Search Results (10,959)

Precision medicine is increasingly applied in the cancer clinic, adapting treatment to genomic alterations of the tumor. However, whether alterations disrupt the function of a protein can depend on if both alleles of a gene are altered. While massively parallel sequencing technologies can identify sequence aberrations, they are limited in resolving the corresponding haplotype information. In this proof-of-concept case study, we applied the linked-read droplet barcode sequencing (DBS) technology to resolve the haplotype complexity of colorectal cancer genomes on paired tumor and normal samples. Several cancer-related genes carried multiple mutations in either one or both haplotypes. Additionally, a number of haplotype-resolved large structural variants and copy number alterations were detected and phased with short somatic variants. Nearly all characterized oncogenic pathways harbored some of the identified short somatic variants. The study demonstrates that linked-read DBS technology can characterize complex genetic variations in a haplotype context and may provide essential information for personalized approaches. Full article

Background/Objectives: Liposarcoma represents a heterogeneous group of mesenchymal malignancies with distinct molecular profiles and clinical behaviors. While localized disease is managed with surgical resection, advanced or metastatic liposarcoma poses a significant therapeutic challenge due to limited response to traditional cytotoxic chemotherapy. This review summarizes current evidence-based systemic therapies and highlights recent advances in subtype-driven treatment strategies. Methods: We review key clinical trials supporting the use of anthracycline regimens, trabectedin, eribulin, and nuclear export inhibition with selinexor, as well as emerging targeted approaches directed at MDM2 and CDK4 amplification. In addition, we discuss the evolving role of immunotherapy, including checkpoint inhibitors and engineered T-cell receptor therapies targeting cancer–testis antigens. Results: Integrating molecular biology with therapeutic development, we emphasize the importance of histologic and genomic classification in guiding treatment selection and clinical trial design. Conclusion: Continued progress in biomarker-driven strategies and rational combination therapies is expected to further refine personalized treatment approaches and improve outcomes for patients with advanced liposarcoma. Full article

mRNA vaccines are a relevant approach in cancer immunotherapy, using messenger RNA to induce immune responses against tumor-associated antigens. In this review, BNT111 and BNT122 are compared as representative off-the-shelf and personalized models. BNT111 is a fixed mRNA vaccine that has demonstrated significant antitumor efficacy against shared melanoma antigens, particularly when combined with immune checkpoint inhibitors. It allows a standardized production via in vitro transcription (IVT) in a cell-free system. Conversely, BNT122 is a personalized vaccine designed to match an individual’s tumor mutations by targeting patient-specific neoantigens to elicit more robust immune responses. It has significant suitability in the adjuvant setting to target minimal residual disease. Despite favorable safety and immunogenicity, the effectiveness of these vaccines is influenced by various factors, including tumor heterogeneity, differences in antigen expression, off-target effects on mRNA-LNP distribution, molecular instability, and complex manufacturing constraints. Neither approach can be directly considered as the definitive optimal vaccine. A comprehensive analysis of their strengths and limitations is vital for a balanced and objective future research direction. Collectively, this emphasizes the need for further improvements in vaccine design and strategies, prioritizing high-quality, safe, and accessible treatments for every cancer-based patient and ensuring their successful integration into healthcare. Full article

Background/Objectives: Psoriasis is a chronic immune-mediated skin disease, with plaque psoriasis being its most prevalent form. Although biologic therapies have significantly improved outcomes for patients with moderate to severe disease, certain anatomical regions often remain resistant to treatment. Given the observed variability in treatment response depending on lesion location, we aimed to explore anatomical site-specific differences in the skin transcriptome. Methods: Using a non-invasive tape-stripping technique, we collected and analyzed 44 psoriatic plaque samples from the scalp, trunk, upper extremities, and lower extremities, followed by differential gene expression and gene ontology analysis. Moreover, we included 80 samples obtained from healthy skin biopsies (GSE54456) to conduct an inflammation-controlled approach. We used two different approaches, an intra-disease approach, in which anatomically different sites were compared, and an inflammation-controlled approach, in which the inflammation bias was reduced. Results: Our findings indicate distinct molecular signatures and biological pathways across different anatomical sites, including differential expression of SERPINB7 and miRNAs such as miR-205 and miR-203a, along with different pathways. Furthermore, our results emphasized the heterogeneity of psoriasis and suggested that site-specific molecular mechanisms may contribute to variations in disease manifestation and treatment response. Conclusions: This study highlights the need for more personalized, site-specific therapeutic strategies. It should be considered an exploratory pilot study, and larger studies with paired samples from multiple anatomical sites within the same patients are needed to validate the identified transcriptomic signatures. Full article

The gut microbiome, often termed the human “second genome”, profoundly influences host physiology through metabolic interactions, immune modulation, and gut–brain axis signaling. Dysbiosis is implicated in the pathogenesis of obesity, inflammatory bowel disease (IBD), malignancies, and neuropsychiatric disorders. However, traditional gut microbiota interventions, such as probiotic supplementation and fecal microbiota transplantation (FMT), still exhibit significant limitations in precision therapeutics. Probiotic intervention fails to achieve precise regulation at the strain or genetic level, and although FMT demonstrates definitive efficacy against recurrent Clostridioides difficile infection (rCDI), its therapeutic outcomes and safety profiles show marked interindividual variability in ulcerative colitis (UC), metabolic syndrome, and other diseases, with insufficient treatment specificity to meet the practical demands of clinical precision intervention. Recent advancements in genome editing technologies, particularly Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)–CRISPR-associated (Cas) proteins systems and base editors, have enabled targeted functional manipulation of specific gut commensals and optimization of community architectures. These engineered strategies, combined with sophisticated delivery systems, demonstrate substantial potential in disease treatment, diagnostic monitoring, and immune modulation. This review systematically examines core editing methodologies, innovative delivery platforms, and targeted design strategies, elucidating their applications in metabolic disorders, IBD, cancer immunotherapy, and neuropsychiatric conditions. We critically analyze current technical bottlenecks and biosafety concerns while prospecting future directions, including in situ editing, artificial intelligence (AI)-driven design, and personalized engineering. Collectively, these insights aim to facilitate the clinical translation of gut microbiome engineering from bench to bedside. Full article

Multi-Agent Reinforcement Learning (MARL) faces key challenges in credit assignment and the curse of dimensionality as agent numbers grow. In cooperative settings, uniform treatment of agents often exacerbates these issues. We argue that an agent’s importance depends on its personalized attributes and environment states and propose concentrating computational resources on key agents while others act simply, alleviating dimensionality explosion and improving generalization. We propose the Decision of Nonsynchronous Framework (DNF), which identifies and prioritizes key agents at each time step for optimized decision-making, while assigning predefined or simplified behaviors to the remaining agents based on computational outcomes. To realize this, we introduce a Core Extractor (CE) architecture that categorizes agents into Priorities Key Agents (PKAs) and followers. Although agents are differentiated by priority, we still adhere to the Centralized Training with Decentralized Execution (CTDE) paradigm. This approach reduces the dimensionality of the joint state-action space, mitigates the dimensionality explosion problem in MARL, and fosters improved collaboration among agents. Experimental results demonstrate that DNF achieves a 100% win rate on multiple SMAC maps, including 3m, 2s3z, and 1c3s5z, and achieves 98.9–100% win rates on challenging hard and super-hard scenarios such as 2c_vs_64zg and Corridor, significantly outperforming baseline methods like QMIX and QPLEX in both final performance and training stability, while incurring only a modest increase in computational overhead. In the continuous MPE, DNF matches or exceeds HAPPO in performance and demonstrates substantially higher time efficiency, with both advantages growing more pronounced as the number of agents increases. Full article

