Temperature Self-Limited Intelligent Thermo-chemotherapeutic Lipid Nanosystem for P-gp Reversal Time Window Matched Pulse Treatment of MDR Tumor.

Mild photothermal therapy (PTT) shows the potential for chemosensitization by tumor-localized P-glycoprotein (P-gp) modulation. However, conventional mild PTT struggles with real-time uniform temperature control, obscuring the temperature-performance relationship and resulting in thermal damage. Besides, the time-performance relationship and the underlying mechanism of mild PTT-mediated P-gp reversal remains elusive. Herein, we developed a temperature self-limiting lipid nanosystem (RFE@PD) that integrated a reversible organic heat generator (metal-phenolic complexes) and metal chelator (deferiprone, DFP) encapsulated phase change material. Upon NIR irradiation, RFE@PD released DFP for blocking ligand-metal charge transfer to self-limit temperature below 45 °C, and rapidly reduced P-gp within 3 h via Ubiquitin-proteasome degradation. Consequently, the DOX·HCl-loaded thermo-chemotherapeutic lipid nanosystem (RFE@PD-DOX) led to dramatically improved drug accumulation and 5-fold chemosensitization in MCF-7/ADR tumor models by synchronizing P-gp reversal and drug pulse liberation, achieving a tumor inhibition ratio of 82.42%. This lipid nanosystem integrated with "intrinsic temperature-control" and "temperature-responsive pulse release" casts new light on MDR tumor therapy.

Massive Chylous Leakage After Endoscopic Thyroidectomy with Central Lymph Node Dissection: A Case Report.

BACKGROUND Massive chylous leakage represents a rare yet potentially life-threatening complication following neck dissection, and its occurrence is even less common in the context of endoscopic thyroid surgery. Chylous leakage poses significant clinical management challenges, encompassing prolonged hospitalization, nutritional deficiencies, electrolyte imbalances, and the potential for infection. It is imperative for surgeons to remain vigilant and proactive in recognizing and managing chylous leakage to mitigate its potential impact on patient outcomes. CASE REPORT A 37-year-old woman presented with a thyroid nodule, and subsequent fine-needle aspiration biopsy confirmed the diagnosis of papillary thyroid carcinoma. She then underwent endoscopic thyroidectomy with central lymph node dissection via a bilateral areola approach and experienced significant postoperative chylous leakage. Various conservative management strategies were used to treat the leak, including fasting, parenteral nutrition, maintenance of electrolyte balance, and continuous infusion of somatostatin. After failure of a series of conservative treatments, the patient underwent a reoperation to address the leak via the initial approach. After identification of the leak site, the residual end of the lymphatic vessel was clamped with a biological clamp, and no further chylous leakage was observed. The drainage was removed 4 days after the second operation, and the patient was discharged on the fifth day. During follow-up, no abnormalities were observed. CONCLUSIONS Managing significant chylous leakage poses a challenge for surgeons. This complication is rare following endoscopic thyroidectomy with central lymph node dissection, and there remains a lack of experience in effective prevention and treatment. We aim to raise awareness through our case report.

A coordinative modular assembly-constructed self-reinforced nano-therapeutic agent for effective antitumor-immune activation.

Immunosuppressive microenvironment and poor immunogenicity are two stumbling blocks in anti-tumor immune activation. Tumor associated macrophages (TAMs) play crucial roles in immunosuppressive microenvironment, while immunogenic cell death (ICD) is a typical strategy to boost immunogenicity. Herein, we developed a coordinative modular assembly-based self-reinforced nanoparticle, (CaO2/TA)-(Fe3+/BSA) which integrated CaO2, Fe3+-tannic acid coordinated networks and albumin under the instruction of molecular dynamics simulation. (CaO2/TA)-(Fe3+/BSA) could significantly enhance Fenton reaction through Fe3+ self-reduction and H2O2 self-sufficiency, and simultaneously increased intracellular accumulation of Ca2+. The self-augmented Fenton reaction with sufficient reactive oxygen species effectively repolarized TAMs and elicited ICD with Ca2+ overload. Besides, (CaO2/TA)-(Fe3+/BSA) was confirmed to self-reinforce deep tumor drug delivery by "treatment-delivery" positive feedback based on gp60-mediated transcytosis and M2-like macrophages repolarization-mediated perfusion promotion. Resultantly, (CaO2/TA)-(Fe3+/BSA) effectively alleviated immunosuppression, provoked local and systemic immune response and potentiated anti-PD-1 antibody therapy. Our strategy highlights a facile and controllable approach to construct penetrated effective antitumor nano-immunotherapeutic agent.

