antibody for Treating Mesothelin-Positive Solid Tumors.

As mesothelin is overexpressed in various types of cancer, it is an attractive target for therapeutic antibodies. T-cell bispecific antibodies bind to target cells and engage T cells via binding to CD3, resulting in target cell killing by T-cell activation. However, the affinity of the CD3-binding arm may influence CD3-mediated plasma clearance or antibody trapping in T-cell-containing tissues. This may then affect the biodistribution of bispecific antibodies. In this study, we used scFab and knob-into-hole technologies to construct novel IgG-based 1 + 1 MG1122-A and 2 + 1 MG1122-B bispecific antibodies against mesothelin and CD3ε. MG1122-B was designed to be bivalent to mesothelin and monovalent to CD3ε, using a 2 + 1 head-to-tail format. Activities of the two antibodies were evaluated in mesothelin-positive tumor cells in vitro and xenograft models in vivo. Although both antibodies exhibited target cell killing efficacy and produced regression of xenograft tumors with CD8+ T-cell infiltration, the antitumor efficacy of MG1122-B was significantly higher. MG1122-B may improve tumor targeting because of its bivalency for tumor antigen. It may also reduce systemic toxicity by limiting the activation of circulating T cells. Thus, MG1122-B may be useful for treating mesothelin-positive solid tumors.

Utility of Human Papillomavirus Testing for Cervical Cancer Screening in Korea.

(1) Background: Cervical cancer is one of the most common cancers in Korean women. This study was performed to discover the utility of HPV (Human Papillomavirus) testing in screening of cervical lesions and to provide the prevalence of HPV and the genotype distribution in a single center of Korea. (2) Methods: A total of 15,141 women who underwent both HPV testing and cervical cytology were enrolled in this retrospective medical record review study. (3) Results: HPV testing showed higher sensitivity than cytology for the detection of histological high-grade squamous lesions. Furthermore, the sensitivity and specificity of HPV testing varied depending on the method used. The BD Onclarity™ HPV assay had higher sensitivity (90%) than the MyHPV CHIP™ kit (all types of HPV: 82%; high-risk HPV: 76%) for high-grade squamous lesions. A combination of MyHPV CHIP™ and cytology detected 90.9% (30/33) of histological high-grade squamous lesions. A combination of BD Onclarity™ HPV assay and cytology detected 96.55% (84/87) of histological high-grade squamous lesions. In addition, HPV prevalence and genotype distribution were different depending on the HPV testing method used. (4) Conclusion: HPV testing showed higher sensitivity than cytology, but the sensitivity and specificity of HPV testing had variation depending on the method used.

Differential expression of HSP90 isoforms and their correlations with clinicopathologic factors in patients with colorectal cancer.

Heat shock protein 90 (HSP90), a molecular chaperone, plays critical roles in cellular protection against various stressful stimuli and in the regulation of cellular growth and apoptosis. HSP90 has four human isoforms; HSP90α, HSP90ß, glucose related protein 94 (GRP94), and tumor necrosis factor (TNF) receptor-associated protein 1 (TRAP1). We evaluated the differential expression of these HSP90 isoforms in colorectal cancer (CRC) and correlated their expression levels with clinicopathological factors and patient survival rates. We performed immunohistochemical staining for HSP90α, HSP90ß, GRP94, and TRAP1 in 129 CRC tumor samples and found that HSP90α expression was significantly associated with advanced pT stage (P = 0.011) and shorter recurrence-free survival (RFS) (P = 0.010), whereas GRP94 expression was correlated with low grade (P = 0.029) and better RFS (P < 0.001). HSP90ß and TRAP1 had no prognostic impact, although HSP90ß expression was positively correlated with tumor size (P = 0.008). Based on our results, HSP90α and GRP94 are potential prognostic biomarkers of CRC. In addition, the differences in expression and functional activities among four HSP90 isoforms imply that isoform selectivity should be seriously considered when HSP90 inhibitors are studied or adopted for the treatment of CRC.

Spatio-Temporal Variations in Stream-Aquifer Interactions Following Construction of Weirs in Korea.

