Case numbers for a randomized clinical trial of boron neutron capture therapy for Glioblastoma multiforme

Boron neutron capture therapy (BNCT) with Na₂B₁₂H₁₁SH (BSH) or p-dihydroxyborylphenylalanine (BPA), and with a combination of both, was compared to radiotherapy with temozolomide, and the number of patients required to show statistically significant differences between the treatments was calculated. Whereas arms using BPA require excessive number of patients in each arm, a two-armed clinical trial with BSH and radiotherapy plus temozolomide is feasible.     

CLARITY‐BPA academic laboratory studies identify consistent low‐dose Bisphenol A effects on multiple organ systems

Bisphenol A (BPA) is a high‐production chemical used in a variety of applications worldwide. While BPA has been documented as an endocrine‐disrupting chemical (EDC) having adverse health‐related outcomes in multiple studies, risk assessment for BPA has lagged due to reliance on guideline toxicology studies over academic ones with end‐points considered more sensitive and appropriate. To address current controversies on BPA safety, the United States National Institute of Environmental Health Sciences (NIEHS), the National Toxicology Program (NTP) and the Food and Drug Administration (FDA) established the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY‐BPA) using the NCTR Sprague‐Dawley rats. The goal of CLARITY‐BPA is to perform a traditional regulatory toxicology study (Core study) in conjunction with multiple behavioural, molecular and cellular studies by academic laboratories focused on previously identified BPA‐sensitive organ systems (Academic studies). Combined analysis of the data from both study types will be undertaken by the NTP with the aim of resolving uncertainties on BPA toxicity. To date, the Core study has been completed and a draft report released. Most of the academic studies have also been finalized and published in peer‐reviewed journals. In light of this important milestone, the PPTOX‐VI meeting held in the Faroe Islands, 27‐30 May 2018 devoted a plenary session to CLARITY‐BPA with presentations by multiple investigators with the purpose of highlighting key outcome. This MiniReview synthesizes the results of three academic studies presented at this plenary session, evaluates recently published findings by other CLARITY‐BPA academic studies to provide an early combined overview of this emerging data and places this in the context of the Core study findings. This co‐ordinated effort revealed a plethora of significant BPA effects across multiple organ systems and BPA doses with non‐monotonic responses across the dose range utilized. Remarkably consistent across most studies, including the Core study, are low‐dose effects (2.5, 25 and 250 μg BPA/kg body‐weight). Collectively, the findings highlighted herein corroborate a significant body of evidence that documents adverse effects of BPA at doses relevant to human exposures and emphasizes the need for updated risk assessment analysis.     

Thyroid effects of endocrine disrupting chemicals

In recent years, many studies of thyroid-disrupting effects of environmental chemicals have been published. Of special concern is the exposure of pregnant women and infants, as thyroid disruption of the developing organism may have deleterious effects on neurological outcome. Chemicals may exert thyroid effects through a variety of mechanisms of action, and some animal experiments and in vitro studies have focused on elucidating the mode of action of specific chemical compounds. Long-term human studies on effects of environmental chemicals on thyroid related outcomes such as growth and development are still lacking. The human exposure scenario with life long exposure to a vast mixture of chemicals in low doses and the large physiological variation in thyroid hormone levels between individuals render human studies very difficult. However, there is now reasonably firm evidence that PCBs have thyroid-disrupting effects, and there is emerging evidence that also phthalates, bisphenol A, brominated flame retardants and perfluorinated chemicals may have thyroid disrupting properties.     

Acute and chronic toxic effects of bisphenol a on Chlorella pyrenoidosa and Scenedesmus obliquus

The acute and chronic toxic effects of Bisphenol A (BPA) on Chlorella pyrenoidosa (C. pyrenoidosa) and Scenedesmus obliquus (S. obliquus) were not well understood. The indoor experiments were carried out to observe and analyze the BPA‐induced changes. Results of the observations showed that in acute tests BPA could significantly inhibit the growth of both algae, whereas chronic exposure hardly displayed similar trend. Superoxide dismutase (SOD) and Catalase (CAT) activities of both algae were promoted in all the treatments. Chlorophyll a synthesis of the two algae exhibited similar inhibitory trend in short‐term treatments, and in chronic tests C. pyrenoidosa hardly resulted in visible influence, whereas in contrast, dose‐dependent inhibitory effects of S. obliquus could be clearly observed. The experimental results indicated that the growth and Chlorophyll a syntheses of S.obliquus were more sensitive in response to BPA than that of C. pyrenoidosa, whereas for SOD andCAT activities, C. pyrenoidosa was more susceptible. This research provides a basic understanding of BPA toxicity to aquatic organisms. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 714–722, 2014.     

Effect of cimetidine on burst-promoting activity of normal T lymphocytes

Summary The effect of cimetidine, an inhibitor of suppressor T lymphocytes, on the burst-promiting activity (BPA) of normal T lymphocytes has been studied. Cimetidine has been shown to increase the BPA of normal T lymphocytes, both when added to the culture and when T lymphocytes were preincubated for 1 h with it. Cimetidine had no direct effect on the in vitro growth of burstforming units (BFU-E). Our results show that CD 8 suppressor T lymphocytes inhibit the in vitro growth of BFU-E in normal conditions, either directly or through inhibition of BPA of CD 4 helper T lymphocytes. Cimetidine has proved to be a useful tool for investigating the hematological role of T-lymphocyte subsets in normal and pathological conditions.This work was supported by a grant of theMinistem delta Ricerca Scientifica e Tecnologica, Italy     

