Search Results (374)

Background: Oral squamous cell carcinoma (OSCC) remains a clinically challenging malignancy characterized by aggressive behavior and limited therapeutic options. Bitter taste receptors (TAS2Rs), expressed across multiple tissues and cancer types, have recently emerged as regulators of tumor biology and immune responses; however, their functional significance in OSCC remains poorly understood. Methods: Immunohistochemical analysis was performed using surgically resected human tongue OSCC specimens and a tissue microarray (TMA) cohort. In parallel, four TAS2R agonists were evaluated in SCC7 cells to assess intracellular calcium responses. RNA sequencing was conducted to analyze transcriptional changes following diphenidol treatment, and functional assays, including proliferation, migration, and apoptosis analyses, were performed in vitro. Antitumor effects were further evaluated in a syngeneic SCC7 mouse model, followed by TUNEL staining and flow cytometry to assess apoptosis and immune cell infiltration. Results: TAS2R38 expression was markedly upregulated in dysplastic and invasive OSCC lesions with predominant nuclear localization and was associated with histological grade and clinical stage, indicating an early and sustained alteration during tumor progression. Among the agonists tested, diphenidol most strongly induced IP₃-dependent intracellular Ca²⁺ elevation. RNA sequencing revealed upregulation of Il1rl1 and Lzts2. Functionally, diphenidol significantly suppressed SCC7 cell proliferation and migration and induced apoptosis in vitro. In vivo, diphenidol reduced tumor volume and weight and increased apoptotic activity. Flow cytometry demonstrated a marked reduction in tumor-infiltrating CD4⁺CD25⁺Foxp3⁺ regulatory T cells, indicating modulation of the tumor immune microenvironment. Conclusions: TAS2R activation by diphenidol suppresses tumor growth through both tumor-intrinsic mechanisms and modulation of the tumor immune microenvironment in OSCC. These findings define TAS2R-mediated calcium signaling as a novel axis linking tumor progression and immunoregulation. Given that diphenidol is a clinically approved drug with an established safety profile, our results provide a strong rationale for TAS2R-targeted drug repurposing strategies in cancer therapy. Full article

Surgical sutures are widely used biomaterials in clinical practice. Like all other biomaterials, they induce a foreign body response after implantation that involves inflammation and angiogenesis. Although it is well known that these processes differ in males and females, sex-specific differences in the tissue response to sutures have not been investigated so far. To do this in the present study, polypropylene sutures were implanted into the dorsal skinfold chamber and subcutaneous flank tissue of male and female mice to assess their acute and chronic effects on the local tissue microenvironment using intravital fluorescence microscopy and immunohistochemistry over 14 and 28 days, respectively. Microhemodynamic parameters and the numbers of rolling and adherent leukocytes in venules next to the implants were comparable in male and female mice. Immunohistochemical analyses on day 14 revealed a stronger neutrophilic (myeloperoxidase (MPO)⁺ cells: 526 ± 29 mm⁻²) and macrophage (CD86⁺ cells: 188 ± 21 mm⁻²; CD163⁺ cells: 269 ± 25 mm⁻²) response, as well as reduced T-cell activation (CD3⁺ cells: 31 ± 4 mm⁻²) in females when compared to males (MPO⁺ cells: 221 ± 25 mm⁻²; CD86⁺ cells: 120 ± 15 mm⁻²; CD163⁺ cells: 101 ± 19 mm⁻²; CD3⁺ cells: 62 ± 13 mm⁻²), while microvessel density and collagen deposition in the forming granulation tissue around the implants did not differ between sexes. In the flank model, there were no detectable sex-specific differences in the chronic foreign body response. These findings demonstrate that polypropylene sutures provoke a stronger early activation of the innate immune system in females, whereas the chronic foreign body response to the implants is comparable in both sexes. Full article

