Multiple Screening Approaches Research Articles

Multilayered screening for multi-targeted anti-Alzheimer's and anti-Parkinson's agents through structure-based pharmacophore modelling, MCDM, docking, molecular dynamics and DFT: a case study of HDAC4 inhibitors.

Alzheimer's disease (AD) and Parkinson's disease (PD) are neurological conditions that primarily impact the elderly having distinctive traits and some similarities in terms of symptoms and progression. The multifactorial nature of AD and PD encourages exploring potentiality of multi-target therapy for addressing these conditions to conventional, the "one drug one target" strategy. This study highlights the searching of potential HDAC4 inhibitors through multiple screening approaches. In this context, structure-based pharmacophore model, ligand profiler mapping and MCDM approaches were performed for target prioritization. Similarly, ligand profiler, MCDM and Docking studies were performed to prioritize multi-targeted HDAC4 inhibitors. These comprehensive approaches unveiled 5 common targets and 5 multi-targeted prioritized compounds consensually. MD simulations, DFT and binding free energy calculations corroborated the stability and robustness of propitious compound 774 across 5 prioritized targets. In conclusion, the screened compound 774 (ChEMBL 4063938) could be a promising multi-targeted therapy for managing AD and PD further rendering experimental validation. The online version contains supplementary material available at 10.1007/s40203-024-00302-4.

IRIS: Discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing

Alternative splicing (AS) is prevalent in cancer, generating an extensive but largely unexplored repertoire of novel immunotherapy targets. We describe Isoform peptides from RNA splicing for Immunotherapy target Screening (IRIS), a computational platform capable of discovering AS-derived tumor antigens (TAs) for T cell receptor (TCR) and chimeric antigen receptor T cell (CAR-T) therapies. IRIS leverages large-scale tumor and normal transcriptome data and incorporates multiple screening approaches to discover AS-derived TAs with tumor-associated or tumor-specific expression. In a proof-of-concept analysis integrating transcriptomics and immunopeptidomics data, weshowed that hundreds of IRIS-predicted TCR targets are presented by human leukocyte antigen (HLA) molecules. We applied IRIS to RNA-seq data of neuroendocrine prostate cancer (NEPC). From 2,939 NEPC-associated AS events, IRIS predicted 1,651 epitopes from 808 events as potential TCR targets for two common HLA types (A*02:01 and A*03:01). A more stringent screening test prioritized 48 epitopes from 20 events with "neoantigen-like" NEPC-specific expression. Predicted epitopes are often encoded by microexons of ≤30 nucleotides. To validate the immunogenicity and T cell recognition of IRIS-predicted TCR epitopes, we performed invitro T cell priming in combination with single-cell TCR sequencing. Seven TCRs transduced into human peripheral blood mononuclear cells (PBMCs) showed high activity against individual IRIS-predicted epitopes, providing strong evidence of isolated TCRs reactive to AS-derived peptides. One selected TCR showed efficient cytotoxicity against target cells expressing the target peptide. Our study illustrates the contribution of AS to the TA repertoire of cancer cells and demonstrates the utility of IRIS for discovering AS-derivedTAs and expanding cancer immunotherapies.

Genetic testing to guide screening for pancreatic ductal adenocarcinoma: Results of a microsimulation model