Survivors of primary gastric lymphoma (PGL) face a significantly elevated and persistent risk of developing second primary malignancies (SPMs), with gastric adenocarcinoma representing the most frequent SPM and standardized incidence ratios reaching up to 16-fold above the general population. This excess risk persists for decades after initial treatment and is associated with increased cause-specific mortality compared to matched primary cancers. Among patients with PGL, approximately 5% develop gastric cancer (with two-thirds being metachronous), and nearly 15% harbor precancerous lesions including atrophic gastritis, intestinal metaplasia, and dysplasia. Beyond gastric malignancies, survivors also experience elevated rates of extra-gastric SPMs, particularly digestive system tumors (43%), respiratory cancers (21%), and urinary tract malignancies (13%). Key risk factors include treatment with immunochemotherapy or radiotherapy, advanced age, male sex, advanced stage at diagnosis, ulcerative-type lymphoma morphology, and persistent Helicobacter pylori (HP) infection. Patients receiving combined chemoradiotherapy demonstrate the highest SPM risk, particularly for gastric and pancreatic cancers. These findings underscore the critical importance of lifelong, risk-adapted surveillance strategies integrating both hematology and gastroenterology follow-up. Annual endoscopic surveillance is recommended for high-risk patients, with intervals adjusted according to lymphoma histology, HP status, and the presence of precancerous gastric lesions. Mandatory HP eradication with confirmation of response is essential for reducing gastric cancer risk. Future research priorities include prospective, standardized studies to better quantify SPM risk, validation of molecular and microbiological biomarkers for individualized risk stratification, and development of predictive models to enable personalized surveillance protocols and improve long-term outcomes in this vulnerable population. Full article

Neuropathic pain remains a major clinical challenge due to its complex pathophysiology and limited treatment efficacy. Recent evidence suggests that vitamin D, beyond its classical role in bone and mineral metabolism, exerts neuroprotective and immunomodulatory effects that may influence pain perception. This review synthesizes current findings on the relationship between vitamin D status and neuropathic pain, highlighting potential mechanisms such as modulation of neuroinflammation, regulation of neuronal excitability, and influence on neurotransmitter pathways. Observational studies frequently report an association between vitamin D deficiency and increased pain severity, while interventional trials indicate that supplementation may alleviate neuropathic symptoms in specific populations. However, results remain heterogeneous, and mechanistic studies are still emerging. Understanding the interplay between vitamin D and neuropathic pain could open new avenues for adjunctive therapeutic strategies and personalized medicine approaches. Further high-quality clinical trials and mechanistic research are warranted to clarify causality and optimize clinical applications. Full article

Background and Objectives: Metastatic renal cell carcinoma (mRCC) remains a lethal disease despite advances with immune checkpoint inhibitors such as nivolumab. However, a substantial proportion of patients exhibit primary resistance or early progression, highlighting the need for reliable and easily accessible prognostic biomarkers. The C-reactive protein–albumin–lymphocyte (CALLY) index is a novel immunonutritional biomarker integrating systemic inflammation, nutritional status, and immune competence. Materials and Methods: In this retrospective single-center study, 91 patients with mRCC treated with nivolumab were analyzed. Patients were stratified into low and high CALLY index groups based on a receiver operating characteristic-derived cut-off (0.322). Survival outcomes were assessed using Kaplan–Meier analysis and Cox regression models. Results: Patients with a low CALLY index demonstrated significantly shorter progression-free survival (4.5 vs. 13.5 months, p < 0.001) and overall survival (9.1 vs. 25.5 months, p = 0.003). Multivariate analysis confirmed the CALLY index as an independent prognostic factor for both progression-free survival (HR: 2.63, p = 0.002) and overall survival (HR: 1.88, p = 0.035). Conclusions: The CALLY index is a simple, cost-effective, and reproducible biomarker that independently predicts survival in nivolumab-treated mRCC. It may serve as a practical tool for risk stratification and personalized treatment planning in the immunotherapy era. Full article

