Skin aging could lead to dermal collagen loss and elastic fiber degradation, ultimately manifesting as skin laxity. We aimed to counteract this by using poly-L-lactic acid (PLLA) microsphere (MS)-based fillers to facilitate long-term volume restoration through collagen regeneration. However, conventional MSs exhibit limitations such as broad size distribution and surface irregularities, which are frequently associated with significant adverse reactions. This study employed shirasu porous glass (SPG) membrane emulsification to fabricate uniform and well-shaped polyethylene glycol-block-poly (L-lactic acid) (PEG-PLLA) MSs. A single-factor experiment was employed to optimize the parameters. The optimal preparation conditions for PEG-PLLA MSs were as follows: PEG-PLLA concentration of 40 mg/mL, polyvinyl alcohol (PVA) concentration of 0.5%, and magnetic stirring speed of 200 rpm. Under the optimal conditions, the average particle size of PEG-PLLA MSs was 58.982 μm, and the span value (SPAN) was 1.367. In addition, a cytotoxicity assay was performed, and the results revealed no significant toxicity of the MSs toward L929 mouse fibroblasts at concentrations below 500 μg/mL. Furthermore, PEG-PLLA MSs significantly enhanced the production of key extracellular matrix (ECM) components—type I collagen (Col-I), type III collagen (Col-III), and hyaluronic acid (HA)—while simultaneously alleviating cellular oxidative stress responses. This work offers a reliable and reproducible fabrication strategy for developing biocompatible MS fillers with controllable particle sizes.

Improving the toughness, antibacterial properties, and flame retardancy of poly(l-lactic acid) (PLLA) is crucial for its use in plastic packaging. However, few studies have achieved simultaneous enhancement with a single additive due to poor interfacial compatibility and low efficiency. To overcome these challenges, a multifunctional additive poly(butylene succinate)-based polyurethane ionomer (PBSUI) was synthesized. Specifically, the flexible polyester segments in PBSUI enhance toughness, while its unique ionic units provide antibacterial performance and flame retardancy. Thanks to this unique structure, the long-standing challenge of achieving good compatibility between additives and PLLA has been effectively addressed. Notably, the PLLA/PBSUI9 blend achieved an elongation at break of 212%, which is 20 times higher than that of pure PLLA, while maintaining a moderate tensile strength of 39.7 MPa. Moreover, the fire safety of PLLA is significantly enhanced even with a low addition of PBSUI. When the PBSUI content reaches 5 wt %, the limiting oxygen index (LOI) value increases to 25.8%, and the UL-94 rating achieves the highest level V-0. In addition, the PLLA/PBSUI blends exhibit excellent antibacterial properties. Even with only 3 wt % PBSUI, the antibacterial activity against both Escherichia coli and Staphylococcus aureus exceeds 99.9%, demonstrating strong potential for practical applications.

Poly(lactic acid-lactic acid) (PLGA) has demonstrated significant application potential in tumor-targeted drug delivery systems due to its excellent biocompatibility, degradability, and multifunctionality for loading various therapeutic agents. PLGA nanoparticles (NPs) can achieve targeted delivery to tumor cells through specific surface modifications and stimulus-responsive release mechanisms, significantly enhancing drug accumulation efficiency at tumor sites while reducing toxic side effects on normal tissues. This review systematically summarizes the fundamental physicochemical properties of PLGA materials and recent advances in tumor-targeting strategies for PLGA NPs. It comprehensively elucidates research breakthroughs in PLGA-based delivery systems regarding stimulus-response mechanisms, passive targeting, active targeting, and tumor combination immunotherapy, while revealing the intrinsic logic of synergistic strategies for enhancing targeting efficiency. Finally, from the perspective of clinical translation and individualized oncology, this review conducts an in-depth assessment of the current challenges and looks forward to future research directions, aiming to provide forward-looking guidance for the development of precision nanomedicine.

