Chemical carcinogenicity revisited 3: Risk assessment of carcinogenic potential based on the current state of knowledge of carcinogenesis in humans

Abstract Over 50 years, we have learned a great deal about the biology that underpins cancer but our approach to testing chemicals for carcinogenic potential has not kept up. Only a small number of chemicals has been tested in animal-intensive, time consuming, and expensive long-term bioassays in rodents. We now recommend a transition from the bioassay to a decision-tree matrix that can be applied to a broader range of chemicals, with better predictivity, based on the premise that cancer is the consequence of DNA coding errors that arise either directly from mutagenic events or indirectly from sustained cell proliferation. The first step is in silico and in vitro assessment for mutagenic (DNA reactive) activity. If mutagenic, it is assumed to be carcinogenic unless evidence indicates otherwise. If the chemical does not show mutagenic potential, the next step is assessment of potential human exposure compared to the threshold for toxicological concern (TTC). If potential human exposure exceeds the TTC, then testing is done to look for effects associated with the key characteristics that are precursors to the carcinogenic process, such as increased cell proliferation, immunosuppression, or significant estrogenic activity. Protection of human health is achieved by limiting exposures to below NOEALs for these precursor effects. The decision tree matrix is animal-sparing, cost effective, and in step with our growing knowledge of the process of cancer formation

Chemical carcinogenicity revisited 1: A unified theory of carcinogenicity based on contemporary knowledge

Abstract Developments in the understanding of the etiology of cancer have profound implications for the way the carcinogenicity of chemicals is addressed. This paper proposes a unified theory of carcinogenesis that will illuminate better ways to evaluate and regulate chemicals. In the last four decades, we have come to understand that for a cell and a group of cells to begin the process of unrestrained growth that is defined as cancer, there must be changes in DNA that reprogram the cell from normal to abnormal. Cancer is the consequence of DNA coding errors that arise either directly from mutagenic events or indirectly from cell proliferation especially if sustained. Chemicals that act via direct interaction with DNA can induce cancer because they cause mutations which can be carried forward in dividing cells. Chemicals that act via non-genotoxic mechanisms must be dosed to maintain a proliferative environment so that the steps toward neoplasia have time to occur. Chemicals that induce increased cellular proliferation can be divided into two categories: those which act by a cellular receptor to induce cellular proliferation, and those which act via non-specific mechanisms such as cytotoxicity. This knowledge has implications for testing chemicals for carcinogenic potential and risk management

Oncological outcomes in an Australian cohort according to the new prostate cancer grading groupings

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: A new 5-tiered grading grouping system has recently been endorsed for reporting of prostate cancer (PCa) grade to better reflect escalating risk of progression and cancer death. While several validations of the new grade groupings have been undertaken, most have involved centralised pathological review by specialist urological pathologists. Methods: Participants included 4268 men with non-metastatic PCa diagnosed between 2006 and 2013 from the multi-institutional South Australia Prostate Cancer Clinical Outcomes Collaborative registry. PCa-specific survival and biochemical recurrence-free survival were compared across the five grade groups using multivariable competing risk regression. Results: For the entire cohort, risk of PCa death increased with increasing grade groups (at biopsy) Adjusted subdistribution-hazard ratios [sHR] and 95% confidence intervals [95%CI] were: 2.2 (1.5–3.6); 2.5 (1.6–4.2); 4.1 (2.6–6.7) and 8.7 (4.5–14.0) for grade groups II (pattern 3 + 4), III (pattern 4 + 3), IV (total score 8) and V (total score 9–10) respectively, relative to grade group I (total score < =6). Clear gradients in risk of PCa death were observed for radical prostatectomy (RP), but were less clear for those who had radiotherapy (RT) with curative intent and those who were managed conservatively. Likewise, risk of biochemical recurrence increased across grade groups, with a strong and clear gradient for men undergoing RP [sHR (95%CI): 2.0 (1.4–2.8); 3.8 (2.9–5.9); 5.3 (3.5–8.0); 11.2 (6.5–19.2) for grade groups II, III, IV and V respectively, relative to grade group I], and a less clear gradient for men undergoing RT. Conclusion: In general, the new five-tiered grade groupings distinguished PCa survival and recurrence outcomes for men with PCa. The absence of a clear gradient for RT may be due to heterogeneity in this patient group

