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2025
Background: The ability of radiotherapy (RT) to drive anti-tumor immunity is limited by adaptive resistance. While RT induces inflammation and recruits activated tumor-infiltrating lymphocytes (TILs), including cytotoxic T lymphocytes (CTLs), the resulting radiation- and IFNγ-dependent PD-L1 expression restores an immunosuppressed tumor microenvironment. Unleashing an effective anti-tumor response may require the precise sequencing of RT and checkpoint blockade immunotherapy (CBI) to block PD-L1 signaling before it can mediate its suppressive effects. Methods: Flank tumors formed in BALB/c mice with syngeneic CT26 colon or 4T1 mammary carcinoma cells were treated with otherwise ineffective doses of ionizing radiation (10 Gy) followed by CBI (0.2 mg anti-PD-L1, i.v.) after 0, 1, 3, 5, or 7 days, comparing tumor response. Anti-PD-L1 delivery was measured by fluorescence, TILs by flow cytometry and immunofluorescence, PD-L1 expression by immunohistochemistry, and tumor size by calipers. Results: In both CT26 and 4T1 tumors, 10 Gy alone resulted in a transient growth delay associated with infiltrating CTLs peaking at 3 days and PD-L1 at 5 days. CTLs returned to baseline after 7 days, consistent with adaptive resistance. Anti-PD-L1 failed to potentiate radiation except when injected 5 days after 10 Gy, which prevented CTL depletion and led to tumor elimination. Potentially contributing to compound effects, anti-PD-L1 penetrated tumors and bound PD-L1 more efficiently after irradiation. Conclusions: Optimal timing to exploit radiation-induced permeability to enhance CBI delivery and interrupt adaptive resistance by blocking PD-L1 as it peaks may offer a general strategy to enhance external beam radiotherapy by protecting activated TILs and potentiating anti-tumor immune response.- Book : 17(3)
- Pub. Date : 2025
- Page : pp.391-391
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2025
AbstractDespite decades of research, the primary proviral function of the HIV-1 Vpr accessory protein remains enigmatic. Vpr is essential for pathogenesisin vivoand for virus replication in myeloid cells, but the underlying cause-and-effect mechanism(s) driving these phenomena are poorly understood. Canonically, Vpr hijacks a cellular ubiquitin ligase complex to target several dozen host proteins for proteasomal degradation. Many of these substrates were recently revealed to be involved in DNA damage repair (DDR), which rationalizes the longstanding observation that Vpr induces constitutive activation of DDR signaling. Here, we use a combination of functional, biochemical, and genetic approaches establish a clear mechanistic link between Vpr-induced DDR signaling and remodeling of the epigenetic landscape to enhance HIV-1 promoter activity during acute infection and virus reactivation from latency. Functional, genetic, and bimolecular fluorescence complementation experiments reveal that Vpr utilizes degradation-dependent and -independent mechanisms to induce epigenetic remodeling and that Vpr segregates into two discrete pools with dedicated activities—A multimeric pool in the nucleus that is associated with chromatin and a monomeric pool associated with DCAF1 in the cytoplasm. Vpr function in remodeling the nuclear environment is present in common HIV-1 subtypes worldwide and provides a mechanistic rationale for its essentiality in virus replication.Author summaryWhile HIV-1 Vpr plays an essential role in virus replication, the molecular mechanisms underlying its essentiality remain enigmatic. Vpr’s best characterized function is the ability to induce the depletion of several dozen host proteins by hijacking a cellular E3-ubiquitin ligase complex. Here, we establish that Vpr promotes global epigenetic remodeling to enhance HIV-1 promoter activity during acute infection and virus reactivation from latency.We demonstrate that epigenetic remodeling activity is linked to Vpr’s ability to induce constitutive DNA damage repair signaling, and that it occurs through both degradation-dependent and -independent mechanisms. Moreover, this Vpr function is present in common HIV-1 subtypes circulating globally. This study provides novel mechanistic insights into how HIV-1 exploits host DNA repair pathways and sheds light on Vpr’s proviral function.- Book : ()
- Pub. Date : 2025
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2025
