The impact of immunopeptidomics: From basic research to clinical implementation.

The immunopeptidome is the set of peptides presented by the major histocompatibility complex (MHC) molecules, in humans also known as the human leukocyte antigen (HLA), on the surface of cells that mediate T-cell immunosurveillance. The immunopeptidome is a sampling of the cellular proteome and hence it contains information about the health state of cells. The peptide repertoire is influenced by intra- and extra-cellular perturbations - such as in the case of drug exposure, infection, or oncogenic transformation. Immunopeptidomics is the bioanalytical method by which the presented peptides are extracted from biological samples and analyzed by high-performance liquid chromatography coupled to tandem mass spectrometry (MS), resulting in a deep qualitative and quantitative snapshot of the immunopeptidome. In this review, we discuss published immunopeptidomics studies from recent years, grouped into three main domains: i) basic, ii) pre-clinical and iii) clinical research and applications. We review selected fundamental immunopeptidomics studies on the antigen processing and presentation machinery, on HLA restriction and studies that advanced our understanding of various diseases, and how exploration of the antigenic landscape allowed immune targeting at the pre-clinical stage, paving the way to pioneering exploratory clinical trials where immunopeptidomics is directly implemented in the conception of innovative treatments for cancer patients.

Artificial intelligence: revolutionizing cardiology with large language models.

Natural language processing techniques are having an increasing impact on clinical care from patient, clinician, administrator, and research perspective. Among others are automated generation of clinical notes and discharge letters, medical term coding for billing, medical chatbots both for patients and clinicians, data enrichment in the identification of disease symptoms or diagnosis, cohort selection for clinical trial, and auditing purposes. In the review, an overview of the history in natural language processing techniques developed with brief technical background is presented. Subsequently, the review will discuss implementation strategies of natural language processing tools, thereby specifically focusing on large language models, and conclude with future opportunities in the application of such techniques in the field of cardiology.

Expanding the clinical application of OPM-MEG using an effective automatic suppression method for the dental brace metal artifact.

Optically pumped magnetometer magnetoencephalography (OPM-MEG) holds significant promise for clinical functional brain imaging due to its superior spatiotemporal resolution. However, effectively suppressing metallic artifacts, particularly from devices such as orthodontic braces and vagal nerve stimulators remains a major challenge, hindering the wider clinical application of wearable OPM-MEG devices. A comprehensive analysis of metal artifact characteristics from time, frequency, and time-frequency perspectives was conducted for the first time using an OPM-MEG device in clinical medicine. This study focused on patients with metal orthodontics, examining the modulation of metal artifacts by breath and head movement, the incomplete regular sub-Gaussian distribution, and the high absolute power ratio in the 0.5-8 Hz band. The existing metal artifact suppression algorithms applied to SQUID-MEG, such as fast independent component analysis (FastICA), information maximization (Infomax), and algorithms for multiple unknown signal extraction (AMUSE), exhibit limited efficacy. Consequently, this study introduced the second-order blind identification (SOBI) algorithm, which utilized multiple time delays for the component separation of OPM-MEG measurement signals. We modified the time delays of the SOBI method to improve its efficacy in separating artifact components, particularly those in the ultralow frequency range. This approach employs the frequency-domain absolute power ratio, root mean square (RMS) value, and mutual information methods to automate the artifact component screening process. The effectiveness of this method was validated through simulation experiments involving four subjects in both resting and evoked experiments. In addition, the proposed method was also validated by the actual OPM-MEG evoked experiments of three subjects. Comparative analyses were conducted against the FastICA, Infomax, and AMUSE algorithms. Evaluation metrics included normalized mean square error, normalized delta band power error, RMS error, and signal-to-noise ratio, demonstrating that the proposed method provides optimal suppression of metal artifacts. This advancement holds promise for enhancing data quality and expanding the clinical applications of OPM-MEG.

Targeting PI3K family with small-molecule inhibitors in cancer therapy: current clinical status and future directions.

