PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection

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  • Article
    A Physics-Informed Neural Network (PINN) Approach to Over-Equilibrium Dynamics in Conservatively Perturbed Linear Equilibrium Systems
    (MDPI, 2025) Dutta, Abhishek; Mukherjee, Bitan; Hosen, Sk Aftab; Turan, Meltem; Constales, Denis; Yablonsky, Gregory
    Conservatively perturbed equilibrium (CPE) experiments yield transient concentration extrema that surpass steady-state equilibrium values. A physics-informed neural network (PINN) framework is introduced to simulate these over-equilibrium dynamics in linear chemical reaction networks without reliance on extensive time-series data. The PINN incorporates the reaction kinetics, stoichiometric invariants, and equilibrium constraints directly into its loss function, ensuring that the learned solution strictly satisfies physical conservation laws. Applied to three- and four-species reversible mechanisms (both acyclic and cyclic), the PINN surrogate matches conventional ODE integration results, reproducing the characteristic early concentration extrema (maxima or minima) in unperturbed species and the subsequent relaxation to equilibrium. It captures the timing and magnitude of these extrema with high accuracy while inherently preserving total mass. Through the physics-informed approach, the model achieves accurate results with minimal data and a compact network architecture, highlighting its parameter efficiency.
  • Article
    Investigation of Few-Layer Graphene-Ubiquitin Interactions with Optical Spectroscopy Techniques
    (MDPI, 2025) Gencay, Burcu; Guler, Gunnur
    Understanding the molecular mechanisms of protein-nanoparticle interactions is crucial for enabling the development of new applications in biomedicine and nanotechnology. Ubiquitin, an important and structurally small functional protein, plays a central role in numerous cellular processes. Therefore, in the current study, we focused on the few-layer graphene (FLG)-Ubiquitin complexes formed by exfoliating FLG structures using only water. Optical spectroscopic techniques (Raman, FT-IR, UV-Vis and circular dichroism) were employed to investigate these complexes on the molecular level. Overall, both CD and FT-IR data reveal that the formation of the FLG-Ubiquitin complexes occurred without inducing disordered structures in the protein. Based on the existence of a blue shift (hypsochromic shift) in the UV-Vis data, the presence of a single tyrosine and two phenylalanine residues in ubiquitin enables the detection of FLG-induced micro-environmental changes, particularly influencing the protein's beta-sheet and alpha-helix structures. The CD spectral results and CDPro quantitative estimations are in line with ATR FT-IR results, confirming the absence of disordered structure formation while altering the protein's chirality. UV-Vis and CD spectroscopy results revealed concentration-dependent trends consistent with FLG-protein interactions that preserve the overall protein structure. This study has potential applications in both academic research and practical usage, particularly in biomedicine and nanotechnology specifically for FLG.
  • Article
    Characterisation of Electro-Brush Plated Nickel Coatings on P-Type (Zr,ti)co Half-Heusler Thermoelectric Materials for Stable Contact Layers
    (MDPI, 2025) Gurtaran, Mikdat; Zhang, Zhenxue; Li, Xiaoying; Dong, Hanshan
    In this study, a highly conductive nickel (Ni) layer was deposited onto a P-type (Zr,Ti)Co(Sn,Sb) half-Heusler (HH) thermoelectric (TE) material using a low-cost electro-brush plating technique. Before depositing Ni on the TE material, the plating process was optimised on a stainless steel (SS) substrate. An optimal medium-rate deposition voltage of 6V was identified on the SS substrate, with the desired thickness, superior mechanical performance, reduced sheet resistance and surface roughness, and enhanced electrical conductivity. The optimised deposition condition was then applied to the P-type (Zr,Ti)Co(Sn,Sb) material, resulting in a Ni layer that significantly enhanced its electrical and thermal stability. After thermal exposure at 500 degrees C for 10 h, the Ni coating effectively protected the TE surface against oxidation and sublimation, suggesting that the interfacial contact properties of P-type (Zr,Ti)Co(Sn,Sb) TE material can be effectively enhanced by depositing a highly conductive, oxidation-resistant Ni layer using the cost-effective, straightforward electro-brush plating technique.
