Monitoring Of Therapeutic Efficacy Research Articles

Progression in Near-Infrared Fluorescence Imaging Technology for Lung Cancer Management.

Lung cancer is a major threat to human health and a leading cause of death. Accurate localization of tumors in vivo is crucial for subsequent treatment. In recent years, fluorescent imaging technology has become a focal point in tumor diagnosis and treatment due to its high sensitivity, strong selectivity, non-invasiveness, and multifunctionality. Molecular probes-based fluorescent imaging not only enables real-time in vivo imaging through fluorescence signals but also integrates therapeutic functions, drug screening, and efficacy monitoring to facilitate comprehensive diagnosis and treatment. Among them, near-infrared (NIR) fluorescence imaging is particularly prominent due to its improved in vivo imaging effect. This trend toward multifunctionality is a significant aspect of the future advancement of fluorescent imaging technology. In the past years, great progress has been made in the field of NIR fluorescence imaging for lung cancer management, as well as the emergence of new problems and challenges. This paper generally summarizes the application of NIR fluorescence imaging technology in these areas in the past five years, including the design, detection principles, and clinical applications, with the aim of advancing more efficient NIR fluorescence imaging technologies to enhance the accuracy of tumor diagnosis and treatment.

A multifunctional nanosystem catalyzed by cascading natural glucose oxidase and Fe3O4 nanozymes for synergistic chemodynamic and photodynamic cancer therapy

The significance of the tumor microenvironment (TME) in tumor initiation and progression is increasingly acknowledged. Conventional therapeutic approaches face limitations within the complex TME, including the restrictions imposed by hypoxia on photodynamic therapy (PDT) and the deficiency of endogenous H₂O₂ affecting chemodynamic therapy (CDT). In response to the TME's characteristics of high metabolism, hypoxia, and weak acidity, a multifunctional nanosystem MNPs/GOD@CS/IR820, which synergistically integrates CDT and PDT, has been developed. This system can actively accumulate at tumor sites under an external magnetic field and release active components in response to the weakly acidic TME. It mitigates the limitations imposed by hypoxia and endogenous H₂O₂ deficiency on PDT and CDT, respectively, thereby enabling synergistic treatment. Additionally, the system's multimodal imaging capabilities facilitate precise tumor localization and real-time, non-invasive in vivo assessment via fluorescence imaging and MRI. In vitro and in vivo evaluations demonstrate significant antitumor efficacy, effectively inhibiting tumor growth and improving survival rates. By comprehensively addressing the challenges posed by the complex TME and enhancing real-time monitoring capabilities, our nanosystem paves the way for personalized and precise cancer treatment. Statement of significanceThis study introduces an innovative MNPs/GOD@CS/IR820 nanosystem that represents a significant advancement in cancer nanomedicine by addressing critical limitations of conventional photodynamic therapy (PDT), particularly in hypoxic tumor microenvironments. By synergistically integrating chemodynamic therapy (CDT) with PDT and incorporating MRI and fluorescence dual-modal imaging capabilities, this multifunctional platform offers enhanced therapeutic efficacy and real-time monitoring. The system's ability to generate oxygen in situ overcomes hypoxia-induced limitations, while its multimodal mechanism of action induces tumor cell apoptosis through multiple pathways. In vitro and in vivo studies demonstrate remarkable antitumor efficacy across diverse cancer types, significantly inhibiting tumor growth and improving survival rates. This comprehensive approach to cancer diagnosis and treatment not only advances precision medicine for targeted, multimodal cancer management but also provides a promising foundation for future clinical applications, potentially transforming cancer treatment strategies and improving patient outcomes.

Terahertz meta-biosensor for subtype detection and chemotherapy monitoring of glioma cells

Rapid and precise identification of glioma subtypes can assist surgeons in quickly determining patients’ conditions and developing treatment plans. However, current methods face challenges such as high cost and limited sensitivity, thereby significantly hindering diagnostic efficiency. In this paper, we proposed a spectral sensing strategy by introducing terahertz biosensors for glioma subtype recognition and therapeutic efficacy monitoring. Our findings demonstrated that both the resonance frequency and amplitude of the transmission spectra varied as the cell increased. The two-dimensional fingerprint diagram could help us rapidly recognize cell subtypes. Additionally, we conducted a theoretical analysis of the sensing performance. We confirmed that the high Q-factor (∼27.8) results from toroidal dipole resonance and examined the impact of dielectric loss and the refractive index of the analyte on the resonance dip. Furthermore, we applied the biosensor in therapeutic drug screening and showed that as the concentration of tubastatin A increased, the resonance frequency shifted from 183.1 GHz to 76.2 GHz. This result indicates that the toroidal dipole constructed by the metasurface enables ultrasensitive light-matter interactions that amplify subtle cellular changes to the resonance spectrum. The proposed THz meta-biosensor demonstrates significant potential for rapid intraoperative recognition of glioma cell subtypes and therapeutic efficacy monitoring.

