Search Results (4,898)

Deoxynivalenol (DON), a Fusarium-derived mycotoxin widely found in grain-based feed, has become a major global environmental contaminant. Reproductive toxicity is one of its most important toxic effects, yet systematic investigations covering both male and female reproductive injury remain limited. This study aimed to establish a combined strategy of network toxicology, molecular docking, molecular dynamics simulation, and single-cell RNA sequencing to evaluate the reproductive toxicity of DON. AKT1, EGFR, PIK3CA, PIK3R1, and SRC were identified as key targets involved in DON-induced reproductive injury. For testicular injury, the prolactin, Ras, HIF-1, and AGE-RAGE signaling pathways were closely associated with DON toxicity. For ovarian injury, the PI3K-Akt, HIF-1, prolactin, insulin, and AGE-RAGE signaling pathways were strongly implicated. Molecular docking demonstrated favorable binding affinities between DON and the hub targets, while molecular dynamics simulation further confirmed the stability of the DON–PIK3CA complex. Single-cell RNA sequencing analysis revealed that these five hub genes were highly expressed in both testicular (SRA667709:SRS3065430) and ovarian (SRA638923:SRS2797100) tissues. These findings deepen current understanding of DON-induced reproductive toxicity, provide new insights into the effects of environmental toxins on reproductive health, and offer a theoretical basis for future studies integrating DON exposure with in vivo validation of core targets and signaling pathways. Full article

Loss of myelinating oligodendrocytes and myelin impairs motor and cognitive functions. Transplantation of autologous oligodendrocyte precursors (OPCs) holds promise for treatment of such diseases, but a protocol to derive human OPCs from a safe, ethical and accessible cell source with the rapidity required to catch the therapeutic window remains to be found. Although we previously generated myelinating glia from rat bone marrow stromal cells (BMSCs), it remains unknown if clinically sourced human BMSCs (hBMSCs) share the same potential. Moreover, whether the multipotency of BMSCs results from diverse progenitors preexisting in the bone marrow or from a single multipotent progenitor population remains unaddressed. Single-cell RNA sequencing data revealed a CD90^hiEGFR⁺PDGFRA⁺ pre-OPC-like subpopulation within hBMSCs. With a small-molecule-based (virus-free and supporting-cell-free) two-step induction protocol designed to expand this pre-OPC population, we generated functional OPCs with high purity in eight days. These derived OPCs showed phenotypic transcriptomes and immunoprofiles. They were also capable of myelinating naked axons when transplanted into myelin-deficient shiverer mice. Results highlight how targeted enrichment and maturation of specific progenitor subpopulations within hBMSCs allows rapid induction of desired cell types. These results place hBMSCs as a robust source of OPCs, unlocking the possibility for cell transplantation therapy for myelin deficiency in the central nervous system. Full article

Background/Objectives: Breast cancer remains the leading cause of cancer-related death among women worldwide. While tools such as Adjuvant Online, PREDICT, OncotypeDx and Mammoprint identify patients at higher risk of relapse who should therefore be offered chemotherapy, there are currently no tools to accurately predict response to chemotherapy, with varied response rates (regardless of subtypes, etc.) of 8–70% reported. Accurately stratifying patients based on their likelihood of benefiting from SoC chemotherapy is therefore critical to guide personalised treatment decisions. Methods: A retrospective cohort of 293 breast cancer patients treated with SoC adjuvant anthracycline-based regimen was analysed. Five biomarkers (TOP2A, PTEN, EGFR, IGF1R, and phospho-mTOR), selected for their prognostic and therapeutic relevance, were assessed using immunohistochemistry (IHC) combined with digital pathology. Results: Biomarker expression was quantified using the digital pathology platform, QuPath, with each marker, when stratified based on high/low expression, demonstrating a significant association with relapse-free survival following SoC chemotherapy in specific subtypes of breast cancer. A composite five-biomarker signature was then generated by integrating the individual biomarker scores to improve prognostic precision. Patients with a five-biomarker signature score greater than zero exhibited a significantly higher likelihood of favourable outcomes following anthracycline-based chemotherapy compared with those with a score of zero or below. Conclusions: This study establishes a novel IHC-based five-biomarker signature capable of predicting patient outcome in the context of SoC chemotherapy. As the signature relies exclusively on IHC, it is simple, cost-effective and readily integratable into routine diagnostic workflows. In addition to its prognostic value, several biomarkers within the panel are potentially actionable, offering opportunities to guide targeted therapies in patients predicted to have poor response to conventional chemotherapy. Full article

Background and Methods: This prospective observational study investigated the prognostic value of the hemoglobin-to-red cell distribution width ratio (HRR) in 278 patients hospitalized with decompensated heart failure (HF). The primary endpoint was a composite of all-cause mortality or HF rehospitalization at 12 months. Multivariable Cox regression was employed to adjust for risk factors including age, sex, NT-proBNP, LVEF, and eGFR. Results: The median HRR was 0.89. During follow-up, the primary endpoint occurred in 167 (60.1%) patients. Unadjusted analysis showed a lower HRR was significantly associated with reduced event-free survival (log-rank p = 0.027). However, after multivariable adjustment, this association was no longer statistically significant (p = 0.240). Older age and male sex remained independent predictors. Conclusions: In patients with decompensated HF, a lower baseline HRR correlates with increased risk but does not maintain independent prognostic value after adjusting for powerful confounders. HRR may serve as a simple, initial marker of risk rather than an independent predictor. Full article

Background: Our study retrospectively investigated the therapeutic effects of SGLT2 inhibitors on multiple outcomes in patients with Type 2 Diabetes, capitalizing on the agent’s proven benefits in glycemic, cardiovascular, and renal systems. Methods: This retrospective cohort study investigated a total of 200 patients with T2DM, 100 SGLT2I-treated and 100 treated without SGLT2Is. Clinical data were retrieved from the electronic health record system of the hospital. Patients were followed for more than 6 months to assess the effects of SGLT2Is on metabolic, biochemical, and renal parameters. Results: In the SGLT2I-treated cohort, a higher prevalence of males, non-geriatrics, and comorbidities such as HF and ASCVD was observed with greater use of concomitant medications (beta-blockers, antithrombotics, antilipidemics). SGLT2I treatments show a greater reduction in FBG (control: −6.3 mg/dL vs. treatment: −24.2 mg/dL; p ≤ 0.05), HbA1c (control: −0.093% vs. treatment: −0.76%; p ≤ 0.001), weight (control: −0.6 kg vs. treatment: −3.6 kg; p ≤ 0.001), SBP (control: 5.8 mmHg vs. treatment: −9.2 mmHg; p ≤ 0.001), and DBP (control: 2.2 mmHg vs. treatment: −4.7 mmHg; p ≤ 0.05) compared to the control group. The analysis of the mean change in eGFR showed no statistically significant difference in both groups. The SGLT2I’s safety profile was favorable, with no difference in adverse events and no cases of euglycemic ketoacidosis or Fournier’s gangrene. Conclusions: In this study, SGLT2Is demonstrated strong clinical efficacy in improving multiple cardiometabolic parameters without compromising patient safety in short-term follow-up. Large-scale and long-term real-world studies are needed to monitor the long-term safety profile, characterize the incidence of rare adverse events in general clinical practice, and validate results from this study. Full article

