Bosnian Journal of Basic Medical Sciences (BJBMS)
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Association between prediabetes and thyroid cancer risk: A meta-analysis
Full text linkPrediabetes, characterized by intermediate hyperglycemia, is increasingly prevalent worldwide. While diabetes has been associated with a heightened risk of various cancers, the relationship between prediabetes and thyroid cancer remains ambiguous. This meta-analysis sought to assess whether prediabetes correlates with an elevated incidence of thyroid cancer. A systematic literature search was conducted across PubMed, Embase, Web of Science, Wanfang, and CNKI to identify longitudinal studies that compared the incidence of thyroid cancer in individuals with prediabetes to those with normoglycemia. Risk ratios (RRs) with 95% confidence intervals (CIs) were aggregated using a random-effects model. Subgroup and sensitivity analyses were performed to identify potential effect modifiers. Six prospective cohort studies, encompassing 5,743,849 participants, were included in the analysis. Overall, prediabetes was not significantly correlated with thyroid cancer incidence (RR = 1.04; 95% CI: 0.98–1.11; p = 0.23; I² = 53%). Subgroup analyses revealed no significant variations based on age, sex, region, follow-up duration, or definition of prediabetes. Notably, a significant association was identified in studies utilizing cancer registries or validated clinical diagnoses (RR = 1.29; 95% CI: 1.04–1.60), in contrast to studies relying solely on ICD-10 codes (RR = 1.01; 95% CI: 0.98–1.05; p for subgroup difference = 0.03). In conclusion, prediabetes was not linked to a significantly increased risk of thyroid cancer overall. However, a potential association was noted in studies employing clinically validated cancer diagnoses. These findings, derived from observational cohorts, should be interpreted cautiously, and further prospective research is necessary to elucidate any causal relationship
The role of reviewers in the era of systematic reviews and meta-analysis: A practical guide for researchers
Full text linkA systematic review with meta-analysis (SRMA) represents the pinnacle of evidence, but its validity depends on methodological rigor. This narrative review synthesizes recommendations from major reporting frameworks— Preferred Reporting Items for Systematic Reviews and Meta‑Analyses 2020 (PRISMA‑2020), Meta‑Analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Overviews of Reviews (PRIOR)—into a concise checklist for peer reviewers. The checklist addresses common sources of bias that often escape editorial assessment. Initially, it outlines how reviewers should assess the rationale for an SRMA by identifying existing syntheses on the same topic and determining whether the new work provides substantive novelty or a significant update. Best practices are summarized for protocol registration, comprehensive search strategies, study selection and data extraction, risk-of-bias evaluation, and context-appropriate statistical modeling, with a specific focus on heterogeneity, small-study effects, and data transparency. Case examples highlight frequent pitfalls, such as unjustified pooling of heterogeneous designs and selective outcome reporting. Guidance is also provided for formulating balanced, actionable review comments that enhance methodological integrity without extending editorial timelines. This checklist equips editors and reviewers with a structured tool for systematic appraisal across clinical disciplines, ultimately improving the reliability, reproducibility, and clinical utility of future SRMAs
Combined SHR and SIRI biomarkers predict increased coronary heart disease risk in type 2 diabetes
Full text linkCoronary heart disease (CHD) is a leading cause of morbidity and mortality; patients with type 2 diabetes mellitus (T2DM) are at particularly high risk, highlighting the need for reliable biomarkers for early detection and risk stratification. We investigated whether combining the stress hyperglycemia ratio (SHR) and systemic inflammation response index (SIRI) improves CHD detection in T2DM. In this retrospective cohort of 943 T2DM patients undergoing coronary angiography, associations of SHR and SIRI with CHD were evaluated using multivariable logistic regression and restricted cubic splines; robustness was examined with subgroup and sensitivity analyses. Discriminative performance was assessed by receiver operating characteristic (ROC) analysis and reclassification metrics (integrated discrimination improvement [IDI], net reclassification improvement [NRI]). Internal validation used bootstrapping, with calibration and discrimination yielding apparent and bias-corrected estimates. Of 943 patients, 600 had CHD. Multivariable models showed SHR (OR=1.68; 95% CI, 1.14–2.46; p=0.008) and SIRI (OR=2.17; 95% CI, 1.54–3.05; p<0.001) were independently associated with CHD, with nonlinear relationships (p for nonlinearity <0.05). Findings were consistent across subgroups and sensitivity analyses. The combined SHR–SIRI model achieved an AUC of 0.813 (95% CI, 0.783–0.843), outperforming SHR alone (AUC=0.773; 95% CI, 0.740–0.805) and SIRI alone (AUC=0.745; 95% CI, 0.713–0.778), and significantly improved NRI and IDI (p <0.05). All models showed strong discrimination and calibration. In conclusion, SHR and SIRI are independently associated with CHD in T2DM, and their combination enhances early identification of high-risk individuals
Small cell lung cancer (SCLC): At the door of targeted therapies
Full text linkSmall-cell lung cancer (SCLC) is a tobacco-associated neuroendocrine tumor comprising ~15% of lung cancers (~150,000 cases/year). For decades, outcomes stagnated: most patients present with extensive-stage disease, screening rarely detects early tumors, surgery is seldom feasible, and platinum–etoposide remained the first-line standard with median overall survival (OS) <12 months. Radiotherapy (including consolidative thoracic RT) and prophylactic cranial irradiation or MRI surveillance offered incremental gains. Two shifts have begun to change the field. First, four transcriptional subtypes (SCLC-A, -N, -P, and inflammatory SCLC-I) support a more personalized approach, with SCLC-I appearing more responsive to immune checkpoint inhibitors (ICI). Second, adding atezolizumab or durvalumab to chemotherapy in extensive-stage SCLC produced a modest median OS gain but, crucially, a tail of long-term survivors. Subsequent trials extended these advances: IMforte suggested benefit from lurbinectedin maintenance with atezolizumab in ES-SCLC, and ADRIATIC demonstrated a landmark OS improvement (~22 months) with durvalumab consolidation after concurrent chemoradiotherapy in limited-stage SCLC. Targeted strategies are now emerging. Delta-like ligand 3 (DLL3), overexpressed in >80% of SCLC, enables T-cell–redirecting therapy: the bispecific T-cell engager (BiTE®) tarlatamab improved OS to 13.6 vs 8.3 months over standard second-line chemotherapy, with manageable cytokine release syndrome and occasional ICANS. B7 homolog 3 (B7-H3, CD276), uniformly expressed across SCLC subtypes and linked to poor prognosis, is another compelling target: the antibody–drug conjugate ifinatamab deruxtecan achieved a 54.8% response rate and meaningful survival in heavily pretreated patients, earning FDA Breakthrough designation. Together, DLL3- and B7-H3–directed therapies (with additional ADCs against Trop-2 and SEZ6 in development) are redefining second-line and later care. Key next steps include optimizing sequencing/combination strategies, managing BiTE® specific toxicities, and developing predictive biomarkers. After decades of futility, SCLC is transitioning from uniform chemotherapy to a precision-medicine paradigm with cautious optimism
Function and mechanism of miRNAs during the process of Klebsiella pneumoniae infection: A review
Full text linkKlebsiella pneumoniae (K. pneumoniae), a Gram-negative bacterium, is a major cause of nosocomial infections and can lead to severe, widespread infections. The rise of hypervirulent and multidrug-resistant K. pneumoniae presents significant challenges to public health. Diseases associated with K. pneumoniae, such as pneumonia, lung injury, peritonitis, and sepsis, have garnered increasing attention. MicroRNAs (miRNAs) are a class of short, endogenously expressed non-coding RNAs that regulate gene expression by inhibiting translation or promoting mRNA degradation. As key regulators of gene expression, miRNAs play a crucial role in K. pneumoniae infections by modulating host inflammatory pathways, suppressing inflammasome activity, regulating cytokine secretion, and facilitating post-translational modifications. Understanding miRNA alterations and their mechanisms during K. pneumoniae infections is of great significance. This comprehensive review explores the functions and mechanisms of miRNAs in K. pneumoniae-induced lung injury, peritonitis, and sepsis. By analyzing differential miRNA expression during infection, we aim to provide new insights and potential directions for future clinical diagnosis and treatment strategies for K. pneumoniae infections