The "Four Major Rivers Restoration Project" was conducted to secure sufficient water resources, introduce comprehensive flood control measures, improve water quality, and restore river ecosystems in Korea. As a part of the project, 16 sites were dredged and weirs were installed in the Han, Geum, Yeongsan, and Nakdong Rivers from late 2010 to early 2012. Groundwater data were obtained from 213 groundwater monitoring wells near the four major rivers to analyze the impacts of weir construction on the nearby groundwater flow system. The groundwater level and chemical characteristics were analyzed to investigate how the groundwater flow system and water quality changed following weir construction. Our results show that the groundwater level immediately increased with increased river levels following weir construction. In addition, the hydrologic condition of some rivers upstream of the weirs was changed from gaining to losing streams. Consequently, the direction of groundwater flow changed from perpendicular to parallel to the river, and groundwater downstream of the weir became recharged from the area upstream of the weir. This should affect groundwater quality, which should become similar to the river water; however, this change has not yet been observed. Therefore, both further monitoring of the groundwater quality and further hydrogeochemical analysis are required for quantitative evaluation of the effects of weir construction in the study area.

Factors related to intentional and unintentional medication nonadherence in elderly patients with hypertension in rural community.

PURPOSE: We assessed medication nonadherence, categorized as intentional or unintentional, and related factors in elderly patients with hypertension, correlating the data with measurement of blood pressure as the final target of medication adherence and other possible influencing factors, such as lifestyle. PATIENTS AND METHODS: Subjects were aged ≥65 years, resided in a rural area, and were taking antihypertensive drugs. The survey was conducted in July 2014. Participants were divided into the following three groups: "Adherence", "Unintentional nonadherence", and "Intentional nonadherence". Individual cognitive components, such as necessity and concern as well as self-efficacy and other related factors, were compared according to adherence groups. The interrelationships between those factors and nonadherence were tested using structural equation modeling analysis. RESULTS: Of the 401 subjects, 182 (45.6%) were in the adherence group, 107 (26.7%) in the unintentional nonadherence group, and 112 (27.9%) in the intentional nonadherence group. Necessity and self-efficacy were found to have a significant direct influence on unintentional nonadherence behaviors (necessity ß=-0.171, P=0.019; self-efficacy ß=-0.433, P<0.001); concern was not statistically significant (ß=-0.009, P=0.909). Necessity was found to have significant direct and indirect impact on intentional nonadherence (direct ß=-0.275, P=0.002; indirect ß=-0.113, P=0.036). Self-efficacy had no significant direct effect on intentional nonadherence though it had the only significant indirect effect on intentional nonadherence (direct ß=-0.055, P=0.515; indirect ß=-0.286, P<0.001). Concern had no significant influence on intentional or on unintentional nonadherence (direct ß=0.132 0.132, P=0.151; indirect ß=-0.006, P=0.909). CONCLUSION: Unintentional nonadherence should be regularly monitored and managed because of its potential prognostic significance. Interventions addressing cognitive factors, such as beliefs about medicine or self-efficacy, are relatively difficult to implement, but are essential to improve medication adherence.

Clonality analysis for normal and cancerous colon tissues with human androgen receptor gene polymerase chain reaction.

We assessed the feasibility of clonality analysis with human androgen receptor gene polymerase chain reaction in terms of the sensitivity and specificity for normal and cancerous colonic tissues taken from fourteen informative cases selected from 22 women with colonic adenocarcinoma. Ten crypts microdissected from each 10-microm-thick cryostat sections and whole tissues were used as samples. DNA was extracted from the samples and amplified with and without prior enzyme digestion. These products were analyzed by capillary electrophoresis for clonality. Of the whole-tissue DNA, none of the normal tissues and seven (50.0%) of the cancerous tissues showed monoclonality. Of the microdissected samples, monoclonality was found in 88.4% (107/121) of normal crypts and 95.9% (117/122) of cancerous crypts. Samples composed of crypts with short and long alleles were found in eight of the 14 normal colonic mucosae, but in none of the cancerous tissues. We concluded that the sensitivity of this method is limited for both whole-tissue DNA and microdissected-tissue DNA, because monoclonality from small samples does not always indicate monoclonality of the entire lesion. The high specificity of this method, however, allows polyclonal results in whole tissues to be confirmed by additional analysis of microdissected tissues.

