Bosnian Journal of Basic Medical Sciences (BJBMS)
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Impact of thyroid immune-related adverse events on clinical outcomes in non-small cell lung cancer (NSCLC) patients treated with checkpoint inhibitor therapy: A single center study
Full text linkImmune checkpoint inhibitors (ICIs) have transformed the treatment landscape for non-small cell lung carcinoma (NSCLC) but are associated with immune-related adverse events (irAEs), including thyroid dysfunction. This study examines the incidence and clinical impact of thyroid dysfunction in NSCLC patients receiving ICIs at the Clinic of Oncology, Clinical Center University of Sarajevo. In this retrospective cohort study of 50 patients with metastatic NSCLC treated with ICIs—either in combination with chemotherapy or as monotherapy for those with programmed death-ligand 1 (PD-L1) expression ≥ 50%—we collected data on demographics, treatment regimens, thyroid function tests, and survival outcomes. Thyroid dysfunction occurred in 24 patients (48%), with 12 (24%) developing hypothyroidism, 4 (8%) developing hyperthyroidism, and 8 (16%) experiencing a transition from hyperthyroidism to hypothyroidism. The incidence of thyroid dysfunction was significantly higher in patients treated with atezolizumab compared to pembrolizumab (P = 0.04), with 87.5% of affected patients receiving atezolizumab. The median time to onset of thyroid dysfunction was 10 cycles (interquartile range [IQR]: 5) for hypothyroidism and six cycles (IQR: 19) for hyperthyroidism. Progression-free survival (PFS) was significantly longer in patients who developed thyroid dysfunction, with the median PFS not reached, compared to a median PFS of 14 months (95% CI: 9.68–18.32) in patients without thyroid dysfunction (P = 0.038). No significant associations were found between thyroid dysfunction and patient age or gender. These findings suggest that thyroid dysfunction is a common irAE in patients with metastatic NSCLC receiving ICIs, particularly atezolizumab, and its development may be associated with improved PFS. Regular monitoring of thyroid function is recommended to promptly identify and manage thyroid abnormalities during ICI therapy, potentially improving patient outcomes
LncRNA interactomes and co-methylation in breast cancer regulation
Full text linkBreast cancer is the most commonly diagnosed malignancy in women. Despite advances in diagnostics and treatment, the key molecular mechanisms underlying its development remain incompletely understood. This study aimed to identify novel lncRNA–miRNA–mRNA regulatory networks potentially involved in breast cancer–associated signaling pathways. Using an RT² lncRNA PCR Array and bioinformatic analysis, we identified seven differentially expressed (DE) lncRNAs. Four of these—ADAMTS9-AS2, HAND2-AS1, HOTAIRM1, and MEG3—were prioritized through integrative evaluation. qPCR confirmed their downregulation and aberrant methylation in breast tumor samples. We observed significant positive expression correlations between the pairs ADAMTS9-AS2–MEG3, HAND2-AS1–MEG3, and HOTAIRM1–MEG3, as well as co-methylation among ADAMTS9-AS2–HAND2-AS1, ADAMTS9-AS2–HOTAIRM1, HAND2-AS1–MEG3, and HAND2-AS1–HOTAIRM1, suggesting coordinated regulation. These findings are consistent with data from GEPIA 2.0. Bioinformatic prediction identified TCF7L2 as a common target gene of these lncRNAs, which is involved in the Wnt, Hippo, and MAPK signaling pathways. We also identified several miRNAs interacting with ADAMTS9-AS2. In a cohort of 50 tumor samples, we confirmed inverse associations between ADAMTS9-AS2 expression and levels of miR-106a-5p (rs = –0.46, p = 0.03) and miR-17-5p (rs = –0.41, p = 0.04). Collectively, these findings reveal novel co-regulated lncRNA–miRNA axes and suggest their involvement in key signaling networks in breast cancer, providing a foundation for future functional studies and potential therapeutic targeting
Predicting overactive bladder from inflammatory markers: A machine learning approach using NHANES 2005–2020
