Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the EP(1) receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene ...derivative 4 which displayed molecular weight of 414.9g/mol and poor in vivo metabolic stability in the rat and resulted in the identification of compound 7i (GSK345931A) which demonstrated good metabolic stability in the rat and lower molecular weight (381.9g/mol). In addition, 7i (GSK345931A) showed measurable CNS penetration in the mouse and rat and potent analgesic efficacy in acute and sub-chronic models of inflammatory pain.
High-throughput screening has become a mainstay of small-molecule probe and early drug discovery. The question of how to build and evolve efficient screening collections systematically for cell-based ...and biochemical screening is still unresolved. It is often assumed that chemical structure diversity leads to diverse biological performance of a library. Here, we confirm earlier results showing that this inference is not always valid and suggest instead using biological measurement diversity derived from multiplexed profiling in the construction of libraries with diverse assay performance patterns for cell-based screens. Rather than using results from tens or hundreds of completed assays, which is resource intensive and not easily extensible, we use high-dimensional image-based cell morphology and gene expression profiles. We piloted this approach using over 30,000 compounds. We show that small-molecule profiling can be used to select compound sets with high rates of activity and diverse biological performance.
To determine in a randomized prospective multi-institutional trial whether the addition of tumor necrosis factor alpha (TNF-alpha) to a melphalan-based hyperthermic isolated limb perfusion (HILP) ...treatment would improve the complete response rate for locally advanced extremity melanoma.
Patients with locally advanced extremity melanoma were randomly assigned to receive melphalan or melphalan plus TNF-alpha during standard HILP. Patient randomization was stratified according to disease/treatment status and regional nodal disease status.
The intervention was completed in 124 patients of the 133 enrolled. Grade 4 adverse events were observed in 14 (12%) of 129 patients, with three (4%) of 64 in the melphalan-alone arm and 11 (16%) of 65 in the melphalan-plus-TNF-alpha arm (P = .0436). There were two toxicity-related lower extremity amputations in the melphalan-plus-TNF-alpha arm, and one disease progression-related upper extremity amputation in the melphalan-alone arm. There was no treatment-related mortality in either arm of the study. One hundred sixteen patients were assessable at 3 months postoperatively. Sixty-four percent of patients (36 of 58) in the melphalan-alone arm and 69% of patients (40 of 58) in the melphalan-plus-TNF-alpha arm showed a response to treatment at 3 months, with a complete response rate of 25% (14 of 58 patients) in the melphalan-alone arm and 26% (15 of 58 patients) in the melphalan-plus-TNF-alpha arm (P = .435 and P = .890, respectively).
In locally advanced extremity melanoma treated with HILP, the addition of TNF-alpha to melphalan did not demonstrate a significant enhancement of short-term response rates over melphalan alone by the 3-month follow-up, and TNF-alpha plus melphalan was associated with a higher complication rate.
INTRODUCTION
Experimental models are essential tools in neurodegenerative disease research. However, the translation of insights and drugs discovered in model systems has proven immensely ...challenging, marred by high failure rates in human clinical trials.
METHODS
Here we review the application of artificial intelligence (AI) and machine learning (ML) in experimental medicine for dementia research.
RESULTS
Considering the specific challenges of reproducibility and translation between other species or model systems and human biology in preclinical dementia research, we highlight best practices and resources that can be leveraged to quantify and evaluate translatability. We then evaluate how AI and ML approaches could be applied to enhance both cross‐model reproducibility and translation to human biology, while sustaining biological interpretability.
DISCUSSION
AI and ML approaches in experimental medicine remain in their infancy. However, they have great potential to strengthen preclinical research and translation if based upon adequate, robust, and reproducible experimental data.
Highlights
There are increasing applications of AI in experimental medicine.
We identified issues in reproducibility, cross‐species translation, and data curation in the field.
Our review highlights data resources and AI approaches as solutions.
Multi‐omics analysis with AI offers exciting future possibilities in drug discovery.
Specific language impairment (SLI) is a common developmental disorder characterized by difficulties in language acquisition despite otherwise normal development and in the absence of any obvious ...explanatory factors. We performed a high-density screen of SLI1, a region of chromosome 16q that shows highly significant and consistent linkage to nonword repetition, a measure of phonological short-term memory that is commonly impaired in SLI. Using two independent language-impaired samples, one family-based (211 families) and another selected from a population cohort on the basis of extreme language measures (490 cases), we detected association to two genes in the SLI1 region: that encoding c-maf-inducing protein (CMIP, minP = 5.5 × 10−7 at rs6564903) and that encoding calcium-transporting ATPase, type2C, member2 (ATP2C2, minP = 2.0 × 10−5 at rs11860694). Regression modeling indicated that each of these loci exerts an independent effect upon nonword repetition ability. Despite the consistent findings in language-impaired samples, investigation in a large unselected cohort (n = 3612) did not detect association. We therefore propose that variants in CMIP and ATP2C2 act to modulate phonological short-term memory primarily in the context of language impairment. As such, this investigation supports the hypothesis that some causes of language impairment are distinct from factors that influence normal language variation. This work therefore implicates CMIP and ATP2C2 in the etiology of SLI and provides molecular evidence for the importance of phonological short-term memory in language acquisition.
This document is the second of 2 companion appropriate use criteria (AUC) documents developed by the American College of Cardiology, American Association for Thoracic Surgery, American Heart ...Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons. The first document (J Am Coll Cardiol 2017;70:1647-1672) addresses the evaluation and use of multimodality imaging in the diagnosis and management of valvular heart disease, whereas this document addresses this topic with regard to structural (nonvalvular) heart disease. While dealing with different subjects, the 2 documents do share a common structure and feature some clinical overlap. The goal of the companion AUC documents is to provide a comprehensive resource for multimodality imaging in the context of structural and valvular heart disease, encompassing multiple imaging modalities.
Using standardized methodology, the clinical scenarios (indications) were developed by a diverse writing group to represent patient presentations encountered in everyday practice and included common applications and anticipated uses. Where appropriate, the scenarios were developed on the basis of the most current American College of Cardiology/American Heart Association Clinical Practice Guidelines.
A separate, independent rating panel scored the 102 clinical scenarios in this document on a scale of 1 to 9. Scores of 7 to 9 indicate that a modality is considered appropriate for the clinical scenario presented. Midrange scores of 4 to 6 indicate that a modality may be appropriate for the clinical scenario, and scores of 1 to 3 indicate that a modality is considered rarely appropriate for the clinical scenario.
The primary objective of the AUC is to provide a framework for the assessment of these scenarios by practices that will improve and standardize physician decision making. AUC publications reflect an ongoing effort by the American College of Cardiology to critically and systematically create, review, and categorize clinical situations in which diagnostic tests and procedures are utilized by physicians caring for patients with cardiovascular diseases. The process is based on the current understanding of the technical capabilities of the imaging modalities examined.
This document is 1 of 2 companion appropriate use criteria (AUC) documents developed by the American College of Cardiology, American Association for Thoracic Surgery, American Heart Association, ...American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons. This document addresses the evaluation and use of multimodality imaging in the diagnosis and management of valvular heart disease, whereas the second, companion document addresses this topic with regard to structural heart disease. Although there is clinical overlap, the documents addressing valvular and structural heart disease are published separately, albeit with a common structure. The goal of the companion AUC documents is to provide a comprehensive resource for multimodality imaging in the context of valvular and structural heart disease, encompassing multiple imaging modalities.
Using standardized methodology, the clinical scenarios (indications) were developed by a diverse writing group to represent patient presentations encountered in everyday practice and included common applications and anticipated uses. Where appropriate, the scenarios were developed on the basis of the most current American College of Cardiology/American Heart Association guidelines.
A separate, independent rating panel scored the 92 clinical scenarios in this document on a scale of 1 to 9. Scores of 7 to 9 indicate that a modality is considered appropriate for the clinical scenario presented. Midrange scores of 4 to 6 indicate that a modality may be appropriate for the clinical scenario, and scores of 1 to 3 indicate that a modality is considered rarely appropriate for the clinical scenario.
The primary objective of the AUC is to provide a framework for the assessment of these scenarios by practices that will improve and standardize physician decision making. AUC publications reflect an ongoing effort by the American College of Cardiology to critically and systematically create, review, and categorize clinical situations where diagnostic tests and procedures are utilized by physicians caring for patients with cardiovascular diseases. The process is based on the current understanding of the technical capabilities of the imaging modalities examined.
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