Search Results (1,023)

Background: This narrative review summarizes recent progress in artificial intelligence (AI), especially radiomics and deep learning, for non-invasive diagnosis and molecular profiling of gliomas. Methodology: A thorough literature search was conducted on PubMed, Scopus, and Embase for studies published from January 2020 to July 2025, focusing on clinical and technical research. In key areas, these studies examine AI models’ predictive capabilities with multi-parametric Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET). Results: The domains identified in the literature include the advancement of radiomic models for tumor grading and biomarker prediction, such as Isocitrate Dehydrogenase (IDH) mutation, O6-methylguanine-dna methyltransferase (MGMT) promoter methylation, and 1p/19q codeletion. The growing use of convolutional neural networks (CNNs) and generative adversarial networks (GANs) in tumor segmentation, classification, and prognosis was also a significant topic discussed in the literature. Deep learning (DL) methods are evaluated against traditional radiomics regarding feature extraction, scalability, and robustness to imaging protocol differences across institutions. Conclusions: This review analyzes emerging efforts to combine clinical, imaging, and histology data within hybrid or transformer-based AI systems to enhance diagnostic accuracy. Significant findings include the application of DL to predict cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletion and chemokine CCL2 expression. These highlight the expanding capabilities of imaging-based genomic inference and the importance of clinical data in multimodal fusion. Challenges such as data harmonization, model interpretability, and external validation still need to be addressed. Full article

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage breakdown, synovial inflammation, and subchondral bone remodeling. Previous studies have shown that cellular communication network factor 3 (CCN3) expression increases with age in cartilage, and its overexpression promotes OA-like changes by inducing senescence-associated secretory phenotypes. This study aimed to investigate the effect of Ccn3 knockout (KO) on OA development using a murine OA model. Destabilization of the medial meniscus (DMM) surgery was performed in wild-type (WT) and Ccn3-KO mice. Histological scoring and staining were used to assess cartilage degeneration and proteoglycan loss. Gene and protein expressions of catabolic enzyme (Mmp9), hypertrophic chondrocyte marker (Col10a1), senescence marker, and cyclin-dependent kinase inhibitor 1A (Cdkn1a) were evaluated. Single-cell RNA sequencing (scRNA-seq) data from WT and Sox9-deficient cartilage were reanalyzed to identify Ccn3⁺ progenitor populations. Immunofluorescence staining assessed CD44 and Ki67 expression in articular cartilage. The effects of Ccn3 knockdown on IL-1β-induced Mmp13 and Adamts5 expression in chondrocytes were examined in vitro. Ccn3 KO mice exhibited reduced cartilage degradation and catabolic gene expression compared with WT mice post-DMM. scRNA-seq revealed enriched Ccn3-Cd44 double-positive cells in osteoblast progenitor, synovial mesenchymal stem cell, and mesenchymal stem cell clusters. Immunofluorescence showed increased CCN3⁺/CD44⁺ cells in femoral and tibial cartilage and meniscus. Ki67⁺ cells were significantly increased in DMM-treated Ccn3 KO cartilage, mostly CD44⁺. In vitro Ccn3 knockdown attenuated IL-1β-induced Mmp13 and Adamts5 expressions in chondrocytes. Ccn3 contributes to OA pathogenesis by promoting matrix degradation, inducing hypertrophic changes, and restricting progenitor cell proliferation, highlighting Ccn3 as a potential therapeutic target for OA. Full article