Cutaneous hypersensitivity reactions to freshwater cyanobacteria – human volunteer studies

BACKGROUND: Pruritic skin rashes associated with exposure to freshwater cyanobacteria are infrequently reported in the medical and scientific literature, mostly as anecdotal and case reports. Diagnostic dermatological investigations in humans are also infrequently described. We sought to conduct a pilot volunteer study to explore the potential for cyanobacteria to elicit hypersensitivity reactions. METHODS: A consecutive series of adult patients presenting for diagnostic skin patch testing at a hospital outpatient clinic were invited to participate. A convenience sample of volunteers matched for age and sex was also enrolled. Patches containing aqueous suspensions of various cyanobacteria at three concentrations were applied for 48 hours; dermatological assessment was made 48 hours and 96 hours after application. RESULTS: 20 outpatients and 19 reference subjects were recruited into the study. A single outpatient produced unequivocal reactions to several cyanobacteria suspensions; this subject was also the only one of the outpatient group with a diagnosis of atopic dermatitis. No subjects in the reference group developed clinically detectable skin reactions to cyanobacteria. CONCLUSION: This preliminary clinical study demonstrates that hypersensitivity reactions to cyanobacteria appear to be infrequent in both the general and dermatological outpatient populations. As cyanobacteria are widely distributed in aquatic environments, a better appreciation of risk factors, particularly with respect to allergic predisposition, may help to refine health advice given to people engaging in recreational activities where nuisance cyanobacteria are a problem

Low-grade oligodendroglioma of the pineal gland: a case report and review of the literature

<p>Abstract</p> <p>Background</p> <p>Gliomas are a very rare subtype of pineal region tumours, whereas oligodendrogliomas of the pineal region are exceedingly rare, since there have been only 3 cases of anaplastic oligodedrogliomas reported this far.</p> <p>Methods-Results</p> <p>We present a case of a low-grade oligodendroglioma arising in the pineal gland of a 37 year-old woman. The patient presented with diplopia associated with a cystic pineal region mass demonstrated on MRI. Total resection was performed and histological examination showed that the cystic wall consisted of tumour cells with a central nucleus a perinuclear halo and minimal pleomorphism. Immnunohistochemical analysis showed that these cells were diffusely positive for CD57, and negative for GFAP, CD10, CD99, cytokeratins, neurofilaments and synaptophysin. FISH analysis was performed in a small number of neoplastic cells, which were not exhausted after immunohistochemistry and did not reveal deletion of 1p and 19q chromosome arms. However, the diagnosis of a low grade oligodendroglioma of the pineal gland was assigned.</p> <p>Conclusion</p> <p>Although the spectrum of tumours arising in the pineal gland is broad, the reports of oligodendrogliomas confined to this location are exceedingly rare, and to the best of our knowledge there is no report of a low-grade oligodendroglioma. However, they should be added in the long list of tumours arising in the pineal gland.</p

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Leads in Arctic pack ice enable early phytoplankton blooms below snow-covered sea ice