Fabry disease is an X-linked lysosomal storage disease that leads to the intracellular accumulation of glycosphingolipids in many tissues and fluids, including the kidneys. We report a single family with Fabry disease that includes seven patients carrying the pathogenic variant c.797A>C in the GLA gene, with remarkable variability in kidney involvement, assessed based on clinical, biological, and histological data. The patients were monitored for 2–9 years, and all received enzyme replacement therapy. Kidney involvement was variable and included severely decreased GFR with significant proteinuria, mildly to moderately decreased GFR with proteinuria, mildly decreased GFR with microalbuminuria or normoalbuminuria, hyperfiltration with normoalbuminuria, and preserved kidney function. All patients who underwent kidney biopsy presented with Fabry-specific lesions and, in some cases, chronic histological damage. This study provides valuable insights into kidney involvement evaluated through kidney biopsy, personalized management strategies for family members according to their phenotype, and long-term follow-up of kidney function. We underscore the importance of molecular screening of the GLA gene in all family members for early identification of the disease and early initiation of specific treatments that can prevent or delay the progression of this disease. Full article

The skin is a complex immunological organ in which reactive oxygen species (ROS)-related pathways and host–microbe interactions synergically maintain immune homeostasis. Dysregulation of several oxidative mechanisms, including lipid peroxidation, mitochondrial dysfunction, ferroptosis, and impaired antioxidant defenses, alongside gut microbiome imbalance, is increasingly recognized as a key modulator of the immune response involved in disease onset and progression. However, their role in immune-mediated dermatoses remains incompletely defined. This narrative review aims to provide a comprehensive overview of the contribution of these altered pathways to the pathogenesis and prognosis of the major immune-mediated skin diseases. Across all conditions examined, elevated oxidative biomarkers, such as malondialdehyde (MDA), advanced glycation end-products (AGEs), advanced oxidation protein products (AOPPs), 8-hydroxydeoxyguanosine (8-OHdG), and reduced antioxidant capacity are consistently reported. Ferroptosis, driven by iron-dependent lipid peroxidation and dysfunction of Glutathione peroxidase 4 (GPX4), emerges as a relevant cell death pathway, particularly in psoriasis and atopic dermatitis (AD). In parallel, dysbiosis of the gut and skin microbiomes, characterized by depletion of short-chain fatty acid (SCFA)-producing taxa such as Faecalibacterium prausnitzii, Bifidobacterium, and Akkermansia muciniphila, has been reported across multiple diseases. Particular attention is given to shared molecular axes, such as the disruption of epithelial barrier integrity, activation of innate and adaptive immune responses, and the role of microbial-derived metabolites in modulating redox signaling, unraveling a bidirectional crosstalk. Emerging therapeutic strategies targeting these bidirectional crosstalks show biological plausibility and promising preliminary results. Integrating redox and microbial profiling into clinical practice may improve patient stratification and foster the development of more personalized therapeutic approaches beyond conventional immunological treatments. Full article

Background: Treatment-resistant depression (TRD) represents a major clinical challenge and is increasingly associated with persistent neuroinflammatory processes. Evidence suggests that dysregulation of the immune system, particularly the imbalance between pro-inflammatory and anti-inflammatory cytokines, contributes to poor therapeutic response. In this context, interleukin-10 (IL-10) has emerged as a key mediator in regulating the inflammatory response. Objective: To systematically analyze the evidence on neuroimmune dysregulation in depression, with an emphasis on TRD, and to evaluate the potential role of IL-10 as a biomarker and modulator of therapeutic response. Methods: A systematic review was conducted in accordance with PRISMA guidelines. Fourteen studies were included, comprising randomized clinical trials, longitudinal studies, a prospective cohort study, and exploratory designs. Methodological quality was assessed using the RoB 2 tool and complementary approaches. Data were integrated through a qualitative analysis focused on inflammatory biomarkers and clinical outcomes. Results: The studies consistently showed an association between elevated levels of pro-inflammatory cytokines, such as IL-6 and TNF-α, and the severity of depressive symptoms, as well as reduced response to conventional treatments. Immunomodulatory interventions, including ketamine, pentoxifylline, and minocycline, were associated with clinical improvement, particularly in patients with elevated baseline inflammation. IL-10 appears to be involved in counter-regulatory neuroimmune processes associated with inflammatory balance. Conclusions: Neuroinflammation plays a central role in TRD. IL-10 may serve as a relevant biomarker and a potential target for personalized therapeutic strategies informed by immune profiles, through modulation of neuroinflammatory pathways. Full article

