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30 pages, 5842 KB  
Article
DTARNU-Net: Dense Tiered Attention Residual Nested U-Net for CT Liver Tumor Segmentation
by Kumar P, Robert P, Parthasarathy Ramadass and Mohd Anul Haq
Bioengineering 2026, 13(9), 992; https://doi.org/10.3390/bioengineering13090992 - 27 Aug 2026
Abstract
Liver tumor segmentation is a significant task in clinical imaging that involves detecting liver tumors and distinguishing them from the surrounding liver tissue in CT scans. Precision segmentation performs important roles in the initial detection of liver cancer, treatment planning, and monitoring disease [...] Read more.
Liver tumor segmentation is a significant task in clinical imaging that involves detecting liver tumors and distinguishing them from the surrounding liver tissue in CT scans. Precision segmentation performs important roles in the initial detection of liver cancer, treatment planning, and monitoring disease development, which also supports doctors, facilitating surgeries and radiation therapy more efficiently. Meanwhile, clinical imaging and segmentation algorithms have been enhanced over the years. The currently prevailing state-of-the-art methods still face multiple difficulties, though, in obtaining precision and reliability in their outcomes. Tumors with irregular shapes, variable sizes, and densities similar to those of surrounding tissues often lead to segmentation inaccuracies and potential misdiagnoses. In this work, we tackle these challenges by developing an advanced process for precise liver tumor segmentation by utilizing CT images from the LiTS dataset. The proposed DTARNU-Net was developed, trained, validated, and evaluated exclusively using the Liver Tumor Segmentation (LiTS) benchmark dataset. No experiments were conducted on the 3D-IRCADbI dataset in this study. All quantitative and qualitative results presented in the manuscript correspond to the LiTS dataset. The LiTS dataset contains contrast-enhanced abdominal CT scans with expert-annotated liver and tumor masks. The proposed model was evaluated using patient-level training, validation, and testing partitions (9:2:2 ratio), and all experiments were independently repeated five times. Statistical significance was assessed using paired Student’s t-test (p < 0.05), and the results confirmed that the performance improvements over competing methods are statistically significant. We introduce a novel three-level pre-processing approach that significantly enhances image quality through histogram equalization, noise removal, smoothing, and sharpening. Our approach is embodied in the Dense Tiered Attention Residual Nested U-Net (DTARNU-Net), a sophisticated model combining the strengths of a Siamese network and a nested U-Net architecture. This model incorporates the ACON-ReLU residual convolution block (A-R), which improves recognition accuracy in regions with subtle changes, reducing missed detection. The presented method enhances trait collaboration and spatial data by utilizing the Brownian Motion-based Butterfly Optimization Algorithm (BM-BOA). This algorithm efficiently integrates low-level trait details with high-level semantic data. The Dense Tiered Attention Residual Module (DTSRM) additionally improves these traits to obtain more precise segmentation. The model achieved segmentation robustness of 96.78% for liver segmentation and 97.00% for liver tumor segmentation on the LiTS dataset. These outcomes indicate that the presented method performs better than the prevailing state-of-the-art methods and has the capability to help computer-assisted detection and treatment by furnishing more precise and reliable liver tumor segmentation. Full article
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22 pages, 523 KB  
Article
The Influence of Statin Therapy on Markers of Endothelial Dysfunction, Endocan and Endoglin, in Postmenopausal Women—A Prospective Study
by Dunja Šojat, Marko Pirić, Maja Lukić, Vesna Horvat, Mario Šafer, Ivan Feldi, Tatjana Bačun and Aleksandar Kibel
Biomedicines 2026, 14(9), 1921; https://doi.org/10.3390/biomedicines14091921 - 27 Aug 2026
Abstract
Background: Postmenopausal women experience an increased risk of cardiovascular diseases due to estrogen deficiency, which induces endothelial dysfunction. Statins primarily lower cardiovascular risk by altering lipid profiles, but they also exert non-lipid-modifying, pleiotropic effects on the vascular endothelium. This prospective observational study was [...] Read more.