© The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Scientific Reports 7 (2017): 40850, doi:10.1038/srep40850.The Arctic icescape is rapidly transforming from a thicker multiyear ice cover to a thinner and largely seasonal first-year ice cover with significant consequences for Arctic primary production. One critical challenge is to understand how productivity will change within the next decades. Recent studies have reported extensive phytoplankton blooms beneath ponded sea ice during summer, indicating that satellite-based Arctic annual primary production estimates may be significantly underestimated. Here we present a unique time-series of a phytoplankton spring bloom observed beneath snow-covered Arctic pack ice. The bloom, dominated by the haptophyte algae Phaeocystis pouchetii, caused near depletion of the surface nitrate inventory and a decline in dissolved inorganic carbon by 16 ± 6 g C m−2. Ocean circulation characteristics in the area indicated that the bloom developed in situ despite the snow-covered sea ice. Leads in the dynamic ice cover provided added sunlight necessary to initiate and sustain the bloom. Phytoplankton blooms beneath snow-covered ice might become more common and widespread in the future Arctic Ocean with frequent lead formation due to thinner and more dynamic sea ice despite projected increases in high-Arctic snowfall. This could alter productivity, marine food webs and carbon sequestration in the Arctic Ocean.This study was supported by the Centre for Ice, Climate and Ecosystems (ICE) at the Norwegian Polar Institute, the Ministry of Climate and Environment, Norway, the Research Council of Norway (projects Boom or Bust no. 244646, STASIS no. 221961, CORESAT no. 222681, CIRFA no. 237906 and AMOS CeO no. 223254), and the Ministry of Foreign Affairs, Norway (project ID Arctic), the ICE-ARC program of the European Union 7th Framework Program (grant number 603887), the Polish-Norwegian Research Program operated by the National Centre for Research and Development under the Norwegian Financial Mechanism 2009–2014 in the frame of Project Contract Pol-Nor/197511/40/2013, CDOM-HEAT, and the Ocean Acidification Flagship program within the FRAM- High North Research Centre for Climate and the Environment, Norway

Leads in Arctic pack ice enable early phytoplankton blooms below snow-covered sea ic

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Accuracy of Urine Circulating Cathodic Antigen (CCA) Test for Schistosoma mansoni Diagnosis in Different Settings of Côte d'Ivoire

We aimed to assess the accuracy of a commercially available rapid diagnostic test for the detection of an infection with the blood fluke Schistosoma mansoni in urine. In total, 446 school children from three different settings of south Côte d'Ivoire provided three stool and three urine samples. Stool samples were examined with the widely used Kato-Katz technique and analyzed with a microscope for S. mansoni eggs. Urine samples were examined with a filtration method for S. haematobium eggs and with a rapid diagnostic test for S. mansoni that is based on detecting circulating cathodic antigens (CCA). We used a commercially available test (designated CCA-A) and an experimental formulation (CCA-B). Examination of nine Kato-Katz thick smears per child revealed a prevalence of S. mansoni in the three settings of 32.9%, 53.1%, and 91.8%. The sensitivity of triplicate Kato-Katz from the first stool sample was comparable to a single CCA-A (47.9–94.2% vs. 56.3–89.6%), and significantly higher than the sensitivity of a single CCA-B test (10.4–75.0%). CCA-A showed a considerably lower specificity than CCA-B (76.9–84.2% vs. 96.7–100%). In the settings studied in south Côte d'Ivoire, the CCA-A test holds promise for the diagnosis of S. mansoni, whereas results with CCA-B were suboptimal

Spatial risk profiling of Plasmodium falciparum parasitaemia in a high endemicity area in Côte d'Ivoire

Background. The objective of this study was to identify demographic, environmental and socioeconomic risk factors and spatial patterns of Plasmodium falciparum parasitaemia in a high endemicity area of Africa, and to specify how this information can facilitate improved malaria control at the district level. Methods. A questionnaire was administered to about 4,000 schoolchildren in 55 schools in western Ĉte d'Ivoire to determine children's socioeconomic status and their habit of sleeping under bed nets. Environmental data were obtained from satellite images, digitized ground maps and a second questionnaire addressed to school directors. Finger prick blood samples were collected and P. falciparum parasitaemia determined under a microscope using standardized, quality-controlled methods. Bayesian variogram models were utilized for spatial risk modelling and mapping of P. falciparum parasitaemia at non-sampled locations, assuming stationary and non-stationary underlying spatial dependence. Results. Two-thirds of the schoolchildren were infected with P. falciparum and the mean parasitaemia among infected children was 959 parasites/μl of blood. Age, socioeconomic status, not sleeping under a bed net, coverage rate with bed nets and environmental factors (e.g., normalized difference vegetation index, rainfall, land surface temperature and living in close proximity to standing water) were significantly associated with the risk of P. falciparum parasitaemia. After accounting for spatial correlation, age, bed net coverage, rainfall during the main malaria transmission season and distance to rivers remained significant covariates. Conclusion. It is argued that a massive increase in bed net coverage, particularly in villages in close proximity to rivers, in concert with other control measures, is necessary to bring malaria endemicity down to intermediate or low levels