The Phosphatidylinositol-3-kinase (PI3K) family is well-known to comprise three classes of intracellular enzymes. Class I PI3Ks primarily function in signaling by responding to cell surface receptor stimulation, while class II and III are more involved in membrane transport. Under normal physiological conditions, the PI3K signaling network orchestrates cell growth, division, migration and survival. Aberrant activation of the PI3K signaling pathway disrupts cellular activity and metabolism, often marking the onset of cancer. Currently, the Food and Drug Administration (FDA) has approved the clinical use of five class I PI3K inhibitors. These small-molecule inhibitors, which exhibit varying selectivity for different class I PI3K family members, are primarily used in the treatment of breast cancer and hematologic malignancies. Therefore, the development of novel class I PI3K inhibitors has been a prominent research focus in the field of oncology, aiming to enhance potential therapeutic selectivity and effectiveness. In this review, we summarize the specific structures of PI3Ks and their functional roles in cancer progression. Additionally, we critically evaluate small molecule inhibitors that target class I PI3K, with a particular focus on their clinical applications in cancer treatment. Moreover, we aim to analyze therapeutic approaches for different types of cancers marked by aberrant PI3K activation and to identify potential molecular targets amenable to intervention with small-molecule inhibitors. Ultimately, we propose future directions for the development of therapeutic strategies that optimize cancer treatment outcomes by modulating the PI3K family.

Calling small variants using universality with Bayes-factor-adjusted odds ratios.

The application of next-generation sequencing in research and particularly in clinical routine requires highly accurate variant calling. Here we describe UVC, a method for calling small variants of germline or somatic origin. By unifying opposite assumptions with sublation, we discovered the following two empirical laws to improve variant calling: allele fraction at high sequencing depth is inversely proportional to the cubic root of variant-calling error rate, and odds ratios adjusted with Bayes factors can model various sequencing biases. UVC outperformed other variant callers on the GIAB germline truth sets, 192 scenarios of in silico mixtures simulating 192 combinations of tumor/normal sequencing depths and tumor/normal purities, the GIAB somatic truth sets derived from physical mixture, and the SEQC2 somatic reference sets derived from the breast-cancer cell-line HCC1395. UVC achieved 100% concordance with the manual review conducted by multiple independent researchers on a Qiagen 71-gene-panel dataset derived from 16 patients with colon adenoma. UVC outperformed other unique molecular identifier (UMI)-aware variant callers on the datasets used for publishing these variant callers. Performance was measured with sensitivity-specificity trade off for called variants. The improved variant calls generated by UVC from previously published UMI-based sequencing data provided additional insight about DNA damage repair. UVC is open-sourced under the BSD 3-Clause license at https://github.com/genetronhealth/uvc and quay.io/genetronhealth/gcc-6-3-0-uvc-0-6-0-441a694.

Intricate effects of post-translational modifications in liver cancer: mechanisms to clinical applications.

Liver cancer is a significant global health challenge, with hepatocellular carcinoma (HCC) being the most prevalent form, characterized by high incidence and mortality rates. Despite advances in targeted therapies and immunotherapies, the prognosis for advanced liver cancer remains poor. This underscores the urgent need for a deeper understanding of the molecular mechanisms underlying HCC to enable early detection and the development of novel therapeutic strategies. Post-translational modifications (PTMs) are crucial regulatory mechanisms in cellular biology, affecting protein functionality, interactions, and localization. These modifications, including phosphorylation, acetylation, methylation, ubiquitination, and glycosylation, occur after protein synthesis and play vital roles in various cellular processes. Recent advances in proteomics and molecular biology have highlighted the complex networks of PTMs, emphasizing their critical role in maintaining cellular homeostasis and disease pathogenesis. Dysregulation of PTMs has been associated with several malignant cellular processes in HCC, such as altered cell proliferation, migration, immune evasion, and metabolic reprogramming, contributing to tumor growth and metastasis. This review aims to provide a comprehensive understanding of the pathological mechanisms and clinical implications of various PTMs in liver cancer. By exploring the multifaceted interactions of PTMs and their impact on liver cancer progression, we highlight the potential of PTMs as biomarkers and therapeutic targets. The significance of this review lies in its potential to inform the development of novel therapeutic approaches and improve prognostic tools for early intervention in the fight against liver cancer.

Miniature mass spectrometers and their potential for clinical point-of-care analysis.

