Long-Term Follow-Up of Cardiac Function and Quality of Life for Patients in NSABP Protocol B-31/NRG Oncology: A Randomized Trial Comparing the Safety and Efficacy of Doxorubicin and Cyclophosphamide (AC) Followed by Paclitaxel With AC Followed by Paclitaxel and Trastuzumab in Patients With Node-Positive Breast Cancer With Tumors Overexpressing Human Epidermal Growth Factor Receptor 2

Purpose Early cardiac toxicity is a risk associated with adjuvant chemotherapy plus trastuzumab. However, objective measures of cardiac function and health-related quality of life are lacking in long-term follow-up of patients who remain cancer free after completion of adjuvant treatment. Patients and Methods Patients in NSABP Protocol B-31 received anthracycline and taxane chemotherapy with or without trastuzumab for adjuvant treatment of node-positive, human epidermal growth factor receptor 2–positive early-stage breast cancer. A long-term follow-up assessment was undertaken for patients who were alive and disease free, which included measurement of left ventricular ejection fraction by multigated acquisition scan along with patient-reported outcomes using the Duke Activity Status Index (DASI), the Medical Outcomes Study questionnaire, and a review of current medications and comorbid conditions. Results At a median follow-up of 8.8 years among eligible participants, five (4.5%) of 110 in the control group and 10 (3.4%) of 297 in the trastuzumab group had a \u3e 10% decline in left ventricular ejection fraction from baseline to a value \u3c 50%. Lower DASI scores correlated with age and use of medications for hypertension, cardiac conditions, diabetes, and hyperlipidemia, but not with whether patients had received trastuzumab. Conclusion In patients without underlying cardiac disease at baseline, the addition of trastuzumab to adjuvant anthracycline and taxane-based chemotherapy does not result in long-term worsening of cardiac function, cardiac symptoms, or health-related quality of life. The DASI questionnaire may provide a simple and useful tool for monitoring patient-reported changes that reflect cardiac function

Immunisation with a Multivalent, Subunit Vaccine Reduces Patent Infection in a Natural Bovine Model of Onchocerciasis during Intense Field Exposure

Human onchocerciasis, caused by the filarial nematode Onchocerca volvulus, is controlled almost exclusively by the drug ivermectin, which prevents pathology by targeting the microfilariae. However, this reliance on a single control tool has led to interest in vaccination as a potentially complementary strategy. Here, we describe the results of a trial in West Africa to evaluate a multivalent, subunit vaccine for onchocerciasis in the naturally evolved host-parasite relationship of Onchocerca ochengi in cattle. Naïve calves, reared in fly-proof accommodation, were immunised with eight recombinant antigens of O. ochengi, administered separately with either Freund's adjuvant or alum. The selected antigens were orthologues of O. volvulus recombinant proteins that had previously been shown to confer protection against filarial larvae in rodent models and, in some cases, were recognised by serum antibodies from putatively immune humans. The vaccine was highly immunogenic, eliciting a mixed IgG isotype response. Four weeks after the final immunisation, vaccinated and adjuvant-treated control calves were exposed to natural parasite transmission by the blackfly vectors in an area of Cameroon hyperendemic for O. ochengi. After 22 months, all the control animals had patent infections (i.e., microfilaridermia), compared with only 58% of vaccinated cattle (P = 0.015). This study indicates that vaccination to prevent patent infection may be an achievable goal in onchocerciasis, reducing both the pathology and transmissibility of the infection. The cattle model has also demonstrated its utility for preclinical vaccine discovery, although much research will be required to achieve the requisite target product profile of a clinical candidate

