Large Screening Research Articles

AI-Powered Virtual Screening of Large Compound Libraries Leads to the Discovery of Novel Inhibitors of Sirtuin-1.

The discovery of new scaffolds and chemotypes via high-throughput screening is tedious and resource intensive. Yet, there are millions of small molecules commercially available, rendering comprehensive in vitro tests intractable. We show how smart algorithms reduce large screening collections to target-specific sets of just a few hundred small molecules, allowing for a much faster and more cost-effective hit discovery process. We showcase the application of this virtual screening strategy by preselecting 434 compounds for Sirtuin-1 inhibition from a library of 2.6 million compounds, corresponding to 0.02% of the original library. Multistage in vitro validation ultimately confirmed nine chemically novel inhibitors. When compared to a competitive benchmark study for Sirtuin-1, our method shows a 12-fold higher hit rate. The results demonstrate how AI-driven preselection from large screening libraries allows for a massive reduction in the number of small molecules to be tested in vitro while still retaining a large number of hits.

Melanoma Detection in Alaska Native, American Indian, Asian, Black, Hispanic, and Pacific Islander Patients in a Large Skin Cancer Screening Initiative

This cohort study investigates patterns in melanoma detection in racial and ethnic minority populations as part of a large, primary care–based screening initiative.

Diversity of myxozoans (Cnidaria) infecting Neotropical fishes in southern Mexico

Myxozoans are a unique group of microscopic parasites that infect mainly fishes. These extremely reduced cnidarians are highly diverse and globally distributed in freshwater and marine habitats. Myxozoan diversity dimension is unknown in Mexico, a territory of an extraordinary biological diversity. This study aimed to explore, for the first time, myxozoan parasite diversity from fishes of the Neotropical region of Mexico. We performed a large morphological and molecular screening using host tissues of 22 ornamental and food fish species captured from different localities of Veracruz, Oaxaca and Chiapas. Myxozoan infections were detected in 90% of the fish species, 65% of them had 1 or 2 and 35% had 3 and up to 8 myxozoan species. Forty-one putative new species were identified using SSU rDNA phylogenetic analyses, belonging to two main lineages: polychaete-infecting (5 species) and oligochaete-infecting (36 species) myxozoans; from those we describe 4 new species: Myxidium zapotecus sp. n., Zschokkella guelaguetza sp. n., Ellipsomyxa papantla sp. n. and Myxobolus zoqueus sp. n. Myxozoan detection increased up to 6 × using molecular screening, which represents 3.7 × more species detected than by microscopy. This study demonstrated that Neotropical fishes from Mexico are hosts of a multitude of myxozoans, representing a source of emerging diseases with large implications for economic and conservation reasons.

Examining the continuum of resistance model in two population-based screening studies in Sweden

In studies recruited on a voluntary basis, lack of representativity may impair the ability to generalize findings to the target population. Previous studies, primarily based on surveys, have suggested that generalizability may be improved by exploiting data on individuals who agreed to participate only after receiving one or several reminders, as such individuals may be more similar to non-participants than what early participants are. Assessing this idea in the context of screenings, we compared sociodemographic characteristics and health across early, late, and non-participants in two large population-based screening studies in Sweden: STROKESTOP II (screening for atrial fibrillation; 6,867 participants) and SCREESCO (screening for colorectal cancer; 39,363 participants). We also explored the opportunities to reproduce the distributions of characteristics in the full invited populations, either by assuming that the non-participants were similar to the late participants, or by applying a linear extrapolation model based on both early and late participants. Findings showed that early and late participants exhibited similar characteristics along most dimensions, including civil status, education, income, and health examination results. Both these types of participants in turn differed from the non-participants, with fewer married, lower educational attainments, and lower incomes. Compared to early participants, late participants were more likely to be born outside of Sweden and to have comorbidities, with non-participants similar or even more so. The two empirical models improved representativity in some cases, but not always. Overall, we found mixed support that data on late participation may be useful for improving representativeness of screening studies.

