Application Of Precision Medicine Research Articles

Cascade genetic testing: an underutilized pathway to equitable cancer care?

The Precision Medicine Initiative was launched upon the potential of genomic information to tailor medical care. Cascade genetic testing represents a powerful application of precision medicine and involves the process of familial diffusion or the "cascade" of genomic risk information. When an individual (proband) is found to carry a cancer-associated germline pathogenic mutation, the information should be cascaded or shared with at-risk relatives. First degree relatives have a 50% likelihood of carrying the same cancer-associated mutation. This process of cascade testing offers at-risk relatives the opportunity for genetic testing and, for those who also carry the cancer-associated mutation, genetically targeted primary disease prevention through intensive cancer surveillance, chemoprevention and risk-reducing surgery, reducing morbidity and preventing mortality. Cascade testing has been designated by the Centers for Disease Control and Prevention as a Tier 1 genomic application for hereditary breast and ovarian cancer. In this manuscript we describe a cascade genetic testing and in particular focus on its potential to provide necessary care to medically underserved and vulnerable populations.

Repeatability and reproducibility of the Forskolin-induced swelling (FIS) assay on intestinal organoids from people with Cystic Fibrosis

BackgroundThe forskolin-induced swelling (FIS) assay measures CFTR function on patient-derived intestinal organoids (PDIOs) and may guide treatment selection for individuals with Cystic Fibrosis (CF). The aim of this study is to demonstrate the repeatability and reproducibility of the FIS assay following a detailed Standard Operating Procedure (SOP), thus advancing the validation of the assay for precision medicine (theranostic) applications. MethodsOver a 2-year period, FIS responses to CFTR modulators were measured in four European labs. PDIOs from six subjects with CF carrying different CFTR genotypes were used to assess the repeatability and reproducibility across the dynamic range of the assay. ResultsTechnical, intra-assay repeatability was high (Lin's concordance correlation coefficient (CCC) 0.95–0.98). Experimental, within-subject repeatability was also high within each lab (CCCs all >0.9). Longer-term repeatability (>1 year) showed more variability (CCCs from 0.67 to 0.95). The reproducibility between labs was also high (CCC ranging from 0.92 to 0.97). Exploratory analysis also found that between-lab percentage of agreement of dichotomized CFTR modulator outcomes for predefined FIS thresholds ranged between 78 and 100 %. ConclusionsThe observed repeatability and reproducibility of the FIS assay within and across different labs is high and support the use of FIS as biomarker of CFTR function in the presence or absence of CFTR modulators.

Revolutionizing personalized medicine with generative AI: a systematic review

BackgroundPrecision medicine, targeting treatments to individual genetic and clinical profiles, faces challenges in data collection, costs, and privacy. Generative AI offers a promising solution by creating realistic, privacy-preserving patient data, potentially revolutionizing patient-centric healthcare.ObjectiveThis review examines the role of deep generative models (DGMs) in clinical informatics, medical imaging, bioinformatics, and early diagnostics, showcasing their impact on precision medicine.MethodsAdhering to PRISMA guidelines, the review analyzes studies from databases such as Scopus and PubMed, focusing on AI's impact in precision medicine and DGMs' applications in synthetic data generation.ResultsDGMs, particularly Generative Adversarial Networks (GANs), have improved synthetic data generation, enhancing accuracy and privacy. However, limitations exist, especially in the accuracy of foundation models like Large Language Models (LLMs) in digital diagnostics.ConclusionOvercoming data scarcity and ensuring realistic, privacy-safe synthetic data generation are crucial for advancing personalized medicine. Further development of LLMs is essential for improving diagnostic precision. The application of generative AI in personalized medicine is emerging, highlighting the need for more interdisciplinary research to advance this field.

Clinical Phenotypes, Serological Biomarkers, and Synovial Features Defining Seropositive and Seronegative Rheumatoid Arthritis: A Literature Review.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder which can lead to long-term joint damage and significantly reduced quality of life if not promptly diagnosed and adequately treated. Despite significant advances in treatment, about 40% of patients with RA do not respond to individual pharmacological agents and up to 20% do not respond to any of the available medications. To address this large unmet clinical need, several recent studies have focussed on an in-depth histological and molecular characterisation of the synovial tissue to drive the application of precision medicine to RA. Currently, RA patients are clinically divided into "seropositive" or "seronegative" RA, depending on the presence of routinely checked antibodies. Recent work has suggested that over the last two decades, long-term outcomes have improved significantly in seropositive RA but not in seronegative RA. Here, we present up-to-date differences in epidemiology, clinical features, and serological biomarkers in seronegative versus seropositive RA and discuss how histological and molecular synovial signatures, revealed by recent large synovial biopsy-based clinical trials, may be exploited to refine the classification of RA patients, especially in the seronegative group.

The role of zyxin in signal transduction and its relationship with diseases.

This review highlighted the pivotal role of zyxin, an essential cell focal adhesions protein, in cellular biology and various diseases. Zyxin can orchestrate the restructuring and dynamic alterations of the cellular cytoskeleton, which is involved in cell proliferation, adhesion, motility, and gene transcription. Aberrant zyxin expression is closely correlated with tumor cell activity and cardiac function in both tumorigenesis and cardiovascular diseases. Moreover, in fibrotic and inflammatory conditions, zyxin can modulate cellular functions and inflammatory responses. Therefore, a comprehensive understanding of zyxin is crucial for deciphering signal transduction networks and disease pathogenesis. Investigating its role in diseases holds promise for novel avenues in early diagnosis and therapeutic strategies. Nevertheless, targeting zyxin as a therapeutic focal point presents challenges in terms of specificity, safety, drug delivery, and resistance. Nonetheless, in-depth studies on zyxin and the application of precision medicine could offer new possibilities for personalized treatment modalities.

Assessing the Occurrence and Influence of Cancer Chemotherapy-Related Pharmacogenetic Alleles in the Chilean Population.

Pharmacogenomic knowledge as a biomarker for cancer care has transformed clinical practice, however, as current guidelines are primarily derived from Eurocentric populations, this limits their application in Latin America, particularly among Hispanic or Latino groups. Despite advancements, systemic chemotherapy still poses challenges in drug toxicity and suboptimal response. This study explores pharmacogenetic markers related to anticancer drugs in a Chilean cohort, filling a gap in Latin American research. Notably, the influence of native South American Mapuche-Huilliche ancestry. To explore pharmacogenetic markers related to anticancer drugs, we utilized an ethnically Admixed Chilean genome-wide association studies (GWAS) dataset of 1095 unrelated individuals. Pharmacogenomic markers were selected from PharmGKB, totaling 36 level 1 and 2 evidence single nucleotide polymorphisms (SNPs) and 571 level 3 SNPs. Comparative analyses involved assessing SNP frequencies across diverse populations from the 1000 Genomes Project. Haplotypes were estimated, and linkage disequilibrium was examined. Ancestry-based association analyses explored relationships between SNPs and Mapuche-Huilliche and European ancestries. Chi-square distribution with p ≤ 0.05 and Bonferroni's multiple adjustment tests determined statistical differences between allele frequencies. Our study reveals significant disparities in SNP frequency within the Chilean population. Notably, dihydropyrimidine dehydrogenase (DPYD) variants (rs75017182 and rs67376798), linked to an increased risk of severe fluoropyrimidine toxicity, exhibit an exceptionally low frequency (minor allele frequency (MAF) < 0.005). Nudix hydrolase 15 (NUDT15) rs116855232, associated with hematological mercaptopurine toxicity, is relatively common (MAF = 0.062), and is further linked to Mapuche-Huilliche ancestry. Thiopurine methyltransferase enzyme (TPMT), implicated in severe toxicity to mercaptopurines, SNPs rs1142345 and rs1800460 of TMPT gene demonstrate higher MAFs in Admixed Americans and the Chilean population (MAF range 0.031-0.057). Finally, the variant in the UDP-glucuronosyltransferase 1 gene (UGT1A1) rs4148323, correlated with irinotecan neutropenia, exhibits the highest MAF in East Asian (MAF = 0.136) and Chilean (MAF = 0.025) populations, distinguishing them from other investigated populations. This study provides the first comprehensive pharmacogenetic characterization of cancer therapy-related SNPs and highlights significant disparities in SNP frequencies within the Chilean population. Our findings underscore the necessity for inclusive research and personalized therapeutic strategies to ensure the equitable and effective application of precision medicine across diverse global communities.