Endometriosis is a chronic, estrogen-dependent inflammatory disease including aberrant local steroidogenesis, inflammation, angiogenesis, oxidative stress, and prostaglandin-mediated pain. Given the elevated adrenergic receptor expression in endometriotic lesions and the potential of terazosin to downregulate Steroidogenic Factor-1 (SF-1), this study aimed to evaluate terazosin as a non-hormonal therapy in a surgically induced rat endometriosis model. Forty female Wistar rats were randomized to sham, untreated endometriosis, leuprolide acetate or terazosin; two postoperative deaths yielded final group sizes of 10/9/10/9. Blinded histopathology verified successful lesion establishment. ELISA quantified SF-1, IL-6, IL-8, TNF-α, NF-κB, VEGF, HIF-1α, and PGE2 in lesion tissue, serum, and peritoneal lavage; oxidative status was assessed by TAS, TOS, and OSI. Compared with untreated endometriosis, terazosin significantly reduced SF-1, PGE2, IL-6, IL-8, TNF-α, VEGF and HIF-1α across compartments (all p < 0.001), comparable to leuprolide (p = 1.000). Terazosin also normalized oxidative stress by decreasing TOS/OSI and restoring TAS in tissue, serum, and peritoneal fluid (p < 0.001). NF-κB decreased in tissue and serum (p < 0.001) but not in peritoneal fluid (p = 0.206). Overall, terazosin produced leuprolide-like molecular benefits without hormonal suppression, supporting repurposing as a candidate non-hormonal therapy, while highlighting the need for longer-duration studies and randomized clinical trials given model and pain-assessment limitations. Full article

Background: Standardized and ethically compliant animal models remain essential for improving translational research in Alzheimer’s disease. Although Aβ_1–42-induced rodent models are widely used, methodological variability continues to limit reproducibility. Methods: We explored the feasibility of a stereotactic intrahippocampal Aβ_1–42 rat model established by bilaterally injecting pre-aggregated peptide into the hippocampus of adult Sprague Dawley rats. Model feasibility and targeting accuracy were assessed intraoperatively. Cognitive performance was evaluated using the Y-maze for spatial recognition memory and the novel object recognition (NOR) test. Histological examination was performed using hematoxylin–eosin (H&E) and Congo red staining to assess cytoarchitecture and to provide supportive evidence of amyloid-like deposits. Results: The surgical procedure was well-tolerated, and the injected animals showed reduced performance in behavioural testing, including reduced spatial recognition memory in the Y-maze and decreased discrimination indices in the NOR test. The animals also showed histological changes, including Congo red-positive birefringent structures consistent with amyloid-like congophilic material. Conclusions: This study presents a feasible experimental framework for intrahippocampal Aβ_1–42 administration, showing behavioural and histological changes under the present experimental conditions. However, further validation, including sham-operated controls and molecular characterization, will be required before these findings can be interpreted as specific to Aβ-driven pathology. Full article

Background/Objectives: Glioblastoma is the most common and aggressive primary malignant brain tumor in adults, characterized by infiltrative growth and poor prognosis. Achieving maximal resection without inducing neurological deficits remains a challenge in glioblastoma surgery. While 5-aminolevulinic acid-based fluorescence-guided surgery supports intraoperative tumor visualization, its reliability is limited by patient variability and weak fluorescence signals. This study proposes a machine learning framework to enhance fluorescence-guided surgery sensitivity by analyzing surgical microscope images at the pixel level. Methods: Fluorescence-mode neurosurgical microscope images of synthetic samples with known Protoporphyrin IX (PPIX) concentrations were used to train three classifiers (Support Vector Machine, Naïve Bayes, Neural Network) for pixel-wise fluorescence detection. In parallel, three contrastive-learning-based Variational Autoencoders (VAE, $\beta$ = 1, 2, 3) were evaluated for detecting weak fluorescence beyond visual perception. Additionally, a regression model was trained to relate pixel features to PPIX concentration. The best-performing VAE ($\beta$ = 1) was subsequently trained on real intraoperative data, and its detection sensitivity was compared to annotations from four experienced surgeons. Results: The proposed model achieved the highest detection rates on synthetic test data when calibrated for 99% specificity. Applied to real intraoperative images, the model revealed fluorescent areas substantially larger than those marked by experienced surgeons. In non-5-ALA control cases, minimal false positives were observed, indicating a specificity exceeding 99.9%. The regression model reliably quantified PPIX concentration in synthetic samples ($R^2=0.92$). Conclusions: By enabling more sensitive and objective fluorescence detection, this approach offers a valuable tool for improving surgical decision-making and facilitating safer, more extensive tumor resections. Full article

Purpose: The aim of this study was to develop a concept for adjustment planning of intraocular lens orientation axes after cataract surgery with implantation of toric intraocular lenses (tIOLs) and to predict the spectacle refraction after tIOL re-alignment. Methods: This calculation concept based on paraxial spherocylindrical vergence transformations uses the actual spherocylindrical refraction at the spectacle plane, corneal power, and the labelled power and measured axis of the implanted tIOL to minimise the refractive cylinder by simulating the rotation of the tIOL in the eye. The axial lens position is derived from simple prediction models using anterior chamber depth and lens thickness or axial length from preoperative biometry or the equivalent tIOL power. The new target axis is predicted together with the spherocylindrical refraction after re-alignment of the tIOL. Results: To show the applicability of this calculation model, we provide four clinical working examples: example 1 deals with keratometric power values; example 2 deals with keratometric curvature values, including surgically induced astigmatism and a statistical posterior astigmatism correction for the cornea (both examples with a thin cornea model); example 3 deals with corneal curvature data for the front and back surface; and example 4 deals with keratometric power data and corneal back surface power data, including surgically induced astigmatism (both examples with a thick cornea model). Conclusions: The effect of tIOL axis adjustment after cataract surgery can be predicted based on actual refraction, corneal power, tIOL power and the measured axis, and a simulation of the tIOL axis rotation enables the best orientation with the lowest refractive cylinder at the spectacle plane to be found. Full article

Background: The optimal timing of adjuvant chemotherapy after cytoreductive surgery in epithelial ovarian cancer remains uncertain, and perioperative wound-healing responses may transiently create a pro-tumorigenic and drug-resistant microenvironment. This study aimed to characterize time-dependent wound-induced transcriptomic alterations and to identify pharmacologic agents capable of reversing these responses. Methods: An ID8 murine ovarian cancer model was used to compare no treatment, anesthesia alone, and anesthesia plus surgical wounding mimicking futile laparotomy. Tumors were collected at baseline, 1 day (T1), 1 week (T2), and 2 weeks (T3) after intervention. RNA sequencing was performed, and wound-specific differentially expressed genes (WsDEGs) were defined by excluding anesthesia- and progression-related signatures. Functional enrichment analyses were conducted, followed by transcriptome-based drug repurposing using the REMEDY platform to identify compounds predicted to reverse wound-induced gene expression profiles. Results: Surgical wounding significantly increased tumor burden at T1. Transcriptomic analyses revealed distinct, time-dependent wound-associated programs. At T1, WsDEGs were enriched in inflammatory signaling, coagulation, angiogenesis, and immune cell migration, with Vorinostat and Homoharringtonine identified as top candidates to counteract these signatures. At T2, pathways related to cell survival, adhesion, and morphogenesis predominated, with LY-2090314, Artesunate, and Birinapant emerging as potential modulators. At T3, cell-cycle regulation and lipid metabolic pathways were dominant, and Fulvestrant, Atorvastatin, Imatinib, and ABT-737 were predicted to inhibit these processes. Conclusions: Perioperative surgical wounding induces dynamic, stage-specific transcriptomic programs that may promote ovarian cancer progression and alter drug responsiveness. These findings support time-adapted perioperative pharmacologic strategies to optimize postoperative cancer therapy. Full article

