Country profile: Australia, New South Wales. From validation to implementation: Progressing tobacco smoking cessation among people with cancer and beyond via relevant authorities.

This paper delineates how a program of tobacco smoking cessation after a cancer diagnosis was achieved by engagement of multiple stakeholders, government, and non-government authorities in one jurisdiction in Australia, New South Wales. While it had become increasingly obvious that smoking cessation imparts benefits akin to other known treatment modalities, knowledge of this generalisation is without benefit unless this information is delivered in a trusted context and means to quit are made available. Against a backdrop of little enthusiasm among clinicians, the Cancer Institute NSW, charged with implementing tobacco control strategies, decided to focus its 2017 annual colloquium on the topic. While the evidence was unequivocal, better clarity was needed that this was indeed a clinical responsibility, and on the resources needed. The Clinical Oncology Society of Australia, (COSA) a non-governmental peak national body representing cancer care professionals, addressed this challenge. The society's governing body resolved to develop a position statement indicating how smoking cessation might be integrated within hospital-based cancer care. The position statement, endorsed by nineteen other cancer and non-cancer organisations, provided reassurance to the Institute to improve record capture of hospital smoking information; upskill all clinical staff and develop an automatic "patient opt out" referral to existing resources such as the Quitline. Early pilot work shows that people newly diagnosed with cancer who smoke and who were advised at that time to quit increased from 55% in 2016 to 72% in 2019.

Withdrawn: Variations in Altered Global Gene Expression caused by Topoisomerase II Poisons Assessed with Reference to Differences in DNA Binding

The article has been withdrawn at the request of the authors of the journal Current Molecular Pharmacology.Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused.The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php. BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Consumption of red and processed meat and breast cancer incidence: A systematic review and meta-analysis of prospective studies.

Prior studies on red and processed meat consumption with breast cancer risk have generated inconsistent results. We performed a systematic review and meta-analysis of prospective studies to summarize the evidence regarding the relation of red meat and processed meat consumption with breast cancer incidence. We searched in MEDLINE and EMBASE databases through January 2018 for prospective studies that reported the association between red meat and processed meat consumption with incident breast cancer. The multivariable-adjusted relative risk (RR) was combined comparing the highest with the lowest category of red meat (unprocessed) and processed meat consumption using a random-effect meta-analysis. We identified 13 cohort, 3 nested case-control and two clinical trial studies. Comparing the highest to the lowest category, red meat (unprocessed) consumption was associated with a 6% higher breast cancer risk (pooled RR,1.06; 95% confidence intervals (95%CI):0.99-1.14; I2 = 56.3%), and processed meat consumption was associated with a 9% higher breast cancer risk (pooled RR, 1.09; 95%CI, 1.03-1.16; I2 = 44.4%). In addition, we identified two nested case-control studies evaluating the association between red meat and breast cancer stratified by N-acetyltransferase 2 acetylator genotype. We did not observe any association among those with either fast (per 25 g/day pooled odds ratio (OR), 1.18; 95%CI, 0.93-1.50) or slow N-acetyltransferase 2 acetylators (per 25 g/day pooled OR, 0.99; 95%CI, 0.91-1.08). In the prospective observational studies, high processed meat consumption was associated with increased breast cancer risk.

Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis.

BACKGROUND: A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the > 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts A-F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens. OBJECTIVES AND METHODS: IARC therefore convened two workshops in which an international Working Group of experts identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens. DISCUSSION: These characteristics provide the basis for an objective approach to identifying and organizing results from pertinent mechanistic studies. The 10 characteristics are the abilities of an agent to 1) act as an electrophile either directly or after metabolic activation; 2) be genotoxic; 3) alter DNA repair or cause genomic instability; 4) induce epigenetic alterations; 5) induce oxidative stress; 6) induce chronic inflammation; 7) be immunosuppressive; 8) modulate receptor-mediated effects; 9) cause immortalization; and 10) alter cell proliferation, cell death, or nutrient supply. CONCLUSION: We describe the use of the 10 key characteristics to conduct a systematic literature search focused on relevant end points and construct a graphical representation of the identified mechanistic information. Next, we use benzene and polychlorinated biphenyls as examples to illustrate how this approach may work in practice. The approach described is similar in many respects to those currently being implemented by the U.S. EPA's Integrated Risk Information System Program and the U.S. National Toxicology Program. CITATION: Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert P, Hecht SS, Bucher JR, Stewart BW, Baan R, Cogliano VJ, Straif K. 2016. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124:713-721; http://dx.doi.org/10.1289/ehp.1509912.

Cancer prevention as part of precision medicine: 'plenty to be done'.

Cancer burden worldwide is projected to rise from 14 million new cases in 2012 to 24 million in 2035. Although the greatest increases will be in developing countries, where cancer services are already hard pressed, even the richest nations will struggle to meet demands of increasing patient numbers and spiralling treatment costs. No country can treat its way out of the cancer problem. Consequently, cancer control must combine improvements in treatment with greater emphasis on prevention and early detection. Cancer prevention is founded on describing the burden of cancer, identifying the causes and evaluating and implementing preventive interventions. Around 40-50% of cancers could be prevented if current knowledge about risk factors was translated into effective public health strategies. The benefits of prevention are attested to by major successes, for example, in tobacco control, vaccination against oncogenic viruses, reduced exposure to environmental and occupational carcinogens, and screening. Progress is still needed in areas such as weight control and physical activity. Fresh impetus for prevention and early detection will come through interdisciplinary approaches, encompassing knowledge and tools from advances in cancer biology. Examples include mutation profiles giving clues about aetiology and biomarkers for early detection, to stratify individuals for screening or for prognosis. However, cancer prevention requires a broad perspective stretching from the submicroscopic to the macropolitical, recognizing the importance of molecular profiling and multisectoral engagement across urban planning, transport, environment, agriculture, economics, etc., and applying interventions that may just as easily rely on a legislative measure as on a molecule.

Priorities for cancer prevention: lifestyle choices versus unavoidable exposures.

Although cancer prevention in the USA and other developed countries focuses on disease attributable to lifestyle factors such as smoking, alcohol intake, sun exposure, and obesity, cancer caused by involuntary exposures is a concern. The term environmental is ambiguously used to distinguish between lifestyle and unavoidable exposures. The general community is said to be vulnerable to carcinogens encountered in pollution, contaminated food, and consumer products. In view of these concerns, assessments of the carcinogenicity of particular chemicals are of little assistance in prevention of cancer. Appraisal of cancer attributable to widespread and localised pollution, pesticides, endocrine disrupting chemicals, and consumer products yields diverse outcomes, from established causation to absence of harm. The precautionary principle is not a practicable approach for unknown carcinogenic risks. Procedures for individuals to reduce exposure to recognised or suspect carcinogens in consumer products are not effective measures for cancer prevention. Anxiety concerning insidious cancer causation could divert attention from proven means of cancer prevention.

What factors do cancer patients believe contribute to the development of their cancer? (New South Wales, Australia).

OBJECTIVE: To analyze Australian cancer patients' beliefs about factors contributing to the development of their cancer. METHODS: As part of a case-control study (The Cancer Council NSW Cancer, Lifestyle and Evaluation of Risk Study), a total of 2,857 cancer patients (open to all types of cancer) were surveyed and via an open-ended question, were asked to specify factors they think contributed to the development of their cancer. Qualitative analysis and categorical techniques were used to analyze the data. RESULTS: About half, 53%, of patients specified at least one contributing factor. The odds of a person specifying a contributing factor increased with time period since diagnosis (p = 0.0006). Patients most frequently specified, respectively: "Stress" (15.4%), "Genetics/hereditary" (10.9%) and "Smoking" (6.2%). Among factors specified the largest proportion (24.1%) was perceived to be "Non-modifiable." CONCLUSION: Cancer patients specified a broad range of factors and agents to which their disease may be attributed. Some of these were poorly correlated with epidemiological rankings of attributable risk factors. The role of psychosocial and genetic factors was overstated. Misconceptions regarding the causes of cancer are a key consideration of health professionals when devising communication strategies around cancer prevention.

Intracellular trafficking as a determinant of AS-DACA cytotoxicity in rhabdomyosarcoma cells.

