Bosnian Journal of Basic Medical Sciences
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Annexins and autoantibodies in autoimmune diseases – Insights into SLE, APS and RA: A review
Full text linkAutoimmune diseases are becoming increasingly prevalent and can cause multi-organ damage through dysregulated immune responses to self-antigens. This review aims to summarize the roles of annexin family proteins and annexin autoantibodies in the mechanisms of autoimmune diseases, as well as their potential diagnostic and therapeutic applications. A targeted PubMed search conducted on August 31, 2025, utilized annexin- and disease-related terms without year restrictions, focusing on English-language, peer-reviewed studies involving humans or recognized animal models. Evidence suggests that Annexin A1 (ANXA1) and formyl peptide receptor 2 (FPR2) signaling can influence inflammatory and T-cell responses. Additionally, Annexin A2 (ANXA2) is associated with organ-targeted injury, such as lupus nephritis (LN) in systemic lupus erythematosus (SLE), through its interactions with anti-double-stranded DNA antibodies (anti-dsDNA). Annexin A5 (ANXA5) serves as an anticoagulant phospholipid "shield," which can be compromised by antiphospholipid antibodies (aPLs), contributing to thrombosis and obstetric complications in antiphospholipid syndrome (APS) and increasing vascular risk in SLE. In rheumatoid arthritis (RA), ANXA1 exhibits context-dependent effects, while ANXA2 promotes synovial proliferation, invasion, and angiogenesis. Dysregulation of annexins has also been observed in primary Sjögren\u27s syndrome (pSS), multiple sclerosis (MS), and systemic sclerosis (SSc). Additionally, the emerging utility of anti-ANXA1, anti-ANXA2, and anti-ANXA5 autoantibodies for phenotyping and risk stratification, including in seronegative antiphospholipid syndrome (SNAPS), highlights their clinical relevance. Overall, annexins and their autoantibodies represent promising biomarkers and therapeutic targets; however, the heterogeneity of assays and the limited availability of prospective multicenter data currently hinder clinical translation
Prediabetes and the risk of incident chronic kidney disease in adults: A systematic review and meta-analysis
Full text linkThe relationship between prediabetes and chronic kidney disease (CKD) remains ambiguous, with varying results across cohort studies. This meta-analysis aimed to assess whether prediabetes is linked to an increased risk of developing incident CKD in the general adult population. A comprehensive search was conducted in PubMed, Embase, and Web of Science from inception to September 28, 2025, for longitudinal observational studies that evaluated CKD risk in individuals with prediabetes compared to those with normoglycemia. Prediabetes was defined by impaired fasting glucose (IFG), impaired glucose tolerance (IGT), elevated glycated hemoglobin (HbA1c), or a combination of these criteria. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Fifteen cohorts comprising 2,854,724 participants were included in the analysis. The results indicated that prediabetes was significantly associated with an increased risk of incident CKD (RR: 1.21, 95% CI: 1.12–1.31; I² = 90%). Subgroup analyses revealed that the association was not significantly influenced by the definitions of prediabetes, study design, demographic characteristics of the population, follow-up duration, or study quality scores (p for subgroup difference all > 0.05). Meta-regression analysis suggested that a higher mean age of the population was inversely correlated with the observed effect size for the relationship between prediabetes and CKD risk (coefficient = -0.030, p = 0.004; adjusted R² = 67%). In conclusion, prediabetes is associated with a modestly elevated risk of developing CKD in the general population, with a potentially stronger correlation observed in younger individuals. These findings indicate an association rather than causality and suggest that early glycemic dysregulation may be linked to subsequent renal risk prior to the onset of overt diabetes
A remarkable year for NSCLC: Seven new FDA approvals in 2025 across molecular targets
Full text linkNon-small cell lung cancer (NSCLC) remains the leading cause of cancer mortality worldwide; however, precision oncology has fundamentally transformed its treatment landscape. In 2025, seven approvals by the U.S. Food and Drug Administration (FDA) further accelerated biomarker-driven care across critical molecular subsets. These include MET-directed and trophoblast cell-surface antigen-2 (TROP-2) antibody-drug conjugates (ADCs), expanded strategies targeting epidermal growth factor receptor (EGFR), notably those addressing exon 20 insertion mutations, a ROS proto-oncogene 1 (ROS1) inhibitor, and various human epidermal growth factor receptor 2 (HER2) options that encompass both tumor-agnostic and mutation-selected approaches. These advancements underscore the necessity for integrated diagnostics—such as next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC)—while also emphasizing ongoing challenges in biomarker selection, therapeutic sequencing, and equitable global implementation
Whole-exome sequencing in obstructive coronary artery disease identifies rare and novel variants in cardiac arrhythmia and pulmonary arterial hypertension–associated genes
Full text linkCoronary artery disease (CAD) represents a complex interplay of genetic, environmental, and lifestyle factors. In this study, we utilized whole-exome sequencing (WES) on 28 patients with obstructive CAD to identify rare variants that may influence clinical outcomes beyond conventional atherosclerotic risk. We examined 74 genes curated from the Genomics England PanelApp, focusing on familial hypercholesterolemia (FH), cardiac arrhythmias (CA), and pulmonary arterial hypertension (PAH), ultimately detecting 8,251 variants. After applying a stringent filtering process with a population maximum allele frequency (PopMax AF) threshold of <0.1%, we identified 68 candidate variants across 23 genes. The majority were associated with CA (47/68, 69%), followed by PAH (12/68, 18%) and FH (9/68, 13%). Notably, 30 variants (44%) were novel, and 18 were categorized as high-impact frameshift mutations. The highest burden of candidate variants was found in the sodium voltage-gated channel alpha subunit 10 (SCN10A), followed by the ryanodine receptor 2 (RYR2), mitochondrial seryl-tRNA synthetase 2 (SARS2), A-kinase anchoring protein 9 (AKAP9), and hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4). Clinical evaluation revealed a pathogenic variant in the low-density lipoprotein receptor (LDLR) and likely pathogenic variants in sodium voltage-gated channel alpha subunit 5 (SCN5A) and potassium voltage-gated channel subfamily Q member 1 (KCNQ1); additionally, nine other variants were predicted to be deleterious, including five novel SCN10A variants. Functional annotation using Gene Ontology (GO) and Human Phenotype Ontology (HPO) highlighted mechanisms impacting cardiac structure, electrical conduction, and lipid homeostasis
Stem cell–based therapies for inherited retinal diseases – Translational advances and clinical evidence: A review
Full text linkInherited retinal diseases (IRDs) represent a genetically diverse group of disorders that result in the progressive degeneration of photoreceptors and/or retinal pigment epithelium (RPE), ultimately leading to significant vision loss and diminished quality of life. Symptoms vary widely, encompassing night blindness, peripheral vision loss, central vision impairment, and total blindness, with disease progression influenced by the specific genetic mutation and inheritance pattern. This narrative review synthesizes recent findings on the pathogenesis of IRDs and examines stem cell-based interventions across preclinical models and early clinical trials. Mutations in genes such as RPE65, ABCA4, and USH2A disrupt critical retinal pathways, contributing to oxidative stress, inflammation, and apoptosis. Stem cell strategies, including pluripotent stem cell-derived RPE/photoreceptor precursors, mesenchymal stem cells, and retinal progenitor cells, offer potential mechanisms for limited cellular replacement and synaptic integration, as well as paracrine neuroprotection and immunomodulation. Current research indicates feasible delivery methods (intravitreal, subretinal, or suprachoroidal) with generally acceptable safety profiles; however, functional improvements in vision are often inconsistent and temporary, and durable vision restoration remains unproven. Significant challenges persist, including immune rejection, tumorigenicity risks, weak engraftment, technical complexity, and regulatory barriers. These issues underscore the necessity for standardized manufacturing processes and well-controlled, long-term clinical trials to advance the field of IRD treatment
Tubeless uniportal VATS in thoracic surgery – Indications, ERAS pathways, and outcomes: A review
Full text linkTubeless uniportal video-assisted thoracoscopic surgery (VATS) is an innovative approach characterized by the use of non-intubated (spontaneous-breathing) anesthesia, the omission of routine postoperative chest drainage, and single-port access. This technique has gained traction in recent years for a variety of thoracic procedures. While practices reported in the literature may differ, this review primarily examines the combined non-intubated and drainless approach. This narrative review provides a comprehensive overview and critical analysis of its current clinical applications, including sympathectomy, pulmonary wedge resection, spontaneous pneumothorax, thymectomy, and early-stage lung cancer. It also addresses essential aspects of perioperative management and procedural indications within enhanced recovery-oriented pathways. A systematic literature search of PubMed, Embase, and Web of Science was conducted to identify pertinent studies published between January 2010 and April 2025. Current clinical reports indicate potential benefits such as reduced postoperative pain, shorter hospital stays, and accelerated recovery. However, the existing evidence largely stems from small, observational studies with varied methodologies, necessitating cautious interpretation. The broader implementation of this technique in more complex procedures depends on the establishment of standardized clinical pathways, the refinement of multidisciplinary perioperative strategies, and validation through multicenter prospective studies. Tubeless uniportal VATS shows promise as a significant advancement in function-preserving and recovery-oriented thoracic surgery
STOP algorithm for bedside mechanical ventilation: Standardized, evidence-based management of critically ill patients
Full text linkThe COVID-19 pandemic revealed significant variability in mechanical ventilation training and bedside practices, highlighting the necessity for standardized, actionable protocols. This study aimed to develop the Standard Training and Operating Procedure (STOP), an evidence-based algorithm designed for managing mechanically ventilated critically ill patients and troubleshooting patient-ventilator interactions. Utilizing the Successive Approximation Model (SAM), we reviewed current guidelines and expert recommendations, created a minimum-viable prototype during a multidisciplinary "savvy start," and refined it through seven iterative review cycles involving 33 frontline clinicians. The finalized tool underwent external evaluation via a Modified-Delphi process within the Checklist for early recognition and treatment of acute illness and injury (CERTAIN) network, engaging 50 clinicians from 19 countries across four continents, with a consensus threshold of ≥70%. STOP consists of eight sequential bedside checkpoints: abnormal vital signs/ventilator alarms, assessment of ventilation adequacy, elevated peak pressure, elevated plateau pressure, lung protection against ventilator-induced lung injury, risk of oxygen toxicity, patient-ventilator asynchrony, and readiness for spontaneous awakening and breathing trials. The Delphi agreement across these steps ranged from 82% to 96%, supporting the tool\u27s face validity and clinical relevance. STOP offers a practical framework to minimize practice variability and enhance the safety of mechanical ventilation; however, prospective implementation studies are necessary to assess its impact on adherence and patient outcomes
Pre-analytical storage effects on ALU- and LINE1-derived cell-free DNA biomarkers in whole blood and plasma
Full text linkCell-free DNA (cfDNA) biomarkers derived from Arthrobacter luteus (ALU) repeats and long interspersed nuclear elements 1 (LINE1) — including ALU-115, ALU-247, LINE1-97, and LINE1-266 concentrations, as well as the integrity ratios ALU-247/115 and LINE1-266/97 — are commonly utilized to assess cfDNA quantity and integrity. This study examined the impact of delayed blood processing and prolonged plasma storage on these biomarkers using quantitative polymerase chain reaction. Blood samples were collected from twelve healthy individuals (6 males; mean age, 65.8 ± 4.69 years) into dipotassium ethylenediaminetetraacetic acid tubes. Plasma cfDNA was extracted after various storage durations and temperatures, with aliquots from immediately processed blood subsequently stored at -80°C for different time intervals. Except for LINE1-97, most biomarkers showed significantly higher levels in plasma isolated from whole blood stored at room temperature compared to plasma processed immediately. Storage at 