Background: Postmenopausal women experience an increased risk of cardiovascular diseases due to estrogen deficiency, which induces endothelial dysfunction. Statins primarily lower cardiovascular risk by altering lipid profiles, but they also exert non-lipid-modifying, pleiotropic effects on the vascular endothelium. This prospective observational study was aimed to evaluate and compare the impact of atorvastatin and rosuvastatin on plasma markers of endothelial dysfunction, endocan and endoglin, in postmenopausal women undergoing primary cardiovascular prevention. Methods: A total of 128 postmenopausal Croatian women (aged 45–70 years) with dyslipidemia were prospectively enrolled and assigned to two treatment groups receiving either atorvastatin or rosuvastatin therapy based on primary care clinical management. Cardiovascular risk was evaluated using the SCORE2 algorithm, and statin doses were titrated up to 16 weeks until target LDL-C values were achieved. Plasma concentrations of endocan and endoglin, alongside lipid profiles, were quantified via ELISA and laboratory analyses before and after the treatment period. Results: Atorvastatin and rosuvastatin therapies significantly decreased plasma concentrations of both endocan and endoglin (p < 0.001 for both groups). No statistically significant differences in the absolute changes in these biomarkers were observed between therapy groups. The reduction in endocan and endoglin levels occurred independently of whether the participants achieved their clinical target LDL-C values. While statin-induced reduction in endoglin was directly driven by the extent of LDL-C lowering, the decrease in endocan occurred independently of lipid changes, with both biomarker reductions being greatest in women with higher baseline levels regardless of statin type or dose. ROC curve analysis demonstrated that neither biomarker had significant clinical discriminatory ability to predict the attainment of target LDL-C levels. Conclusions: Atorvastatin and rosuvastatin treatment was associated with significant reductions in plasma endocan and endoglin concentrations in postmenopausal women receiving primary cardiovascular prevention. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Current Progress and Future Challenges)
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14 pages, 3072 KB  
Article
AKT Inhibitor Capivasertib as a Target for Osimertinib Combination Therapy in Lung Adenocarcinoma with EGFR Mutation
by Takuya Tokunaga, Yuka Ishihara, Aya Harada Takeda, Yuya Tomioka, Ayako Nagata, Mayuko Kato, Takayuki Suetsugu, Keiko Mizuno, Kazuhiro Ueda and Naohiko Seki
Genes 2026, 17(9), 1016; https://doi.org/10.3390/genes17091016 - 27 Aug 2026
Abstract
Background/Objective: An analysis of microRNA (miRNA) expression signatures in lung adenocarcinoma (LUAD) harboring EGFR mutations revealed that multiple miRNAs, including miR-126-3p, were suppressed in cancer tissues. This study focused on miR-126-3p and aimed to identify therapeutic target genes regulated by miR-126-3p [...] Read more.
Background/Objective: An analysis of microRNA (miRNA) expression signatures in lung adenocarcinoma (LUAD) harboring EGFR mutations revealed that multiple miRNAs, including miR-126-3p, were suppressed in cancer tissues. This study focused on miR-126-3p and aimed to identify therapeutic target genes regulated by miR-126-3p in LUAD harboring EGFR mutations and evaluate their potential for combination therapy with EGFR tyrosine kinase inhibitors. Methods: The antitumor function of miR-126-3p was analyzed by the ectopic expression of miR-126-3p into LUAD cells with EGFR mutation. The target genes of miR-126-3p were identified through an analysis of the TargetScan, Genecodis 4 and TCGA databases. The Chou–Talalay method was used to determine the potential synergistic effects of selected drug combinations. Results: The expression of miR-126-3p attenuated the malignant transformation of LUAD cells through targeting the “EGFR tyrosine kinase inhibitor resistance pathway”. We focused on AKT2 among the genes involved in this pathway. Capivasertib was recently approved as the first inhibitor of oncogenic AKT signaling. Therefore, we investigated the effect of combination therapy comprising osimertinib and capivasertib on LUAD cell viability. Combination therapy synergistically reduced cell viability in both PC9 and H1975 cells, with combination index values of 0.61 and 0.14, respectively, at Fa = 0.5. Conclusions: Our miRNA-based analysis is an excellent strategy for identifying therapeutic targets that enhance the effects of EGFR inhibitors on LUAD. Full article
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14 pages, 896 KB  
Article
Clinical and Laboratory Predictors of Bone Mineral Density Trajectories and Osteoporosis Progression: A Retrospective Longitudinal Cohort Study
by Layal K. Jambi and Saeed M. Kabrah
J. Clin. Med. 2026, 15(17), 6581; https://doi.org/10.3390/jcm15176581 - 26 Aug 2026
Abstract
Background: Whether routinely available laboratory measures are associated with longitudinal bone mineral density (BMD) change in clinical practice remains uncertain, particularly when treatment exposure and other major skeletal determinants are incompletely recorded. This study examined BMD trajectories and incident osteoporosis in a Saudi [...] Read more.
Background: Whether routinely available laboratory measures are associated with longitudinal bone mineral density (BMD) change in clinical practice remains uncertain, particularly when treatment exposure and other major skeletal determinants are incompletely recorded. This study examined BMD trajectories and incident osteoporosis in a Saudi dual-energy X-ray absorptiometry (DXA) cohort. Anti-osteoporosis therapy, glucocorticoid exposure and menopausal status were unavailable, limiting causal interpretation. Methods: This retrospective longitudinal cohort included DXA examinations performed at King Saud University Medical City (KSUMC), Riyadh, from 2016 to 2021. The trajectory analysis comprised 2147 patients with at least two scans and a minimum one-year interval. Diagnostic category was based on the lowest T-score across the lumbar spine, bilateral femoral necks and distal radius. Twenty linear mixed-effects (LME) models evaluated time-by-biomarker interactions with Benjamini–Hochberg correction. Cox proportional hazards (PH) regression was the primary analysis of incident osteoporosis among 789 patients without osteoporosis at baseline. Results: During 2045 person-years of observation, 107 patients developed osteoporosis (5.2 events per 100 person-years). No event occurred among 124 patients with normal baseline BMD, compared with 107 events among 665 patients with baseline osteopenia (log-rank p < 0.001). In the complete-case Cox model (n = 384; 53 events; C-index = 0.679), baseline osteopenia had a hazard ratio (HR) of 3.12 (95% Confidence interval (CI) 0.89–10.97; p = 0.076); no modelled covariate reached statistical significance. None of the 20 time-by-biomarker interactions remained significant after multiplicity correction (smallest q = 0.214). Four nominal terms with raw p < 0.10 were below the measurement-based clinical threshold and were compatible with chance variation. Conclusions: No routinely measured biomarker demonstrated clinical utility for identifying BMD trajectory in this cohort. Baseline DXA category separated the observed progression pattern, although this partly reflects the distance from the diagnostic threshold and should not be interpreted as a validated prediction model. The principal contribution is a carefully characterised null result. Prospective studies with explicit treatment tracking and repeated bone-turnover measurements are required for confirmation. Full article
(This article belongs to the Section Orthopedics)
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14 pages, 560 KB  
Article
Can Biomarker-Based Monitoring Detect the Early Development of Diastolic Dysfunction During Chemotherapy?