  • Article
    Locoregional Treatment in De Novo Bone-Only Metastatic Breast Cancer: Prospective, Multi-Institutional Real-World Data, BOMETIN, Protocol MF14-1a
    (MDPI, 2025) Soran, Atilla; Demirors, Berkay; Aytac, Ozgur; Ozbas, Serdar; Dogan, Lutfi; Lucci, Anthony
    Introduction: The impact of locoregional treatment (LRT) on survival in de novo bone-only metastatic breast cancer (dnBOMBC) is controversial. This study aims to assess the effect of LRT on survival, utilizing international, prospectively acquired data in this cohort of patients. Materials and Methods: Patients with dnBOMBC were divided into two groups: those receiving systemic therapy only (ST) and those undergoing LRT. Further, patients who received LRT were divided into two subgroups: those who received ST after LRT (LRT+ST group) and those who received ST prior to LRT (ST+LRT group). Factors associated with disease progression, including solitary or multiple bone metastases, were analyzed. Results: There was a total of 744 patients with dnBOMBC treated at each of the participating institutions between 2014 and 2022, with 372 (50%) participants in each arm. Median follow-up was 48 months (32-66, 25-75%). Patients in the LRT group were significantly younger than the ST group [50 (42, 60) vs. 55 (44, 66), p = 0.0001]. There were no significant differences in grade, HER2 status, triple-negative status, receipt of hormonal therapy, or intervention to metastatic sites. During follow-up, 58% (n = 217) of patients in the ST group and 32% (n = 120) of patients in the LRT group died (p < 0.001). Local progression was observed in 20% of the patients in the ST group, whereas 9% progressed in the LRT group (p = 0.0001). Systemic progression occurred more in the ST group; 66% (n = 244) compared to 41% (n = 152) of patients in the LRT group (p < 0.001). The hazard of death was 64% lower in the LRT group than in the ST group (HR: 0.36, 95% CI: 0.29-0.45, p < 0.0001). The burden of metastatic disease differed significantly between the two groups, with a higher rate of solitary bone metastases in the LRT group compared to the ST group (50% vs. 24%, p < 0.001). However, the LRT group had better overall survival (OS) for both solitary (HR: 0.38, 95% Cl: 0.26-0.55) and multiple (HR: 0.38, 95% Cl: 0.29-0.51) bone metastasis patients. Within the LRT group, survival rates were similar whether the breast surgery was performed before or after ST. Multivariate Cox analysis showed that LRT and ER/PR positivity significantly decrease the hazard of death (p < 0.05). Conclusions: Analysis of this large multi-institutional patient cohort provides further evidence that LRT is associated with longer OS and lower locoregional recurrence rates in patients with dnBOMBC. In breast cancer patients with bone-only metastases at presentation, the decision for LRT should be made through a multidisciplinary approach with consideration of surgical therapy at the primary tumor.