Precision medicine for respiratory diseases: A current viewpoint.

In the realm of respiratory illnesses, despite the immense costs and efforts invested in diagnosis and treatment, numerous patients with chronic respiratory conditions or malignancies do not respond well to existing therapies. Delayed diagnoses and inadequate treatments contribute to these challenges, along with adverse reactions or treatment limitations due to side-effects. However, recent advancements in understanding respiratory diseases have paved the way for personalized medical treatments, considering individual genetic, molecular and environmental factors. Precision medicine, which accommodates individual differences in disease susceptibility and response to treatments, aims to improve patient care by aligning medical research with tailored therapies. Innovative technologies, such as genomic sequencing and biomarker identification contribute to this approach, allowing for customized treatments and the identification of effective therapies. Additionally, the application of precision medicine in lung cancer treatment exemplifies the forefront of individualized care within respiratory medicine. Several studies have explored the role of precision medicine in managing respiratory infectious diseases, asthma and idiopathic pulmonary fibrosis, aiming to categorize diseases more accurately and design targeted therapies. The ultimate goal is to enhance treatment effectiveness, minimize adverse events, and shift towards a patient-centered approach to managing respiratory conditions. Despite limitations, precision medicine holds promise for improving patient outcomes and emphasizing personalized care in respiratory medicine.

Utility of polygenic scores across diverse diseases in a hospital cohort for predictive modeling

Polygenic scores estimate genetic susceptibility to diseases. We systematically calculated polygenic scores across 457 phenotypes using genotyping array data from China Medical University Hospital. Logistic regression models assessed polygenic scores’ ability to predict disease traits. The polygenic score model with the highest accuracy, based on maximal area under the receiver operating characteristic curve (AUC), is provided on the GeneAnaBase website of the hospital. Our findings indicate 49 phenotypes with AUC greater than 0.6, predominantly linked to endocrine and metabolic diseases. Notably, hyperplasia of the prostate exhibited the highest disease prediction ability (P value = 1.01 × 10−19, AUC = 0.874), highlighting the potential of these polygenic scores in preventive medicine and diagnosis. This study offers a comprehensive evaluation of polygenic scores performance across diverse human traits, identifying promising applications for precision medicine and personalized healthcare, thereby inspiring further research and development in this field.

Optimizing the Use of Next-Generation Sequencing Assays in Patients With Urothelial Carcinoma: Recommendations by the 2023 San Raffaele Retreat Panel

BackgroundThe application of precision medicine in clinical practice implies a thorough evaluation of actionable genomic alterations to streamline therapeutic decision making. Comprehensive genomic profiling of tumor via next-generation sequencing (NGS) represents a great opportunity but also several challenges. During the 2023 San Raffaele Retreat, we aimed to provide expert recommendations for the optimal use of NGS in urothelial carcinoma (UC). Materials and MethodsA modified Delphi method was utilized, involving a panel of 12 experts in UC from European and United States centers, including oncologists, urologists, pathologists, and translational scientists. An initial survey, conducted before the meeting, delivered 15 statements to the panel. A consensus was defined when ≥70% agreement was reached for each statement. Statements not meeting the consensus threshold were discussed during the meeting. ResultsNine of the 15 statements covering patient selection, cancer characteristics, and type of NGS assay, achieved a consensus during the survey. The remaining six statements addressing the optimal timing of NGS use, the ideal source of tumor biospecimen for NGS testing, and the subsequent need to evaluate the germline nature of certain genomic findings were discussed during the meeting, leading to unanimous agreement at the end of the conference. ConclusionThis consensus-building effort addressed multiple unanswered questions regarding the use of NGS in UC. The opinion of experts was in favor of broader use of NGS. In a setting where recommendations/guidelines may be limited, these insights may aid clinicians to provide informed counselling and raise the bar of precision and personalized therapy.