Full text linkOveractive bladder (OAB), a prevalent condition characterized by urgency and nocturia, imposes significant burdens on both quality of life and healthcare systems. Emerging evidence implicates systemic inflammation in OAB pathogenesis; however, the role of complete blood count (CBC)-derived inflammatory biomarkers remains underexplored. This cross-sectional study analyzed data from 35,394 participants in the National Health and Nutrition Examination Survey (NHANES, 2005–2020) to evaluate associations between CBC-derived biomarkers—such as the Systemic Immune-Inflammation Index (SII), Systemic Inflammation Response Index (SIRI), and Neutrophil-to-Lymphocyte Ratio (NLR)—and OAB (defined by an OAB Symptom Score ≥3). Multivariable logistic regression, threshold analysis, and machine learning models (Random Forest [RF], Extreme Gradient Boosting) were employed, adjusting for sociodemographic, lifestyle, and clinical covariates. Elevated levels of SII, SIRI, NLR, Monocyte-to-Lymphocyte Ratio (MLR), and Neutrophil-MLR (NMLR) were significantly associated with increased OAB risk (all P < 0.05), with adjusted odds ratios for the highest quartiles ranging from 1.21 (SII; 95% CI: 1.10–1.34) to 1.31 (NMLR; 1.19–1.44). Nonlinear associations were observed, with inflection points (e.g., NLR = 1.071, MLR = 0.174) marking abrupt increases in risk. RF models showed strong predictive performance (area under the curve = 0.89 for training; 0.76 for testing), identifying SII and SIRI as key predictors. Subgroup analyses demonstrated consistent associations across most demographic groups, with the exception of hyperlipidemia, which modified the effects of SIRI, NLR, and NMLR. These findings highlight the role of systemic inflammation in OAB and suggest that CBC-derived biomarkers could serve as cost-effective tools for risk stratification. The integration of epidemiological analysis and machine learning enhances our understanding of OAB’s inflammatory underpinnings, although longitudinal studies are needed to establish causal relationships and therapeutic implications
Passenger lymphocyte syndrome – Epidemiology, pathogenesis, diagnosis, treatment and future directions: A review
Full text linkPassenger lymphocyte syndrome (PLS) is a hematological complication that can occur following transplantation, characterized by donor-derived memory B lymphocytes producing antibodies against the recipient\u27s blood cells. This review examines the pathophysiology, diagnostic approaches, and treatment strategies aimed at enhancing clinical management and standardizing therapeutic protocols for PLS. A literature search was conducted using Web of Science and PubMed to identify relevant publications on PLS, resulting in 79 studies. Studies were selected based on predefined criteria, including a focus on human donor-derived alloimmunity, documented blood group antigen-antibody interactions, transplantation context, clinical data on outcomes or management, and methodological validity. Only studies containing actual patient data and substantive discussions about PLS were included. PLS commonly presents as hemolytic anemia, accompanied by elevated lactate dehydrogenase (LDH) levels, indirect hyperbilirubinemia, and reduced haptoglobin levels. Diagnosis is primarily based on clinical manifestations and laboratory tests, including the direct antiglobulin test (DAT) and antibody screening. Differential diagnosis is crucial for excluding drug-induced hemolytic anemia and thrombotic microangiopathy. Current treatment strategies for PLS focus on halting hemolysis and restoring hematological balance. First-line treatment includes donor-compatible red blood cell transfusions and high-dose corticosteroids, while refractory cases may necessitate rituximab or plasmapheresis. Despite advancements in PLS management, challenges persist, including delayed diagnosis due to self-limiting cases and a lack of standardized treatment protocols. Future research should incorporate genomic and proteomic biomarkers for accurate diagnosis and risk prediction. Developing mechanism-driven therapies targeting donor lymphocytes and establishing global consensus frameworks can enhance monitoring, improve graft survival, and optimize transplant recipient outcomes.
