Potential Of Precision Medicine Research Articles

Molecular Characterization and Therapeutic Opportunities in KRAS Wildtype Pancreatic Ductal Adenocarcinoma

Purpose: To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC). Patients and Methods: We investigated 27 patients with KRASWT PDAC at our institution. Clinical data were obtained via chart review. Tumor specimens for each subject were interrogated for somatic single nucleotide variants, insertion and deletions, and copy number variants by DNA sequencing. Gene fusions were detected from RNA-seq. A patient-derived organoid (PDO) was developed from a patient with a MET translocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial. Results: Transcriptomic analysis showed our cohort may be stratified by the relative gene expression of the KRAS signaling cascade. The PDO derived from our patient harboring a TFG-MET rearrangement was found to have in vitro sensitivity to the multi-tyrosine kinase inhibitor crizotinib. The patient was enrolled in the phase 2 SPARTA clinical trial and received monotherapy with vebrelitinib, a c-MET inhibitor, and achieved a partial and durable response. Conclusions: KRASWT PDAC is molecularly distinct from KRASMUT and enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role in KRASWT PDAC. Our report of a KRASWT PDAC patient with TFG-MET rearrangement who responded to a cMET inhibitor further supports the pursuit of precision oncology in this sub-population. Identification of targetable mutations, perhaps through approaches like RNA-seq, can help enable precision-driven approaches to select optimal treatment based on tumor characteristics.

Hi-GeoMVP: a hierarchical geometry-enhanced deep learning model for drug response prediction.

Personalized cancer treatments require accurate drug response predictions. Existing deep learning methods show promise but higher accuracy is needed to serve the purpose of precision medicine. The prediction accuracy can be improved with not only topology but geometrical information of drugs. A novel deep learning methodology for drug response prediction is presented, named Hi-GeoMVP. It synthesizes hierarchical drug representation with multi-omics data, leveraging graph neural networks and variational autoencoders for detailed drug and cell line representations. Multi-task learning is employed to make better prediction, while both 2D and 3D molecular representations capture comprehensive drug information. Testing on the GDSC dataset confirms Hi-GeoMVP's enhanced performance, surpassing prior state-of-the-art methods by improving the Pearson correlation coefficient from 0.934 to 0.941 and decreasing the root mean square error from 0.969 to 0.931. In the case of blind test, Hi-GeoMVP demonstrated robustness, outperforming the best previous models with a superior Pearson correlation coefficient in the drug-blind test. These results underscore Hi-GeoMVP's capabilities in drug response prediction, implying its potential for precision medicine. The source code is available at https://github.com/matcyr/Hi-GeoMVP. Supplementary data is available at Bioinformatics online.

A Comprehensive Review of Platelet-Rich Plasma and Its Emerging Role in Accelerating Bone Healing.

This comprehensive review delves into the emerging role of platelet-rich plasma (PRP) in accelerating bone healing. PRP, a blood-derived product rich in platelets and growth factors, has garnered attention for its regenerative potential. The review begins by defining PRP and providing a historical background, highlighting its significance in expediting bone healing. PRP's composition and preparation methods, including centrifugation techniques and commercial kits, are explored. Mechanistically, PRP operates by releasing growth factors, chemotaxis, and angiogenesis, elucidating its cellular effects. Applications in fracture healing and orthopaedic surgeries, such as joint arthroplasty and spinal fusion, are discussed, emphasising the promising outcomes in clinical trials. Safety considerations, patient selection criteria, and the need for PRP preparation and application standardisation are underscored. The review outlines ongoing research trends, potential technological advancements, and unexplored areas in paediatric applications and inflammatory bone disorders. The implications for clinical practice involve informed decision-making, optimised protocols, and interdisciplinary collaboration. In conclusion, the future of PRP in bone healing holds exciting prospects, with the potential for precision medicine, integration with emerging therapies, expanded applications, and enhanced technological innovations shaping its trajectory in orthopaedics and regenerative medicine.

PANCDR: precise medicine prediction using an adversarial network for cancer drug response.