Radiotracer Innovations in Breast Cancer Imaging: A Review of Recent Progress.

This review focuses on the pivotal role of radiotracers in breast cancer imaging, emphasizing their importance in accurate detection, staging, and treatment monitoring. Radiotracers, labeled with radioactive isotopes, are integral to various nuclear imaging techniques, including positron emission tomography (PET) and positron emission mammography (PEM). The most widely used radiotracer in breast cancer imaging is 18F-fluorodeoxyglucose (18F-FDG), which highlights areas of increased glucose metabolism, a hallmark of many cancer cells. This allows for the identification of primary tumors and metastatic sites and the assessment of tumor response to therapy. In addition to 18F-FDG, this review will explore newer radiotracers targeting specific receptors, such as estrogen receptors or HER2, which offer more personalized imaging options. These tracers provide valuable insights into the molecular characteristics of tumors, aiding in tailored treatment strategies. By integrating radiotracers into breast cancer management, clinicians can enhance early disease detection, monitor therapeutic efficacy, and guide interventions, ultimately improving patient outcomes. Ongoing research aimed at developing more specific and sensitive tracers will also be highlighted, underscoring their potential to advance precision medicine in breast cancer care.

The use of 7T MRI in multiple sclerosis: review and consensus statement from the North American Imaging in Multiple Sclerosis Cooperative.

The use of ultra-high-field 7-Tesla (7T) MRI in multiple sclerosis (MS) research has grown significantly over the past two decades. With recent regulatory approvals of 7T scanners for clinical use in 2017 and 2020, the use of this technology for routine care is poised to continue to increase in the coming years. In this context, the North American Imaging in MS Cooperative (NAIMS) convened a workshop in February 2023 to review the previous and current use of 7T technology for MS research and potential future research and clinical applications. In this workshop, experts were tasked with reviewing the current literature and proposing a series of consensus statements, which were reviewed and approved by the NAIMS. In this review and consensus paper, we provide background on the use of 7T MRI in MS research, highlighting this technology's promise for identification and quantification of aspects of MS pathology that are more difficult to visualize with lower-field MRI, such as grey matter lesions, paramagnetic rim lesions, leptomeningeal enhancement and the central vein sign. We also review the promise of 7T MRI to study metabolic and functional changes to the brain in MS. The NAIMS provides a series of consensus statements regarding what is currently known about the use of 7T MRI in MS, and additional statements intended to provide guidance as to what work is necessary going forward to accelerate 7T MRI research in MS and translate this technology for use in clinical practice and clinical trials. This includes guidance on technical development, proposals for a universal acquisition protocol and suggestions for research geared towards assessing the utility of 7T MRI to improve MS diagnostics, prognostics and therapeutic efficacy monitoring. The NAIMS expects that this article will provide a roadmap for future use of 7T MRI in MS.

Implantable and wireless-controlled antibacterial patch for deep abscess eradication and therapeutic efficacy monitoring

Pyogenic abscesses in deep organs represent severe bacterial infections that can be life-threatening. Traditional photodynamic and sonodynamic hybrid therapy (PDT/SDT) faces various limitations when treating deep organ abscess, including difficulties in drug release control, limited penetration of external laser, a hypoxic microenvironment, and challenges in therapeutic efficacy monitoring. To address these issues, we developed an implantable and wireless-controlled antibacterial patch integrated with modules for on-demand drug release, light control and therapeutic efficacy monitoring, providing a comprehensive solution to the clinical challenges of PDT/SDT in treating deep organ abscess. This self-adhesive and miniaturized patch can easily attach to internal tissues, and be wirelessly powered and controlled by external ultrasound. Initially, ultrasound powered the patch’s drug release module through the lead zirconate titanate piezoelectric transducer (PZT), providing distinct electrical-thermal release signals for indocyanine green (ICG) and hemoglobin (Hb). This ensured that Hb was released first to generate oxygen, alleviating the hypoxic microenvironment at the infection site, followed by the release of ICG as both a photosensitizer and sonosensitizer. Subsequently, ultrasound directly activated the sonosensitizer and powered the µLEDs in the light control module, ultimately initiating SDT/PDT hybrid antibacterial treatment. The therapeutic efficacy monitoring module in the patch used hydrogels with infection detection capabilities to provide timely feedback on the treatment status of the infected lesions, enabling doctors to rapidly adjust treatment plans and significantly improve the flexibility and effectiveness of treatments. Both in vitro and in vivo experiments have demonstrated that the patch can completely cure pyogenic liver abscesses. This research also exhibits promise for extending the application of the patch to treat other types of deep infections.