Mass spectrometry (MS) has become a powerful technique for clinical applications with high sensitivity and specificity. Different from conventional MS diagnosis in laboratory, point-of-care (POC) analyses in clinics require mass spectrometers and analytical procedures to be friendly for novice users and applicable for on-site clinical diagnosis. The recent decades have seen the progress in the development of miniature mass spectrometers, providing a promising solution for clinical POC applications. In this review, we report recent advances of miniature mass spectrometers and their exploration in clinical applications, mainly including the rapid analysis of illegal drugs, on-site monitoring of therapeutic drugs, and detection of biomarkers. With improved analytical performance, miniature mass spectrometers are also expected to apply to more and more clinical applications. Some promising POC analyses that can be performed by miniature mass spectrometers in the future are discussed. Lastly, we also provide our perspectives on the challenges in technical development of miniature mass spectrometers for clinical POC analysis.

Research progress on measurement methods and clinical applications of corneal elastic modulus.

Various corneal diseases are strongly associated with corneal biomechanical characteristics, and early measurement of patients' corneal biomechanics can be utilized in their diagnosis and treatment. Measurement methods for corneal biomechanical characteristics are classified into ex vivo and in vivo. Some of these methods can directly measure certain corneal biomechanical parameters, while others require indirect calculation through alternative methods. However, due to diversities in measurement techniques and environmental conditions, significant differences may exist in the corneal mechanical properties measured by these two methods. Therefore, comprehensive research on current measurement methods and the exploration of novel measurement techniques may have great clinical significance. The corneal elastic modulus, a critical indicator in corneal biomechanics, reflects the cornea's ability to return to its initial shape after undergoing stress. This review aims to provide a comprehensive summary of the corneal elastic modulus, which is a critical biomechanical parameter, and discuss its direct, indirect, and potential measurement methods and clinical applications.

Mechanisms and clinical landscape of N6-methyladenosine (m6A) RNA modification in gastrointestinal tract cancers.

Epigenetics encompasses reversible and heritable chemical modifications of non-nuclear DNA sequences, including DNA and RNA methylation, histone modifications, non-coding RNA modifications, and chromatin rearrangements. In addition to well-studied DNA and histone methylation, RNA methylation has emerged as a hot topic in biological sciences over the past decade. N6-methyladenosine (m6A) is the most common and abundant modification in eukaryotic mRNA, affecting all RNA stages, including transcription, translation, and degradation. Advances in high-throughput sequencing technologies made it feasible to identify the chemical basis and biological functions of m6A RNA. Dysregulation of m6A levels and associated modifying proteins can both inhibit and promote cancer, highlighting the importance of the tumor microenvironment in diverse biological processes. Gastrointestinal tract cancers, including gastric, colorectal, and pancreatic cancers, are among the most common and deadly malignancies in humans. Growing evidence suggests a close association between m6A levels and the progression of gastrointestinal tumors. Global m6A modification levels are substantially modified in gastrointestinal tumor tissues and cell lines compared to healthy tissues and cells, possibly influencing various biological behaviors such as tumor cell proliferation, invasion, metastasis, and drug resistance. Exploring the diagnostic and therapeutic potential of m6A-related proteins is critical from a clinical standpoint. Developing more specific and effective m6A modulators offers new options for treating these tumors and deeper insights into gastrointestinal tract cancers.

Therapeutic peptides in the treatment of digestive inflammation: Current advances and future prospects.

Digestive inflammation is a widespread global issue that significantly impacts quality of life. Recent advances have highlighted the unique potential of therapeutic peptides for treating this condition, owing to their specific bioactivity and high specificity. By specifically targeting key proteins involved in the pathological process and modulating biomolecular functions, therapeutic peptides offer a novel and promising approach to managing digestive inflammation. This review explores the development history, pharmacological characteristics, clinical applications, and regulatory mechanisms of therapeutic peptides in treating digestive inflammation. Additionally, the review addresses pharmacokinetics and quality control methods of therapeutic peptides, focusing on challenges such as low bioavailability, poor stability, and difficulties in delivery. The role of modern biotechnologies and nanotechnologies in overcoming these challenges is also examined. Finally, future directions for therapeutic peptides and their potential impact on clinical applications are discussed, with emphasis placed on their significant role in advancing medical and therapeutic practices.

The therapeutic effects of saikosaponins on depression through the modulation of neuroplasticity: From molecular mechanisms to potential clinical applications.

