MicroRNAs (miRs) are deregulated in cancer and leukemia. Restoring aberrantly downregulated tumor suppressor miRs or antagonizing overexpressed oncogenic miRs in malignant cells by synthetic RNA oligonucleotides represents a potentially novel therapeutic approach in cancer and leukemia. However, given the complex networking and concurrent deregulation of miRs in malignant cells, an effective approach may require concurrent targeting of multiple miRs. Cassette dosing involves simultaneous administration of a mixture of oligonucleotides from same or different structural classes. However, information on cassette dosing pharmacokinetics, tissue distribution and bioactivity of synthetic miRs is lacking. In this study, three synthetic 2'-methoxyphosphorothioate-miRs (2'-MeOPSmiR16-1, 2'-MeOPSmiR29b and 2'-MeOPSantagomiR155) were administered i.v. to C57BL/6 mice as a mixture, each at 7.5mg/kg. Analysis of concentrations of individual miR in plasma and major organ tissues (bone marrow, spleen, liver, brain, heart, kidney and lung) was performed. The mRNA and protein levels of miR's bio-targets were monitored sequentially after dosing up to 24 hours. Our results demonstrated that these synthetic miRs retain their different individual pharmacokinetic properties and all display three-compartmental pharmacokinetics. 2'-MeOPSmiR16-1 has the longest plasma gamma half-life of 2508 minutes and lowest total body clearance of 0.0054 L/min*kg, whereas 2'-MeOPSmiR29b has the shortest gamma half-life of 510.6 minutes and highest total body clearance of 0.042 L/min*kg. The tissue concentrations of all three 2'-MeOPS-modified miR(s)/antagomiR were measurable from 5 minutes to at least 24 hours after dosing, indicating that these concurrently delivered oligonucleotides can reach organ tissues. Importantly, there were biological activities of the concurrently administered miRs which persisted, as shown by the downregulation of specific targets in tested tissues, albeit with variations. Brain was one of the most sensitive tissues with respect to downregulation of mRNA and protein levels of four measured bio-targets (e.g. Bcl-2, Mcl-1, DNMT3a and DNMT3b) despite its relatively low miR/antagomiRs levels. We conclude that cassette dosing is applicable to 2'-MeOPS-modified synthetic miRs that are tissue-deliverable and biofunctional without any additional formulation requirement. This study supports future exploration of miR-involved combination therapies.

Glutamine and leucine are important mTORC1 modulators, although their roles are not precisely defined. In HepG2 and HeLa cells glutamine-free incubation lowers mTORC1 activity, although cell leucine is not decreased. mTORC1 activity, suppressed by amino acid-free incubation, is completely rescued only if essential amino acids (EAA) and glutamine are simultaneously restored, although cell leucine is higher in the absence than in the presence of glutamine. Thus, glutamine stimulates mTORC1 independent of cell leucine, suggesting the existence of two distinct stimulatory signals from either glutamine or EAA.

AIMS/HYPOTHESIS: Ethnicity and gestational diabetes mellitus (GDM) are both risk factors for the development of type 2 diabetes. However, it is uncertain whether ethnicity modifies the effect of GDM on diabetes risk. We aimed to determine the risk of diabetes following pregnancy with and without GDM for Chinese and South Asian women compared with white women. METHODS: Using healthcare databases, all 1,050,108 women aged 20-49 with live births between January 1995 and June 2008 in Ontario were identified. They were followed for up to 15 years for the diagnosis of diabetes. RESULTS: The age-standardised prevalences of GDM were 4.1%, 7.1% and 2.9% for Chinese, South Asian and white women, respectively. The cumulative incidence of diagnosed diabetes at the median follow-up time of 7.6 years was 16.5% and 1.8% for Chinese women with and without GDM, 31.8% and 3.6% for South Asian women with and without GDM, and 25.7% and 1.8% for white women with and without GDM. The presence of GDM conferred an increase in the risk for diabetes after pregnancy of more than 13-fold in white women, but only a nine- to tenfold increase among Chinese and South Asian women. CONCLUSIONS/INTERPRETATION: Although one-third of South Asian women with GDM were diagnosed with diabetes within 8 years postpartum, the incremental impact of GDM on diabetes risk was not as strong among Chinese and South Asian women as it was among white women.

Non-healing wounds cause considerable patient morbidity and represent a significant economic burden. Central to wound repair is re-epithelialisation, a crucial process involving the modulation of cell adhesion to allow keratinocyte migration to cover the exposed underlying tissues. The cellular mechanisms regulating the earliest stages of re-epithelialisation are unclear. We present the first direct evidence that protein kinase C alpha (PKCα) plays an important role in regulating wound re-epithelialisation. In PKCα(-/-) mice re-epithelialisation is delayed while in novel bi-transgenic mice over-expressing constitutively active PKCα it is accelerated. These effects are not due to changes in keratinocyte proliferation, apoptosis or intrinsic cell motility. Instead they correlate with changes in desmosomal adhesiveness, delay being preceded by retained desmosomal hyper-adhesiveness and acceleration with a rapid switch to desmosomal Ca(2+)-dependence. We demonstrate mechanistic conservation in acute human wounds where PKCα localises to wound edge desmosomes, which become Ca(2+)-dependent. However, in chronic wounds PKCα remains cytoplasmic and desmosomes fail to switch from the hyper-adhesive state. These results throw new mechanistic light on the earliest stages of wound re-epithelialisation and suggest activation of PKCα as a new therapeutic strategy for non-healing wounds. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