Although multimodal therapeutic management has significantly improved outcome in prostate cancer (PCa) patients, treatment options for castrate-resistant disease remain challenging. Plant-derived mistletoe extracts have supported cancer patients and are, therefore, widely used as complementary medicine. However, mechanisms behind possible mistletoe benefits to PCa patients remain to be explored. The present study was designed to evaluate the effect of mistletoe extracts from four different host trees (Tiliae, Populi, Salicis, and Crataegi) on the growth and proliferation of PCa cell lines in vitro. PC3, DU145, and LNCaP cells were used to evaluate tumor cell growth (MTT assay) and proliferation (BrdU incorporation assay). Clonogenicity, apoptosis, cell cycle, and cell-cycle-regulating proteins (cyclin-dependent kinases (CDKs) and cyclins) were investigated, as was CD44 standard and splice variant expression and integrin α and β receptors. SiRNA knockdown studies were employed to investigate the functional relevance of integrins. All mistletoe extracts significantly inhibited cell growth in a dose-dependent manner and cell proliferation and clonogenicity were suppressed. Populi and Salicis induced cell-cycle arrest in the G2/M phase and increased apoptosis. Both extracts down-regulated CDK1 and cyclin A and altered CD44 expression. Integrins α5 in all cell lines and α6 in DU145 and LNCaP were particularly diminished. Knocking down α5 and α6 induced cell growth inhibition in DU145. Mistletoe extracts block the growth and proliferation of PCa cells in vitro and therefore qualify for use in future animal studies to evaluate mistletoe as an adjunct to standard PCa treatment. Full article

Colorectal cancer (CRC) remains a major contributor to global cancer-related mortality, with rising incidence observed in several regions, including Saudi Arabia. This review compiles and critically analyzes recent preclinical research from Saudi-based institutions that investigates the anti-CRC potential of natural and synthetic compounds. Numerous natural products such as Nigella sativa, Moringa oleifera, Curcuma longa, and marine-derived metabolites have demonstrated cytotoxic effects through pathways involving apoptosis induction, reactive oxygen species (ROS) generation, and inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and cyclooxygenase-2 (COX-2). In parallel, synthetic and semi-synthetic agents, including C4–G4 (semi-synthetic hybrids designed from flavonoids and benzoxazole scaffolds that act as dual epidermal growth factor receptor (EGFR)/COX-2 inhibitors)), oxazole derivatives, and camptothecin-based nanocarriers, exhibit promising anti-tumor activity via molecular targeting of cyclin-dependent kinase 8 (CDK8), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and β-catenin pathways. Selected in vivo studies primarily utilizing xenograft and chemically induced rodent models have shown reductions in tumor volume and modulation of apoptotic and inflammatory biomarkers. Additionally, green-synthesized metallic nanoparticles (NPs) and polyethylene glycol (PEG)-modified carriers have been investigated to improve bioavailability and tumor targeting of lead compounds. While these findings are encouraging, the majority remain in preclinical phases. Limitations such as poor solubility, lack of pharmacokinetic data, and absence of clinical trials impede translational progress. This review highlights the need for standardized evaluation protocols, mechanistic validation, and region-specific clinical studies to assess efficacy and safety. Given Saudi Arabia’s rich biodiversity and growing research capacity under national strategies like Vision 2030, the country is well-positioned to contribute meaningfully to CRC drug discovery. By integrating bioactive natural products, rationally designed synthetics, and advanced delivery platforms, a pipeline of innovative CRC therapeutics tailored to local and global contexts may be realized. Full article

Protein kinases are important molecules of Alzheimer’s Disease (AD), driving neuronal demise and the emergence of the disease’s destructive hallmarks. Cdk5 has recently been highlighted as a key therapeutic target for AD. This study evaluated the expression levels of Cdk5 and Mcl1 (Cdk5’s substrate) in blood samples of 61 AD, 55 Mild Cognitive Impairment (MCI), and 57 Geriatric Controls (GC), and explored the in vitro inhibition of Cdk5. The serum levels of Cdk5 and Mcl1 were measured by Surface Plasmon Resonance (SPR) and verified by Western blot and RT-PCR. Molecular modeling and simulation studies were used to identify a potent hit targeting Cdk5 and validated by binding studies using SPR. The peptide rescue effect was analyzed by MTT assay in the AD cellular model. SPR analysis revealed a significant change in Cdk5 and Mcl1 levels in the serum samples of AD and MCI compared to GC. Results were validated by Western blot and RT-PCR. Binary logistic regression analysis revealed that the concentration of both Cdk5 and Mcl1 was independently associated with disease after adjusting for certain parameters. ROC analysis established an optimum diagnostic cutoff value for Cdk5 [24.97 ng/µL (AUC-0.90)] and Mcl1 [23.08 ng/µL (AUC-0.94)] with high sensitivity and specificity. The peptide YCWS strongly binds to Cdk5′s ATP binding site, confirmed by molecular modeling and SPR. In the AD cellular model, peptide YCWS rescued neurotoxicity, increased Mcl1 levels, and reduced destructive hallmarks by inhibiting Cdk5. It can be concluded that Cdk5 is a promising molecule as a circulatory biomarker for the diagnosis of the early stages of AD, and its peptide inhibitor YCWS is a potential therapeutic agent. Full article

Cellular senescence plays a critical role in tumorigenesis and is recognized as a hallmark of colorectal cancer (CRC). Emerging evidence suggests that 5-fluorouracil (5-FU)-induced senescence may contribute to chemoresistance and tumor recurrence. Here, we investigated the effect of 5-FU on colon cancer cell senescence and whether MM-129 (pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine sulfonamide) can antagonize this activity. Senescence was identified by the expression of senescence-associated β-galactosidase (SA-β-gal) and cyclin-dependent kinase inhibitor 1A (p21) using qPCR, microscopy, flow cytometry, and immunohistochemistry. We also measured interleukin 6 (IL-6) and tumor necrosis factor (TNF-α) as key SASP cytokines, along with E-cadherin (CDH1), a marker of epithelial integrity. The SIRT1/STAT3 pathway was evaluated to elucidate the mechanism of MM-129′s action. MM-129 counteracted 5-FU-induced senescence in colon cancer models, reducing p21 levels in zebrafish xenografts and the number of SA-β-gal-positive cells in vitro and in tumor tissues from DLD-1 and HT-29 mouse xenografts. MM-129 also inhibited senescence-associated responses by suppressing SASP cytokines (IL-6, TNF-α) and restoring E-cadherin (CDH1), and it modulated the SIRT1/STAT3 axis, which may underlie the observed senotherapeutic effects. In conclusion, MM-129 represents a novel senotherapeutic candidate. By modulating the SIRT1/STAT3 axis, it may suppress the SASP and weaken pro-survival signaling, thereby facilitating selective clearance of senescent cells. Integrating senotherapeutics with conventional cancer therapies may enhance efficacy and open new avenues for translational research. Full article

Background/Objectives: Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with a poor prognosis and limited therapeutic options. This study aimed to repurpose methylstat, a selective histone demethylase inhibitor, as a novel anti-glioma agent. We characterized its anti-proliferative efficacy, elucidated mechanisms of cell cycle regulation, and evaluated its blood–brain barrier (BBB) permeability potential. Methods: Compounds with transcriptional profiles enriched for cell cycle arrest and tumor-suppressive pathways were identified via Connectivity Map (CMAP) analysis. Methylstat was selected based on its high connectivity score and favorable physicochemical properties. In vitro assays were performed to evaluate its effects on cell viability, proliferation, cell cycle progression, and expression of related molecular markers in U251 and HOG glioma cell lines. Molecular docking and 200 ns molecular dynamics (MD) simulations were performed to evaluate the binding mode and stability of the Methylstat–JMJD2A complex. An in vitro BBB model was established to assess the ability of Methylstat to cross the BBB. Results: Methylstat significantly inhibited glioma cell proliferation in a dose-dependent manner without inducing apoptosis. It caused G1-phase arrest in U251 cells and G2-phase arrest in HOG cells. Mechanistically, methylstat downregulated cyclins and cyclin-dependent kinases via the p53/p21 pathway. Additionally, methylstat reduced the expression of JMJD2A and its downstream targets, including PDK1, AKT, and mTOR. Molecular docking studies and 200 ns MD simulations confirmed the stable binding of methylstat to the catalytic pocket of JMJD2A, effectively inhibiting its enzymatic activity. HPLC analysis confirmed that methylstat could penetrate the in vitro BBB model to varying extents. Conclusions: Methylstat is a promising small-molecule agent that effectively suppresses glioma cell growth by modulating key cell cycle regulators. Its ability to cross the BBB highlights its potential as a novel therapeutic strategy for GBM and other brain tumors. Full article

Background/Objectives: Estrogen deficiency-related menopause is associated with various physical and psychological symptoms. Although hormone replacement therapy (HRT) effectively alleviates these symptoms, its long-term use is associated with several side effects such as an increased risk of breast cancer and cardiovascular disease. Consequently, there is a growing interest in some plant-derived phytoestrogens that are considered safer alternatives to estrogen. Recent studies on Scrophularia buergeriana confirmed their anti-inflammatory and antioxidant properties; however, their effects on menopausal health remain unclear. Therefore, the aim of this study was to investigate the estrogen-like effects of S. buergeriana root (SB-R) extract, a potential phytoestrogen. Methods: Briefly, the MCF-7 cell line, a widely used in vitro model for assessing estrogen-like activity, was treated with SB-R extract and 17β-estradiol (E2; positive control) in the presence or absence of ICI 182,780 (Fulvestrant), an estrogen receptor antagonist. An E-screen assay and flow cytometry were performed to assess the effects of the treatments on cell proliferation and the cell cycle, respectively. Additionally, Western blotting and immunofluorescence assays were performed to elucidate the potential mechanisms underlying the estrogen-like effects of SB-R. Result: Treatment with SB-R extract promoted MCF-7 cell proliferation in a manner similar to E2. However, ICI 182,780 co-treatment inhibited the SB-R extract-induced increase in MCF-7 cell proliferation. Additionally, SB-R extract promoted cell cycle progression by increasing the proportion of cells in the S and G2/M phases. Moreover, Western blotting and immunofluorescence assays showed that SB-R extract increased the expression of estrogen receptor alpha (ERα). Furthermore, SB-R treatment activated downstream signaling pathways by enhancing AKT and ERK phosphorylation and upregulated the expression of cell cycle regulators, including cyclin D1, cyclin dependent kinase 4 (CDK4), cyclin E1, and cyclin dependent kinase 2 (CDK2). Conclusions: SB-R exhibits estrogen-like activity by activating ERα-mediated AKT and ERK pathways and thereby increasing the expression of proteins involved in cell cycle regulation. This makes it a promising phytoestrogen candidate and a safer alternative to conventional hormonal therapy for alleviating menopausal symptoms. Full article

Two series of tricyclic thieno[3,2-d]pyrimidines were synthesized, achieving yields of up to 97%. The tricyclic thieno[3,2-d]pyrimidines examined in this study are synthetic analogs of the deoxyvasicinone alkaloids, where the thiophene ring substitutes for the benzene ring. A systematic investigation was conducted on the scaffold-hopping strategy of these alkaloids, emphasizing the selective synthesis and anticancer properties of thieno[3,2-d]pyrimidines. The anticancer evaluation was performed on human cancer cell lines, specifically cervical HeLa and colon HT-29 carcinoma cells. Additional bioassays included cell migration analyses, cell cycle progression, apoptosis, and molecular docking analyses. Furthermore, molecular docking studies showed that the most active small molecule 6e is likely to disrupt the cell cycle process through targeting CDKs (Cyclin-dependent kinases), leading to the inhibition of tumor cell proliferation. Full article

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor in adults, has a poor prognosis due to rapid recurrence and treatment resistance. This review examines the evolution of radiotherapy (RT) for GBM management, from whole-brain RT to modern techniques like intensity-modulated RT (IMRT) and volumetric modulated arc therapy (VMAT), guided by 2023 European Society for Radiotherapy and Oncology (ESTRO)-European Association of Neuro-Oncology (EANO) and 2025 American Society for Radiation Oncology (ASTRO) recommendations. The standard Stupp protocol (60 Gy/30 fractions with temozolomide [TMZ]) improves overall survival (OS) to 14.6 months, with greater benefits in O6-methylguanine-DNA methyltransferase (MGMT)-methylated tumors (21.7 months). Tumor Treating Fields (TTFields) extend median overall survival (mOS) to 31.6 months in MGMT-methylated patients and 20.9 months overall in supratentorial GBM (EF-14 trial). However, 80–90% of recurrences occur within 2 cm of the irradiated field due to tumor infiltration and radioresistance driven by epidermal growth factor receptor (EGFR) amplification, phosphatase and tensin homolog (PTEN) mutations, cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions, tumor hypoxia, and tumor stem cells. Pseudoprogression, distinguished using Response Assessment in Neuro-Oncology (RANO) criteria and positron emission tomography (PET), complicates response evaluation. Targeted therapies (e.g., bevacizumab; PARP inhibitors) and immunotherapies (e.g., pembrolizumab; oncolytic viruses), alongside advanced imaging (multiparametric magnetic resonance imaging [MRI], amino acid PET), support personalized RT. Ongoing trials evaluating reirradiation, hypofractionation, stereotactic radiosurgery, neoadjuvant therapies, proton therapy (PT), boron neutron capture therapy (BNCT), and AI-driven planning aim to enhance efficacy for GBM IDH-wildtype, but phase III trials are needed to improve survival and quality of life. Full article

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder, which is a developmental and epileptic encephalopathy occurring in 1 in every 40,000 to 60,000 live births, was the subject of this computational investigation. This study provided a comprehensive list of missense variants (156) seen in the human population within the CDKL5 protein. Furthermore, the list of CDKL5 binding partners was updated to include four new entries. Computational modeling resulted in 3D structure models of twenty-four CDKL5-target protein complexes. The CDKL5 stability changes upon the above-mentioned missense mutations that were modeled, and it was shown that the corresponding folding free energy changes (ΔΔG_folding) caused by pathogenic variants are much larger than the ΔΔG_folding caused by benign variants. The same observation was made for the binding free energy change (ΔΔG_binding). This resulted in a protocol that allowed for the reclassification of missense variants with unknown or conflicting significance into pathogenic or benign. It was demonstrated that such reclassification is more reliable than using leading tools for pathogenicity predictions, since the latter failed to correctly predict known pathogenic/benign variants. Furthermore, the study demonstrated that pathogenicity is linked with the disturbance of thermodynamics quantities such as ΔΔG_folding and ΔΔG_binding, paving the way for development of therapeutic solutions. Full article

Background: Prostate cancer (PCa) is the primary contributor to male cancer-related mortality and currently lacks effective treatment options. The Modified Guizhi Fuling Decoction (MGFD) is used in clinical practice to treat multiple tumors. This research focused on the mechanisms of action (MOA) in MGFD that inhibit PCa. Methods: The impact of MGFD on PCa cells (PC3 and DU145) was examined via Cell Counting Kit-8, wound healing assays, and transwell assays. To determine the MOA, high-throughput sequencing based high-throughput screening (HTS²) was utilized along with network pharmacology. Results: The findings indicated that MGFD suppressed the proliferation, migration, and invasion of PCa cells. We then utilized the HTS² assay to generate 270 gene expression profiles from PCa cells perturbed by MGFD. Large-scale transcriptional analysis highlighted three pathways closely associated with PCa: the TNF signaling pathway, cellular senescence, and FoxO signaling pathway. Through the combination of network pharmacology and bioinformatics, we discovered four primary targets through which MGFD acts on PCa: AKT serine/threonine kinase 1 (AKT1), Caspase-8 (CASP8), Cyclin-Dependent Kinase 1 (CDK1), and Cyclin D1 (CCND1). Finally, molecular docking demonstrated that the potential bioactive compounds baicalein, quercetin, and 5-[[5-(4-methoxyphenyl)-2-furyl] methylene] barbituric acid strongly bind to CDK1, AKT1, and CASP8, respectively. Conclusions: This research shows that MGFD displays encouraging anticancer effects via various mechanisms. Its multi-target activity profile underscores its promise as a potential therapeutic option for PCa treatment and encourages additional in vivo validation studies. Full article