Depression is a major global health issue that urgently requires innovative and precise treatment options. In this context, saikosaponin has emerged as a promising candidate, offering a variety of therapeutic benefits that may be effective in combating depression. This review delves into the multifaceted potential of saikosaponins in alleviating depressive symptoms. We summarized the effects of saikosaponins on structural and functional neuroplasticity, elaborated the regulatory mechanism of saikosaponins in modulating key factors that affect neuroplasticity, such as inflammation, the hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, and the brain-gut axis. Moreover, this paper highlights existing gaps in current researches and outlines directions for future studies. A detailed plan is provided for the future clinical application of saikosaponins, advocating for more targeted researches to speed up its transition from preclinical trials to clinical practice.

Therapeutic potential of natural antisense transcripts and various mechanisms involved for clinical applications and disease prevention.

Antisense transcription, a prevalent occurrence in mammalian genomes, gives rise to natural antisense transcripts (NATs) as RNA molecules. These NATs serve as agents of diverse transcriptional and post-transcriptional regulatory mechanisms, playing crucial roles in various biological processes vital for cell function and immune response. However, when their normal functions are disrupted, they can contribute to human diseases. This comprehensive review aims to establish the molecular foundation linking NATs to the development of disorders like cancer, neurodegenerative conditions, and cardiovascular ailments. Additionally, we evaluate the potential of oligonucleotide-based therapies targeting NATs, presenting both their advantages and limitations, while also highlighting the latest advancements in this promising realm of clinical investigation.Abbreviations: NATs- Natural antisense transcripts, PRC1- Polycomb Repressive Complex 1, PRC2- Polycomb Repressive Complex 2, ADARs- Adenosine deaminases acting on RNA, BDNF-AS- Brain-derived neurotrophic factor antisense transcript, ASOs- Antisense oligonucleotides, SINEUPs- Inverted SINEB2 sequence-mediated upregulating molecules, PTBP1- Polypyrimidine tract binding protein-1, HNRNPK- heterogeneous nuclear ribonucleoprotein K, MAPT-AS1- microtubule-associated protein tau antisense 1, KCNQ1OT- (KCNQ1 opposite strand/antisense transcript 1, ERK- extracellular signal-regulated kinase 1, USP14- ubiquitin-specific protease 14, EGF- Epidermal growth factor, LSD1- Lysine Specific Demethylase 1, ANRIL- Antisense Noncoding RNA in the INK4 Locus, BWS- Beckwith-Wiedemann syndrome, VEGFA- Vascular Endothelial Growth component A.

Advances in the study of LNPs for mRNA delivery and clinical applications.

Messenger ribonucleic acid (mRNA) was discovered in 1961 as an intermediary for transferring genetic information from DNA to ribosomes for protein synthesis. The COVID-19 pandemic brought worldwide attention to mRNA vaccines. The emergency use authorization of two COVID-19 mRNA vaccines, BNT162b2 and mRNA-1273, were major achievements in the history of vaccine development. Lipid nanoparticles (LNPs), one of the most superior non-viral delivery vectors available, have made many exciting advances in clinical translation as part of the COVID-19 vaccine and therefore has the potential to accelerate the clinical translation of many gene drugs. In addition, due to these small size, biocompatibility and excellent biodegradability, LNPs can efficiently deliver nucleic acids into cells, which is particularly important for current mRNA therapeutic regimens. LNPs are composed cationic or pH-dependent ionizable lipid bilayer, polyethylene glycol (PEG), phospholipids, and cholesterol, represents an advanced system for the delivery of mRNA vaccines. Furthermore, optimization of these four components constituting the LNPs have demonstrated enhanced vaccine efficacy and diminished adverse effects. The incorporation of biodegradable lipids enhance the biocompatibility of LNPs, thereby improving its potential as an efficacious therapeutic approach for a wide range of challenging and intricate diseases, encompassing infectious diseases, liver disorders, cancer, cardiovascular diseases, cerebrovascular conditions, among others. Consequently, this review aims to furnish the scientific community with the most up-to-date information regarding mRNA vaccines and LNP delivery systems.

Approaches for posaconazole therapeutic drug monitoring and their clinical benefits.