What is new in LC-MS proteomics: Techniques and applications in IVIVE and precision medicine

What is new in LC-MS proteomics: Techniques and applications in IVIVE and precision medicine

The biomarkers for maintenance Cancer stem cell features can be applicable in precision medicine of head and neck squamous cell carcinoma

Cancer stem cells (CSCs) play a crucial role in tumor relapse, proliferation, invasion, and drug resistance in head and neck squamous cell carcinoma (HNSCC). This narrative review aims to synthesize data from articles published between 2019 and 2023 on biomarkers for detecting CSCs in HNSCC and changes in molecular pathways, genetics, epigenetics, and non-coding RNAs (ncRNAs) in CSCs relevant to precision medicine approaches in HNSCC management. The search encompassed 41 in vitro studies and 22 clinical studies. CSCs exhibit diverse molecular profiles and unique biomarker expression patterns, offering significant potential for HNSCC diagnosis, treatment, and prognosis, thereby enhancing patient survival. Their remarkable self-renewal ability and adaptability are closely linked to tumorigenicity development and maintenance. Assessing biomarkers before and after therapy can aid in identifying various cell types associated with cancer progression and relapse. Screening for CSCs, senescent tumor cells, and cells correlated with the senescence process post-treatment has proven highly beneficial. However, the clinical application of precision medicine in HNSCC management is hindered by the lack of specific and definitive CSC biomarkers. Furthermore, our limited understanding of CSC plasticity, governed by genomic, transcriptomic, and epigenomic alterations during tumorigenesis, as well as the bidirectional interaction of CSCs with the tumor microenvironment, underscores the need for further research. Well-designed studies involving large patient cohorts are, therefore, essential to establish a standardized protocol and address these unresolved queries.

The Application of Precision Medicine in Structural Heart Diseases: A Step towards the Future.

The personalized applications of 3D printing in interventional cardiology and cardiac surgery represent a transformative paradigm in the management of structural heart diseases. This review underscores the pivotal role of 3D printing in enhancing procedural precision, from preoperative planning to procedural simulation, particularly in valvular heart diseases, such as aortic stenosis and mitral regurgitation. The ability to create patient-specific models contributes significantly to predicting and preventing complications like paravalvular leakage, ensuring optimal device selection, and improving outcomes. Additionally, 3D printing extends its impact beyond valvular diseases to tricuspid regurgitation and non-valvular structural heart conditions. The comprehensive synthesis of the existing literature presented here emphasizes the promising trajectory of individualized approaches facilitated by 3D printing, promising a future where tailored interventions based on precise anatomical considerations become standard practice in cardiovascular care.

Fully integrated and automated centrifugal microfluidic chip for point-of-care multiplexed molecular diagnostics

Public health events caused by pathogens have imposed significant economic and societal burdens. However, conventional methods still face challenges including complex operations, the need for trained operators, and sophisticated instruments. Here, we proposed a fully integrated and automated centrifugal microfluidic chip, also termed IACMC, for point-of-care multiplexed molecular diagnostics by harnessing the advantages of active and passive valves. The IACMC incorporates multiple essential components including a pneumatic balance module for sequential release of multiple reagents, a pneumatic centrifugation-assisted module for on-demand solution release, an on-chip silicon membrane module for nucleic acid extraction, a Coriolis force-mediated fluid switching module, and an amplification module. Numerical simulation and visual validation were employed to iterate and optimize the chip's structure. Upon sample loading, the chip automatically executes the entire process of bacterial sample lysis, nucleic acid capture, elution quantification, and isothermal LAMP amplification. By optimizing crucial parameters including centrifugation speed, direction of rotation, and silicone membrane thickness, the chip achieves exceptional sensitivity (twenty-five Salmonella or forty Escherichia coli) and specificity in detecting Escherichia coli and Salmonella within 40 min. The development of IACMC will drive advancements in centrifugal microfluidics for point-of-care testing and holds potential for broader applications in precision medicine including high-throughput biochemical analysis immune diagnostics, and drug susceptibility testing.

Brexanolone Treatment in a Real-World Patient Population: A Case Series and Pilot Feasibility Study of Precision Neuroimaging.

Brexanolone is approved for postpartum depression (PPD) by the United States Food and Drug Administration. Brexanolone has outperformed placebo in clinical trials, but less is known about the efficacy in real-world patients with complex social and medical histories. Furthermore, the impact of brexanolone on large-scale brain systems such as changes in functional connectivity (FC) is unknown. We tracked changes in depressive symptoms across a diverse group of patients who received brexanolone at a large medical center. Edinburgh Postnatal Depression Scale (EPDS) scores were collected through chart review for 17 patients immediately prior to infusion through approximately 1 year postinfusion. In 2 participants, we performed precision functional neuroimaging (pfMRI), including before and after treatment in 1 patient. pfMRI collects many hours of data in individuals for precision medicine applications and was performed to assess the feasibility of investigating changes in FC with brexanolone. The mean EPDS score immediately postinfusion was significantly lower than the mean preinfusion score (mean change [95% CI]: 10.76 [7.11-14.40], t (15) = 6.29, P < 0.0001). The mean EPDS score stayed significantly lower at 1 week (mean difference [95% CI]: 9.50 [5.23-13.76], t (11) = 4.90, P = 0.0005) and 3 months (mean difference [95% CI]: 9.99 [4.71-15.27], t (6) = 4.63, P = 0.0036) postinfusion. Widespread changes in FC followed infusion, which correlated with EPDS scores. Brexanolone is a successful treatment for PPD in the clinical setting. In conjunction with routine clinical care, brexanolone was linked to a reduction in symptoms lasting at least 3 months. pfMRI is feasible in postpartum patients receiving brexanolone and has the potential to elucidate individual-specific mechanisms of action.

Abstract 2060: Automation of 3D cancer spheroid assay for compound screening

Abstract Finding efficient drug combinations to treat cancer patients is critical for therapy success. Accordingly, there is a critical need to develop methods for efficient testing drug efficacy to discover new therapeutic targets. 3D cancer models are highly valuable tools for cancer research and drug development. However, the complexity of performing 3D assays remains a hurdle for adopting these methods for compound screening. To alleviate the bottlenecks that come with labor-intensive manual protocols we developed cell culture automation methods using CellXpress.ai instrument. The instrument enables automation of 2D or 3D culture for prolonged complex workflows. The CellXpress.ai provides automated plating, passaging, media exchanges, monitoring organoids, alone with compound treatment and the end point assays with high content image analysis. In the present study we describe full automation of imaging, analysis, and cell culture process which enables scaling up complex 3D cell-based assays and compound screening. As an example of 3D protocol, we automated culture and imaging of colorectal cancer 3D spheroids formed from HCT116 cell line in U-shape low attachment plates. HCT116 cells were expanded in 2D, then spheroids were formed after automated dispensing of cell suspension into U-shape 96 or 384 plates. After 48h spheroids were treated with 12 anti-cancer compounds, at multiple concentrations for 3-5 days, then stained and imaged. Cell plating, compound additions, media exchange, and staining were performed automatically by CellXpressAI instrument. During the culture spheroids were monitored using transmitted light, with immediate analysis of phenotypic changes, including inhibition of growth or spheroid disintegration. For endpoint assay spheroids were stained with combination of Hoechst nuclear stain and viability dyes Calcein AM and EtHD, then imaged, and analyzed for multiple read-outs including spheroid size, marker intensities, and live-dead cell scoring. We observed concentration-dependent inhibition of spheroid growth and cell death in response to anti-cancer compounds and evaluated effective compound concentrations for cytotoxic or cytostatic effects. Cell culture process automation for 3D assays, powered by imaging and image analysis has a potential to bring 3D biology into another level, allowing to increase throughput and reproducibility, and enabling variety of high throughput drug discovery and precision medicine applications. Citation Format: Oksana Sirenko, Angeline Lim, Astrid Michlmayr, Zhisong Tong, Emilie Keidel, Felix Spira. Automation of 3D cancer spheroid assay for compound screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2060.