2547 Background: Immune checkpoint inhibitors (ICIs) have remarkably improved survival in advanced non-small-cell lung cancer (NSCLC), with about 30%～40% of patients achieving long-term responses. However, biomarkers for predicting progression remain undefined. Circulating tumor DNA (ctDNA) has demonstrated its ability to predict recurrence in resected NSCLC, but its potential to forecast progression following prolonged responses to ICIs requires investigation. Methods: CR1STAL study is a multicenter, prospective cohort study investigating ctDNA surveillance to monitor progression risk in advanced NSCLC treated with first-line ICIs (NCT05198154). Patients with advanced NSCLC with long-term responses, defined as a PFS of about 1 year, were enrolled. Peripheral blood samples were collected alongside radiographic evaluations. ctDNA was detected using a personalized tumor-informed assay. Somatic variants were identified using a targeting 1,021 genes, followed by the design of individualized target-capture. ctDNA-positive was defined as the detection of ctDNA at any time during surveillance. The primary endpoint was PFS, defined as the time from enrollment until progression or death. Secondary endpoints included OS and ORR. Exploratory endpoints included the association between ctDNA features and survival, and comparison to other biomarkers. Results: We analyzed 199 sample from 42 NSCLC patients. The median age was 60.5 years with 88.1% male, and 64.3% at stage IV. The median number of sample collections was 4, with a median follow-up time of 24.7 months. ctDNA was detected in 54.8% of patients (23/42), with 82.7% of patients (19/23) showing ctDNA-positive occurring within 2 years of ICIs treatment. A total of 23 PFS events were observed. The ctDNA-positive group showed significantly worse PFS compared to the negative group (HR: 7.65, p < 0.001), with a positive predictive value of 90.0% and a specificity of 88.2%. Additionally, ctDNA-positive provided a median lead time of 6.6 months prior to radiological progression. ctDNA-positive significantly associated with poorer OS (HR: 68.42, p = 0.003) and lower ORR (60.9% vs 89.5%, p = 0.036). 18 exhibited clonal mutations. Compared to the ctDNA-negative group, the patients with clone had significantly worse PFS (HR: 9.38, p < 0.001) than those with subclone (HR: 4.16, p = 0.063). The ctDNA positivity rate was 84.6% in cases of local progression, 80.0% in distant metastases with brain exhibiting lower positivity rates. Additionally, peripheral CEA showed inferior predictive value for PFS (HR: 1.76, p = 0.303) than ctDNA. Conclusions: ctDNA has emerged as a promising biomarker for predicting progression risk of ICIs in advanced NSCLC patients with long-term responses. ctDNA surveillance enables earlier detection of progression and supports treatment adjustments through adaptive therapy. Clinical trial information: NCT05198154 .

Effective regenerative strategies for spinal cord injury (SCI) depend on promoting neuronal regeneration and suppressing inflammation, both requiring substantial energy. Succinic acid-based materials have attracted attention for enhancing cellular energy through the tricarboxylic acid (TCA) cycle and mitochondrial electron transport. However, succinic potential to exacerbate inflammation complicates therapeutic use, making it crucial to understand how these materials regulate microglial polarization. Here, we presented a degradable bioenergy hydrogel system by integrating succinic acid (SA) into chitosan (CS), yielding an energy-active unit. Upon implantation, degradation of chitosan released energy-active units, which were transported into Bv2 microglial cells via SLC13A3, thereby engaging mitochondrial electron transport chain and the TCA cycle. At optimized concentrations, these energy-active units facilitated M2 polarization of Bv2 cells, augmenting adenosine triphosphate (ATP) levels and driving anti-inflammatory factor expression to support tissue repair. Conversely, excess concentrations triggered mitochondrial reverse electron transport, elevating reactive oxygen species (ROS) production, impairing ATP synthase, and enhancing pro-inflammatory factor release via SLC25A10mediated succinate export. This concentration-dependent effect underscores the nuanced role of succinic acid in modulating microglial polarization states. Furthermore, degradation of CSSA fragments activated the AMPKmTOR and cAMP signaling pathways, significantly boosting ATP synthesis and fostering M2 microglial polarization. Our findings offer a novel avenue to enhance SCI repair by modulating cellular energy balance and refining the inflammatory milieu, while establishing critical concentration parameters for the deployment of succinic acid-based biomaterials in tissue regeneration contexts.

Alzheimer's disease (AD) is characterized by significant clinical and molecular heterogeneity, influenced by genetic and demographic factors. Using an unbiased, network-driven approach, we analyzed the cerebrospinal fluid (CSF) proteome from 431 individuals (483 samples), including 111 African American participants, to identify core protein modules associated with AD, race, sex, and age. Our analysis revealed ten co-expression modules linked to distinct biological pathways and cell types, many of which correlated with established AD biomarkers such as β-amyloid, tau, and phosphorylated tau. To further resolve disease heterogeneity, we applied a proteomic subtyping approach, identifying six distinct CSF subtypes spanning the clinical and pathological spectrum. These subtypes were validated across independent cohorts, with many aligning with previously defined AD subtypes, including those linked to neuronal hyperplasticity, immune activation, and blood-brain barrier (BBB) integrity. Notably, the BBB subtype, enriched with African Americans and men, was characterized by low CSF tau, high CSF/serum albumin ratios, and reduced synaptic protein levels. This subtype also exhibited increased levels of proteolytic enzymes, including thrombin and matrix metalloproteases, that cleave tau. Plasma dilution into the neuronal hyperplastic AD subtype CSF led to reduced tau and synaptic protein module levels, indicating that plasma protease activity contributes to tau and synaptic protein depletion independent of underlying brain pathology. These findings highlight the impact of BBB integrity on CSF tau levels, particularly in men and African Americans, and underscore the need for diversity-informed AD biomarker strategies to improve diagnostics and therapeutic targeting across populations.

The development of carrier-free drug delivery systems (CDDS) for tailored drug combinations posed a significant challenge, particularly in achieving efficient co-assembly while maintaining therapeutic efficacy. Herein, we proposed a co-assembly strategy based on molecular engineering. Paclitaxel (PTX) and 7-ethyl-10-hydroxycamptothecin (SN38) were chemically modified with tert-butoxycarbonyl (BOC) groups. The successful incorporation of the BOC groups was confirmed by proton nuclear magnetic resonance and mass spectrometry analyses. Further characterization using polarized light microscopy and X-ray diffraction revealed that this modification significantly reduced the crystallinity of both drugs, while simultaneously disrupting their original ordered stacking structure. Molecular dynamics simulations indicated that BOC modification increased molecular spacing, reduced stacking density, and expanded molecular volume, resulting in a looser molecular packing arrangement. This structural alteration enabled the modified drug molecules to efficiently coassemble with α-tocopherol succinate (α-TOS) into spherical nanoparticles at a nearly predefined mass ratio. The resulting nanoparticles exhibited a high drug loading capacity of 52.66% and remained stable at 4 °C for over 50 days. Notably, these nanoparticles displayed controllable release characteristics at pH 5.0. Both in vitro and in vivo studies demonstrated the BOC-modified drugs retained their bioactivity. When co-assembled with α-TOS, the nanoparticles exhibited a significant synergistic antitumor effect and suppressed tumor metastasis through downregulation of matrix metalloproteinase-9 (MMP-9) expression. This study provided a solid theoretical foundation and innovative approach for the development of CDDS, utilizing molecular-scale regulation for drug co-assembly.

Background: Pembrolizumab and tislelizumab have shown substantial clinical benefits in perioperative treatment of resectable non-small cell lung cancer (NSCLC), yet no direct head-to-head trial has established which is optimal. This study, for the first time, aimed to directly compare the efficacy and safety of neoadjuvant pembrolizumab plus chemotherapy versus tislelizumab plus chemotherapy in resectable NSCLC using real-world data. Methods: Data of patients with resectable NSCLC treated with neoadjuvant pembrolizumab plus chemotherapy or tislelizumab plus chemotherapy followed by radical resection between December 2017 and August 2023 at the Second Xiangya Hospital of Central South University were retrospectively analyzed. Patients aged 18 years and above, diagnosed with biopsy-proven and treatment-na & iuml;ve clinical stage II-IIIb NSCLC were included in the study. Patients with autoimmune disease, pulmonary interstitial disease, acute infection, or systemic immunosuppression were excluded. Data that may affect treatment efficacy were collected, including age, sex, body mass index (BMI), smoking history, comorbidities, pulmonary function, pathological type, clinical stage, programmed cell death-ligand 1 (PD-L1) tumor proportion score (TPS), dosage of neoadjuvant therapy, duration from final therapy to surgery and chemotherapy regimens, and compared between the two groups. The follow-up was performed through outpatient visits or telephone calls. The last follow-up was set in June 2024. Results: A total of 126 patients were included and divided into the pembrolizumab (n=62) and tislelizumab (n=64) groups with a median follow-up time of 26.3 months. The mean age at diagnosis was 59.76 years (standard deviation, 7.05 years) and 103 patients (81.75%) were current or former smoker. Squamous cell carcinoma (SCC) (102, 80.95%) was the most common histological type, followed by adenocarcinoma (18, 14.29%), large cell neuroendocrine carcinoma (2, 1.59%) and sarcomatoid carcinoma (2, 1.59%). Although there was a lower proportion of SCC (72.58% vs. 89.06%, P=0.02) and a lower use of paclitaxel (75.81% vs. 96.88%, P=0.004) in the pembrolizumab group in the overall cohort, the baseline characteristics between two groups were balanced in the SCC cohort. No significant differences in objective response rate, percentage of primary tumors with no viable tumor cells, pathologic and lymph node downstaging, pathological complete response and major pathological response existed between the two groups in both cohorts. Additionally, disease-free survival and overall survival were similar between the two groups in both cohorts. No significant differences in the postoperative complications and grade 3/4 toxicity profiles existed in both cohorts. Conclusions: This real-world evidence study supports the non-inferiority of neoadjuvant pembrolizumab plus chemotherapy versus tislelizumab plus chemotherapy in terms of efficacy and safety in patients with resectable NSCLC. We believe that our findings could be an important reference for future studies comparing pembrolizumab- and tislelizumab-based treatment combinations in the neoadjuvant setting.

Targeted modulation of metal ion homeostasis in tumor cells has emerged as a promising method for cancer therapy. However, the coordination efficiency and stability of different metal ions posed significant challenges for current multi-metal ions delivery systems. In this study, we presented an innovative strategy that utilized a single-metal ion nanoregulator capable of precisely modulating intracellular dual-metal ion homeostasis. This nanoregulator induced endoplasmic reticulum (ER) stress and cuproptosis, which worked synergistically to inhibit tumor growth. Specifically, a calcium-selective chelator, BAPTA (BA), formed a metal coordination complex with copper ions (Cu2+), which remained stable in the physiological environment but disassembled upon internalized by tumor cells. Once inside, the released BA selectively chelated intracellular calcium ions (Ca2+), depleting ER Ca2+ stores and triggering ER stress. This stress activated the PERK/p-eIF2 alpha/ATF4/CHOP apoptotic pathway, leading to tumor cell apoptosis. Meanwhile, Cu2+ induced cuproptosis and was reduced to Cu+ in the cytosol, where it consumed hydrogen peroxide and generated cytotoxic hydroxyl radicals. These radicals induced oxidative stress, which, combined with glutathione depletion, further amplified ER stress and promoted tumor cell apoptosis. Both in vitro and in vivo experiments exhibited that the nanoregulator effectively suppressed tumor growth through apoptosis and cuproptosis pathways, with favorable biocompatibility. This study highlighted the synergistic roles of copper and calcium ions in tumor therapy and introduced a novel strategy for modulating intracellular dual-metal ion homeostasis, offering more efficient and low toxicity anticancer treatments.

