Human umbilical cord vessels (HUCV) release dopamine and nitric oxide (NO). This study aims to verify whether HUCV release nitrocatecholamines such as 6-nitrodopamine (6-ND).
Liquid chromatography ...coupled to tandem mass spectrometry (LC-MS/MS) was used to identify 6-ND release from HUCV rings incubated in Krebs-Henseileit's solution. Vascular reactivity of HUCV rings was tested (with and without endothelium integrity) by suspension of the rings in an organ bath under isometric tension and application of 6-ND and other known mediators.
LC-MS/MS revealed a basal release of 6-ND from endothelium intact from both human umbilical artery (HUA) and vein (HUV). The endothelium intact release was inhibited by the pre-treatment with NO synthesis inhibitor L-NAME (100 μM). In contrast to dopamine, noradrenaline and adrenaline, 6-ND did not contract HUCV, even in presence of L-NAME or ODQ. 6-ND (10 μM) produced a rightward shift of the concentration-response curves to dopamine (pA2: 5.96 in HUA and 5.72 in HUV). Contractions induced by noradrenaline and adrenaline were not affected by pre-incubation with 6-ND (10 μM).
In U-46619 (10 nM) pre-contracted endothelium intact tissues, 6-ND and the dopamine D2-receptor antagonist haloperidol induced concentration-dependent relaxations of HUA and HUV. Incubation with the dopamine D1-receptor antagonist SCH-23390 (10 nM) abolished relaxation induced by fenoldopam but did not affect those induced by 6-ND.
6-ND is released by HUCV and acts as a selective dopamine D2-receptor antagonist in this tissue. This represents a novel mechanism by which NO may modulate vascular reactivity independently of cGMP production.
•HUCV releases 6-ND but only in endothelium intact sections. The endothelium intact release was inhibited by the pre-treatment with L-NAME.•Unlike dopamine, noradrenaline and adrenaline, 6-ND did not contract HUCV, nor in the presence of L-NAME nor ODQ.•6-ND caused a rightward shift of the concentration-response curves to dopamine but did not affect the responses of noradrenaline and adrenaline.•6-ND caused a concentration-dependent inhibition of the contractions induced by the dopamine D2-receptor agonist sumanirole in HUCV.•6-ND is suggestibly acting as a dopaminergic antagonist, with selectivity for the D2-receptor.•6-ND represents a novel mechanism by which NO may modulate vascular reactivity independently of cGMP production.
Background
The Neoadjuvant Breast Symphony Trial (NBRST) demonstrated the 70-gene risk of distant recurrence signature, MammaPrint, and the 80-gene molecular subtyping signature, BluePrint, precisely ...determined preoperative pathological complete response (pCR) in breast cancer patients. We report 5-year follow-up results in addition to an exploratory analysis by age and menopausal status.
Methods
The observational, prospective NBRST (NCT01479101) included 954 early-stage breast cancer patients aged 18–90 years who received neoadjuvant chemotherapy and had clinical and genomic data available. Chemosensitivity and 5-year distant metastasis-free survival (DMFS) and overall survival (OS) were assessed. In a post hoc subanalysis, results were stratified by age (≤ 50 vs. > 50 years) and menopausal status in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) tumors.
Results
MammaPrint and BluePrint further classified 23% of tumors to a different subtype compared with immunohistochemistry, with more precise correspondence to pCR rates. Five-year DMFS and OS were highest in MammaPrint Low Risk, Luminal A-type and HER2-type tumors, and lowest in MammaPrint High Risk, Luminal B-type and Basal-type tumors. There was no significant difference in chemosensitivity between younger and older patients with Low-Risk (2.2% vs. 3.8%;
p
= 0.64) or High-Risk tumors (14.5% vs. 11.5%;
p
= 0.42), or within each BluePrint subtype; this was similar when stratifying by menopausal status. The 5-year outcomes were comparable by age or menopausal status for each molecular subtype.
Conclusion
Intrinsic preoperative chemosensitivity and long-term outcomes were precisely determined by BluePrint and MammaPrint regardless of patient age, supporting the utility of these assays to inform treatment and surgical decisions in early-stage breast cancer.
The Savannah River Site stores approximately 36 million gallons of radioactive and hazardous waste that contains approximately 245 million curies. The waste is sent through various chemical processes ...to reduce its volume and to separate various components. The facility plans to replace formic acid (a chemical used to reduce soluble mercury) with glycolic acid. Recycle solution with glycolate may flow back to the tank farm, where the glycolate can generate hydrogen gas by thermal and radiolytic mechanisms. The current analytical method for detecting glycolate (ion chromatography) in supernatant requires a large dilution to reduce interference from the nitrate anions. Hydrogen nuclear magnetic resonance is an analytical method that requires less sample dilution. It takes advantage of the CH2 group in glycolate. Liquid samples were spiked with four different levels of glycolate to build a calibration line, as it is recommended in the standard addition method. The detection and quantitation limits determined were 1 and 5 ppm, respectively, for 32 scans, which is well below the process limit of 10 ppm. In one test, 800 scans of a supernatant spiked with 1 ppm glycolate resulted in a ‐CH2 peak with a signal‐to‐noise ratio of 36.
