Next, we created a novel small molecule incorporating an electrophilic di-chloro platinum moiety that preferentially alkylated M40 and H44 residues. The compound, designated T2Pt, covalently cross-linked wild-type but not M40A/H44A PCNA, irreversibly
inhibited PCNA/PIP-box interactions, and mildly alkylated plasmid DNA in vitro. In cells, T2Pt persistently induced cell cycle arrest, activated ATR-Chk1 signaling and modestly induced DNA strand breaks, features typical of cellular replication stress. Despite sustained activation of the replication stress response by the compound and its modestly genotoxic nature, T2Pt demonstrated little activity in clonogenic survival assays as a single agent, yet sensitized cells to cisplatin. The discovery of T2Pt represents an original effort directed at the development of irreversible PCNA inhibitors and sets the stage for the discovery of analogues MI-503 more selective for PCNA over other cellular nucleophiles. (C) 2014 Elsevier Ltd. All rights reserved.”
“Background: Primary care physicians
(PCPs) treat many women of reproductive age who need contraceptive and preconception counseling.\n\nStudy Design: To evaluate perceptions of rates of unintended pregnancy, we distributed an online survey in 2009 to 550 PCPs trained in General Internal Medicine or Family Medicine practicing in Western Pennsylvania, Central Pennsylvania, Rhode Island or Oregon.\n\nResults: Surveys were completed by 172 PCPs (31%). The majority (54%) of respondents underestimated the prevalence of unintended Syk inhibitor pregnancy in the United States [on average, by 23 +/- 8 (mean +/- SD) percentage points], and 81% underestimated the risk of pregnancy among women using no contraception [on average, by 35 +/- 20 (mean +/- SD) percentage points]. PCPs also frequently underestimated contraceptive failure rates with typical use: 85% underestimated the failure rate for oral contraceptive pills, 62% for condoms and 16% for contraceptive injections. PCPs more often overestimated the failure rate of intrauterine
devices (17%) than other prescription methods. In adjusted models, male PCPs were significantly more likely to underestimate the rate of unintended pregnancy in the United States than find more female PCPs [adjusted odds ratio (95% confidence interval): 2.17 (1.01-4.66)].\n\nConclusions: Many PCPs have inaccurate perceptions of rates of unintended pregnancy, both with and without use of contraception, which may influence the frequency and the content of the contraceptive counseling they provide. (C) 2012 Elsevier Inc. All rights reserved.”
“Although translocation is an important conservation tool in the effort to create self-sustaining wild populations of threatened species, avian translocations have a high failure rate and causes for failure are poorly understood.