Findings from the University of East Anglia's evaluation of the Ipswich/Suffolk multi-agency strategy on prostitution following the five murders in 2006

This paper provides a summary of the main findings of an evaluation of a new multi-agency Strategy set up to tackle on-street sex-working, after five prostitutes were murdered in the English county town of Ipswich. It focuses on the outcomes of the Strategy’s four objectives, including their cost-effectiveness. It also offers an insight into the lives of the women who were previously involved in street sex-working, the means by which the Strategy helped them to move towards exiting this work, and the ways in which younger people identified as being at risk of entering it might be prevented from doing so

Examining hope as a transdiagnostic mechanism of change across anxiety disorders and CBT treatment protocols.

Hope is a trait that represents the capacity to identify strategies or pathways to achieve goals and the motivation or agency to effectively pursue those pathways. Hope has been demonstrated to be a robust source of resilience to anxiety and stress and there is limited evidence that, as has been suggested for decades, hope may function as a core process or transdiagnostic mechanism of change in psychotherapy. The current study examined the role of hope in predicting recovery in a clinical trial in which 223 individuals with 1 of 4 anxiety disorders were randomized to transdiagnostic cognitive behavior therapy (CBT), disorder-specific CBT, or a waitlist controlled condition. Effect size results indicated moderate to large intraindividual increases in hope, that changes in hope were consistent across the five CBT treatment protocols, that changes in hope were significantly greater in CBT relative to waitlist, and that changes in hope began early in treatment. Results of growth curve analyses indicated that CBT was a robust predictor of trajectories of change in hope compared to waitlist, and that changes in hope predicted changes in both self-reported and clinician-rated anxiety. Finally, a statistically significant indirect effect was found indicating that the effects of treatment on changes in anxiety were mediated by treatment effects on hope. Together, these results suggest that hope may be a promising transdiagnostic mechanism of change that is relevant across anxiety disorders and treatment protocols.R01 MH090053 - NIMH NIH HHSAccepted manuscrip

Ketoconazole- and Metyrapone-Induced Reductions on Urinary Steroid Metabolites Alter the Urinary Free Cortisol Immunoassay Reliability in Cushing Syndrome

Introduction: Twenty-four-hour urinary free cortisol (24h-UFC) is the most used test for follow-up decision-making in patients with Cushing syndrome (CS) under medical treatment. However, 24h-UFC determinations by immunoassays (IA) are commonly overestimated because of steroid metabolites' cross-reaction. It is still uncertain how ketoconazole (KTZ)- and metyrapone (MTP)-induced changes on the urinary steroid metabolites can alter the 24h-UFC*IA determinations' reliability. Methods: 24h-UFC was analyzed by IA and gas chromatography-mass spectrometry (GC-MS) in 193 samples (81 before treatment, 73 during KTZ, and 39 during MTP) from 34 CS patients. In addition, urinary steroidome was analyzed by GC-MS on each patient before and during treatment. Results: Before treatment, 24h-UFC*IA determinations were overestimated by a factor of 1.75 (95% CI 1.60-1.94) compared to those by GC-MS. However, during KTZ treatment, 24h-UFC*IA results were similar (0.98:1) to those by GC-MS (95% CI, 0.83-1.20). In patients taking MTP, IA bias only decreased 0.55, resulting in persistence of an overestimation factor of 1.33:1 (95% CI, 1.09-1.76). High method agreement between GC-MS and IA before treatment (R2 = 0.954) declined in patients under KTZ (R2 = 0.632) but not in MTP (R2 = 0.917). Upper limit normal (ULN) reductions in patients taking KTZ were 27% larger when using 24h-UFC*IA compared to 24h-UFC*GC-MS, which resulted in higher false efficacy and misleading biochemical classification of 15% of patients. Urinary excretion changes of 22 urinary steroid metabolites explained 86% of the 24h-UFC*IA interference. Larger urinary excretion reductions of 6β-hydroxy-cortisol, 20α-dihydrocortisol, and 18-hydroxy-cortisol in patients with KTZ elucidated the higher 24h-UFC*IA bias decrement compared to MTP-treated patients. Conclusion: KTZ and MTP alter the urinary excretion of IA cross-reactive steroid metabolites, thus decreasing the cross-reactive interference of 24h-UFC*IA determinations present before treatment. Consequently, this interference reduction in 24h-UFC*IA leads to loss of method agreement with GC-MS and high risk of overestimating the biochemical impact of KTZ and MTP in controlling CS because of poor reliability of reference ranges and ULN

