Search Results (185)

Obesity and metabolic dysfunction are established risk factors for luminal breast cancer, yet current preclinical models inadequately recapitulate the complex metabolic and immune interactions driving tumorigenesis. To develop and characterize an immunocompetent rat model of luminal breast cancer induced by chronic exposure to a cafeteria diet mimicking Western obesogenic nutrition, female rats were fed a cafeteria diet or standard chow from weaning. Metabolic parameters, plasma biomarkers (including leptin, insulin, IGF-1, adiponectin, and estrone), mammary gland histology, tumor incidence, and gene expression profiles were longitudinally evaluated. Gene expression was assessed by PCR arrays and qPCR. A subgroup underwent dietary reversal to assess the reversibility of molecular alterations. Cafeteria diet induced significant obesity (mean weight 426.76 g vs. 263.09 g controls, p < 0.001) and increased leptin levels without altering insulin, IGF-1, or inflammatory markers. Histological analysis showed increased ductal ectasia and benign lesions, with earlier fibroadenoma and luminal carcinoma development in diet-fed rats. Tumors exhibited luminal phenotype, low Ki67, and elevated PAI-1 expression. Gene expression alterations were time point specific and revealed early downregulation of ID1 and COX2, followed by upregulation of MMP2, THBS1, TWIST1, and PAI-1. Short-term dietary reversal normalized several gene expression changes. Overall tumor incidence was modest (~12%), reflecting early tumor-promoting microenvironmental changes rather than aggressive carcinogenesis. This immunocompetent cafeteria diet rat model recapitulates key metabolic, histological, and molecular features of obesity-associated luminal breast cancer and offers a valuable platform for studying early tumorigenic mechanisms and prevention strategies without carcinogen-induced confounders. Full article

Purpose: Neoadjuvant endocrine therapy (NET) represents a valuable treatment option for hormone receptor-positive (HR+)/HER2-negative breast cancer, particularly in postmenopausal women. This study aimed to evaluate the clinical and histopathological efficacy of NET and to explore early and late changes in Ki-67 and progesterone receptor (PgR) expression as indicators of endocrine response. Methods: A prospective cohort of 127 postmenopausal patients with stage cT1–4N0–3M0 HR+/HER2− breast cancer was enrolled between 2019 and 2021. Patients received NET (mostly letrozole) for a mean of 7.7 months. In 80 cases, a second core biopsy was performed after four weeks. Tumor size, histological grade, and biomarkers (Ki-67, PgR) were assessed pre- and post-treatment. Results: NET led to a significant reduction in tumor size, with median shrinkage of 47.0% (from 32.0 mm to 17.0 mm, p < 0.0001). Breast-conserving surgery (BCS) was performed in 52.2% of patients and lymph node negativity (pN0) was observed in 50.4%. Median Ki-67 decreased from 20.0% at baseline to 5.0% after four weeks (p < 0.0001) and remained low in surgical specimens (median 5.0%, p < 0.0001). In 33.3% of patients, Ki-67 dropped below 2.7%, and 67.0% showed a concordant decrease in both Ki-67 and PgR. PgR expression declined significantly during treatment (p < 0.0001). HER2 status conversion was noted in 6.4% of patients during treatment. Pathological complete response (pCR) occurred in 3.5%, while minimal or moderate residual disease (RCB I–II) was identified in 71.3% of cases. Conclusions: NET effectively reduced tumor burden and histological aggressiveness, enabling higher rates of BCS. Early reduction in Ki-67 and PgR may serve as surrogate markers of endocrine responsiveness, supporting their use for treatment stratification and monitoring during NET in HR+/HER2− breast cancer. Full article