by Anca Daniela Farcaş, Cerasela Mihaela Goidescu, Mirela Anca Stoia, Florin Petru Anton, Andrada Viorica Pârvu, Camil Horia Eusebiu Crişan and Diana Larisa Mocan Hognogi
Medicina 2026, 62(9), 1634; https://doi.org/10.3390/medicina62091634 - 26 Aug 2026
Abstract
Background and Objectives: Although modern oncologic therapies have substantially improved cancer survival and overall prognosis, they have also led to an increasing burden of cardiovascular toxicity. Preventing severe complications such as heart failure and death remains a major priority, while maintaining the need [...] Read more.
Background and Objectives: Although modern oncologic therapies have substantially improved cancer survival and overall prognosis, they have also led to an increasing burden of cardiovascular toxicity. Preventing severe complications such as heart failure and death remains a major priority, while maintaining the need for effective and potentially curative cancer therapy. Careful patient monitoring and early detection of cardiovascular complications may allow the timely implementation of cardioprotective strategies and treatments that could delay or prevent myocardial toxicity. Materials and Methods: A total of 92 women with breast cancer were enrolled in a prospective observational cohort study. All patients received an anthracycline-based chemotherapy regimen, cyclophosphamide, docetaxel and trastuzumab. Biomarker assessment, including NT-proBNP, high-sensitivity cardiac troponin I (hs-cTnI), Gal-3, and GDF-15, was performed at baseline and at the initiation of trastuzumab-based therapy. A comprehensive diastolic function assessment was performed, including transmitral Doppler flow parameters and tissue velocities. Patients were followed for 12 months, and all cardiovascular events occurring during the follow-up period were recorded. Results: Biological and ecocardiographic parameters were analyzed and multiple models of prediction were made. To identify predictors of estimated left ventricular filling pressure (eLVFP), stepwise multiple linear regression analyses were performed, and four significant predictors of left ventricular end-diastolic filling pressure were identified: one echocardiographic parameter (baseline LV filling pressure) and three biological variables (changes in Gal-3, GDF-15, and hs-cTnI levels after treatment). The overall regression model was highly significant (p < 0.001) and explained 77.07% of the variance in the dependent variable. Gal-3 was the strongest predictor of left ventricular filling pressure (p < 0.001). Conclusions: The regression analyses suggest that this phenotype is multifactorial, with echocardiographic indices capturing the functional component and circulating biomarkers reflecting complementary aspects of the underlying biological response. This multimodal approach may therefore help identify patients with early treatment-related cardiac changes and potentially those at increased risk of subsequent CTRCD, particularly during a period when conventional LVEF-based surveillance may still appear reassuring. Full article
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14 pages, 2344 KB  
Article
Crosstalk Between mTOR and NF-κB Signaling Pathways in Clear Cell Renal Cell Carcinoma
by Melanie Glueck, Alexandra Lucaciu, Sumedha Inukollu, Rushendhiran Kesavan, Amelie Janssen, Josef Pfeilschifter, Julien Subburayalu, Ramesh K. Krishnan and Rajkumar Vutukuri
Int. J. Mol. Sci. 2026, 27(17), 7636; https://doi.org/10.3390/ijms27177636 - 26 Aug 2026
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of renal cell carcinoma (RCC), representing approximately 80% of cases globally. Despite improved diagnosis and therapy, treatment of aggressive or metastatic ccRCC remains challenging due to acquisition of primary or [...] Read more.
Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of renal cell carcinoma (RCC), representing approximately 80% of cases globally. Despite improved diagnosis and therapy, treatment of aggressive or metastatic ccRCC remains challenging due to acquisition of primary or secondary resistance. Among the dysregulated signaling mechanisms identified in ccRCC, the mechanistic target of rapamycin (mTOR) and the nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) pathways play central roles in regulating various biological functions such as metabolism, inflammation, tumor growth, and survival. However, the molecular crosstalk between mTOR and NF-κB signaling in ccRCC progression and therapeutic resistance remains poorly understood. Therefore, in our current study, we aimed to investigate the interplay between mTOR and NF-κB signaling in ccRCC. We analyzed tumor tissue samples from human ccRCC patients. For validation of mTOR and NF-κB signaling, we used two human ccRCC cell lines, A498 and 786-O. Using pharmacological inhibitors of mTOR and IKK/NF-κB signaling, Torin-1 and MLN120B, respectively, we assessed the functional relationship between these two pathways employing immunoblotting, EdU-based immunocytochemistry, and functional assays. Our findings reveal that both mTOR and NF-κB pathways are aberrantly activated in human ccRCC tissues. Phosphorylation of IκBα, S6, and 4E-BP1 was increased compared with matched adjacent control tissue. In A498 and 786-O cells, pharmacological inhibition of mTOR or IKK/NF-κB altered key readouts of the reciprocal pathway, including AKT, S6, 4E-BP1, IκBα and p65 phosphorylation. Both inhibitors reduced cell number and EdU incorporation, with stronger anti-proliferative effects observed after Torin-1 treatment. Pharmacological inhibition of either pathway altered key readouts of the other pathway, supporting a reciprocal functional association between mTOR- and NF-κB-associated signaling in the ccRCC models analyzed. Our findings support a functional association between mTOR- and NF-κB-associated signaling in the ccRCC models and provide a rationale for further mechanistic studies evaluating combined pathway modulation. Full article
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24 pages, 2522 KB  
Article
Formulation Screening and Characterization of PLGA-Based Injectable In Situ Gel Loaded with Progesterone
by Zhihan Zhu, Yu Liu and Linglin Feng
Pharmaceuticals 2026, 19(9), 1347; https://doi.org/10.3390/ph19091347 - 26 Aug 2026
Abstract
Objective: Conventional progesterone (P4) formulations suffer from low bioavailability, severe local irritation, and poor patient adherence due to P4’s poor aqueous solubility. This work aimed to develop and screen a biodegradable PLGA/NMP (Poly(lactic-co-glycolic acid)/N-methyl-2-pyrrolidone) injectable in situ gel for sustained P4 delivery to [...] Read more.
Objective: Conventional progesterone (P4) formulations suffer from low bioavailability, severe local irritation, and poor patient adherence due to P4’s poor aqueous solubility. This work aimed to develop and screen a biodegradable PLGA/NMP (Poly(lactic-co-glycolic acid)/N-methyl-2-pyrrolidone) injectable in situ gel for sustained P4 delivery to overcome these clinical limitations. Significance: Commercial oral, vaginal, and oil-based intramuscular P4 preparations cannot maintain stable long-term drug exposure, and they cause injection-site pain/inflammation. The screened in situ depot system reduces administration frequency and local tissue irritation, supporting convenient luteal phase support and pregnancy maintenance. Methods: Nine formulations with variable P4 loading (10–50% w/w) and PLGA concentration (15–55% w/w) were fabricated. Formulations were screened via three core endpoints: injectability (injection force and discharge rate), in vitro sustained release in 10% Hydroxypropyl-β-cyclodextrin (HP-β-CD)-Phosphate-buffered saline (PBS) sink medium, and 7-day subcutaneous histocompatibility in rats. high-performance liquid chromatography (HPLC) was validated for progesterone quantification; Hematoxylin and eosin (H&E) staining assessed local inflammatory responses. Results: Formulations with progesterone ≤ 30% w/w and PLGA ≤ 35% w/w exhibited acceptable injectability (injection force < 50 N; discharge rate > 79%). Higher PLGA concentrations suppressed initial burst release (16.74% at 8 h for 35% PLGA vs. 29.8% for 20% PLGA). All formulations formed stable ellipsoidal subcutaneous depots and completed progesterone release within 4 days. Histopathology revealed only mild local inflammation (histological score = 1) without severe necrosis, superior to highly irritating oil injections in formulation control groups. Conclusions: The screened PLGA-based progesterone in situ gel resolves critical drawbacks of traditional progesterone dosage forms. This low-irritation, sustained-release injectable platform provides a scalable industrial formulation candidate for long-acting hormone therapy. Full article
(This article belongs to the Section Pharmaceutical Technology)
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16 pages, 890 KB  
Article
Real-World Effectiveness and Safety of Esketamine Nasal Spray in Treatment-Resistant Depression: A Retrospective Observational Study
by Mostafa A. Sayed Ali, Palanisamy Amirthalingam, Hanan Alshareef, Mohammed Zayed Alassiry, Ahmed Samir Elshenawy, Sayed Hosam Eldin Mansour and Ahmed Aljabri
Healthcare 2026, 14(17), 2717; https://doi.org/10.3390/healthcare14172717 - 26 Aug 2026
Viewed by 52
Abstract
Background/Objectives: This study evaluated the real-world effectiveness and safety of intranasal esketamine plus oral antidepressants compared with venlafaxine-based oral antidepressant therapy in adults with moderate-to-severe treatment-resistant depression (TRD). Methods: This retrospective cohort study used electronic medical records from a mental health [...] Read more.