An automatic measure for speech intelligibility in dysarthrias-validation across multiple languages and neurological disorders.

Dysarthria, a motor speech disorder caused by muscle weakness or paralysis, severely impacts speech intelligibility and quality of life. The condition is prevalent in motor speech disorders such as Parkinson's disease (PD), atypical parkinsonism such as progressive supranuclear palsy (PSP), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Improving intelligibility is not only an outcome that matters to patients but can also play a critical role as an endpoint in clinical research and drug development. This study validates a digital measure for speech intelligibility, the ki: SB-M intelligibility score, across various motor speech disorders and languages following the Digital Medicine Society (DiMe) V3 framework. The study used four datasets: healthy controls (HCs) and patients with PD, HD, PSP, and ALS from Czech, Colombian, and German populations. Participants' speech intelligibility was assessed using the ki: SB-M intelligibility score, which is derived from automatic speech recognition (ASR) systems. Verification with inter-ASR reliability and temporal consistency, analytical validation with correlations to gold standard clinical dysarthria scores in each disease, and clinical validation with group comparisons between HCs and patients were performed. Verification showed good to excellent inter-rater reliability between ASR systems and fair to good consistency. Analytical validation revealed significant correlations between the SB-M intelligibility score and established clinical measures for speech impairments across all patient groups and languages. Clinical validation demonstrated significant differences in intelligibility scores between pathological groups and healthy controls, indicating the measure's discriminative capability. The ki: SB-M intelligibility score is a reliable, valid, and clinically relevant tool for assessing speech intelligibility in motor speech disorders. It holds promise for improving clinical trials through automated, objective, and scalable assessments. Future studies should explore its utility in monitoring disease progression and therapeutic efficacy as well as add data from further dysarthrias to the validation.

Circulating tumor DNA mutation analysis: advances in its application for early diagnosis of hepatocellular carcinoma and therapeutic efficacy monitoring.

In recent years, the detection and analysis of circulating tumor DNA (ctDNA) have emerged as a new focus in the field of cancer research, particularly in the early diagnosis of hepatocellular carcinoma (HCC) and monitoring of therapeutic efficacy. ctDNA, which refers to cell-free DNA fragments released into the bloodstream from tumor cells upon cell death or shedding, carries tumor-specific genetic and epigenetic alterations, thereby providing a non-invasive approach for cancer diagnosis and prognosis. The concentration of ctDNA in the blood is higher compared to that in healthy individuals or other liquid biopsies from early-stage cancers, which is closely associated with the early diagnosis and comprehensive sequencing studies of HCC. Recent studies have indicated that sequential ctDNA analysis in patients receiving primary or adjuvant therapy for HCC can detect treatment resistance and recurrence before visible morphological changes in the tumor, making it a valuable basis for rapid adjustment of treatment strategies. However, this technology is continuously being optimized and improved. Challenges such as enhancing the accuracy of ctDNA sequencing tests, reducing the burden of high-throughput sequencing on a large number of samples, and controlling variables in the assessment of the relationship between ctDNA concentration and tumor burden, need to be addressed. Overall, despite the existing challenges, the examination and analysis of ctDNA have opened up new avenues for early diagnosis and therapeutic efficacy monitoring in hepatocellular carcinoma, expanding the horizons of this field.

Mn(II)-Aloe-Emodin Nanoscale Coordination Polymer Enhances Ferroptosis by Synergistically Enhancing Reactive Oxygen Species Generation via the Nrf2-GPX4 Axis.