Background: The introduction of targeted therapy in oncology has led to several challenges. These medicines are relatively new in clinical practice and are not well known to specialists with regard to adverse drug reactions (ADRs) and potential drug–drug interactions (pDDIs). In addition, cancer affects multiple body systems, including weight loss, anemia, liver and kidney function, depression, and pain. Patients frequently have comorbidities, leading to polypharmacy and the use of special foods, nutritional supplements, and herbal products for self-medication. Identification of pDDIs is essential, as concomitant use of multiple medicinal products increases the risk of ADRs and may compromise treatment. Objective: This study aims to retrospectively review and analyze data on ADRs and pDDIs in the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors and to evaluate the relationship between them. Method: EudraVigilance and UpToDate^® Lexidrug™ application were used to screen suspected ADRs and pDDIs, respectively. Descriptive statistical analysis was performed. Results: After reviewing Line Listing Reports (LLRs) from 2021 to 2023 in EudraVigilance, the number of suspected adverse drug reactions (ADRs) reported was higher when drug interactions classified as risk categories D and X were identified, compared with cases involving EGFR inhibitor monotherapy or other drug combinations. Of the 144 cases involving category D and/or X interactions, 63 demonstrated a possible association with the reported ADRs of EGFR inhibitors. The most common pDDIs detected were erlotinib–ranitidine (14 cases, category D) and osimertinib–amiodarone (13 cases, category D). Conclusions: Although EGFR inhibitors improve overall and progression-free survival in NSCLC, screening for pDDIs before treatment is essential to improve safety and quality of life. Full article

Background: Chronic low-grade inflammation plays a central role in the pathogenesis of type 2 diabetes (T2DM) and its complications. Neopterin, a marker of macrophage activation and Th1-mediated immune response, has been associated with cardiovascular disease and metabolic disorders. However, its relationship with diabetic autonomic neuropathy remains insufficiently investigated. Methods: We conducted a cross-sectional study including 129 participants (93 with T2DM and 36 with obesity without carbohydrate disturbances). Clinical, anthropometric, and biochemical assessments were performed. Cardiovascular autonomic neuropathy was evaluated using Ewing cardiovascular reflex tests and sudomotor dysfunction scoring. Neopterin concentrations were measured in serum. Correlation, ROC, and logistic regression analyses were performed. Results: Neopterin levels were not significantly different between T2DM and obesity groups. No differences were observed in patients with versus without peripheral neuropathy, nephropathy, or retinopathy. However, neopterin levels were significantly higher in individuals with cardiovascular autonomic neuropathy (p = 0.013). Neopterin correlated with cardiovascular autonomic neuropathy score, sudomotor dysfunction, fasting glucose, fasting insulin, and HOMA-IR. It showed a moderate negative monotonic correlation with eGFR (Spearman’s rho = −0.41, p< 0.001). In multivariable logistic regression adjusted for age, HbA1c, BMI, eGFR, and diabetes duration, each 1-SD increase in neopterin was associated with 2.67-fold higher odds of cardiovascular autonomic neuropathy (95% CI 1.21–5.89; p = 0.015). Conclusions: Circulating neopterin is independently associated with cardiovascular autonomic neuropathy in T2DM but not with classical microvascular complications. These findings suggest a potential role of immune-mediated mechanisms in the pathogenesis of diabetic cardiovascular autonomic neuropathy. Full article

Background and Objectives: Combining osimertinib (OSI) with pemetrexed (PEM) can enhance antitumor efficacy; however, the benefit is schedule-dependent. Our previous pharmacodynamic (PD) study showed that concurrent PEM + OSI is limited by OSI-induced G1 arrest, attenuating early PEM cytotoxicity. In contrast, sequential PEM→OSI allows PEM to fully induce S-phase arrest and DNA damage but elicits a pro-survival EGFR rebound; subsequent OSI suppresses this rebound and promotes apoptosis of damaged cells, yielding strong synergy. Here, we investigated whether pharmacokinetic (PK) drug–drug interactions (DDIs) contribute to this synergy and predicted the relative advantage of PEM→OSI versus PEM + OSI under clinically relevant conditions using a PK/PD approach. Method and Results: Potential PK-DDIs were assessed at cellular uptake, plasma exposure, and intratumoral distribution levels. No meaningful PK-DDIs were observed, supporting a primary PD-driven synergy. We integrated mouse PK with in vitro/in vivo PD data to build a mechanistic Quantitative System Pharmacology (QSP)–PK–PD model linking drug disposition to folate biology, Epidermal Growth Factor Receptor (EGFR) signaling, and tumor growth inhibition. The model recapitulated schedule dependence and explained PEM→OSI superiority: PEM initiates damage and EGFR compensatory rebound, after which OSI suppresses EGFR signaling and enhances apoptosis. In contrast, concurrent PEM + OSI induced G1 arrest, reduced the pool of damaged apoptosis-susceptible cells, and weakened the synergy. Global sensitivity analysis identified intrinsic OSI sensitivity and the pro-apoptotic protein Bim as key determinants; reduced OSI sensitivity or Bim activity diminished the advantage of the sequential strategy. The simulations indicated that OSI can start 48 h after PEM exposure (no extended drug holiday is needed) and that the PEM→OSI benefit remains robust across heterogeneity, including BIM-deletion polymorphisms and inter-individual variability in tumor drug sensitivity. Conclusions: This mechanism-based QSP–PK–PD framework connects whole-body PK to core PD processes, explains schedule-dependent synergy, and supports optimization of sequencing intervals and identification of likely responders. Full article

Background: The updated Schwartz and CKiDU25 bedside (SCr-based) formulae for the estimated glomerular filtration rate (eGFR) in children are defined by a constant term (with the latter formula dependent upon age and sex) multiplied by the ratio of patient’s height (m) to SCr (mg/dL). However, the Schwartz formula can severely underestimate the measured GFR (mGFR) at higher mGFR levels. Methods: For a single-center cohort of 92 pediatric kidney transplant recipients, we statistically determined if the log{eGFR} at 1 mo and 6 mo post-transplant might further depend upon patient demographics or height, indicating the inadequacy of these formulae for properly predicting the mGFR. We also determined how the log{SCr} at 1 mo and 6 mo post-transplant might depend upon patient demographics and height, helping to corroborate any arrived-at improved functional form for the eGFR. Results: Overall, our cohort received good-quality donor kidneys; however, both eGFR formulae calculated that the percentage of recipients with an eGFR < 60 mL/min/1.73 m² at 1 mo and 6 mo post-transplant was 26–28%. Furthermore, neither the updated Schwartz nor the CKiDU25 bedside formulae adequately controlled for the influence of patient height on SCr; in fact, the patient height squared was superior to its unidimensional value at accounting for the sharp increase in SCr that normally occurs as children grow from infancy to young adulthood (p < 0.000001 at mo1, p = 0.000003 at mo6 for the updated Schwartz bedside formula; p = 0.0009 at mo1, p = 0.005 at mo6 for the CKiDU25 bedside formula). The log{SCr} was also best fitted by a linear regression model that controlled for the log{patient height squared} (p < 0.000001 at both mo1 and mo6). Conclusions: A statistically more accurate eGFR formula should be based on using a power function (power > 1) for patient height rather than its unidimensional value. Full article

Background/Objectives: Cardiorenal syndrome type 2 (CRS-2) is characterized by progressive renal dysfunction caused by chronic heart failure (HF) and is associated with increased morbidity and mortality. However, the prognostic value of renal biomarkers in patients with CRS-2 hospitalized for decompensated HF remains unclear. Methods: This prospective observational cohort study included 200 consecutive patients hospitalized for decompensated HF in the Intensive Care Unit of the Clinic for Internal Medicine at the University Clinical Centre Tuzla between April and October 2025. CRS-2 was defined as chronic HF with chronic kidney disease persisting for ≥3 months before admission according to KDIGO criteria. Patients were followed for three months. The primary composite outcome was all-cause mortality or initiation of renal replacement therapy. Results: CRS-2 was identified in 130 patients (65.0%) and was associated with higher in-hospital mortality (32.3% vs. 11.4%, p = 0.002) and three-month mortality (44.6% vs. 21.4%, p = 0.002). Within the CRS-2 subgroup, patients who experienced the primary composite outcome had higher admission levels of cystatin C and urinary albumin-to-creatinine ratio (UACR) and lower estimated glomerular filtration rate (eGFR). ROC analysis demonstrated moderate discriminative ability of cystatin C (AUC 0.739) and UACR (AUC 0.733). In Cox regression analysis, cystatin C (HR 1.534, 95% CI 1.263–1.863, p < 0.001) and UACR (HR 1.003, 95% CI 1.001–1.006, p = 0.001) were significantly associated with the primary composite outcome. Conclusions: Renal dysfunction markers, particularly cystatin C and albuminuria, are associated with early adverse outcomes in CRS-2 patients hospitalized for decompensated HF. Routine assessment of these biomarkers may provide additional prognostic information and support risk assessment in this high-risk population. Full article

