Search Results (3,399)

Background/Objectives: Tumor-infiltrating lymphocytes (TILs) are recognized predictors of response to neoadjuvant chemotherapy (NACT) and prognosis in breast cancer, particularly in triple-negative (TN) and HER2-positive subtypes. However, the additional predictive value of morphological features of the inflammatory infiltrate beyond TIL quantification is not fully established. We aimed to assess the predictive value of TILs for response to NACT in breast cancer and to determine whether morphological characteristics of the inflammatory infiltrate enhance predictive accuracy. Methods: We analyzed 477 patients with stage II–III breast cancer treated with NACT between 2009 and 2016. Diagnostic core needle biopsies were prospectively re-evaluated. TILs were quantified according to International TILs Working Group recommendations. Morphological features of the infiltrate, including cell composition (lymphocytic vs. plasma cell-rich), heterogeneity, and localization, were evaluated using standardized criteria. Pathologic complete response (pCR) was defined as absence of invasive tumor in the breast and in the axillary lymph nodes (ypT0/Tis ypN0). Univariate and multivariate logistic regression analyses were performed to assess the predictive value of TILs (quantitative and morphological assessment) to achieve pCR for the entire cohort and by surrogate molecular subtype. Results: A TIL cutoff of >20% was identified as optimal for predicting pCR. High TILs were significantly associated with high-grade tumors, elevatedKi67, HER2-positive and TN subtypes, presence of plasma cells, and intraepithelial and heterogeneous infiltrates. In the overall cohort, TILs > 20% significantly increased the likelihood of pCR (OR 3.9, 95%IC 2.5–6.0, p < 0.001) and was an independent predictor of pCR. A combined variable incorporating TIL level and homogeneity improved predictive performance, with homogeneously high TILs emerging as a strong predictor of pCR (OR 5.521, 95%CI 3.174–9.603, p < 0.01). Plasma cell-rich and intraepithelial infiltrates were also associated with higher pCR rates (respectively, OR 2.7, 95%CI 1.5–5.0, p = 0.001 and OR 2.8, 95%CI 1.6–5.0, p < 0.001). Subtype-specific analyses confirmed the predictive value of TILs in TN tumors, but not in HER2-positive ones. Notably, in luminal B-like tumors, high TILs were the only independent predictor of response (OR 17.982, 95%CI 3.115–103.815, p = 0.001). Conclusions: TIL assessment on routine H&E-stained biopsies is a robust predictor of response to NACT in breast cancer that is readily available, cost-neutral and does not require additional techniques. Integration of simple morphological features significantly enhances predictive accuracy and may refine treatment stratification, particularly in luminal B-like tumors. Full article

Across the world’s electrical substations, water-treatment plants, and manufacturing lines, a single engineer with valid credentials and a laptop can today push new control logic to a programmable logic controller (PLC) and change the physical behaviors of safety-critical equipment within minutes. Firmware and ladder-logic updates on SCADA and industrial IoT systems are privileged operations: an attacker installing a malicious update controls the physical process. Existing protections concentrate install authority in a single party with no externally verifiable record; compromise of the vendor key, the engineering workstation, or any operator credential suffices to deliver an attacker-chosen payload to a PLC. CertiFlash binds every update to four independent approvals: a vendor signature, a FROST-Ed25519 threshold signature from an operator quorum, a per-session nonce from the PLC, and a monotonic counter. Every decision is recorded in an append-only Merkle transparency log. The PLC verifies the aggregate with a standard RFC 8032 Ed25519 verifier, requiring no FROST-specific device code. Four security properties (authenticity, authorization, rollback resistance, auditability) are machine-checked in Tamarin under a Dolev–Yao adversary with up to t − 1 compromised operators and corroborated through ten attack scenarios. The implementation runs with concurrent Modbus TCP and Siemens S7 traffic, blocks all attacks, signs in 27–192 ms (k = 3–10), keeps ML-DSA-65 within 6% of Ed25519 from 1 KiB to 10 MiB, and sustains 30.1 updates/s on 100 PLCs. The operator-quorum signature remains FROST-Ed25519: the design is partially post-quantum in the evaluated version. The framework maps to IEC 62443-3-3 SR 3.4 and NIS2 Article 21(2)(d–e). Full article