The integration of artificial intelligence (AI) in education has made significant advancements in personalized learning and adaptive instruction. However, current systems remain limited by three critical gaps: (a) fragmented architectures that decouple technical performance from ethical governance, (b) the treatment of fairness and accountability as external constraints rather than embedded design principles, and (c) reliance on single-modality data that inadequately represents complex learning environments. These restrictions hinder scalability and limit the capacity of AI systems to deliver equitable, transparent, and context-aware educational experiences. This study aims to address these challenges by designing and validating an ethics-aware, multi-agent conceptual framework for adaptive education in which personalization and responsible AI are co-developed as integrated system properties. The proposed architecture uses five coordinated agents: perception, pedagogy, assessment, feedback, and ethics monitoring. These five agents share one knowledge layer containing learner profiles, domain models, competency structures, interaction histories, and machine-readable policy rules. A four-stage feedback loop comprises: (a) outcome aggregation, (b) system evaluation and validation, (c) teacher review and intervention, and (d) agent update and policy refinement. It enables real-time adaptation, teacher oversight, and iterative system improvement. Adopting a design science research (DSR) methodology and mixed-methods evaluation across functional, pedagogical, ethical, and system-level dimensions, the proposed framework is expected to demonstrate improved learner modeling accuracy, enhanced knowledge tracing, and more robust multimodal engagement analysis compared to centralized and single-modality approaches. Based on design science evaluation against established benchmarks and component-level validation in a simulated learning management system (LMS), this theoretical framework is projected to improve learner modeling accuracy, enhance knowledge tracing, and enable more robust multimodal engagement analysis compared with centralized and single-modality approaches. These projections constitute theoretically derived hypothesis and remain subject to empirical validation in live deployment studies. This study’s theoretical contribution lies in demonstrating that ethics-by-design and adaptive personalization are architecturally compatible and mutually reinforcing design principles. Full article

Pharmacomicrobiomics is the study of drug–microbiome interactions. It examines the dynamic relationship between the drug, the host, and the microbiome, and has become a rapidly evolving area in the realm of pharmacology and personalized medicine. Emerging evidence demonstrates that the gut microbiome can influence the pharmacodynamics and pharmacokinetics of drugs through various mechanisms, while drugs can simultaneously alter microbial composition. Treatment approaches include regular targeted pharmaceutical therapies (e.g., antibiotics, antidepressants) and alternative treatment approaches (e.g., CAM treatments such as supplements and herbs). Microbiome-based medication treatment is an alternative treatment approach that has been studied extensively in the last decade. This article reviews the current knowledge on drug–microbiome interactions across multiple therapeutic systems, including cardiovascular, central nervous system, gastrointestinal, respiratory, endocrine, oncologic, musculoskeletal, anti-infective therapies, and supplements (such as melatonin). We also highlight the various pathways by which microbes can alter the mechanisms (such as drug absorption), bioavailability, efficacy, and incidence of adverse effects, along with highlighting the clinical implications of drug-induced dysbiosis. Full article

Melanoma adjuvant therapy has substantially improved recurrence-free and distant metastasis-free survival in patients with resected high-risk disease, and more recently, these advances have extended to earlier stages. However, important unmet needs remain, including the management of stage IIIA disease, the optimal treatment strategy after relapse on adjuvant therapy, and the identification of biomarkers capable of refining patient selection. This review summarizes recent advances and unresolved questions in the adjuvant and neoadjuvant treatment of melanoma. We discuss novel systemic strategies, including immune checkpoint inhibitor combinations and personalized neoantigen mRNA vaccines, together with the expanding role of neoadjuvant approaches. We also examine prognostic and predictive tools—such as clinicopathologic models, circulating tumor DNA, serum biomarkers, tumor microenvironment features, and gene expression profiling—that may help better define recurrence risk and therapeutic benefit. Current evidence suggests that although modern therapies have changed the natural history of resected melanoma, a substantial proportion of patients are still overtreated or undertreated when treatment decisions are based on stage alone. Future progress will depend on integrating biological risk stratification with clinical staging and optimizing treatment sequencing across adjuvant and neoadjuvant settings. Full article