Pharmacogenomics aims to provide personalized therapy to patients based on their genetic variability. However, accurate prediction of cancer drug response (CDR) is challenging due to genetic heterogeneity. Since clinical data are limited, most studies predicting drug response use preclinical data to train models. However, such models might not be generalizable to external clinical data due to differences between the preclinical and clinical datasets. In this study, a Precision Medicine Prediction using an Adversarial Network for Cancer Drug Response (PANCDR) model is proposed. PANCDR consists of two sub-models, an adversarial model and a CDR prediction model. The adversarial model reduces the gap between the preclinical and clinical datasets, while the CDR prediction model extracts features and predicts responses. PANCDR was trained using both preclinical data and unlabeled clinical data. Subsequently, it was tested on external clinical data, including The Cancer Genome Atlas and brain tumor patients. PANCDR outperformed other machine learning models in predicting external test data. Our results demonstrate the robustness of PANCDR and its potential in precision medicine by recommending patient-specific drug candidates. The PANCDR codes and data are available at https://github.com/DMCB-GIST/PANCDR.

Expert-based collaborative analysis of the situation and prospects of biomarker test implementation in oncology in Spain

PurposeBiomarkers as screening for precision medicine is a fundamental step. The purpose of this article is twofold. First, tohighlight the existing barriers in the implementation of Precision Medicine in Spain, with a special emphasis on barriersin access to the determination of biomarkers. Second, to provide a Roadmap that can help implement Precision Medicineequitably at the national level and optimize the use of biomarkers.MethodsA systematic review of literature (SRL) and a focus group (FG) with multidisciplinary experts has been carried out in 2023.Participants were contacted individually, and discourse analysis was processed anonymously.ResultsWe carried out a quantitative (SRL) and a qualitative approach (FG). The discourse analysis and roadmap were sentindividually to each expert for approval.ConclusionsThe potential of Precision Medicine has not been fulfilled in Spain. While several regional initiatives are in place, anational plan or strategy around Precision Medicine and use of biomarkers is lacking. In a general context of rapidprogress at a global and European level, including the 2021 Europe’s Beating Cancer Plan, it is time to define andimplement a National Plan to make the promise come true. While some comparable countries within Europe – such asthe UK or France – are mature enough to adopt such strategies, in Spain there is still a long way to go. We consider thatthe different strands of work outlined in the Roadmap can be used as basis for such purpose.

Single-cell landscape and spatial transcriptomic analysis reveals macrophage infiltration and glycolytic metabolism in kidney renal clear cell carcinoma.

The present study investigates the clinical relevance of glycolytic factors, specifically PGAM1, in the tumor microenvironment of kidney renal clear cell carcinoma (KIRC). Despite the established role of glycolytic metabolism in cancer pathophysiology, the prognostic implications and key targets in KIRC remain elusive. We analyzed GEO and TCGA datasets to identify DEGs in KIRC and studied their relationship with immune gene expression, survival, tumor stage, gene mutations, and infiltrating immune cells. We explored Pgam1 gene expression in different kidney regions using spatial transcriptomics after mouse kidney injury analysis. Single-cell RNA-sequencing was used to assess the association of PGAM1 with immune cells. Findings were validated with tumor specimens from 60 KIRC patients, correlating PGAM1 expression with clinicopathological features and prognosis using bioinformatics and immunohistochemistry. We demonstrated the expression of central gene regulators in renal cancer in relation to genetic variants, deletions, and tumor microenvironment. Mutations in these hub genes were positively associated with distinct immune cells in six different immune datasets and played a crucial role in immune cell infiltration in KIRC. Single-cell RNA-sequencing revealed that elevated PGAM1 was associated with immune cell infiltration, specifically macrophages. Furthermore, pharmacogenomic analysis of renal cancer cell lines indicated that inactivation of PGAM1 was associated with increased sensitivity to specific small-molecule drugs. Altered PGAM1 in KIRC is associated with disease progression and immune microenvironment. It has diagnostic and prognostic implications, indicating its potential in precision medicine and drug screening.

