Suppression of mid-infrared plasma resonance due to quantum confinement in delta-doped silicon

The classical Drude model provides an accurate description of the plasma resonance of three-dimensional materials, but only partially explains two-dimensional systems where quantum mechanical effects dominate such as P:$\delta$-layers - atomically thin sheets of phosphorus dopants in silicon that induce novel electronic properties beyond traditional doping. Previously it was shown that P:$\delta$-layers produce a distinct Drude tail feature in ellipsometry measurements. However, the ellipsometric spectra could not be properly fit by modeling the $\delta$-layer as discrete layer of classical Drude metal. In particular, even for large broadening corresponding to extremely short relaxation times, a plasma resonance feature was anticipated but not evident in the experimental data. In this work, we develop a physically accurate description of this system, which reveals a general approach to designing thin films with intentionally suppressed plasma resonances. Our model takes into account the strong charge density confinement and resulting quantum mechanical description of a P:$\delta$-layer. We show that the absence of a plasma resonance feature results from a combination of two factors: i), the sharply varying charge density profile due to strong confinement in the direction of growth; and ii), the effective mass and relaxation time anisotropy due to valley degeneracy. The plasma resonance reappears when the atoms composing the $\delta$-layer are allowed to diffuse out from the plane of the layer, destroying its well-confined two-dimensional character that is critical to its novel electronic properties

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Quasiclassical Trajectory Studies of the Hyperthermal N(⁴S) + D₂ → Nd(x³Σˉ) + D Reaction

Hyperthermal reactions, such as O(3P) + HCl, are known to occur within rocket plumes and around space vehicles in low earth orbit and have been widely studied using quasiclassical trajectory calculations (QCT) among other theoretical methods. The reaction of N(2D) + H2 has been widely studied using various experimental and theoretical techniques, however little attention has been given to reactions with the ground state N atom, N(4S), due to its low reactivity. In this study, we present QCT calculations on the reaction of N(4S) + D2 and comparisons to current experimental work will also be discussed

Water oxidation by mononuclear ruthenium complexes with TPA-based ligands

The synthesis, characterization, and water oxidation activity of mononuclear ruthenium complexes with tris(2-pyridylmethyl)amine (TPA), tris(6-methyl-2-pyridylmethyl)amine (Me 3TPA), and a new pentadentate ligand N,N-bis(2-pyridinylmethyl)-2,2′-bipyridine-6-methanamine (DPA-Bpy) have been described. The electrochemical properties of these mononuclear Ru complexes have been investigated by both experimental and computational methods. Using Ce IV as oxidant, stoichiometric oxidation of water by [Ru(TPA)(H 2O) 2] 2+ was observed, while Ru(Me 3TPA)(H 2O) 2] 2+ has much less activity for water oxidation. Compared to [Ru(TPA)(H 2O) 2] 2+ and [Ru(Me 3TPA)(H 2O) 2] 2+, [Ru(DPA-Bpy)(H 2O)] 2+ exhibited 20 times higher activity for water oxidation. This study demonstrates a new type of ligand scaffold to support water oxidation by mononuclear Ru complexes. © 2011 American Chemical Society

Use of AD Informer Set compounds to explore validity of novel targets in Alzheimer's disease pathology

Abstract Introduction A chemogenomic set of small molecules with annotated activities and implicated roles in Alzheimer's disease (AD) called the AD Informer Set was recently developed and made available to the AD research community: https://treatad.org/data‐tools/ad‐informer‐set/. Methods Small subsets of AD Informer Set compounds were selected for AD‐relevant profiling. Nine compounds targeting proteins expressed by six AD‐implicated genes prioritized for study by Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT‐AD) teams were selected for G‐protein coupled receptor (GPCR), amyloid beta (Aβ) and tau, and pharmacokinetic (PK) studies. Four non‐overlapping compounds were analyzed in microglial cytotoxicity and phagocytosis assays. Results The nine compounds targeting CAPN2, EPHX2, MDK, MerTK/FLT3, or SYK proteins were profiled in 46 to 47 primary GPCR binding assays. Human induced pluripotent stem cell (iPSC)‐derived neurons were treated with the same nine compounds and secretion of Aβ peptides (Aβ40 and Aβ42) as well as levels of phosphophorylated tau (p‐tau, Thr231) and total tau (t‐tau) peptides measured at two concentrations and two timepoints. Finally, CD1 mice were dosed intravenously to determine preliminary PK and/or brain‐specific penetrance values for these compounds. As a final cell‐based study, a non‐overlapping subset of four compounds was selected based on single‐concentration screening for analysis of both cytotoxicity and phagocytosis in murine and human microglia cells. Discussion We have demonstrated the utility of the AD Informer Set in the validation of novel AD hypotheses using biochemical, cellular (primary and immortalized), and in vivo studies. The selectivity for their primary targets versus essential GPCRs in the brain was established for our compounds. Statistical changes in tau, p‐tau, Aβ40, and/or Aβ42 and blood–brain barrier penetrance were observed, solidifying the utility of specific compounds for AD. Single‐concentration phagocytosis results were validated as predictive of dose–response findings. These studies established workflows, validated assays, and illuminated next steps for protein targets and compounds

AD Informer Set: Chemical tools to facilitate Alzheimer's disease drug discovery

Abstract Introduction The portfolio of novel targets to treat Alzheimer's disease (AD) has been enriched by the Accelerating Medicines Partnership Program for Alzheimer's Disease (AMP AD) program. Methods Publicly available resources, such as literature and databases, enabled a data‐driven effort to identify existing small molecule modulators for many protein products expressed by the genes nominated by AMP AD and suitable positive control compounds to be included in the set. Compounds contained within the set were manually selected and annotated with associated published, predicted, and/or experimental data. Results We built an annotated set of 171 small molecule modulators targeting 98 unique proteins that have been nominated by AMP AD consortium members as novel targets for the treatment of AD. The majority of compounds included in the set are inhibitors. These small molecules vary in their quality and should be considered chemical tools that can be used in efforts to validate therapeutic hypotheses, but which will require further optimization. A physical copy of the AD Informer Set can be requested on the Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT‐AD) website. Discussion Small molecules that enable target validation are important tools for the translation of novel hypotheses into viable therapeutic strategies for AD