BACKGROUND: Rhabdomyosarcoma (RMS) is a malignant soft tissue sarcoma derived from skeletal muscle precursor cells, which accounts for 5-8% of all childhood malignancies. Disseminated RMS represents a major clinical obstacle, and the need for better treatment strategies for the clinically aggressive alveolar RMS subtype is particularly apparent. Previously, we have shown that the acridine-4-carboxamide derivative AS-DACA, a known topoisomerase II poison, is potently cytotoxic in the alveolar RMS cell line RH30, but is 190-fold less active in the embryonal RMS cell line RD. Here, we investigate the basis for this selectivity, and demonstrate in these RMS lines, and in an AS-DACA- resistant subclone of RH30, that AS-DACA-induced cytotoxicity correlates with the induction of DNA double strand breaks. RESULTS: We show that inhibition of the multidrug-resistance associated protein (MRP1) has no effect on AS-DACA sensitivity. By exploiting the pH-dependent fluorescence properties of AS-DACA, we have characterized its intracellular distribution, and show that it concentrates in the cell nucleus, as well as in acidic vesicles of the membrane trafficking system. We show that fluorescence microscopy can be used to determine the localization of AS-DACA to the nuclear and cytoplasmic compartments of RMS cells grown as spheroids, penetrance being much greater in RH30 than RD spheroids, and that the vesicular signal leads the way into the spheroid mass. EEA1 and Rab5 proteins, molecular markers expressed on early-endosomal vesicles, are reduced by >50% in the sensitive cell lines. CONCLUSION: Taking the evidence as a whole, suggests that endosomal vesicle trafficking influences the toxicity of AS-DACA in RMS cells.

Effects of DNA minor groove binding agents on global gene expression.

The capacity of two minor groove binding agents that differ in their DNA sequence selectivity to modulate gene expression in human leukaemia cells was investigated. The chosen compounds were the chromomycin A3, a GC selective minor groove binder, and alkamin, an AT selective minor groove binder. As revealed by DNA microarray analysis of 6000 genes, at equitoxic doses, 5×IC(50) values for growth inhibition, the two drugs disturbed transcription, resulting in both up- and down-regulation of many hundreds of genes, 24 h after drug exposure. Direct comparisons between the most affected genes and also the cluster analysis indicated a relatively low degree of similarity between the tow expression profiles. Moreover, the ontological and the pathway responses also indicated a distinguished biological responses. Chromomycin treatment was characterized by many negative impacts on the important cellular functions and by the activation for those functions that usually take the cells towards apoptosis. In the second biological profile, the domination of many positive functions might indicate that the cells were attempting to overcome and repair the alkamin assault. Examples of these functions are positive regulation of gene expression, positive regulation of macromolecule biosynthetic processes, the cell cycle pathway and DNA repair.

Virulence for chickens of Clostridium perfringens isolated from poultry and other sources.

Clostridium perfringens type A is the most common cause of poultry necrotic enteritis (NE). Of the four "major" toxins, type A strains produce only alpha toxin (CPA), which has long been considered a major factor in pathogenesis of NE. We investigated the virulence for poultry of type A strains from a variety of enteric sources. Newly-hatched CornishxRock chicks were fed a low protein diet for one week, a high protein diet for a second week, and then challenged with log-phase cultures of C. perfringens, mixed 3:4 (v/v) with high protein feed. Strain JGS4143 [genotype A, beta2 positive (cpb2(pos)), from a field case of NE] produced gross lesions compatible with NE in >85% of challenged birds. However, strains JGS1714 (enterotoxigenic genotype A, cpb2(pos), human food poisoning), JGS1936 (genotype A, cpb2(neg), bovine neonatal enteritis), JGS4142 (genotype A, cpb2(pos), bovine jejunal hemorrhage syndrome), JGS1473 (genotype A, cpb2(pos), chicken normal flora), JGS1070 (genotype C, cpb2(pos), porcine hemorrhagic enteritis), JGS1882 (genotype A, cpb2(pos), porcine neonatal enteritis), JGS1120 (ATCC 13124, genotype A, cpb2(neg), gas gangrene), JGS4151 (strain 13, genotype A, cpb2(pos), canine), and JGS4303 (SM101, enterotoxigenic genotype A, cpb2(neg), human food poisoning) failed to produce disease. In vivo passage failed to increase virulence of the non-NE strains. NE strains must have specific poultry-associated virulence attributes, such as the recently identified NetB and other factors, which allow for the development of disease.

In vitro assessment of novel transcription inhibitors and topoisomerase poisons in rhabdomyosarcoma cell lines.

