Somatic gene mutation analysis of triple negative breast cancers.

OBJECTIVES: The aims of this study were to analyze triple negative breast cancer (TNBC) using an expanded next generation sequencing (NGS) assay, assess the clinical relevance using a recently described database, and correlate tumor morphology with detected genetic alterations. METHODS: DNA was isolated from twenty primary TNBCs and genes of interest were enriched and sequenced with hybrid capture, followed by variant detection and functional and clinical annotation. The JAX-CTP™ assay detects actionable variants in the form of single nucleotide variations, small insertions and deletions (≤50 bp), and copy number variants in 358 genes in specimens containing a neoplastic cell content of ≥50%. The JAX-CKB is a comprehensive database that curates tumor phenotype, genetic variant and protein effect, therapeutic relevance, and available treatment options. RESULTS: 18/20 (90%) of TNBCs contained at least one somatic mutation detected by the JAX-CTP™. MYC amplification was the most common alteration, present in 75% of tumors. TP53, AURKA, and KDR mutations were each present in 30% (6/20) of cases. Related recruiting clinical trials, extracted from JAX-CKB, included 166 for breast cancer, of which 17 were specific to only the TNBC subtype. All 17 trials were testing at least one therapy that targets a mutation identified in this sample set. The majority (89%) of tumors with basal-like histologic features had MYC amplification. CONCLUSIONS: The expanded gene panel identified a variety of clinically actionable gene alterations in TNBCs. The identification of such variants increases the possibility for new therapeutic interventions and clinical trial eligibility for TNBC patients.

Heat loss through the glabrous skin surfaces of heavily insulated, heat-stressed individuals.

Insulation reduces heat exchange between a body and the environment. Glabrous (nonhairy) skin surfaces (palms of the hands, soles of the feet, face, and ears) constitute a small percentage of total body surface area but contain specialized vascular structures that facilitate heat loss. We have previously reported that cooling the glabrous skin surfaces is effective in alleviating heat stress and that the application of local subatmospheric pressure enhances the effect. In this paper, we compare the effects of cooling multiple glabrous skin surfaces with and without vacuum on thermal recovery in heavily insulated heat-stressed individuals. Esophageal temperatures (T(es)) and heart rates were monitored throughout the trials. Water loss was determined from pre- and post-trial nude weights. Treadmill exercise (5.6 km/h, 9-16% slope, and 25-45 min duration) in a hot environment (41.5 degrees C, 20-30% relative humidity) while wearing insulating pants and jackets was used to induce heat stress (T(es)>or=39 degrees C). For postexercise recovery, the subjects donned additional insulation (a balaclava, winter gloves, and impermeable boot covers) and rested in the hot environment for 60 min. Postexercise cooling treatments included control (no cooling) or the application of a 10 degrees C closed water circulating system to (a) the hand(s) with or without application of a local subatmospheric pressure, (b) the face, (c) the feet, or (d) multiple glabrous skin regions. Following exercise induction of heat stress in heavily insulated subjects, the rate of recovery of T(es) was 0.4+/-0.2 degrees C/h(n=12), but with application of cooling to one hand, the rate was 0.8+/-0.3 degrees C/h(n=12), and with one hand cooling with subatmospheric pressure, the rate was 1.0+/-0.2 degrees C/h(n=12). Cooling alone yielded two responses, one resembling that of cooling with subatmospheric pressure (n=8) and one resembling that of no cooling (n=4). The effect of treating multiple surfaces was additive (no cooling, DeltaT(es)=-0.4+/-0.2 degrees C; one hand, -0.9+/-0.3 degrees C; face, -1.0+/-0.3 degrees C; two hands, -1.3+/-0.1 degrees C; two feet, -1.3+/-0.3 degrees C; and face, feet, and hands, -1.6+/-0.2 degrees C). Cooling treatments had a similar effect on water loss and final resting heart rate. In heat-stressed resting subjects, cooling the glabrous skin regions was effective in lowering T(es). Under this protocol, the application of local subatmospheric pressure did not significantly increase heat transfer per se but, presumably, increased the likelihood of an effect.

Synthesis, utility, and X-ray crystal structure of novel complexes of baccatin III with imidazole and 2-propanol.

Baccatin III forms crystalline complexes 4 and 5 with imidazole and 2-propanol, respectively. These compounds are useful in the purification of baccatin III from mixtures of taxanes derived from plant-cell fermentation.

A crystallization-induced stereoselective glycosidation reaction in the synthesis of the anticancer drug etoposide.

The anticancer drug etoposide, 1, is prepared in 79% overall yield from readily available 4'-demethyl-4-epipodophyllotoxin, 3, and 4, 6-O-ethylidene-2,3-O-dibenzyl-D-glucose, 4, via a crystallization-induced stereoselective glycosidation reaction followed by catalytic hydrogenation.