Search Results (668)

Gastrointestinal (GI) cancers represent a diverse group of malignancies that remain a major cause of cancer-related morbidity and mortality worldwide. Their management is increasingly complex, reflecting differences in tumor biology, anatomical location, stage, and molecular profile. In recent years, advances in molecular diagnostics, immunotherapy, and targeted treatment have moved clinical decision-making beyond a purely organ- and stage-based approach toward more individualized, biomarker-guided care. This narrative review summarizes established and emerging biological and targeted therapies used in esophageal, gastric and gastroesophageal junction, colorectal, pancreatic, hepatocellular, and biliary tract cancers. It focuses on immune checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4; HER2-directed monoclonal antibodies and antibody–drug conjugates; antiangiogenic and anti-EGFR therapies; and newer strategies involving CLDN18.2, FGFR2b, and tumor-agnostic alterations such as NTRK fusions. The review also considers the predictive biomarkers used to guide treatment selection and the growing integration of systemic therapy with surgery in neoadjuvant, perioperative, adjuvant, and conversion settings. However, clinical efficacy alone does not determine whether new treatments become part of routine practice. Regulatory approval, reimbursement, access to molecular testing, and the availability of specialized multidisciplinary care are equally important. The rapidly evolving treatment landscape for GI cancers therefore requires clinical decisions that account for tumor biology, anatomical resectability, molecular eligibility, expected benefit, treatment-related toxicity, and local access to therapy. Expanding access to comprehensive biomarker testing and effective molecularly guided treatments will be essential to translate progress in precision oncology into more personalized and equitable care for patients with GI cancers. Full article

Immune checkpoint inhibitors (ICIs) have significantly changed the treatment landscape of several gastrointestinal (GI) malignancies, particularly microsatellite instability-high (MSI-H) and mismatch repair-deficient (dMMR) tumors. However, most GI cancers remain resistant to current PD-1/PD-L1-based immunotherapy because of complex and highly suppressive tumor microenvironments characterized by immune stromal exclusion, myeloid-driven immune suppression, defective antigen presentation, and adaptive immune resistance mechanisms. Emerging evidence suggests that alternative inhibitory pathways, including lymphocyte activation gene-3 (LAG-3), T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and V-domain Ig suppressor of T-cell activation (VISTA), contribute substantially to persistent T-cell dysfunction and resistance to checkpoint blockade. This review summarizes the immune landscape of GI malignancies and discusses the biological mechanisms underlying resistance to current ICIs. We highlight the evolving role of next-generation immune checkpoints, ongoing clinical development of novel inhibitors, and emerging combination strategies involving chemotherapy, anti-angiogenic therapy, radiation, bispecific antibodies, and tumor microenvironment modulation. In addition, we discuss current limitations in biomarker development and the growing role of circulating tumor DNA, spatial immune profiling, and multi-omics approaches in patient selection. Finally, we explore future directions aimed at improving precision immunotherapy and expanding durable responses across GI cancers. Full article

Background: Immune checkpoint inhibitors and adoptive T-cell therapies have substantially improved cancer treatment outcomes, but their use is often limited by immune-related toxicities, including cytokine release syndrome. The role of interleukin (IL)-17A in tumor immunity remains controversial, hindering its therapeutic applications in cancer. A concern is that application of IL-17 blocking agents to release cytokine storms caused by tumor immunotherapy reverses anti-tumor immunity. Methods: In this study, we evaluated the effect of IL-17A blockade alone and in combination with anti–PD (programmed cell death)-1 therapy or tumor-specific CD8⁺ T cells in melanoma, colon, and lung tumors, and in UVB-induced skin carcinogenesis. Results: Our results showed that blocking IL-17A inhibited tumor development, and did not impair the efficacy of tumor immunotherapies with checkpoint inhibitors or tumor-specific T cells. Combined treatment with anti-IL-17A and anti-PD-1 antibodies significantly enhanced tumor suppression compared to single-agent therapies in all tested tumor models. Moreover, IL-17A blockade improved the efficacy of adoptive CD8⁺ T-cell therapy. Mechanistic analyses revealed that the combination therapy increased infiltration of activated antigen-specific CD8⁺ T cells in tumors. In none of the tested tumor models did IL-17A blockade negatively affect the efficacy of tumor immunotherapy with checkpoint inhibitors or T-cell therapy. Conclusions: These findings suggest that the combined application of anti-IL-17A blocking agents with current tumor immunotherapy at the same time is a promising strategy to enhance the efficacy and potentially diminish immune-related adverse effects. Full article

Pseudomonas aeruginosa is an important opportunistic pathogen associated with diverse healthcare-associated infections and increasing antimicrobial resistance. This systematic review evaluated antimicrobial treatment regimens, clinical outcomes, and pharmacokinetic/pharmacodynamic (PK/PD) considerations in P. aeruginosa infections. A systematic review was conducted according to PRISMA guidelines. PubMed/MEDLINE and the Cochrane Library were searched for studies published between January 2000 and March 2026. Data on antimicrobial therapies, clinical and microbiological outcomes, and PK/PD parameters were extracted. Study quality was assessed using the NHLBI quality assessment tool. Narrative synthesis was performed for all eligible studies, and a quantitative meta-analysis was conducted for studies with standardized outcome data. Of the 982 records identified, 249 studies met the inclusion criteria, and 34 were included in the quantitative meta-analysis. The evidence base was highly heterogeneous regarding study design, patient populations, infection types, and treatment regimens. Respiratory infections, particularly in cystic fibrosis patients, accounted for most studies. Quantitative synthesis showed no consistent superiority of any antimicrobial regimen (or combination of them), while treatment outcomes were influenced by infection characteristics, antimicrobial resistance patterns, and PK/PD factors. No universally superior antimicrobial regimen was identified for Pseudomonas aeruginosa infections. Some novel and promising treatment options have been identified, such as anti-Pseudomonas aeruginosa LPS monoclonal antibody panobacumab and inhaled Clostridium butyricum delivered via oxygen-driven nebulization. Two novel treatment modalities did not yield a clinically relevant effect, namely, the bispecific monoclonal antibody MEDI3902 (gremubamab) and the IC43 Pseudomonas aeruginosa vaccine. Treatment effectiveness appears to depend on clinical context, antimicrobial susceptibility, and PK/PD considerations, highlighting the need for further standardized research. Full article

Background/Objectives: Nontuberculous mycobacterial pulmonary disease (NTM-PD) has been associated with myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)-positive ANCA-associated vasculitis (AAV). However, clinical factors associated with MPO-ANCA positivity in patients with NTM-PD remain unclear. This study determined the frequency of MPO-ANCA positivity among tested patients with NTM-PD and explored the clinical factors associated with MPO-ANCA positivity. Methods: This study retrospectively analyzed patients aged ≥15 years old with NTM-PD who were treated at Tokyo Shinagawa Hospital and underwent MPO-ANCA testing between April 2020 and March 2024. Clinical data, including nontuberculous mycobacterial species, serum Mycobacterium avium complex (MAC) antibody titers, radiographic findings, and nodule, infiltration/consolidation, cavity, and ectasis scores, were collected from their electronic medical records. Patients were classified into MPO-ANCA-positive and negative groups, and clinical factors were compared. Results: Among 109 patients with NTM-PD, 49 underwent testing for MPO-ANCA and proteinase 3 (PR3)-ANCA. MPO-ANCA was positive in five patients (10.2%), whereas PR3-ANCA was positive in one (2.0%). Among the five MPO-ANCA-positive patients, three had MAC antibody titers above the upper limit of measurement (>10 U/mL), and one developed AAV with biopsy-proven pauci-immune crescentic glomerulonephritis and mononeuritis multiplex. The MAC antibody titer was significantly higher in the MPO-ANCA-positive group than in the MPO-ANCA-negative group [10.0 (3.89–10.0) vs. 1.92 (0.19–6.19) U/mL, p = 0.038]. Conclusions: MPO-ANCA positivity was observed in a subset of tested patients with NTM-PD and was associated with higher MAC antibody titers. These findings suggest that chronic MAC-related antigen exposure or local pulmonary disease activity in NTM-PD may be associated with MPO-ANCA positivity. Full article

Objectives: Novel agents such as brentuximab vedotin and anti-PD-1 antibodies, together with PET-adapted intensified strategies, have improved outcomes in advanced-stage classical Hodgkin lymphoma (cHL). However, their applicability remains limited in many middle-income countries because of restricted drug availability, reimbursement barriers, and toxicity concerns. Therefore, real-world data on the effectiveness of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) remains essential. Methods: We conducted a retrospective two-center study including 95 patients with newly diagnosed cHL treated with first-line ABVD. Baseline characteristics, treatment response, progression-free survival (PFS), overall survival (OS), and mortality were compared between early-stage (I–II, n = 33) and advanced-stage (III–IV, n = 62) disease. Results: The median age was 38 years (range, 18–73), and 69.5% were male; 65% had advanced-stage. Complete response rates were high in both early-stage (97%) and advanced-stage (95.2%) patients. Median PFS (21 vs. 23 months; p = 0.994) and OS (23 vs. 25 months; p = 0.848) were similar. Five-year OS was 84.3% for early-stage and 98% for advanced-stage patients (p = 0.292), while five-year PFS was 55.3% and 29.6% (p = 0.526). Mortality rates were comparable. Conclusions: In this real-world cohort, first-line ABVD achieved high response rates and favorable long-term survival in advanced-stage cHL, supporting its continued use as a frontline treatment option, particularly in settings where access to novel therapies may be limited. Full article

Objectives: AC02, a novel synthetic peptide derived from ACTH, is being developed as a potential therapeutic alternative to porcine ACTH_1-39 for use in infantile spasms. Methods: The study comprised single-ascending dose cohorts (0.02, 0.04, 0.08, 0.16 mg/kg AC02) and multiple-ascending dose cohorts (0.04, 0.08 mg/kg AC02 daily for 5 days). A separate positive-control arm received porcine ACTH_1-39 (25 U/day for 5 days). PD effects (free and total cortisol) were compared head-to-head with the positive control. Plasma concentrations of AC02, porcine ACTH_1-39, free and total cortisol were quantified by validated LC-MS/MS methods, and anti-drug antibody responses were measured using a validated electrochemiluminescence bridging immunoassay. Population PK/PD modeling characterized the concentration–response relationships for free cortisol. Results: Across the 0.02–0.16 mg/kg dose range, AC02 exhibited approximately dose-proportional pharmacokinetics and no accumulation after multiple doses. At 0.04 and 0.08 mg/kg, the baseline-corrected effects on free cortisol were generally consistent with those of porcine ACTH_1-39. Dynamic monitoring of the free cortisol fraction revealed a biphasic pattern across all groups: an early peak followed by a later rise. Total cortisol, by contrast, showed only a monophasic decline, indicating the limitations of total cortisol as a sole PD biomarker. No unexpected safety signals were observed. At 0.04 mg/kg, AC02 demonstrated pharmacodynamic responses comparable to those of marketed ACTH product based on the biologically active component of free cortisol, with favorable safety and pharmacokinetic profiles. Conclusions: This first-in-human study demonstrates that AC02 has favorable pharmacokinetic properties, and an acceptable safety profile. Full article

Drug resistance remains a significant challenge in the clinical treatment of acute myeloid leukemia (AML). Therefore, there is an urgent need to develop a novel combinatorial therapy strategy, aiming to overcome drug resistance and improve therapeutic outcomes in AML. Herein, we developed a covalent organic framework bispecific nanosystem, namely glucose oxidase-loaded iron porphyrin covalent organic framework coated with bone marrow stromal cell membrane and functionalized with anti-CD3 and anti-PD-L1 antibodies (abbreviated FeC-G@M-C&P). The fabricated FeC-G@M-C&P displayed good cascade catalytic activity. The bone marrow stromal cell membrane endowed the nanosystem with robust targeting ability, which further triggered abundant reactive oxygen species (ROS) production for chemodynamic therapy. Moreover, bone marrow stromal cell membrane component suppressed the migration and adhesion of C1498 cells by interfering with the CXCR4/CXCL12 axis. Meanwhile, anti-CD3 and anti-PD-L1 antibodies improved T cell activation, relieved immune suppression, and jointly enhanced T cell-mediated immune responses against leukemia cells. Experimental results indicated that the FeC-G@M-C&P plus T cells group showed better anti-leukemia effects compared with other groups, which can be attributed to the integration of chemodynamic therapy, CXCR4/CXCL12 axis blockade therapy and immunotherapy. Collectively, the fabricated nanosystem provided a promising approach for the combined treatment of AML. Full article