BACKGROUND: Although there has been progress in developing T-cell receptor (TCR)-based biomarkers to predict clinical benefit (CB) in patients treated with immune checkpoint blockade (ICB) therapy, studies on the circulating TCR repertoire in non-small cell lung cancer (NSCLC) remain limited. Therefore, further investigation and validation of the TCR repertoire as a potential biomarker for predicting the benefit of immune checkpoint inhibitor therapy are needed. METHODS: Blood samples were collected from patients with advanced NSCLC before initiating anti-programmed cell death 1 (anti-PD-1) antibody treatment in combination with chemotherapy. Next-generation sequencing was used to analyze the complementarity-determining region 3 (CDR3) of the T cell receptor beta (TRB)gene. Richness, Shannon diversity indices, and the usage of variable and joining genes were studied. TCR repertoire metrics were then correlated with CB, progression-free survival (PFS), and overall survival (OS). RESULTS: We found that the number of unique clones and richness index were comparable between the clinical benefit (CB) and no-clinical benefit (non-CB) groups. A high number of unique clones and a higher richness index were correlated with clinical benefit among patients treated with chemoimmunotherapy (ChIO) therapy. However, despite this association, a statistically non-significant correlation was observed between any of the TCR repertoire metrics and PFS or OS in patients treated with ChIO. Higher TRBJ2-1 frequencies were associated with clinical benefit. Most clonotypes contained CDR3 fragments ranging from 12 to 16 amino acids in length. However, visualization of the relative similarity of TCR repertoires using multidimensional scaling analysis revealed that TCR repertoires of the benefit group could not be separated from those of the benefit group. CONCLUSION: The circulating TCR repertoire may serve as a potential tool for predicting clinical outcomes of anti-PD-1 plus chemotherapy, aiding the selection of patients likely to experience clinical benefit. Further large-scale prospective studies are required to validate these findings.

Background: Emotional distress (ED), with hallmarked symptoms of depression and anxiety, is prevalent among patients with cancer. The association between ED and immunotherapy efficacy is garnering increasing attention in cancer management. We have previously reported the patient with ED demonstrated shorter progression-free survival (PFS) and lower objective response rate (ORR) in non-small-cell lung cancer (NSCLC) (1). We report the results of overall survival (OS). Methods: STRESS-LUNG-1 study is a prospective observational cohort study to investigate the association between ED and efficacy of first-line treatment of immune checkpoint inhibitors (ICIs) in advanced NSCLC (NCT05477979). Stage IIIB-IV NSCLC treated with first-line therapy of ICIs were enrolled. ED was assessed by Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale. Primary end point was investigator-assessed PFS. Secondary end points included ORR, OS and quality of life. Results: A total of 227 NSCLC patients were enrolled with 111 patients (48.9%) presence of ED. Patients in the ED group have a higher proportion of female and non-squamous. The remaining baseline characteristics were well-balanced. The data cutoff was 31 October 2024. With a median follow-up of 26.8 months and OS maturity at 50.2%, the median OS for the overall population was 24.8 months. The patients with baseline ED exhibited poorer OS outcomes. Median OS was not reached with no ED group versus 19.3 months with ED group (HR=1.86, 95% CI 1.28 to 2.71; p=0.001). Besides, compared with the no ED group, the mild ED group (HR=1.81, 95% CI 1.18 to 2.79; p=0.007) and the moderate-to-severe ED group (HR=1.91, 95% CI 1.21 to 3.03; P=0.005) had an increased risk of OS events. Conclusions: Patients with pretreated ED exhibited worse clinical responses to immunotherapy in advanced NSCLC, highlighting the significance of addressing ED in cancer management. Reference: 1. Zeng Y, Hu CH, Li YZ, et al. Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer. Nat Med. 2024;30(6):1680-8.

