Bosnian Journal of Basic Medical Sciences (BJBMS)
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Tumor glucose reprogramming suppresses cuproptosis: A review
Get PDFCuproptosis is a copper-dependent form of regulated cell death that begins when ferredoxin 1 (FDX1) reduces Cu²⁺ to Cu¹⁺, allowing the ion to bind lipoylated enzymes of the tricarboxylic-acid (TCA) cycle, drive protein aggregation, dismantle iron–sulphur clusters and trigger fatal proteotoxic stress. Most tumours, despite accumulating copper, evade this fate through glucose-metabolic rewiring. First, oncogenic stabilisation of hypoxia-inducible factor-1 alpha (HIF-1α) and MYC increases pyruvate dehydrogenase kinase (PDK) activity, which phosphorylates and inactivates the pyruvate dehydrogenase complex (PDC), shrinking the lipoylated target pool in mitochondria and cutting the feed into the TCA cycle. Second, glycolytic signalling suppresses cuproptosis-promoting genes such as FDX1 and dihydrolipoamide S-acetyltransferase while inducing the negative regulator glutaminase (GLS), further lowering copper sensitivity. Third, diversion of glycolytic intermediates into the pentose-phosphate pathway (PPP) supplies abundant nicotinamide adenine dinucleotide phosphate (NADPH), whereas enhanced glutamine catabolism furnishes glutamate; together these fuels expand reduced glutathione (GSH) and metallothionein (MT) pools that chelate Cu¹⁺ and quench reactive oxygen species exactly where cuproptosis is executed. Consequently, glycolysis-dependent cancer cells are far less sensitive to copper-ionophore drugs such as elesclomol or disulfiram than respiration-dependent counterparts, and clinical datasets consistently link high PDK and low PDC-subunit expression with poor prognosis. These insights highlight rational combination strategies: re-activating the TCA cycle with PDK inhibitors, draining PPP- or GLS-driven NADPH/GSH supply, and concurrently delivering copper ionophores could reopen the cuproptotic trap in tumours. Validating such approaches in vivo, charting upstream regulators of FDX1 and mapping crosstalk between cuproptosis and other lethal programmes remain key steps toward exploiting this copper-centred vulnerability in cancer therapy
Sepsis toxicity network reconstruction—Dynamic signaling and multi-organ injury: A review
Get PDFSepsis is a complex systemic disease in which systemic toxicity—arising from inflammation–immune dysregulation, oxidative stress, programmed cell death (apoptosis, pyroptosis, ferroptosis), and metabolic reprogramming—drives multi-organ injury. The aim of this review was to synthesize how signaling pathways evolve within and between key organs (lungs, liver, kidneys, heart) and to evaluate whether multi-omics integration and network modeling can identify critical toxic nodes and predict disease progression. We conducted a narrative review of English-language mechanistic studies published between 2015 and 2025 in PubMed, Web of Science, and Scopus, supplemented by bibliography screening, while excluding case reports, conference abstracts, and non-mechanistic work. The evidence depicts a high-dimensional systemic network that remodels over time, with early pro-inflammatory modules transitioning toward immunosuppression and organ-specific injury patterns, while inter-organ propagation is mediated by damage-associated molecular patterns (DAMPs), exosomes, and metabolites. Oxidative stress and mitochondrial dysfunction, via reactive oxygen species (ROS), couple to pyroptosis and ferroptosis to reinforce toxicity loops, and computational approaches such as dynamic Bayesian networks (DBN) and graph neural networks (GNN) delineate regulatory hubs and support forecasting. Therapeutic progress has concentrated on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), the NOD-, leucine-rich repeat and pyrin domain–containing protein 3 (NLRP3) inflammasome, and glutathione peroxidase 4 (GPX4), alongside artificial intelligence (AI)–assisted personalized toxicity maps and dynamic early-warning systems, though challenges remain in specificity, safety, and resistance. In conclusion, sepsis can be conceived as a temporally staged systemic toxicity network, and when combined with multi-omics, DBN/GNN modeling, and AI-enabled decision support, this framework offers a path toward individualized, mechanism-based care, while requiring rigorous validation to ensure clinical durability
Molecular and immune characteristics of neuroendocrine bladder carcinoma — Implications for diagnosis, prognosis, and therapy: A review
Get PDFNeuroendocrine bladder carcinoma (NEBC) is a rare but highly aggressive histologic subtype of bladder cancer with poor prognosis, often driven by delayed diagnosis and limited therapeutic options; despite widespread use of next-generation sequencing, its cellular origin remains unclear and controversial. We aimed to synthesize up-to-date molecular and immune features of NEBC and translate them into practical guidance for diagnosis and treatment. We performed a narrative review of English-language studies indexed in PubMed and Web of Science (January 2000–August 2025) using predefined keywords, integrating genomic, transcriptomic, immunohistochemical, and clinical outcome data. Key findings indicate frequent co-occurrence and probable common clonal origin with urothelial bladder carcinoma, with hallmark TP53 and RB1 alterations, prevalent APOBEC-driven mutagenesis, and recurrent TERT promoter mutations; tumor mutation burden is heterogeneous but can be high. Despite this, NEBC commonly exhibits an immune-cold or immune-excluded microenvironment characterized by low PD-L1 expression and T-cell dysfunction, which may blunt responses to immune checkpoint inhibitor monotherapy. Diagnostic practice still relies on morphology supported by immunohistochemistry (synaptophysin, chromogranin A, CD56, GATA3), with emerging tools such as INSM1 and a decision-tree model using synaptophysin, CD117, and GATA3 that improve accuracy. Therapeutically, neoadjuvant chemotherapy—most commonly EP or IA—followed by radical cystectomy improves outcomes compared with initial cystectomy alone, while metastatic disease is typically managed with EP chemotherapy and radiotherapy with limited durability. Early data support immunotherapy, particularly immune checkpoint inhibitors, and suggest potential benefit from chemoimmunotherapy; a prospective trial of neoadjuvant anti-PD-L1 plus EP is underway, and antibody-drug conjugates and bladder-sparing multimodality strategies are emerging. In conclusion, comprehensive molecular and immune characterization is critical to refine diagnosis, optimize patient selection, and accelerate prospective trials that evaluate neoadjuvant chemotherapy, chemoimmunotherapy, and targeted approaches in NEBC
Tumor budding in preoperative breast biopsies predicts sentinel lymph node metastasis
Get PDFSentinel lymph node biopsy (SLNB) is a pivotal technique employed to assess the necessity for axillary lymph node dissection (ALND), evaluated during the preoperative phase through clinical and radiological findings. The preoperative identification of sentinel lymph node metastasis has gained paramount importance in the surgical management of breast cancer. Tumor budding (TB) has emerged as a significant prognostic marker across various cancers, including breast cancer, where it is instrumental in detecting lymph node metastasis. This study aims to investigate the role of tumor budding in predicting sentinel lymph node metastasis in preoperative breast biopsies. We included patients diagnosed with breast cancer, specifically those with invasive ductal carcinoma (IDC), who underwent preoperative needle biopsy and subsequent evaluation of postoperative surgical specimens, as well as SLNB at our medical center. The histological slides of these cases were reevaluated, and tumor cell clusters comprising up to four cells were classified as TB. Lymph nodes exhibiting tumor cell involvement, limited to macrometastasis, were classified as positive. A total of 65 patients were enrolled in the study. Among these, 36 patients exhibited TB in their preoperative biopsies, while 29 did not. The median tumor sizes were 20 mm (range: 6–50 mm) in the TB-positive group and 19 mm (range: 2–50 mm) in the TB-negative group (p=0.3). Sentinel lymph node metastasis was detected in 18 patients with TB, compared to only five patients without TB, a difference that was statistically significant (p=0.006). We conclude that evaluating tumor budding in breast tru-cut specimens, in conjunction with clinical and radiological findings, may enhance the preoperative assessment of breast cancer cases requiring SLNB
Dantrolene use across surgical and medical care at Mayo Clinic from 2010 to 2024: Indications, frequency, and value for identifying malignant hyperthermia
Get PDFDantrolene is the definitive treatment for malignant hyperthermia (MH), a rare and life-threatening disorder. This retrospective study aimed to achieve two objectives: (1) to characterize the indications and frequency of dantrolene administration in both medical and surgical settings, and (2) to evaluate whether perioperative dantrolene may serve as a surrogate marker for identifying MH cases. Using pharmacy records, we identified hospitalized patients who received dantrolene between 2010 and 2024. Each recipient underwent a chart review to examine the clinical context of dantrolene administration. A total of 1,199,450 inpatient pharmacy records were reviewed, revealing 118 patients who received dantrolene, resulting in an incidence rate of 1 in 10,165 hospital admissions (95% CI: 1 in 8,488 to 1 in 12,280). Among these, 87 patients (74%) received oral dantrolene: 84 for chronic spasticity, two for neuroleptic malignant syndrome, and one as preoperative prophylaxis due to a history of MH. The remaining 31 patients (26%) received intravenous dantrolene. Seventeen patients received perioperative dantrolene for suspected MH; of these, nine cases (53%) were subsequently clinically confirmed as MH. Based on these findings and the total number of surgical procedures involving general anesthesia (n=885,127), the estimated prevalence of MH following general anesthesia was calculated to be 1 in 98,328 exposures (95% CI: 1 in 51,813 to 1 in 215,054). Dantrolene was administered at an approximate rate of 1 per 10,000 hospital admissions, primarily in oral formulation for chronic spasticity. Among the patients who received perioperative dantrolene, approximately half were confirmed to have MH, resulting in an estimated MH prevalence of 1 in 100,000 patients exposed to general anesthesia
