Measurement of polarization-transfer to bound protons in carbon and its virtuality dependence

We measured the ratio $P_{x}/P_{z}$ of the transverse to longitudinal components of polarization transferred from electrons to bound protons in $^{12}\mathrm{C}$ by the $^{12}\mathrm{C}(\vec{e},e'\vec{p})$ process at the Mainz Microtron (MAMI). We observed consistent deviations from unity of this ratio normalized to the free-proton ratio, $(P_{x}/P_{z})_{^{12}\mathrm{C}}/(P_{x}/P_{z})_{^{1}\mathrm{H}}$, for both $s$- and $p$-shell knocked out protons, even though they are embedded in averaged local densities that differ by about a factor of two. The dependence of the double ratio on proton virtuality is similar to the one for knocked out protons from $^{2}\mathrm{H}$ and $^{4}\mathrm{He}$, suggesting a universal behavior. It further implies no dependence on average local nuclear density

Components of polarization-transfer to a bound proton in a deuteron measured by quasi-elastic electron scattering

We report the first measurements of the transverse ($P_{x}$ and $P_{y}$) and longitudinal ($P_{z}$) components of the polarization transfer to a bound proton in the deuteron via the $^{2}\mathrm{H}(\vec{e},e'\vec{p})$ reaction, over a wide range of missing momentum. A precise determination of the electron beam polarization reduces the systematic uncertainties on the individual components, to a level that enables a detailed comparison to a state-of-the-art calculation of the deuteron that uses free-proton electromagnetic form factors. We observe very good agreement between the measured and the calculated $P_{x}/P_{z}$ ratios, but deviations of the individual components. Our results cannot be explained by medium modified electromagnetic form factors. They point to an incomplete description of the nuclear reaction mechanism in the calculation

Comparison of recoil polarization in the 12C(e⃗,e′p⃗)^{12}{\rm C}(\vec{e},{e}'\vec{p}) process for protons extracted from ss and pp shell

We present first measurements of the double ratio of the polarization transfer components $(P^{\prime}_{\!x} \!/ P^{\prime}_{\!z} )_p/ (P^{\prime}_{\!x} \!/ P^{\prime}_{\!z} )_s$ for knock-out protons from $s$ and $p$ shells in $^{12}{\rm C}$ measured by the $^{12}{\rm C}(\vec{e},{e}'\vec{p}\,)$ reaction in quasi-elastic kinematics. The data are compared to theoretical predictions in relativistic distorted-wave impulse approximation. Our results show that differences between $s$- and $p$-shell protons, observed when compared at the same initial momentum (missing momentum) largely disappear when the comparison is done at the same proton virtuality. We observe no density-dependent medium modifications for protons from $s$ and $p$ shells with the same virtuality in spite of the large differences in the respective nuclear densities

The influence of Fermi motion on the comparison of the polarization transfer to a proton in elastic e⃗p\vec ep and quasi-elastic e⃗A\vec eA scattering

A comparison between polarization-transfer to a bound proton in quasi-free kinematics by the A$(\vec{e},e'\vec p)$ knockout reaction and that in elastic scattering off a free proton can provide information on the characteristics of the bound proton. In the past the reported measurements have been compared to those of a free proton with zero initial momentum. We introduce, for the first time, expressions for the polarization-transfer components when the proton is initially in motion and compare them to the $^2$H data measured at the Mainz Microtron (MAMI). We show the ratios of the transverse ($P_x$) and longitudinal ($P_z$) components of the polarization transfer in $^2\textrm{H}(\vec{e},e'\vec p)\textrm{n}$, to those of elastic scattering off a "moving proton", assuming the proton's initial (Fermi) momentum equals the negative missing momentum in the measured reaction. We found that the correction due to the proton motion is up to 20\% at high missing momentum. However the effect on the double ratio $\frac{(P_x/P_z)^A}{(P_x/P_z)^{^1\!\textrm{H}}}$ is largely canceled out, as shown for both $^2$H and $^{12}$C data. This implies that the kinematics is not the primary cause for the deviations between quasi-elastic and elastic scattering reported previously

Combination Early-Phase Trials of Anticancer Agents in Children and Adolescents

PURPOSEThere is an increasing need to evaluate innovative drugs for childhood cancer using combination strategies. Strong biological rationale and clinical experience suggest that multiple agents will be more efficacious than monotherapy for most diseases and may overcome resistance mechanisms and increase synergy. The process to evaluate these combination trials needs to maximize efficiency and should be agreed by all stakeholders.METHODSAfter a review of existing combination trial methodologies, regulatory requirements, and current results, a consensus among stakeholders was achieved.RESULTSCombinations of anticancer therapies should be developed on the basis of mechanism of action and robust preclinical evaluation, and may include data from adult clinical trials. The general principle for combination early-phase studies is that, when possible, clinical trials should be dose- and schedule-confirmatory rather than dose-exploratory, and every effort should be made to optimize doses early. Efficient early-phase combination trials should be seamless, including dose confirmation and randomized expansion. Dose evaluation designs for combinations depend on the extent of previous knowledge. If not previously evaluated, limited evaluation of monotherapy should be included in the same clinical trial as the combination. Randomized evaluation of a new agent plus standard therapy versus standard therapy is the most effective approach to isolate the effect and toxicity of the novel agent. Platform trials may be valuable in the evaluation of combination studies. Patient advocates and regulators should be engaged with investigators early in a proposed clinical development pathway and trial design must consider regulatory requirements.CONCLUSIONAn optimized, agreed approach to the design and evaluation of early-phase pediatric combination trials will accelerate drug development and benefit all stakeholders, most importantly children and adolescents with cancer.</p

Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 lysine 27 trimethylation

Down syndrome confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (B-ALL)1 and polysomy 21 is the most frequent somatic aneuploidy amongst all B-ALLs2. Yet, the mechanistic links between chr.21 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chr.21q22 confers murine progenitor B cell self-renewal in vitro, maturation defects in vivo, and B-ALL with either BCR-ABL or CRLF2 with activated JAK2. Chr.21q22 triplication suppresses H3K27me3 in progenitor B cells and B-ALLs, and “bivalent” genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells. Strikingly, human B-ALLs with polysomy 21 are distinguished by their overexpression of genes marked with H3K27me3 in multiple cell types. Finally, overexpression of HMGN1, a nucleosome remodeling protein encoded on chr.21q223–5, suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo