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At least 19 recordsLinked to original sources
PubMed2026

Base editing for precision therapeutics.

Base editing (BE), the precise installation of single-nucleotide changes in DNA or RNA without inducing double-strand breaks, holds substantial therapeutic promise for correcting single-nucleotide variants, which constitute more than half of the known pathogenic genetic variants. Recent advances have improved base editor specificity, efficiency, and delivery, enabling clinically oriented procedures. Clinically, BE has shown early success or strong translational promise in sickle cell disease, β-thalassemia, leukemia (via CAR T and epitope engineering), hypercholesterolemia (PCSK9 and ANGPTL3), alpha-1-antitrypsin deficiency, and glycogen storage disease type Ia. Key remaining challenges include bystander editing within the activity window, residual off-target DNA and RNA editing, delivery constraints (payload size, tissue targeting, and redosing limits), immunogenicity, and the need for durable long-term safety evidence across relevant cell types and disease contexts. Continued technological refinements, careful preclinical validation, and rigorous clinical assessment will be essential to fully realize BE's transformative potential in precision medicine.

Humans↗
PubMed2026

Beyond antibiotics: artificial intelligence-enabled anti-infective ecosystems for next-generation precision therapeutics against antimicrobial resistance.

The rapid global expansion of antimicrobial resistance (AMR) threatens to undermine decades of progress in infectious disease management and highlights the limitations of conventional antibiotic-centered therapeutic strategies. Although emerging technologies-including antimicrobial peptides, bacteriophage therapy, CRISPR-based antimicrobials, microbiome therapeutics, anti-virulence approaches, nanotechnology-enabled drug delivery, and artificial intelligence (AI)-have individually demonstrated considerable promise, they are predominantly being developed as independent interventions rather than as coordinated components of an integrated therapeutic strategy. This Perspective proposes the Intelligent Anti-Infective Ecosystem (IAIE) as a conceptual systems-level framework that computationally integrates multimodal diagnostics, pathogen genomics, microbiome profiling, AI-assisted decision support, programmable precision therapeutics, ecological monitoring, and longitudinal clinical feedback within a continuously learning dynamically optimized workflow. Unlike existing paradigms that primarily optimize individual technologies or therapeutic decisions, IAIE emphasizes closed-loop coordination among complementary antimicrobial approaches to support precision-guided infection management while preserving microbiome integrity and mitigating resistance selection pressure. We further outline the core components, operational principles, translational challenges, and technology readiness of the major therapeutic platforms that could contribute to such an ecosystem, while distinguishing clinically established interventions from emerging experimental strategies. Importantly, IAIE should be interpreted as a prospective conceptual architecture rather than an existing clinical platform. Its proposed clinical value remains to be established through sequential computational, preclinical, and prospective clinical investigations using standardized microbiological, ecological, and patient-centered outcome measures. By framing antimicrobial innovation within an responsive systems perspective, IAIE provides a roadmap for future multidisciplinary research aimed at integrating artificial intelligence and systems microbiology to enable sustainable management of antimicrobial resistance.

Humans↗
PubMed2026

Epilepsy: Bridging Epidemiological Landscapes, Molecular Mechanisms, and Emerging Precision Therapeutics.

Epilepsy ranks among the most prevalent neurological disorders worldwide, and recent years have witnessed significant advancements in understanding its epidemiological features, pathophysiological mechanisms, diagnostic methodologies, and therapeutic approaches. This review systematically examines the epidemiology of epilepsy, highlighting pronounced regional and population-based disparities, particularly the substantial treatment gap observed in low-income countries. Regarding pathogenesis, epilepsy development involves aberrant ion channel function, neuroinflammatory processes, dysregulation of the mTOR signaling pathway, and genetic predispositions. Diagnostic innovations, including ultra-high field magnetic resonance imaging, artificial intelligence-enhanced electroencephalogram analysis, and liquid biopsy techniques, have markedly enhanced the precision of epileptogenic focus localization and etiological identification. Genetic investigations have uncovered numerous epilepsy-associated genes, thereby underpinning the advancement of targeted therapies. Therapeutically, novel antiepileptic drugs, neuromodulation modalities such as vagus nerve stimulation and deep brain stimulation, alongside gene therapy, have expanded treatment options for refractory epilepsy. Nonetheless, global epilepsy management continues to confront challenges including limited drug accessibility, social stigma, and pharmacoresistance. The future trajectory emphasizes individualized and precision medicine approaches, integrating genomics, biomarker discovery, and intelligent monitoring technologies to foster comprehensive improvements in epilepsy diagnosis and treatment.

epidemiology↗
PubMed2025

Design of precision therapeutics for a CKD risk allele by targeting Shroom3-Rock interaction.

Enhancer variants in Shroom3 associate with renal fibrosis (TIF), but with reduced albuminuria. Detailed mechanisms for these pleiotropic effects are unclear. Here, we focus on identifying the specific profibrotic Shroom3 motif and separating this from its anti-proteinuric function. Given the role for Rho-kinases (Rock) in TIF, and the interaction of Rock with Shroom3 ASD2-domain, we hypothesized that Shroom3-mediated Rock-activation is crucial for profibrotic function. To test this, we develop transgenic tools that overexpress wild-type- (WT-Sh3) or ASD2-domain deletion- Shroom3 (ASD2Δ-Sh3). During TIF, Shroom3 and Rock co-expression occur in injured tubular cells and fibroblasts. In tubular- & fibroblast- lines, ASD2Δ-Sh3 overexpression reduce Rock activation, and pro-fibrotic/pro-inflammatory transcripts downstream of TGFβ1/Wnt/Ctnnb1-signaling vs WT-Sh3. In vivo, inducible global-, or tubular-specific-, but not fibroblast-specific-, ASD2Δ-Sh3 overexpression mitigate TIF, vs WT-Sh3 overexpression. Importantly, ASD2Δ-Sh3 mice do not develop albuminuria, while overexpression of a distinct Fyn-binding deficient mutant Shroom3 (FBDM-Sh3) induces albuminuria. We then develop small molecule inhibitors of Shroom3-Rock interaction (P2Is) and confirm Rock inhibition with these agents in WT-Sh3 cell lines. Our lead P2I from these studies, BT1137, mitigates Rock-activation, profibrotic signaling and TIF in WT-Sh3 mice. Hence, we delineate the profibrotic Shroom3 motif and develop therapeutics for kidney disease from Shroom3 excess.

Animals↗
PubMed2026

Decoding context-dependent sirtuin pharmacology in cancer: Metabolic-epigenetic switches and precision therapeutic targeting.

Sirtuins (SIRT1-SIRT7) are a family of NAD+-dependent lysine deacetylases that possess mono-ADP-ribosyltransferase activity and integrate cellular metabolic status with chromatin regulation, genome maintenance, redox homeostasis, immune responses, and adaptation to cancer therapies. Their translational value has been obscured by a recurring paradox: the same isoform may constrain malignant transformation in one setting yet support metastatic competence, stemness, immune evasion, or drug resistance in another. This review reframes that paradox as a measurable problem of context. We define a SIRT context code in which NAD+ availability and compartmentalization, subcellular localization, PTM state, chromatin occupancy, oncogenic genotype, cell lineage, and tumor microenvironment jointly determine sirtuin output. Using recent mechanistic and translational evidence, we summarize how sirtuins regulate metabolic switching, histone acetylation and lactylation, genome stability, cancer-associated fibroblast programs, regulatory T-cell enrichment, cancer stem-cell plasticity, angiogenesis, and resistance to DNA-damaging, targeted, and immune therapies. We further argue that successful sirtuin pharmacology will require context matching rather than indiscriminate activation or inhibition. Priorities include spatial and single-cell biomarker discovery, compartment-specific NAD+ measurements, PTM-resolved activity assays, structure-guided isoform-selective agents, and degrader strategies targeting non-catalytic scaffolding functions. Sirtuins should therefore be viewed as metabolic-epigenetic decision nodes rather than fixed oncogenes or tumor suppressors. However, the evidence remains predominantly preclinical, and our search identified no clinical-stage oncology trials of direct sirtuin modulators using prospective biomarker stratification, underscoring that this framework remains translationally aspirational rather than clinically validated.

Humans↗
PubMed2026

Targeted Nanoparticle Delivery CRISPR/Cas9: overcoming biological barriers, enhancing stability, and improving therapeutic precision.

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) has emerged as a promising gene-editing platform for genetic disorders; however, its in vivo application remains limited by low delivery efficiency and biological barriers. Many CRISPR payloads fail to reach target sites due to extracellular degradation, immune clearance, and intracellular trafficking limitations. This review examines the interplay between biological barriers and nanoparticle engineering strategies for CRISPR/Cas9 delivery. A barrier-oriented engineering approach is proposed as a central framework, encompassing ligand-based surface modification for enhanced targeting and uptake, improved circulation stability via PEGylation and biomimetic coatings, and optimized payload release through endosomal escape strategies. Stimulus-responsive nanoparticle systems further enable spatiotemporal control over payload release. Nuclear targeting strategies, including optimization of nuclear localization signals (NLS) and exploitation of endogenous trafficking pathways, are highlighted as key factors for improving genome-level editing efficiency. Despite these advances, major challenges-including limited intracellular delivery efficiency, insufficient targeting precision, and safety concerns-continue to hinder clinical translation. Future directions highlight artificial intelligence-driven nanoparticle design, personalized delivery systems, and next-generation CRISPR platforms. Overall, an integrated, barrier-oriented engineering strategy is essential for advancing CRISPR/Cas9 delivery toward clinical applications, ultimately advancing global good health and well-being.

CRISPR/Cas9↗
PubMed2003

COX-3 the enzyme and the concept: steps towards highly specialized pathways and precision therapeutics?

Cyclooxygenases (COXs) catalyse the key rate-limiting step in prostanoid and thromboxane biosynthesis and are targets of non-steroidal anti-inflammatory drugs (NSAIDs). Until recently, the presence of only two isoforms-COX-1 and COX-2-remained in question because the potent anti-pyretic and analgesic effects of acetaminophen (paracetamol, tylenol ben-u-ron) could not be explained by either COX-1 or COX-2 blockades. A novel COX-1 splice variant termed COX-3, sensitive to acetaminophen, was recently discovered by Simmons et al., and is considered to play a key role in the biosynthesis of prostanoids known to be important mediators in pain and fever. Drugs that preferential block COX-1 also appear to act at COX-3. However the existence of COX-3 at the nucleotide sequence level in humans has been called to question. A functional COX-3 in humans is still to come underlining that the concept of COX-3 is still attractive. Here, we discuss some of the implications drawn from the identification of additional functional cyclooxygenase members in the generation of bioactive autacoids.

Acetaminophen↗
PubMed2026

The mighty microproteins: from versatile cellular regulators to precision medicine therapeutics.

Microproteins, are tiny proteins encoded by small open reading frame (sORF), translation of these non-canonical open reading frames (ncORFs) has been implicated in diverse biological processes and diseases. This review summarizes recent developments in the discovery, biogenesis, and functional characterization of microproteins, and their involvement in various disease, with special focus on their roles in cancer, cardiovascular, metabolic, neurodegenerative and immune-related disorders. We emphasize the regulation of key cellular pathways by microproteins, including mitochondrial homeostasis, apoptosis, metabolic reprogramming, and immune signaling, all of which affect disease initiation and progression. Emerging evidence also supports their potential as disease biomarkers and therapeutic candidates for precision medicine. Finally, the review critically discusses the current challenges including discrepancies in microprotein annotation, the limitations of ribosome profiling and proteogenomic approaches, the gap between computationally predicted and experimentally validated microproteins, and the need for rigorous orthogonal validation by means of CRISPR-based genome editing, ribosome release assays, mutational analysis, high-resolution mass spectrometry, and functional studies. Finally, we review recent development of AI-assisted ORF prediction, single-cell translatomics, spatial proteomics, and integrated multi-omics as emerging technologies reshaping. Microprotein discovery and functional annotation. Finally, we discuss the translational potential of microproteins and highlight the remaining challenges to clinical application, including peptide stability, pharmacokinetics, tissue-specific delivery, immunogenicity, and the need for rigorous preclinical and clinical validation. Together, this review provides an updated and critical overview of the rapidly evolving microprotein field and highlights future research priorities for translating these molecules into clinically useful biomarkers and precision therapeutics.