Cholesterol, the essential building block of cellular membranes, has proven to be a useful tool for increasing the biocompatibility and bioavailability of drug delivery systems in cancer treatment. Resveratrol, a natural polyphenolic compound with promising anticancer properties, faces significant limitations due to its low solubility and bioavailability, hindering its clinical utility. Therefore, in the present study, we aimed to design cholesterol-functionalized cyclodextrin nanosponges (Chol-NSs) with a tunable cholesterol content to optimize resveratrol encapsulation and delivery. Both formulations, free carbonyl diimidazole (CDI) NSs and functionalized Chol-NSs, demonstrated high drug loading and encapsulation efficiency. In vitro experiments revealed that cholesterol incorporation significantly improved the cellular uptake of nanocarriers and potentiated the cytotoxic effects of resveratrol on breast cancer cells. Importantly, both free CDI NSs and functionalized Chol-NSs, even at varying cholesterol percentages, demonstrated a safe profile against both fibroblast and breast cancer cell lines. These results indicate that cholesterol-functionalized nanosponges represent a promising platform for the effective and safe delivery of natural compounds in cancer therapy.- Book : 26(3)
- Pub. Date : 2025
- Page : pp.1213-1213
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2025
- Book : ()
- Pub. Date : 2025
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2025
Diagnostic radiology is the most significant contributor to irradiation in the general population. Unnecessary irradiation of workers, patients, and the public during radiological procedures should be significantly reduced without affecting the medical diagnostic value. This study was conducted to analyze and evaluate the radiation dose rate, radiation protection facilities and radiation worker dose of Radiology Installation of Pariaman Regional Hospital. The method of determining the radiation dose rate at the Radiology Instalansi of Pariaman Hospital uses a PDR 303 gamma surveymeter and the rooms to be measured are CT-Scan rooms, conventional X-rays and mammography. Collecting data on radiation protection facilities, then it will be analyzed based on Nuclear Energy Regulatory Agency Regulation No. 4 of 2020 and radiation worker dose data in 2023 will be analyzed based on Nuclear Energy Regulatory Agency Regulation No. 4 of 2013. The results of the study showed that the radiation dose rate around the CT-Scan room was found to be (0.24-1.61) μSv/hour, the conventional X-ray room with irradiation using the minimum exposure factor obtained a radiation dose rate around the room ranging from (0.013-0.33) μSv/hour and with the maximum exposure factor obtained a dose rate around the room of (0.33-1.08) μSv/hour and the mammography room obtained a radiation dose rate of (0.03-0.40) μSv/hour. The radiology room facilities used by Pariaman Hospital are in accordance with the standards set by Nuclear Energy Regulatory Agency Regulation No. 4 of 2020. And the dose rate received by radiation workers at Pariaman Hospital is below the Dose Limit Value set by Nuclear Energy Regulatory Agency Regulation No. 4 of 2013. Based on the results of this study, it is found that there are several measurement points in the CT-Scan and conventional X-ray rooms that exceed the community dose limit value.- Book : 21(3)
- Pub. Date : 2025
- Page : pp.269-269
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2025
In this work, the primary objective was to achieve a complete and detailed structural assignment of the 1H and 13C nuclear magnetic resonance (NMR) data for kaurenoic acid (KA) (ent-kaur-16-en-19-oic acid), a widely studied natural diterpene with various reported biological activities. To facilitate this, the kaurenoic acid methyl ester (ent-methyl-kaur-16-en-19-oate) was also elucidated, leveraging its slight structural differences and the corresponding variations in chemical shifts. The comprehensive assignment was accomplished through the analysis of spectra obtained from each sample, enabling the measurement of all hydrogen homonuclear coupling constants and the clarification of signal multiplicity in the 1H-NMR spectra. Consequently, NMR techniques such as 1H-NMR, 13C{1H}, g-COSY, g-HSQC, g-HMBC, and J-resolved experiments were employed. Additionally, two different software programs, FOMSC3 and NMR_MultiSim, were utilized to simulate 1H-NMR signals, which further assisted in the complete assignment. Furthermore, different deuterated solvents were used to clarify overlapping regions and enrich the dataset.- Book : ()
- Pub. Date : 2025
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2025
Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, defined by its limited therapeutic options and poor outcomes. This study investigated the therapeutic potential of targeting Na+ homeostasis in TNBC cells to induce TNBC inhibition. For this purpose, BALB/c mice were inoculated with 4T1-Luc2 breast cancer cells and treated with the Na+ ionophore monensin (8 mg/kg) or vehicle alone. Tumor development and cellular Na+ content were assessed using vivo live imaging techniques, while intracellular Na+ variations and cytotoxicity were evaluated through live cell analysis. Monensin treatment increased Na+ levels in cancerous tissues and reduced TNBC mass (monensin: 0.146 ± 0.06; vehicle: 0.468 ± 0.2 cm3; p < 0.001). This treatment induced extensive necrosis in TNBC tumors while preserving the structural and functional integrity of healthy organs and maintaining the proliferative activity of both tumor and normal tissues. Monensin did not alter the expression of proliferating nuclear antigen (PCNA) in 4T1-Luc2 cells but triggered cytotoxicity preceded by intracellular Na+ accumulation. Na+-free conditions prevented both Na+ accumulation and 4T1-Luc2 cell death. Thus, monensin exerts its antitumor effects in TNBC through a Na+-dependent and tumor-specific cytotoxic mechanism, without inducing cytostatic effects on normal or transformed tissues. Collectively, these findings underscore the potential of Na+ ionophores as promising therapeutic agents for TNBC.- Book : 14(3)
- Pub. Date : 2025
- Page : pp.185-185
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2025
The operation of floating nuclear power plants is subject to a number of environmental factors in addition to the typical working temperature and pressure loads. These include marine environmental loads, which can cause fatigue damage and therefore must be taken into account. The fatigue analysis of marine structures frequently employs frequency domain methods, whereas the fatigue analysis of pressure equipment predominantly utilizes time-domain methods. At present, there is no comprehensive and accessible approach for conducting a fatigue analysis of pressure equipment in floating nuclear power plants. In light of the aforementioned considerations, this paper puts forth a novel approach to evaluating fatigue damage based on the principle of damage combination. This article presents a finite element model of pressure equipment and a methodology for calculating the transfer function of such equipment under wave loads. The frequency domain method is employed to calculate the fatigue damage caused by wave loads, with consideration given to both the working temperature and pressure load. The stress time history curve of pressure-bearing equipment is then calculated using the time-domain method. Subsequently, the fatigue damage caused by thermal pressure loads is obtained through a combination of the rainflow counting method and cumulative damage theory, with verification conducted using time-domain calculations. In comparison to alternative damage combination methodologies, the novel approach offers more precise and straightforward damage calculations, with promising potential for integration into engineering design.- Book : 13(2)
- Pub. Date : 2025
- Page : pp.236-236
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2025
- Book : ()
- Pub. Date : 2025
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2025
The aim of this study was to investigate the antioxidant capacity of fruit wines and their protective effects against hydrogen peroxide-induced oxidative stress in rat synaptosomes in vitro. The wines were produced from strawberries and drupe fruits (i.e., plum, sweet cherry, peach, and apricot) through microvinification with a pure S. cerevisiae yeast culture. Fruit wines were produced with and without added sugar before the start of fermentation, whereas subvariants with and without pits were only applied to drupe fruit wines. First, synaptosomes were treated with the wines, while oxidative stress was induced with H2O2. Subsequently, the activities of antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx)) and the content of malondialdehyde (MDA), an indicator of membrane injury, were determined. In addition, the Briggs–Rauscher reaction (BR) was used to evaluate the inhibition capacity against free radicals. All investigated fruit wines increased the activity of the studied antioxidant enzymes and decreased MDA content compared to the corresponding controls (synaptosomes treated with H2O2). After synaptosomal treatment with plum wine, the highest activities were observed for SOD (5.57 U/mg protein) and GPx (0.015 U/mg protein). Strawberry wine induced the highest CAT activity (0.047 U/mg protein) and showed the best ability to reduce lipid peroxidation, yielding the lowest MDA level (2.68 nmol/mg). Strawberry, plum, and sweet cherry wines were identified as samples with higher antioxidant activity in both principal component analysis (PCA) and hierarchical cluster analysis (HCA). Finally, plum wine exhibited the highest inhibitory activity in the BR reaction (397 s). The results suggest that fruit wines could be considered potential functional food due to their protective effects against oxidative stress.- Book : 14(2)
- Pub. Date : 2025
- Page : pp.155-155
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