Ferroptosis induction is particularly promising for cancer therapy when the apoptosis pathway is compromised. Current strategies in nanomedicine for inducing ferroptosis primarily focus on promoting the accumulation of reactive oxygen species (ROS). However, the presence of intracellular antioxidants, such as nuclear factor erythroid 2-related factor 2 (Nrf2), can limit the effectiveness of such therapy by activating detoxification systems and eliminating ROS. To overcome this challenge, we developed a synergistic ferroptosis-inducing agentby modifying manganese (Mn2+)-1,8-dihydroxy-3-hydroxymethyl-anthraquinone (aloe-emodin, AE) with polyvinyl pyrrolidone (PVP) to create nanoparticles (MAP NPs). In the tumor microenvironment, these NPs degraded and released AE and Mn(II), facilitating the generation of ROS and Mn(IV) through a Fenton-like reaction between hydrogen peroxide (H2O2) and Mn(II). Mn(IV) subsequently interacts with glutathione (GSH) to induce a cyclic catalytic effect, and the depletion of GSH diminished the activation of glutathione-dependent peroxidase 4 (GPX4). Furthermore, AE inhibits the activity of Nrf2 and depleted GSH, thereby synergistically enhancing antitumor efficacy. Here it is demonstrated that MAP NPs effectively generate a robust ROS storm within tumor cells, suggesting that high-performance ferroptosis therapy is effective. Additionally, the inclusion of Mn(II) in the MAP NPs enables real-time monitoring of therapeutic efficacy via magnetic resonance T1-weighted contrast imaging.

Advancements in Single-cell RNA Sequencing Technology in the Study of the Tumor Microenvironment in Lung Cancer

The immune microenvironment plays a key role in the development and progression of tumors. In recent years, with the rapid advancement of high-throughput sequencing technologies, researchers have gained a deeper understanding of the composition and function of immune cells in the tumor microenvironment. However, traditional bulk sequencing technologies are limited in resolving heterogeneity at the single-cell level, constraining a comprehensive understanding of the complexity of the tumor microenvironment. The advent of single-cell RNA sequencing technology has brought new opportunities to uncover the heterogeneity of the immune microenvironment in lung cancer. Currently, T-cell-centered immunotherapy in clinical settings is prone to side effects affecting prognosis, such as immunogenic drug resistance or immune-related pneumonia, with the key factor being changes in the interactions between immune cells and tumor cells in the tumor microenvironment. Single-cell RNA sequencing technology can reveal the origins and functions of different subgroups within the tumor microenvironment from perspectives such as intercellular interactions and pseudotime analysis, thereby discovering new cell subgroups or novel biomarkers, providing new avenues for uncovering resistance to immunotherapy and monitoring therapeutic efficacy. This review comprehensively discusses the newest research techniques and advancements in single-cell RNA sequencing technology for unveiling the heterogeneity of the tumor microenvironment after lung cancer immunotherapy, offering insights for enhancing the precision and personalization of immunotherapy. .

Tumor biomarkers for diagnosis, prognosis and targeted therapy.

Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.

Diagnosis and Intensive Care in Children’s Diabetic Acidosis: an Interdisciplinary Viewpoint

Diabetic ketoacidosis (DKA) is the main cause of death and disability in children with type I diabetes mellitus (T1DM). Children’s mortality from T1DM reaches 1% in developed countries and 13% in developing countries. The main cause of death in DKA is cerebral edema, clinical manifestations of which develop in 0.5–0.9% of children with DKA, while mortality riches 24%.Objective. Developing recommendations to prevent life-threatening complications of children with DKA using analysis of literature data and consolidated opinion of experts on the issues of intensive care in children with T1DM.Materials and methods. We analyzed and discussed studies in diagnosis and treatment of DKA in children with type 1 diabetes and 1200 literature sources since January 1970, published in Russian peer-reviewed scientific journals and international publications presented in the online repository Medline (Pubmed). The search for publications was carried out using the keywords: «children», «DKA», «DM1», «dehydration», «cerebral edema».Results. We considered issues of epidemiology, pathogenesis, clinical manifestations, diagnosis, intensive care for DKA, as well as clinical and diagnosis, treatment, prevention of cerebral edema issues in children. Limitations of the study were the small number of modern studies with a high level of evidence (randomized controlled trials, meta-analyses) over the past 5 years on DKA in children.Conclusion. Taking into account the national and international experience, joint recommendations on a consensus format were developed and formulated for the diagnosis of DKA, its leading complications and treatment recommendations for children with T1DM and DKA. Timely and accurate diagnosis of DKA, intensive therapy options based on proven therapeutic efficacy, laboratory and clinical monitoring are warranted to interrupt the DKA pathogenesis, prevent the development of life-threatening conditions, and improve treatment outcomes for children with DKA.