Associations between organochlorine pesticides and cognition in U.S. elders: National Health and Nutrition Examination Survey 1999-2002.

There is limited evidence about whether background exposure to organochlorine pesticides is related to impairment of cognitive function in general populations. This study was performed to investigate cross-sectional associations between serum concentrations of organochlorine pesticides and cognitive function, a predictor of dementia, among U.S. elders without overt dementia. Study subjects were 644 elders aged 60-85, participating in the National Health and Nutrition Examination Survey 1999-2002. We selected 6 organochlorine pesticides (p,p'-dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodiphenyldichloroethylene (DDE), trans-nonachlor, oxychlordane, heptachlor epoxide, and ß-hexachlorocyclohexane) which were commonly detected in current general population. Cognitive function was assessed with the Digit-Symbol Substitution Test. All 6 compounds showed statistically significant or marginally significant inverse associations with cognitive score after adjusting for covariates including education levels. The strongest association was observed with p,p'-DDT. With the outcome of low cognitive score defined as <25th percentile, elders in the highest quartile of p,p'-DDT, p,p'-DDE, and ß-hexachlorocyclohexane had 2 to 3 times higher risks than those in the lowest quartile. In particular, when their concentrations were further divided with the cutoff points of 90th and 95th percentiles, p,p'-DDT in the highest 5th percentile showed 6.5 (95% confidence interval: 2.6-16.3) times higher risk of low cognitive score. On the other hand, non-persistent pesticides like organophosphates or pyrethroid showed little association with this cognitive score. The potential role of background exposure to organochlorine pesticides in the development of dementia should be explored in future prospective studies and in-vitro/in-vivo experimental studies.

Paradoxical Associations of Insulin Resistance With Total and Cardiovascular Mortality in Humans.

BACKGROUND: Insulin resistance is linked to many human chronic diseases. Paradoxically, however, impaired insulin signaling contributes to longevity in various organisms and is suggested as an adaptive mechanism against external stressors, including obesity. We formulated a novel hypothesis that insulin resistance can be beneficial in obese humans, insofar as it does not cause glucose dysmetabolism. METHODS: N = 5,241 participants aged ≥40 with normal fasting glucose were combined across the 1988-1994 and 1999-2004 National Health and Nutrition Examination Survey datasets. Mean follow-up period was 6.6 years. Insulin resistance was measured with homeostasis model assessment (HOMA-IR). Outcomes were all causes (n = 724), cardiovascular diseases (CVD, n = 316), and cancer mortality (n = 190). RESULTS: Supporting the hypothesis, obese persons with high HOMA-IR showed a decreased risk of total and CVD mortality compared to those with the lowest HOMA-IR. Adjusted hazard ratios were 1.0, 0.8, 0.4, and 0.4 (p(trend) = .02) for all death and 1.0, 0.6, 0.2, and 0.2 (p(trend) < .01) for CVD death. On the other hand, lean persons with high HOMA-IR showed about twice the total and CVD mortality compared to persons with the lowest HOMA-IR (p(trend) < .01, respectively). CONCLUSIONS: Insulin resistance in obese individuals may begin as an adaptive mechanism and can be beneficial if it is not associated with glucose dysmetabolism. In contrast, insulin resistance in lean individuals associated with higher risk of total and CVD mortality. Insulin resistance may be multifaceted and conventional approaches to regard insulin resistance itself as a pathological condition may be reconsidered in this light.

Enhancement of the tumor penetration of monoclonal antibody by fusion of a neuropilin-targeting peptide improves the antitumor efficacy.