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease

Lack of co-crystal formation with cyclotriphosphazenes : a cautionary tale

CITATION: Wahl, H., Haynes, D. A. & Le Roex, T. 2016. Lack of co-crystal formation with cyclotriphosphazenes : a cautionary tale. South African Journal of Chemistry, 69:35–43, doi:10.17159/0379-4350/2016/v69a5.The original publication is available at http://www.scielo.org.zaENGLISH ABSTRACT: The attempted formation of co-crystals with a series of cyclotriphosphazene derivatives has been investigated. Despite numerous attempts, only one co-crystal was obtained. The crystal structure of this material, [hexakis(4-pyridyloxy)-cyclotriphosphazene][ terephthalic acid]2.5, is presented here. The crystal structures of 2,2-bis(4-formylphenoxy)-4,4,6,6-bis[spiro(2’,2”-dioxy- 1’,1”-biphenylyl]cyclo-triphosphazene and hexakis(4-cyanophenoxy)cyclotriphosphazene are also reported for the first time. The extremely low rate of co-crystal occurrence in these materials cannot be explained, despite the consideration of several possibilities. This serves as a cautionary tale – co-crystal formation is not necessarily straightforward.http://www.scielo.org.za/scielo.php?script=sci_abstract&pid=S0379-43502016000100005&lng=en&nrm=iso&tlng=enPublisher's versio

Guest Exchange in a Robust Hydrogen-Bonded Organic Framework: Single-Crystal to Single-Crystal Exchange and Kinetic Studies

The salt 3,4-lutidinium pamoate crystallizes as its hemihydrate, forming a hydrogen-bonded organic framework with tetrahydrofuran (THF) as a guest in channels in the structure (<b>1·THF</b>). Extensive investigation has shown this framework to be highly robust: the THF in the channels can be exchanged for 20 different compounds, with 13 of these exchanges occurring in a single-crystal to single-crystal manner. The THF can also be exchanged for the volatile solids pyrazine or iodine, both via single-crystal to single-crystal transformations. Stepwise exchange of solvents is also possible, with a sequence of five exchanges occurring before the crystals begin to deteriorate. Investigation of the kinetics of exchange in <b>1·THF</b> revealed that exchange occurs according to a deceleratory kinetic model for contracting volume

Selectivity Behavior of a Robust Porous Organic Salt Based on the Pamoate Ion

The selectivity of a porous hydrogen-bonded framework, <b>1</b>, toward various solvent mixtures has been investigated. Framework <b>1</b>, which is the hydrate of 3,4-lutidinium pamoate, crystallizes as its THF solvate, <b>1·THF</b>. Solvent exchange can take place either by exposing crystals of <b>1·THF</b> to solvent vapors or by immersing the crystals in a solvent. Framework <b>1</b> shows preferential inclusion of particular solvents when exposed to mixed solvent vapors, or to mixed solvents in the liquid form. Analysis showed that solvents are included in the same ratios when exposed to mixed solvents in the liquid or vapor phase, despite the significant differences in mole ratios between the liquid and vapor phases due to the different vapor pressures of the solvents investigated. In some cases, when immersed in solvent mixtures containing acetonitrile or acetone, <b>1·THF</b> recrystallizes as an acetonitrile or acetone solvate of 3,4-lutidinium pamoate. The crystal structures of these two new solvates are also reported

A Series of Polymorphs of Hexakis(4-fluorophenoxy)cyclotriphosphazene

A series of conformational polymorphs of hexakis­(4-fluorophenoxy)­cyclotriphosphazene have been identified and characterized. Three of the four polymorphs are previously unreported. Thermal analysis coupled with variable temperature powder X-ray diffraction has shown that conversion between polymorphs occurs at well-defined temperatures. The high temperature form is metastable at room temperature and is never obtained from solution. Two forms are observed in solution crystallization experiments, a monoclinic form and a triclinic form. Slurry experiments revealed that the triclinic form is the most stable at room temperature. The fourth polymorph is observed only at low temperatures. Interconversion between three of the polymorphs occurs in a single-crystal to single-crystal manner

A Series of Polymorphs of Hexakis(4-fluorophenoxy)cyclotriphosphazene

A series of conformational polymorphs of hexakis­(4-fluorophenoxy)­cyclotriphosphazene have been identified and characterized. Three of the four polymorphs are previously unreported. Thermal analysis coupled with variable temperature powder X-ray diffraction has shown that conversion between polymorphs occurs at well-defined temperatures. The high temperature form is metastable at room temperature and is never obtained from solution. Two forms are observed in solution crystallization experiments, a monoclinic form and a triclinic form. Slurry experiments revealed that the triclinic form is the most stable at room temperature. The fourth polymorph is observed only at low temperatures. Interconversion between three of the polymorphs occurs in a single-crystal to single-crystal manner