Uterine leiomyosarcoma (LMS) is a rare and aggressive malignancy with diagnostic challenges, particularly in cases with overlapping histological features with atypical leiomyoma or smooth muscle tumors of uncertain malignant potential. We report a comparative immunohistochemical analysis of LMS, leiomyoma, and adjacent myometrium obtained from a 40-year-old woman with discordant pathological diagnoses. LMS tissue showed increased Ki67 and NTS/NTSR1 immunoreactivity together with a distinctive cytoplasmic localization of estrogen receptor beta (ERβ), in contrast to the predominantly nuclear localization observed in leiomyoma and normal myometrium. Importantly, focal areas within adjacent morphologically non-neoplastic myometrium exhibited an immunophenotype resembling LMS, including cytoplasmic ERβ localization and increased Ki67 and NTS/NTSR1 expression. These observations suggest a potential association between ERβ subcellular localization, NTS/NTSR1 signaling, and molecular alterations occurring during uterine smooth muscle tumorigenesis. However, given the single-case nature of this report, these findings should be considered exploratory and require validation in larger studies. The diagnostic message conveyed by these images may assist in the interpretation of diagnostically challenging cases and provide a basis for future investigation. Full article

New copper(II) (C1) and palladium(II) (C2) complexes with S,O-tetradentate ligand (L) derived from thiosalicylic and thiopropionic acids were synthesized. In cell-based assays, (C1) exhibited the most pronounced activity within the tested compound series and was therefore advanced for mechanistic evaluation in 4T1 triple-negative breast cancer cells. (C1) significantly reduced 4T1 cell viability by inducing early and late apoptosis, accompanied by mitochondrial membrane depolarization and enhanced cytochrome C release. Consistently, (C1) increased the Bax/Bcl-2 ratio, promoting a pro-apoptotic shift. In parallel, (C1) triggered autophagy, as evidenced by decreased p62 and LC3B levels, induced G0/G1 cell-cycle arrest, and suppressed proliferative signaling by downregulating Ki67, cyclin D, and phosphorylated AKT. The DNA-binding studies showed moderate to strong affinity, favoring minor groove binding, with higher affinity for (C1) than for (C2). Tryptophan fluorescence quenching indicated a strong interaction with BSA via a predominantly static mechanism, more pronounced for (C1). Molecular docking at the DNA and BSA binding sites corroborated experimental findings and suggested favorable interactions between the complexes and apoptosis-related proteins (CASP3, BAX, and BCL2). The integrated experimental and computational data identify (C1) as a biologically active compound with multimodal biological effects in vitro, supporting further structural optimization and mechanistic investigation. Full article

Background/Objectives: Fraxetin (7,8-dihydroxy-6-methoxycoumarin), a coumarin constituent of Cortex Fraxini (Qinpi) used in traditional Chinese medicine, is metabolised mainly by UGT1A9, but its potential to inhibit UGT enzymes and cause herb–drug interactions (HDIs) is largely unstudied. Methods: Fraxetin and four related coumarins were screened against 11 recombinant human UGTs; isoforms inhibited ≥80% underwent full kinetic analysis with 4-methylumbelliferone as probe. Binding was examined by molecular docking on AlphaFold structures with PLIP, triplicate 100 ns molecular dynamics, and MM/GBSA and MM/PBSA free-energy calculations, and interaction risk by FDA 2020 in vitro–in vivo extrapolation (IVIVE). Results: Fraxetin alone inhibited both UGT1A1 and UGT1A9 by >80% and was characterised in detail, acting as a mainly competitive mixed-type inhibitor (UGT1A1 IC₅₀ 15.99 μM, K_i 8.32 μM; UGT1A9 IC₅₀ 8.44 μM, K_i 5.90 μM). A structure–activity comparison identified a dual-element pharmacophore comprising the C-6 methoxy group and the 7,8-dihydroxycoumarin aglycone. MM/GBSA favoured UGT1A9 over UGT1A1 (ΔΔG = −4.06 kcal/mol, p = 0.005), concordant with the kinetic ranking. IVIVE predicted a borderline systemic signal (R₁ > 1.02) but an intestinal R_1,gut approximately five- to seven-fold above the high-risk threshold of 11 after capping the luminal concentration at fraxetin aqueous solubility. Conclusions: This is the first characterisation of fraxetin as a moderate-potency inhibitor of UGT1A1 and UGT1A9 and points to a previously under-recognised herb–drug interaction risk concentrated in the intestinal lumen rather than systemically; the finding constitutes an interaction signal requiring clinical confirmation rather than an established risk. Full article

Background: Pituitary adenylate cyclase-activating polypeptide (PACAP) functions as an anti-atherogenic neuropeptide. Maxadilan, a PAC1 receptor agonist, offers atheroprotection by acting downstream of vascular inflammation caused by hypercholesterolemia. This study aims to explore how PACAP and Maxadilan influence migration and apoptosis in human coronary artery smooth muscle cells (HCASMCs). Methods: To investigate the role of PACAP deficiency in the pathogenesis of atherosclerosis under standard chow (SC) in vivo, PACAP^−/−-mice were crossed with ApoE^−/−-mice to generate PACAP^−/−/ApoE^−/−-mice. The whole aorta was isolated and stained with OilRedO (ORO). Atherosclerotic lesions and lumen stenosis in the brachiocephalic trunk were quantified using ImageJ 1.54p (Fiji). To further investigate the role of PACAP and Maxadilan in the pathogenesis of atherosclerosis with special respect to HCASMC under a lipid-enriched environment, HCASMCs were treated with oxLDL, with or without PACAP or Maxadilan. Uptake and accumulation of oxLDL were analyzed using Bodipy^TM493/503, and cell viability was assessed with PrestoBlue^®. Cell migration was evaluated using the scratch assay and the MRI wound-healing tool in ImageJ (Fiji). Mitochondrial morphology was examined with MitoTracker Green and the MiNA tool in ImageJ (Fiji). Apoptotic processes were analyzed by Western blot, immunocytofluorescence staining, and ELISA. Results: In vivo, PACAP^−/−/ApoE^−/−-mice showed increased lumen stenosis and decreased plaque burden compared with ApoE^−/−-mice. In vitro, PACAP enhanced the viability of oxLDL-treated HCASMCs, while neither PACAP nor Maxadilan influenced lipid content in HCASMCs, regardless of oxLDL presence. Both oxLDL and PACAP slowed cell migration, but Maxadilan increased migration in oxLDL-treated HCASMCs. The protein level of the proliferation marker Ki67 was reduced in cells treated with oxLDL and Maxadilan. Additionally, BAX, which promotes intrinsic apoptosis, was elevated in HCASMCs stimulated with Maxadilan and oxLDL. Investigations of mitochondrial morphology indicated that oxLDL and PACAP increased the individual and network structures, with a decrease in branches per network. Conclusion: Our data highlight the complex role of the PACAP/PAC1 system in vascular pathology and suggest that selective modulation—such as targeted PAC1 activation or PACAP supplementation—could lead to new strategies for stabilizing atherosclerotic plaques. In the long term, this could improve the balance between plaque formation and vascular function. Full article

The oncocytic variant of adrenocortical carcinoma (OACC) represents an exceptional type of adrenal malignancy, with heterogenous presentation. Currently, the genetic and molecular spectrum remains an open matter. A 20-year-old adult was accidentally found with a 7.2 cm adrenal tumor and underwent an open right adrenalectomy with OACC confirmation. Post-adrenalectomy positron emission tomography/computed tomography was negative. Immunohistochemistry was positive for calretin, inhibin, steroidogenic factor 1; Ki67 of 20%. Microsatellite instability was 7.61. Lin–Weiss–Bisceglia score showed 2 major criteria [mitoses 6/50 HPF + positive atypical mitoses], the reticuline algorithm (disrupted reticuline network + mitoses 6/50 HPF) was consistent for a malignant behavior, the Helsinki score was of 48. Next generation sequencing identified a likely pathogenic variant of CEL gene (heterozygote, c.539-2A>G) in peripheral blood and two pathogenic variants in the tumor: exon 48, NF1 gene [c.7159_7164del p.(N2387_F2388del)] and exon 6, TP53 gene [c.596delG p.(G199Efs*48)]. Polycystic ovary syndrome type A has been diagnosed as teenager with no phenotype change before the tumor detection. After surgery, oocyte retrieval and cryopreservation upon ovarian stimulation protocol (OSP) was performed before starting mitotane therapy. To the best of our knowledge, this is a novel genetic configuration in OACC with an impact on prognosis to be determined. Hyperandrogenemia stands on a dual source (potential CEL-driven insulin resistance for the ovary and OACC-originating for the adrenal glands). Also, this is the first case to receive OSP in OACC, noting that a tailored multidisciplinary management is mandatory. Full article

Background/Objectives: There remains a need for additional prognostic markers in classic follicular lymphoma (cFL) to identify aggressive disease. Immunohistochemical stains such as Ki-67, MYC, and p53 have shown variable associations with histologic grade and adverse outcomes. In this study, we aimed to assess intrafollicular Ki-67, MYC, and p53 expression in cFL via immunohistochemistry, quantified by both manual and digital methods, and evaluate their relation to histologic grade and clinical outcomes. Methods: We evaluated 37 cases of cFL from 2000 to 2019 and performed immunohistochemistry for Ki-67, MYC, and p53 on tumor microarray tissue. Stains were assessed within follicles by digital pathology means on QuPath software and via manual low-power estimates. Results:MYC expression was greater in FL3A compared to FL1–2 across all digital and manual scoring methods (all p < 0.05). Ki-67 and p53 expression did not differ by histologic grade group. No biomarker showed a significant association with adverse clinicopathologic features or outcomes, including FLIPI risk group, bulky disease, clinical stage, event-free survival, or overall survival. Manual and digital scores demonstrated strong correlations for all markers (ρ = 0.71–0.89, all p < 0.001). Conclusions: In our cohort, MYC expression was increased in FL3A compared to FL1–2, while no intrafollicular biomarker measurement was associated with adverse clinicopathologic features or clinical outcomes in exploratory analyses. These findings should be interpreted with caution in light of our limited cohort size. Strong concordance between manual and digital scoring supports the feasibility of digital IHC quantification in cFL. Full article

The P(IA-HBP-AA-AM)/MMT composite was successfully synthesized via in situ polymerization and characterized using FTIR, XRD, TGA, and other techniques. The material was then applied as an adsorbent for the removal of heavy metals from simulated mining-contaminated water (prepared based on the typical ionic composition of real mining wastewater). Static adsorption experiments revealed that P(IA-HBP-AA-AM)/MMT composite could efficiently remove Pb(II) from contaminated water, and the adsorption behavior was well described by the pseudo-second-order kinetic model and the Langmuir isotherm model. Thermodynamic analysis indicated that the adsorption of Pb(II) onto the P(IA-HBP-AA-AM)/MMT composite was an endothermic and spontaneous process. At pH = 4.5 and T = 45 °C, the maximum adsorption capacity obtained from model fitting was 249.38 mg/g. The material exhibited strong selectivity for Pb(II), even in the presence of competing metal ions such as Cd(II), Zn(II), Al(III), Fe(III), K(I), and Na(I). Moreover, after five adsorption–desorption cycles, it still retained approximately 90% of its Pb(II) removal efficiency. Furthermore, dynamic adsorption experiments showed that the saturation adsorption capacity of Pb(II) reached 178.7 mg/g, with a column utilization efficiency of approximately 41%. These findings demonstrate the promising potential of P(IA-HBP-AA-AM)/MMT composite for the removal of Pb(II) from mining-contaminated water. Full article

Background: The tumor immune microenvironment, particularly the role of cytotoxic CD8+ T lymphocytes, is crucial in cancer progression but remains poorly understood in pituitary neuroendocrine tumors (PitNETs). The significance of CD8+ cell infiltration varies across PitNET subtypes, suggesting a complex interplay with tumor cell lineage. This study aimed to characterize the distribution of CD8+ tumor-infiltrating lymphocytes across different PitNET subtypes defined by the current WHO classification and to explore their association with clinicopathological features. Methods: We conducted a retrospective study on 40 surgically resected PitNETs. All cases were classified based on immunohistochemical expression of pituitary hormones and lineage-specific transcription factors (PIT-1, TPIT, SF-1). CD8+ lymphocyte density was quantified using immunohistochemistry and calculated as cells/mm². Exploratory statistical analysis was performed based on non-parametric tests to compare CD8+ cell density across tumor subtypes and with parameters like tumor size, invasiveness (Knosp grade), and proliferation index (Ki-67). Findings are to be treated as observational trends. Results: The highest density of CD8+ lymphocytes was observed in plurihormonal PIT-1-positive tumors [17.61 cells/mm² (IQR: 17.61–60.36)], followed by somatotroph [13.2 (6.6–15.72)] and mammosomatotroph [13.83 (0–21.38)] tumors. A difference in CD8+ density was found between PIT-1-positive and PIT-1-negative tumors (n1 = 34, n2 = 6, U = 49.5, p_exact = 0.050, r = 0.33); the medium effect size indicates a possible lineage-related trend. Another difference was observed between SF-1-positive and SF-1-negative tumors (p = 0.025), with SF-1 lineage tumors showing the lowest infiltration. No correlations were found between CD8+ density and tumor size, Knosp grade, or Ki-67 index. Conclusions: The distribution of intratumoral CD8+ T lymphocytes in PitNETs is highly heterogeneous and appears to be strongly dictated by the transcription factor-defined tumor lineage rather than by traditional clinicopathological markers of aggressiveness. PIT-1 lineage tumors harbor a more active immune microenvironment, while SF-1 lineage tumors are relatively ‘immune-poor’. These findings highlight the immunological diversity of PitNETs and support further investigation of the tumor immune landscape. Collaborative multi-institutional studies are required to validate these trends. Full article

LRRK1 is essential for osteoclast-mediated bone resorption, and loss of LRRK1 function causes osteopetrosis in mice and humans. However, the mechanisms by which LRRK1 regulates osteoclast activity remain incompletely defined. We previously identified that phosphorylation of OSTM1 at threonine 328 and serine 329 was compromised in LRRK1-deficient osteoclasts. To test the role for OSTM1 phosphorylation in LRRK1 regulation of osteoclast functions, we expressed a phosphomimetic OSTM1 variant in LRRK1-null osteoclasts. Overexpression of phosphomimetic, but not a dephosphomimetic variant, partially restored resorptive activity in LRRK1-deficient osteoclasts in vitro. To test OSTM1’s role in rescuing defective bone resorption in Lrrk1-null mice, we generated Ostm1-T328E/S329D knock-in (KI) mice and crossed them onto the Lrrk1-deficient background. Ostm1-T328E/S329D KI mice displayed normal skeletal development and bone remodeling. When crossed to the Lrrk1-deficient background, OSTM1-T328E/S329D expression increased osteoclast resorptive activity and bone formation and partially improved trabecular architecture, although bone volume remained unchanged. These findings demonstrate that OSTM1 phosphorylation contributes to LRRK1-dependent regulation of osteoclast function and identify the LRRK1–OSTM1 pathway as a mechanistic node controlling bone resorption. Our work provides new insight into the molecular basis of LRRK1-mediated osteoclast function and highlights OSTM1 phosphorylation as a potential therapeutic target for metabolic bone diseases. Full article