BackgroundFirst-degree relatives (FDRs) of patients with pancreatic ductal adenocarcinoma (PDAC) have elevated PDAC risk, partially due to germline genetic variants. We evaluated the potential effectiveness of genetic testing to target MRI-based screening among FDRs. MethodsWe used a microsimulation model of PDAC, calibrated to Surveillance, Epidemiology, and End Results (SEER) data, to estimate the potential life expectancy (LE) gain of screening for each of the following groups of FDRs: individuals who test positive for each of eight variants associated with elevated PDAC risk (e.g., BRCA2, CDKN2A); individuals who test negative; and individuals who do not test. Screening was assumed to take place if LE gains were achievable. We simulated multiple screening approaches, defined by starting age and frequency. Sensitivity analysis evaluated changes in results given varying model assumptions. ResultsFor women, 92% of mutation carriers had projected LE gains from screening for PDAC, if screening strategies (start age, frequency) were optimized. Among carriers, LE gains ranged from 0.1 days (ATM+ women screened once at age 70) to 510 days (STK11+ women screened annually from age 40). For men, LE gains were projected for all mutation carriers, ranging from 0.2 days (BRCA1+ men screened once at age 70) to 620 days (STK11+ men screened annually from age 40). For men and women who did not undergo genetic testing, or for whom testing showed no variant, screening yielded small LE benefit (0–2.1 days). ConclusionsGenetic testing of FDRs can inform targeted PDAC screening by identifying which FDRs may benefit.

Identification of interacting proteins of Arabidopsis cyclophilin38 (AtCYP38) via multiple screening approaches reveals its possible broad functions in chloroplasts

AtCYP38, a thylakoid lumen localized immunophilin, is found to be essential for photosystem II assembly and maintenance, but how AtCYP38 functions in chloroplast remains unknown. Based on previous functional studies and its crystal structure, we hypothesize that AtCYP38 should function via binding its targets or cofactors in the thylakoid lumen. To identify potential interacting proteins of AtCYP38, we first adopted ATTED-II and STRING web-tools, and found 12 proteins functionally related to AtCYP38. We then screened a yeast two-hybrid library including an Arabidopsis genome wide cDNA with different domain of AtCYP38, and five thylakoid lumen-localized targets were identified. In order to specifically search interacting proteins of AtCYP38 in the thylakoid lumen, we generated a yeast two-hybrid mini library including the thylakoid lumenal proteins and lumenal fractions of thylakoid membrane proteins, and we obtained six thylakoid membrane proteins and nine thylakoid lumenal proteins as interacting proteins of AtCYP38. The interactions between AtCYP38 and several potential targets were further confirmed via pull-down and co-immunoprecipitation assays. Together, a couple of new potential candidate interacting proteins of AtCYP38 were identified, and the results will lay a foundation for unveiling the regulatory mechanisms in photosynthesis by AtCYP38.

Virus Diversity and Loads in Crickets Reared for Feed: Implications for Husbandry.

Insects generally have high reproductive rates leading to rapid population growth and high local densities; ideal conditions for disease epidemics. The parasites and diseases that naturally regulate wild insect populations can also impact when these insects are produced commercially, on farms. While insects produced for human or animal consumption are often reared under high density conditions, very little is known about the microbes associated with these insects, particularly those with pathogenic potential. In this study we used both target-free and targeted screening approaches to explore the virome of two cricket species commonly reared for feed and food, Acheta domesticus and Gryllus bimaculatus. The target-free screening of DNA and RNA from a single A. domesticus frass sample revealed that only 1% of the nucleic acid reads belonged to viruses, including known cricket, insect, bacterial and plant pathogens, as well as a diverse selection of novel viruses. The targeted screening revealed relatively high levels of Acheta domesticus densovirus, invertebrate iridovirus 6 and a novel iflavirus, as well as low levels of Acheta domesticus volvovirus, in insect and frass samples from several retailers. Our findings highlight the value of multiple screening approaches for a comprehensive and robust cricket disease monitoring and management strategy. This will become particularly relevant as-and-when cricket rearing facilities scale up and transform from producing insects for animal feed to producing insects for human consumption.

Enhancement of COVID-19 symptom-based screening with quality-based classifier optimisation

Efforts of the scientific community led to the development of multiple screening approaches for COVID-19 that rely on machine learning methods. However, there is a lack of works showing how to tune the classification models used for such a task and what the tuning effect is in terms of various classification quality measures. Understanding the impact of classifier tuning on the results obtained will allow the users to apply the provided tools consciously. Therefore, using a given screening test they will be able to choose the threshold value characterising the classifier that gives, for example, an acceptable balance between sensitivity and specificity. The presented work introduces the optimisation approach and the resulting classifiers obtained for various quality threshold assumptions. As a result of the research, an online service was created that makes the obtained models available and enables the verification of various solutions for different threshold values on new data. © 2021 The Author(s).

Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer without a targeted form of therapy. Unfortunately, up to 70% of patients with TNBC develop resistance to treatment. A known contributor to chemoresistance is dysfunctional mitochondrial apoptosis signaling. We set up a phenotypic small-molecule screen to reveal vulnerabilities in TNBC cells that were independent of mitochondrial apoptosis. Using a functional genetic approach, we identified that a "hit" compound, BAS-2, had a potentially similar mechanism of action to histone deacetylase inhibitors (HDAC). An in vitro HDAC inhibitor assay confirmed that the compound selectively inhibited HDAC6. Using state-of-the-art acetylome mass spectrometry, we identified glycolytic substrates of HDAC6 in TNBC cells. We confirmed that inhibition or knockout of HDAC6 reduced glycolytic metabolism both in vitro and in vivo. Through a series of unbiased screening approaches, we have identified a previously unidentified role for HDAC6 in regulating glycolytic metabolism.

Evaluating the Criterion Validity and Classification Accuracy of Universal Screening Measures in Reading

Educators use universal screening to identify students who may be at risk for not meeting proficiency on the state assessment. Given the potential high-stakes of state tests, using accurate screeners is critical. Independent research is emerging on screeners such as the Measures of Academic Progress (MAP), a computer adaptive test, and the Strategic Teaching Evaluation of Progress (STEP), a developmental reading assessment. This study evaluated the criterion-related validity of MAP and STEP with a state assessment. Additionally, the utility of each screener to distinguish between students at risk and not at risk was evaluated using multiple screening approaches. Participants were two cohorts (Cohort 1 N = 255; Cohort 2 N = 122) of children enrolled in two public charter schools. MAP and STEP were administered in spring of second grade and fall of third grade. Results suggested MAP and STEP scores were significant strong predictors of third-grade state assessment scores. STEP scores explained a small amount of variance in state assessment scores beyond MAP scores alone. Findings support using MAP and STEP to identify students who may be at risk; however, MAP is sufficient as a single screener, using locally derived cut-scores or cut-scores linked to the state assessment.

Premalignant neoplasms of the anus and perianal skin

Squamous cell carcinoma of the anal canal is preceded by a spectrum of premalignant lesions known as anal intraepithelial neoplasia (AIN). AIN is caused by infection with the human papilloma virus (HPV), and the pathogenesis mimics that of cervical cancer. It is most commonly associated with HIV infection and high-risk sexual behavior. Symptoms of AIN may mimic benign processes. Multiple screening approaches exist for detecting HPV and dysplasia, but so far there is no standard algorithm. Several treatment options for AIN exist, although recurrence remains high. Regular surveillance by a surgeon is key after successful treatment. Extramammary perianal Paget׳s disease (EMPD) is another premalignant lesion. It is an intraepithelial adenocarcinoma that may or may not be associated with underlying malignancy. There are limited cases reported in the literature, and a staging method has been proposed. Both AIN and EMPD will be discussed in the following chapter.

The Molecular Profiles of Neural Stem Cell Niche in the Adult Subventricular Zone

Neural stem cells (NSCs) reside in a unique microenvironment called the neurogenic niche and generate functional new neurons. The neurogenic niche contains several distinct types of cells and interacts with the NSCs in the subventricular zone (SVZ) of the lateral ventricle. While several molecules produced by the niche cells have been identified to regulate adult neurogenesis, a systematic profiling of autocrine/paracrine signaling molecules in the neurogenic regions involved in maintenance, self-renewal, proliferation, and differentiation of NSCs has not been done. We took advantage of the genetic inducible fate mapping system (GIFM) and transgenic mice to isolate the SVZ niche cells including NSCs, transit-amplifying progenitors (TAPs), astrocytes, ependymal cells, and vascular endothelial cells. From the isolated cells and microdissected choroid plexus, we obtained the secretory molecule expression profiling (SMEP) of each cell type using the Signal Sequence Trap method. We identified a total of 151 genes encoding secretory or membrane proteins. In addition, we obtained the potential SMEP of NSCs using cDNA microarray technology. Through the combination of multiple screening approaches, we identified a number of candidate genes with a potential relevance for regulating the NSC behaviors, which provide new insight into the nature of neurogenic niche signals.