Influence of intravenous iron therapy on mortality and cardiovascular events of patients on hemodialysis: A meta-analysis
Full text linkIntravenous (IV) iron is widely utilized to manage anemia in patients undergoing maintenance hemodialysis; however, its long-term safety remains uncertain. This meta-analysis aimed to evaluate the impact of IV iron on all-cause mortality and major adverse cardiovascular events (MACEs) within this population. We conducted a systematic search of PubMed, Embase, Cochrane Library, Web of Science, Wanfang, and CNKI up to March 2025 for randomized controlled trials (RCTs) that compared IV iron with placebo/usual care, oral iron, or varying doses of IV iron in adult hemodialysis patients. The primary outcomes assessed were all-cause mortality and MACEs. Data were synthesized using a random-effects model, and the quality of evidence was evaluated employing the GRADE approach. A total of fifteen RCTs involving 4,257 patients were included in the analysis. Compared to placebo/usual care, IV iron did not significantly affect all-cause mortality (OR: 1.36; 95% CI: 0.60–3.09) or MACEs (OR: 0.81; 95% CI: 0.43–1.55), with a moderate level of evidence. Furthermore, IV iron demonstrated no significant differences in mortality (OR: 0.58; 95% CI: 0.18–1.90) or MACEs (OR: 2.47; 95% CI: 0.37–16.34) when compared to oral iron, although the quality of evidence in this comparison was very low. High-dose IV iron was associated with a reduced mortality rate compared to low-dose IV iron (OR: 0.81; 95% CI: 0.67–0.97), though this result was influenced by a single large study. In conclusion, IV iron does not appear to increase mortality or MACEs relative to placebo or oral iron. While high-dose IV iron may decrease mortality, the evidence remains limited, indicating a need for further research
Atherogenic index of plasma and risk of diabetic nephropathy in type 2 diabetes: A meta‑analysis
Full text linkThe atherogenic index of plasma (AIP) is a lipid-based biomarker associated with cardiovascular and renal risks in individuals with type 2 diabetes mellitus (T2DM). However, its relationship with diabetic nephropathy (DN) remains inadequately defined. This meta-analysis aims to assess the association between AIP and DN in T2DM patients. We conducted a comprehensive search in PubMed, Embase, and Web of Science for observational studies that compared the incidence or prevalence of DN across varying AIP levels in T2DM populations. Data were synthesized using a random-effects model to account for potential heterogeneity. A total of eleven datasets from ten studies, encompassing 25,773 T2DM patients, were included in the analysis. The pooled results indicated that higher AIP levels are significantly associated with DN (risk ratio [RR] = 1.51, 95% confidence interval [CI]: 1.36–1.67; p < 0.001). Subgroup analyses revealed a stronger association in patients aged 58 years or older (RR = 1.66) compared to those younger than 58 years (RR = 1.35; p for subgroup difference = 0.02). Similar associations were observed across different study designs, sex distributions, AIP cutoff values, definitions of DN, and quality scores (p for subgroup difference all > 0.05). Meta-regression analysis further indicated that older age positively influenced the strength of the association (coefficient = 0.018, p = 0.03). In conclusion, elevated AIP levels are significantly associated with diabetic nephropathy in T2DM patients, particularly among older individuals
Remimazolam vs propofol for postoperative delirium in adults undergoing general anesthesia: A meta-analysis
Full text linkPostoperative delirium (POD) is a prevalent and serious complication in adults undergoing surgery with general anesthesia. Remimazolam, an innovative ultra-short-acting benzodiazepine, has been identified as a potential alternative to propofol due to its advantageous pharmacological properties. However, its impact on POD remains uncertain. This study conducted a systematic review and meta-analysis following PRISMA guidelines. A comprehensive search of the PubMed, Embase, Cochrane Library, Web of Science, CNKI, and Wanfang databases was performed up to March 29, 2025. Randomized controlled trials (RCTs) comparing remimazolam and propofol in adult surgical patients under general anesthesia, specifically reporting on POD incidence, were included. A random-effects model was utilized to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs), accounting for heterogeneity. The analysis included seventeen RCTs encompassing 3,133 patients. Overall, remimazolam significantly decreased the risk of POD compared to propofol (OR: 0.71, 95% CI: 0.52–0.97, p = 0.03; I² = 36%). Sensitivity analyses, which involved excluding one study at a time, yielded consistent results, reinforcing the robustness of the findings. Subgroup analyses revealed uniform effects across different study designs (single-blind vs. double-blind; OR: 0.73 vs. 0.64; p = 0.71) and age groups (adults vs. elderly; OR: 0.64 vs. 0.72; p = 0.79). A trend toward greater benefit was observed in studies with longer follow-up periods (7 days: OR: 0.42) and in those employing the CAM or CAM-ICU for POD diagnosis, although subgroup differences were not statistically significant. In conclusion, remimazolam is associated with a significantly reduced risk of POD compared to propofol in adults undergoing general anesthesia
Neuropeptide S pathway in PTSD and neuropsychiatric disorders: A review