Background: The recent implementation of perioperative immunotherapy has demonstrated a survival benefit for resectable non-small cell lung cancer (NSCLC) patients. However, there still remains uncertain that which of the immunotherapy regimens for adjuvant, neoadjuvant, and the combination of both has the best effectiveness and safety. We conducted a network meta-analysis to determine the most effective treatment approach.Methods: The randomized controlled trials (RCTs) with perioperative immunotherapy were searched comprehensively, which included primary endpoints of overall survival (OS), disease-free survival (DFS), event-free survival (EFS), objective response rate (ORR) and adverse events (AEs) ≥ 3. A Bayesian fixed-effects consistency model was used to compare the different treatment regimens.Results: Nine RCTs with a total of 7652 patients were involved. The combination of activated cytotoxic killer T cells, dendritic cells, and platinum doublet chemotherapy demonstrated superior OS benefits. In contrast, toripalimab combined with surgery and then followed by additional toripalimab was more effective in improving DFS and EFS. Compared to other treatments such as atezolizumab, durvalumab combined with surgery followed by more durvalumab, intramuscular recMAGE-A3 with AS15 immunostimulant, and pembrolizumab-toripalimab plus surgery followed by more toripalimab showed better efficacy, with hazard ratios of 0.49 (0.32-0.75), 0.59 (0.37-0.93), 0.39 (0.26-0.58), and 0.53 (0.35-0.80) respectively.Conclusions: In the treatment of resectable NSCLC, perioperative immunotherapy brings better efficacy than chemotherapy alone and shows acceptable safety. Neoadjuvant therapy combined with adjuvant treatment is more effective in enhancing survival benefits compared to other treatment options.Funding: This research did not receive any specific grant from funding agencies in the public,commercial, or not-for-profit sectors.Declaration of Interest: The author(s) have no potential conflicts of interest to disclose.

As a natural cationic polymer material, the application of chitosan hydrogel for bone tissue engineering has been greatly limited due to its poor mechanical strength. Enzymatic mineralization has drawn increased attention to effectively improve the mechanical properties of hydrogels. In this study, carboxymethyl chitosan (CMCS) hydrogels cross-linked with different concentrations of genipin (2.5 %, 5 % and 10 %) were prepared and further mineralized through enzyme-induced biomimetic mineralization. The mechanical properties of the CMCS hydrogels were significantly increased as a result of mineralization, showing improvement of 1200-1500 % on storage moduli, and even exhibiting certain tensile behavior with the elongation rate of 30-35 %, likely due to the uniform formation and small size of mineralized products. Interestingly, the cationicity of chitosan also exerted an important modulation effect and the mineralization behavior and mechanical properties of mineralized hydrogels. In addition, the enzymatic mineralized hydrogels showed enhanced biocompatibility and osteogenic differentiation in-vitro, likely due to its superior mechanical properties and the introduction of calcium phosphate biominerals. In vivo experiments further suggest excellent bone-forming activity for the enzymatic mineralized hydrogels. Overall, tuning cationicity and enzymatic mineralization provide an effective approach for the preparation of chitosan hydrogels with superior mechanical and biological properties for bone tissue engineering application.