OBJECTIVE: This review examines the progress of research on posaconazole therapeutic drug monitoring (TDM) that has focused on differences in the TDM of posaconazole after clinical application in different formulations and in different populations, the factors that affect posaconazole concentrations, the advantages of posaconazole TDM in terms of clinical efficacy and cost savings, and measurement methods. METHODS: A literature search (2006 to 2024) was performed in PubMed and Embase with the following search terms: noxafil, posaconazole hydrate, posaconazole, drug monitoring, therapeutic drug monitoring, and TDM. Abstracts of review articles, prospective studies, and retrospective studies were reviewed. RESULTS: TDM should be implemented earlier for posaconazole tablets and injections than for oral posaconazole suspensions. Posaconazole TDM is beneficial for improving clinical efficacy, and the incidence of breakthrough invasive fungal infections (IFIs) can be significantly reduced by gradually adjusting the posaconazole dose in response to TDM in patients with inadequate trough concentrations. Early TDM allows more patients to achieve target therapeutic posaconazole concentrations. TDM can also facilitate dose adjustments, which reduce the cost of this expensive drug. Different assay techniques, including chromatography, microbiological detection, chemofluorimetry, paper spray mass spectrometry, and capillary electrophoresis, can be used for posaconazole TDM. CONCLUSIONS: Posaconazole TDM has potential clinical utility and cost-saving benefits and could improve the outcomes of IFI treatment.

Circulating Tumor DNA in Diffuse Large B-Cell Lymphoma: from Bench to Bedside?

OPINION STATEMENT: Diffuse large B-cell lymphoma (DLBCL) is a curable disease with variable outcomes due to underlying heterogeneous clinical and molecular features-features that are insufficiently characterized with our current tools. Due to these limitations, treatment largely remains a "one-size-fits-all" approach. Circulating tumor DNA (ctDNA) is a novel biomarker in cancers that is increasingly utilized for risk stratification and response assessment. ctDNA is readily detectable from the plasma of patients with DLBCL but has not yet been incorporated into clinical care to guide treatment. Here, we describe how ctDNA sequencing represents a promising technology in development to personalize the care of patients with DLBCL. We will review the different types of ctDNA assays being studied and the rapidly growing body of evidence supporting the utility of ctDNA in different treatment settings in DLBCL. Risk stratification by estimation of tumor burden and liquid genotyping, molecular response assessment during treatment, and monitoring for measurable residual disease (MRD) to identify therapy resistance and predict clinical relapse are all potential applications of ctDNA. It is time for clinical trials in DLBCL to utilize ctDNA as an integral biomarker for patient selection, response-adapted designs, and surrogate endpoints. As more ctDNA assays become commercially available for routine use, clinicians should consider liquid biopsy when treatment response is equivocal on imaging. Incorporating MRD may also guide decision-making if patients experience severe treatment toxicities. Though important barriers remain, we believe that ctDNA will soon be ready to transition from bench to bedside to individualize treatment for our patients with DLBCL.

Progress in research on induced sputum in asthma: a narrative review.

OBJECTIVE: To explore the clinical significance of induced sputum in asthma through a retrospective analysis of induced sputum in patients with asthma. DATA SOURCES: The data and references cited in this article were obtained from PubMed, Sci-Hub, and Web of Science. STUDY SELECTION: Observational studies with reliable data were selected. CONCLUSIONS: The cytological count, -omics, and pathogen detection of induced sputum are helpful for the clinical diagnosis of asthma and in guiding medication choices.

Comprehensive review of composition, properties, clinical applications, and future perspectives of calcium-enriched mixture (CEM) cement: a systematic analysis.

This review aims to comprehensively explore calcium-enriched mixture (CEM) cement as a crucial biomaterial in dentistry/endodontics. With its growing clinical relevance, there is a need to evaluate its composition, chemical/physical/biological properties, clinical applications, and future perspectives to provide clinicians/researchers with a detailed understanding of its potential in endodontic procedures. Through systematic analysis of available evidence, we assess the advantages/limitations of CEM cement, offering valuable insights for informed decision-making in dental/endodontic practice. Our findings highlight the commendable chemical/physical properties of CEM cement, including handling characteristics, alkalinity, color stability, bioactivity, biocompatibility, sealing ability, and antimicrobial properties. Importantly, CEM cement has shown the potential in promoting regenerative processes, such as dentinogenesis and cementogenesis. It has demonstrated successful outcomes in various clinical applications, including vital pulp therapy techniques, endodontic surgery, open apices management, root resorption/perforation repair, and as an orifice/root canal obturation material. The efficacy and reliability of CEM cement in diverse clinical scenarios underscore its effectiveness in endodontic practice. However, we emphasize the need for well-designed clinical trials with long-term follow-up to further substantiate the full potential of CEM cement. This review serves as a robust reference for researchers/practitioners, offering an in-depth exploration of CEM cement and its multifaceted roles in contemporary dentistry/endodontics.