Microproteins↗
PubMed2001

Arterial compliance to stratify cardiovascular risk: more precision in therapeutic decision making.

The focus of attention in preventing and treating cardiovascular (CV) disease today is shifting toward the arterial wall. Evidence has been accumulating for several years that protecting the endothelium is key to reducing CV risk. Endothelial dysfunction results in reduced compliance, or increased arterial stiffness, particularly in the smaller arteries. This abnormality is characteristic of patients with hypertension but may also be seen in normotensive patients before the appearance of clinical disease. Reduced arterial compliance is also seen in patients with diabetes and in smokers, and is part of a vicious cycle that further elevates blood pressure, aggravates atherosclerosis, and leads to increased CV risk. Although other factors are involved, the damage to the endothelium results in reduced secretion of nitric oxide, which influences smooth muscle growth, migration, and contraction, as well as influencing inflammation and clotting. Arterial compliance can be measured by several techniques, most of which are invasive or otherwise not clinically appropriate. Pulse contour analysis is a newly developed noninvasive method that allows for easy, in-office measurement of arterial elasticity to identify patients at risk for CV events before disease becomes clinically apparent. Further research is needed to confirm whether this method offers a means of improving risk stratification and therapeutic decision making.

Arteries↗
PubMed2026

Epigenetic and Transcriptional Regulatory Networks Underlying Psoriasis Pathogenesis.

Psoriasis is a chronic, immune-mediated dermatologic disorder characterized by the hyperproliferation of keratinocytes and dysregulated immune signaling. Although genome-wide association studies have identified susceptibility loci, the multifactorial nature of the disease underlines the importance of nongenetic regulatory mechanisms. Among these epigenetic modifications are those that critically link genetic predisposition with environmental stimuli. This review offers an in-depth overview of the current insights into the role of epigenetic regulation in the pathophysiology of psoriasis. Key mechanisms, including aberrant DNA methylation, histone post-translational modifications (eg, H3K27ac, H3K4me3), and dysregulated noncoding RNAs, are discussed in the context of inflammatory signaling and immune cell function. This review also explores how environmental factors such as UV radiation and air pollution induce the epigenetic reprogramming that perpetuates the proinflammatory state. Furthermore, it highlights the translational potential of targeting epigenetic regulators and epigenome-editing technologies, including clustered regularly interspaced short palindromic repeats (CRISPR) fusion systems, as precision therapeutic strategies. In parallel, advances in single-cell epigenomics, spatial transcriptomics, and the profiling of circulating biomarkers offer novel diagnostic tools. Despite advances, challenges persist, including the limited predictive value of preclinical models and variable epigenetic profiles. Positioning epigenetics as the bridge between genetic risk, environmental triggers, and therapeutic advances, this review presents a framework for precision medicine in psoriasis.