Background and Objectives: The accuracy of breast cancer diagnosis depends on the concordance between imaging features and pathological findings. While BI-RADS (Breast Imaging Reporting and Data System) provides standardized risk stratification, its correlation with histologic grade and immunohistochemical markers remains underexplored. This study assessed the diagnostic performance of BI-RADS 3, 4, and 5 classifications and their association with tumor grade and markers such as ER, PR, HER2, and Ki-67. Materials and Methods: In this prospective study, 67 women aged 33–82 years (mean 56.4) underwent both mammography and ultrasound. All lesions were biopsied using ultrasound-guided 14G core needles. Imaging characteristics (e.g., margins, echogenicity, calcifications), histopathological subtype, and immunohistochemical data were collected. Statistical methods included logistic regression, Chi-square tests, and Spearman’s correlation to assess associations between BI-RADS, histology, and immunohistochemical markers. Results: BI-RADS 5 lesions showed a 91% malignancy rate. Evaluated features included spiculated margins, pleomorphic microcalcifications, and hypoechoic masses with posterior shadowing, and were correlated with histological and immunohistochemical results. Invasive tumors typically appeared as irregular, hypoechoic masses with posterior shadowing, while mucinous carcinomas mimicked benign features. Higher BI-RADS scores correlated significantly with increased Ki-67 index (ρ = 0.76, p < 0.001). Logistic regression yielded an AUC of 0.877, with 93.8% sensitivity and 80.0% specificity. Conclusions: BI-RADS scoring effectively predicts malignancy and correlates with tumor proliferative markers. Integrating imaging, histopathology, and molecular profiling enhances diagnostic precision and supports risk-adapted clinical management in breast oncology. Full article

Background/Objectives: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with poor prognosis, particularly in metastatic cases. The Ki-67 proliferation index is a recognized marker of tumor aggressiveness, yet its role in guiding diagnostic imaging and surgical decision-making remains underexplored. This study evaluates Ki-67’s predictive value for metastasis at diagnosis, leveraging artificial intelligence (AI) to inform personalized, minimally invasive strategies for ACC management. Methods: We retrospectively analyzed 53 patients with histologically confirmed ACC from the Adrenal-ACC-Ki67-Seg dataset in The Cancer Imaging Archive. All patients had Ki-67 indices from surgical specimens and preoperative contrast-enhanced CT scans. Descriptive statistics, t-tests, ANOVA, and multivariable logistic regression evaluated associations between Ki-67, tumor size, age, and metastasis. Random Forest classifiers—with and without the Synthetic Minority Oversampling Technique (SMOTE)—were developed to predict metastasis. A Ki-67-only model served as a baseline comparator. Model performance was assessed using the area under the curve (AUC) and DeLong’s test. Results: Patients with metastatic disease had significantly higher Ki-67 indices (mean 39.4% vs. 21.6%, p < 0.05). Logistic regression identified Ki-67 as the sole significant predictor (OR = 1.06, 95% CI: 1.01–1.12). The Ki-67-only model achieved an AUC of 0.637, while the SMOTE-enhanced Random Forest achieved an AUC of 0.994, significantly outperforming all others (p < 0.001). Conclusions: Ki-67 is significantly associated with metastasis at ACC diagnosis and demonstrates independent predictive value in regression analysis. However, integration with machine learning models incorporating tumor size and age significantly improves overall predictive accuracy, supporting AI-assisted risk stratification and precision imaging strategies in adrenal cancer care. Full article

Terpenes represent a structurally diverse class of natural compounds with increasing scientific interest due to their potential anti-inflammatory properties. This study investigates the in silico binding behavior of six plant-derived terpenes—α-pinene, β-pinene, menthol, camphor, limonene, and linalool—against four key enzymes in the arachidonic acid (AA) metabolic pathway: cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and phospholipase A2 (PLA₂). AA serves as a reference for binding energy comparison. Blind rigid-body molecular docking is performed using AutoDock 4.2 and the Lamarckian Genetic Algorithm, with 100 runs per ligand–enzyme pair and the energy-based selection of optimal poses. The analysis includes binding energy (ΔG), inhibition constants (Ki), root-mean-square deviation (RMSD), and residue-level interactions. Several terpenes exhibit favorable binding energies and inhibition constants across the evaluated enzymes. For COX-1 and COX-2, menthol and camphor show low Ki values, indicating stable binding. Menthol and limonene also show the strongest affinities for PLA₂, exceeding AA. The focus is on compounds with potential to modulate arachidonic acid metabolism. In this context, β-pinene engages the catalytic site of PLA₂, linalool forms multiple contacts within key regions of 5-LOX, and menthol, α-pinene, and β-pinene align with functionally important regions in both COX isoforms. These targeted interactions suggest that the highlighted compounds may selectively interfere with enzymatic activity in inflammation-related pathways. By modulating key steps in AA metabolism, these terpenes may influence the biosynthesis of pro-inflammatory mediators, offering a promising avenue for the development of safer, plant-derived anti-inflammatory agents. The findings lay the groundwork for further experimental validation and the structure-based optimization of terpene-derived modulators. Full article

