Search Results (174)

The global agricultural sector faces the dual challenge of increasing productivity while mitigating environmental impacts caused by synthetic agrochemicals and massive agro-industrial waste. This review examines the transition to “Biostimulants 4.0,” a circular economy paradigm driven by the valorization of biomass residues into high-value biological inputs through nanotechnology and Artificial Intelligence (AI). Our analysis highlights that green extraction methods, specifically enzymatic hydrolysis, preserve bioactive integrity and reduce carbon emissions by up to 23.2 times compared to synthetic nitrogen production. Furthermore, waste-derived formulations and nanoscale smart-delivery systems dramatically enhance crop performance; for instance, chitosan nanoparticles can achieve up to a 471% increase in specific growth metrics through sustained-release pathways. To move the industry beyond empirical trial-and-error, the integration of AI-driven predictive models now achieves up to 87% accuracy in forecasting biostimulant efficacy. Finally, we contrast global regulatory frameworks and evaluate the monetization of biostimulant-driven carbon sequestration, capable of generating high-integrity credits priced up to $35 per tonne, as a critical economic pathway to accelerate commercial adoption and incentivize a resilient, decarbonized agricultural system. Full article

Clear cell renal cell carcinoma (ccRCC) accounts for approximately 75% of renal cell carcinomas and is defined by near-universal VHL inactivation, leading to constitutive HIF stabilisation, metabolic reprogramming, and an immunologically distinct tumour microenvironment (TME). Although ccRCC is characterised by abundant immune infiltration, this paradoxically correlates with poor prognosis, reflecting a TME that imposes interconnected physical, immunological, and metabolic barriers to effective immunotherapy. Chimeric antigen receptor (CAR)-based therapies have revolutionised the treatment of haematological malignancies, but their translation to ccRCC has encountered substantial hurdles. The first-in-human trial targeting carbonic anhydrase IX (CAIX) was limited by on-target off-tumour toxicity and CAR immunogenicity—lessons that fundamentally reshaped the field. CD70 has since emerged as the dominant clinical target, expressed in over 80% of ccRCCs with a highly restricted normal tissue distribution. The phase I COBALT-RCC trial of CTX130, an allogeneic CRISPR-Cas9-edited CD70-directed CAR-T cell product, provided formal proof of concept, achieving disease control in 81.3% of heavily pretreated patients and a durable complete response now exceeding three years—the first such sustained remission reported for any CAR-T cell product in a solid malignancy. Nevertheless, the low frequency of durable responses and universal loss of CAR-T cell persistence by day 28 underscore that major barriers remain. Beyond CD70, the field has diversified across multiple platforms, including CAR–natural killer (NK) cells, CAR–natural killer T (NKT) cells, and CAR–macrophages, each offering distinct biological advantages. This review synthesises current knowledge of the ccRCC TME, the preclinical landscape of CAR-based therapies, and emerging clinical evidence from more than 30 registered trials. We discuss target antigens; engineering strategies to overcome TME barriers, including cytokine armouring, chemokine receptor co-expression, switch receptors, and metabolic reprogramming; and rational combination approaches. We argue that the convergence of optimised target selection, cellular engineering, combination strategies, and biomarker-driven trial design may ultimately improve outcomes for patients with ccRCC. However, achieving a cure remains an aspirational goal, and significant barriers must first be overcome. Full article

Sjögren’s disease (SjD) remains one of the few major systemic autoimmune diseases without an approved disease-modifying therapy, despite decades of pathogenic insight and several randomised trials. We contend that these repeated failures reflect not intrinsic therapeutic refractoriness, but trial designs insufficiently aligned with the underlying biological heterogeneity of SjD. We propose a tripartite framework in which SjD is organised around three dominant biological axes: an interferon-driven systemic axis, a B-cell/lymphoproliferative axis, and a symptom/fibro-structural axis. Each axis carries its own characteristic biomarkers, histopathology, prognostic features, candidate endpoints, and therapeutic targets, and each implies a distinct trial enrolment strategy. Recent positive trials—phase III for ianalumab in NEPTUNUS-1/2, phase 2b for iscalimab in TWINSS, phase 2 for nipocalimab in DAHLIAS, and phase 2 for dazodalibep in a phenotype-defined symptom-dominant cohort—illustrate that meaningful clinical benefit becomes detectable once stratification is aligned to biology. By integrating molecular endotypes, validated biomarkers, composite endpoints, and phenotype-matched therapies onto a single explicit architecture, SjD shifts from a recurring example of translational failure to a model for precision medicine in heterogeneous autoimmune disease. The central message is that SjD may be less intrinsically treatment-resistant than it has historically been treatment-mistargeted. Full article

Background/Objectives: Telomeres are critical biomarkers of biological aging, with shortened leukocyte telomere length strongly linked to all-cause mortality and age-related disease risk. Although exercise modulates telomere dynamics, the field’s evolution from descriptive measurements to mechanistic inquiries involving redox biology and epigenetics remains incompletely mapped. This study systematically characterized the global research landscape of telomere–exercise science over 25 years to establish a strategic evidence base for precision exercise prescription. Methods: A bibliometric analysis was conducted on 858 publications from the Web of Science Core Collection (2000–2025). CiteSpace and VOSviewer were used for keyword co-occurrence analysis, strategic thematic mapping, and citation burst detection to visualize global research trends and identify emerging frontiers. Results: Annual publication volume grew from 2 (2000) to 71 (2025), with a compound annual growth rate of 15.4%. China emerged as one of the leading global contributors. Thematic analysis revealed a paradigm shift from descriptive leukocyte telomere length studies toward mechanistic investigations of oxidative stress, mitochondrial homeostasis, and epigenetic clocks. Keyword network analysis confirmed oxidative stress and inflammation as central hubs, mediating telomere protection via redox regulation and non-canonical telomerase functions. Conclusions: Exercise preserves telomere integrity primarily through redox–mitochondrial homeostasis, hormesis-driven antioxidant upregulation, and non-canonical telomerase activation. For aging populations and individuals at metabolic risk, aerobic training and high-intensity interval training (HIIT) are recommended as first-line non-pharmacological interventions for healthspan extension. Leukocyte telomere length and telomerase activity should be integrated as biomarkers in preventive medicine practice. Future large-scale randomized controlled trials incorporating multi-omics approaches and sex-stratified analyses are warranted to establish individualized dose–response guidelines for precision exercise prescription. Full article

Background: Renal vasculitis encompasses a heterogeneous spectrum of disorders where vascular inflammation leads to organ dysfunction. Given that renal involvement is the primary determinant of long-term morbidity, timely diagnosis and intervention are paramount. This review aims to synthesize recent pathogenic insights and evaluate how these mechanistic breakthroughs are reshaping current diagnostic and therapeutic paradigms. Methods: A narrative review of the literature was performed to analyze the pathophysiology, diagnosis, and management of pediatric renal vasculitis. The analysis synthesizes current clinical guidelines and recent trial data, highlighting the transition toward biomarker-driven precision medicine for refined disease assessment and management. Results: Diagnosis remains multimodal, necessitating the integration of clinical, laboratory, and histopathological data. In ANCA-associated vasculitis (AAV), recent evidence has challenged the traditional “pauci-immune” concept. Management of pediatric IgA vasculitis utilizes a risk-stratified approach, whereas cryoglobulinemic vasculitis requires targeted trigger elimination. Across all pediatric syndromes, there is a shift toward minimizing corticosteroid exposure and utilizing individualized frameworks. Conclusions: Despite substantial progress in targeted biological therapies and reduced corticosteroid burden, the long-term morbidity of pediatric renal vasculitis remains substantial. Outcomes are dictated by a synergy of disease-specific and patient-specific factors. Addressing persistent unmet needs in the field requires further refinement of individualized management protocols and the continued validation of dynamic biomarkers, alongside the implementation of pediatric-specific guidelines and age-appropriate outcome measures. Full article

Background and Objectives: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous type 2 inflammatory disease for which biologic therapies have expanded treatment options; however, biomarkers capable of guiding biologic selection remain poorly defined. This systematic review aimed to evaluate the available evidence regarding predictive and prognostic biomarkers associated with currently available biologic agents for CRSwNP (omalizumab, dupilumab, mepolizumab, benralizumab, reslizumab, and tezepelumab). Materials and Methods: A systematic search of PubMed/MEDLINE, Embase, Google Scholar, and the Cochrane Library identified studies published between January 2006 and September 2025. Results: Twenty-five eligible studies, including 12 randomized controlled trials, 12 systematic reviews/meta-analyses, and one indirect treatment comparison study, were analyzed. Multiple biomarkers, including blood eosinophils, total IgE, periostin, eotaxins, eosinophil cationic protein, IL-5, TARC, PARC, and urinary leukotriene E4, were evaluated across biologics targeting IgE, IL-4/IL-13, and IL-5 pathways. Conclusions: Although several biomarkers reflected the modulation of type 2 inflammation and disease activity, no validated biomarker has reliably predicted the superiority of one biologic over another. Nasal IL-5 showed potential for predicting the response to anti-IL-5 therapy but requires further validation. Current evidence supports biomarker use primarily for confirming type 2 inflammation rather than guiding biologic selection. Prospective biomarker-driven and head-to-head comparative studies are needed to enable precision medicine approaches in CRSwNP. Full article

Gallbladder cancer (GBC) is an aggressive tumor that, together with the cholangiocarcinomas, constitutes the spectrum of biliary tract cancer (BTC). These tumors are characterized by a frequently late diagnosis, marked genomic heterogeneity, variable response to cytotoxic therapies, and poor overall survival in advanced stages. Nevertheless, the characterization of the tumor microenvironment (TME) and the identification of actionable molecular targets have driven the development of biological therapies. This review summarizes current and emerging evidence on monoclonal antibodies, bispecific antibodies, and antibody–drug conjugates (ADCs) in the management of GBC. The analysis addresses the early exploration of autoantibodies as potential diagnostic biomarkers, mechanistic hypotheses of immune evasion, and the clinical translation of targeted agents in the metastatic setting. Additionally, we critically discuss the extrapolation of data from global BTC trials to the specific GBC setting, the integration of population genetics into epidemiological studies such as the EULAT Eradicate GBC initiative, and the preliminary status of immunotherapy in perioperative scenarios. Full article

Introduction: Esophagectomy has traditionally been considered mandatory after neoadjuvant therapy for locally advanced esophageal cancer. However, recent evidence has challenged this paradigm and motivated interest in organ-preservation strategies with active surveillance in patients achieving clinical complete response (cCR). Methods: A literature search was performed using PubMed/MEDLINE, ScienceDirect, and Embase databases to identify relevant studies related to non-operative management (NOM) of esophageal cancer. Evidence was synthesized qualitatively with a critical focus on the biological rationale of NOM, diagnostic limitations of response-assessment, oncologic outcomes associated with surveillance strategies and the evolving role of molecular biomarkers. Results: The safety of NOM with active surveillance is tightly linked to the diagnostic accuracy of response assessment. Although structured multimodal response assessment protocols combining endoscopy, endoscopic ultrasound, and PET-CT have shown acceptable performance, residual clinically undetectable disease might persist in some patients. Evidence from the SANO trial has suggested non-inferior short-term survival outcomes of NOM compared with immediate esophagectomy in carefully selected patients with cCR after neoadjuvant chemoradiotherapy treated within specialized centers. Nevertheless, long-term oncologic outcomes remain unknown, and uncertainty persists regarding the broader applicability of this strategy outside specialized multidisciplinary settings. Emerging biomarker-driven approaches including PD-L1 expression, microsatellite instability, and circulating tumor DNA (ctDNA) may further refine response assessment and help identify patients most suitable for organ-preservation strategies. Conclusions: Active surveillance represents a promising alternative to immediate esophagectomy in selected patients with cCR after neoadjuvant therapy. However, further studies with longer follow-up and standardized surveillance protocols are still needed to safely implement this strategy outside trial settings. Full article