Full text linkPost-traumatic stress disorder (PTSD) is a multidimensional illness that seldom occurs alone: roughly 80 % of patients also meet criteria for anxiety, depression, chronic pain, substance-use, eating or cognitive disorders. Converging genetic, neurochemical and behavioural findings implicate the neuropeptide S (NPS) system—acting through its G-protein-coupled NPS receptor (NPSR)—as a common regulator of these diverse phenotypes. This narrative review surveys studies published 2000–2024 in PubMed, Embase and Web of Science that examine NPS/NPSR involvement in core PTSD features and typical comorbidities. The functional rs324981 A/T polymorphism, which boosts NPSR surface expression and signalling, consistently associates with greater PTSD risk and symptom severity. In rodent models, exogenous NPS reduces anxiety- and fear-like behaviours, speeds fear-memory extinction, stabilises the hypothalamic-pituitary-adrenal axis, enhances dopaminergic tone and elevates hippocampal brain-derived neurotrophic factor (BDNF)—changes concordant with symptom relief. Additional work shows that NPS lessens pain affect, dampens alcohol and opioid intake, eases withdrawal-induced anxiety and lowers food consumption, hinting at a multimodal therapeutic profile. These effects converge on limbic and mid-brain circuits (amygdala, ventral tegmental area, locus coeruleus, paraventricular nucleus) and engage oxytocinergic, adenosinergic and endocannabinoid pathways. Translation remains limited by NPS’s rapid degradation, poor blood–brain-barrier penetration and scarcity of brain-penetrant NPSR ligands, but advances in intranasal delivery, lipid-acylated analogues, biased NPSR agonists and “humanised” NPSR-variant models offer promising solutions. Collectively, current pre-clinical and genetic evidence positions the NPS–NPSR axis as a versatile therapeutic target for both core PTSD symptoms and their disabling comorbidities, warranting rigorous translational studies to refine mechanism, optimise drug-like properties and test clinical efficacy
Neoadjuvant stereotactic radiosurgery for brain metastases: Current evidence and clinical perspectives
Full text linkNeoadjuvant stereotactic radiosurgery (SRS) has emerged as a promising strategy for managing brain metastases, offering several advantages over traditional postoperative approaches. By delivering targeted radiation prior to surgical resection, neoadjuvant SRS aims to enhance local tumor control, reduce the risk of leptomeningeal dissemination, and optimize treatment efficiency. Recent findings suggest that neoadjuvant SRS provides comparable, if not superior, local control compared to postoperative SRS, while exhibiting lower rates of radiation necrosis and leptomeningeal disease. However, uncertainties persist regarding optimal dosing regimens, treatment timing, and patient selection criteria, as factors such as tumor size, volume, and histology may significantly influence clinical outcomes. Additionally, while neoadjuvant SRS addresses challenges related to target delineation and delays associated with postoperative treatment, its long-term efficacy and integration with systemic therapies require further investigation. This review consolidates evidence from recent retrospective and prospective studies, focusing on key outcomes such as local control rates, radiation toxicity profiles, and overall survival
IRF5 variants and rheumatoid arthritis susceptibility in women from Central Mexico
Full text linkRheumatoid arthritis (RA) is a chronic autoimmune disease in which dysregulated interferon regulatory factor 5 (IRF5) may amplify pro-inflammatory pathways; prior genetic studies of IRF5 single-nucleotide variants (SNVs) in RA are inconsistent across populations and have not included mestizo Mexicans or evaluated rs59110799 in RA. We aimed to test whether four IRF5 SNVs (rs2004640G/T, rs2070197T/C, rs10954213G/A, rs59110799G/T) confer susceptibility to RA in women from Central Mexico. In a case–control study of 239 women with RA and 231 female controls (all self-identified Mexican-Mestizos, ≥3 generations), genotyping was performed by real-time PCR with TaqMan® probes; 80% of samples were duplicated (100% concordance) and control genotypes conformed to Hardy–Weinberg equilibrium. Association was assessed under allelic and multiple genetic models using logistic regression adjusted for age and birthplace, with Bonferroni correction for 23 tests (α=0.0022). Haplotype and linkage disequilibrium (LD) were analyzed with Haploview; putative functional effects were explored in silico (SNPinfo; GTEx). The minor alleles rs2004640T [OR=1.69, 95% CI 1.29–2.21; p=1.2×10⁻⁴], rs2070197C [OR=1.85, 1.39–2.46; p=2.0×10⁻⁵], and rs10954213A [OR=1.47, 1.12–1.93; p=0.002] were associated with increased RA risk after correction. Genotype-based associations were observed for rs2004640 (codominant and recessive) and rs2070197 (codominant, dominant, recessive). rs59110799G/T showed no significant association after correction (dominant model OR=1.69, 1.15–2.48; p=0.007). Nine haplotypes were identified; the haplotype carrying all four risk alleles (TCAT) was not associated, and two haplotypes with nominal signals (GCAG, TTGT) had control frequencies <1% and were excluded; variants were not in strong LD (r²<0.80). Our findings—providing the first evaluation of these IRF5 variants in Mexican women and the first report of rs59110799 in RA—support a role for IRF5 (rs2004640, rs2070197, rs10954213) in RA susceptibility in this Latin American population. Given the female-only design and moderate statistical power, replication and functional studies are warranted