Background: Overexpression of programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) induces immune evasion by cancer cells. Nivolumab and pembrolizumab (anti-PD-1 antibodies) are used to treat advanced non-small cell lung cancer (NSCLC). However, objective response rates are limited (20–30%), indicating that individual tumor microenvironments may differ according to immune evasion processes. Therefore, the development of biomarkers predictive of responders to immune checkpoint inhibitors is necessary. Activation of the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (NRF2/KEAP1) signaling pathway promotes lung cancer cell growth and resistance to chemotherapy, radiotherapy, targeted therapy, and PD-1/PD-L1 inhibition. The present study investigated whether NRF2 expression in NSCLC is associated with clinicopathological factors, the expression levels of intratumoral PD-L1 and CD8, and the efficacy of anti-PD-1 monotherapy. Methods: NRF2, PD-L1, and CD8 expression on tumor cells and tumor-infiltrating lymphocytes were examined by immunohistochemistry in 54 patients with advanced adenocarcinoma (N = 40) and squamous cell carcinoma (N = 14) treated with nivolumab or pembrolizumab. Histological subtypes, tumor stages, and other clinicopathological features were compared with their expression levels. Results: Weak NRF2 staining was significantly correlated with high levels of PD-L1 and CD8+ tumor-infiltrating lymphocytes, and a favorable response to treatment with nivolumab or pembrolizumab in NSCLC. Progression-free survival of patients treated with anti-PD-1 therapy differed according to the different NRF2 levels. Conclusions: NRF2 overexpression in NSCLC is associated with resistance to PD-1 blockade monotherapy. Full article

Squamous cell lung cancer (SqCLC) accounts for 20–30% of non-small cell lung cancer (NSCLC) and remains associated with a poorer prognosis compared with adenocarcinoma. Despite advances in treatment, 5-year overall survival for advanced (stage IV) disease remains below 10–15%. Unlike non-squamous NSCLC, SqCLC is characterized by a high tumor mutational burden and complex genomic landscape dominated by alterations in tumor suppressor genes and lineage survival pathways including TP53, CDKN2A, PIK3CA, FGFR1, SOX2, and the NFE2L2/KEAP1 oxidative stress pathway, as well as dysregulation of the NOTCH signaling pathway, but it harbors relatively few actionable oncogenic drivers, resulting in limited treatments for targeted therapy. HER2 alterations can occur by multiple mechanisms, including activating mutations, gene amplifications, and protein overexpression. They comprise a very small percentage of NSCLC, with HER2 mutations reported in approximately 1–3% and HER2 amplifications observed roughly in 2–4%. While HER2 alterations are well characterized in lung adenocarcinoma, the prevalence, genomic context, and clinical significance of HER2 alterations in SqCLC remain incompletely defined. Advances in next-generation sequencing have led to improved ability to detect HER2 alterations and facilitated the development of HER2 targeted therapies. Available treatments for advanced/metastatic SqCLC have been historically limited to platinum-doublet chemotherapy, with immune checkpoint inhibitors such as anti-PD-1/PD-L1 newly emerging in the past decade. Selective HER2 tyrosine kinase inhibitors and HER2 antibody/drug conjugates have shown improved efficacy in HER2-altered NSCLC as shown in DESTINY-LUNG02 and BEAMION LUNG-1 trials; however, most of the enrolled patients had non-squamous histology, with minimal or no SqCLC-specific efficacy data reported. Future progress in HER2-altered SqCLC will require inclusion of SqCLC in HER2 basket trials, incorporation of comprehensive molecular profiling and standardized HER2 testing in squamous histology. This review summarizes the current state of knowledge of HER2 biology in SqCLC and highlights areas for future directions for precision oncology in SqCLC. Full article

