Concurrent DNA Copy‐Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients

Somatic mosaicism for DNA copy‐number alterations (SMC‐CNAs) is defined as gain or loss of chromosomal segments in somatic cells within a single organism. As cells harboring SMC‐CNAs can undergo clonal expansion, it has been proposed that SMC‐CNAs may contribute to the predisposition of these cells to genetic disease including cancer. Herein, the gross genomic alterations (>500 kbp) were characterized in uninvolved mammary glandular tissue from 59 breast cancer patients and matched samples of primary tumors and lymph node metastases. Array‐based comparative genomic hybridization showed 10% (6/59) of patients harbored one to 359 large SMC‐CNAs (mean: 1,328 kbp; median: 961 kbp) in a substantial portion of glandular tissue cells, distal from the primary tumor site. SMC‐CNAs were partially recurrent in tumors, albeit with considerable contribution of stochastic SMC‐CNAs indicating genomic destabilization. Targeted resequencing of 301 known predisposition and somatic driver loci revealed mutations and rare variants in genes related to maintenance of genomic integrity: BRCA1 (p.Gln1756Profs*74, p.Arg504Cys), BRCA2 (p.Asn3124Ile), NCOR1 (p.Pro1570Glnfs*45), PALB2 (p.Ser500Pro), and TP53 (p.Arg306*). Co‐occurrence of gross SMC‐CNAs along with point mutations or rare variants in genes responsible for safeguarding genomic integrity highlights the temporal and spatial neoplastic potential of uninvolved glandular tissue in breast cancer patients.     

Prenatal Exposure to Phthalate Esters and Behavioral Syndromes in Children at 8 Years of Age: Taiwan Maternal and Infant Cohort Study

Background: Few studies have shown an association between prenatal phthalate exposure and adverse effects on neurodevelopment and behavior in young children.Objectives: We aimed to assess the relationship between prenatal exposure to phthalate esters and behavior syndromes in children at 8 years of age.Methods: A total of 122 mother–child pairs from the general population in central Taiwan were studied from 2000 to 2009. Mono-methyl phthalate (MMP), mono-ethyl phthalate (MEP), mono-butyl phthalate (MBP), mono-benzyl phthalate (MBzP), and three di-(2-ethylhexyl) phthalate (DEHP) metabolites—mono-2-ethylhexyl, mono-2-ethyl-5-hydroxyhexyl, and mono-2-ethyl-5-oxohexyl phthalates (MEHP, MEHHP, and MEOHP)—were measured in maternal urine collected during the third trimester of pregnancy using liquid chromatography–electrospray ionization–tandem mass spectrometry. Behavioral syndromes of children at 8 years of age were evaluated using the Child Behavior Checklist (CBCL). Associations between log₁₀-transformed creatinine-corrected phthalate concentrations and standardized scores of the CBCL were estimated using linear regression models or multinomial logistic regressions with adjustments for potential confounders.Results: Externalizing problem scores were significantly higher in association with a 1-unit increase in log₁₀-transformed creatinine-corrected concentrations of maternal MBP (β = 4.29; 95% CI: 0.59, 7.99), MEOHP (β = 3.74; 95% CI: 1.33, 6.15), and MEHP (β = 4.28 ; 95% CI: 0.03, 8.26) after adjusting for the child’s sex, intelligence, and family income. Meanwhile, MBP and MEOHP were significantly associated with Delinquent Behavior and Aggressive Behavior scores. The same pattern was found for borderline and/or clinical ranges.Conclusions: Our findings suggest positive associations between maternal DEHP and dibutyl phthalate (DBP) exposure and externalizing domain behavior problems in 8-year-old children.Citation: Lien YJ, Ku HY, Su PH, Chen SJ, Chen HY, Liao PC, Chen WJ, Wang SL. 2015. Prenatal exposure to phthalate esters and behavioral syndromes in children at 8 years of age: Taiwan Maternal and Infant Cohort Study. Environ Health Perspect 123:95–100; http://dx.doi.org/10.1289/ehp.1307154     

Sudden Visual Deterioration as the First Symptom of Chronic Kidney Failure

Purpose

We report here a unique case of a sudden loss of vision as the first symptom of an advanced chronic nephropathy.