Molecular aspects of Angelman Syndrome: Defining the new path forward
Get PDFAs a rare neuro-genetic disease, Angelman syndrome (AS) affects about 15 to 500 thousand people worldwide. The AS is an imprinting genomic disease characterized by the loss of function of the maternal UBE3A gene, located in the 15q11-q13. This gene encodes a ~100 kDa protein, the Ubiquitin-protein ligase E3A (UBE3A), that participates in the ubiquitination process, one of the post-translational protein modifications. In the brain, under normal conditions, the paternal allele of the UBE3A gene is silenced, with only the maternal allele being active. However, in individuals with AS, the maternal loss of function of this gene leads to the complete absence of UBE3A expression, resulting in multiple pathological features. Clinically, children diagnosed with AS exhibit a characteristic behavioral phenotype, including a happy demeanor, frequent and unmotivated laughter, movement, speech impairment, severe intellectual disability, and sleep problems. Since its discovery in 1965, significant progress has been made in understanding the genetic and pathophysiological aspects of AS. However, despite these advances, the molecular mechanisms underlying the disease remain incompletely understood, and no effective treatment currently exists. Current therapies focus solely on symptom management, and no approach has yet succeeded in reactivating the silenced paternal UBE3A allele. Therefore, this review highlights the epigenetic aspects involved in the AS in order to provide a better understanding and clarification of the mechanisms, hopefully paving the way for future research to improve the treatment of affected individuals
Neoadjuvant immunochemotherapy for resectable esophageal cancer: A study on efficacy and safety
Get PDFThe combination of immunosuppressants and chemotherapy has reshaped the treatment landscape for esophageal cancer (EC). This study aimed to evaluate the effectiveness and safety of a neoadjuvant immunochemotherapy (nICT) regimen in patients with resectable EC. A total of 99 eligible patients were included. Data on patient characteristics, nICT regimens, surgical approaches, postoperative outcomes, adverse events (AEs) related to neoadjuvant therapy and surgery, overall survival (OS), and disease-free survival (DFS) were collected. OS, DFS, and safety were the primary endpoints. Cox regression analysis was used to identify prognostic factors in the overall population. Additionally, exploratory research was conducted to assess the clinical value of blood immune indicators in predicting tumor regression. Following surgery, 99.0% of patients achieved complete resection (R0). After neoadjuvant therapy, the number of patients with stage T0N0 increased, with complete or moderate responses being the most common outcomes according to American Joint Committee on Cancer (AJCC)/ College of American Pathologists (CAP)-tumor regression grading (TRG) evaluations (64.7%). The one-year OS and DFS rates were 91.6% and 49.3%, respectively. Grade ≥3 AEs related to neoadjuvant therapy occurred in 21.2% of patients, with gastrointestinal reactions being the most frequent (16 cases, 16.2%). No treatment-related deaths were reported. Grade ≥3 surgery-related AEs occurred in 10.1% of patients, with anastomotic leakage being the most common (six cases, 6.1%). Several factors were associated with significantly improved OS, including chemotherapy regimens combining paclitaxel with platinum, surgical approaches using laparoscopy or thoracotomy (left or right), an interval of ≤34 days between the last treatment and surgery, and the absence of positive lymph node detection. Higher cT staging was significantly associated with worse DFS. Blood immune markers, such as the neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) were found to predict tumor regression in EC patients. In summary, nICT demonstrated favorable effectiveness and safety in resectable EC. The choice of platinum-based chemotherapy agents, rather than the type of immunosuppressant, was associated with prognosis. Moreover, a shorter interval (≤34 days) between the final nICT administration and surgery was linked to improved outcomes
DPP4 rs17574 polymorphism and elevated DPP4 levels linked to fatty liver in subclinical atherosclerosis: GEA study findings