Advances in the application of extracellular vesicles derived from three-dimensional culture of stem cells.

Stem cells (SCs) have been used therapeutically for decades, yet their applications are limited by factors such as the risk of immune rejection and potential tumorigenicity. Extracellular vesicles (EVs), a key paracrine component of stem cell potency, overcome the drawbacks of stem cell applications as a cell-free therapeutic agent and play an important role in treating various diseases. However, EVs derived from two-dimensional (2D) planar culture of SCs have low yield and face challenges in large-scale production, which hinders the clinical translation of EVs. Three-dimensional (3D) culture, given its ability to more realistically simulate the in vivo environment, can not only expand SCs in large quantities, but also improve the yield and activity of EVs, changing the content of EVs and improving their therapeutic effects. In this review, we briefly describe the advantages of EVs and EV-related clinical applications, provide an overview of 3D cell culture, and finally focus on specific applications and future perspectives of EVs derived from 3D culture of different SCs.

Mesenchymal stromal cells derived from various tissues: Biological, clinical and cryopreservation aspects: Update from 2015 review.

Mesenchymal stromal cells (MSCs) have become one of the most investigated and applied cells for cellular therapy and regenerative medicine. In this update of our review published in 2015, we show that studies continue to abound regarding the characterization of MSCs to distinguish them from other similar cell types, the discovery of new tissue sources of MSCs, and the confirmation of their properties and functions that render them suitable as a therapeutic. Because cryopreservation is widely recognized as the only technology that would enable the on-demand availability of MSCs, here we show that although the traditional method of cryopreserving cells by slow cooling in the presence of 10% dimethyl sulfoxide (Me2SO) continues to be used by many, several novel MSC cryopreservation approaches have emerged. As in our previous review, we conclude from these recent reports that viable and functional MSCs from diverse tissues can be recovered after cryopreservation using a variety of cryoprotectants, freezing protocols, storage temperatures, and periods of storage. We also show that for logistical reasons there are now more studies devoted to the cryopreservation of tissues from which MSCs are derived. A new topic included in this review covers the application in COVID-19 of MSCs arising from their immunomodulatory and antiviral properties. Due to the inherent heterogeneity in MSC populations from different sources there is still no standardized procedure for their isolation, identification, functional characterization, cryopreservation, and route of administration, and not likely to be a "one-size-fits-all" approach in their applications in cell-based therapy and regenerative medicine.

Phototherapy for vitiligo: A narrative review on the clinical and molecular aspects, and recent literature.

BACKGROUND: Vitiligo is characterized by depigmented patches resulting from loss of melanocytes. Phototherapy has emerged as a prominent treatment option for vitiligo, utilizing various light modalities to induce disease stability and repigmentation. AIMS AND METHODS: This narrative review aims to explore the clinical applications and molecular mechanisms of phototherapy in vitiligo. RESULTS AND DISCUSSION: The review evaluates existing literature on phototherapy for vitiligo, analyzing studies on hospital-based and home-based phototherapy, as well as outcomes related to stabilization and repigmentation. Narrowband ultra-violet B, that is, NBUVB remains the most commonly employed, studied and effective phototherapy modality for vitiligo. Special attention is given to assessing different types of lamps, dosimetry, published guidelines, and the utilization of targeted phototherapy modalities. Additionally, the integration of phototherapy with other treatment modalities, including its use as a depigmenting therapy in generalized/universal vitiligo, is discussed. Screening for anti-nuclear antibodies and tailoring approaches for non-photo-adapters are also examined. CONCLUSION: In conclusion, this review provides a comprehensive overview of phototherapy for vitiligo treatment. It underscores the evolving landscape of phototherapy and offers insights into optimizing therapeutic outcomes and addressing the challenges ahead. By integrating clinical evidence with molecular understanding, phototherapy emerges as a valuable therapeutic option for managing vitiligo, with potential for further advancements in the field.