ABSTRACTBackground and PurposeThe indications of prophylactic extended‐field radiotherapy (EFRT) remain uncertain. This study aims to identify the risk factors for para‐aortic lymph node (PALN) metastases in locally advanced cervical cancer (LACC) and determine which part of patients may benefit from prophylactic EFRT.Materials and MethodsBetween January 2015 and July 2023, a single‐center retrospective analysis was performed on patients with stages IB3 and IIA2‐IVA cervical cancer. Lymph node involvement was assessed using positron emission tomography/computed tomography (PET/CT). Risk factors were evaluated by logistic regression. A prediction nomogram model was developed and validated.ResultsAmong 329 patients, 64 (19.5%) had PALN metastases. Univariate analysis indicated that tumor size > 5.3 cm, tumor maximum standardized uptake value (SUVmax) > 9.8, bilateral pelvic lymph node (PLN) metastases, the number of positive PLNs ≥ 3, and T3–T4 stages were related to PALN metastases. After multivariate logistic analysis, it was found that tumor size > 5.3 cm (odds ratio [OR] = 3.129, 95% confidence interval [CI] = 1.536–6.374, p = 0.002), and the number of positive PLNs ≥ 3 (OR = 11.260, 95% CI = 3.506–36.158, p < 0.001) were independent risk factors. The C‐index of the nomogram was 0.886 (95% CI = 0.844–0.927). The calibration plot showed that the nomogram was well‐fitted. Decision curve analysis (DCA) exhibited excellent clinical utility.ConclusionTumor size > 5.3 cm and the number of positive PLNs ≥ 3 are independent risk factors of PALN metastases. The nomogram shows pretty good accuracy, which may provide a valuable reference for guiding patients who are very likely to develop PALN metastases to receive prophylactic EFRT.

A primary challenge in spinal cord injury repair is the presence of an energy deficit, exacerbated by the injury itself, thereby intensifying the dilemma of insufficient energy. Hence, we posit a hypothesis suggesting that the adoption of a direct energy-supply material strategy has the potential to enhance in situ cellular energy levels, facilitating the acceleration of neuronal differentiation and axonal elongation. We successfully designed a degradable bioenergetic hydrogel by introducing succinic acid (SA), a key intermediate in tricarboxylic acid (TCA) cycle, into chitosan (CS) as an energy-active unit, which was released in a sustained degradation-mediated fashion once implanted. The degraded energy-active units, after being internalized, increased bioenergetic levels via oxidative phosphorylation (OXPHOS) by facilitating TCA flux, thereby contributing to a at least 1.5-fold increase in the expression levels of neuronal differentiation-related markers in vitro, as well as the enhanced spinal cord injury repair and functional recovery in vivo. Further mechanism analysis demonstrated that the upregulation of the bioenergetic basis had the potential to induce neuronal differentiation through the AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) axis. Additionally, the adenosine triphosphate (ATP) itself acted as a signaling molecule via the P2X7 receptor, leading to the upregulation of intracellular calcium ion-MAPK signal cascades, ultimately promoting neuronal differentiation. Overall, these findings have the potential to significantly alter our understanding of cell metabolism and energy homeostasis, transforming them from passive observers to critical factors in guiding nerve regeneration, and may have implications for future design of bioenergetic-active materials.

The resected pIIIA-N2 non-small-cell lung cancer (NSCLC) patients who could benefit from postoperative radiotherapy (PORT) are not well-defined. The study explored the role of PORT on EGFR mutant and wild- type NSCLC patients. We retrospectively searched for resected pIIIA-N2 lung adenocarcinoma patients who underwent EGFR mutation testing. 80 patients with EGFR wild-type and 85 patients with EGFR mutation were included. 62 patients received PORT. In overall population, the median disease-free survival (DFS) was improved in PORT arm compared to non-PORT arm (22.9 vs. 16.1 months; p = 0.036), along with higher 2-year locoregional recurrence-free survival (LRFS) rate (88.3% vs. 69.3%; p = 0.004). In EGFR wild- type patients, PORT was associated with a longer median DFS (23.3 vs. 17.2 months; p = 0.044), and a higher 2-year LRFS rate (86.8% vs. 61.9%; p = 0.012). In EGFR mutant patients, PORT was not significantly correlated with improved survival outcomes. EGFR wild-type may a biomarker to identify the cohort that benefits from PORT.