Methods and Results

A 25-year-old man was referred to the Department of Ophthalmology with sudden visual deterioration presumptively diagnosed as bilateral retinitis. The patient had never been under any medical care before and had never had any clinical signs of any chronic disease. He underwent an ophthalmic examination with optical coherence tomography (OCT). Based on the clinical features, OCT scans and systemic blood pressure (BP) assessment (225/145 mm Hg), the patient was definitely diagnosed with hypertensive retinopathy and choroidopathy due to hypertensive crisis. After urgent diagnostic procedures, the patient was diagnosed with a chronic kidney disease at stage 5 in the course of chronic glomerulonephritis. Immediately, a renal replacement therapy was started and the patient was qualified for renal transplantation.

Conclusion

Adolescents with an unclear picture of retinal lesions, who have neither a history nor clinical signs of a systemic disease, should undergo careful systemic screening with BP assessment. A sudden deterioration of vision may be the first symptom of a previously undiagnosed severe systemic disease (very rare chronic) that requires immediate treatment.Key Words: Hypertensive crisis, Hypertensive choroidopathy, Hypertensive retinopathy, Chronic renal failure     

Comparison of Abdominal Visceral Adipose Tissue Area Measured by Computed Tomography with That Estimated by Bioelectrical Impedance Analysis Method in Korean Subjects

We evaluated the concordance between visceral fat area (VFA) estimated by bioelectrical impedance analysis (BIA) or computed tomography (CT) in Korean subjects with a wide range in age and body mass index (BMI). In 1006 individuals (mean age 55.2 ± 11.8 (19–87) years, mean BMI 26.0 ± 3.5 (17–46) kg/m², 48.9% men), VFA quantified by CT was compared with VFA using multifrequency BIA machines within 15 days. Concordance rates were compared by age or BMI using correlation analysis, Bland-Altman plots, and intraclass correlation coefficient (ICC). Using BIA data, we established a regression formula to reflect CT-VFA. The mean VFAs by CT and BIA were 131.9 ± 57.3 cm² and 110.5 ± 33.9 cm², respectively (r = 0.605, p < 0.001). The mean difference was 21.4 ± 45.6 cm², tending to increase with BMI. In women with BMI <25 kg/m² or age <50 years, the VFAs by BIA were similar to those by CT (ICC = 0.496 in BMI <25 kg/m² and ICC = 0.638 in age <50 years). However, the difference was greater in men with BMI ≥25 kg/m² or age ≥50 years. Applying our formula, the difference between estimations decreased to 0.2 ± 38.2cm². VFA estimated by BIA correlated well with that by CT, but a more accurate formula is needed to match CT data, particularly in older men or subjects with a high BMI.     

Effect of VIPS fabrication parameters on the removal of acetic acid by supported liquid membrane using a PES–graphene membrane support

In this study, the removal of acetic acid by supported liquid membrane (SLM) using hybrid polyethersulfone (PES)–graphene membrane prepared by vapor induced phase separation (VIPS) was investigated. The effects of graphene loading, coagulation bath temperature, air exposure time, and air humidity on the morphology, mechanical strength, porosity, and contact angle of the membrane were analyzed. The performance and stability of the hybrid membrane as a SLM support for acetic acid removal were studied. The best PES–graphene membrane support was produced at a coagulation bath temperature of 50 °C, an air exposure time of 30 s and air humidity of 80%. The fabricated membrane has a symmetrical micropore cellular structure, high porosity and high contact angle. Under specific SLM conditions, almost 95% of acetic acid was successfully removed from 10 g L⁻¹ aqueous acetic acid solution. The hybrid membrane remains stable for more than 116 h without suffering any membrane breakage during the continuous SLM process.

In this study, the removal of acetic acid by supported liquid membrane (SLM) using hybrid polyethersulfone (PES)–graphene membrane prepared by vapor induced phase separation (VIPS) was investigated.     