Addressable TV Advertising Enhances Advertising Effectiveness

As TV consumption evolves from traditional linear programming to more on-demand viewing, advertising is also changing, seeking to tailor content to best match the interests of viewers. Addressable advertising is an interactive form of advertising that combines online data personalization with on-demand TV content with the aim of addressing individual viewers and improving advertising outcomes. This study investigated whether audience engagement with advertising (indexed by self-report liking, attention, and memory for an advertisement) was affected by addressability and the screen size on which the content was viewed. Using a limited capacity model of information processing and the elaboration likelihood model as its theoretical bases as well as a physiological measure of attention, we found that people both prefer and remember addressable advertisements more than those that are not relevant to them. In addition, viewing advertisements on large screens improved attention and retention for the content relative to smaller screens.

The hazards of delivering a public loan guarantee scheme: An analysis of borrower and lender characteristics

Using data between 2009 and 2020, we provide a detailed description of the borrowers within the Enterprise Finance Guarantee (EFG) loan portfolio, analyse time to default and how it differs across lender types. For limited companies, we match additional financial and non-financial data from public and proprietary databases and profile the characteristics of EFG companies within the population of limited companies. Employing hazard models we find loans granted to unincorporated businesses by the medium-sized financial institutions are associated with a much lower hazard than those provided by smaller local lending institutions and not-for-profit agencies. Moreover, we find some evidence that loans to limited companies, issued by the big UK banking groups, have a significantly lower default than those from medium-sized financial institutions. Large banks screen out high-risk firms. We argue that smaller lenders are able to price the risks rejected by the larger banks, using a wider range of credit information. JEL codes: G01, G21, L52, D25

Bicyclic peptides: Paving the road for therapeutics of the future

AbstractBicyclic peptides have emerged as one of the driving forces within the constrained peptide family. Due to their unique pharmaceutical attributes, peptide bicycles have garnered a reputation as promising therapeutics of the future. Combining advantages of small molecule therapeutics and biologics, the target binding qualities of this highly constrained class of molecules have been likened to those of antibodies. Over the past 5 years, the field of bicyclic peptides has advanced significantly. New bicyclic secondary peptide metabolites have been discovered in aquatic organisms and, importantly, a diverse assortment of bicyclic peptides has been synthesized de novo, exploring new chemical scaffolds. Biocompatible synthetic strategies that are suitable for large library screening platforms have helped to progress bicyclic peptides into clinical trials. This review aims to provide a comprehensive overview of the most recent progress in the field.

Predicting the Mitochondrial Toxicity of Small Molecules: Insights from Mechanistic Assays and Cell Painting Data.

Mitochondrial toxicity is a significant concern in the drug discovery process, as compounds that disrupt the function of these organelles can lead to serious side effects, including liver injury and cardiotoxicity. Different in vitro assays exist to detect mitochondrial toxicity at varying mechanistic levels: disruption of the respiratory chain, disruption of the membrane potential, or general mitochondrial dysfunction. In parallel, whole cell imaging assays like Cell Painting provide a phenotypic overview of the cellular system upon treatment and enable the assessment of mitochondrial health from cell profiling features. In this study, we aim to establish machine learning models for the prediction of mitochondrial toxicity, making the best use of the available data. For this purpose, we first derived highly curated datasets of mitochondrial toxicity, including subsets for different mechanisms of action. Due to the limited amount of labeled data often associated with toxicological endpoints, we investigated the potential of using morphological features from a large Cell Painting screen to label additional compounds and enrich our dataset. Our results suggest that models incorporating morphological profiles perform better in predicting mitochondrial toxicity than those trained on chemical structures alone (up to +0.08 and +0.09 mean MCC in random and cluster cross-validation, respectively). Toxicity labels derived from Cell Painting images improved the predictions on an external test set up to +0.08 MCC. However, we also found that further research is needed to improve the reliability of Cell Painting image labeling. Overall, our study provides insights into the importance of considering different mechanisms of action when predicting a complex endpoint like mitochondrial disruption as well as into the challenges and opportunities of using Cell Painting data for toxicity prediction.