Major depressive disorder (MDD) is a complex and heterogeneous psychiatric disorder with a high prevalence. Neuroinflammation may define biologically distinct patient subgroups with different mechanisms, clinical phenotypes, and treatment responses. This narrative review integrates current evidence around three linked questions: how neuroinflammatory processes contribute to depression, how biomarkers can identify clinically relevant inflammatory phenotypes, and how these findings can inform anti-inflammatory treatment strategies. The major mechanisms discussed include microglial activation and neuroimmune signaling, hypothalamic–pituitary–adrenal axis dysregulation and glucocorticoid receptor resistance, kynurenine pathway alterations, and cytokine-driven impairment of neurogenesis and synaptic plasticity. These pathways interact with stress responses, neurotransmitter systems, and neuronal function, while their expression may vary according to sex, age, hormonal status, disease stage, and treatment exposure. These interconnected pathways may contribute to depressive symptoms by disrupting neurotransmitter systems and impairing neural plasticity. In addition, this review discusses several candidate biomarkers, including C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF) and transforming growth factor-β1 (TGF-β), which may support patient stratification, treatment prediction, and assessment of target engagement. Clinical trials of anti-inflammatory agents have shown inconsistent and generally modest effects in unselected MDD populations. By integrating mechanistic evidence with biomarker-guided therapeutic implications, this review aims to clarify how neuroinflammatory research may inform more precise and individualized treatment strategies for depression. Full article

Vericiguat is currently indicated for patients with heart failure with reduced ejection fraction (HFrEF) following recent clinical worsening, based on evidence demonstrating a reduction in cardiovascular death or heart failure hospitalization in a high-risk population. While this positioning is clinically justified, it may underestimate the broader pathophysiological context in which soluble guanylate cyclase (sGC) stimulation may be relevant, particularly in phases of persistent biological activation following apparent clinical stabilization. In routine practice, acute coronary syndromes (ACS), acute heart failure (AHF), and chronic HFrEF are approached as distinct clinical entities. However, these conditions often represent sequential manifestations of a continuous disease trajectory driven by persistent endothelial dysfunction, impaired nitric oxide–sGC–cyclic guanosine monophosphate (NO–sGC–cGMP) signaling, and residual vascular risk. In this perspective, we revisit the mechanistic and clinical rationale for vericiguat and propose a reframing of its therapeutic role. Its greatest utility may lie in patients with recently worsening HFrEF who remain biologically vulnerable after stabilization. Extension of this concept to post-ACS populations remains hypothesis-generating and is not supported by direct clinical evidence. This “post-stabilization vulnerable state” represents a clinically recognizable yet insufficiently targeted phase, characterized by ongoing biological activation despite apparent clinical improvement. Adopting a continuum-based view of cardiovascular disease may improve alignment between pathophysiology and treatment, refine patient selection, and inform future trial design focused on this early post-event window. Importantly, this perspective is hypothesis-generating and reflects an effort to align emerging mechanistic insights with clinical trajectory, rather than to extend current indications beyond the available evidence base. Full article

Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous hematologic malignancy in which intensive induction chemotherapy remains the standard therapeutic platform for medically fit adults. In recent years, however, the frontline treatment paradigm has progressively evolved from a purely cytotoxic approach toward a biologically informed strategy. This shift has been driven by the identification of recurrent molecular alterations—particularly FLT3 and IDH1/2 mutations—as well as renewed interest in antibody-based therapies and the growing recognition that relapse, resistance, and measurable residual disease (MRD) are shaped by clonal architecture rather than blast burden alone. This review examines the development of targeted therapies combined with intensive chemotherapy in AML. We discuss the biological rationale for combination approaches and summarize the key clinical studies that have defined current practice, including trials evaluating FLT3 inhibitors, gemtuzumab ozogamicin, IDH inhibitors, and venetoclax-based strategies. We also address the role of targeted therapy across different treatment phases, including induction, consolidation, and post-remission settings, and analyze emerging data regarding MRD-guided treatment strategies, mechanisms of resistance, and integration with allogeneic hematopoietic stem cell transplantation. The integration of targeted agents with intensive chemotherapy is reshaping frontline AML therapy and represents a critical step toward precision medicine. While genotype-directed strategies—such as FLT3 inhibition—have already demonstrated survival benefit, optimal patient selection, treatment sequencing, and duration remain areas of active investigation. Future progress will likely depend on MRD-driven treatment adaptation, improved understanding of clonal evolution, and the development of rational multi-agent combinations capable of achieving deeper and more durable remissions. Full article

Tumor localization during pulmonary surgery has become increasingly challenging with the earlier detection of smaller and smaller lung nodules. Concomitantly, minimally invasive surgical (MIS) techniques have been increasingly adopted within the field of thoracic surgical oncology. Surgeons face growing challenges not only with locating these small tumors, but also with immediate margin assessment, reduced tactile feedback, and nodal assessment. Intraoperative molecular imaging (IMI) has emerged as a promising adjunct to address these challenges by enabling real-time visualization of malignant tissue during pulmonary resection. In its current form, IMI integrates systemically administered, tumor-targeting near-infrared fluorophores with fluorescence-capable imaging platforms to enhance intraoperative decision-making. Early clinical experiences in thoracic surgery suggest particular utility in the localization of small or nonpalpable pulmonary nodules and for improved margin assessment during MIS. Despite encouraging preliminary data, widespread adoption of IMI remains limited by biologic variability in target expression, optical depth constraints, false-positive fluorescence in inflammatory tissue, and challenges in workflow integration. Applications for nodal evaluation, staging, and longer-term oncologic outcome improvement remain investigational. Addressing these multifaceted barriers will be essential for the translation of IMI from a promising, experimental adjunct to a more broadly implementable surgical technology. This work summarizes the current state of IMI in thoracic surgical oncology, highlighting key translational studies, established and emerging clinical applications, and critical limitations within the current landscape. The authors also outline future directions for the field, including quantitative fluorescence interpretation, standardized reporting, and outcomes-driven clinical trials evaluating margin adequacy, recurrence, staging impact, and cost-effectiveness to support widespread evidence-based implementation. Full article

Non-Hodgkin lymphoma (NHL) encompasses a biologically diverse group of malignancies for which the integration of precision medicine has markedly reshaped therapeutic strategies. Recent advances in molecular profiling, target identification, and drug development have led to the introduction of highly selective agents capable of overcoming resistance mechanisms and improving outcomes in relapsed or refractory disease. This review highlights three targeted therapies—pirtobrutinib, brentuximab vedotin, and belinostat—and their evolving roles in modern NHL management. Pirtobrutinib, a next-generation, non-covalent Bruton tyrosine kinase (BTK) inhibitor, demonstrates preserved activity in patients previously treated with covalent BTK inhibitors (BTKi), addressing a critical unmet need in B-cell lymphomas. Brentuximab vedotin, an antibody–drug conjugate targeting CD30, has significantly improved therapeutic precision by delivering cytotoxic agents directly to lymphoma cells and has become a central component of treatment for CD30-expressing NHL subtypes. Belinostat, a broad-spectrum histone deacetylase (HDAC) inhibitor, offers a mechanistically distinct epigenetic approach, particularly in peripheral T-cell lymphomas (PTCL), where conventional chemotherapy has limited efficacy. Together, these agents exemplify three complementary paradigms of precision oncology in NHL: kinase signaling inhibition, antigen-directed cytotoxic delivery, and epigenetic modulation. This review synthesizes current evidence, clinical trial data, and future perspectives regarding the integration of pirtobrutinib, brentuximab vedotin, and belinostat into evolving treatment paradigms. Cumulatively, these therapies illustrate both the progress and the ongoing challenges of biomarker-driven treatment in NHL, including resistance mechanisms, toxicity management, optimal therapeutic sequencing, and variability in evidence maturity across targeted strategies. While pirtobrutinib and brentuximab vedotin are supported by increasingly robust clinical evidence in selected lymphoma subtypes, the role of belinostat remains constrained by modest response rates and limited randomized data, underscoring the continued need for biomarker refinement and more precisely individualized therapeutic approaches in NHL precision medicine. Full article

