The Joint European Compound Library:boosting precompetitive research

The Joint European Compound Library (JECL) is a new high-throughput screening collection aimed at driving precompetitive drug discovery and target validation. The JECL has been established with a core of over 321000 compounds from the proprietary collections of seven pharmaceutical companies and will expand to around 500000 compounds. Here, we analyse the physicochemical profile and chemical diversity of the core collection, showing that the collection is diverse and has a broad spectrum of predicted biological activity. We also describe a model for sharing compound information from multiple proprietary collections, enabling diversity and quality analysis without disclosing structures. The JECL is available for screening at no cost to European academic laboratories and SMEs through the IMI European Lead Factory (http://www.europeanleadfactory.eu/)

Does religion make a difference? : assessing the effects of Christian affiliation and practice on marital solidarity and divorce in Britain, 1985-2005

Marital breakdown rates were examined among 15,714 adults from the British Social Attitudes dataset for 1985-2005. Separation and divorce peaked at around 50 years of age, and increased significantly over the period of study. Ratios of separation or divorce were compared between respondents who had no religious affiliation and (a) Christian affiliates who attended church at least once a month, (b) Christian affiliates who attended church, but less than once a month, and (c) Christian affiliates who never attended church. The results showed that active Christians were 1.5 times less likely to suffer marital breakdown than non-affiliates, but there was no difference between affiliates who never attended church and those of no religion. Christians who attended infrequently were 1.3 times less likely to suffer marital breakdown compared to non-affiliates, suggesting that even infrequent attendance at church may have some significance for predicting the persistence of martial solidarity

Contagion and Trade: Why Are Currency Crises Regional?

Currency crises tend to be regional; they affect countries in geographic proximity. This suggests that patterns of international trade are important in understanding how currency crises spread, above and beyond any macroeconomic phenomena. We provide empirical support for this hypothesis. Using data for five different currency crises (in 1971, 1973, 1992, 1994, and 1997) we show that currency crises affect clusters of countries tied together by international trade. By way of contrast, macroeconomic and financial influences are not closely associated with the cross-country incidence of speculative attacks. We also show that trade linkages help explain cross-country correlations in exchange market pressure during crisis episodes, even after controlling for macroeconomic factors.

Differentiated State of Initiating Tumor Cells Is Key to Distinctive Immune Responses Seen in H-Ras

Heterogeneity in tumor immune responses is a poorly understood yet critical parameter for successful immunotherapy. In two doxycycline-inducible models where oncogenic H-RasG12V is targeted either to the epidermal basal/stem cell layer with a Keratin14-rtTA transgene (K14Ras), or committed progenitor/suprabasal cells with an Involucrin-tTA transgene (InvRas), we observed strikingly distinct tumor immune responses. On threshold doxycycline levels yielding similar Ras expression, tumor latency, and numbers, tumors from K14Ras mice had an immunosuppressed microenvironment, whereas InvRas tumors had a proinflammatory microenvironment. On a Rag1-/- background, InvRas mice developed fewer and smaller tumors that regressed over time, whereas K14Ras mice developed more tumors with shorter latency than Rag1+/+ controls. Adoptive transfer and depletion studies revealed that B-cell and CD4 T-cell cooperation was critical for tumor yield, lymphocyte polarization, and tumor immune phenotype in Rag1+/+ mice of both models. Coculture of tumor-conditioned B cells with CD4 T cells implicated direct contact for Th1 and regulatory T cell (Treg) polarization, and CD40-CD40L for Th1, Th2, and Treg generation, a response not observed from splenic B cells. Anti-CD40L caused regression of InvRas tumors but enhanced growth in K14Ras, whereas a CD40 agonist mAb had opposite effects in each tumor model. These data show that position of tumor-initiating cells within a stratified squamous epithelial tissue provokes distinct B- and CD4 T-cell interactions, which establish unique tumor microenvironments that regulate tumor development and response to immunotherap

TGFβ1 Overexpression by Keratinocytes Alters Skin Dendritic Cell Homeostasis and Enhances Contact Hypersensitivity

Overexpression of transforming growth factor beta-1 (TGFβ1) in mouse epidermis causes cutaneous inflammation and keratinocyte hyperproliferation. Here we examined acute effects of TGFβ1 overproduction by keratinocytes on skin dendritic cells (DCs). TGFβ1 induction for 2 and 4 days increased the numbers and CD86 expression of B220+ plasmacytoid DCs (pDCs) and CD207+CD103+, CD207−CD103−CD11b+, and CD207−CD103−CD11b− dermal DCs (dDCs) in skin-draining lymph nodes (SDLNs). The dermis of TGFβ1-overexpressing mice had significantly more pDCs, CD207+CD103+ dDCs, and CD207−CD11b+ dDCs in the absence of increased dermal proliferation. Application of dye, tetramethyl rhodamine iso-thiocyanate (TRITC), in dibutylpthalate (DBP) solution after TGFβ1 induction increased the numbers of TRITC+CD207− dDCs in SDLNs, and augmented TRITC/DBP-induced Langerhans cell (LC) migration 72hours post TRITC treatment. Consistent with this, LC migration was increased in vitro by TGFβ1 overexpression in skin explants and by exogenous TGFβ1 in culture media. Transient TGFβ1 induction during DNFB sensitization increased contact hypersensitivity responses by 1.5-fold. Thus, elevated epidermal TGFβ1 alone is sufficient to alter homeostasis of multiple cutaneous DC subsets, and enhance DC migration and immune responses to contact sensitizers. These results highlight a role for keratinocyte-derived TGFβ1 in DC trafficking and in the initiation of skin inflammation