Canavanine induces insulin release via activation of imidazoline I3 receptors

The aim of the present study was to identify the effect of canavanine on the imidazoline receptor because canavanine is a guanidinium derivative that has a similar structure to imidazoline receptor ligands. Transfected Chinese hamster ovary‐K1 cells expressing imidazoline receptors (nischarin (NISCH)‐CHO‐K1 cells) were used to elucidate the direct effects of canavanine on imidazoline receptors. In addition, the imidazoline I₃ receptor has been implicated in stimulation of insulin secretion from pancreatic β‐cells. Wistar rats were used to investigate the effects of canavanine (0.1, 1 and 2.5 mg/kg, i.v.) on insulin secretion. In addition the a specific I₃ receptor antagonist KU14R (4 or 8 mg/kg, i.v.) was used to block I₃ receptors. Canavanine decreased blood glucose by increasing plasma insulin in rats. In addition, canavanine increased calcium influx into NISCH‐CHO‐K1 cells in a manner similar to agmatine, the endogenous ligand of imidazoline receptors. Moreover, KU12R dose‐dependently attenuated canavanine‐induced insulin secretion in HIT‐T15 pancreatic β‐cells and in the plasma of rats. The data suggest that canavanine is an agonist of I₃ receptors both in vivo and in vitro. Thus, canavanine would be a useful tool in imidazoline receptor research.     

Diastereoselective synthesis of novel spiro indanone fused pyrano[3,2-c]chromene derivatives following hetero-Diels–Alder reaction and in vitro anticancer studies

The development of concise methods for the synthesis of small functionalised spirocyclic molecules is important in the search of new bioactive molecules. To contribute this, here we represent a diastereoselective oxa-hetero-Diels–Alder reaction for the synthesis of novel spiro indanone fused pyrano[3,2-c]chromene derivatives and studied their in vitro anticancer activities. Using previously less explored cyclic ketone i.e. indane-1,3-dione and 3-vinyl-2H-chromene derivatives, we obtained novel spiro-heterocyclic frameworks at the interphase between “drug-like” molecules and natural products. Various spiro indanone fused pyrano[3,2-c]chromene derivatives were synthesized regiospecifically bearing a quaternary stereocenter in high yields (up to 85%) with excellent diastereoselectivity in toluene using 4 Å MS as additive under reflux condition at 120 °C. In vitro cytotoxic studies of these compounds against MCF-7 (breast cancer), HCT-116 (colon cancer), H-357 (oral cancer), MD-MB-231(Breast cancer) cell lines were evaluated by MTT {3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide} assay in vitro. The screening results revealed that many of the compounds are showing moderate to high levels of anticancer activities against the tested cancer cell lines and some displayed potent inhibitory activities in comparison to the commercial anticancer drug 5-fluorouracil (5-FU). Among the series, compound 3′c showed most potent cytotoxicity (15.0–27.5 μM) in three cancer cell lines (MCF-7, HCT-116 and MD-MB-231).

Synthesis of novel spiro indanone fused pyrano[3,2-c]chromene derivatives following hetero-Diels–Alder reaction has been demonstrated and evaluated for their in vitro anticancer activity.     

Evaluation of angiogenesis, p-53 tissue protein expression and serum VEGF in patients with endometrial cancer

Endometrial carcinoma occurs mostly in post-menopausal women. Classical methods of prognostication, as FIGO stage and histopathologic grade, could be improved by applying additional techniques, utilizing molecular biology and immunochemistry. p-53 tumor suppressor gene, the most commonly mutated gene in human cancers has been shown to play an important role in the biology of gynecologic carcinomas. Angiogenesis, a process of formation of new vessels, being connected to tumors progression and metastatic potential was shown to be linked with tumor suppressor genes expression. The aim of the study was to evaluate relationships between intensity of tumor angiogenesis, serum levels of Vascular Endothelial Growth Factor (VEGF) and tissue p-53 protein expression in endometrial adenocarcinoma. Angiogenic Point's Density (APD) was calculated in hot spots areas using the morphometric appliance. For detection of p53 protein in tumor samples, LSAB + Kit Alkaline Phosphatase (DAKO) was used. VEGF levels were assessed in patient's blood sampled before the operation. Overexpression of p53 protein was found in tumor tissue in 35.2% of cases and mean angiogenic points density was greater in p53 positive cases. Serum levels of VEGF were above the cut off level in 54.5% of patients, in those cases angiogenesis was also elevated. In cases of p53 overexpression, VEGF levels tended to be greater as compared with p53 negative cases. In conclusion, our study demonstrated that angiogenesis was more intensive in p53 positive cases, confirming the hypothesis of tumor suppressor-gene regulation of the process of neovascularization. Serum levels of VEGF were borderline-significantly higher in cases of p53 overexpression, they were also correlated to the angiogenesis. Joint assessment of angiogenesis and tumor suppressor genes expression may contribute to reliable evaluation of the biology of endometrial carcinoma.