Background/Objectives: Treatment of locally advanced rectal cancer (LARC) very often requires a neoadjuvant multimodal approach. Neoadjuvant treatment (NAT) encompasses treatments like chemoradiotherapy (CRT), short-course radiotherapy (SCRT), radiotherapy (RT) or a combination of either of these two with additional induction or consolidation chemotherapy, namely total neoadjuvant treatment (TNT). In case of complete radiological and clinical response, the non-operative watch-and-wait strategy can be adopted in selected patients. This strategy is impacted by a regrowth rate of approximately 30%. Predicting biomarkers of tumor response to NAT could improve guidance of clinicians during clinical decision making, improving treatment outcomes and decreasing unnecessary treatment exposure. To this day, there is no validated biomarker to predict tumor response to any NAT strategies in clinical use. Most research focused on CRT neglects the study of other regimens. Methods: We conducted a narrative literature review which aimed at summarizing the status of biomarkers predicting tumor response to NAT other than CRT in LARC. Results: Two hundred and fourteen articles were identified. After screening, twenty-one full-text articles were included. Statistically significant markers associated with improved tumor response pre-treatment were as follows: low circulating CEA levels; BCL-2 expression; high cellular expression of Ku70, MIB-1(Ki-67) and EGFR; low cellular expression of VEGF, hPEBP4 and nuclear β-catenin; the absence of TP53, SMAD4, KRAS and LRP1B mutations; the presence of the G-allel of LCS-6; and MRI features such as the conventional biexponential fitting pseudodiffusion (Dp) mean value and standard deviation (SD), the variable projection Dp mean value and lymph node characteristics (short axis, smooth contour, homogeneity and Zhang et al. radiomic score). In the interval post-treatment and before surgery, significant markers were as follows: a reduction in the median value of circulating free DNA, higher presence of monocytic myeloid-derived suppressor cells, lower presence of CTLA4+ or PD1+ regulatory T cells and standardized index of shape changes on MRI. Conclusions: Responders to neoadjuvant SCRT and RT tended to have a tumor microenvironment with an immune–active phenotype, whereas responders to TNT tended to have a less active tumor profile. Although some biomarkers hold great promise, scarce publications, inconsistent results, low statistical power, and low reproducibility prevent them from reliably predicting tumor response following NAT. Full article

The venom of Nemopilema nomurai jellyfish represents a promising source of bioactive compounds with potential pharmacological applications. In our previous work, we identified two novel angiotensin-converting enzyme (ACE)-inhibitory peptides—IVGRPLANG (896.48 Da) and IGDEPRHQYL (1227.65 Da)—isolated from N. nomurai venom hydrolysates via papain digestion. In this study, we conducted a detailed biochemical and computational characterization of these peptides. The IC₅₀ values were determined to be 23.81 µM for IVGRPLANG and 5.68 µM for IGDEPRHQYL. Kinetic analysis using Lineweaver–Burk plots revealed that both peptides act as competitive ACE inhibitors, with calculated inhibition constants (K_i) of 51.38 µM and 5.45 µM, respectively. To assess the structural stability of the ACE–peptide complexes, molecular dynamics simulations were performed. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analyses provided insights into complex stability, while interaction fraction analysis elucidated key bond types and residue–ligand contacts involved in binding. Furthermore, a network pharmacology approach was employed to predict therapeutic targets within the renin–angiotensin–aldosterone system (RAAS). Eleven target proteins were identified: IVGRPLANG was associated with REN, ACE, CTSB, CTSS, and AGTR2; IGDEPRHQYL was linked to REN, AGT, AGTR1, AGTR2, KNG1, and BDKR2. Molecular docking analyses using HADDOCK software (version 2.4) were conducted for all targets to evaluate binding affinities, providing further insight into the peptides’ therapeutic potential. Full article

Objective: Central neurocytomas (CNs), classified as CNS (central nervous system) grade 2 tumors, are exceptionally rare tumors, accounting for approximately 0.1–0.5% of all intracranial neoplasms, and are typically characterized by a benign clinical course and frequent association with hydrocephalus. This study aims to present a comprehensive analysis of surgical and adjuvant therapies for CN. Methods: The study comprised all patients who underwent microsurgical tumor removal in our center over the past decade (2013–2023). Clinical manifestations, surgical and adjuvant therapy approaches, MRI and histological findings, clinical outcomes, and recurrence-free survival were evaluated. Results: A total of eleven patients (six men, mean age of 28.0 years; five women, mean age of 53.6 years) underwent surgical treatment. Intraventricular tumors were the most common (72.7%, n = 8). The predominant presenting symptoms were headache and visual disturbances. All tumors exhibited contrast enhancement on MRI. Hydrocephalus was present in five patients. The Ki67 proliferation index ranged from 2% to 10%, with nine patients exhibiting Ki67 > 3%. The median recurrence-free survival was 38.0 months (IQR: 25.0–53.0). The most severe postoperative complications included aphasia, hemiparesis, and memory impairment, resulting in a postoperative Karnofsky Performance Status (KPS) below 70% in five patients. Follow-up assessments showed significant symptomatic improvement in all affected patients. Conclusions: Gross total resection is the recommended first-line therapy with favorable neurological outcomes and for atypical CN as well. Adjuvant radiotherapy should be reserved for tumor progression and recurrence. The role of adjuvant chemotherapy remains unclear, but it may be an option for CN with a high proliferation index. Full article

This paper presents a standardized apparatus and method for testing the accuracy of mobile phone apps designed to measure concrete crack widths. The apparatus comprises a standardized crack-width calibration plate (CWCP) and a simulated wall (SW), along with a pose adjusting and fixing device (PAFD) and a spatial distance measuring assemblage (SDMA). The test method employs an innovative two-stage procedure associated with the SDMA to calculate the distances (K_i) from the phone’s four corners to the SW. The phone’s position is adjusted using the PAFD until the four monitored K_i values match the target K_i. An app installed on the phone then measures crack widths on the CWCP. A standard experimental procedure was established to assess the accuracy of a preliminary Android app in measuring concrete crack widths, with results presented and discussed. This apparatus and method, grounded in their underlying physical meaning, can realistically simulate actual engineering conditions precisely and cost-effectively. Full article

Objectives: To assess amide proton transfer weighted (APTw) MR imaging capabilities in differentiating high-grade glial tumors across alpha-thalassemia/mental retardation X-linked (ATRX) expression, tumor-suppressor protein p53 expression (p53), O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation, isocitrate dehydrogenase (IDH) status, and proliferation marker Ki-67 (Ki-67 index) as a preoperative diagnostic aid. Material & Methods: A total of 42 high-grade glioma WHO grade 4 (HGG) patients were evaluated prospectively (30 males and 12 females). All patients were examined using conventional MRI, including the following: T1w-MPRAGE pre- and post-contrast administration, conventional T2w and 3D FLAIR, and APTw imaging with a 3T MR scanner. Receiver operating characteristic (ROC) curves were calculated for the APTw% mean, median, and max signal for the different molecular biomarkers. A logistic regression model was constructed for combined mean and median APTw% signals for p53 expression. Results: The whole-tumor max APTw% signal could significantly differentiate MGMTp from non-MGMTp HGG, p = 0.035. A cutoff of 4.28% max APTw% signal yielded AUC (area under the curve) = 0.702, with 70.6% sensitivity and 66.7% specificity. The mean/median APTw% signals differed significantly in p53 normal versus p53-overexpressed HGG s: 1.81%/1.83% vs. 1.15%/1.18%, p = 0.002/0.006, respectively. Cutoffs of 1.25%/1.33% for the mean/median APTw% signals yielded AUCs of 0.786/0.757, sensitivities of 76.9%/76.9%, and specificities of 50%/66.2%, p = 0.002/0.006, respectively. A logistic regression model with a combined mean and median APTw% signal for p53 status yielded an AUC = 0.788 and 76.9% sensitivity and 66.2% specificity. ATRX-, IDH- wild type (wt) vs. mutation (mut), and the level of Ki-67 did not differ significantly, but trends were found: IDH-wt and low Ki-67 showed higher mean/median/max APTw% signals vs. IDH-mut and high Ki-67, respectively. ATRX-wt vs. mutation showed higher mean and median APTw% signals but lower max APTw% signal. Conclusions: APTw imaging can potentially be a useful marker for the stratification of p53 expression and MGMT status in high-grade glioma in the preoperative setting and potentially aid surgical decision-making. Full article

Diffuse large B-cell lymphoma is a prevalent subtype of adult non-Hodgkin lymphoma; noted for its biological and clinical variability. Background and Objectives: This study seeks to assess the expression and prognostic implications of Ki-67, MYC, and BCL2 utilising immunohistochemistry on a cohort of Romanian patients diagnosed with DLBCL while also addressing the limitations imposed by the absence of fluorescence in situ hybridisation testing in resource-constrained settings. Materials and Methods: A single-centre, retrospective study involved 66 cases of formalin-fixed, paraffin-embedded tissue specimens obtained from patients with this lymphoma. Results: The median age at diagnosis was 61.81 years, with most individuals being 60 years or older; 59.1% of the patients were male. Our study identified that 65.2% of the cases belonged to the non-GCB subtype (ABC). MYC-positive expression was observed in 5 out of 66 cases (7.6%), and BCL2 protein expression exhibited a trend toward statistical significance, indicating a lower overall survival for BCL-2-positive patients. The expression of Ki-67 demonstrated a significant correlation with variations in overall survival (OS) (p < 0.001). Patients with low Ki-67 expression had an average survival duration of 76.39 months, contrasting with individuals exhibiting high Ki-67 expression, with a mean survival of 38.98 months. In conclusion, MYC, BCL2, and Ki-67 may be valuable prognostic indicator biomarkers. Conclusions: The prognostic significance of each biomarker varies based on the established cut-off point value. Future research should examine the relationship between protein biomarkers, morphological characteristics, and clinical outcomes in Romanian patients diagnosed with DLBCL, aiming to elucidate clinical ramifications and foster effective management. Full article

Background: Patients with jejunoileal neuroendocrine tumors (JINETs) can live for many years despite liver metastases. Evidence suggests that tumor heterogeneity is prognostically important, hence the selection of Ki67 hotspots for tumor grading. According to the stepwise metastasis model, clonal hotspots should predominate in the metastases. However, an alternative view holds that the polyclonality of metastases is consistent with origin from genetically heterogeneous clusters of disseminated cells. The shortcomings of Ki67 grading are also being recognized, thus renewing the search for other prognostic parameters. Methods: A 20-year retrospective study that paired JINETs and hepatic metastases was conducted by analyzing them for various parameters. Results: There were 43 patients (mean follow-up of 7.234 years); 14 were dead due to the disease, 22 were alive with the disease, and 7 were alive with no evidence of the disease. Most JI NETs (22/30) were grade 1, eight were grade 2, and none were grade 3. Tumor grades for both the primaries and liver metastases were not prognostic (p-values = 0.1260 and 0.2566, respectively). Seventeen of the 41 JI NETs showed mesenteric fibrogenesis (MF), and 18 had EMVI, with a high level of agreement between these parameters (92.68%) (kappa value 0.85), and both were strongly associated with poor outcomes. Conclusions: JINETs and their liver metastases tend to have low proliferation rates. However, an important mechanism in the metastatic cascade appears to be mesenteric fibrogenesis. It encases vessels, which enhances extramural vascular invasion, thereby conveying clusters of tumor cells to the liver. This supports the polyclonal nature of tumor progression rather than origin from hotspot aberrant clones. Full article