OBJECTIVE To examine the effect of a blended educational intervention (in-class and independent learning modules) developed to enhance Ohio PHN confidence in 25 disaster surge competencies that address the PHN role and skills in Preparedness, Response, and Recovery. DESIGN AND SAMPLE This was a quasi-experimental one group pre and post design. Participants (N = 54) completed pre- and postintervention surveys to evaluate intervention impact on self-perceived confidence and need for further training in the 25 competencies. MEASURES Parallel pre and post surveys assessed participant evaluation of confidence and need for further competency training. Paired t tests and repeated measures ANOVA compared pre- and postsurvey results. RESULTS Confidence in Preparedness, Response, and Recovery PHN disaster surge competencies significantly increased, whereas self-perceived need for further competency training correspondingly significantly decreased. CONCLUSIONS A blended learning approach to disaster surge training effectively improved PHNs confidence in competency achievement and reduced perceived need for further training.

Flow coefficients v_{n} for n=2, 3, 4, characterizing the anisotropic collective flow in Au+Au collisions at sqrt[s_{NN}]=200  GeV, are measured relative to event planes Ψ_{n}, determined at large rapidity. We report v_{n} as a function of transverse momentum and collision centrality, and study the correlations among the event planes of different order n. The v_{n} are well described by hydrodynamic models which employ a Glauber Monte Carlo initial state geometry with fluctuations, providing additional constraining power on the interplay between initial conditions and the effects of viscosity as the system evolves. This new constraint can serve to improve the precision of the extracted shear viscosity to entropy density ratio η/s.

PURPOSE: A preoperative machine check is imperative, yet machine faults are missed despite experience. We hypothesized that a simulation training session would improve junior residents' ability to perform a machine check beyond the level of final year residents who received only didactic training. METHODS: In 2005, an experiential machine check training session was introduced into residency training at the postgraduate year 1 (PGY-1) level. Three weeks later, the simulation residents were asked to perform a machine check and detect ten preset faults. The control group consisted of PGY-5 residents who had received a didactic anesthesia machine lecture during their residency; these control residents were asked to perform the same machine check as the simulation residents. Data were collected from 2005 to 2008 with each cohort of incoming PGY-1 residents and graduating PGY-5 residents. When the first group of PGY-1 residents became PGY-5 residents in 2009, they were invited to return for a retention test. In all tests, the number of faults detected was recorded, and the machine check was evaluated using a checklist. RESULTS: Thirty-seven simulation residents and 27 control residents participated in the study. Simulation residents had significantly higher checklist scores than the control residents, and they identified more machine faults (both P < 0.001). Twenty-one simulation residents repeated the study in their senior year, and they continued to achieve higher checklist scores and identify more machine faults than the control residents (both P < 0.001). CONCLUSION: Our results suggest that an experiential training session allowed junior residents to achieve skills superior to those of senior colleagues after a five-year residency. This training was retained for two to four years as they continued to outperform their comparative controls.

A formal [2 + 2] cycloaddition-cycloreversion (CA-CR) between N,N'-dicyanoquinone diimides (DCNQIs) and electron-rich alkynes was explored, providing a new class of π-conjugated donor-acceptor chromophores. These DCNQI adducts exist in the solid state as single diastereoisomers, but as two interconverting diastereoisomers in solution. Solid- and solution-state evidence for intramolecular charge transfer (CT) was obtained; additionally, the DCNQI adducts exhibit positive solvatochromism and significant solution-state third-order polarizabilities.

Back-to-back hadron pair yields in d+Au and p+p collisions at sqrt[s_{NN}]=200  GeV were measured with the PHENIX detector at the Relativistic Heavy Ion Collider. Rapidity separated hadron pairs were detected with the trigger hadron at pseudorapidity |η|<0.35 and the associated hadron at forward rapidity (deuteron direction, 3.0<η<3.8). Pairs were also detected with both hadrons measured at forward rapidity; in this case, the yield of back-to-back hadron pairs in d+Au collisions with small impact parameters is observed to be suppressed by a factor of 10 relative to p+p collisions. The kinematics of these pairs is expected to probe partons in the Au nucleus with a low fraction x of the nucleon momenta, where the gluon densities rise sharply. The observed suppression as a function of nuclear thickness, p_{T}, and η points to cold nuclear matter effects arising at high parton densities.

We present measurements of J/ψ yields in d+Au collisions at sqrt[s_{NN}]=200  GeV recorded by the PHENIX experiment and compare them with yields in p+p collisions at the same energy per nucleon-nucleon collision. The measurements cover a large kinematic range in J/ψ rapidity (-2.2<y<2.4) with high statistical precision and are compared with two theoretical models: one with nuclear shadowing combined with final state breakup and one with coherent gluon saturation effects. In order to remove model dependent systematic uncertainties we also compare the data to a simple geometric model. The forward rapidity data are inconsistent with nuclear modifications that are linear or exponential in the density weighted longitudinal thickness, such as those from the final state breakup of the bound state.