Correlation between CNA and mRNA Expression Observed in TCGA Datasets

FADD exhibits a significant increase in expression during tumor progression.

Neural structures are widely distributed in the oral and maxillofacial region and play important roles in the progression of head and neck squamous cell carcinoma (HNSCC). Herein, we delineate the dynamic transition trajectory of Schwann cells during cancer initiation and progression and identify a Schwann cell subpopulation, HLA-DR+ Schwann cell, that induced by cancer cells and enriched as HNSCC progression. With the in vitro coculture assay and a Schwann cell-targeted gene engineering in vivo model, we demonstrate that Schwann cells are educated by HNSCC cells via the NRG1/ERBB3 axis, activate the downstream JAK/STAT signaling pathway, and acquire immunoregulatory and protumor phenotypes. Furthermore, HLA-DR+ Schwann cells are found to secrete CCL2 to induce a protumor macrophage subpopulation (Il1β. Mph), which promotes CD4+ T cell accumulation via CXCL10/CXCR3 for HLA-DR+ Schwann cells and assists them in shaping the cancer-neuron-immune niche and facilitating HNSCC progression. The tumor suppression effects of CCL2 inhibitor (Pirfenidone) and CXCR3 inhibitor (AMG487) are validated in the orthotopic tumor model. Our findings reveal the mechanism of how HLA-DR+ Schwann cells generate cancer-neuron-immune niche, provide insights into tumor neurology, and lay foundations for therapeutics development for HNSCC patients.

Denosumab is a humanized monoclonal antibody targeting receptor activator of nuclear factor-κB ligand(RANKL)and is commonly used in the treatment of osteoporosis and cancer-related bone metastases.However,the per-sistent use of denosumab has been associated with an increasing incidence of denosumab-related osteonecrosis of the jaw(DRONJ),particularly following tooth extraction.This expert consensus aims to develop clinical management guidelines for the perioperative period of tooth extraction in patients who are currently receiving or have previously received deno-sumab therapy.The consensus covers the definition,etiology,epidemiology,staging,and risk factors of DRONJ,focus-ing on preoperative assessment,risk-based prevention strategies,minimally invasive surgical techniques,and postopera-tive follow-up protocols.The core management strategy for DRONJ emphasizes individualized decision-making based on a comprehensive preoperative assessment of medication history,local infection,and systemic conditions.The main risk factors for DRONJ include high-dose and long-term denosumab therapy,preexisting oral infections,such as peri-odontitis and periapical periodontitis,and invasive dental procedures,including tooth extraction,diabetes,and concomi-tant use of glucocorticoids or antiangiogenic agents.Core preventive measures include strict perioperative oral care,risk assessment-based antibiotic prophylaxis,long-term drug holidays,which were developed by dentists and physicians prio-ritizing the primary disease,and minimally invasive surgical techniques for managing trauma,preserving local blood sup-ply,thoroughly removing infected tissues,and ensuring tight wound closure.This consensus highlights the importance of multidisciplinary collaboration between dental and clinical medicine experts in managing DRONJ.High-quality research is necessary to provide an evidence-based foundation for optimizing DRONJ prevention and treatment strategies.

6049 Background: Immune checkpoint inhibitors (ICIs) are the standard treatment for recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (HNC) after failure of platinum-based chemotherapy; however, the clinical benefit remains limited, with reported overall response rate (ORR) of approximately 13% and median progression-free survival (PFS) of about 2 months in the second line setting. GT201 is an autologous TIL therapy engineered to express membrane-bound IL-15 (mbIL-15), which may enhance immune activation in the tumor microenvironment and promote durable response. We report preliminary safety and efficacy results from an open-label, single-arm study evaluating GT201 in combination with the PD-1 inhibitor toripalimab in patients with R/M HNC (NCT06190275). Methods: The primary endpoint was safety, including treatment-emergent adverse events (TEAEs) graded per CTCAE v5.0. Secondary endpoints included ORR, disease control rate (DCR), PFS, duration of response (DOR), and overall survival (OS), assessed per RECIST v1.1. Results: As of November 30, 2025, 6 patients with R/M HNC were treated (median age of 57 years; median 1 prior line of therapy). Histology indicated 5 squamous cell carcinoma and 1 lymphoepithelial carcinoma. All patients received 1–2 cycles of bridge therapy, followed by lymphodepletion (low-dose in 5 patients; intermediated-dose in 1 patient), GT201 infusion (5×10 9 -5×10 10 viable cells), and high-dose IL-2 (600,000 IU/Kg; 4-6 doses). Five patients subsequently received toripalimab; one patient progressed prior to PD-1 inhibitor treatment. Maximum follow-up was 15.5 months. Most of AEs were Grade 1-2. Grade ≥ 3 AEs were primarily related to lymphodepletion and IL-2, and included cytopenia, neutropenia, lymphocytopenia, monocytopenia, hypokalemia, rash, and increased bilirubin; all resolved or improved to Grade ≤ 2 within 14 days. The ORR was 66.7% (4/6), including 2 complete response (CR) and 2 partial response(PR); DCR was 83.3% (5/6). One patient with CR remains progress-free exceeding 12 months. Median PFS and OS have not yet been reached. GT201 cells expanded robustly and persisted in peripheral blood for at least 6 months post-infusion. Conclusions: GT201 combined with toripalimab demonstrated a manageable safety profile and encouraging antitumor activity in heavily pretreated R/M HNC, supporting further clinical development of this combination. Clinical trial information: NCT06190275 . Research Sponsor: Grit Biotechnology.

Bisphosphonates (BPs), widely used anti-resorptive agents for osteoporosis and cancer-related bone metastasis, can paradoxically contribute to medication-related osteonecrosis of the jaw (MRONJ). Our previous work showed that periodontal ligament stem cells (PDLSCs) from MRONJ patients display severely impaired osteogenesis; however, how BPs directly regulate PDLSC function remains unclear. In this study, human PDLSCs were exposed to graded concentrations of zoledronate (ZOL, 0.01–10 μM) to characterize dose-dependent effects on cell viability, apoptosis, and osteogenic differentiation. High-dose ZOL markedly reduced proliferation, induced apoptosis, and strongly inhibited osteogenesis. In contrast, low-dose ZOL promoted osteogenic differentiation in vitro, enhanced mineralization, and increased ectopic bone formation in vivo. Transcriptomic and molecular analyses revealed that ZOL activated Wnt/β-catenin and MAPK signaling, and blockade of either pathway attenuated the osteogenic enhancement. These findings demonstrate a double-edged-sword effect of BPs on PDLSCs: low-dose ZOL enhances osteogenesis through coordinated activation of Wnt/β-catenin and MAPK pathways, whereas high-dose exposure is cytotoxic and suppresses regenerative potential. The results underscore the necessity of precise BP dose control to maximize periodontal regeneration while minimizing MRONJ risk.

FADD and CCND1 co-inhibition restrained cell proliferation

BACKGROUND:Fibrous dysplasia (FD) is a rare osseous disorder with limited understanding. This study aimed to evaluate the clinical characteristics of craniofacial FD (CFD) and orbital FD (OFD), explore vision impairment mechanisms, and identify recurrence risk factors. METHODS:A retrospective analysis was conducted on 54 CFD patients across three centers, including 30 patients with orbit involved. RESULTS:OFD patients exhibited higher prevalences of polyostotic FD and McCune-Albright syndrome, and more often underwent debulking rather than radical surgery. Vision impairment was primarily attributed to compressive and stretched optic neuropathy. Polyostotic involvement (p = 0.034) was a risk factor of subjective recurrence. Surgery age < 16 years (p = 0.046) and abnormal body mass index (p = 0.002) were associated with greater postoperative lesion regrowth volume. CONCLUSIONS:OFD patients exhibit distinct clinical features. Optic canal decompression is not required for all OFD-related vision loss patients. Recurrence risk should be thoroughly assessed before surgery.

Combined PHA-767491 and Abemaciclib markedly restricted cell growth in chr11q13.3-amplified cells

BACKGROUND:Reconstruction of mandibular symphysis defects using deep circumflex iliac artery (DCIA) flap remains challenging due to the unique morphology and high technical requirements. Virtual surgical planning (VSP) and template-guided workflows may improve accuracy and efficiency. METHODS:This retrospective study evaluated clinical outcomes of patients with mandibular symphysis defects applied with DCIA flap. The primary outcome was morphological accuracy of actual post-operative model (APM) relative to virtual preoperative model (VPM), including deviations in superimposition, graft length, intercondylar (ICL) and intergonial (IGL) length, coronal (CMA), axial (AMA) and sagittal (SMA) mandibular angles. The secondary outcome was perioperative complication rates and functional outcomes. RESULTS:Thirty-one patients were included between 2018 and 2023 (18 with double-segment and 13 with triple-segment bone graft). All cases utilized VSP and Resection & Cutting-Osteotomy-Trimming (Re-COT) template system. Baseline and peri-operative parameters were comparable between groups. Double-segment procedures took significantly less time than triple-segment procedures (P=0.028). Superimposition deviations of neo-mandible and bone graft were negligible between the groups (P=0.357 and 0.242, respectively). The linear deviations were all similar between the two groups: bone graft length (P=0.224), ICL (P=0.722) and IGL (P=0.488). Left-side CMA deviation was significantly lower in double-segment group compared with triple-segment group (1.35 (0.68, 1.78) vs. 1.80 (1.50, 2.20), P=0.015). Rest of the angular deviations, including right-side CMA, AMA and SMA in both sides, all showed comparable results (P>0.05). CONCLUSIONS:DCIA flap reconstruction guided by VSP and Re-COT template system is a reliable method for restoring symphyseal mandibular defects, ensuring high anatomical accuracy and procedural efficiency.

