New Nanotech Design Improves Drug Efficacy, Lowers Toxicity

Most mental health problems associated with psychological distress originate with activation of centrally regulated stress pathways, yet a diverse range of central nervous system and somatic disease states can be influenced by exposure to severe or unrelenting stress. The goal of this chapter is to provide a conceptual framework to guide the development of pharmacological intervention strategies. We propose that careful consideration of the relationship between the timing of stressful life experiences, pharmacological intervention, and the ultimate expression of disease symptomatology is critical for the development of pharmacological interventions to treat stress-related disorders. We review a range of physiological systems that are known to be activated by stress, offering potentially new targets for drug development efforts, and argue that participant selection is a key predictor of drug efficacy trials. In doing so, we point toward inflammatory signaling pathways as a potential final common mediator of multiple stress-related disease states.

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High resolution structural and functional MRI of the hippocampus in young adults with Down syndrome

Brain Communications ◽

10.1093/braincomms/fcab088 ◽

2021 ◽

Author(s):

Katherine A Koenig ◽

Se-Hong Oh ◽

Melissa R Stasko ◽

Elizabeth C Roth ◽

H Gerry Taylor ◽

...

Keyword(s):

Down Syndrome ◽

Functional Connectivity ◽

Cortical Thickness ◽

Right Hemisphere ◽

Gray Matter Volume ◽

Drug Efficacy ◽

Structure And Function ◽

7 Tesla ◽

Whole Brain ◽

And Function

Abstract Down syndrome is the phenotypic consequence of trisomy 21, with clinical presentation including both neurodevelopmental and neurodegenerative components. Although the intellectual disability typically displayed by individuals with Down syndrome is generally global, it also involves disproportionate deficits in hippocampally-mediated cognitive processes. Hippocampal dysfunction may also relate to Alzheimer’s disease-type pathology, which can appear in as early as the first decade of life and becomes universal by age 40. Using 7-tesla MRI of the brain, we present an assessment of the structure and function of the hippocampus in 34 individuals with Down syndrome (mean age 24.5 years ± 6.5) and 27 age- and sex-matched typically developing healthy controls. In addition to increased whole-brain mean cortical thickness and lateral ventricle volumes (p < 1.0 × 10−4), individuals with Down syndrome showed selective volume reductions in bilateral hippocampal subfields CA1, dentate gyrus, and tail (p < 0.005). In the group with Down syndrome, bilateral hippocampi showed widespread reductions in the strength of functional connectivity, predominately to frontal regions (p < 0.02). Age was not related to hippocampal volumes or functional connectivity measures in either group, but both groups showed similar relationships of age to whole-brain volume measures (p < 0.05). Finally, we performed an exploratory analysis of a subgroup of individuals with Down syndrome with both imaging and neuropsychological assessments. This analysis indicated that measures of spatial memory were related to mean cortical thickness, total gray matter volume, and right hemisphere hippocampal subfield volumes (p < 0.02). This work provides a first demonstration of the usefulness of high-field MRI to detect subtle differences in structure and function of the hippocampus in individuals with Down syndrome, and suggests the potential for development of MRI-derived measures as surrogate markers of drug efficacy in pharmacological studies designed to investigate enhancement of cognitive function.

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Drosophila RASopathy Models Identify Disease Subtype Differences and Biomarkers of Drug Efficacy

iScience ◽

10.1016/j.isci.2021.102306 ◽

2021 ◽

pp. 102306

Author(s):

Tirtha K. Das ◽

Jared Gatto ◽

Rupa Mirmira ◽

Ethan Hourizadeh ◽

Dalia Kaufman ◽

...

Keyword(s):

Drug Efficacy ◽

Disease Subtype ◽

Subtype Differences

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Rapid visualized assessment of drug efficacy in live mice with a selectable marker-free autoluminescent Klebsiella pneumoniae

Biosensors and Bioelectronics ◽

10.1016/j.bios.2020.112919 ◽

2021 ◽

Vol 177 ◽

pp. 112919

Author(s):

Xirong Tian ◽

Yamin Gao ◽

Shuai Wang ◽

H.M. Adnan Hameed ◽

Wei Yu ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Selectable Marker ◽

Drug Efficacy ◽

Marker Free

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Common Treatment, Common Variant: Evolutionary Prediction of Functional Pharmacogenomic Variants

Journal of Personalized Medicine ◽

10.3390/jpm11020131 ◽

2021 ◽

Vol 11 (2) ◽

pp. 131

Author(s):

Laura B. Scheinfeldt ◽

Andrew Brangan ◽

Dara M. Kusic ◽

Sudhir Kumar ◽

Neda Gharani

Keyword(s):