Efficacy of convection enhanced delivery of MTX110 (soluble panobinostat) in preclinical Diffuse Intrinsic Pontine Glioma models using metabolic hyperpolarized 13C imaging

BackgroundDiffuse intrinsic pontine glioma (DIPG) usually occurs in children and has poor outcomes despite treatment. Large drug screens have identified the pan-histone deacetylate inhibitor panobinostat as a promising agent, however clinical response might be hampered by limited blood brain barrier penetration. Hyperpolarized 13C magnetic resonance (MR) metabolic imaging has successfully been applied to non-invasively assess metabolic activity of cancer therapies. Here, we use in vitro and in vivo DIPG models to validate the therapeutic efficacy of MTX110, an aqueous form of panobinostat delivered by convection enhanced delivery (CED) and apply metabolic imaging. MethodsMTX110 inhibitory effect was assessed in 11 DIPG cell lines. Caspase 3/7 levels were measured to assess mode of cell death. FACS analysis was utilized to determine impact on cell cycle. Hyperpolarized 13C imaging determined changes in pyruvate and lactate levels after treatment. In vivo activity of CED of MTX110 was assessed in a patient-derived xenograft rat model and tissue half-life of MTX110 was determined using mass spectrometry. ResultsMTX110 showed similar IC50 to panobinostat ranging from 5.34 nM and 47.96 nM. Anti-proliferative effects of MTX110 are mediated by G1 cell cycle arrest and subsequent apoptosis. Drug treatment led to reduced pyruvate to lactate conversion. CED of MTX110 significantly prolonged survival of tumor-bearing rats (p = 0.0372) with no signs of systemic toxicity. Tissue half-life after single CED of MTX110 is 2 h. ConclusionsOur results demonstrate that CED of MTX110, has potent antitumor activity with limited systemic toxicity and that hyperpolarized 13C imaging is able to assess metabolic impact.

SynBa: improved estimation of drug combination synergies with uncertainty quantification.

There exists a range of different quantification frameworks to estimate the synergistic effect of drug combinations. The diversity and disagreement in estimates make it challenging to determine which combinations from a large drug screening should be proceeded with. Furthermore, the lack of accurate uncertainty quantification for those estimates precludes the choice of optimal drug combinations based on the most favourable synergistic effect. In this work, we propose SynBa, a flexible Bayesian approach to estimate the uncertainty of the synergistic efficacy and potency of drug combinations, so that actionable decisions can be derived from the model outputs. The actionability is enabled by incorporating the Hill equation into SynBa, so that the parameters representing the potency and the efficacy can be preserved. Existing knowledge may be conveniently inserted due to the flexibility of the prior, as shown by the empirical Beta prior defined for the normalized maximal inhibition. Through experiments on large combination screenings and comparison against benchmark methods, we show that SynBa provides improved accuracy of dose-response predictions and better-calibrated uncertainty estimation for the parameters and the predictions. The code for SynBa is available at https://github.com/HaotingZhang1/SynBa. The datasets are publicly available (DOI of DREAM: 10.7303/syn4231880; DOI of the NCI-ALMANAC subset: 10.5281/zenodo.4135059).

A landscape of response to drug combinations in non-small cell lung cancer

Combination of anti-cancer drugs is broadly seen as way to overcome the often-limited efficacy of single agents. The design and testing of combinations are however very challenging. Here we present a uniquely large dataset screening over 5000 targeted agent combinations across 81 non-small cell lung cancer cell lines. Our analysis reveals a profound heterogeneity of response across the tumor models. Notably, combinations very rarely result in a strong gain in efficacy over the range of response observable with single agents. Importantly, gain of activity over single agents is more often seen when co-targeting functionally proximal genes, offering a strategy for designing more efficient combinations. Because combinatorial effect is strongly context specific, tumor specificity should be achievable. The resource provided, together with an additional validation screen sheds light on major challenges and opportunities in building efficacious combinations against cancer and provides an opportunity for training computational models for synergy prediction.

Large scale application of the Finnish diabetes risk score in Latin American and Caribbean populations: a descriptive study.