The diagnostic value of GICA used for intraoperative lymph node FNA-Tg measurement to evaluate thyroid cancer metastases.

Objective: It is crucial to diagnose lymph node (LN) metastases (LNM) before or during thyroid carcinoma surgery. Measurement of thyroglobulin (Tg) in the fine needle aspirate washout (FNA-Tg) is useful to assist in the diagnosis of LNM for papillary thyroid carcinoma (PTC). This study aimed to assess the diagnostic performance of a new technique based on a colloidal gold-based immunochromatographic assay (GICA) for intraoperative FNA-Tg in diagnosing LNM. Clinical trial information: This study is registered with chictr.org.cn, ID: ChiCTR2200063561 (registered 11 September, 2022). Methods: This prospective study enrolled 51 PTC patients who underwent cervical LN dissection. A total of 150 LNs dissected from the central and lateral compartments were evaluated by FNA-Tg-GICA at three different time points and compared with frozen sections and the conventional Tg measurement method electrochemiluminescence immunoassay (ECLIA). Receiver operating characteristic curve (ROC) and area under the curve (AUC), cutoff value to discriminate benign and malignant LNs, sensitivity, specificity, and accuracy were provided. Results: The cutoff value of FNA-Tg to predict LNM was 110.83 ng/mL for ECLIA and 13.19 ng/mL, 38.69 ng/mL, and 77.17 ng/mL for GICA at 3, 10, and 15 min, respectively. There was no significant difference between the AUCs of GICA at different time points compared to using ECLIA and frozen sections. Besides, the diagnostic performance of GICA and ECLIA showed no significant difference in evaluating LNM from central and lateral compartments or between the TgAb-positive subgroup and TgAb-negative subgroup. Conclusion: GICA is a promising method for intraoperative FNA-Tg measurement and has high value in predicting LNM. It may be a novel alternative or supplementary method to frozen section or ECLIA.

PGR-KITLG signaling drives a tumor-mast cell regulatory feedback to modulate apoptosis of breast cancer cells.

The immune microenvironment constructed by tumor-infiltrating immune cells and the molecular phenotype defined by hormone receptors (HRs) have been implicated as decisive factors in the regulation of breast cancer (BC) progression. Here, we found that the infiltration of mast cells (MCs) informed impaired prognoses in HR(+) BC but predicted improved prognoses in HR(-) BC. However, molecular features of MCs in different BC remain unclear. We next discovered that HR(-) BC cells were prone to apoptosis under the stimulation of MCs, whereas HR(+) BC cells exerted anti-apoptotic effects. Mechanistically, in HR(+) BC, the KIT ligand (KITLG), a major mast cell growth factor in recruiting and activating MCs, could be transcriptionally upregulated by the progesterone receptor (PGR), and elevate the production of MC-derived granulin (GRN). GRN attenuates TNFα-induced apoptosis in BC cells by competitively binding to TNFR1. Furthermore, disruption of PGR-KITLG signaling by knocking down PGR or using the specific KITLG-cKIT inhibitor iSCK03 potently enhanced the sensitivity of HR(+) BC cells to MC-induced apoptosis and exerted anti-tumor activity. Collectively, these results demonstrate that PGR-KITLG signaling in BC cells preferentially induces GRN expression in MCs to exert anti-apoptotic effects, with potential value in developing precision medicine approaches for diagnosis and treatment.