Classical Hodgkin lymphoma (cHL) remains one of the most curable hematologic malignancies, with long-term survival exceeding 80–90% in most contemporary series. However, a subset of patients experience primary refractory disease, relapse, treatment-related toxicity, or late complications associated with conventional chemotherapy and radiotherapy. Over the last decade, major advances in frontline treatment have transformed the therapeutic landscape of cHL through the incorporation of targeted therapy and immune checkpoint inhibition into first-line regimens. Brentuximab vedotin (BV), an anti-CD30 antibody–drug conjugate, and programmed death-1 (PD-1) inhibitors such as nivolumab and pembrolizumab have significantly improved outcomes in advanced-stage disease and are increasingly being explored in limited-stage settings. The ECHELON-1 trial established BV-AVD as superior to ABVD in advanced-stage disease with improved progression-free survival and overall survival, while the SWOG S1826 study demonstrated superior progression-free survival and reduced toxicity with nivolumab-AVD compared with BV-AVD. Based on the SWOG S1826 data, nivolumab-AVD is emerging as the preferred frontline standard for most fit patients with advanced-stage cHL, though this remains an area of evolving practice. PET-adapted strategies remain a critical backbone of treatment optimization even in the era of novel agents, enabling individualized de-escalation or escalation based on early metabolic response. These advances have shifted frontline treatment paradigms toward chemotherapy de-escalation, PET-adapted strategies, and immune-based treatment approaches. In parallel, the role of radiotherapy continues to evolve with efforts aimed at minimizing long-term toxicity without compromising cure rates, particularly in PET-negative patients with limited-stage disease. This review summarizes the biological rationale, pivotal clinical trials, evolving treatment strategies, current guideline recommendations, and future directions in first-line treatment of cHL, with emphasis on evidence-based incorporation of novel agents and practical implications for modern clinical practice. Full article

The pro-metastatic gene MDA-9/Syntenin-1 and its tandem PDZ domains (PDZ1 and PDZ2) provide established targets for intervening in tumor progression and metastasis. Recently, we generated and validated MDA-9/Syntenin-1 antagonists targeting a single PDZ domain (PDZ1i) or both PDZ domains (IVMT-Rx-3) in carcinomas and melanoma. Data reveal that IVMT-Rx-3 possesses immunomodulatory and anti-angiogenic properties, in addition to its well-established anti-invasive capabilities. Despite its significant druggable properties, it cannot be delivered orally, limiting its clinical potential. Here, we characterized an oral microemulsion (ME) formulation of IVMT-Rx-3, IVMT-Rx-3-ME to enhance intestinal permeability, bioavailability, and therapeutic efficacy. Physicochemical analyses demonstrated that the optimized formulation produced a stable IVMT-Rx-3-ME with high drug content (>90%). In vitro permeability and dissolution assays confirmed improved membrane transport and solubility compared with the free drug dispersion control. Pharmacokinetic studies in rats revealed that the ME enabled rapid absorption and sustained systemic exposure, whereas the free drug showed negligible bioavailability. In murine metastatic melanoma models, oral IVMT-Rx-3-ME suppressed tumor growth and lung metastases, and when combined with anti-PD-L1 antibody, produced synergistic antitumor effects with minimal toxicity. Collectively, these findings highlight IVMT-Rx-3-ME as a potent and viable oral metronomic chemotherapy platform for metastatic melanoma, with enhanced combinatorial translational potential with immunotherapies. Full article

Objectives: To describe the scientific evidence regarding adjuvant treatment for stage III and IV cutaneous melanoma and the unresolved issues in this setting. Methods: This review examines the main studies on adjuvant medical therapies approved over the years by the Food and Drug Administration and European Medicines Agency together with the main evidence related to the treatments referred to in the National Comprehensive Cancer Network and European Society of Clinical Oncology guidelines at the time of submission (May 2026) for stage III and IV cutaneous melanoma. A particular focus on immunotherapy (interferon, ipilimumab, and anti-PD-1 antibodies, both as monotherapy and in combination) and targeted therapy with anti-BRAF agents, either as monotherapy or in combination with MEK inhibitors, is given. Besides that, this work also evaluates the role of radiation therapy and addresses some unresolved issues, such as adjuvant therapy in stage IIIA and treatment selection in BRAF-mutated melanoma. Results: Adjuvant therapy for stage III and IV cutaneous melanoma has evolved over the years, starting with interferon and progressing to the use of immunocheckpoint inhibitors and targeted therapy. However, not all treatments that have proven effective in metastatic disease have subsequently played a role in the adjuvant setting. Conclusions: Currently, adjuvant treatment for stage III and IV cutaneous melanoma involves the use of anti-PD-1 antibodies (nivolumab and pembrolizumab) and dabrafenib plus trametinib if the patient has a BRAF V600 mutation. It was not possible to identify the adjuvant therapy of choice for BRAF-mutated melanoma, and several factors must be considered when deciding between immunotherapy and targeted therapy. The role of radiation therapy remains controversial and could be discussed by the multidisciplinary team as part of the adjuvant strategy in selected patients. Likewise, adjuvant therapy for stage IIIA melanoma should be carefully evaluated in light of the risk–benefit ratio. Full article