Two solvent suppression NMR programs (presaturation and pulse sculpting) in combination with the standard addition method (SAM) detected glycolate (a hydrogen gas generator) in radioactive supernatant at a lower concentration (1 ppm) than ion chromatography. Similarly, solvent suppression detected methanol at less than 1 ppm in radioactive supernatant.
Background
Pertuzumab became a standard part of neoadjuvant therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancers approximately halfway through Neoadjuvant Breast ...Registry Symphony Trial (NBRST) enrollment, providing a unique opportunity to determine biologically which clinical HER2+ patients benefit most from dual targeting. As a neoadjuvant phase 4 study, NBRST classifies patients by both conventional and molecular subtyping.
Methods
Of 308 clinical HER2+ patients enrolled in NBRST between 2011 and 2014 from 62 U.S. institutions, 297 received neoadjuvant chemotherapy (NCT) with HER2-targeted therapy and underwent surgery. This study compared the pathologic complete response (pCR) rate of BluePrint versus clinical subtypes with treatment, specifically differences between trastuzumab (T) treatment and trastuzumab and pertuzumab (T/P) treatment.
Results
In this study, 60% of the patients received NCT-T, and 40% received NCT-T/P. The overall pCR rate (ypT0/isN0) was 47%. BluePrint classified 161 tumors (54%) as HER2 type, with a pCR rate of 65%. This was significantly higher than the pCR rate for the 91 HER2+ tumors (31%) classified as luminal (18%) (
p
= 0.00001) and the 45 tumors (15%) classified as basal (44%) (
p
= 0.0166). The patients treated with T/P had higher pCR rates than those treated with trastuzumab alone. The difference was most pronounced in the BluePrint luminal patients (8 vs. 31%). The highest pCR was reached by the BluePrint HER2-type patients treated with T/P (76%).
Conclusions
The addition of pertuzumab leads to increased pCR rates for all HER2+ patient groups except for the BluePrint basal-type patients. This better response was most pronounced for the BluePrint luminal-type patients.
Vitrification of Low Activity Waste in the Hanford Waste Treatment and Immobilization Plant generates a condensate stream from the off-gas processes. Components in this stream are partially volatile ...and accumulate to high concentrations through recycling, which impacts the waste glass loading and facility throughput. The primary radionuclide that vaporizes and accumulates in the stream is
99
Tc. This program is investigating Tc removal via reductive precipitation with stannous chloride to examine the potential for diverting this stream to an alternate disposition path. Research has shown stannous chloride to be effective, and this paper describes results of recent experiments performed to further mature the technology.
A principal goal at the Savannah River Site (SRS) is to safely dispose of the large volume of liquid nuclear waste held in many storage tanks. In-tank ion exchange (IX) columns are being considered ...for cesium removal. The spherical form of resorcinol formaldehyde ion exchange resin (sRF) is being evaluated for decontamination of dissolved saltcake waste at SRS, which is generally lower in potassium and organic components than the Hanford waste. The sRF performance with SRS waste was evaluated in two phases: resin batch contacts and IX column testing with both simulated and actual dissolved salt waste. The tests, equipment, and results are discussed.
A principal role of the DOE Savannah River Site is to safely dispose of a large volume of liquid nuclear waste held in many storage tanks. An in-tank ion exchange unit is being considered for cesium ...removal to accelerate waste processing. This unit is planned to have a relatively high bed height to diameter ratio (10:1). Complicating the design is the need to cool the ion exchange media; therefore, the ion exchange column will have a central cooling core making the flow path annular. To separate cesium from waste the media being considered is made of resorcinol formaldehyde resin deposited on spherical plastic beads and is a substitute for a previously tested resin made of crystalline silicotitanate. This spherical media not only has an advantage of being mechanically robust, but, unlike its predecessor, it is also reusable, that is, loaded cesium can be removed through elution and regeneration. Resin regeneration leads to more efficient operation and less spent resin waste, but its hydraulic performance in the planned ion exchange column was unknown. Moreover, the recycling process of this spherical resorcinol formaldehyde causes its volume to significantly shrink and swell. To determine the spherical media's hydraulic demand a linearly scaled column was designed and tested. The waste simulant used was prototypic of the wastes' viscosity and density. This paper discusses the hydraulic performance of the media that will be used to assist in the design of a full-scale unit.
Fine powders of monosodium titanate effectively remove strontium and plutonium from alkaline salt supernatant. At the Savannah River Site, larger, porous particles with monosodium titanate were ...desired for continuous column operations. The internal gelation process was used to make hydrous titanium oxide microspheres with 32 and 50 wt% monosodium titanate. With actual supernatant, the microspheres with 50 wt% monosodium titanate produced average batch distribution coefficients of 35,000 mL/g for plutonium and 99,000 mL/g for strontium. These microspheres were tested using a simulant and a flow rate of 5.3 bed volumes per hour. The plutonium removal dropped from 99% to 94% while the strontium removal remained nearly 100%. The microspheres exhibited good flow performance and no particle degradation.
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