Objective Based on plasma lipidomics combined with machine learning approaches,this study aimed to screen molecular biomarkers for the diagnosis of early-stage lung cancer in elderly patients and to evaluate their diagnostic performance.Methods This was a retrospective diagnostic study consisting of two parts.The first part involved molecular biomarker screening.Elderly patients with early-stage lung cancer(early lung cancer group),patients with benign pulmonary nodules(benign nodule group),and contemporaneous healthy in-dividuals undergoing physical examinations(healthy control group)were enrolled from Peking University People's Hospital between November 2023 and November 2024.In addition,early-stage lung cancer patients and healthy controls meeting the inclusion criteria from a previous study of our research group were included as an independent validation cohort.Plasma samples were collected from all subjects,and untargeted lipidomics analysis was per-formed using high-performance liquid chromatography-mass spectrometry.Principal component analysis and or-thogonal partial least squares discriminant analysis were used to evaluate metabolic differences between groups.L1-regularized support vector machine combined with incremental feature selection was employed to screen diag-nostic biomarkers for early-stage lung cancer.Model performance was assessed using receiver operating character-istic curves,calibration curves,Brier scores,and decision curve analysis.The second part involved functional validation of the molecular biomarkers using the human lung adenocarcinoma cell line A549,with palmitoylcarni-tine(CAR 16:0)selected as a representative biomarker for functional validation via CCK-8 and cell scratch as-says.Results A total of 36 patients in the early lung cancer group,35 patients in the benign nodule group,and 41 healthy controls were enrolled,along with an independent validation cohort of 110 individuals(59 patients with early-stage lung cancer and 51 healthy controls).The principal component analysis results demonstrated that quality control samples were tightly aggregated at the centroid of all samples,reflecting robust instrument perform-ance and dependable data quality.Orthogonal partial least squares discriminant analysis revealed significant meta-bolic differences between the early lung cancer group and the control group(benign nodule group+healthy con-trol group)(R2X = 0.406,R2Y = 0.529,Q2Y = 0.44).L1-regularized support vector machine identified five carnitine-related lipids-palmitoleoylcarnitine(CAR 16:1),palmitoylcarnitine,α-linolenoylcarnitine(CAR 18:3),linoleoylcarnitine(CAR 18:2),and oleoylcarnitine(CAR 18:1)-as diagnostic biomarkers for early-stage lung cancer,all with stability values>98％.In the screening scenario(early lung cancer group vs.be-nign nodule group+healthy control group),the model based on these five biomarkers achieved an area under the curve(AUC)of 0.895(95％CI:0.700-1.000)for diagnosing early-stage lung cancer,with a sensitivity of 98.4％,specificity of 63.9％,and accuracy of 75.0％.For differentiating early-stage lung cancer from benign pulmonary nodules,the model yielded an AUC of 0.877(95％CI:0.797-0.965),sensitivity of 86.1％,and specificity of 80.0％.For differentiating early-stage lung cancer from healthy controls,the model yielded an AUC of 0.929(95％CI:0.877-0.988),sensitivity of 94.4％,and specificity of 85.4％.Calibration and decision curve analyses demonstrated good model calibration and overall net benefit for patients with early-stage lung canc-er.In the independent validation cohort,the model achieved an AUC of 0.874(95％CI:0.781-0.940)for di-agnosing early-stage lung cancer,with a sensitivity of 86.4％,specificity of 82.4％,and accuracy of 84.5％.In vitro experiments showed that palmitoylcarnitine inhibited the proliferation and migration of A549 cells,with a half-maximal inhibitory concentration of 57.12 μmol/L.Conclusions The five plasma carnitine-related lipids screened based on untargeted lipidomics and machine learning may serve as potential molecular biomarkers for the diagnosis of early-stage lung cancer in elderly patients.The high-sensitivity characteristic of the model makes it particularly suitable for screening scenarios in early-stage lung cancer.

Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is characterised by hyperactivation of the cyclin-dependent kinase 4/6 (CDK4/6) pathway. As immunotherapy has become the first-line treatment for HNSCC, resistance to anti-programmed death-1 (PD-1) agents has emerged as a pivotal challenge. This prospective, single arm, phase II study (NCT05721443) evaluated the efficacy and safety of dalpiciclib, a CDK4/6 inhibitor, combined with cetuximab in patients with anti-PD-1-resistant, HPV-negative recurrent and/or metastatic HNSCC. Patients diagnosed with p16-negative R/M HNSCC resistant to first-line anti-PD-1 therapy without prior cetuximab treatment were enroled. Patients received oral dalpiciclib (150 mg daily on days 1-21 of each 28-day cycle) and intravenous cetuximab (400 mg/m2 on day 1 of cycle 1, followed by 250 mg/m2 weekly in each cycle). The primary endpoint was objective response rate (ORR), secondary endpoints were overall survival, progression-free survival, duration of response, and safety. Between March 2023 and November 2024, a total of 28 patients were enroled. The ORR was 67.9

Clarifying the role of chr11q13.3 and the related genes in this amplicon in HNSCC

Correlation between Chr11q13.3 Amp and FADD staining and clinicopathologic characteristics in 64 HNSCC cases in 9h cohort.

Correlation between FADD and clinicopathologic characteristics in 238 HNSCC cases in JS cohort.

Natural killer (NK) cells frequently exhibit an exhausted state, which facilitates immune escape of circulating tumor cells (CTCs). However, the underlying mechanisms of NK cell dysfunction remain elusive. In this study, we identified a novel immune evasion mechanism whereby tumor cells deliver Vimentin to NK cells via NKp46-dependent trogocytosis, thereby impairing NK cell cytotoxicity. We observed the expression of nonendogenous proteins in NK cells isolated from CTCs from oral cancer patients but not in those from nondetectable patients. High-throughput proteomic analysis, flow cytometry, and confocal microscopy revealed that vimentin, a protein that is not endogenously expressed in NK cells, was significantly enriched in NK cells via NKp46-dependent trogocytosis. The tail domain of trogocytosed vimentin competed with CDC42 for binding to ARHGEF7 and inhibited its exchange activity. This disruption impaired CDC42-mediated actin polymerization, thus suppressing NK cell cytotoxicity. By delivering vimentin to NK cells, CTCs can suppress and evade attacks from NK cells. Crucially, pharmacological inhibition of vimentin trogocytosis increased the efficacy of NK cells in clearing CTCs in vivo and that of NK cell-based adoptive immunotherapies. Clinically, the frequency of vimentin (+) NK cells is correlated with the CTC burden and tumor recurrence in cancer patients. Our study reveals that trogocytosis acts as a conduit for the tumor-induced exhaustion of NK cells and proposes targeting Vimentin transfer as a therapeutic strategy to counteract tumor recurrence.

FADD overexpression accelerated S-phase entry

The immunosuppressive tumor microenvironment limits the efficacy of therapies that target metabolism. Here we show a strategy of dual metabolic regulation that simultaneously reprogramming glycolysis in cancer cells and fructose metabolism in tumor-associated macrophages, transforms the metabolic ecosystem from pro-tumor to antitumor, eliciting systemic immunity. Through pan-cancer single-cell analysis, we identified a metabolic division of labor: cancer cells exhibit hyperactive glycolysis, while immunosuppressive macrophages display elevated fructose metabolism. We uncovered that manganese ions (Mn2+) selectively suggest a potential inhibitory effect on glycolysis, induce pyroptosis, yet paradoxically upregulate fructose metabolism in M2-like macrophages, creating an exploitable vulnerability. To harness this dual activity, we engineered a 3D-printed nanoporous Cu-Mn alloy (CuMn) that provides sustained intratumoral release of Mn2+ and delivers a fructokinase inhibitor. In a bilateral breast carcinoma model, a single intratumoral implantation of this platform suppressed primary tumor growth and eradicated distant untreated lesions. Therapeutic efficacy was associated with macrophage reprogramming, which remodeled the immune microenvironment, alleviated T cell exhaustion, and inhibited distant tumor growth, suggesting potential systemic antitumor effects. Local delivery of the nano platform offers a strategy to overcome tumor immunosuppression and enhance cancer immunotherapy.