Felix Frankfurter

Originally published in 1960. Felix Frankfurter, a controversial figure in American judicial history, completed more than twenty-one years of service on the Supreme Court. This book is the first extended treatment of his political performance as a justice. It portrays the influence that he, both as teacher and jurist, exerted in the growth of public law over fifty years. He has exerted his influence not only through his writing but also through his personal acquaintance with many important persons in and out of government service. Beyond examining the career of one man, Thomas opens up a wider window on the history of legal thought. The main value of the book, though, lies in its presentation of the philosophy of one leading twentieth-century educator and jurist

Building Public Issues Education Capacity to Address Health and Wellness: Recommendations from a Survey of Extension Professionals

A national Web-based survey administered through the University of Maryland assessed Cooperative Extension\u27s involvement in public policy education specific to health and wellness. Respondents included Family Consumer Sciences administrators, faculty, and staff. The majority of respondents agreed that public policy education was within the scope of their responsibilities, critical to their programs, and helpful in raising citizens\u27 interest and commitment to healthier communities. However, public policy education efforts would benefit from a more integrated approach across the national Extension system in terms of policy focus and Extension professionals\u27 roles and level of involvement

Developing, monitoring, and reporting of fidelity in aphasia trials: Core recommendations from the collaboration of aphasia trialists (CATs) trials for aphasia panel

Background: Developing, monitoring, and reporting of fidelity are essential and integral components to the design of randomised controlled trials (RCTs) in stroke and aphasia. Treatment fidelity refers to the degree to which an intervention is delivered as intended and is directly related to the quality of the evidence generated by RCTs. Clear documentation of treatment fidelity in trials assists in the evaluation of the clinical implications of potential benefits attributed to the intervention. Consideration of the implementation requirements of a research-based intervention as intended in a clinical context is necessary to achieve similar outcomes for a clinical population. Despite this, treatment fidelity is rarely reported in RCTs of aphasia intervention. Aim: To describe fidelity strategies and develop core recommendations for developing, monitoring, and reporting of fidelity in aphasia intervention RCTs. Scope: Relevant conceptual frameworks were considered. The Behaviour Change Consortium comprehensive framework of fidelity was adopted. It includes five areas: study design, training providers, delivery of treatment, treatment receipt, and treatment enactment. We explored fidelity in RCTs with a range of complex aphasia interventions (e.g., ASK, Big CACTUS, COMPARE, FCET2EC, POLAR, SUPERB, and VERSE) and described how different trial design factors (e.g., phase of trial, explanatory vs. pragmatic, number and location of sites, and number and type of treatment providers) influenced the fidelity strategies chosen. Strategies were mapped onto the five areas of the fidelity framework with a detailed exploration of how fidelity criteria were developed, measured, and monitored throughout each trial. This information was synthesised into a set of core recommendations to guide aphasia researchers towards the adequate measurement, capture, and reporting of fidelity within future aphasia intervention studies. Conclusions/Recommendations: Treatment fidelity should be a core consideration in planning an intervention trial, a concept that goes beyond treatment adherence alone. A range of strategies should be selected depending on the phase and design of the trial being undertaken and appropriate investment of time and costs should be considered

Mucedorus: the last ludic playbook, the first stage Arcadia

This article argues that two seemingly contradictory factors contributed to and sustained the success of the anonymous Elizabethan play Mucedorus (c. 1590; pub. 1598). First, that both the initial composition of Mucedorus and its Jacobean revival were driven in part by the popularity of its source, Philip Sidney's Arcadia. Second, the playbook's invitation to amateur playing allowed its romance narrative to be adopted and repurposed by diverse social groups. These two factors combined to create something of a paradox, suggesting that Mucedorus was both open to all yet iconographically connected to an elite author's popular text. This study will argue that Mucedorus pioneered the fashion for “continuations” or adaptations of the famously unfinished Arcadia, and one element of its success in print was its presentation as an affordable and performable version of Sidney's elite work. The Jacobean revival of Mucedorus by the King's Men is thus evidence of a strategy of engagement with the Arcadia designed to please the new Stuart monarchs. This association with the monarchy in part determined the cultural functions of the Arcadia and Mucedorus through the Interregnum to the close of the seventeenth century

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer