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Society of Toxicologic Pathology Digital Pathology and Image Analysis Special Interest Group Article*: Opinion on the Application of Artificial Intelligence and Machine Learning to Digital Toxicologic Pathology
No full textToxicologic pathology is transitioning from analog to digital methods. This transition seems inevitable due to a host of ongoing social and medical technological forces. Of these, artificial intelligence (AI) and in particular machine learning (ML) are globally disruptive, rapidly growing sectors of technology whose impact on the long-established field of histopathology is quickly being realized. The development of increasing numbers of algorithms, peering ever deeper into the histopathological space, has demonstrated to the scientific community that AI pathology platforms are now poised to truly impact the future of precision and personalized medicine. However, as with all great technological advances, there are implementation and adoption challenges. This review aims to define common and relevant AI and ML terminology, describe data generation and interpretation, outline current and potential future business cases, discuss validation and regulatory hurdles, and most importantly, propose how overcoming the challenges of this burgeoning technology may shape toxicologic pathology for years to come, enabling pathologists to contribute even more effectively to answering scientific questions and solving global health issues.*This article is a product of a Special Interest Group of the Society of Toxicologic Pathology (STP). The views expressed in this article are those of the authors and do not necessarily represent the policies, positions, or opinions of the STP
Mating suppresses alarm response in zebrafish
No full textMating and flight from threats are innate behaviors which enhance species survival. Stimuli to these behaviors often are contemporaneous and conflicting. How such conflicts are resolved, and where in the brain such decisions are made, are both poorly understood. For teleosts, olfactory stimuli are key elements of mating and threat responses. For example, zebrafish manifest a stereotypical escape response when exposed to alarm substance released from injured conspecific skin (“skin extract”). We find that when mating, fish ignore this threatening stimulus. Water conditioned by the mating fish (“mating water”) suffices to suppress much of the alarm response behavior. By 2-photon imaging of calcium transients, we mapped the regions of the brain responding to skin extract and to mating water. In the telencephalon, we found regions where the responses overlap, and also one region (medial Dp), to be predominantly activated by skin extract, and another, Vs, to be predominantly activated by mating water. When mating water and skin extract were applied simultaneously, the alarm-specific response was suppressed, while the mating water-specific response was retained, corresponding to the dominance of mating over flight behavior. The choice made, for reproduction over escape, is opposite to that of mammals, presumably reflecting how the balance affects species survival
MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21
No full textIntrinsic resistance of unknown mechanism impedes the clinical utility of inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) in malignancies other than breast cancer. Here, we used melanoma patient-derived xenografts (PDXs) to study the mechanisms for CDK4/6i resistance in preclinical settings. We observed that melanoma PDXs resistant to CDK4/6i frequently displayed activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, and inhibition of this pathway improved CDK4/6i response in a p21-dependent manner. We showed that a target of p21, CDK2, was necessary for proliferation in CDK4/6i-treated cells. Upon treatment with CDK4/6i, melanoma cells up-regulated cyclin D1, which sequestered p21 and another CDK inhibitor, p27, leaving a shortage of p21 and p27 available to bind and inhibit CDK2. Therefore, we tested whether induction of p21 in resistant melanoma cells would render them responsive to CDK4/6i. Because p21 is transcriptionally driven by p53, we coadministered CDK4/6i with a murine double minute (MDM2) antagonist to stabilize p53, allowing p21 accumulation. This resulted in improved antitumor activity in PDXs and in murine melanoma. Furthermore, coadministration of CDK4/6 and MDM2 antagonists with standard of care therapy caused tumor regression. Notably, the molecular features associated with response to CDK4/6 and MDM2 inhibitors in PDXs were recapitulated by an ex vivo organotypic slice culture assay, which could potentially be adopted in the clinic for patient stratification. Our findings provide a rationale for cotargeting CDK4/6 and MDM2 in melanoma
Automating Automation – How Close are We to Artificial Intelligence Impact?
No full textIn terms of consistency, repeatability, known errors, and sheer volume, there exists perhaps no better collection of data for computer learning than that emerging from automated processes. Many common lab procedures now run in parallel, miniaturized experiments – DNA synthesis, target screening, organoid culture, genetic analysis, organic reactions, safety assays – which are poised for extensive curation and algorithm development over the next 10 years. Our piece will briefly outline each area and offer opinions about how close we are to having artificial intelligence (AI), deep learning (DL) or machine learning (ML) influence each scientific domain
"Setting our sights on infectious diseases" Meeting Summary
No full textIn May 2019, the Wellcome Centre for Anti-Infectives Research (WCAIR) at the University of Dundee, UK,
54 held an international conference with the aim of discussing some key questions around discovering new medicines for infectious
55 diseases and a particular focus on diseases affecting Low and Middle Income Countries. There is an urgent need for new drugs
56 to treat most infectious diseases. We were keen to see if there were lessons that we could learn across different disease areas and
57 between the preclinical and clinical phases with the aim of exploring how we can improve and speed up the drug discovery,
58 translational, and clinical development processes. We started with an introductory session on the current situation and then
59 worked backward from clinical development to combination therapy, pharmacokinetic/pharmacodynamic (PK/PD) studies,
60 drug discovery pathways, and new starting points and targets. This Viewpoint aims to capture some of the learnings
Revealing molecular determinants of hERG blocker and activator binding