Developing a national strategy to prevent dementia: Leon Thal Symposium 2009

Among the major impediments to the design of clinical trials for the prevention of Alzheimer's disease (AD), the most critical is the lack of validated biomarkers, assessment tools, and algorithms that would facilitate identification of asymptomatic individuals with elevated risk who might be recruited as study volunteers. Thus, the Leon Thal Symposium 2009 (LTS'09), on October 27–28, 2009 in Las Vegas, Nevada, was convened to explore strategies to surmount the barriers in designing a multisite, comparative study to evaluate and validate various approaches for detecting and selecting asymptomatic people at risk for cognitive disorders/dementia. The deliberations of LTS'09 included presentations and reviews of different approaches (algorithms, biomarkers, or measures) for identifying asymptomatic individuals at elevated risk for AD who would be candidates for longitudinal or prevention studies. The key nested recommendations of LTS'09 included: (1) establishment of a National Database for Longitudinal Studies as a shared research core resource; (2) launch of a large collaborative study that will compare multiple screening approaches and biomarkers to determine the best method for identifying asymptomatic people at risk for AD; (3) initiation of a Global Database that extends the concept of the National Database for Longitudinal Studies for longitudinal studies beyond the United States; and (4) development of an educational campaign that will address public misconceptions about AD and promote healthy brain aging.

Efficiency and Validity of Commonly Used Substance Abuse Screening Instruments in Public Psychiatric Patients

ABSTRACT Background: The more commonly used screening instruments for substance abuse were largely developed for addictive populations. We compared several alcohol and drug abuse scales to determine their efficiency and validity for psychiatric patients. Method: The subjects were 100 consecutively admitted patients to a public psychiatric facility. DSM-III-R diagnoses, obtained from the alcohol and drug scales of the SCID-P, were the criterion measure. Methods of reliability included inter-rater agreement, estimates of internal consistency, and repeat test administration. Sensitivity, specificity and more infrequently used accuracy indices, such as likelihood ratios and Receiver Operating Characteristic (ROC) analysis, were utilized to assess scale validity. Results: First, the reliability of all scales was high. Second, the instruments generally demonstrated highly acceptable levels of screening accuracy. Third, the intake evaluation was as reliable and valid as screening after admission on the unit. Finally, instruments were least discriminating for current problems (past 30 days). Conclusions: Lifetime measures were found to be reliable and valid for public psychiatric patients but further research is needed on increasing the accuracy of screening for current substance abuse problems and the effectiveness of multiple screening approaches.

The conformation of an inhibitor bound to the gastric proton pump

Substituted imidazo[1,2- a]pyridines are pharmaceutically important small molecule inhibitors of the gastric H +/K +-ATPase, the membrane-bound therapeutic target for peptic ulcer disease. A non-perturbing analytical technique, rotational resonance NMR spectroscopy, was used to measure a precise (to ±0.2 Å) distance between atomic sites in a substituted imidazo[1,2- a]pyridine, TMPIP, bound to H +/K +-ATPase at its high-affinity site in the intact, native membrane. The structural analysis of the enzyme–inhibitor complex revealed that the flexible moiety of TMPIP adopts a ` syn-type' conformation at its site of action. Hence, the conformation of an inhibitor has been resolved directly under near-physiological conditions, providing a sound experimental basis for rational design of many active compounds of pharmaceutical interest. Chemically restraining the flexible moiety of compounds like TMPIP in the syn-type binding conformation was found to increase activity by over 2 orders of magnitude. Such information is normally only available after extensive synthesis of related compounds and multiple screening approaches.