The prevalence of type 2 diabetes (T2D) continues to increase in the Americas. Identifying people at risk for T2D is critical to the prevention of T2D complications, especially cardiovascular disease. This study gauges the ability to implement large population-based organized screening campaigns in 19 Latin American and Caribbean countries to detect people at risk for T2D using the Finnish Diabetes Risk Score (FINDRISC). This cross-sectional descriptive analysis uses data collected in a sample of men and women 18 years of age or older who completed FINDRISC via eHealth during a Guinness World Record attempt campaign between October 25 and November 1, 2021. FINDRISC is a non-invasive screening tool based on age, body mass index, waist circumference, physical activity, daily intake of fruits and vegetables, history of hyperglycemia, history of antihypertensive drug treatment, and family history of T2D, assigning a score ranging from 0 to 26 points. A cut-off point of ≥ 12 points was considered as high risk for T2D. The final sample size consisted of 29,662 women (63%) and 17,605 men (27%). In total, 35% of subjects were at risk of T2D. The highest frequency rates (FINDRISC ≥ 12) were observed in Chile (39%), Central America (36.4%), and Peru (36.1%). Chile also had the highest proportion of people having a FINDRISC ≥15 points (25%), whereas the lowest was observed in Colombia (11.3%). FINDRISC can be easily implemented via eHealth technology over social networks in Latin American and Caribbean populations to detect people with high risk for T2D. Primary healthcare strategies are needed to perform T2D organized screening to deliver early, accessible, culturally sensitive, and sustainable interventions to prevent sequelae of T2D, and reduce the clinical and economic burden of cardiometabolic-based chronic disease.

P-428 Impact of chemotherapy exposure using 4-hydroperoxycyclophosphamide on a male germ cell line (GC1-spg) and testes from prepubertal mouse

Abstract Study question What are the dynamics of the toxicity from 4-hydroperoxycyclophosphamide (4-HC) on male germ cell line and prepubertal mouse testes? Summary answer Chemotherapy has dose- and time- dependent harmful effects on genes regulating apoptosis and survival in the two different models. What is known already Fertility preservation strategies offered to prepubertal boys during oncological treatment are limited. The development of a noninvasive pharmacological protection of spermatogenic cells during oncological treatments would be a major advancement in the field. Studies in the female gonad have shown that chemotherapy exposure alters the expression profile of miRNAs and that miRNA-mimics administration could be used as an innovative tool to protect germ cells during gonadotoxic treatment. This project aims to assess the acute effect of 4-HC exposure on apoptosis and proliferation in spermatogonia in order to evaluate the differential miRNAs expression profile in male germ cells following gonadotoxic insult. Study design, size, duration GC-1 spermatogonial (GC1-spg) cells were cultured for 48h and exposed during the last 24h to different doses of 4-HC (20, 30 and 50µM) before assessing apoptosis and proliferation to evaluate the gonadotoxic dose of this agent. Cells were then exposed to 4-HC-50µM and apoptosis/proliferation were evaluated after 1,4,8,12,16,20 and 24h to establish the acute timepoint of gonadotoxicity. Similar experiments were then conducted on post-natal day 3 mouse testes during a culture of 24h. (N = 3) Participants/materials, setting, methods Histological analyses were performed to detect early apoptosis within spermatogonia cells using DDX4 and Cleaved Caspase 3 (CC3) co-immunostaining. DNA damages were evaluated on testes using TUNEL assay. A large screening of apoptosis gene expression was performed on cells with Taqman array (RT-qPCR). Apoptosis and cell proliferation were further assessed in both models through gene expression analyses of CC3 and Ki-67, respectively. Main results and the role of chance After 24 hours of in vitro exposure, a significant increase of apoptosis was observed in the cells treated with 30 µM of 4-HC and 50 µM of 4-HC, reflected by a higher level of CC3 expression in those two conditions compared to the control and the 4-HC-20 µM conditions. The panel screening of apoptosis gene expression performed on cells exposed to 20µM 4-HC during 24h showed no significant difference of expression between the control and the treated condition, sustaining the absence of harmful effect of 4-HC at this concentration in our model. The different timepoint analyses on cells using 50µM 4-HC have shown that chemotherapy-induced CC3 expression occurs approximatively 20 hours after the initiation of the treatment (p = 0.014). Similarly, there is a significant increase of apoptosis in prepubertal mouse testes following exposure to 50 µM of 4-HC compared to control, while no significant effect was observed at 20 µM 4-HC exposure. In both models, no change in proliferation through Ki-67 gene expression analyses was observed between non-treated and treated conditions. Finally, histological analyses performed on newborn mouse testes previously exposed or not to 4-HC revealed an increase of DNA fragmentation in the treated testes compared to control. Limitations, reasons for caution The use of a mouse cell line and in vitro cultured mouse testes is a limitation because of the species barrier. The direct exposure to chemotherapy (compared to in vivo models) can influence the level of toxic damage. Wider implications of the findings Those data characterize the dynamics of the toxic effect of 4-HC on spermatogonia. They will precise the optimal temporal window to detect the modifications in miRNA profiles by sequencing, to address the expression alterations and provide new targets to reduce cyclophosphamide gonadotoxic effects on the testicular germ cells. Trial registration number not applicable