4°C resulted in fragment-specific effects: ALU-247/115 levels remained stable at 3 hours but decreased at 6 hours, while LINE1-266/97 levels increased at both time points. For plasma stored at -80°C, ALU-derived biomarkers remained stable for up to 12 months; however, LINE1-97 levels significantly declined, accompanied by a corresponding increase in LINE1-266/97 as early as one month after freezing. These findings indicate that both storage duration and temperature significantly impact the measured levels of ALU- and LINE1-derived cfDNA biomarkers. Consequently, standardization of pre-analytical handling of blood and plasma is crucial for studies evaluating cfDNA quantity and integrity
Mechanistic insights into psoriasis and type 2 diabetes mellitus comorbidity – Implications for treatment: A review
Full text linkPsoriasis is a chronic systemic inflammatory disease primarily affecting the skin, yet it is increasingly recognized for its systemic implications, particularly its strong association with type 2 diabetes mellitus (T2DM). This review synthesizes recent mechanistic and clinical evidence to elucidate the shared pathways linking psoriasis and T2DM, as well as to explore therapeutic strategies for this comorbidity. We conducted a narrative review of studies published between January 2020 and October 2025, encompassing preclinical models, clinical trials, and high-quality reviews that address pathogenesis and treatment. Key findings indicate that shared genetic loci and molecular pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, the IL-23/Th17 axis, and mitochondrial dysfunction associated with the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, contribute to both cutaneous inflammation and systemic metabolic dysregulation. Additionally, adipokine imbalances and chronic low-grade inflammation exacerbate insulin resistance and psoriatic skin pathology. Therapeutically, IL-17/IL-23 inhibitors, metformin, glucagon-like peptide 1 (GLP-1) receptor agonists, and other immunomodulatory strategies demonstrate potential in addressing both dermatologic and metabolic features. These insights reinforce the notion of psoriasis as a systemic disorder with significant metabolic consequences, highlighting the need for integrated, multidisciplinary management. Future research should concentrate on precise gene-environment interactions, biomarker validation, and the development of treatments that simultaneously target both skin and metabolic pathology to advance precision medicine for patients with psoriasis-T2DM comorbidity
MTX pathway gene variants, erythrocyte methotrexate polyglutamates, and treatment outcomes in rheumatoid arthritis
Full text linkRheumatoid arthritis (RA) exhibits significant inter-patient variability in response to and toxicity from methotrexate (MTX). The clinical utility of erythrocyte methotrexate polyglutamates (MTXPGs) and MTX-pathway pharmacogenetics remains uncertain. This study investigates the relationships between MTX-pathway gene polymorphisms, erythrocyte MTXPG levels, and MTX treatment outcomes in RA. In a single-center, cross-sectional cohort study conducted in southern Fujian from 2017 to 2020, we analyzed 140 Han Chinese RA patients who had been receiving stable low-dose oral MTX (7.5–15 mg/week) for at least three months. Genotyping was performed using MassARRAY, and MTXPG levels 1–6 were quantified in red blood cells via LC-MS/MS. Data on treatment efficacy (measured by ACR20 and clinical scales) and MTX-related adverse drug reactions (ADRs) were collected, with associations analyzed through univariate and multivariable models. MTXPG levels 1–3 were detectable in all patients, while longer-chain MTXPGs were infrequent. The SLCO1B1 521T>C polymorphism was independently associated with lower levels of MTXPG1 (B=−1.119), MTXPG2 (B=−0.924), and total MTXPG (B=−0.849), all with P-values ≤0.045. However, MTXPG levels did not correlate with MTX efficacy or ADRs. The GGH 401C>T polymorphism was associated with a reduced ACR20 response (OR=0.421, p=0.021) and higher visual analog scale (VAS) and patient global assessment (PGA) scores. Additionally, the variants SLCO1B1 521T>C and ABCB1 3435C>T were linked to higher scores in the Patient Health Global Assessment (PHGA) and Health Assessment Questionnaire (HAQ). In this low-dose MTX cohort, erythrocyte MTXPGs did not predict clinical outcomes. However, variants in SLCO1B1, GGH, and ABCB1 emerged as exploratory candidate markers for MTX response, warranting validation in larger prospective cohorts