Proceedings Virtual Imaging Trials in Medicine 2024

This submission comprises the proceedings of the 1st Virtual Imaging Trials in Medicine conference, organized by Duke University on April 22-24, 2024. The listed authors serve as the program directors for this conference. The VITM conference is a pioneering summit uniting experts from academia, industry and government in the fields of medical imaging and therapy to explore the transformative potential of in silico virtual trials and digital twins in revolutionizing healthcare. The proceedings are categorized by the respective days of the conference: Monday presentations, Tuesday presentations, Wednesday presentations, followed by the abstracts for the posters presented on Monday and Tuesday

Effectiveness and cost-effectiveness of an educational intervention for practice teams to deliver problem focused therapy for insomnia: rationale and design of a pilot cluster randomised trial

Background: Sleep problems are common, affecting over a third of adults in the United Kingdom and leading to reduced productivity and impaired health-related quality of life. Many of those whose lives are affected seek medical help from primary care. Drug treatment is ineffective long term. Psychological methods for managing sleep problems, including cognitive behavioural therapy for insomnia (CBTi) have been shown to be effective and cost effective but have not been widely implemented or evaluated in a general practice setting where they are most likely to be needed and most appropriately delivered. This paper outlines the protocol for a pilot study designed to evaluate the effectiveness and cost-effectiveness of an educational intervention for general practitioners, primary care nurses and other members of the primary care team to deliver problem focused therapy to adult patients presenting with sleep problems due to lifestyle causes, pain or mild to moderate depression or anxiety. Methods and design: This will be a pilot cluster randomised controlled trial of a complex intervention. General practices will be randomised to an educational intervention for problem focused therapy which includes a consultation approach comprising careful assessment (using assessment of secondary causes, sleep diaries and severity) and use of modified CBTi for insomnia in the consultation compared with usual care (general advice on sleep hygiene and pharmacotherapy with hypnotic drugs). Clinicians randomised to the intervention will receive an educational intervention (2 × 2 hours) to implement a complex intervention of problem focused therapy. Clinicians randomised to the control group will receive reinforcement of usual care with sleep hygiene advice. Outcomes will be assessed via self-completion questionnaires and telephone interviews of patients and staff as well as clinical records for interventions and prescribing. Discussion: Previous studies in adults have shown that psychological treatments for insomnia administered by specialist nurses to groups of patients can be effective within a primary care setting. This will be a pilot study to determine whether an educational intervention aimed at primary care teams to deliver problem focused therapy for insomnia can improve sleep management and outcomes for individual adult patients presenting to general practice. The study will also test procedures and collect information in preparation for a larger definitive cluster-randomised trial. The study is funded by The Health Foundation

Joint AAPM Task Group 282/EFOMP Working Group Report: Breast dosimetry for standard and contrast‐enhanced mammography and breast tomosynthesis

: Currently, there are multiple breast dosimetry estimation methods for mammography and its variants in use throughout the world. This fact alone introduces uncertainty, since it is often impossible to distinguish which model is internally used by a specific imaging system. In addition, all current models are hampered by various limitations, in terms of overly simplified models of the breast and its composition, as well as simplistic models of the imaging system. Many of these simplifications were necessary, for the most part, due to the need to limit the computational cost of obtaining the required dose conversion coefficients decades ago, when these models were first implemented. With the advancements in computational power, and to address most of the known limitations of previous breast dosimetry methods, a new breast dosimetry method, based on new breast models, has been developed, implemented, and tested. This model, developed jointly by the American Association of Physicists in Medicine and the European Federation for Organizations of Medical Physics, is applicable to standard mammography, digital breast tomosynthesis, and their contrast-enhanced variants. In addition, it includes models of the breast in both the cranio-caudal and the medio-lateral oblique views. Special emphasis was placed on the breast and system models used being based on evidence, either by analysis of large sets of patient data or by performing measurements on imaging devices from a range of manufacturers. Due to the vast number of dose conversion coefficients resulting from the developed model, and the relative complexity of the calculations needed to apply it, a software program has been made available for download or online use, free of charge, to apply the developed breast dosimetry method. The program is available for download or it can be used directly online. A separate User's Guide is provided with the software