Metastatic colorectal cancer (mCRC) accounts for 90% of CRC-related mortality. This review synthesizes insights from comparative genomics tracing evolutionary trajectories from primary tumor to disseminated disease. Multi-region sequencing reveals metastatic seeding often occurs early—before clinical detection—challenging linear progression models. The metastatic bottleneck reduces clonal diversity while enriching for dissemination-competent traits including SMAD4 loss, PTEN inactivation and metabolic reprogramming. Organ-specific adaptation yields distinct molecular signatures: liver metastases exhibit Wnt hyperactivation and TGF-β-driven immune suppression; peritoneal tumors display mucinous features; brain metastases show HER2 enrichment. The immune microenvironment evolves toward immunosuppressive configurations, with Microsatellite instability high (MSI-H) tumors acquiring B2M or JAK1/2 mutations. Circulating tumor DNA (ctDNA) enables real-time tracking of clonal dynamics, detecting molecular residual disease months before radiographic progression. Therapeutic resistance follows predictable evolutionary trajectories—from RAS/BRAF mutations to EGFR ectodomain alterations, HER2/MET amplifications and lineage plasticity—with metastasis-specific mechanisms including microenvironmental protection and cellular dormancy. The clinical future lies in interception: leveraging liquid biopsies for early detection, targeting both tumor-intrinsic vulnerabilities and permissive metastatic niches and adapting therapy dynamically to anticipate resistance. Understanding this genomic odyssey is essential for transforming mCRC into a controllable chronic condition. Full article

Background: Hyperuricemia frequently coexists with type 2 diabetes mellitus (T2DM), contributing to a heterogeneous patient population. While previous analyses compared the overall longitudinal effects of allopurinol and SGLT2 inhibitors in this cohort, it remains unclear whether baseline metabolic heterogeneity modifies treatment response. This study aimed to determine whether data-driven metabolic clustering identifies phenotypic subgroups with prognostic or predictive relevance in hyperuricemic T2DM. Methods: In a retrospective cohort of 224 patients with T2DM and hyperuricemia, model-based clustering was applied to age, diabetes duration, body mass index (BMI), serum uric acid (sUA), HbA1c, eGFR, and sex. A sensitivity analysis excluded outliers, yielding 207 patients. Longitudinal trajectories of eGFR and sUA were assessed using linear mixed-effects models and individual slopes. Effect modification by cluster was tested via three-way interactions and analysis of covariance. Results: Clustering identified two groups with weak separation: an adipose–metabolic cluster (n = 116; exclusively male, BMI 33.1 ± 5.7 kg/m², sUA 478 ± 62 µmol/L) and a lean–metabolic cluster (n = 91; exclusively female, BMI 31.3 ± 6.0 kg/m², sUA 426 ± 67 µmol/L). Treatment-agnostic analyses showed no differences in eGFR and sUA slopes or in all-cause mortality across clusters. In both clusters, SGLT2 inhibitors yielded significantly more favourable eGFR slopes than allopurinol, while sUA reductions were comparable across treatments. No significant three-way interactions were detected. Conclusions: In this cohort, although baseline metabolic characteristics differ among patients, using the selected baseline variables, no clinically actionable treatment-relevant phenotypes were identified. Full article