The untapped potential of seascape genomics in the North Pacific

Seascape genomics provides a powerful framework to evaluate the presence and strength of environmental pressures on marine organisms, as well as to forecast long term species stability under various perturbations. In the highly productive North Pacific, forage fishes, key trophic links across ecosystems, are also contending with a rapidly warming climate and a litany of associated oceanographic changes (e.g., changes in salinity, dissolved oxygen, pH, primary production, etc.). These changes can place substantial selective pressures on populations over space and time. While several population genomics studies have targeted forage fishes in the North Pacific, none have formally analyzed the interactions between genotype and environment. However, when population genomics studies provide collection location information and other critical data, it is possible to supplement a published genomic dataset with environmental data from existing public databases and perform “post hoc seascape genomics” analyses. In reviewing the literature, we find pertinent metadata (dates and locations of sample collection) are rarely provided. We identify specific factors that may impede the application of seascape genomics methods in the North Pacific. Finally, we present an approach for supplementing data in a reproducible way to allow for post hoc seascape genomics analysis, in instances when metadata are reported. Overall, our goal is to demonstrate – via literature review – the utility and importance of seascape genomics to understanding the long term health of forage fish species in the North Pacific

Liver-Targeting of Interferon-Alpha with Tissue-Specific Domain Antibodies

PMCID: PMC3581439This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

The Application of Novel Research Technologies by the Deep Pelagic Nekton Dynamics of the Gulf of Mexico (DEEPEND) Consortium

The deep waters of the open ocean represent a major frontier in exploration and scientific understanding. However, modern technological and computational tools are making the deep ocean more accessible than ever before by facilitating increasingly sophisticated studies of deep ocean ecosystems. Here, we describe some of the cutting-edge technologies that have been employed by the Deep Pelagic Nekton Dynamics of the Gulf of Mexico (DEEPEND; www.deependconsortium.org) Consortium to study the biodiverse fauna and dynamic physical-chemical environment of the offshore Gulf of Mexico (GoM) from 0 to 1,500 m

Non-Invasive Imaging of Cysteine Cathepsin Activity in Solid Tumors Using a 64Cu-Labeled Activity-Based Probe

The papain family of cysteine cathepsins are actively involved in multiple stages of tumorigenesis. Because elevated cathepsin activity can be found in many types of human cancers, they are promising biomarkers that can be used to target radiological contrast agents for tumor detection. However, currently there are no radiological imaging agents available for these important molecular targets. We report here the development of positron emission tomography (PET) radionuclide-labeled probes that target the cysteine cathepsins by formation of an enzyme activity-dependent bond with the active site cysteine. These probes contain an acyloxymethyl ketone (AOMK) functional group that irreversibly labels the active site cysteine of papain family proteases attached to a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) tag for labeling with 64Cu for PET imaging studies. We performed biodistribution and microPET imaging studies in nude mice bearing subcutaneous tumors expressing various levels of cysteine cathepsin activity and found that the extent of probe uptake by tumors correlated with overall protease activity as measured by biochemical methods. Furthermore, probe signals could be reduced by pre-treatment with a general cathepsin inhibitor. We also found that inclusion of a Cy5 tag on the probe increased tumor uptake relative to probes lacking this fluorogenic dye. Overall, these results demonstrate that small molecule activity-based probes carrying radio-tracers can be used to image protease activity in living subjects

Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism

Ubiquitin specific peptidase 7 (USP7) is a deubiquitinating enzyme (DUB) that removes ubiquitin tags from specific protein substrates in order to alter their degradation rate and sub-cellular localization. USP7 has been proposed as a therapeutic target in several cancers because it has many reported substrates with a role in cancer progression, including FOXO4, MDM2, N-Myc, and PTEN. The multisubstrate nature of USP7, combined with the modest potency and selectivity of early generation USP7 inhibitors, has presented a challenge in defining predictors of response to USP7 and potential patient populations that would benefit most from USP7-targeted drugs. Here, we describe the structureguided development of XL177A, which irreversibly inhibits USP7 with sub-nM potency and selectivity across the human proteome. Evaluation of the cellular effects of XL177A reveals that selective USP7 inhibition suppresses cancer cell growth predominantly through a p53-dependent mechanism: XL177A specifically upregulates p53 transcriptional targets transcriptome-wide, hotspot mutations in TP53 but not any other genes predict response to XL177A across a panel of similar to 500 cancer cell lines, and TP53 knockout rescues XL177A-mediated growth suppression of TP53 wild-type (WT) cells. Together, these findings suggest TP53 mutational status as a biomarker for response to USP7 inhibition. We find that Ewing sarcoma and malignant rhabdoid tumor (MRT), two pediatric cancers that are sensitive to other p53-dependent cytotoxic drugs, also display increased sensitivity to XL177A

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant