Potentiation of Carboplatin-Mediated DNA Damage by the Mdm2 Modulator Nutlin-3a in a Humanized Orthotopic Breast-to-Lung Metastatic Model

Triple-negative breast cancers (TNBC) are typically resistant to treatment, and strategies that build upon frontline therapy are needed. Targeting the murine double minute 2 (Mdm2) protein is an attractive approach, as Mdm2 levels are elevated in many therapy-refractive breast cancers. The Mdm2 protein-protein interaction inhibitor Nutlin-3a blocks the binding of Mdm2 to key signaling molecules such as p53 and p73α and can result in activation of cell death signaling pathways. In the present study, the therapeutic potential of carboplatin and Nutlin-3a to treat TNBC was investigated, as carboplatin is under evaluation in clinical trials for TNBC. In mutant p53 TMD231 TNBC cells, carboplatin and Nutlin-3a led to increased Mdm2 and was strongly synergistic in promoting cell death in vitro. Furthermore, sensitivity of TNBC cells to combination treatment was dependent on p73α. Following combination treatment, γH2AX increased and Mdm2 localized to a larger degree to chromatin compared with single-agent treatment, consistent with previous observations that Mdm2 binds to the Mre11/Rad50/Nbs1 complex associated with DNA and inhibits the DNA damage response. In vivo efficacy studies were conducted in the TMD231 orthotopic mammary fat pad model in NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NSG) mice. Using an intermittent dosing schedule of combined carboplatin and Nutlin-3a, there was a significant reduction in primary tumor growth and lung metastases compared with vehicle and single-agent treatments. In addition, there was minimal toxicity to the bone marrow and normal tissues. These studies demonstrate that Mdm2 holds promise as a therapeutic target in combination with conventional therapy and may lead to new clinical therapies for TNBC

A co-registration investigation of inter-word spacing and parafoveal preview: Eye movements and fixation-related potentials

Participants’ eye movements (EMs) and EEG signal were simultaneously recorded to examine foveal and parafoveal processing during sentence reading. All the words in the sentence were manipulated for inter-word spacing (intact spaces vs. spaces replaced by a random letter) and parafoveal preview (identical preview vs. random letter string preview). We observed disruption for unspaced text and invalid preview conditions in both EMs and fixation-related potentials (FRPs). Unspaced and invalid preview conditions received longer reading times than spaced and valid preview conditions. In addition, the FRP data showed that unspaced previews disrupted reading in earlier time windows of analysis, compared to string preview conditions. Moreover, the effect of parafoveal preview was greater for spaced relative to unspaced conditions, in both EMs and FRPs. These findings replicate well-established preview effects, provide novel insight into the neural correlates of reading with and without inter-word spacing and suggest that spatial selection precedes lexical processing

Mentoring adolescents to prevent drug and alcohol use.

Objectives: Assess effectiveness of mentoring to prevent adolescent alcohol/drug use. Conclusions: All four RCTs were in the US, and included “deprived” and mostly minority adolescents. Participants were young (in two studies age 12, and in two others 9-16). All students at baseline were non-users of alcohol and drugs. Two RCTs found mentoring reduced the rate of initiation of alcohol, and one of drug usage. The ability of the interventions to be effective was limited by the low rates of commencing alcohol and drug use during the intervention period in two studies (the use of marijuana in one study increased to 1% in the experimental and to 1.6% in the control group, and in another study drug usage rose to 6% in the experimental and 11% in the control group). However, in a third study there was scope for the intervention to have an effect as alcohol use rose to 19% in the experimental and 27% in the control group. The studies assessed structured programmes and not informal mentors

Risk-benefit considerations in evaluating commensal anticoagulant rodenticide impacts to wildlife

Evaluation of the possible impacts of rodenticides on wildlife must be conducted in the context of risk-benefit considerations. Harmful introduced pests (e.g., commensal rats and mice) historically have required management around human habitation for economic and public health reasons. Disparate views of limited data have accumulated concerning the wildlife impacts resulting from commensal rodent control activities. The founding of the Rodenticide Registrants Task Force (RRTF), a trade association that includes all the major manufacturers and importers of anticoagulant rodenticide products (and bromethalin, a non-anticoagulant rodenticide) in the U.S., is described. The potential for anticoagulant dispersion in wildlife via primary and secondary routes is considered. Toxicology and pharmacokinetic studies are analyzed to obtain a better understanding of the biological and toxicological significance of low levels of rodenticide in animal tissue. A framework to address rodenticide impact to wildlife is presented. It is based upon the example of long-term cooperative efforts in England involving government, environmental, and manufacturer groups

Global confinement in the MST (Madison Symmetric Torus) reversed field pinch

Global confinement measured in the first six months of MST full design operation is summarized. Central electron temperature and enhancement of resistivity over the Z = 1 Spitzer value are similar to other RFP experiments for the same value of I/N. As in several other RFP experiments, energy confinement time and poloidal beta are found to decrease with increasing plasma current, with maximum values of {tau}{sub E} {approximately} 1 ms and {beta}{sub p} {approximately} 10%. Particle transport may be approximated with a diffusion coefficient D {approximately} 40 m{sup 2}/s for a discharge studied with a 1-d particle-neutral code. A more elaborate code, incorporating heat and impurity transport, indicates an increase of Z{sub eff} with I/N. This code also reveals that the toroidal magnetic field decays resistively between discrete dynamo events, at the rate given by the measured global resistivity. Edge suprathermal electrons are observed as on other RFPs, with temperatures comparable to the central electron temperature and carrying a current density at least 15% of the total measured with an insertable magnetic coil array. Radial magnetic profiles measured with this array may be matched with a Modified Polynomial Function Model equilibrium for a value of {beta}{sub p} which is a factor of two larger than measured, but which is required due to the large values of {Theta} for a given F found in MST discharges ({Theta} = 1.85 at F= {minus}0.15). 15 refs., 14 figs

Edge fluctuations in the MST (Madison Symmetric Torus) reversed field pinch

Edge magnetic and electrostatic fluctuations are measured in the Madison Symmetric Torus (MST) reversed field pinch. At low frequency ( {tilde p}{sub e}/p{sub e} where {tilde {phi}} and {tilde p}{sub e} are the fluctuating potential and pressure, respectively). From measurements of the fluctuating density, temperature, and potential we infer that the electrostatic fluctuation induced transport of particles and energy can be substantial. 13 refs., 11 figs

Turbulent transport in the MST reversed-field pinch

Measurements of edge turbulence and the associated transport are ongoing in the Madison Symmetric Torus (R = 1.5 m, a = 0.52 m) reversed-field pinch using magnetic and electrostatic probes. Magnetic fluctuations are dominated by m = 1 and n {approximately} 2R/a tearing modes. Particle losses induced by magnetic field fluctuations have been found to be ambipolar ( = O). Electrostatic fluctuations are broadband and turbulent, with mode widths {delta}m {approximately} 3--7 and {delta}n {approximately}70--150. Particle, parallel current, and energy transport arising from coherent motion with the fluctuating {tilde E}xB drift has been measured. Particle transport via this channel is comparable to the total particle loss from MST. Energy transport (from /B{sub o}) due to electrostatic fluctuations is relatively small, and parallel current transport (from /B{sub o}) may be small as well