Humans↗
PubMed2025

Precision diagnostic and therapeutic interventions in rare genetic neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs) include a broad spectrum of phenotypes spanning from intellectual disability (ID) to developmental delay (DD) and autism spectrum disorder (ASD). As neurodevelopmental phenotypes are a common presenting feature of an underlying genetic condition, professional medical organizations recommend genetic testing for all individuals with a NDD. When testing is pursued, identified genetic differences can lead to personalized clinical management with early diagnosis supporting the development of surveillance and intervention for co-occurring adverse health outcomes. Despite this, barriers to testing have prevented individuals from receiving a genetics referral and testing. Current therapeutic modalities including small molecule drugs, gene therapies, and antisense oligonucleotide therapies have emerged and shown promise in preclinical trials with therapeutic drugs gaining FDA approval. However, translational challenges are extensive, especially for identifying biomarkers of drug effects in the CNS. In this review, we discuss diagnostic approaches and clinical utility of genetic testing for rare genetic neurodevelopmental disorders, emerging development of individualized therapies, and progress for current therapeutics in addition to challenges with clinical translation and delivery. We will highlight opportunities for early diagnosis and treatment that are steadily gaining ground in favor of optimizing long-term health outcomes and improving quality of life for neurodiverse individuals. IMPACT: The path from genomics to therapeutics for neurodevelopmental disorders continues to present multiple opportunities and challenges. While emerging genome-wide sequencing and gene editing technologies deliver increased diagnostic yields and alternatives to life-long small molecule therapies, clinical translation has been challenging due to inherent cost and genetic heterogeneity. Limited access to genetic testing despite practice guidelines remains a barrier towards precision therapeutics for rare neurodevelopmental disorders, while pre-clinical investigations face obstacles when translating to human subjects. This review will summarize the impact of existing successes in diagnosis and therapeutics for neurodevelopmental disorders while highlighting ongoing challenges and areas of future opportunities.

Humans↗
PubMed2026

Targeting ncRNA control networks with engineered exosomes to overcome therapy resistance in thyroid cancer.

Papillary thyroid cancer (PTC) is the most prevalent endocrine malignancy, accounting for over 90% of thyroid cancers. While differentiated thyroid cancers (DTCs) typically have favorable outcomes, a significant subset progresses to radioactive iodine-refractory (RAIR) disease, characterized by impaired iodine uptake and a 10-year survival rate below 10%. Genetic alterations and dysregulated signaling pathways underlie this transition. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs), play critical regulatory roles in tumor biology and may be transported via exosomes, facilitating intercellular communication and contributing to RAIR-PTC. This systematic review, conducted according to PRISMA 2020 guidelines, evaluated the role of exosomal ncRNAs in RAIR-PTC. A comprehensive search of PubMed, PubMed Central, and Google Scholar identified studies published within the past 15 years in English. Following stringent quality appraisal, studies with a non-bias score above 40% were included. Of 961 identified publications, 96 high-quality studies met inclusion criteria. Evidence indicates that therapy resistance in RAIR-PTC is driven by convergent ncRNA regulatory networks that suppress sodium-iodide symporter (NIS) expression and activate oncogenic pathways, most notably MAPK, PI3K/AKT/mTOR, and Wnt/β-catenin signaling. Multiple ncRNAs converge on key regulatory nodes, forming redundant circuits that sustain dedifferentiation, metabolic adaptation, and impaired iodide transport. Several consistently dysregulated ncRNAs directly or indirectly regulate NIS expression and trafficking, highlighting actionable targets. Exosomes emerge as biologically compatible, programmable delivery vehicles capable of transporting therapeutic ncRNA payloads independent of endogenous packaging mechanisms. These findings support a precision therapeutic paradigm in which engineered exosomes reprogram ncRNA networks to restore iodine-handling pathways and overcome therapy resistance in RAIR-PTC.

Humans↗
PubMed2001

Image-guided robotic delivery system for precise placement of therapeutic agents.