Endovascular biopsy in neurointerventional surgery: A systematic review.

Endothelial cells (ECs) continuously line the cerebrovasculature. Molecular aberrations in the ECs are hallmarks and contributory factors to the development of cerebrovascular diseases, including intracranial aneurysms and arteriovenous malformations (AVMs). Endovascular biopsy has been introduced as a method to harvest ECs and obtain relevant biologic information. We aimed to summarize the literature on endovascular biopsy in neurointerventional surgery. We conducted a comprehensive literature search in multiple databases, identifying eligible studies focusing on neurosurgical applications of endovascular biopsy. The systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The relevant information was collected, including study characteristics, biopsy techniques, and key findings. Nine studies met the inclusion criteria and were included. The studies involved the collection of ECs using various endovascular devices including coils, guide wires, different stents, and forceps. Endothelial-enrichment techniques, such fluorescence-activated cell sorting (FACS), collected ECs and facilitated downstream applications of bulk or single-cell RNA sequencing (scRNAseq). The studies provided insights into gene expression profiles and identified potential biomarkers associated with intracranial aneurysms. However, challenges were observed in obtaining an adequate number of ECs and identifying consistent biomarkers. Endovascular biopsy of endothelial cells (ECs) in cerebrovascular pathologies shows promise for gene expression profiling. However, many studies have been limited in sample size and underpowered to identify "signature genes" for aneurysm growth or rupture. Advancements in minimally invasive biopsy methods have potential to facilitate applications of precision medicine in the treatment of cerebrovascular disorders.

Toward reproducible tumor organoid culture: focusing on primary liver cancer.

Organoids present substantial potential for pushing forward preclinical research and personalized medicine by accurately recapitulating tissue and tumor heterogeneity in vitro. However, the lack of standardized protocols for cancer organoid culture has hindered reproducibility. This paper comprehensively reviews the current challenges associated with cancer organoid culture and highlights recent multidisciplinary advancements in the field with a specific focus on standardizing liver cancer organoid culture. We discuss the non-standardized aspects, including tissue sources, processing techniques, medium formulations, and matrix materials, that contribute to technical variability. Furthermore, we emphasize the need to establish reproducible platforms that accurately preserve the genetic, proteomic, morphological, and pharmacotypic features of the parent tumor. At the end of each section, our focus shifts to organoid culture standardization in primary liver cancer. By addressing these challenges, we can enhance the reproducibility and clinical translation of cancer organoid systems, enabling their potential applications in precision medicine, drug screening, and preclinical research.

Abstract P494: Gene-Level Gene-Environment Interaction Testing Reveals Rare Variants With Large Impacts on the Omega-3 Fatty Acid-Inflammation Relationship

