Free radicals trapped in methyl alpha-D-mannopyranoside X-irradiated at 77 K: an ESR/ENDOR study

Four free radicals are trapped in methyl alpha-D-mannopyranoside X-irradiated and maintained at 77 K. All four have been identified, with high confidence levels, using ESR and ENDOR spectroscopy. One, an alkoxy radical located at O4, is characterized by a gmax of 2.059, an isotropic beta hydrogen hyperfine coupling (hfc) of 98 MHz, and small interactions due to gamma or delta hydrogens. The second, a secondary dioxyalkyl radical due to loss of hydrogen from C1 is characterized by one beta hfc with an isotropic component of 19.03 MHz. The third, a secondary hydroxyalkyl radical due to loss of hydrogen from C2 is characterized by two nonexchangeable hydrogens with isotropic beta interactions of 22.45 and 6.44 MHz and one exchangeable hydrogen with an isotropic beta interaction of 9.88 MHz. The fourth is a .CH2OR radical that is formed by the net loss of hydrogen from the methyl group.     

Mammals as prey: Estimating ingestible size

Most mammals have deformable bodies, making it difficult to measure the size of living or freshly killed ones accurately. Because small rodents are common prey of many snakes, and because nearly all snakes swallow their prey whole, we explored four methods for determining the ingestible size (the smallest cross‐sectional area that the largest part of the rodent can be made into without breaking bones or dislocating joints) of 100 intact rodents, including 50 Musmusculus and 50 Rattus norvegicus. Cross‐sectional areas derived from maximal height and width of specimens at rest or the same specimens wrapped snout to pelvic girdle are roughly 1.5× higher than areas calculated either by the height and width of the same specimens rolled into cylinders or by volumetric displacement. Rolling rodents into cylinders reduces cross‐sectional area by straightening the vertebral column, lengthening the abdominal cavity, elevating the sternum, compressing the thoracic cavity, and protracting the shoulder joint, that is, changes similar to those seen in rodents eaten by snakes. Reduced major axis regression of the smallest attainable cross‐sectional area, y, on mass, x, shows that y (in log mm²) approximates 1.53x (in log grams)^0.69 for rats and 1.63x^0.64 for mice. Our results suggest that visual cues provided by live rodents might lead most predators, like snakes, to overestimate ingestible size and hence rarely attack prey too large to ingest. J. Morphol. 2012. © 2012 Wiley Periodicals, Inc.     

Contraceptive Use and Pregnancy Outcomes among Opioid Drug-Using Women: A Retrospective Cohort Study

Objective

The contraceptive needs of illicit opioid users differ from non-drug users but are poorly understood. The aim of this study was to describe contraceptive use and pregnancy outcomes in opioid-using women, and to examine their association with a range of risk factors.

Method

This retrospective cohort study used UK general practice records, Treatment Outcomes Profile and National Drug Treatment Monitoring System data, and a nested data validation exercise. A cohort of 376 women aged 20–61 years were in active treatment for opioid addiction in October 2010 at two specialised primary care practices in North-East England. Outcomes were age-adjusted prevalence estimates for contraceptive use and pregnancy outcomes in users of illicit opioids. The association between lifestyle-related risk factors and contraception was explored.

Results

Drug-using women made lower use of planned (non-condom) contraception (24% vs 50%, p<0.001), had more frequent pregnancy terminations (0.46 vs. 0.025, p = 0.004) and higher annual incidence of chlamydia (1.1% vs. 0.33%, p<0.001), when compared with age-matched population data. Specifically, there was low use of oral contraceptives (4% vs. 25%, p<0.001), IUCD (1% vs. 6%, p<0.001), and sterilisation (7% vs. 6%, p = 0.053), but higher rates of injectable contraceptives (6% vs. 3%, p = 0.003). A total of 64% of children aged <16 years born to this group did not live with their mother. No individual risk factor (such as sex-working) significantly explained the lower use or type of non-condom contraception.

Conclusions

This is the first study to describe planned contraceptive use among drug-users, as well as the association with a range of risk factors and pregnancy outcomes. The low uptake of planned contraception, set against high rates of terminations and sexually transmitted disease demonstrates the urgent clinical need to improve contraceptive services, informed by qualitative work to explore the values and beliefs influencing low contraceptive uptake.     

Design and activity of AP endonuclease-1 inhibitors

Apurinic/apyrimidinic endonuclease-1/redox effector factor-1 (APE-1) is a critical component of base excision repair that excises abasic lesions created enzymatically by the action of DNA glycosylases on modified bases and non-enzymatically by hydrolytic depurination/depyrimidination of nucleobases. Many anticancer drugs generate DNA adducts that are processed by base excision repair, and tumor resistance is frequently associated with enhanced APE-1 expression. Accordingly, APE-1 is a potential therapeutic target to treat cancer. Using computational approaches and the high resolution structure of APE-1, we developed a 5-point pharmacophore model for APE-1 small molecule inhibitors. One of the nM APE-1 inhibitors (AJAY-4) that was identified based on this model exhibited an overall median growth inhibition (GI₅₀) of 4.19 μM in the NCI-60 cell line panel. The mechanism of action is shown to be related to the buildup of abasic sites that cause PARP activation and PARP cleavage, and the activation of caspase-3 and caspase-7, which is consistent with cell death by apoptosis. In a drug combination growth inhibition screen conducted in 10 randomly selected NCI-60 cell lines and with 20 clinically used non-genotoxic anticancer drugs, a synergy was flagged in the SK-MEL-5 melanoma cell line exposed to combinations of vemurafenib, which targets melanoma cells with V600E mutated BRAF, and AJAY-4, our most potent APE-1 inhibitor. The synergy between AJAY-4 and vemurafenib was not observed in cell lines expressing wild-type B-Raf protein. This synergistic combination may provide a solution to the resistance that develops in tumors treated with B-Raf-targeting drugs.

Electronic supplementary material

The online version of this article (doi:10.1007/s12154-015-0131-7) contains supplementary material, which is available to authorized users.