Background: Gynecological cancers include collections of cancers with diverse cellular and molecular characteristics that often develop drug resistance, making them treatment-resistant. Biomolecule–drug conjugates (BDCs), especially antibody–drug conjugates (ADCs), have revolutionized the targeted therapy of cancer; however, the creation of these entities has so far been achieved by empirical, resource-intensive design methods. Objective: The aim of this review is to critically analyze how AI can be used for the rational design and optimization of high-affinity BDCs for gynecological cancer treatment. Methods and discussion: Recent advances in machine learning (ML)- and deep learning (DL)-based methods to predict biomolecule-target binding affinity, structural compatibility, linker stability, payload selection, trafficking in the cell, and biomolecule resistance mechanisms are summarized. The review also explores the possibilities for incorporation of structural, chemical, biological, and multi-omics data to enhance specificity, efficacy, and safety of conjugates. Besides antibody-based systems, AI-assisted design approaches with peptides, aptamers, and hybrid biomolecular systems are also included. This review also highlights parameters and experimental/numerical validation restrictions related to data quality, interpretability of models, regulatory aspects, etc. Conclusions: AI-based conjugate engineering is increasingly moving BDC development from a largely ‘trial and error’ approach to a more predictive and data-driven approach. While there are still challenges to be addressed in terms of translations and validations, the potential of AI approaches in the field of precision oncology and the development of more personalized treatment is promising in the context of gynecological cancers. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) exhibits high post-resection relapse and early systemic dissemination rates. The level of circulating tumor cells (CTCs) correlates with early metastatic failure, motivating CTC interception strategies. Methods: In this hypothesis-driven review, we synthesized the contemporary evidence on PDAC staging and therapy, CTC detection (including portal versus peripheral sampling), and circulating tumor DNA (ctDNA)-based minimal residual disease (MRD), and evaluated the translational rationale for CTC-targeted adoptive immunotherapy focusing on CEACAM6 and CAR-T cells. Results: Prospective studies report higher portal versus peripheral CTC yields and stronger associations with relapse; tumor-informed ctDNA positivity in peri-operative and surveillance windows predicts shorter disease-free survival. CEACAM6 is overexpressed in PDAC and linked to invasion and metastasis, supporting antigen selection. However, target overexpression alone does not establish clinical suitability for adoptive cell transfer. Consequently, its therapeutic implementation must contend with assay heterogeneity, on-target/off-tumor risks, and the lack of interventional outcome data in PDAC, all of which remain key hurdles. Conclusions: CTC-targeting is biologically plausible and operationally measurable in PDAC. Consequently, a CEACAM6-directed CAR-T approach is proposed as a potential strategy for the interception of minimal residual disease (MRD). Randomized and biomarker-selected trials with composite MRD-clearance endpoints (CTC < LOQ and ctDNA-negative) may be justified to validate this interventional hypothesis. Full article