Visually evaluating drug efficacy in living cells using COF-based fluorescent nanoprobe via CHA amplified detection of miRNA and simultaneous apoptosis imaging

BackgroundsCancer is a highly fatal disease which is close relative of miRNA aberrant expression and apoptosis disorders. Elucidation of the therapeutic efficacy through investigating the changes in miRNA and apoptosis holds immense importance in advancing the development of miRNA-based precision therapy. However, it remains a challenge as how to visually evaluate the efficacy during protocol optimization of miRNA-based anticancer drugs at the cellular level. Therefore, exploring effective and noninvasive methods for real-time monitoring of therapeutic efficacy in living cells is of great significance. ResultsHerein, we reported a novel fluorescent nanoprobe COF–H1/H2-Peptide for visually evaluating drug efficacy in living cells through amplified imaging of low-abundant miRNA-221 with catalytic hairpin assembly (CHA) circle amplification, as well as simultaneous caspase-3 imaging. With strong stability and good biocompatibility, this newly fabricated amplified nanoprobe showed high sensitivity and specificity for the detection of miRNA-221 and caspase-3, and the limit of detection (LOD) of miRNA-221 was as low as 2.79 pM. The fluorescent imaging results showed that this amplified nanoprobe could not only detect caspase-3 in living cells, but also effectively detect low levels of miRNA-221 with increasing anticancer drug concentration and treatment time. The smart nanoprobe had effective performance for optimizing miRNA-based drug treatment schedules by dual-color fluorescence imaging. SignificanceThis nanoprobe combined CHA amplified detection of intracellular miRNA-221 and synchronous apoptosis imaging, with excellent sensitivity for the detection of cellular low-level miRNA, enabling the realization of real-time assessment of the efficacy of miRNA-based therapy in living cells. This work presents a promising approach for revealing the regulatory mechanisms between miRNAs and apoptosis in cancer occurrence, development, and treatment.

In-vivo assessment of a rat rectal tumor using optical-resolution photoacoustic endoscopy.

Optical-resolution photoacoustic endoscopy (OR-PAE) has been proven to realize imaging on the vascular network in the gastrointestinal (GI) tract with high sensitivity and spatial resolution, providing morphological information. Various photoacoustic endoscopic catheters were developed to improve the resolution and adaptivity of in-vivo imaging. However, this technology has not yet been validated on in-vivo GI tumors, which generally feature angiogenesis. The tumor causes thickened mucosa and neoplasia, requiring large depth-of-field (DOF) in imaging, which contradicts to high-resolution imaging. In this work, a novel catheter was developed with a high resolution of ∼27 µm, providing a matched DOF of ∼400 µm to cover the vessels up to the submucosa layer. Optical-resolution photoacoustic endoscopic imaging was first performed on in-vivo rat rectal tumors. In addition, to further characterize the vessel morphology, tumor-suspected regions and normal regions were selected for quantification and analysis of vessel dimension distribution and tortuosity. All the results suggest that the OR-PAE has great application potential in tumor diagnosis, evaluation, and monitoring of therapeutic efficacy.

A novel subpopulation of monocytes with a strong interferon signature indicated by SIGLEC-1 is present in patients with in recent-onset type 1 diabetes.

Type 1 diabetes is a T cell-mediated autoimmune disease characterised by pancreatic beta cell destruction. In this study, we explored the pathogenic immune responses in initiation of type 1 diabetes and new immunological targets for type 1 diabetes prevention and treatment. We obtained peripheral blood samples from four individuals with newly diagnosed latent autoimmune diabetes in adults (LADA) and from four healthy control participants. Single-cell RNA-sequencing (scRNA-seq) was performed on peripheral blood mononuclear cells to uncover transcriptomic profiles of early LADA. Validation was performed through flow cytometry in a cohort comprising 54 LADA, 17 adult-onset type 2 diabetes, and 26 healthy adults, matched using propensity score matching (PSM) based on age and sex. A similar PSM method matched 15 paediatric type 1 diabetes patients with 15 healthy children. Further flow cytometry analysis was performed in both peripheral blood and pancreatic tissues of non-obese diabetic (NOD) mice. Additionally, cell adoptive transfer and clearance assays were performed in NOD mice to explore the role of this monocyte subset in islet inflammation and onset of type 1 diabetes. The scRNA-seq data showed that upregulated genes in peripheral T cells and monocytes from early-onset LADA patients were primarily enriched in the IFN signalling pathway. A new cluster of classical monocytes (cluster4) was identified, and the proportion of this cluster was significantly increased in individuals with LADA compared with healthy control individuals (11.93% vs 5.93%, p=0.017) and that exhibited a strong IFN signature marked by SIGLEC-1 (encoding sialoadhesin). These SIGLEC-1+ monocytes expressed high levels of genes encoding C-C chemokine receptors 1 or 2, as well as genes for chemoattractants for T cells and natural killer cells. They also showed relatively low levels of genes for co-stimulatory and HLA molecules. Flow cytometry analysis verified the elevated levels of SIGLEC-1+ monocytes in the peripheral blood of participants with LADA and paediatric type 1 diabetes compared with healthy control participants and those with type 2 diabetes. Interestingly, the proportion of SIGLEC-1+ monocytes positively correlated with disease activity and negatively with disease duration in the LADA patients. In NOD mice, the proportion of SIGLEC-1+ monocytes in the peripheral blood was highest at the age of 6 weeks (16.88%), while the peak occurred at 12 weeks in pancreatic tissues (23.65%). Adoptive transfer experiments revealed a significant acceleration in diabetes onset in the SIGLEC-1+ group compared with the SIGLEC-1- or saline control group. Our study identified a novel group of SIGLEC-1+ monocytes that may serve as an important indicator for early diagnosis, activity assessment and monitoring of therapeutic efficacy in type 1 diabetes, and may also be a novel target for preventing and treating type 1 diabetes. RNA-seq data have been deposited in the GSA human database ( https://ngdc.cncb.ac.cn/gsa-human/ ) under accession number HRA003649.

P079 Low-intensity Pulsed Ultrasound reflects the status of mucosal injury and repair through stage-specific miRNAs in experimental model of Ulcerative Colitis

Abstract Background Diagnosis and therapeutic efficacy monitoring of Ulcerative Colitis (UC) are based on a multidisciplinary approach comprising symptomatology and invasive endoscopic assessment coupled to the histopathological characterization of gut tissue biopsies. New technologies that non-invasively reflect tissue-specific changes remains an unmet need. Here we exploited Low Intensity Pulsed Ultrasound (LIPUS) to induce tissue stage-specific miRNAs in circulating blood as a non-invasive approach to reflect the status of the colonic mucosa in experimental model of colitis. Methods Based on our previous study, LIPUS was applied at a frequency of 38 kHz and at an intensity of 0 (as control) or 150 mW/cm2 for 3 min, using a device dedicated for in vivo studies. Acute and chronic colitis were induced in C57BL/6N mice (5 animals/group) by administration of 2 and 2.5% ad libitum dextran sodium sulfate (DSS) respectively in their drinking water for 7 days for the acute and three cycles of 7 days for the chronic model. miRNA array profiling was performed on extracellular vesicles (EVs) isolated from plasma of both acute and chronic models, at both active and remission state, 2 h after LIPUS stimulation. miRNA were correlated to the mucosal status by multiplexed immunofluorescence staining using Opal Multiplex IHC (CD4, CD8, CD68, pan-cytokeratin and CD31 markers) and EVs characterized by MACSplex surface epitope detection. Results An enrichment of EVs characterized mainly by stromal and immune cell surface markers was found in both acute and chronic inflammatory states, LIPUS stimulation significantly modulated miRNA profiles and clearly discriminated between active acute and chronic phases. 61 miRNAs in acute and 28 in chronic colitis were specifically and significantly upregulated by LIPUS in the active phase, with a fold change ranging from 2 to 1500 compared to control. Both acute and chronic disease showed a miRNA profile coherent with the active inflammatory state of intestinal mucosa. Only 10 and 23 miRNAs were upregulated in acute and chronic remission respectively. The enhancement of miR-18a-3p and miR-301b-3p in the recovery phases correlated to instetin with reduced immune cell infiltration and epithelial layer regeneration. Conclusion An optimal LIPUS dosage that non-invasively targets the colon induces the tissue to release specific miRNAs that reflect the mucosal status. LIPUS may open a new era of non-image ultrasound diagnostics that works as disruptive liquid biopsy allowing the detection of tissue biomarkers for monitoring IBD disease progression.