Muscle satellite (stem) cells (MSCs) reside in skeletal muscle and are essential for myogenesis. Thus, MSCs are widely used in cultured meat research. This study aimed to identify substances that promote MSC proliferation and differentiation while maintaining their intrinsic properties, with the long-term goal of replacing fetal bovine serum (FBS) for bovine MSC cultivation. Therefore, this study evaluated the effects of six growth factors (TGF-β, HGF, PDGF, insulin, IGF-1, and EGF) and the cytokine IL-2 on bovine MSCs. Each factor was applied during the proliferation and differentiation of MSCs, and the proliferation rate, differentiation rate, and expression of relevant mRNA and proteins were analyzed. Insulin most effectively promoted MSC proliferation and differentiation. Specifically, insulin increased cell proliferation rates, proliferation markers Ki67 and PCNA expressions, and markers of differentiation, such as myotube formation and creatine kinase activity, alongside the expressions of MYOD, MYOG, and MYH. Furthermore, insulin suppressed low FBS-induced reductions in proliferation and differentiation markers. This study suggests insulin can promote MSC proliferation and differentiation and reduce FBS usage. Thus, this study provides a potential means of cultivating MSCs on a large scale for cultured meat production. Full article

Background/Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the resistant pathogenic microorganisms that poses a global health threat due to its resistance to β-lactam antibiotics where the protein penicillin-binding protein 2a (PBP2a) plays a crucial role in its resistance. This study explores the potential of phytochemicals from Uvaria chamae, a plant with known medicinal properties, to serve as dual-site inhibitors of PBP2a, targeting both the active and allosteric sites. Methods: Phytochemicals previously identified in U. chamae were subjected to molecular docking and molecular dynamics simulations to evaluate their binding affinities and stability at PBP2a’s active and allosteric sites. The compounds’ pharmacokinetic profiles were predicted in silico using SwissADME tools. Root-mean-square deviation (RMSD), radius of gyration, and binding free energy were analyzed for dynamic stability. Results: Among the evaluated compounds, Uvarinol and Dichamanetin demonstrated high binding affinities compared to the co-crystallized ligand and standard antibiotics like ceftaroline. Uvarinol exhibited the highest binding affinity at both sites, with a docking score of −14.94 kcal/mol and a predicted inhibition constant (Ki) of 0.01 nM. Molecular dynamics simulations further confirmed the robust stability of Uvarinol and Dichamanetin, as indicated by consistently lower RMSD values relative to the co-crystallized ligand. Pharmacokinetic predictions revealed favorable drug-likeness and low toxicity, although Uvarinol showed limited gastrointestinal absorption. Conclusions: Uvarinol and Dichamanetin show promise as dual-site PBP2a inhibitors, offering a novel strategy to combat MRSA resistance. Their structural and pharmacokinetic properties make them viable candidates for further development, though experimental validation and formulation optimization are necessary to overcome bioavailability challenges. Full article

Background: In Saudi Arabia, breast cancer is the most common malignancy among women, significantly impacting cancer-related morbidity and mortality. The country’s unique demographics and rapid socioeconomic development contribute to distinct breast cancer patterns. Objective: To analyze demographic and pathological characteristics of breast cancer with an emphasis on associations between the Ki67 proliferation index, tumor stages, and molecular subtypes. Materials and Methods: An analytical cross-sectional study was conducted on 294 breast cancer patients from 2013 to 2019, recruited from the Comprehensive Cancer Center at King Fahad Medical City, Riyadh, Saudi Arabia. A one-way ANOVA and logistic regression were used to identify risk factors associated with elevated Ki67 levels. Significance was set at a 95% confidence level. Results: The mean age of patients was 51.58. Among them, 67% were overweight/obese, 21.1% were diabetic, and 17% were hypertensive. Approximately 28.9% of all tumors were classified as T3, 46.9% as Grade III, and 40% as Stage IV. Invasive ductal carcinomas (83.9%) were the most common. ER, PR, and HER2 expression were positive in 63.4%, 54.3%, and 34.9% of patients, respectively, with a high Ki67 index in 50.7%. As compared to Grade I cancer, grade II cancer increased the likelihood of elevated Ki67 by 41 times (p = 0.001), Grade III cancer by 7.43 times (p = 0.001), and Stage IV cancer by 2.26 times (p = 0.03). Conversely, invasive lobular carcinomas and other cancer types were significantly less likely to have high Ki67 levels (p < 0.05). Conclusions: Elevated Ki67 appeared to predict higher tumor grades and certain molecular subtypes cancer. Full article