No full textThe Kv11.1 potassium channel, encoded by the human ether-a-go-go-related gene (hERG), plays an essential role in the cardiac action potential. hERG blockade by small molecules can induce "torsade de pointes" arrhythmias and sudden death; as such, it is an important off-target to avoid during drug discovery. Recently, a cryo-EM structure of the open channel state of hERG was reported, opening the door to in silico docking analyses and interpretation of hERG structure-activity relationships, with a view to avoiding blocking activity. Despite this, docking directly to this cryo-EM structure has been reported to yield binding modes that are unable to explain known mutagenesis data. In this work, we use molecular dynamics simulations to sample a range of channel conformations and run ensemble docking campaigns at the known hERG binding site below the selectivity filter, composed of the central cavity and the four deep hydrophobic pockets. We identify a hERG conformational state allowing discrimination of blockers vs non-blockers from docking; furthermore, the binding pocket agrees with mutagenesis data and blocker binding modes fit the hERG blocker pharmacophore. We then use the same protocol to identify a binding pocket in the hERG channel pore for hERG activators, again agreeing with reported mutagenesis. Our approach may be useful in drug discovery campaigns to prioritize candidate compounds based on hERG liability via virtual docking screens
A comparative study of in vitro assays for predicting the non-specific binding of PET imaging agents in vivo
No full textAbstract: Non-specific binding (NSB) is a key parameter in optimizing PET imaging tracers. We compared the ability of three available methods to predict NSB: LIMBA, rat fu,brain and CHI(IAM). Even though NSB is often associated with lipophilicity, we observed that logD does not correlate with any of these assays, clearly indicating that lipophilicity, while influencing NSB, is insufficient to predict it. A cross-comparison of the methods showed that all three correlate and are useful predictors of NSB. The three assays however rank the molecules slightly differently, illustrating the challenge of comparing molecules within a narrow chemical space. We also noted that CHI(IAM) values more effectively predict VNS, a measure of in vivo NSB in the human brain. CHI(IAM) measurements might be a closer model of the actual physicochemical interaction between PET tracer candidates and cell membranes, and seems to be the method of choice for the optimization of in vivo NSB
Modulation of Microglia by Voluntary Exercise or CSF1R Inhibition Prevents Age-Related Loss of Functional Motor Units
No full textAge-related loss of skeletal muscle innervation by motor neurons leads to impaired neuromuscular function and is a well-established clinical phenomenon. However, the underlying pathogenesis remains unclear. Studying mice, we find that the number of motor units (MUs) can be maintained by counteracting neurotoxic microglia in the aged spinal cord. We observe that marked innervation changes, detected by motor unit number estimation (MUNE), occur prior to loss of muscle function in aged mice. This coincides with gene expression changes indicative of neuronal remodeling and microglial activation in aged spinal cord. Voluntary exercise prevents loss of MUs and reverses microglia activation. Depleting microglia by CSF1R inhibition also prevents the age-related decline in MUNE and neuromuscular junction disruption, implying a causal link. Our results suggest that age-related changes in spinal cord microglia contribute to neuromuscular decline in aged mice and demonstrate that removal of aged neurotoxic microglia can prevent or reverse MU loss
A Phase II Study of the Efficacy and Safety of the MET Inhibitor Capmatinib (INC280) in Patients with Advanced Hepatocellular Carcinoma
No full textBackground: Objectives of this phase II study were to determine the clinical activity of the MET tyrosine kinase inhibitor capmatinib (INC280) in patients with MET-dysregulated advanced hepatocellular carcinoma (HCC), and assess the safety, pharmacokinetics, and correlation of biomarkers with response.
Study Design: This phase II, open-label, single-arm study evaluated twice-daily (BID) oral capmatinib in a dose-determining part, utilizing a Bayesian Logistic Regression Model (BLRM) subject to Escalation with Overdose Control criteria, safety, pharmacokinetic, and pharmacodynamic information to determine a recommended dose for expansion (RDE) evaluating efficacy in patients with MET-dysregulated HCC.
Results: Thirty-eight patients received treatment. In the dose-determining part, patients received capmatinib 300 mg BID capsules (n = 8), and in the expansion, patients received 600 mg BID capsules (n = 28) or 400 mg BID tablets (n = 2) based on the BLRM and other relevant clinical data. No qualifying (drug-related, dose-limiting) adverse events (AEs) were observed during the first 28 days of treatment, and the RDE was 600 mg BID capsules (equivalent pharmacokinetics to 400 mg BID tablets). The most common any-causality AEs were nausea (42%), vomiting (37%), and diarrhea (34%). In the expansion part, in a subgroup of 10 patients with MET-high HCC, the overall response rate was 30%, including one durable complete response (>600 days) and two partial responses (one durable [>600 days]).
Conclusions: Single-agent capmatinib at the RDE is tolerable with a manageable safety profile. Antitumor activity was seen in a subset of patients with MET-dysregulated (MET-high) HCC
The long and winding road in pharmaceutical development of canakinumab, a human anti-IL-1 antibody
No full textAbstract
Interleukin-1beta (IL-1) is an ancient and evolutionary conserved cytokine, which orchestrates in vertebrates innate immune responses triggered by infections. While temporally limited induction of IL-1 protects the organism against traumatic or infectious insults, its chronic production in unabated inflammation causes or enhances clinical manifestations of disease in almost all organ systems. Therefore, pharmacological targeting of IL-1 in a variety of clinical inflammatory conditions may provide symptomatic relief or profound disease modification. The discovery of proteolytic processing of the inactive pro-IL-1to mature, active and secreted IL-1 by the inflammasome/caspase I complex inspired drug discovery programs towards low molecular weight inhibitors across the Pharma industry. Approved and marketed IL-1 pathway drugs today, however, are biologics targeting either IL-1, or the IL-1 receptor. Canakinumab is a human monoclonal antibody that binds to human IL-1 with high affinity and neutralizes its biological activity. This review describes the unique preclinical and clinical development journey of canakinumab starting from a rare genetic autoinflammatory disease and a systemic juvenile form of arthritis to further rare monogenetic periodic fever syndromes, and leading to non-orphan diseases, such as gout, myocardial infarction, and lung cancer