The effectiveness of conventional solid tumor treatment is limited by the systemic toxicity and lack of specificity of chemotherapeutic agents. Present treatment modalities are frequently insufficient to eliminate competent cancer cells without exceeding the limits of toxicity to normal tissue. The coming generation of cancer therapeutics depends on the precise targeting and sustained release of antitumor agents to overcome these limitations. We are developing an image-guided, robotic system for precise intratumoral placement of anticancer drugs and sustained release devices to advance this new treatment paradigm. The robotic system will use intraoperatively obtained computed tomographic (CT) images from a mobile CT scanner for guidance. The concept is to track patient anatomy and localize instruments using currently available optical tracking technology. Tracking will also be used to register patient anatomy with the images. The physician can then use the registered image to select an appropriate tumor target and entry location and to plan the instrument path. This path will then be transmitted to the robot, which orients and drives the instrument to the desired target under physician control. Achievement of the target is confirmed via intraoperative CT. This system will provide instrument guidance that is precise, direct, and controllable. Error due to poor target visualization and hand unsteadiness should be reduced greatly. The basic components of the system (robot, mobile CT, tracking) have been demonstrated in our laboratory, and the integration of the components is in progress. In future work, we plan to fuse preoperative PET imaging with intraoperative CT to allow functional as well as anatomic image guidance.

Antineoplastic Agents↗
PubMed2025

Worldwide Innovative Network (WIN) Consortium in Personalized Cancer Medicine: Bringing next-generation precision oncology to patients.

The human genome project ushered in a genomic medicine era that was largely unimaginable three decades ago. Discoveries of druggable cancer drivers enabled biomarker-driven gene- and immune-targeted therapy and transformed cancer treatment. Minimizing treatment not expected to benefit, and toxicity-including financial and time-are important goals of modern oncology. The Worldwide Innovative Network (WIN) Consortium in Personalized Cancer Medicine founded by Drs. John Mendelsohn and Thomas Tursz provided a vision for innovation, collaboration and global impact in precision oncology. Through pursuit of transcriptomic signatures, artificial intelligence (AI) algorithms, global precision cancer medicine clinical trials and input from an international Molecular Tumor Board (MTB), WIN has led the way in demonstrating patient benefit from precision-therapeutics through N-of-1 molecularly-driven studies. WIN Next-Generation Precision Oncology (WINGPO) trials are being developed in the neoadjuvant, adjuvant or metastatic settings, incorporate real-world data, digital pathology, and advanced algorithms to guide MTB prioritization of therapy combinations for a diverse global population. WIN has pursued combinations that target multiple drivers/hallmarks of cancer in individual patients. WIN continues to be impactful through collaboration with industry, government, sponsors, funders, academic and community centers, patient advocates, and other stakeholders to tackle challenges including drug access, costs, regulatory barriers, and patient support. WIN's collaborative next generation of precision oncology trials will guide treatment selection for patients with advanced cancers through MTB and AI algorithms based on serial liquid and tissue biopsies and exploratory omics including transcriptomics, proteomics, metabolomics and functional precision medicine. Our vision is to accelerate the future of precision oncology care.

Humans↗
PubMed1988

Therapeutical aspects of intrarenal artery aneurysms.

The relative infrequency of aneurysms of the branches of the renal artery produces some indecision as to the surgeon's therapeutical choice. The purpose of this study is to carefully examine the indications for surgical treatment and to select precise therapeutical criteria on the basis of 8 patients in whom aneurysms of the main renal artery or of its branches were diagnosed from 1978 to 1986. In 1 patient, the disease was bilateral with a ruptured main artery aneurysm. 5 aneurysms were treated surgically (the ruptured one by nephrectomy, 2 by ex situ revascularization and 2 by in situ revascularization). In the remaining cases, only periodical controls were performed. In 4 surgically treated patients, angiographic follow-up demonstrated a regular renal revascularization and in 1 patient a thrombosis on the site of the anastomosis. On the basis of personal experience, surgical treatment is required for aneurysms larger than 1.5 cm in size without or with partial calcification, aneurysms occurring in pregnant women or in patients likely to conceive in the future, expanding aneurysms, and renin-mediated hypertension. The introduction of microsurgical techniques and renal preservation makes it possible for the urologist to chose between various therapeutical means for the treatment of intrarenal aneurysms. Reconstruction of anatomical continuity of the arterial supply avoiding unnecessary operative demolishment is feasible.

Aneurysm↗