Background/Objectives: Photobiomodulation (PBMT) has been shown to improve tissue healing; however, the best protocol for different clinical challenges is not clearly determined. Despite the good previous outcomes of the PBMT in healing of the third molar surgical sites, the ideal protocol of PBMT was not determined. The objective of this split-mouth double-blinded randomized clinical trial was to compare the effect of photobiomodulation (PBMT) with red and infrared wavelengths combined and PBMT with only red wavelength on the healing of post-extraction alveoli of third molars. Methods: Twenty patients underwent third molar extraction. The alveoli were treated randomly in a split mouth model with: PBMT with red laser (R-PBMT) or PBMT with red and infrared laser combined (IR-R-PBMT). PBMT was applied immediately, and 3 and 7 days after surgery. Patients were clinically evaluated in relation to repair (bleeding, exudate, color, and consistency of the tissues), degree of the edema, and through the application of a VAS scale (pain, edema, bleeding, chewing, and mouth opening) in the baseline period, and 3, 7, 14, 30, and 90 days after the surgical procedure. In addition, bone tissue density and structure were measured by radiographic analysis at 7 and 90 days postoperatively. Results: Clinical analysis showed that IR-R-PBMT induce more reduction in the edema 7 days after surgery compared with the R-PBMT; however, no significant differences were noted between groups in other parameters. Conclusions: IR-R-PBMT reduces the edema after 7 days of third molar extraction compared with the R-PBMT. Registration: This study was registered with the Brazilian Registry of Clinical Trials (REBEC-RBR-103g7j28; date of registration 12 July 2023) under number U1111-1297-6962. Full article

Background: The perioperative period in cancer surgery is characterized by transient metabolic and inflammatory perturbations that may influence early postoperative biochemical dynamics. Surgical stress induces insulin resistance, hyperglycemia, cytokine activation, and metabolic shifts that interact with tumor cell signaling pathways. Intravenous lidocaine has been associated with anti-inflammatory and systemic stabilizing effects beyond analgesia. We investigated whether perioperative lidocaine administration during robotic-assisted radical prostatectomy (RARP) is associated with early postoperative prostate-specific antigen (PSA) dynamics within the context of perioperative metabolic–inflammatory modulation. Methods: In this single-center retrospective cohort study, 180 patients undergoing RARP for localized or locally advanced prostate cancer were stratified according to perioperative intravenous lidocaine exposure. The primary endpoint was undetectable PSA (<0.1 ng/mL) at 6–12 weeks postoperatively. Secondary endpoints included PSA detectability at 3 and 6 months and time to first detectable PSA. Multivariable logistic and Cox regression models were adjusted for established oncologic risk factors. Perioperative glycemic variation, intraoperative lactate dynamics, and postoperative IL-6 levels were analyzed as indicators of stress-induced metabolic activation. Results: Lidocaine exposure was independently associated with higher odds of undetectable PSA at 6–12 weeks (OR 2.10, 95% CI 1.15–3.85) and at subsequent time points. In Cox analysis, lidocaine was associated with a reduced hazard of PSA detectability (HR 0.58, 95% CI 0.37–0.92). Patients receiving lidocaine demonstrated significantly attenuated perioperative hyperglycemia, lower lactate elevation, and reduced IL-6 response. Conclusions: Perioperative intravenous lidocaine administration during RARP was associated with more favorable early PSA dynamics and attenuation of perioperative metabolic–inflammatory activation. Given the retrospective and non-randomized design of the study, these findings should be interpreted as associative and hypothesis-generating, and warrant confirmation in prospective controlled investigations. Full article

Precise and smooth actuation is a central requirement in surgical robotics, where small tracking errors or oscillations can directly affect task quality and safety. This paper studies the control of an induction-motor-driven surgical joint using a sliding-mode strategy enhanced by fractional-order operators and implemented within a DTC–SVM structure. The motivation is to improve motion smoothness and disturbance rejection without sacrificing the fast dynamic response offered by direct torque control. A dynamic model of the actuator is developed by combining the electrical equations of the induction motor with the mechanical dynamics of a robotic joint, including inertia, viscous friction, gravity-induced torque, and Coulomb friction. Fractional-order sliding surfaces are introduced for both position and flux regulation, and the closed-loop stability is examined through Lyapunov-based arguments. Simulation results show accurate trajectory tracking with limited overshoot and smooth transient responses. The motor speed remains well regulated, while stator flux and currents stay within admissible bounds. The electromagnetic torque adapts to load variations with reduced ripple, and the rotor pulsation remains bounded. Within the limits of numerical evaluation, these results indicate that the proposed fractional-order sliding-mode DTC–SVM scheme is suitable for precision-oriented surgical robotic actuation. Full article

There is no approved drug therapy for schwannomas associated with NF2-related schwannomatosis (NF2-SWN). Neither life-saving surgical resection or radiation are curative and can compound the debilitating neurological effects of the schwannomas. We previously identified fimepinostat, a dual histone deacetylase (HDAC)/phosphoinositide-3 kinase (PI3K) inhibitor, as a promising drug candidate with pro-apoptotic effects on NF2-related schwannomas. This preclinical study used the pharmaceutical formulation of fimepinostat to confirm its efficacy in schwannomas and identify pro-apoptotic signaling pathways. Fimepinostat was tested in human schwannoma model cells, patient-derived primary vestibular and non-vestibular schwannoma cells, and in a sciatic nerve allograft model. The signaling pathways leading to caspase-3-dependent apoptosis were elucidated using immune assays, flow cytometry, imaging, proteome, and acetylome analysis. Acute exposure to fimepinostat led to p21-dependent cell cycle inhibition, upregulation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL R2), and downregulation of tumor necrosis factor receptor 1 (TNFR1), Yes-associated protein (YAP), and inhibitors of apoptosis. Moreover, fimepinostat downregulated cytokine and chemokine secretion increased by merlin loss in schwannoma cells. Fimepinostat is a promising new drug intervention for NF2-SWN patients with the potential to promote tumor regression. Full article

Mesial temporal lobe epilepsy (TLE) is the most common and severe form of focal epilepsy. This review examines the diverse mechanisms by which the GABAergic system contributes both to seizure generation and to protective processes that limit epileptogenesis and seizure progression in TLE. We focus on findings from established animal models of TLE as well as studies of surgically resected tissue from patients who had undergone therapeutic intervention. Experimental models include sustained electrical stimulation of the perforant path, as well as the kainic acid (KA) and Li-pilocarpine models. Although these paradigms induce status epilepticus (SE) through distinct mechanisms, they ultimately converge on prolonged excitation of hippocampal CA3 pyramidal neurons and interconnected regions of the hippocampus and broader limbic network. In response to epileptic seizures, GABA synthesis is enhanced, as evidenced by the marked upregulation of the GABA-synthesizing enzymes GAD65 and GAD67, along with their ectopic expression in glutamatergic mossy fibers of the hippocampus. Shortly after acute seizures, a transient expression of the embryonic GAD67 splice variant, GAD25, is observed, although its functional significance remains unclear. At the receptor level, animal models of TLE show upregulation of GABA_A receptor subunits α2, α4, β3, and γ2, accompanied by downregulation of α5 and δ subunits, suggesting reduced tonic inhibition. In contrast, hippocampal tissue from patients with TLE exhibits pronounced upregulation of α5 and δ subunits, indicative of enhanced extrasynaptic tonic inhibition. Similarly, whereas GABA_A receptor subunits are mildly downregulated in animal models, they are consistently upregulated across hippocampal subfields in human TLE, pointing toward strengthened GABAergic inhibition. Conversely, genetic variants of GABA_A receptor subunits and autoantibodies targeting these receptors can contribute to the etiology of epilepsy, often with onset in childhood. Moreover, degeneration or functional silencing of specific GABAergic interneuron populations—such as parvalbumin-positive neurons in the subiculum—can induce epilepsy in rodent models and is likewise associated with TLE in humans. Full article

Background: Abdominal aortic aneurysm (AAA) is a vascular disease with a high mortality rate upon rupture (85–90%). Surgical repair remains the most effective intervention, whereas pharmacological treatments to prevent aneurysm expansion or rupture are limited. Vascular smooth muscle cells (VSMCs) play a crucial role in AAA pathogenesis, and metabolic dysregulation is increasingly recognized as a contributor to disease progression. This study investigated metabolic changes in VSMCs and their association with AAA pathology using untargeted metabolomics. Methods: Angiotensin II (Ang II) was used to stimulate rat VSMCs and induce AAA in ApoE−/− mice. Untargeted metabolomic analysis was performed using liquid chromatography–tandem mass spectrometry to detect metabolite changes. Differential metabolites were identified using orthogonal partial least squares discriminant analysis, and metabolic pathways were analyzed using Kyoto Encyclopedia of Genes and Genomes and metabolic set enrichment analysis. Results: In Ang II-treated VSMCs, 54 differential metabolites (24 upregulated; 30 downregulated) were identified, whereas 470 differential metabolites (206 upregulated; 264 downregulated) were detected in mouse aortas. Three metabolites—carnitine, lysophosphatidylcholine (0:0/20:4), and 5-hydroxyeicosatetraenoic acid—were common in both models and were enriched in bile secretion and tryptophan metabolism pathways. The carnitine–FXR signaling axis emerged as a potential therapeutic target. Conclusions: This study revealed Ang II-induced metabolic changes in VSMCs and their association with AAA pathology. The carnitine–FXR signaling axis may contribute to AAA development, providing new directions for diagnostic biomarkers and therapeutic targets. Future studies should validate these findings in human AAA samples to determine their clinical relevance. Full article

Background/Objectives: Insulin and glucagon are key hormones in metabolic regulation. There are limited comparative data on how common rodent anesthetic regimens influence hormone secretion, leading to misinterpretation of results. We aimed to compare the effects of several anesthetic regimens on insulin and glucagon secretion using the physiologically relevant isolated perfused rat pancreas model. Methods: Six commonly used rodent anesthetic regimens were assessed for their ability to induce surgical depth of anesthesia. Once achieved, the pancreas was vascularly isolated and perfused. After euthanasia, the pancreas was stimulated with glucose and glucagon-like peptide-1 (GLP-1). Insulin and glucagon were measured in the effluent using radioimmunoassay. Results: Anesthesia with Hypnorm^® (fentanyl/fluanisone)/midazolam produced the most physiological responses, meaning that insulin was secreted in response to hyperglycemia and GLP-1, and glucagon was secreted under hypoglycemia. Ketamine/dexmedetomidine anesthesia abolished insulin dynamic secretion and blunted glucagon secretion. Isoflurane/buprenorphine anesthesia partially suppressed insulin secretion, but it still followed a physiological pattern in response to glucose fluctuations. However, it abolished the dynamic glucagon responses to glucose. Three additional anesthetic regimens failed to produce surgical depth anesthesia and were therefore not further analyzed. Conclusions: Different anesthetic regimens altered pancreatic hormone secretion. Fentanyl/fluanisone/midazolam was associated with dynamic insulin and glucagon secretion, whereas ketamine/dexmedetomidine and isoflurane/buprenorphine altered the pattern and/or magnitude of hormone secretion. Overall, the choice of anesthesia is a critical variable in animal experimentation for metabolic studies and may confound the interpretation of results. Full article

Background: Glioblastoma (GBM) is a lethal, highly invasive, and recurrent brain tumor. Standard treatment combines maximal surgical resection, radiation, and chemotherapy; however, such approaches are often infeasible for tumors in eloquent brain regions. Objective: Histotripsy is a noninvasive, nonthermal ultrasound-based mechanical ablation modality that employs focused acoustic energy for targeted tissue destruction. This study aimed to investigate the feasibility, safety, and therapeutic effect of a one-time transcranial histotripsy treatment in a pre-clinical murine GBM model. Methods: GL261 GBM cells were orthotopically implanted into C56BL/6 mouse brains. Transcranial histotripsy was performed using a stereotactically guided 2 MHz transducer targeting either lower (25%) or higher (75%) tumor volume, with 5 or 10 pulses per location (PPL) administered. Tumor growth and cerebral injury were monitored with weekly magnetic resonance imaging (MRI) following treatment. At the study endpoint, hematoxylin and eosin (H&E) histology assessed residual tumor burden and histotripsy-induced tissue changes. Results: Mice receiving 5 PPL high-percent treatment (>30 sites) showed a statistically significant median survival extension of 5 days (18.5%) compared to untreated controls. MRI demonstrated marked tumor volume reduction in the high-percent treatment group at week 4, while H&E confirmed increased tumor necrosis and cellular damage in the treated cohort. Conclusions: Single-session, incisionless transcranial histotripsy was well tolerated and conferred mild yet meaningful survival advantages in this GBM model. These results support ongoing exploration of histotripsy, alone or in combination with existing therapies, for safe and effective treatment of challenging brain tumors. Full article