Charged aggregation‐induced emission luminogens for bioimaging and phototherapy

AbstractAggregation‐induced emission luminogens (AIEgens) have received sustained attention in almost all fields of luminescent materials such as selective biochemical sensors, liquid crystals, and anti‐counterfeiting identification. However, the application of neutral AIEgens in the biomedical field is often greatly limited due to their low water solubility. By introducing charges into AIEgens, AIEgens are endowed with good water solubility as well as specific binding ability to bioorganic molecules or special materials with opposite charges, thus expanding the application range of AIEgens. In this review, we focus on the design strategy of charged AIEgens and then summarize the wide applications of charged AIEgens in light‐guided treatments integrating simultaneous phototherapy and real‐time monitoring of therapeutic efficacy. Finally, we conclude with the challenges and application prospects of charged AIEgens. We hope that this review will provide valuable guidance for further expanding the application of charged AIEgens in the field of biological imaging and phototherapy.

Radiosynthesis of [18F]brequinar for in vivo PET imaging of hDHODH for potential studies of acute myeloid leukemia and cancers.

Dihydroorotate dehydrogenase (DHODH), an enzyme that plays a critical role in the de novo pyrimidine biosynthesis, has been recognized as a promising target for the treatment of diseases that involve cellular proliferation, such as autoimmune diseases and cancers. Pharmacological inhibition of human DHODH (hDHODH) that offers a potential therapeutic strategy for the treatment in adult subjects with acute myeloid leukemia (AML) has recently been supported by phase I/II clinical trials for the treatment of patients with relapsed/refractory AML. To facilitate the development of optimized hDHODH inhibitors, the presence of an in vivo imaging probe that is able to demonstrate in vivo target engagement is critical and desirable. Brequinar is one of the most potent hDHODH inhibitors so far discovered. In this work, we use a copper-mediated radiofluorination (CMRF) strategy and compare the chemical design and radiosynthesis starting from either pinacole boronate p-nitrobenzyl ester (4) or tributylstannate (tin) p-nitrobenzyl ester (5), chosen for their suitability as a precursor to [18F]brequinar. We report here the design, synthesis, radiolabeling and characterization of [18F]brequinar, and a preliminary PET imaging study of DHODH in vivo. This study provides the strategies to create [18F]brequinar, the first hDHODH inhibitor PET radiotracer, which will facilitate its use as a tool (theranostics) for hDHODH drug development and for diagnosis and monitoring therapeutic efficacy in AML and cancers.

Epigenetic alterations in creatine transporter deficiency: a new marker for dodecyl creatine ester therapeutic efficacy monitoring.

Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in the Slc6a8 gene. The impaired creatine uptake in the brain leads to developmental delays with intellectual disability. We hypothesized that deficient creatine uptake in CTD cerebral cells impact methylation balance leading to alterations of genes and proteins expression by epigenetic mechanism. In this study, we determined the status of nucleic acid methylation in both Slc6a8 knockout mouse model and brain organoids derived from CTD patients' cells. We also investigated the effect of dodecyl creatine ester (DCE), a promising prodrug that increases brain creatine content in the mouse model of CTD. The level of nucleic acid methylation was significantly reduced compared to healthy controls in both in vivo and in vitro CTD models. This hypo-methylation tended to be regulated by DCE treatment in vivo. These results suggest that increased brain creatine after DCE treatment restores normal levels of DNA methylation, unveiling the potential of using DNA methylation as a marker to monitor the drug efficacy.

Circulating tumor DNA: current implementation issues and future challenges for clinical utility.

Over the past decades, liquid biopsy, especially circulating tumor DNA (ctDNA), has received tremendous attention as a noninvasive detection approach for clinical applications, including early diagnosis of cancer and relapse, real-time therapeutic efficacy monitoring, potential target selection and investigation of drug resistance mechanisms. In recent years, the application of next-generation sequencing technology combined with AI technology has significantly improved the accuracy and sensitivity of liquid biopsy, enhancing its potential in solid tumors. However, the increasing integration of such promising tests to improve therapy decision making by oncologists still has complexities and challenges. Here, we propose a conceptual framework of ctDNA technologies and clinical utilities based on bibliometrics and highlight current challenges and future directions, especially in clinical applications such as early detection, minimal residual disease detection, targeted therapy, and immunotherapy. We also discuss the necessities of developing adynamic field of translational cancer research and rigorous clinical studies that may support therapeutic strategy decision making in the near future.