HER2-positive breast cancer represents a biologically aggressive subtype associate with poor prognosis, despite advances in targeted therapies. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), initially approved for hormone-receptor-positive, HER2-negative disease, are now being explored in HER2-positive settings due to their mechanistic synergy with the HER2 signaling pathway. This review synthesizes evolving clinical evidence from trials and highlights further research into biomarker discovery. CDK4/6i may redefine treatment paradigms in HER2-positive breast cancer, offering a potential, non-chemotherapy option with durable benefit in select patient populations. Full article

Pancreatic neuroendocrine tumors (pNETs) are rare malignancies, accounting for 1–2% of pancreatic cancers, with an incidence of ≤1 case per 100,000 individuals annually. Originating from pancreatic endocrine cells, pNETs display significant clinical and biological heterogeneity. Traditional classification based on proliferative grading does not fully capture the complex mechanisms involved, such as oxidative stress, mitochondrial dysfunction, and tumor-associated macrophage infiltration. Recent advances in molecular profiling have revealed key oncogenic drivers, including MEN1 (menin 1), DAXX (death domain–associated protein), ATRX (alpha thalassemia/mental retardation syndrome X-linked), CDKN1B (cyclin-dependent kinase inhibitor 1B) mutations, chromatin remodeling defects, and dysregulation of the mTOR pathway. Somatostatin receptors, particularly SSTR2, play a central role in tumor biology and serve as important prognostic markers, enabling the use of advanced diagnostic imaging (e.g., Gallium-68 DOTATATE PET/CT) and targeted therapies like somatostatin analogs and peptide receptor radionuclide therapy (PRRT). Established biomarkers such as Chromogranin A and the Ki-67 proliferation index remain vital for diagnosis and prognosis, while emerging markers, like circulating tumor DNA and microRNAs, show promise for enhancing disease monitoring and diagnostic accuracy. This review summarizes the molecular landscape of pNETs and highlights genomic, transcriptomic, proteomic, and epigenomic factors that support the identification of novel diagnostic, prognostic, and therapeutic biomarkers, ultimately advancing personalized treatment strategies. Full article

Cyclin-dependent kinase (CDK)4/6 inhibitors have become a key component of adjuvant treatment for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) early breast cancer who are at high risk of recurrence. The addition of abemaciclib and ribociclib to standard endocrine therapy has demonstrated clinically meaningful improvements in invasive disease-free survival, supported by the monarchE and NATALEE trials, respectively. With expansion of patient eligibility for CDK4/6 inhibitors, multidisciplinary coordination among medical oncologists, surgeons, nurses, pharmacists, and other health care providers is critical to optimizing patient identification, monitoring, and management of adverse events. This expert guidance document provides practical recommendations for implementing adjuvant CDK4/6 inhibitor therapy in routine clinical practice, incorporating insights from multiple specialties and with patient advocacy representation. Key considerations include patient selection based on clinical trial data, treatment duration, dosing schedules, adverse event profiles, monitoring requirements, drug–drug interactions, and patient-specific factors such as tolerability, cost, and quality of life. This guidance aims to support Canadian clinicians in effectively integrating CDK4/6 inhibitors into clinical practice, ensuring optimal patient outcomes through a multidisciplinary and patient-centric approach. Full article