Get PDFDipeptidyl peptidase-4 (DPP4) concentrations are known to correlate with nonalcoholic fatty liver (FL), which is also associated with subclinical atherosclerosis (SA). This study aimed to determine whether DPP4 concentrations and the DPP4 rs17574 polymorphism are associated with FL in individuals with SA. The study included 378 participants with SA, of whom 143 had FL and 235 did not. DPP4 serum concentrations were measured using a Bioplex system, and DPP4 rs17574 genotypes were determined using TaqMan assays. Logistic regression was used to assess the relationships between FL, DPP4 concentrations, and rs17574 genotypes. Overall, DPP4 concentrations did not differ significantly between individuals with and without FL. No significant differences in DPP4 levels were observed among DPP4 genotypes in the total sample. However, within the FL group, significant differences in DPP4 concentration were observed across genotypes: AA genotype (134 [106–175] ng/mL), AG genotype (128 [114–149] ng/mL), and GG genotype (80 [71–117] ng/mL); P = 0.019. The DPP4 rs17574 polymorphism was associated with FL under a recessive model (P = 0.037). DPP4 concentration was also significantly associated with FL: the likelihood of presenting with FL increased by 6.2% for every 10 ng/mL increase in DPP4 levels (P = 0.009). These findings suggest that DPP4 concentration may serve as a biochemical risk marker for FL in individuals with SA. Moreover, the rs17574 polymorphism may influence DPP4 protein levels, particularly in those with FL. To our knowledge, this is the first study to describe an association between DPP4 concentration, the rs17574 polymorphism, and FL. Assessing DPP4 levels may offer a novel and effective strategy for risk stratification of FL in SA populations
Comprehensive analysis of angiogenesis and stemness-related genes in chemotherapy and immunotherapy of bladder cancer
Get PDFTumor angiogenesis and cancer stem cells (CSCs) are critical features of malignancies. Research has shown that CSCs promote blood vessel formation, while increased vasculature, in turn, supports CSC proliferation—creating a detrimental feedback loop that drives disease progression. However, studies investigating vascularization and stem-like properties in bladder cancer (BLCA) remain limited. In our investigation, we applied clustering techniques and LASSO methodology to assess the significance of vascularization- and stemness-related genes in predicting responses to chemotherapy and immunotherapy in BLCA. Using multivariate Cox regression analysis, we identified Von Hippel–Lindau (VHL) as the primary prognostic marker associated with both vascularization and stem-like traits. Tissue array analysis of 40 BLCA specimens, combined with molecular docking simulations, revealed interactions between HDAC6 and VHL that influence stem-like behavior and angiogenesis in BLCA. Additionally, VHL showed strong correlations with treatment responses to both chemotherapy and immunotherapy in BLCA. In conclusion, our findings highlight the critical role of vascularization- and stemness-related genes in determining therapeutic outcomes in BLCA and underscore the regulatory relationship between VHL and HDAC6 in modulating treatment response
Profiling of sesquiterpenoid fractions from Artemisia annua L. and testing their in vitro anti-SARS-CoV-2 activity
Get PDFThe current state of research on the anti‑SARS‑CoV‑2 potential of artemisinin‑related compounds has identified arteannuin B as a potent inhibitor of the nCoV‑2019BetaCov/Wuhan/WiV04/2019 and BetaCov/Italy/CDG1/2020 strains of the virus. The aim of this work was to fractionate the targeted sesquiterpenoid compounds, arteannuin B and artemisinin, from the complex matrix of the crude ethanolic leaf extract of Artemisia annua L. using high‑speed countercurrent chromatography (HSCCC) and to test the simplified or purified fractions against the genomically characterized Alpha SARS‑CoV‑2 variant in vitro. This is the first detailed in vitro anti‑SARS‑CoV‑2 study using an analytically characterized supercritical fluid extract of A. annua L. The preparative HSCCC method enabled the isolation of purified arteannuin B in a single chromatographic step, which was confirmed by LC‑ESI‑QTOF‑MS/MS. The MS data confirmed the selectivity of the HSCCC method for the targeted fractionation of artemisinin from the complex matrix, as it was successfully separated from the EtOH crude extract without co‑elution with arteannuin B. Antiviral activity determined by quantitative real‑time PCR (qRT‑PCR) yielded half‑maximal effective concentrations (EC₅₀) of 93.7 µg/mL (SC‑CO₂ extract), 173.5 µg/mL (EtOH extract), 187.3 µg/mL (artemisinin knockout fraction), 38.1 µg/mL (arteannuin B fraction), and >100 µg/mL (artemisinin). The arteannuin B fraction was highly active at 50 µg/mL (p < 0.0001) and 100 µg/mL (p < 0.0001), and inhibited the amplification of the SARS‑CoV‑2 N and RdRp genes by 84% and 100%, respectively. An important contribution of this study is the demonstration of the antiviral activity of arteannuin B against the Alpha variant of SARS‑CoV‑2, which is known to have increased infectivity and transmissibility