  • Article
    Citation - WoS: 1
    Citation - Scopus: 1
    A Pragmatic Grouping Model for Bone-Only De Novo Metastatic Breast Cancer (MetS Protocol MF22-03)
    (MDPI, 2025) Goktepe, Berk; Demirors, Berkay; Senol, Kazim; Ozbas, Serdar; Sezgin, Efe; Lucci, Anthony; Soran, Atilla
    De novo metastatic breast cancer (dnMBC) accounts for 3-10% of newly diagnosed cases, with 20-40% presenting as a bone-only metastatic disease, which can achieve survival outcomes exceeding 10 years with multimodal therapy. However, the role of multimodal therapy remains controversial in the guidelines. Objective: This study aims to identify dnBOMBC subgroups to develop a pragmatic staging system for guiding locoregional therapy decisions. Materials and Methods: Data from the MF07-01 phase III randomized trial (2021, median follow-up time (mFT): 40 months (range 1-131)) and the BOMET prospective multi-institutional registry trial (2021, mFT: 34 months (range 25-45)) were combined for analysis, including only patients who presented with bone-only metastases. Exclusion criteria were patients under 18 and those with a history of prior cancer or cancer metastases. Patients with missing data and positive surgical margins were excluded. Out of 770 patients, 589 were included. Survival analyses were first conducted according to molecular subgroups, after which patients were further stratified by hormone receptor status, human epidermal human epidermal growth factor receptor 2 (HER2) status, tumor grade, and clinical T (cT) stage. Group A (GrA) included hormone receptor (HR)-positive, low- or intermediate-grade tumors at any cT; HR-positive, high-grade tumors with cT0-3; or any HER2-positive tumors. Group B (GrB) included HR-positive, high-grade tumors with cT4 disease or any triple-negative (TN) tumors. Results: The hazard of death (HoD) was 43% lower in GrA than in GrB. Median OS was 65 months (39-104) for GrA patients and 44 months (28-72) for GrB patients (HR 0.57, 95% CI 0.41-0.78, p = 0.0003). Primary tumor surgery (PTS) significantly improved OS in GrA patients, regardless of the number of metastases (solitary: HR, 0.375, 95% CI 0.259-0.543, p < 0.001; multiple: HR 0.435, 95% CI 0.334-0.615, p < 0.001). Conversely, GrB patients did not experience a significant benefit from PTS. Conclusions: This study demonstrates that GrA patients have better OS than GrB patients, and PTS reduces the HoD in GrA patients compared to systemic therapy alone. These findings support using a modified staging system in dnBOBMC to identify patients who may benefit from multimodal therapy including PTS.
  • Article
    Role of Long Non-Coding RNA X-Inactive Transcript (XIST) in Neuroinflammation and Myelination: Insights From Cerebral Organoids and Implications for Multiple Sclerosis
    (MDPI, 2025) Pepe, Nihan Aktas; Acar, Busra; Zararsiz, Gozde Erturk; Guner, Serife Ayaz; Sen, Alaattin
    Background/Objectives: X-inactive-specific transcript (XIST) is a factor that plays a role in neuroinflammation. This study investigated the role of XIST in neuronal development, neuroinflammation, myelination, and therapeutic responses within cerebral organoids in the context of Multiple Sclerosis (MS) pathogenesis. Methods: Human cerebral organoids with oligodendrocytes were produced from XIST-silenced H9 cells, and the mature organoids were subsequently treated with either FTY720 or DMF. Gene expression related to inflammation and myelination was subsequently analyzed via qRT-PCR. Immunofluorescence staining was used to assess the expression of proteins related to inflammation, myelination, and neuronal differentiation. Alpha-synuclein protein levels were also checked via ELISA. Finally, transcriptome analysis was conducted on the organoid samples. Results: XIST-silenced organoids presented a 2-fold increase in the expression of neuronal stem cells, excitatory neurons, microglia, and mature oligodendrocyte markers. In addition, XIST silencing increased IL-10 mRNA expression by 2-fold and MBP and PLP1 expression by 2.3- and 0.6-fold, respectively. Although XIST silencing tripled IBA1 protein expression, it did not affect organoid MBP expression. FTY720, but not DMF, distinguished MBP and IBA1 expression in XIST-silenced organoids. Furthermore, XIST silencing reduced the concentration of alpha-synuclein from 300 to 100 pg/mL, confirming its anti-inflammatory role. Transcriptomic and gene enrichment analyses revealed that the differentially expressed genes are involved in neural development and immune processes, suggesting the role of XIST in neuroinflammation. The silencing of XIST modified the expression of genes associated with inflammation, myelination, and neuronal growth in cerebral organoids, indicating a potential involvement in the pathogenesis of MS. Conclusions: XIST may contribute to the MS pathogenesis as well as neuroinflammatory diseases such as and Alzheimer's and Parkinson's diseases and may be a promising therapeutic target.
  • Article
    Citation - WoS: 21
    Citation - Scopus: 22
    High-Dose Exposure To Polymer-Coated Iron Oxide Nanoparticles Elicits Autophagy-Dependent Ferroptosis in Susceptible Cancer Cells
    (MDPI, 2023) Lomphithak, Thanpisit; Helvacıoğlu, Selin; Armenia, Ilaria; Keshavan, Sandeep; Ovejero, Jesus G.; Baldi, Giovanni; Ravagli, Costanza; Grazú, Valeria; Fadeel, Bengt
    Ferroptosis, a form of iron-dependent, lipid peroxidation-driven cell death, has been extensively investigated in recent years, and several studies have suggested that the ferroptosis-inducing properties of iron-containing nanomaterials could be harnessed for cancer treatment. Here we evaluated the potential cytotoxicity of iron oxide nanoparticles, with and without cobalt functionalization (Fe2O3 and Fe2O3@Co-PEG), using an established, ferroptosis-sensitive fibrosarcoma cell line (HT1080) and a normal fibroblast cell line (BJ). In addition, we evaluated poly (ethylene glycol) (PEG)-poly(lactic-co-glycolic acid) (PLGA)-coated iron oxide nanoparticles (Fe3O4-PEG-PLGA). Our results showed that all the nanoparticles tested were essentially non-cytotoxic at concentrations up to 100 mu g/mL. However, when the cells were exposed to higher concentrations (200-400 mu g/mL), cell death with features of ferroptosis was observed, and this was more pronounced for the Co-functionalized nanoparticles. Furthermore, evidence was provided that the cell death triggered by the nanoparticles was autophagy-dependent. Taken together, the exposure to high concentrations of polymer-coated iron oxide nanoparticles triggers ferroptosis in susceptible human cancer cells.
  • Article
    Citation - WoS: 9
    Citation - Scopus: 8
    Astragalus Saponins, Astragaloside Vii and Newly Synthesized Derivatives, Induce Dendritic Cell Maturation and T Cell Activation
    (MDPI, 2023) Yakuboğulları, Nilgün; Çağır, Ali; Bedir, Erdal; Sağ, Duygu
    Astragaloside VII (AST VII), a triterpenic saponin isolated from Astragalus species, shows promise as a vaccine adjuvant, as it supported a balanced Th1/Th2 immune response in previous in vivo studies. However, the underlying mechanisms of its adjuvant activity have not been defined. Here, we investigated the impact of AST VII and its newly synthesized semi-synthetic analogs on human whole blood cells, as well as on mouse bone marrow-derived dendritic cells (BMDCs). Cells were stimulated with AST VII and its derivatives in the presence or absence of LPS or PMA/ionomycin and the secretion of cytokines and the expression of activation markers were analyzed using ELISA and flow cytometry, respectively. AST VII and its analogs increased the production of IL-1β in PMA/ionomycin-stimulated human whole blood cells. In LPS-treated mouse BMDCs, AST VII increased the production of IL-1β and IL-12, and the expression of MHC II, CD86, and CD80. In mixed leukocyte reaction, AST VII and derivatives increased the expression of the activation marker CD44 on mouse CD4+ and CD8+ T cells. In conclusion, AST VII and its derivatives strengthen pro-inflammatory responses and support dendritic cell maturation and T cell activation in vitro. Our results provide insights into the mechanisms of the adjuvant activities of AST VII and its analogs, which will be instrumental to improve their utility as a vaccine adjuvant. © 2023 by the authors.