Background/Objectives: This study evaluated the real-world effectiveness and safety of intranasal esketamine plus oral antidepressants compared with venlafaxine-based oral antidepressant therapy in adults with moderate-to-severe treatment-resistant depression (TRD). Methods: This retrospective cohort study used electronic medical records from a mental health hospital between January 2023 and December 2025. Adults with moderately severe or severe major depressive disorder who had not responded adequately to at least two antidepressant trials received esketamine plus oral antidepressants or venlafaxine-based therapy. The outcomes were changes in the Patient Health Questionnaire-9 (PHQ-9) score, remission, response, minimal clinically important difference (MCID) without response or remission, and documented adverse events at 28 days, 3 months, and 6 months. Propensity score matching was used for continuous follow-up of the PHQ-9 outcomes. Results: The analytic baseline cohort included 82 patients treated with intranasal esketamine-based therapy and 87 treated with venlafaxine-based therapy. The esketamine group had greater baseline depression severity and more previous antidepressant failures. At 3 months, no patients who continued treatment in either group met the remission criterion, one esketamine-treated patient achieved a response, and 37/61 (60.7%) esketamine-treated patients and 23/72 (31.9%) venlafaxine-treated patients achieved MCID without response or remission. At 6 months, remission remained absent; 27/61 (44.3%) esketamine-treated patients and 9/72 (12.5%) venlafaxine-treated patients met the response criterion, whereas 34/61 (55.7%) and 63/72 (87.5%) achieved MCID without response or remission, respectively. In propensity score-matched analyses, follow-up PHQ-9 scores were 1.02 points lower at 3 months (average treatment effect [ATE], −1.02; 95% CI, −1.70 to −0.35; p = 0.003) and 1.94 points lower at 6 months (ATE, −1.94; 95% CI, −3.17 to −0.71; p = 0.002) in the esketamine group than in the venlafaxine group. Dissociation and dizziness were documented more often in the esketamine group, whereas sexual dysfunction was documented more often in the venlafaxine group. Conclusions: In this retrospective routine care cohort, esketamine was used in patients with more complex TRD and was associated with modestly lower matched follow-up PHQ-9 scores. The observational design, baseline imbalance, and attrition precluded causal conclusions. Full article
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12 pages, 461 KB  
Article
Academic Performance, Admission Pathways, and Educational Disruption as Predictors of Professional Licensure Success: Evidence from Physical Therapy Education
by Onchuma Mueangson, Parinya Vongvaivanichakul, Nantanatch Chaiyamaneerat, Haswanee Purong, Amissaanis Doloh and Nusree Hayisa-I
Int. Med. Educ. 2026, 5(3), 90; https://doi.org/10.3390/ime5030090 - 26 Aug 2026
Viewed by 59
Abstract
This study investigated academic and environmental predictors of national licensing examination success among physical therapy graduates in Thailand, examining overall academic achievement, domain-specific competencies (Code 01: Law/Ethics/Administration; Code 02: Techniques; Code 03: Clinical), admission pathway, and COVID-19-related online-learning disruption. This retrospective cohort study [...] Read more.
This study investigated academic and environmental predictors of national licensing examination success among physical therapy graduates in Thailand, examining overall academic achievement, domain-specific competencies (Code 01: Law/Ethics/Administration; Code 02: Techniques; Code 03: Clinical), admission pathway, and COVID-19-related online-learning disruption. This retrospective cohort study analyzed 342 graduates (2020–2023) using multivariable logistic regression and Pearson correlation, with GPA-based predictors rescaled per 0.1-point increase. Undergraduate GPAX and Code 02/03 grades were the strongest positive predictors of both first-attempt and annual licensing success (adjusted OR range 1.35–1.74, all p < 0.001). Online-learning duration reduced first-attempt odds by 24% (OR = 0.757, p = 0.036) but did not affect annual success, while TCAS admission round was a significant negative predictor of first-attempt success only in the model excluding domain-specific scores (OR = 0.671, p = 0.011); Code 01 score was not significant in any model. These findings indicate that domain-specific academic performance, rather than general achievement or admission pathway, was the strongest predictor of licensing success, underscoring the value of early monitoring of coursework performance for identifying at-risk students. Full article
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31 pages, 13323 KB  
Article
Probing the Capsid: pH-Driven Gating at the AAV 5-Fold Pore and Its Role in Peptide Ligand Binding
by Arianna Minzoni, Benjamin Bobay, Shriarjun Shastry, Eduardo Barbieri, Brandon Brino, Crystal Collazo, Shizuo Kamita, Danni Wang, Ciera Khuu, Alexander Polgar, Joseph Siino, Sushmita Koley, Peyton Russelburg, Mark Snyder, Christopher Belisle, Michael Daniele and Stefano Menegatti
Pharmaceutics 2026, 18(9), 1053; https://doi.org/10.3390/pharmaceutics18091053 - 25 Aug 2026
Viewed by 173
Abstract
Background/Objectives: Adeno-associated virus (AAV) capsids undergo pH-dependent conformational gating at the 5-fold symmetry pore, but how these structural dynamics shape serotype-specific behavior and affinity-ligand recognition remains unclear, particularly for the clinically important serotypes AAV8 and AAV9. This study aimed to establish a pH-resolved [...] Read more.
Background/Objectives: Adeno-associated virus (AAV) capsids undergo pH-dependent conformational gating at the 5-fold symmetry pore, but how these structural dynamics shape serotype-specific behavior and affinity-ligand recognition remains unclear, particularly for the clinically important serotypes AAV8 and AAV9. This study aimed to establish a pH-resolved structural framework linking 5-fold pore dynamics to peptide-ligand recognition and to translate this framework into sequence-based design principles for affinity capture of gene therapy vectors. Methods: AAV8 and AAV9 5-fold capsid assemblies were subjected to 500 ns molecular dynamics simulations under acidic (pH 5), neutral (pH 7), and basic (pH 9) conditions, with analysis of pore volume, inter-residue contact networks, electrostatic potential, and solvent-accessible surface area. In parallel, affinity chromatography using three mixed-mode peptide ligands (RVVAVYRI, TTFRAHHI, and TYHHHHII) was performed on clarified HEK293 lysates containing AAV8 or AAV9, with capsid yield, host-cell-protein clearance, and transduction activity assessed by ELISA, SEC-HPLC, and flow-cytometry-based transduction assays. Results: AAV8 displayed a heterogeneous, bimodal pore conformational landscape at pH 7, whereas AAV9 exhibited a discrete gate-like transition with maximal pore constriction at physiological pH; both serotypes showed pore-proximal contact remodeling with distinct network topologies. Experimentally, TYHHHHII achieved the highest selectivity for genome-containing capsids at pH 7, with transduction activity enrichment factors of 2.82 (AAV8) and 5.61 (AAV9), while TTFRAHHI provided the broadest operational pH range for bulk capsid recovery. Conclusions: These findings establish a structural framework linking pH-dependent pore dynamics to affinity ligand recognition and suggest practical sequence-design rules for ligand engineering: clustered histidines for neutral-pH selectivity, Arg-containing motifs for broad-pH robustness, and aromatic or hydrophobic residues for reinforcement of capsid binding. Full article
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19 pages, 1119 KB  
Article
Plasma p-Tau217 and SPECT-Based eZIS in Mild Cognitive Impairment: Concordance Analysis with Validation in an Amyloid PET Sub-Cohort
by I-Lun Huang, Hiroshi Matsuda, Ya-Tang Pai and Ming-Chyi Pai
Diagnostics 2026, 16(17), 2702; https://doi.org/10.3390/diagnostics16172702 - 24 Aug 2026
Viewed by 222
Abstract
(1) Background/Objectives: Blood-based biomarkers have emerged as practical tools for identifying Alzheimer’s disease (AD) pathology in patients with mild cognitive impairment (MCI). Among them, plasma phosphorylated Tau217 (p-Tau217) demonstrates strong associations with cerebral amyloid deposition. In parallel, the easy Z-score Imaging System [...] Read more.
(1) Background/Objectives: Blood-based biomarkers have emerged as practical tools for identifying Alzheimer’s disease (AD) pathology in patients with mild cognitive impairment (MCI). Among them, plasma phosphorylated Tau217 (p-Tau217) demonstrates strong associations with cerebral amyloid deposition. In parallel, the easy Z-score Imaging System (eZIS), a quantitative brain perfusion SPECT analysis tool, has been widely used to detect characteristic AD-related hypoperfusion patterns. Although both measures reflect distinct AD processes, the relationship between plasma p-Tau217 and eZIS in MCI remains unclear. (2) Methods: This retrospective study included 62 patients with MCI who underwent plasma p-Tau217 testing and brain perfusion SPECT with eZIS analysis. Associations between plasma p-Tau217 and the three eZIS indices (severity, extent, and ratio) were evaluated. Exploratory subgroup analyses were performed using a previously reported plasma p-Tau217 threshold of 0.63 pg/mL. In addition, a validation sub-cohort of 21 participants who underwent plasma p-Tau217 testing, eZIS, and amyloid PET was analyzed to assess concordance with cerebral amyloid pathology. (3) Results: Among the three eZIS indices, severity demonstrated the highest sensitivity relative to elevated plasma p-Tau217 levels. However, all eZIS indices showed limited discriminative performance. Optimal eZIS cutoff values derived from the present cohort were higher than previously reported thresholds. In the amyloid PET-validated sub-cohort, plasma p-Tau217 demonstrated closer concordance with amyloid positivity than any individual eZIS parameter. The reduced performance of eZIS appeared to be associated with advanced age, substantial vascular burden, white matter lesions, and cerebral atrophy. (4) Conclusions: Plasma p-Tau217 showed a stronger association with cerebral amyloid pathology than eZIS indices in this elderly MCI cohort. Nevertheless, eZIS may provide complementary information regarding downstream neurodegenerative and cerebrovascular processes that are not directly captured by plasma biomarkers. This integrated approach highlights plasma p-Tau217 as a primary screening tool for amyloid pathology to guide disease-modifying therapies (DMTs), alongside eZIS for tracking follow-up mixed co-pathologies. Full article
(This article belongs to the Special Issue Recent Advances in Radiomics for Medical Imaging: Second Edition)
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36 pages, 5259 KB  
Review
Hydrogels for Local Drug Delivery in Biofilm-Associated Periprosthetic Joint Infection: Current Progress and Future Directions
by Karolina Kraus, Paweł Mikziński, Bindu Subhadra and Emil Paluch
Microorganisms 2026, 14(9), 1882; https://doi.org/10.3390/microorganisms14091882 - 24 Aug 2026
Viewed by 124
Abstract
Periprosthetic joint infection (PJI) remains one of the most serious complications of arthroplasty, largely due to the formation of microbial biofilms on implant surfaces. Biofilm-associated infections exhibit increased tolerance to antimicrobial therapy and host immune responses, making eradication difficult and often requiring repeated [...] Read more.