Development of a predictive model for identifying women vulnerable to HIV in Chicago

IntroductionResearchers in the United States have created several models to predict persons most at risk for HIV. Many of these predictive models use data from all persons newly diagnosed with HIV, the majority of whom are men, and specifically men who have sex with men (MSM). Consequently, risk factors identified by these models are biased toward features that apply only to men or capture sexual behaviours of MSM. We sought to create a predictive model for women using cohort data from two major hospitals in Chicago with large opt-out HIV screening programs.MethodsWe matched 48 newly diagnosed women to 192 HIV-negative women based on number of previous encounters at University of Chicago or Rush University hospitals. We examined data for each woman for the two years prior to either their HIV diagnosis or their last encounter. We assessed risk factors including demographic characteristics and clinical diagnoses taken from patient electronic medical records (EMR) using odds ratios and 95% confidence intervals. We created a multivariable logistic regression model and measured predictive power with the area under the curve (AUC). In the multivariable model, age group, race, and ethnicity were included a priori due to increased risk for HIV among specific demographic groups.ResultsThe following clinical diagnoses were significant at the bivariate level and were included in the model: pregnancy (OR 1.96 (1.00, 3.84)), hepatitis C (OR 5.73 (1.24, 26.51)), substance use (OR 3.12 (1.12, 8.65)) and sexually transmitted infections (STIs) chlamydia, gonorrhoea, or syphilis. We also a priori included demographic factors that are associated with HIV. Our final model had an AUC of 0.74 and included healthcare site, age group, race, ethnicity, pregnancy, hepatitis C, substance use, and STI diagnosis.ConclusionsOur predictive model showed acceptable discrimination between those who were and were not newly diagnosed with HIV. We identified risk factors such as recent pregnancy, recent hepatitis C diagnosis, and substance use in addition to the traditionally used recent STI diagnosis that can be incorporated by health systems to detect women who are vulnerable to HIV and would benefit from preexposure prophylaxis (PrEP).

Aging effects on extrapersonal (far-space) attention: cancellation and line bisection performance from 179 healthy adults

ABSTRACT Assessment of cognitive impairments is a vital part of clinical practice. Cancellation (visual search) and line bisection are commonly used tasks to assess visuospatial attention. Despite the fact visuospatial attention is engaged in both near (within reach) and far-space (out of reach), most studies have been conducted in near-space alone. Moreover, despite their use in clinical practice, it is unclear whether cancellation and bisection tasks are related. Here, we investigated the impact of aging on cancellation and line bisection performance in far-space in a large healthy sample. We provide preliminary age-graded norms for assessing visuospatial attention in far-space calculated from a sample of 179 healthy adults, between the ages of 18–94 (mean age = 49.29). Cancellation and line bisection were presented on a large screen in far-space and completed using a wireless remote. Aging was accompanied by longer task duration for both tasks, slower search speed and poorer quality of search. However, there was no significant effect of aging on line bisection error. There was a significant correlation between the two tasks in that longer task duration in line bisection was associated with slower search speed and poorer quality of search. Overall, participants presented a leftward bias during cancellation and line bisection akin to pseudoneglect. Moreover, we found that irrespective of age, search speed was faster in males than females. We offer novel evidence that performance on cancellation and line bisection tasks are related to one another in far-space, but are also sensitive to age-related decline, and even sex differences.

K teorii nukleatsii ionnykh soley iz vodnykh rastvorov

The theory of nucleation of ionic salts from aqueous solution is critically analyzed and further developed in two limiting cases of sparingly and highly soluble strong electrolytes. In the case of sparingly soluble colloids with a relatively large screening length (compared to the radius of the critical nucleus), the classical nucleation theory is modified by taking into account the influence of the critical nucleus charge on the nucleation rate, which was disregarded in earlier models. In the opposite limit of highly soluble colloids which are characterized by a relatively small screening length, the influence of the critical nucleus charge on the nucleation rate can be neglected with good accuracy. However, the discrepancy with earlier models, mainly related to the value of the pre-exponential factor, can reach several orders of magnitude.