Dietary omega-3 fatty acid (dN3FA) intake affects plasma N3FA (pN3FA) concentrations, circulating biomarkers of chronic inflammation such as high-sensitivity C-reactive protein (hsCRP), and ultimately cardiometabolic disease risk. Genetic variation may modify the N3FA-inflammation relationship, facilitating applications in precision medicine and possibly explaining variable intervention trial responses. Here, we explored the dual hypothesis that pN3FA mediates the dN3FA-hsCRP relationship and that genetic variants across the frequency spectrum modify this association. Regression models in the UK Biobank (N = 342,120) tested main effects of oily fish intake (a primary dietary source of N3FA; measured by food frequency questionnaire) on hsCRP and its mediation by pN3FA (measured by nuclear magnetic resonance; N = 188,701). Three genome-wide interaction studies tested modification of the dN3FA-hsCRP (“full”), dN3FA-pN3FA (“upstream”), and pN3FA-hsCRP (“downstream”) associations. Regression covariates included demographics, lifestyle indicators, socioeconomic measures, and genetic principal components. Variant-specific GWIS were followed by gene-level enrichment testing using the MAGMA tool. Replication of gene-based signals was conducted in the Women’s Genome Health Study (WGHS; N = 23,294) by testing the interaction of the top variant in each gene with total dN3FA impacting hsCRP. Oily fish intake associated most strongly with hsCRP compared to other questionnaire-based estimates of fish or fish oil intake, with statistical evidence that plasma N3FA mediated approximately 100% of this diet-inflammation relationship. While the “full” genetic interaction analysis did not produce any FDR-significant gene-level interactions, the “upstream” analysis uncovered nine genes, including a cluster containing the biologically-relevant fatty acid desaturases FADS1 and FADS2 , and the “downstream” analysis uncovered four genes. Primary variant interaction effect sizes were small (e.g., -0.02 std. dev. bN3FA / std. dev. fish / allele for the top FADS1 variant rs174560), but in-depth follow-up at these genes revealed allelic spectra including rare variants with substantially larger effects (e.g., -0.11 for a FADS1 missense variant with allele frequency of 0.14%, after conditioning on rs174560). WGHS results supported the overall robustness of the findings (consistent interaction effect signs at 8/10 loci), replicated specific signals (p = 0.04 for FADS1 rs174560), and implicated additional inflammatory biomarkers (e.g., fibrinogen and ICAM-1 for the top GLTSCR1 variant). In conclusion, we report (1) the novel epidemiological finding that pN3FA fully mediates the dN3FA-hsCRP relationship, and (2) specific genes with large-effect rare variants that modify the upstream (absorption) and downstream (inflammatory pathways) components of this relationship.

Therapeutic Peptides, Proteins and their Nanostructures for Drug Delivery and Precision Medicine.

Peptide and protein nanostructures with tunable structural features, multifunctionality, biocompatibility and biomolecular recognition capacity enable development of efficient targeted drug delivery tools for precision medicine applications. In this review article, we present various techniques employed for the synthesis and self-assembly of peptides and proteins into nanostructures. We discuss design strategies utilized to enhance their stability, drug-loading capacity, and controlled release properties, in addition to the mechanisms by which peptide nanostructures interact with target cells, including receptor-mediated endocytosis and cell-penetrating capabilities. We also explore the potential of peptide and protein nanostructures for precision medicine, focusing on applications in personalized therapies and disease-specific targeting for diagnostics and therapeutics in diseases such as cancer.

OrgaSegment: deep-learning based organoid segmentation to quantify CFTR dependent fluid secretion

Epithelial ion and fluid transport studies in patient-derived organoids (PDOs) are increasingly being used for preclinical studies, drug development and precision medicine applications. Epithelial fluid transport properties in PDOs can be measured through visual changes in organoid (lumen) size. Such organoid phenotypes have been highly instrumental for the studying of diseases, including cystic fibrosis (CF), which is characterized by genetic mutations of the CF transmembrane conductance regulator (CFTR) ion channel. Here we present OrgaSegment, a MASK-RCNN based deep-learning segmentation model allowing for the segmentation of individual intestinal PDO structures from bright-field images. OrgaSegment recognizes spherical structures in addition to the oddly-shaped organoids that are a hallmark of CF organoids and can be used in organoid swelling assays, including the new drug-induced swelling assay that we show here. OrgaSegment enabled easy quantification of organoid swelling and could discriminate between organoids with different CFTR mutations, as well as measure responses to CFTR modulating drugs. The easy-to-apply label-free segmentation tool can help to study CFTR-based fluid secretion and possibly other epithelial ion transport mechanisms in organoids.