The limited localization and penetration of monoclonal antibodies (mAb) into solid tumors restricts their antitumor efficacy. Here, we describe a solid tumor-targeting antibody with enhanced tumor penetration activity. We designed a 22-residue peptide (A22p), which was extracted from the C-terminal basic region of semaphorin 3A (Sema3A) but modified to have higher affinity with neuropilin receptors (NRP), and genetically fused it to the C-terminus of Fc of human immunoglobulin G1 via a 15-residue (G4S)3 linker, generating Fc-A22p, for the bivalent binding to NRPs. In contrast to Fc or the monovalent A22p peptide alone, Fc-A22p homed to tumor vessels and induced vascular permeability through VE-cadherin downregulation and penetrated tumor tissues by interacting with NRPs in mice bearing human tumor xenografts. We extended the Fc-A22p platform by generating mAb-A22p antibodies of two clinically approved solid tumor-targeting mAbs, the anti-EGF receptor mAb cetuximab (erbitux), and the anti-Her2 mAb trastuzumab (herceptin). The mAb-A22p antibodies retained the intrinsic antigen binding, natural Fc-like biophysical properties, and productivity in mammalian cell cultures, comparable with those of the parent mAbs. In mouse xenograft tumor models, the mAb-A22p antibodies more efficiently homed to tumor vessels and spread into the extravascular tumor parenchyma, which significantly enhanced antitumor efficacy compared with the parent mAbs. Our results suggest that mAb-A22p is a superior format for solid tumor-targeting antibodies due to its enhanced tumor tissue penetration and greater antitumor efficacy compared with conventional mAbs.

Prospective associations between persistent organic pollutants and metabolic syndrome: a nested case-control study.

OBJECTIVE: Exposure to persistent organic pollutants (POPs) has recently been linked to metabolic syndrome (MetS) and some MetS components. However, prospective evidence in humans is scarce, and the nature of the dose-response relationship is unclear. We evaluated the association between POPs and MetS using a nested-case control study within a community-based Korean cohort. METHOD: The study subjects were 64 patients newly diagnosed with MetS during a 4-year follow-up, and the controls were 182 subjects without MetS. Concentrations of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) were measured in stored serum collected at baseline. RESULTS: The concentrations of most PCBs and some OCPs such as ß-hexachlorocyclohexane, hexachlorobenzene, oxychlordane, and heptachlor epoxide predicted the risk for MetS. The POP exposure and MetS showed an inverted U-shaped or a linear association with plateau rather than a linear dose-response association. When the summary measure of the PCBs and OCPs was used, the adjusted odds ratios (ORs) across the quartiles of the summary measure were 1.0, 1.3, 3.8 (95% confidence interval, 1.3-10.7), and 2.1 (Pquadratic=0.013) after adjusting for potential confounders. In the analyses of each of the five MetS components, POP exposure was mainly associated with an increased risk for glucose and lipid metabolism disturbances. CONCLUSION: This study demonstrated that chronic exposure to a mixture of PCBs and OCPs can increase the risk for MetS within the low-dose background exposure range of POPs. As the findings of this study suggest a nonmonotonic dose-response relationship, in vitro and in vivo experimental studies are needed to understand the underlying mechanisms.

Associations of organochlorine pesticides and polychlorinated biphenyls in visceral vs. subcutaneous adipose tissue with type 2 diabetes and insulin resistance.

Background exposure to organochlorine (OC) pesticides and polychlorinated biphenyls (PCBs) has been linked to type 2 diabetes. As OC pesticides and PCBs mainly accumulate in adipose tissue and there are physiological and clinical differences between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), we explored if there were associations of OC pesticides and PCBs in VAT or SAT with type 2 diabetes and insulin resistance. Participants were 50 patients with or without type 2 diabetes who underwent surgery for either cancer or benign liver or gallbladder lesions. We analyzed 14 OC pesticides and 22 PCB congeners in both VAT and SAT. Insulin resistance was estimated using homeostasis model assessment (HOMA). Although concentrations of OC pesticides and PCBs were strongly correlated between VAT and SAT, absolute concentrations differed substantially between them. In particular, concentrations of all PCBs were consistently about 5-10 times higher in VAT than SAT, but these patterns were independent of diabetes status. Some OC pesticides or PCBs, such as dichlorodiphenyltrichloroethanes (DDTs), chlordanes, and PCBs with 5 or less chlorides showed significant associations with diabetes or insulin resistance. For example, when tertiles of concentration-based summary measures were used, adjusted ORs were 1.0, 2.3, and 9.0 (P trend=0.02) for DDTs in VAT and 1.0, 2.1, and 5.7 (P trend=0.08) for PCBs with 5 or less chlorides. This study generally confirmed previous findings using serum concentrations. It would be useful to study pharmacodynamics of POPs in VAT and SAT further.