  • Review
    Citation - WoS: 96
    Citation - Scopus: 112
    Therapeutic Potential of Luteolin on Cancer
    (MDPI, 2023) Çetinkaya, Melisa; Baran, Yusuf
    Cancer is a global concern, as the rate of incidence is increasing each year. The challenges related to the current chemotherapy drugs, such as the concerns related to toxicity, turn to cancer therapeutic research to discover alternative therapy strategies that are less toxic to normal cells. Among those studies, the use of flavonoids-natural compounds produced by plants as secondary metabolites for cancer therapy-has been a hot topic in cancer treatment. Luteolin, a flavonoid that has been present in many fruits, vegetables, and herbs, has been identified to exhibit numerous biological activities, including anti-inflammatory, antidiabetic, and anticancer properties. The anticancer property of Luteolin has been extensively researched in many cancer types and has been related to its ability to inhibit tumor growth by targeting cellular processes such as apoptosis, angiogenesis, migration, and cell cycle progression. It achieves this by interacting with various signaling pathways and proteins. In the current review, the molecular targets of Luteolin as it exerts its anticancer properties, the combination therapy that includes Luteolin with other flavonoids or chemotherapeutic drugs, and the nanodelivery strategies for Luteolin are described for several cancer types.
  • Article
    Citation - WoS: 4
    Citation - Scopus: 4
    Interferon Gamma-Inducible Nampt in Melanoma Cells Serves as a Mechanism of Resistance To Enhance Tumor Growth
    (MDPI, 2023) Barba, Cindy; Ekiz, Hüseyin Atakan; Tang, William Weihao; Ghazaryan, Arevik; Hansen, Mason; Lee, Soh-Hyun; Voth, Warren Peter
    Simple Summary The tumor microenvironment is complex, with interacting immune and tumor cells. Immune cells release inflammatory cytokines, including interferons (IFNs), that drive tumor clearance. However, evidence suggests that tumor cells can also utilize IFNs to enhance growth and survival in certain cases. We demonstrate that interferon gamma (IFN gamma) mediates the metabolic reprogramming of melanoma cells by inducing the essential NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) gene through STAT1 binding to the NAMPT locus. NAMPT is constitutively expressed in cells during normal homeostasis. However, melanoma cells have higher energetic demands and increased NAMPT. We show that IFN gamma signaling upregulates NAMPT in melanoma cells, increasing cell proliferation and survival. Further, STAT1-inducible Nampt promotes melanoma growth in mice. We provide evidence that melanoma cells directly respond to IFN gamma-activated STAT1 by increasing Nampt, which improves their fitness during tumor immunity. Elucidating mechanisms that regulate NAMPT expression can lead to enhanced therapeutic approaches with immunotherapies that utilize IFN signaling to improve patient outcomes. (1) Background: Immune cells infiltrate the tumor microenvironment and secrete inflammatory cytokines, including interferons (IFNs), to drive antitumor responses and promote tumor clearance. However, recent evidence suggests that sometimes, tumor cells can also harness IFNs to enhance growth and survival. The essential NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) gene is constitutively expressed in cells during normal homeostasis. However, melanoma cells have higher energetic demands and elevated NAMPT expression. We hypothesized that interferon gamma (IFN gamma) regulates NAMPT in tumor cells as a mechanism of resistance that impedes the normal anti-tumorigenic effects of IFN gamma. (2) Methods: Utilizing a variety of melanoma cells, mouse models, Crispr-Cas9, and molecular biology techniques, we explored the importance of IFN gamma-inducible NAMPT during melanoma growth. (3) Results: We demonstrated that IFN gamma mediates the metabolic reprogramming of melanoma cells by inducing Nampt through a Stat1 binding site in the Nampt gene, increasing cell proliferation and survival. Further, IFN/STAT1-inducible Nampt promotes melanoma in vivo. (4) Conclusions: We provided evidence that melanoma cells directly respond to IFN gamma by increasing NAMPT levels, improving their fitness and growth in vivo (control n = 36, SBS KO n = 46). This discovery unveils a possible therapeutic target that may improve the efficacy of immunotherapies involving IFN responses in the clinic.