Beyond the smart city: a communications-led agenda for twentyfirst century cities

Abstract Digital media technologies, from networked sensors to large video screens and mobile devices, have become pervasive urban infrastructure in the twentyfirst century. The dominant framework for understanding the integration of digital technology into urban space has been smart city discourse. In this article, I will argue that this framework, as it has so far been articulated, is inadequate to maximizing the social potential of digital urban infrastructure. Digital urban infrastructure not only changes how cities look, but how they function as social settings. I will propose the ‘communicative city’ as an alternative framework for thinking about digitally mediated cities. The communicative city offers an opportunity to consider networked urban space as a test case in which key problematics of contemporary globalized media are materially instantiated. It is the frontier zone at which everyday experiences of embodied media and new forms of communicative agency collide with powerful logics of tracing and tracking, and the widespread deployment of new forms of automation and machine learning as techniques of urban governance.

G8 screening and health-care use in patients with cancer

G8 screening and health-care use in patients with cancer

DIPG-22. TRIPTOLIDE AS A POTENTIALLY PROMISING THERAPY FOR DIFFUSE MIDLINE GLIOMA

Abstract Diffuse Midline Gliomas (DMG) are amongst the most lethal pediatric brain tumors. Children diagnosed with DMG face a grim prognosis of 9-11 months from diagnosis. Over 85% of DMG patients harbor mutation affecting histone-encoding genes (H3.1K27M, H3.3K27M) leading to genome hypomethylation and transcriptional disruption. Despite decades of clinical studies, the development of an effective therapy remains a challenge. Triptolide is a diterpenoid triepoxide compound inhibiting cell growth and exhibiting preclinical antitumor activity. A large drug screen conducted by the NCI using DMG cell lines identified triptolide as a candidate for reducing DMG cell viability. To further investigate triptolide and its potential for clinical intervention, we used DMG preclinical in vitro and in vivo models. In vitro viability assays with triptolide alone and in combination with other therapeutic drugs (ONC201 and ONC206), were carried out using seven DMG cell lines. Single treatment with triptolide resulted in a significant decrease in DMG cell viability and combination with both ONC201 and ONC206 showed additivity. Triptolide’s toxicity was assessed in vivo through direct injections into the yolk sac of zebrafish. Preliminary data demonstrated how triptolide has higher toxicity compared to un-injected and DMSO control groups. However, a major limitation of triptolide’s clinical utility is its low solubility. Therefore, for in vivo studies, we used minnelide, a water-soluble analog of triptolide, with potent antitumor properties. Studies were performed in eleven RAG2 female mice. PDX tumor-bearing mice were treated with minnelide and ONC201 for three weeks as single or in combination. Survival studies showed no significance in minnelide monotherapy. However, minnelide + ONC201 combination therapy resulted in significant (p=0.01) survival of PDX models. Our current studies investigate the efficacy of a higher dose of minnelide in vivo. Our goal is to establish minnelide potential as a combination strategy for the treatment of children diagnosed with DMG.

Fast Twist Angle Mapping of Bilayer Graphene Using Spectroscopic Ellipsometric Contrast Microscopy.

Twisted bilayer graphene provides an ideal solid-state model to explore correlated material properties and opportunities for a variety of optoelectronic applications, but reliable, fast characterization of the twist angle remains a challenge. Here we introduce spectroscopic ellipsometric contrast microscopy (SECM) as a tool for mapping twist angle disorder in optically resonant twisted bilayer graphene. We optimize the ellipsometric angles to enhance the image contrast based on measured and calculated reflection coefficients of incident light. The optical resonances associated with van Hove singularities correlate well to Raman and angle-resolved photoelectron emission spectroscopy, confirming the accuracy of SECM. The results highlight the advantages of SECM, which proves to be a fast, nondestructive method for characterization of twisted bilayer graphene over large areas, unlocking process, material, and device screening and cross-correlative measurement potential for bilayer and multilayer materials.