α-synuclein (α-syn) aggregation in dopaminergic neurons is a central event in Parkinson’s disease (PD) pathogenesis. Immunotherapeutic strategies targeting α-syn, including passive and active approaches, aim to inhibit aggregation, propagation, and toxicity of pathological species while promoting their clearance via immune mechanisms. This review summarizes α-syn directed immunotherapies evaluated in in silico, in vitro, and in vivo models, as well as early phase clinical trials, focusing on how epitope selection and antibody formats influence efficacy, safety, and target engagement. Data on monoclonal antibody, peptide, and protein-based vaccines, and structure-guided immunogens were analyzed, integrating behavioral, neuropathological, proteomic, and structural outcomes alongside biomarker development for α-syn species in cerebrospinal fluid and peripheral compartments. Clinical evidence indicates that several candidates induce sustained anti-α-syn antibody responses with acceptable safety profiles and signs of pharmacodynamic engagement, including reductions in free or oligomeric α-syn. However, consistent long-term clinical benefits remain unproven, highlighting the gap between preclinical success and disease modification in humans. Advances in structural biology and proteomics support rational epitope selection and improved immunogen design, reinforcing α-syn-targeted immunotherapy as a promising yet experimental strategy for PD, and highlighting the need for mechanistically oriented, biomarker-driven clinical trials initiated in well-characterized prodromal and early-stage cohorts. Full article

Background/Objectives: Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have transformed cancer treatment, yet therapeutic responses remain limited in many solid tumors due to poor and uneven drug distribution within the tumor microenvironment (TME). Here, we evaluated whether co-formulation of an anti-PD-1 antibody (RMP1-14, murine surrogate for pembrolizumab) with Imagent^® microbubble/liposome (MBLP) complexes and ultrasound activation could enhance tumor-specific delivery while reducing systemic exposure. Methods: Immunocompetent MC-38 colorectal tumor-bearing mice (B6(Cg)-Tyrc-2J/J, 7-week-old females) received isotype control, isotype/MBLP/US, RMP1-14 alone, RMP1-14/MBLP, or RMP1-14/MBLP/US. Survival was analyzed by Kaplan–Meier curves, tumor necrosis by H&E staining, antibody biodistribution by immunohistochemistry, and tumor perfusion by laser speckle imaging. Results: No significant differences in tumor size or body weight were observed between groups. Survival analysis showed significant improvements in the RMP1-14 (p = 0.013) and RMP1-14/MBLP/US (p = 0.047) groups versus isotype controls, with the RMP1-14/MBLP/US group achieving the longest mean survival (57.8 days vs. 26.5 days for RMP1-14 alone) and complete tumor regression in 2/8 mice. The RMP1-14/MBLP/US group demonstrated significantly greater tumor necrosis than all other groups. Immunohistochemical analysis confirmed a 6.1-fold increase in intratumoral antibody accumulation with MBLP/US versus RMP1-14 alone (p = 0.0003), alongside significantly reduced off-target exposure in spleen, liver, kidney, and heart. Laser speckle imaging revealed a transient ~30% increase in tumor perfusion during MBLP/US treatment, consistent with cavitation-mediated hemodynamic effects. Conclusions: These findings demonstrate that MBLP/US co-formulation enhances intratumoral delivery of checkpoint inhibitors, improves survival, and reduces systemic organ exposure, representing a promising platform to improve the efficacy and safety profile of antibody-based immunotherapy. Full article