Fas凋亡相关基因在双酚A诱导成年雄性大鼠生殖毒性中的作用

目的探讨Fas凋亡途径相关基因在双酚A（BPA）诱导成年雄性大鼠生殖毒性中的作用。方法 40只成年Wistar雄性大鼠随机等分为4组：溶媒对照组（玉米油）和低、中、高剂量BPA喂养组（10、50、250μg/kg·bw/d）。大鼠在喂养35周后处死,称量睾丸、附睾、肝、肾及心脏重量并计算脏器系数;观察精子形态及计算精子畸形率。采用荧光实时定量PCR（RT-PCR）测定睾丸组织中自杀相关因子（Fas/Fas-L）、天冬氨酸特异酶切的半胱氨酸蛋白酶3（Caspase-3）mRNA含量。结果高剂量BPA喂养大鼠精子畸形率以及睾丸组织中Fas-L mRNA及Caspase-3 mRNA含量高于对照组,差异均有显著性（P!0.05）。结论在BPA的人体每日容许摄入量水平下（TDI=50μg/kg·bw/d）,未观察到生殖细胞损伤的效应;但长期经膳食暴露高剂量BPA（250μg/kg·bw/d）可致成年雄性大鼠生殖细胞损伤,其机制可能与BPA上调Fas-L mRNA和Caspase-3的表达有关。     

A comparative study on the effects of alpha-hexachlorocyclohexane and its metabolite beta-pentachlorocyclohexene on growth and monooxygenase activities in rat liver

The present study adds support to the hypothesis that β-pentachlorocyclohexene (β-PCH) is a primary intermediate in α-hexachlorocyclohexane (α-HCH)4 metabolism in the rat. Degradation of α-HCH to β-PCH was shown to occur in vitro and in vivo, partially by non-enzymic catalysis. β-PCH accumulated in liver and adipose tissue of α-HCH treated rats, which had received the glutathione-lowering agent diethyl maleate. β-PCH disappears from the body much more rapidly than the parent compound α-HCH: about 50 per cent of a single i.p. dose were degraded within 2.5 hr, while half-life of α-HCH is known to be approximately 130 hr. To maintain equimolar liver concentrations, β-PCH must be given in doses 100-fold higher than α-HCH. β-PCH and α-HCH were fed for a period of ten days at various dose levels to give steady-state liver concentrations. It was found that β-PCH has similar hepatic effects to α-HCH: both agents induced liver growth and a phenobarbital-type pattern of monooxygenase activities, as measured by the following substrates: aminopyrine, ethylmorphine, benzphetamine, 4-nitroanisole, aniline, benzo[α]pyrene, ethoxyresorufin and 2,5-diphenyl-oxazole. Threshold doses for these effects were 30–43 μmoles/kg/day for β-PCH and 1.0–1.7 μmoles/kg/day for α-HCH. However, on the basis of molar hepatic concentrations β-PCH was a more potent inducer than α-HCH (2–10 times). Threshold concentrations ranged from 0.4 to 0.6 nmoles β-PCH/g liver and from 0.7 to 1.5 nmoles α-HCH/g liver. β-PCH concentrations in livers of rats treated even with high doses of α-HCH were below the threshold for induction of liver growth and of monooxygenase increases. It is, therefore, highly unlikely that β-PCH is responsible for the effect of α-HCH on rat livers.     

Developmental toxicity of estrogenic chemicals on rodents and other species

ABSTRACT  Antenatal sex-hormone exposure induces lesions in mouse reproductive organs, which are similar to those in humans exposed in utero to a synthetic estrogen, diethylstilbestrol. The developing organisms including rodents, fish and amphibians are particularly sensitive to exposure to estrogenic chemicals during a critical window. Exposure to estrogens during the critical period induces long-term changes in reproductive as well as non-reproductive organs, including persistent molecular alterations. The antenatal mouse model can be utilized as an indicator of possible long-term consequences of exposure to exogenous estrogenic compounds including possible environmental endocrine disrupters. Many chemicals released into the environment potentially disrupt the endocrine system in wildlife and humans, some of which exhibit estrogenic activity by binding to the estrogen receptors. Estrogen responsive genes, therefore, need to be identified to understand the molecular basis of estrogenic actions. In order to understand molecular mechanisms of estrogenic chemicals on developing organisms, we are identifying estrogen responsive genes using cDNA microarray, quantitative RT-PCR, and differential display methods, and genes related to the estrogen-independent vaginal changes in mice induced by estrogens during the critical window. In this review, discussion of our own findings related to endocrine distuptor issue will be provided.     

Correlation of 18F-BPA and 18F-FDG uptake in head and neck cancers

Background and purposeThe aim of this study was to compare the accumulation of 4-borono-2-¹⁸F-fluoro-phenylalanine (¹⁸F-BPA) with that of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) in head and neck cancers, and to assess the usefulness of ¹⁸F-FDG PET for screening candidates for boron neutron capture therapy (BNCT).Material and methodsTwenty patients with pathologically proven malignant tumors of the head and neck were recruited from March 2012 to January 2014. All patients underwent both whole-body ¹⁸F-BPA PET/CT and ¹⁸F-FDG PET/CT within 2 weeks of each other. The uptakes of ¹⁸F-BPA and ¹⁸F-FDG at 1 h after injection were evaluated using the maximum standardized uptake value (SUVmax).ResultsThe accumulation of ¹⁸F-FDG was significantly correlated with that of ¹⁸F-BPA. The SUVmax of ¹⁸F-FDG ⩾5.0 is considered to be suggestive of high ¹⁸F-BPA accumulation.Conclusions¹⁸F-FDG PET might be an effective screening method performed prior to ¹⁸F-BPA for selecting patients with head and neck cancer for treatment with BNCT.