Periprosthetic joint infection (PJI) remains one of the most serious complications of arthroplasty, largely due to the formation of microbial biofilms on implant surfaces. Biofilm-associated infections exhibit increased tolerance to antimicrobial therapy and host immune responses, making eradication difficult and often requiring repeated surgical interventions. Consequently, there is a growing need for effective local therapeutic strategies capable of delivering high concentrations of antimicrobial agents directly to the site of infection while minimizing systemic toxicity. Hydrogels have emerged as promising drug delivery platforms for the management of biofilm-associated PJI. Their biocompatibility, injectability, high water content, and tunable physicochemical properties enable controlled and localized release of therapeutic agents within the infected peri-implant environment. This narrative review summarizes recent advances in hydrogel-based approaches, including antibiotic-loaded hydrogels, systems incorporating anti-biofilm enzymes, bacteriophage-loaded formulations, and nanoparticle-enhanced platforms. It also highlights future research directions, with particular emphasis on the need for expanded clinical studies to facilitate the translation of emerging hydrogel-based therapies into clinical practice. Further development of these systems should focus on the incorporation of novel therapeutic agents into hydrogel platforms, aiming to enhance biofilm eradication and improve treatment outcomes in patients with PJI. Particular attention is given to stimuli-responsive (“smart”) hydrogels that release therapeutic payloads in response to infection-related triggers such as pH changes, with emphasis on the need for expanded clinical studies to facilitate the translation of emerging hydrogel-based therapies into clinical practice. Further development of these systems should focus on the incorporation of novel therapeutic agents into hydrogel platforms, aiming to enhance biofilm eradication and improve treatment outcomes in patients with PJI. Full article
(This article belongs to the Special Issue Bacterial Biofilms in Health and Disease)
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19 pages, 1653 KB  
Article
Associations of OPRM1, COMT, and ABCB1 Variants with Opioid Analgesic Response in Acute Renal Colic: A Candidate-Gene Study
by Sıtkı Ün, Ramazan Sabırlı, İbrahim Türkçüer, Gergana Lengerova, Martina Bozhkova, Steliyan Petrov and Aylin Köseler
Pharmaceuticals 2026, 19(9), 1343; https://doi.org/10.3390/ph19091343 - 24 Aug 2026
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Abstract
Background: Acute renal colic is a common urological emergency characterized by substantial interindividual variability in analgesic response. Pharmacogenetic variation in OPRM1, COMT, and ABCB1 may contribute to differences in opioid efficacy and pain control. This study primarily evaluated the associations [...] Read more.
Background: Acute renal colic is a common urological emergency characterized by substantial interindividual variability in analgesic response. Pharmacogenetic variation in OPRM1, COMT, and ABCB1 may contribute to differences in opioid efficacy and pain control. This study primarily evaluated the associations of OPRM1 A118G (rs1799971), COMT Val158Met (rs4680), and ABCB1 C3435T (rs1045642) polymorphisms with opioid analgesic response in patients with acute renal colic. As a secondary exploratory analysis, genotype and allele frequencies were compared between patients and healthy controls. Methods: This prospective case–control study included 150 patients with acute renal colic and 100 healthy controls. Genotyping was performed using TaqMan SNP Genotyping Assays based on real-time polymerase chain reaction. Genotype frequencies were compared between groups using dominant and recessive genetic models, and Hardy–Weinberg equilibrium was assessed. In addition, genotype–phenotype associations were evaluated using pain severity, early analgesic response, initial opioid dose, rescue analgesic requirement, and multivariable logistic regression analyses. Results: In the secondary exploratory case–control analysis, no statistically significant differences in genotype or allele frequencies of OPRM1 rs1799971, COMT rs4680, or ABCB1 rs1045642 were observed between patients with acute renal colic and healthy controls. Within the patient cohort, however, genotype–phenotype analyses identified differences in early analgesic outcomes. Baseline-adjusted 30 min VAS differed according to OPRM1, COMT, and ABCB1 genotype, with the most pronounced difference observed for ABCB1 rs1045642. Patients with the ABCB1 TT genotype had higher adjusted 30 min VAS scores and showed a pattern of greater opioid requirement and more frequent rescue analgesia. In exploratory multivariable analysis, the ABCB1 TT genotype was associated with higher odds of inadequate early analgesic response (adjusted OR = 2.74, 95% CI 1.18–6.37; p = 0.019). Given the limited number of outcome events, this adjusted association should be considered preliminary and hypothesis-generating. Conclusions: No significant differences in the distributions of the polymorphisms investigated were observed between patients with acute renal colic and healthy controls. Within the patient group, ABCB1 genetic variation was associated with early opioid analgesic response, although this finding should be considered preliminary and requires confirmation in larger prospective pharmacogenetic studies before clinical implementation. Any potential future pharmacogenetic application should be considered as an adjunct to established first-line renal–colic management and specifically in patients for whom opioid therapy is clinically indicated. Full article
(This article belongs to the Section Pharmacology)
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13 pages, 1837 KB  
Article
Factors Influencing Walking Improvement After Immersive Virtual Reality Training with a Bodyweight-Supporting System in Poststroke Patients: A Prospective Single-Arm Study
by Kanta Kitabayashi, Naoto Ogura, Naoki Yoshioka and Wataru Kakuda
Neurol. Int. 2026, 18(9), 162; https://doi.org/10.3390/neurolint18090162 - 24 Aug 2026
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Abstract
Objectives: We developed an original protocol for standing balance and walking function training using immersive virtual reality (IVR) combined with a bodyweight-supporting (BWS) system. The purpose of this study was to evaluate the feasibility of IVR training in poststroke patients and to identify [...] Read more.
Objectives: We developed an original protocol for standing balance and walking function training using immersive virtual reality (IVR) combined with a bodyweight-supporting (BWS) system. The purpose of this study was to evaluate the feasibility of IVR training in poststroke patients and to identify clinical characteristics associated with walking improvement. Methods: A total of 22 poststroke patients admitted to a rehabilitation ward were enrolled. All participants received conventional physical therapy daily, and IVR training was initiated when balance recovery plateaued. The original IVR training was conducted for 10 consecutive days using a BWS system, enabling safe and repetitive practice of standing weight shifting and advanced stepping tasks, with task difficulty individually adjusted. Primary outcomes were the Berg Balance Scale (BBS), Functional Reaching Test (FRT), and walking time on the 10-m walk test (10 MWT). Changes in 10 MWT (Δ10 MWT) were calculated, and participants were dichotomized into good and poor walking improvement groups based on Δ10 MWT to compare baseline clinical characteristics (e.g., BBS, FRT, and Functional Ambulation Categories [FAC]) between the groups. Receiver operating characteristic (ROC) curve analyses were conducted to identify cutoff values associated with greater improvements in walking. Results: BBS, FRT, and 10 MWT improved significantly after the 10-day IVR training (p < 0.01). ROC analyses identified FAC ≤ 3 and BBS ≤ 42 before training as cutoff values associated with greater improvement in walking performance. Conclusions: Our proposed IVR training approach using a BWS system could be safely implemented and might improve standing balance and walking function in poststroke patients with a balance disability. Full article
(This article belongs to the Special Issue Novel Rehabilitation for Post-Stroke Patients)
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12 pages, 1343 KB  
Article
Prognostic Value of a Novel Risk Score Combining Psoas Muscle Density and ALBI Grade in Localized Renal Cell Carcinoma
by Tomoyuki Makino, Kouji Izumi, Ryunosuke Nakagawa, Taiki Kamijima, Suguru Kadomoto, Renato Naito, Hiroaki Iwamoto, Hiroshi Yaegashi, Kazuyoshi Shigehara, Takahiro Nohara and Atsushi Mizokami
Med. Sci. 2026, 14(5), 509; https://doi.org/10.3390/medsci14050509 - 24 Aug 2026
Viewed by 117
Abstract
Background: Sarcopenia, systemic inflammation, and malnutrition are established poor prognostic factors in renal cell carcinoma (RCC). This study investigated the utility of a novel preoperative score combining psoas muscle density (PMD)—an imaging-based indicator of muscle quality—and the albumin–bilirubin (ALBI) grade—a blood-based biomarker of [...] Read more.
Background: Sarcopenia, systemic inflammation, and malnutrition are established poor prognostic factors in renal cell carcinoma (RCC). This study investigated the utility of a novel preoperative score combining psoas muscle density (PMD)—an imaging-based indicator of muscle quality—and the albumin–bilirubin (ALBI) grade—a blood-based biomarker of liver reserve and systemic nutritional status—for predicting disease-free survival (DFS) and overall survival (OS) in patients undergoing curative surgery for RCC. Methods: This retrospective observational study included 274 patients with non-metastatic RCC treated with radical or partial nephrectomy. Preoperative computed tomography was utilized to measure PMD, defining “low PMD” as a value below the sex-specific median (males: 47.75 Hounsfield Units [HU]; females: 46.25 HU). “Worsened ALBI” was defined as an ALBI grade ≥ 2. Patients were stratified into three risk categories: Score 0 (both normal, n = 122), Score 1 (either abnormal, n = 114), and Score 2 (both abnormal, n = 38). Results: Kaplan–Meier analysis revealed a highly significant, stepwise decline in both DFS and OS as the risk score increased (log–rank p < 0.001 and p = 0.004, respectively). Multivariate Cox regression identified the combined risk score as a robust, independent prognostic factor for DFS (Score 1: HR 1.93, 95% CI 1.11–3.37, p = 0.020; Score 2: HR 3.58, 95% CI 1.82–7.02, p < 0.001). Furthermore, after adjusting for age and comorbidities, the score remained an independent predictor of poor OS (Score 1: HR 2.35, 95% CI 1.08–5.13, p = 0.032; Score 2: HR 3.01, 95% CI 1.16–7.82, p = 0.024). The combined model synergistically enhanced risk stratification accuracy compared to evaluating either factor independently. Conclusions: The concurrent presence of preoperative low PMD and a worsened ALBI grade is a powerful, independent predictor of poor prognosis in localized RCC. Derived solely from routine preoperative imaging and laboratory tests, this straightforward scoring system effectively captures the structural and immunometabolic dimensions of cancer cachexia and host vulnerability. This tool can significantly aid in personalizing postoperative surveillance strategies and identifying high-risk patients who may warrant closer postoperative surveillance or who might be considered as high-risk candidates for adjuvant therapy discussions. Full article
(This article belongs to the Section Cancer and Cancer-Related Research)
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