Efficient task assignment for mobile robots is a crucial challenge in modern intralogistics. This paper presents an integrated cyber-physical framework combining predictive tree search on switching max-plus linear systems with a physical IoT-based dispatch interface. The scheduling problem is modelled as a discrete event system, where standard max-plus algebra captures robot synchronization, and a switching mechanism represents alternative resource assignments. To address real-world operational disturbances, the predictive model is enhanced with a fault-tolerant control (FTC) mechanism that dynamically estimates and adapts to non-stationary transport delays. The resulting decision space, which grows exponentially with the prediction horizon, is explored via a predictive tree search algorithm utilizing a quadratic cost function to penalize excessive and uneven transport times. The physical dispatch layer is realized using KIS.BOX IoT devices acting as operator-controlled stations, communicating with the central controller via a WebSocket/STOMP event stream and a lightweight REST API. Simulation results obtained in a Blender 3D environment demonstrate that the proposed FTC predictive strategy significantly reduces the variance of task completion times under fault conditions compared to a baseline First-In-First-Out approach. Furthermore, the IoT integration successfully simulates and validates the feasibility of human-in-the-loop task injection within a realistic, stochastic scenario. Full article

A therapeutic antibody, CSL305, has been developed, which combines inhibition of the complement classical and lectin pathways via complement C2 binding with an ability to act as an antagonist of the neonatal Fc receptor (FcRn). CSL305 binds to human C2 (huC2) but shows no binding or activity against mouse C2 precluding its use in mouse models of disease to fully assess in vivo efficacy. To circumvent this, a mouse strain was developed that replaced the expression of mouse C2 with huC2 by homologous recombination. These mice (huC2 “knock-in”; KI) were shown to express huC2 protein and to have complement activity. Interestingly, male huC2-KI mice showed much stronger complement activity compared to female mice and were also sensitive to inhibition by CSL305. Two models of disease using male huC2-KI mice were then used to assess the in vivo efficacy of CSL305. The first was an attenuated passive anti-glomerular basement membrane (GBM) glomerulonephritis model involving complement activation as its primary mechanism of action. CSL305 showed dose-dependent inhibition of disease as measured by urine albumin, with reductions in kidney cellular infiltration and plasma C3 cleaved fragments C3b/C3c/iC3b also observed. The second model was a collagen autoantibody-induced arthritis (CAIA) mouse model. Here, CSL305 showed a significant and dose-dependent inhibition of clinical score in both prophylactic and therapeutic settings, mediated exclusively via its FcRn mechanism of action. Although the animal models used in this study were found to preclude the demonstration of a synergistic effect on both mechanisms, CSL305 does act in vivo as both a complement inhibitor and as a FcRn antagonist to ameliorate disease. Full article

Severe subacute exposure to aluminium chloride (AlCl₃) impairs renal function and induces cortical tubular injury; however, the concomitant balance between injury and repair in tubular epithelia remains incompletely defined. Accordingly, we aimed to use a high-dose regimen of AlCl₃ (100 mg·kg⁻¹·day⁻¹ for 30 days, oral gavage) as a standardised renal stressor in male Wistar rats to quantify shifts along the injury–repair balance in the renal cortex and to test whether L-carnitine (LC) pretreatment (200 mg·kg⁻¹·day⁻¹) can attenuate these shifts. Twenty rats were assigned to four groups: control, LC alone, AlCl₃ alone, and LC followed 60 min later by AlCl₃. On day 31, we assessed body-weight gain, renal functional markers, blinded cortical lesion scoring, quantitative histochemistry, and immunohistochemical profiling of cleaved caspase-3 (apoptotic signalling) and Ki-67 (proliferative engagement) within the same cortical compartment. AlCl₃ exposure produced a severe renal stress phenotype compared with controls, reducing body-weight gain from 99.8 ± 8.6 to 24.0 ± 8.3 g and increasing serum urea and creatinine from 26.40 ± 3.21 to 48.60 ± 5.81 mg/dL and from 0.606 ± 0.063 to 0.956 ± 0.147 mg/dL, respectively. Cortical injury increased from 0 (0–0) in controls to 15 (15–15) after AlCl₃ exposure. AlCl₃ also reduced strong PAS area from 97.92 ± 1.10% to 52.37 ± 14.68% and protein optical density from 0.353 ± 0.020 to 0.269 ± 0.039, while increasing collagen area fraction from 6.92 ± 1.67% to 18.40 ± 3.02% and cleaved caspase-3 from 1.0 (1.0–2.0) to 12.0 (12.0–12.0). Ki-67 labelling declined from 17.80 ± 3.35% to 6.00 ± 1.58%, indicating suppressed proliferative engagement. Compared with AlCl₃ alone, LC pretreatment showed partial protection, with higher body-weight gain (70.0 ± 15.6 g), lower serum urea and creatinine (21.40 ± 2.30 mg/dL and 0.580 ± 0.084 mg/dL), lower cortical injury burden [3 (3–4)], greater strong PAS area (89.25 ± 2.67%), higher protein optical density (0.354 ± 0.012), lower collagen area fraction (12.26 ± 1.70%), lower cleaved caspase-3 [4.0 (4.0–6.0)], and higher Ki-67 labelling (10.60 ± 2.30%). Residual cortical injury, persistent collagen elevation, and incomplete Ki-67 preservation indicate that LC pretreatment attenuated, but did not fully prevent, AlCl₃-induced renal cortical alterations. Overall, high-burden AlCl₃ exposure not only enhanced cell loss but also impaired regenerative renewal, whereas LC pretreatment partially preserved this injury–repair balance. Full article

Background: Acquired tolerance to temozolomide (TMZ) remains one of the main obstacles to enduring therapeutic success in glioblastoma (GBM). While tumor-derived extracellular vesicles are known to orchestrate therapy evasion by horizontally transferring molecules across the tumor microenvironment, the precise regulatory roles of specific exosomal circular RNAs (circRNAs) in establishing this refractory state require further elucidation. Methods: The expression of circ_0050688 in TMZ-resistant GBM clinical tissues and cell lines was evaluated. Exosomes derived from resistant cells were isolated and confirmed via transmission electron microscopy (TEM) and marker analysis. PKH67 fluorescent tracking was utilized to visually demonstrate exosome internalization by sensitive recipient cells. Biological functions, including the expression of the multidrug resistance protein P-glycoprotein (P-gp) and the proliferation marker Ki-67, were evaluated. The competing endogenous RNA mechanism was validated using RNA FISH, dual-luciferase reporters, and functional rescue experiments. In vivo efficacy was determined using subcutaneous xenograft mouse models. Results: Clinical and in vitro analyses revealed that circ_0050688 is upregulated in TMZ-refractory GBM, predicting adverse patient survival. Through PKH67-based tracing, we confirmed that resistant cells actively secrete circ_0050688-enriched exosomes, which are subsequently engulfed by drug-sensitive bystander cells. This vesicular transfer directly instigates a chemoresistant and highly proliferative phenotype, marked by elevated P-gp and Ki-67 levels. At the molecular level, circ_0050688 operates as a molecular decoy for miR-508-5p, thereby preventing the suppression of its downstream target, MDM2. Functionally, circ_0050688 depletion eradicated these aggressive traits and restored TMZ vulnerability across both cellular and murine xenograft models. Furthermore, rescue assays confirmed that this circ_0050688-driven chemoresistance is fundamentally dependent on the miR-508-5p/MDM2 signaling axis. Conclusions: Current data uncover an intercellular signaling network driven by vesicular circ_0050688, which functions as a mobile oncogene to reshape the TMZ-refractory microenvironment. Targeting this exosomal circ_0050688/miR-508-5p/MDM2 network to suppress P-gp and Ki-67 expression represents a highly promising therapeutic strategy for refractory GBM. Full article