In Silico ◽

Drug Efficacy ◽

Common Variant ◽

Genomic Research ◽

Whole Genome Sequencing Data ◽

Mendelian Disease ◽

Allele Frequency Distribution ◽

Sequencing Data ◽

Patient Race ◽

The Impact

Pharmacogenomics holds the promise of personalized drug efficacy optimization and drug toxicity minimization. Much of the research conducted to date, however, suffers from an ascertainment bias towards European participants. Here, we leverage publicly available, whole genome sequencing data collected from global populations, evolutionary characteristics, and annotated protein features to construct a new in silico machine learning pharmacogenetic identification method called XGB-PGX. When applied to pharmacogenetic data, XGB-PGX outperformed all existing prediction methods and identified over 2000 new pharmacogenetic variants. While there are modest pharmacogenetic allele frequency distribution differences across global population samples, the most striking distinction is between the relatively rare putatively neutral pharmacogene variants and the relatively common established and newly predicted functional pharamacogenetic variants. Our findings therefore support a focus on individual patient pharmacogenetic testing rather than on clinical presumptions about patient race, ethnicity, or ancestral geographic residence. We further encourage more attention be given to the impact of common variation on drug response and propose a new ‘common treatment, common variant’ perspective for pharmacogenetic prediction that is distinct from the types of variation that underlie complex and Mendelian disease. XGB-PGX has identified many new pharmacovariants that are present across all global communities; however, communities that have been underrepresented in genomic research are likely to benefit the most from XGB-PGX’s in silico predictions.

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Analytical validation of a real-time hydrolysis probe PCR assay for quantifying Plasmodium falciparum parasites in experimentally infected human adults

Malaria Journal ◽

10.1186/s12936-021-03717-y ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Claire Y. T. Wang ◽

Emma L. Ballard ◽

Zuleima Pava ◽

Louise Marquart ◽

Jane Gaydon ◽

...

Keyword(s):

Clinical Trials ◽

Plasmodium Falciparum ◽

18S Rrna ◽

Drug Efficacy ◽

18S Rrna Gene ◽

Molecular Techniques ◽

Qpcr Assay ◽

Rrna Gene ◽

Analytical Sensitivity ◽

Blood Samples

Abstract Background Volunteer infection studies have become a standard model for evaluating drug efficacy against Plasmodium infections. Molecular techniques such as qPCR are used in these studies due to their ability to provide robust and accurate estimates of parasitaemia at increased sensitivity compared to microscopy. The validity and reliability of assays need to be ensured when used to evaluate the efficacy of candidate drugs in clinical trials. Methods A previously described 18S rRNA gene qPCR assay for quantifying Plasmodium falciparum in blood samples was evaluated. Assay performance characteristics including analytical sensitivity, reportable range, precision, accuracy and specificity were assessed using experimental data and data compiled from phase 1 volunteer infection studies conducted between 2013 and 2019. Guidelines for validation of laboratory-developed molecular assays were followed. Results The reportable range was 1.50 to 6.50 log10 parasites/mL with a limit of detection of 2.045 log10 parasites/mL of whole blood based on a parasite diluted standard series over this range. The assay was highly reproducible with minimal intra-assay (SD = 0.456 quantification cycle (Cq) units [0.137 log10 parasites/mL] over 21 replicates) and inter-assay (SD = 0.604 Cq units [0.182 log10 parasites/mL] over 786 qPCR runs) variability. Through an external quality assurance program, the QIMR assay was shown to generate accurate results (quantitative bias + 0.019 log10 parasites/mL against nominal values). Specificity was 100% after assessing 164 parasite-free human blood samples. Conclusions The 18S rRNA gene qPCR assay is specific and highly reproducible and can provide reliable and accurate parasite quantification. The assay is considered fit for use in evaluating drug efficacy in malaria clinical trials.

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A Computational Approach for Pathway-Based Systemic Drug Influence

Processes ◽

10.3390/pr9061063 ◽

2021 ◽

Vol 9 (6) ◽

pp. 1063

Author(s):

Shinuk Kim

Keyword(s):

Gene Networks ◽

Drug Targets ◽

Drug Repositioning ◽

Drug Efficacy ◽

Rapid Expansion ◽

Gene Sets ◽

Development Risks ◽

Drug Influence ◽

Potential Drug Targets ◽

Systemic Drug

Drug repositioning is a well-known method used to reduce the time, cost, and development risks involved in bringing a new drug to the market. The rapid expansion of high-throughput datasets has enabled computational research that can suggest new potential uses for existing drugs. Some computational methods allow the prediction of potential drug targets of a given disease from a systematic network. Despite numerous efforts, the path of many drugs’ efficacy in the human body remains unclear. Therefore, the present study attempted to understand drug efficacy by systematically focusing on functional gene sets. The purpose of this study was to carry out modeling to identify systemic gene networks (called drug paths) in drug-specific pathways. In our results, we found five different paths for five different drugs.

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