Enhancing Antisense Oligonucleotide-Based Therapeutic Delivery with DG9, a Versatile Cell-Penetrating Peptide.

Antisense oligonucleotide-based (ASO) therapeutics have emerged as a promising strategy for the treatment of human disorders. Charge-neutral PMOs have promising biological and pharmacological properties for antisense applications. Despite their great potential, the efficient delivery of these therapeutic agents to target cells remains a major obstacle to their widespread use. Cellular uptake of naked PMO is poor. Cell-penetrating peptides (CPPs) appear as a possibility to increase the cellular uptake and intracellular delivery of oligonucleotide-based drugs. Among these, the DG9 peptide has been identified as a versatile CPP with remarkable potential for enhancing the delivery of ASO-based therapeutics due to its unique structural features. Notably, in the context of phosphorodiamidate morpholino oligomers (PMOs), DG9 has shown promise in enhancing delivery while maintaining a favorable toxicity profile. A few studies have highlighted the potential of DG9-conjugated PMOs in DMD (Duchenne Muscular Dystrophy) and SMA (Spinal Muscular Atrophy), displaying significant exon skipping/inclusion and functional improvements in animal models. The article provides an overview of a detailed understanding of the challenges that ASOs face prior to reaching their targets and continued advances in methods to improve their delivery to target sites and cellular uptake, focusing on DG9, which aims to harness ASOs' full potential in precision medicine.

Advance on fiber optic‐based biosensors for precision medicine: From diagnosis to therapy

AbstractPrecision medicine that takes individual variability into account is a new way to minimize the individual variability for precise diagnosis and to establish the certain strategies of efficient therapy. Due to miniaturization sensing area, remoting detection, and flexible operation of light, fiber optics have been successfully used to develop in vitro, wearable, and implanted biosensors, exhibiting high potential in precision medicine from the diagnosis in vitro to therapy in vivo. When modified with the recognition element, the fiber optic‐based biosensor enables the point of care testing for the detection of disease biomarkers. Meanwhile, the fiber optics packaged in a needle/catheter also monitor the medical Internet of things for the continuous assessment of human health. Moreover, the light from the cladding or leaky mode in the fiber optics excites the strong photothermal effect for therapy. The fiber optic‐based biosensor addressed the drawbacks of plasmonic photothermal therapy that limited penetration depths and non‐selectivity therapy. When integrated with a photothermal agent, the fiber optic‐based biosensors provide in situ information for the diagnosis as well as specifically and efficiently kill the tumor cells in deep tissues. In this review, we summarized the advances of fiber optic‐based biosensors in the diagnosis in vitro and therapy in vivo. The challenges and prospection of the fiber optic‐based biosensor application in precision medicine were also explored in depth.

Microdevices for cancer stem cell culture as a predictive chemotherapeutic response platform.

Microfluidic platforms for clinical use are a promising translational strategy for cancer research specially for drug screening. Identifying cancer stem cells (CSC) using sphere culture techniques in microfluidic devices (MDs) showed to be better reproducing physiological responses than other in vitro models and allow the optimization of samples and reagents. We evaluated individual sphere proliferation and stemness toward chemotherapeutic treatment (CT) with doxorubicin and cisplatin in bladder cancer cell lines (MB49-I and J82) cultured in MDs used as CSC treatment response platform. Our results confirm the usefulness of this device to evaluate the CT effect in sphere-forming efficiency, size, and growth rate from individual spheres within MDs and robust information comparable to conventional culture plates was obtained. The expression of pluripotency genetic markers (Oct4, Sox2, Nanog, and CD44) could be analyzed by qPCR and immunofluorescence in spheres growing directly in MDs. MDs are a suitable platform for sphere isolation from tumor samples and can provide information about CT response. Microfluidic-based CSC studies could provide information about treatment response of cancer patients from small samples and can be a promising tool for CSC-targeted specific treatment with potential in precision medicine. KEY MESSAGES: We have designed a microfluidic platform for CSC enriched culture by tumor sphere formation. Using MDs, we could quantify and determine sphere response after CT using murine and human cell lines as a proof of concept. MDs can be used as a tumor-derived sphere isolation platform to test the effect of antitumoral compounds in sphere proliferation.

Exploring the Attitudes, Beliefs and Perceptions of Undergraduate and Graduate Students in Bangladesh towards Precision Medicine and Pharmacogenomics Practice: A Qualitative Study

This paper aims to explore the perception of precision medicine (PM) and pharmacogenomics (PGx) among undergraduate and graduate students in Bangladesh. A cross-sectional survey was conducted among students from different universities across the country. The results of the survey showed that the majority of students had a positive attitude towards precision medicine and pharmacogenomics, perceiving it as a means to improve diagnosis and treatment accuracy. Furthermore, the majority of students also expressed a willingness to learn more about precision medicine and pharmacogenomics, suggesting that there is potential for these practices to be utilized in Bangladesh. Particularly in this study, 337 students from life science and relevant programs participated. The results of our study showed that 84% of graduate students and 74% of undergraduate students thought PM was a promising healthcare model. In addition, 39% of students are highly encouraged to pursue their post-graduation in the subject areas of PGx and PM in order to support patients. The majority (62%) thought that patient privacy was the ethical concern most closely related to pharmacogenomic testing, while 19% of respondents thought that data confidentiality was the key issue. The findings of this study provide insight into the potential of precision medicine and pharmacogenomics in Bangladesh and suggest that further research into the attitudes of healthcare professionals should be conducted in order to take full advantage of the potential of these practices.

From precision medicine to precision care: Choosing and using precision medicine in the context of multimorbidity.

Rapid advances in precision medicine promise dramatic reductions in morbidity and mortality for a growing array of conditions. To realize the benefits of precision medicine and minimize harm, it is necessary to address real-world challenges encountered in translating this research into practice. Foremost among these is how to choose and use precision medicine modalities in real-world practice by addressing issues related to caring for the sizable proportion of people living with multimorbidity. Precision medicine needs to be delivered in the broader context of precision care to account for factors that influence outcomes for specific therapeutics. Precision care integrates a person-centered approach with precision medicine to inform decision making and care planning by taking multimorbidity, functional status, values, goals, preferences, social and societal context into account. Designing dissemination and implementation of precision medicine around precision care would improve person-centered quality and outcomes of care, target interventions to those most likely to benefit thereby improving access to new therapeutics, minimize the risk of withdrawal from the market from unanticipated harms of therapy, and advance health equity by tailoring interventions and care to meet the needs of diverse individuals and populations. Precision medicine delivered in the context of precision care would foster respectful care aligned with preferences, values, and goals, engendering trust, and providing needed information to make informed decisions. Accelerating adoption requires attention to the full continuum of translational research: developing new approaches, demonstrating their usefulness, disseminating and implementing findings, while engaging patients throughout the process. This encompasses basic science, preclinical and clinical research and implementation into practice, ultimately improving health. This article examines challenges to the adoption of precision medicine in the context of multimorbidity. Although the potential of precision medicine is enormous, proactive efforts are needed to avoid unintended consequences and foster its equitable and effective adoption.

Intracellular activated logic nanomachines based on framework nucleic acids for low background detection of microRNAs in living cells.

DNA molecular machines based on DNA logic circuits show unparalleled potential in precision medicine. However, delivering DNA nanomachines into real biological systems and ensuring that they perform functions specifically, quickly and logically remain a challenge. Here, we developed an efficient DNA molecular machine integrating transfer-sensor-computation-output functions to achieve high fidelity detection of intracellular biomolecules. The introduction of pH nanoswitches enabled the nanomachines to be activated after entering the cell, and the spatial-confinement effect of the DNA triangular prism (TP) enables the molecular machine to process complex information at the nanoscale, with higher sensitivity and shorter response time than diffuse-dominated logic circuits. Such cascaded activation molecular machines follow the logic of AND to achieve specific capture and detection of biomolecules in living cells through a multi-hierarchical response, providing a new insight into the construction of efficient DNA molecular machines.

Urine and serum metabolic profiling combined with machine learning for autoimmune disease discrimination and classification.

Precision diagnosis and classification of autoimmune diseases (ADs) is challenging due to the obscure symptoms and pathological causes. Biofluid metabolic analysis has the potential for disease screening, in which high throughput, rapid analysis and minimum sample consumption must be addressed. Herein, we performed metabolomic profiling by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) in urine and serum samples. Combined with machine learning (ML), metabolomic patterns from urine achieved the discrimination and classification of ADs with high accuracy. Furthermore, metabolic disturbances among different ADs were also investigated, and provided information of etiology. These results demonstrated that urine metabolic patterns based on MALDI-MS and ML manifest substantial potential in precision medicine.

Robust Navigation Control of a Microrobot With Hysteresis Compensation

Navigation control of microrobots in vivo has great potential in precision medicine and has attracted considerable attention in recent years. The control performance of the existing methods is considerably affected by hysteresis nonlinearity. This article presents a robust control method that can overcome hysteresis influence in navigating a microrobot actuated by an electromagnetic coil system. A motion planner that combines the breadth-first search (BFS) method and genetic algorithm (GA) is used to plan a reliable and flexible trajectory for the microrobot navigation. To compensate for hysteresis nonlinearity existing in the system, the Prandtl–Ishlinskii (PI) model is introduced. A robust controller that integrates adaptive sliding mode control (ASMC) and nonlinear disturbance observer is designed to guarantee the stability and accuracy of the microrobot in motion. Experiments have been performed to demonstrate the effectiveness of the proposed approach. The success of this research will advance the microrobot navigation for in vivo applications. Note to Practitioners—The motivation of this article is to eliminate the effect of hysteresis caused by the electromagnetic system on microrobot motion. Existing research on hysteresis compensation mostly uses inverse model or online model identification, which is not suitable for real-time control of the microrobot. In addition, the disturbance and uncertainty caused by the microfluidic environment at different flow rates will also affect the control performance of the microrobot. To solve the above problems, an adaptive robust control method is developed in this article. Experimental results have shown that the proposed method can successfully control the microrobot in the in vitro and in vivo environment.

Dawn of Precision Medicine in Psoriatic Arthritis.

The establishment of precision medicine is considered particularly important in heterogeneous autoimmune diseases (e.g., psoriatic arthritis, systemic lupus erythematosus), which reveal clinical and molecular heterogeneity. The selection of optimal treatment strategies for individual patients may be more important and complex in autoimmune diseases than in other diseases. Two factors are important in precision medicine: patient stratification and use of targeted. When both factors work, patients are likely to have good outcomes. However, research into precision medicine and its practice in systemic autoimmune diseases is lacking. In contrast, the usefulness of peripheral immune cell phenotyping in the evaluation of immunological characteristics and stratification into subgroups of individual patients with systemic autoimmune diseases such as immunoglobulin 4-related disease, systemic lupus erythematosus, and anti-neutrophil cytoplasmic antibody-related vasculitis was reported. Furthermore, the potential of precision medicine using biological disease-modifying antirheumatic drugs based on peripheral immune cell phenotyping was recently demonstrated for psoriatic arthritis in the clinical setting. Precision medicine has not yet been sufficiently investigated in real world clinical settings. However, a dawn of precision medicine has emerged. We should shed further light on precision medicine in PsA and other autoimmune diseases. Here, we first review the usefulness of peripheral immune cell phenotyping in systemic autoimmune diseases and the potential of precision medicine in PsA based on this method.

From Microenvironment Remediation to Novel Anti-Cancer Strategy: The Emergence of Zero Valent Iron Nanoparticles.

Accumulated studies indicate that zero-valent iron (ZVI) nanoparticles demonstrate endogenous cancer-selective cytotoxicity, without any external electric field, lights, or energy, while sparing healthy non-cancerous cells in vitro and in vivo. The anti-cancer activity of ZVI-based nanoparticles was anti-proportional to the oxidative status of the materials, which indicates that the elemental iron is crucial for the observed cancer selectivity. In this thematic article, distinctive endogenous anti-cancer mechanisms of ZVI-related nanomaterials at the cellular and molecular levels are reviewed, including the related gene modulating profile in vitro and in vivo. From a material science perspective, the underlying mechanisms are also analyzed. In summary, ZVI-based nanomaterials demonstrated prominent potential in precision medicine to modulate both programmed cell death of cancer cells, as well as the tumor microenvironment. We believe that this will inspire advanced anti-cancer therapy in the future.

Therapeutic challenges at the preclinical level for targeted drug development for Opisthorchis viverrini-associated cholangiocarcinoma

Introduction Cholangiocarcinoma (CCA) is a malignant tumor of bile duct epithelium with the highest incidence found in Thailand. Some patients are considered suitable for adjuvant therapy and surgical resection is currently the curative treatment for CCA patients. Tumor recurrence is still a hurdle after treatment; hence, finding novel therapeutic strategies to combat CCA is necessary for improving outcome for patients. Areas covered We discuss targeted therapies and other novel treatment approaches which includes protein kinase inhibitors, natural products, amino acid transporter-based inhibitors, immunotherapy, and drug repurposing. We also examine the challenges of tumor heterogeneity, cancer stem cells (CSCs), the tumor microenvironment, exosomes, multiomics studies and the potential of precision medicine. Expert opinion Because CCA is difficult to diagnose at the early stage, the traditional treatment approaches are not effective for many patients and most tumors recur. Consequently, researchers are exploring multi-aspect molecular carcinogenesis to uncover molecular targets for further development of novel targeted drugs.

The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery.

Antisense oligonucleotides (ASOs) are used to selectively inhibit the translation of disease-associated genes via Ribonuclease H (RNaseH)-mediated cleavage or steric hindrance. They are being developed as a novel and promising class of drugs targeting a wide range of diseases. Despite the great potential and numerous ASO drugs in preclinical research and clinical trials, there are many limitations to this technology. In this review we will focus on the challenges of ASO delivery and the strategies adopted to improve their stability in the bloodstream, delivery to target sites, and cellular uptake. Focusing on liposomal delivery, we will specifically describe liposome-incorporated growth factor receptor-bound protein-2 (Grb2) antisense oligodeoxynucleotide BP1001. BP1001 is unique because it is uncharged and is essentially non-toxic, as demonstrated in preclinical and clinical studies. Additionally, its enhanced biodistribution makes it an attractive therapeutic modality for hematologic malignancies as well as solid tumors. A detailed understanding of the obstacles that ASOs face prior to reaching their targets and continued advances in methods to overcome them will allow us to harness ASOs’ full potential in precision medicine.

Precision Medicine in Osteosarcoma: MATCH Trial and Beyond.

Osteosarcoma (OS) is a rare bone malignant tumour with a poor prognosis in the case of recurrence. So far, there is no agreement on the best systemic therapy for relapsed OS. The availability of next generation sequencing techniques has recently revolutionized clinical research. The sequencing of the tumour and its matched normal counterpart has the potential to reveal a wide landscape of genetic alterations with significant implications for clinical practice. The knowledge that the genomic profile of a patient’s tumour can be precisely mapped and matched to a targeted therapy in real time has improved the development of precision medicine trials (PMTs). PMTs aiming at determining the effectiveness of targeted therapies could be advantageous for patients with a tumour refractory to standard therapies. Development of PMTs for relapsed OS is largely encouraging and is in its initial phase. Assessing OS features, such as its rarity, its age distribution, the technical issues related to the bone tissue origin, and its complex genomic landscape, represents a real challenge for PMTs development. In this light, a multidisciplinary approach is required to fully exploit the potential of precision medicine for OS patients.

A review of functional nanotechnology: Its use and potential in precision medicine

From targeted drug delivery to detecting early markers of diseases, DNA-based nano-objects establish control mechanisms for a wide array of biomedical applications