PURPOSE: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Current chemotherapy regimes include the topoisomerase II poison etoposide and the transcription inhibitor actinomycin D. Poor clinical response necessitate identification of new agents to improve patient outcomes. METHODS: We assessed the in vitro cytotoxicity (MTT assay) of DNA intercalating agents in five established human RMS cell lines. These include novel classes of transcription inhibitors and topoisomerase poisons, previously shown to have potential as anti-cancer agents. RESULTS: Amongst the former agents, bisintercalating bis(9-aminoacridine-4-carboxamides) linked through the 9-position, and bis(phenazine-1-carboxamides) linked via their side chains, are compared with established transcription inhibitors. Amongst the latter, monofunctional acridine-4-carboxamides related to N-[2-(dimethylamino)ethyl]acridine-4-carboxamide, DACA, are compared with established topoisomerase poisons. CONCLUSIONS: Our findings specifically highlight the topoisomerase poison 9-amino-DACA, its 5-methylsulphone derivative, AS-DACA, and the bis(phenazine-1-carboxamide) transcription inhibitor MLN944/XR5944, currently in phase I trial, as candidates for further research into new agents for the treatment of RMS.

Effects of DNA threading bis(9-aminoacridine-4-carboxamides) on global gene expression.

The capacity of series of DNA-threading bis(9-aminoacridine-4-carboxamides) comprising ethylmorpholino, ethylpiperidine and N-methylpiperidin-4-yl sidechains joined by different linkers, to modulate gene expression in human leukaemia cells was investigated. The chosen compounds provided the opportunity for probing the relationships between the structure ligand structure and the drug effects on transcription, information that might lead to a greater understanding of their potential as antitumour agents. As revealed by DNA microarray analysis of 6000 genes, at equitoxic doses, 5xIC(50) values for growth inhibition, all of the drugs perturb transcription, resulting in both up- and down-regulation of many hundreds of genes, 24 h after drug exposure. Under these conditions, the capacity to inhibit transcription decreases in the order C3NC3 morpholino > C2pipC2 morpholino > C8 piperidine > C8NMP > C2pipC2 piperidine. Cluster analysis segregated the examined agents into two groups: the first included C2pipC2 morpholino and C3NC3 morpholino and the second C2pipC2 piperidine, C8 piperidine and C8NMP. This classification agreed with the ontological analysis for the markedly up-regulated genes that showed a relatively specific profile for each group. Interestingly, the general up-regulation responses for the first group (C3NC3 morpholino and C2pipC2 morpholino) indicated marked up-regulation amongst the transcription gene set, which suggests that the transcription machinery is the main target for the members of this group. While in the second group (C2pipC2 piperidine, C8 piperidine, C8NMP), the general up-regulation responses for the three agents are dominated by the protein modification process ontological class, implying at least involvement of topoisomerase poisoning in their mode of action.

Banding carcinogenic risks in developed countries: A procedural basis for qualitative assessment.

Readily achieved comparative assessment of carcinogenic risks consequent upon environmental exposures may increase understanding and contribute to cancer prevention. Procedures for hazard identification and quantitative risk assessment are established, but limited when addressing novel exposures to previously known carcinogens or any exposure to agents having only suspected carcinogenic activity. To complement other means of data evaluation, a procedure for qualitative assessment of carcinogenic risk is described. This involves categorizing the relevant carcinogen and circumstances under which exposure occurs. The categories for carcinogens are those used for hazard identification and involve whether the agent is (1) a recognized carcinogen for humans; (2) probably or (3) possibly carcinogenic for humans; (4) characterized by inadequate evidence of carcinogenicity; or (5) lacking carcinogenicity. Exposure is categorized by whether it is one which (1) establishes the agent as a recognized carcinogen; (2) is taken into account in establishing carcinogenicity status; (3) is distinct from those providing clearest evidence of carcinogenicity; (4) is not characterized in relation to carcinogenicity; or (5) involves an exposure in which absence of carcinogenic outcome is observed. These two categories of evidence allow the risk inherent in a situation to be banded as indicative of a proven, likely, inferred, unknown or unlikely carcinogenic outcome, and further characterized using sub-bands. The procedure has been applied to about fifty situations. For recognized carcinogens, including asbestos and polycyclic aromatic hydrocarbons, risks consequent upon occupational exposure, the impact of point source pollution, residence near contaminated sites and general environmental exposure are allocated across the proven band and a likely sub-band. For solvents, pesticides and other compounds having less clearly established carcinogenicity, impact on residents living near a production site, or near earlier related industrial activity is allocated to certain inferred sub-bands. Unknown carcinogenic outcome, which identifies exposure to an agent with inadequate evidence of carcinogenicity rather than being indicative of equivocal or negative data in any context, indicates both the impact of certain pollutants and user-exposure to some consumer products. Situations allocated to the unlikely risk band principally involve certain consumer products. Overall, such risk assessment may be of greatest worth in focusing community attention on proven causes of cancer and associated preventive measures.