The rise of ‘fend for yourself Federalism’ is fraying America’s welfare state

Federalism in the United States means that the national government has some responsibilities assigned to it under the Constitution with the majority of governance left up to the states. In new research, Anne Daguerre and Tim Conlan look at how the ‘cooperative federalism’ of previous years, where states and the federal government share power, has now fallen away due to increasing political polarization, and how this pattern is causing the country’s welfare state to become more fragmented and disjointed

Match high-speed running distances are often suppressed following return from hamstring strain injury in professional footballers

Background: High-speed running is commonly implicated in the genesis of hamstring injury. The success of hamstring injury management is typically quantified by the duration of time loss or reinjury rate. These metrics do not consider any loss in performance after returning to play from hamstring injury. It is not known to what extent high-speed running is altered on return to play after such injury. Hypothesis: Match high-speed running distance will change after returning from hamstring injury. Study Design: Non-randomized cohort. Level of Evidence: Level 3. Methods: Match high-speed running distance in highest level professional football (soccer, Rugby League, Rugby Union, and Australian Rules) were examined for a minimum of 5 games prior and subsequent to hamstring strain injury for individual differences using a linear regression models approach. A total of 22 injuries in 15 players were available for analysis. Results: Preinjury cumulative high-speed running distances were strongly correlated for each individual (r2 = 0.92-1.0; P < 0.0001). Pre- and postinjury high-speed running data were available for a median of 15 matches (range, 6-15). Variance from the preinjury high-speed running distance was significantly less (P = 0.0005) than the post injury values suggesting a suppression of high-speed running distance after returning from injury. On return to play, 7 of the 15 players showed a sustained absolute reduction in preinjury high-speed running distance, 7 showed no change, and 1 player (only) showed an increase. Analysis of subsequent (second and third injury) return to play showed no differences to return from the index injury. Conclusion: Return to play was not associated with return to high-speed running performance for nearly half of the players examined, although the same number showed no difference. Persisting deficits in match high-speed running may exist for many players after hamstring strain injury. Clinical Relevance: Returning to play does not mean returning to (high-speed running) performance for nearly half of the high-level professional football players examined in this study. This suggests that successful return to play metrics should be expanded from simple time taken and recurrence to include performance

A RAGE-Targeted Antibody-Drug Conjugate: Surface Plasmon Resonance as a Platform for Accelerating Effective ADC Design and Development

Antibodies, antibody-like molecules, and therapeutics incorporating antibodies as a targeting moiety, such as antibody-drug conjugates, offer significant potential for the development of highly efficacious drugs against a wide range of disorders. Despite some success, truly harnessing the superior targeting properties of these molecules requires a platform from which to effectively identify the best candidates for drug development. To streamline the development of antibody-drug conjugates targeting gynecological cancers within our laboratory, we incorporated surface plasmon resonance analysis (Biacore™ T200) into our development toolkit. Antibodies, selected based on positive ELISA screens as suitable for development as antibody-drug conjugates, were evaluated using surface plasmon resonance to determine a wide range of characteristics including specificity, kinetics/affinity, the effect of linker binding, the impact of the drug to antibody ratio, and the effect of endosomal pH on antibody-antigen binding. Analysis revealed important kinetics data and information regarding the effect of conjugation and endosomal pH on our antibody candidates that correlated with cell toxicity and antibody internalization data. As well as explaining observations from cell-based assays regarding antibody-drug conjugate efficacies, these data also provide important information regarding intelligent antibody selection and antibody-drug conjugate design. This study demonstrates the application of surface plasmon resonance technology as a platform, where detailed information can be obtained, supporting the requirements for rapid and high-throughput screening that will enable enhanced antibody-drug conjugate development

Antibody drug conjugates against the receptor for advanced glycation end products (RAGE), a novel therapeutic target in endometrial cancer

Background The treatment of endometrial cancer (EC), the most common gynecological cancer, is currently hampered by the toxicity of current cytotoxic agents, meaning novel therapeutic approaches are urgently required. Methods A cohort of 161 patients was evaluated for the expression of the receptor for advanced glycation end products (RAGE) in endometrial tissues. The present study also incorporates a variety of in vitro methodologies within multiple cell lines to evaluate RAGE expression and antibody-drug conjugate efficacy, internalisation and intercellular trafficking. Additionally, we undertook in vivo bio-distribution and toxicity evaluation to determine the suitability of our chosen therapeutic approach, together with efficacy studies in a mouse xenograft model of disease. Results We have identified an association between over-expression of the receptor for advanced glycation end products (RAGE) and EC (H-score = Healthy: 0.46, SD 0.26; Type I EC: 2.67, SD 1.39; Type II EC: 2.20, SD 1.34; ANOVA, p < 0.0001). Furthermore, increased expression was negatively correlated with patient survival (Spearman’s Rank Order Correlation: ρ = − 0.3914, p < 0.05). To exploit this association, we developed novel RAGE-targeting antibody drug conjugates (ADC) and demonstrated the efficacy of this approach. RAGE-targeting ADCs were up to 100-fold more efficacious in EC cells compared to non-malignant cells and up to 200-fold more cytotoxic than drug treatment alone. Additionally, RAGE-targeting ADCs were not toxic in an in vivo pre-clinical mouse model, and significantly reduced tumour growth in a xenograft mouse model of disease. Conclusions These data, together with important design considerations implied by the present study, suggest RAGE-ADCs could be translated to novel therapeutics for EC patients

Federalism, the Bush Administration, and the Transformation of American Conservatism

Most recent Republican presidents have proposed signature federalism initiatives intended to devolve power or sort out federal and state functions. The Bush administration has not propounded an explicit federalism policy of this sort, but its approach to federalism can be gleaned from analyzing presidential advocacy of legislation and constitutional amendments, fiscal policies, administrative actions, and judicial policies. What emerges from this analysis is an administration that has been surprisingly dismissive of federalism concerns and frequently an agent of centralization. In one sense, Bush is merely the latest in a string of presidents who have sacrificed federalism considerations to specific policy goals when the two have come in conflict. However, the administration's behavior is somewhat surprising, given the president's background as a governor and the fact that he has been the first Republican president to enjoy Republican control of Congress since 1954. Our explanation for the Bush approach begins with the president's lack of any philosophical commitment to federalism and explores the changing status of federalism concerns within conservative ideology. Any explanation for the Bush approach should account for this shifting political dynamic, which has seen Republicans in recent years become increasingly supportive of exerting federal authority on behalf of their economic and social objectives, encouraging Democrats at times to become more supportive of state authority. Copyright 2007, Oxford University Press.