Platinum–acridine hybrid agents show low-nanomolar potency in chemoresistant non-small cell lung cancer (NSCLC), but high systemic toxicity in vivo. To reduce the promiscuous genotoxicity of these agents and improve their pharmacological properties, a modular build–click–screen approach was used to evaluate a small library of twenty hybrid agents containing truncated and extended chromophores of varying basicities. Selected derivatives were resynthesized and tested in five NSCLC cell lines representing large cell, squamous cell, and adenocarcinomas. 7-Aminobenz[c]acridine was identified as a promising scaffold in a hybrid agent (P1–B1) that maintained submicromolar activity in several of the DNA-repair proficient and p53-mutant cancer models, while showing improved tolerability in mice by 32-fold compared to the parent platinum–acridine (P1–A1). The distribution and DNA/RNA adduct levels produced by the acridine- and benz[c]acridine-based analogues in NCI-H460 cells (confocal microscopy, ICP-MS), and their ability to bind G-quadruplex forming DNA sequences (CD spectroscopy, HR-ESMS) were studied. P1–B1 emerges as a less genotoxic, more tolerable, and potentially more target-selective hybrid agent than P1–A1.

Cadmium and lead have been classified as carcinogens by the International Agency for Research on Cancer. However, their associations with breast cancer risk are unknown despite their persistence in the environment and ubiquitous human exposure. We examined associations of circulating levels of cadmium and lead with breast cancer risk in three case-control studies nested within the Cancer Prevention Study-II (CPS-II) LifeLink Cohort, European Prospective Investigation into Cancer and Nutrition - Italy (EPIC-Italy) and the Northern Sweden Health and Disease Study (NSHDS) cohorts. Metal levels were measured in stored erythrocytes from 1,435 cases and 1,433 controls using inductively coupled plasma-mass spectrometry. Summary relative risks (RR) and 95% confidence intervals (CI) were calculated using random-effects models with each study result weighted by the within- and between-study variances. I values were calculated to estimate proportion of between study variation. Using common cut-points, cadmium levels were not associated with breast cancer risk in the CPS-II cohort (continuous RR = 1.01, 95% CI 0.76-1.34), but were inversely associated with risk in the EPIC- Italy (continuous RR = 0.80, 95% CI 0.61-1.03) and NSHDS cohorts (continuous RR = 0.73, 95% CI 0.54-0.97). The inverse association was also evident in the meta-analysis (continuous RR = 0.84, 95% CI 0.69-1.01) with low between-study heterogeneity. Large differences in lead level distributions precluded a meta-analysis of their association with breast cancer risk; no associations were found in the three studies. Adult cadmium and lead levels were not associated with higher risk of breast cancer in our large meta-analysis.

The role of metals in breast cancer is of interest because of their carcinogenic and endocrine disrupting capabilities. Evidence from epidemiologic studies remains elusive and prior studies have not investigated metal mixtures. In a case-cohort nested within the Sister Study cohort (enrolled 2003-2009; followed through September 2017), we measured 15 metals in toenails collected at enrollment in a race-stratified sample of 1495 cases and a sub-cohort of 1605 women. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for each metal using Cox regression and robust variance. We used quantile g-computation to estimate the joint association between multiple metals and breast cancer risk. Average follow-up was 7.5 years. There was little evidence supporting an association for individual metals and breast cancer. An exception was molybdenum, which was associated with reduced incidence of overall breast cancer risk (3rd vs. 1st tertile HR=0.82 (95% CI: 0.67, 1.00)). An inverse association for antimony was observed among non-Hispanic Black women. Pre-defined groups of metals (all, non-essential, essential, and metalloestrogens) were not strongly associated with breast cancer. This study offers little support for metals individually or as mixtures as risk factors for breast cancer. Mechanisms for inverse associations with some metals warrant further study.

2017) Longterm viable bioaerosol sampling using a temperature-and humidity-controlled filtration apparatus, a laboratory investigation using culturable E.coli., Aerosol Science and Technology, 51:5, 576-586, ABSTRACT Sampling for culturable (e.g., viable) aerosolized microbes (bioaerosols) is a useful means to provide information for public health monitoring and studies. However, it is challenging to maintain microbe culturability when sampling at high flow rates (>12 L/min) and extended periods of time (4 h). We developed a first-generation, viable bioaerosol collection system (VBCS) utilizing temperature (T) and relative humidity (RH)-conditioned filtration at a flow rate of 25 L/min. A twostage system of tube-in-shell Nafion TM exchange units provides cooling to 10 C and RH conditioning to 80-95%. Aerosol particles are collected on a polyurethane nanofiber filter providing a physical collection efficiency of >95% for sizes 0.06-10 mm. The T and RH conditions at the collection filter are maintained, despite changes to ambient conditions. The initial testing of the VBCS was done under indoor, laboratory conditions with aerosolized, vegetative E. coli. A scenario of a 30-min challenge of bioaerosol followed by continued sampling of clean air for various times was used to judge culturability maintenance under extended-term sampling. An initial loss of culturability upon collection onto the filter was observed; 23 § 13% relative to 4-mm all-glass impinger. However once collected, 98% of culturability was maintained for an additional 4.5 h of sampling. An exponential decay in culturability was observed from 8 h to 15 h of sampling. Also, 24h cold storage of the filters collected was studied. The VBCS is based on the use of dry filter cassettes, needs minimal maintenance, and preserves culturability of vegetative bacteria for >4 h. EDITOR Tiina Reponen

No abstract