Loss of epithelial polarity is a critical driver of tumor progression; however, how core polarity regulators interface with oncogenic signaling pathways in hepatocellular carcinoma (HCC) remains incompletely defined. LLGL scribble cell polarity complex component 1 (LLGL1) is an evolutionarily conserved polarity protein with well-established tumor-suppressive roles in multiple epithelial malignancies. Nevertheless, how LLGL1 loss shapes oncogenic signaling outputs and cellular phenotypes in HCC remains unclear. In this study, we investigated the consequences of LLGL1 knockout (KO) in epithelial-like Huh-7 HCC cells. LLGL1 loss resulted in enhanced proliferative capacity and increased clonogenic potential, accompanied by altered cell-cycle distribution characterized by reduced G1-phase and increased S-phase fractions (p < 0.001). At the signaling level, LLGL1 KO cells displayed potentiated EGFR-driven RAS/MAPK pathway activation, with increased EGFR phosphorylation, enhanced downstream RAF1–MEK–ERK–RSK signaling, elevated EGFR abundance, and selective modulation of RAF1 protein levels. Functionally, LLGL1 loss markedly enhanced migratory and invasive behavior (p < 0.0001). Despite increased motility, LLGL1 KO cells exhibited remodeling of epithelial–mesenchymal transition (EMT)-associated markers without evidence of a classical EMT program. Collectively, these findings position LLGL1 loss as a central factor associated with altered MAPK signaling, EMT marker remodeling, and tumor-promoting cellular phenotypes in HCC. Full article

Background: Chronic kidney disease (CKD) affects up to 40% of patients with diabetes mellitus and has important implications for metformin safety. Although estimated glomerular filtration rate (eGFR)-based dosing is recommended, there is no consensus on the optimal estimating equation, which may lead to inconsistent treatment decisions. Methods: This retrospective study analyzed 46,788 Thai patients with diabetes from 2014 to 2024. eGFR was calculated using five equations, and CKD stages and metformin eligibility were evaluated according to U.S. FDA and KDIGO guidelines. Results: Median eGFR differed significantly across equations (p-value < 0.001), with the highest values observed using CKD-EPI 2009 and the lowest using Cockcroft–Gault. Among 30,805 metformin users, 0.6–3.7% had eGFR < 30 mL/min/1.73 m² depending on the equation used. Agreement with CKD-EPI 2009 ranged from 96 to 99 than 1% (≈3% with Cockcroft–Gault) were unnecessarily excluded from metformin therapy. CKD-EPI 2021 yielded approximately 4.5 mL/min/1.73 m² higher eGFR values, reclassifying 19% of patients to a better CKD stage. Conclusions: Differences among eGFR equations affect CKD staging and metformin eligibility. CKD-EPI 2009, CKD-EPI 2021, S-MDRD, and Thai GFR showed good agreement, whereas Cockcroft–Gault may underestimate renal function, potentially excluding patients who could safely continue metformin. Until outcome data are available, the widely used CKD-EPI equation remains the preferred reference due to its consistency with other standard equations. Further prospective studies are needed to evaluate the clinical impact of equation choice on metformin management. Full article

Oral squamous cell carcinoma (OSCC) remains a major global health burden due to aggressive invasion, early metastasis, therapeutic resistance, and poor long-term survival. Beyond tumor-intrinsic genetic and epigenetic alterations, accumulating evidence highlights the critical role of the tumor microenvironment in shaping OSCC progression and clinical outcomes. Cancer-associated fibroblasts (CAFs) and immune cells orchestrate tumor initiation, immune evasion, and recurrence through extracellular matrix remodeling, cytokine signaling, angiogenesis, and metabolic and redox regulation. Key oncogenic pathways, including EGFR/PI3K/AKT/mTOR, TGF-β, Wnt, and Notch, integrate with non-coding RNA networks to reinforce stemness, epithelial–mesenchymal transition, and therapy resistance. Moreover, PD-1/PD-L1-mediated immune escape, CAF-driven biomechanical remodeling, and metabolic reprogramming such as aerobic glycolysis and lipid metabolism contribute to OSCC heterogeneity. This review synthesizes current insights into OSCC across genomic, epigenetic, metabolic, and microenvironmental dimensions, emphasizing CAF biology, immune landscape reprogramming, and non-coding RNA regulation. We further discuss emerging biomarkers, liquid biopsy approaches, and targeted therapeutic strategies, providing a system-level framework for biomarker-guided stratification and precision combination therapies in OSCC. Full article