Enhanced membrane protein production in HEK293T cells via ATF4 gene knockout: A CRISPR-Cas9 mediated approach
Full text linkHEK293T cells are extensively utilized for therapeutic protein production due to their human origin, which enables accurate post-translational modifications. This study aimed to enhance membrane protein production in HEK293T cells by knocking out the ATF4 gene using CRISPR-Cas9 technology. The ATF4 gene was edited by infecting HEK293T cells with a lentivirus carrying optimized single-guide RNA (ATF4-KO-3) and Cas9 genes. Comparative evaluations were conducted using all-in-one and two-vector systems. Genome sequencing and membrane protein productivity of ATF4-knockout (KO) cells were compared to wild-type (WT) cells using next-generation sequencing (NGS) and a membrane protein isolation kit, respectively. Single-cell analysis confirmed gene editing patterns, with NGS verifying the intended deletions. Membrane protein production was also assessed indirectly via flow cytometry, analyzing cells expressing Membrane-GFP. Compared to WT cells, ATF4-KO cells exhibited a significant increase in membrane protein production, with a 52.2 ± 19.0% improvement. Gene editing efficiency was compared between the two delivery systems, with the two-vector system demonstrating higher efficiency based on T7 endonuclease I assays. Western blot analysis confirmed ATF4 suppression and increased expression of membrane proteins, including E-cadherin and CD63. Quantitative analysis via PAGE revealed a 77.2 ± 30.6% increase in purified membrane protein yields, consistent with the observed enhancements. Flow cytometry using Membrane-GFP further demonstrated a 22.9 ± 9.7% increase in productivity. In summary, ATF4 knockout significantly enhances membrane protein production in HEK293T cells, offering potential improvements in biopharmaceutical manufacturing by enabling more efficient protein synthesis
Long-term smoking contributes to aging frailty and inflammatory response
Full text linkIn recent years, the health challenges linked to frailty in the elderly, particularly those worsened by cigarette smoke, have become more pronounced. However, quantitative studies examining the impact of smoking dosage on frailty in this population remain limited. To address this gap, we developed a model using smoke-exposed elderly mice. Fifteen-month-old C57BL/6J mice were exposed to smoke from two burning cigarettes for 15 min in a whole-body chamber. This exposure occurred 4, 6, and 8 times daily for 30 days, representing low, medium, and high smoking dosages, respectively. Frailty levels were assessed through rotation and grip strength tests, alongside lung histopathology and inflammatory factor protein expression analyses across the three dosage groups. Additionally, we used the Gene Expression Omnibus (GEO) database to validate the correlation between frailty and inflammation in elderly smokers, facilitating cross-comparisons between animal model findings and human sample data. Our results show that mice exposed to high-dose smoking were significantly more prone to frailty, with notable reductions in maximal grip strength (P < 0.01) and drop time (P < 0.001). Among human samples, 69.2% of elderly smokers exhibited a frailty phenotype, compared to just 15.4% of nonsmokers. Both smoking-exposed mice and elderly smokers demonstrated upregulation of tumor necrosis factor-α (TNF-α) and interleukin-1 β (IL-1β) in lung tissue and serum. Mechanistically, this upregulation activates the NF-κB signaling pathway. Our findings quantitatively link smoking-induced frailty to increased levels of TNF-α and IL-1β, providing experimental evidence for the diagnosis and prevention of frailty in elderly populations
Advancing ICU mortality prediction in community-acquired pneumonia: Combining fibrinogen-to-albumin ratio, CT severity score, PSI, and CURB-65
Full text linkCommunity-acquired pneumonia (CAP) is a leading cause of ICU admissions, with significant morbidity and mortality. Traditional risk stratification tools, such as CURB-65, the pneumonia severity index (PSI), and computed tomography severity scores (CT-SS) are widely used for prognosis but could be improved by incorporating novel biomarkers. This retrospective study evaluated the fibrinogen-to-albumin ratio (FAR) as an additional predictor of 30-day mortality in ICU patients with CAP. A total of 158 CAP patients admitted to a tertiary care ICU were included. Baseline data encompassed demographic, clinical, laboratory, and radiological parameters, including FAR, CURB-65, PSI, and CT-SS. Logistic regression and receiver operating characteristic curve (ROC) analyses were conducted to assess mortality predictors. The 30-day mortality rate was 70.88% (112/158). Higher FAR, PSI, CURB-65, CT-SS, and lactate levels were independently associated with increased mortality (P < 0.05). FAR demonstrated strong discriminatory power (area under the receiver operating characteristic [AUROC]: 0.704) and significantly improved the predictive accuracy of established models. Adding FAR to PSI increased the AUROC from 0.705 to 0.791 (P = 0.009), while combining FAR, CT-SS, and PSI yielded the highest predictive accuracy (AUROC: 0.844, P = 0.032). These findings suggest that FAR, which reflects both inflammation and nutritional status, complements traditional risk assessment tools by providing a dynamic perspective. Integrating FAR into existing models enhances the identification of high-risk patients, enabling timely interventions and more efficient resource allocation in the ICU
Thymoquinone and 3HQ synergy inhibits CTX-M-15 ESBL
Full text linkBacterial infections remain a significant cause of mortality worldwide, further aggravated by the escalating issue of antibiotic resistance. Extended-Spectrum Beta-Lactamases (ESBLs) pose a substantial challenge, capable of hydrolyzing various beta-lactam antibiotics. The slow pace of drug discovery, coupled with the rapid emergence of drug-resistant bacteria, underscores the urgent need for innovative therapeutic solutions. Thymoquinone (TQ), derived from the seeds of Nigella sativa, has demonstrated notable antibacterial activity against Gram-negative bacteria, including Escherichia coli and Pseudomonas aeruginosa. Previous research has established the efficacy of quinoxaline derivatives, such as 3-hydrazinoquinoxaline-2-thiol (3HQ), against Methicillin-Resistant Staphylococcus aureus (MRSA). This study investigates the potential synergy between 3HQ and TQ against various clinical strains of ESBL. The minimum inhibitory concentrations (MICs) of TQ and 3HQ were evaluated against 18 clinical ESBL strains, revealing MIC values ranging from 16 to 128 µg/mL for both compounds. Furthermore, the interaction between TQ and 3HQ was assessed using a checkerboard assay, which demonstrated a 100% synergistic interaction, with a fractional inhibitory concentration index (FICI) of less than 0.5 against the ESBL strains. Docking and molecular dynamics simulations indicated that TQ exhibits a strong binding affinity and interaction profile comparable to that of RPX-7063. In contrast, 3-hydrazinoquinoxaline-2-thiol targets a different active site, potentially enhancing thymoquinone\u27s binding efficiency. Collectively, these compounds may effectively inhibit CTX-M-15, as evidenced by their docking scores and interaction profiles. Further investigations, including in vivo studies, are essential to validate these findings. This research suggests a promising strategy for developing more effective treatments for ESBL infections, emphasizing the need for in vivo validation
Deep learning predicts HER2 status in invasive breast cancer from multimodal ultrasound and MRI
Full text linkThe preoperative human epidermal growth factor receptor type 2 (HER2) status of breast cancer is typically determined by pathological examination of a core needle biopsy, which influences the efficacy of neoadjuvant chemotherapy (NAC). However, the highly heterogeneous nature of breast cancer and the limitations of needle aspiration biopsy increase the instability of pathological evaluation. The aim of this study was to predict HER2 status in preoperative breast cancer using deep learning (DL) models based on ultrasound (US) and magnetic resonance imaging (MRI). The study included women with invasive breast cancer who underwent US and MRI at our institution between January 2021 and July 2024. US images and dynamic contrast-enhanced T1-weighted MRI images were used to construct DL models (DL-US: the DL model based on US; DL-MRI: the model based on MRI; and DL-MRI&US: the combined model based on both MRI and US). All classifications were based on postoperative pathological evaluation. Receiver operating characteristic analysis and the DeLong test were used to compare the diagnostic performance of the DL models. In the test cohort, DL-US differentiated the HER2 status of breast cancer with an AUC of 0.842 (95% CI: 0.708–0.931), and sensitivity and specificity of 89.5% and 79.3%, respectively. DL-MRI achieved an AUC of 0.800 (95% CI: 0.660–0.902), with sensitivity and specificity of 78.9% and 79.3%, respectively. DL-MRI&US yielded an AUC of 0.898 (95% CI: 0.777–0.967), with sensitivity and specificity of 63.2% and 100.0%, respectively