A multi-label learning model for predicting drug-induced pathology in multi-organ based on toxicogenomics data.

Drug-induced toxicity damages the health and is one of the key factors causing drug withdrawal from the market. It is of great significance to identify drug-induced target-organ toxicity, especially the detailed pathological findings, which are crucial for toxicity assessment, in the early stage of drug development process. A large variety of studies have devoted to identify drug toxicity. However, most of them are limited to single organ or only binary toxicity. Here we proposed a novel multi-label learning model named Att-RethinkNet, for predicting drug-induced pathological findings targeted on liver and kidney based on toxicogenomics data. The Att-RethinkNet is equipped with a memory structure and can effectively use the label association information. Besides, attention mechanism is embedded to focus on the important features and obtain better feature presentation. Our Att-RethinkNet is applicable in multiple organs and takes account the compound type, dose, and administration time, so it is more comprehensive and generalized. And more importantly, it predicts multiple pathological findings at the same time, instead of predicting each pathology separately as the previous model did. To demonstrate the effectiveness of the proposed model, we compared the proposed method with a series of state-of-the-arts methods. Our model shows competitive performance and can predict potential hepatotoxicity and nephrotoxicity in a more accurate and reliable way. The implementation of the proposed method is available at https://github.com/RanSuLab/Drug-Toxicity-Prediction-MultiLabel.

Dual-Mode FEN1 Activity Detection Based on Nt.BstNBI-Induced Tandem Signal Amplification.

Flap endonuclease 1 (FEN1) is a structure-specific nuclease that cleaves the 5' single-stranded protrusion (also known as 5' flap) during Okazaki fragment processing. It is overexpressed in various types of human cancer cells and has been considered as an important biomarker for cancer diagnosis. However, conventional methods for FEN1 assay usually suffer from complicated platform and laborious procedures with a limited sensitivity. Here, we developed a dual-signal method for sensitive detection of FEN1 on the basis of duplex-specific nuclease actuated cyclic enzymatic repairing-mediated signal amplification. Once the 5' flap of the double-flap DNA substrate was cleaved by target FEN1, the cleaved 5' flap initiated strand-displacement amplification to produce plenty of G-rich DNA (G) sequences. These G sequences that self-assembled into G-quadruplexes in the presence of hemin revealed horseradish-peroxidase-like catalytic activities as well as fluorescence enhancement of thioflavin T. The UV-vis signal showed a good linear relationship with the logarithm of FEN1 activity ranging from 0.03 to 1.5 U with a detection limit of 0.01 U. The fluorescence signal correlated linearly with the logarithm of FEN1 activity ranging from 0.001 to 1.5 U with a detection limit of 0.75 mU. In addition, FEN1 can be visualized not only by colorimetry but also by fluorescence (under ice-water mixture conditions). This reliable, accurate, and convenient method would be a potential powerful tool in point-of-care testing applications and therapeutic response assessment.

Molecularly Engineered Lignin-Derived Additives Enable Fire-Retardant, UV-Shielding, and Mechanically Strong Polylactide Biocomposites.

From a perspective of sustainable development and practical applications, there has been a great need for the design of advanced polylactide (PLA) biocomposites that are flame-retardant, ultraviolet (UV)-resistant, and mechanically strong by using biomass-derived additives. Unfortunately, the achievement of a desirable performance portfolio remains unsatisfactory because of improper design strategies. Herein, we report the design of lignin-derived multifunctional bioadditives (TP-g-lignin) with tunable chemical compositions through graft polymerization of a phosphorus-/nitrogen-containing vinyl monomer (TP). Our results show that the incorporation of 5.0 wt % of TP-g-lignin (at a lignin-to-TP ratio of 1:4 by mass) enables PLA to achieve a desirable flame retardancy rating meeting the UL-94 V-0 industrial standard requirements. Meanwhile, the final PLA composite exhibits an exceptional UV-shielding capability. Moreover, with 5.0 wt % of the bio-derived additive, the elastic modulus of PLA is increased by ∼26%, while mechanical strength is fully retained due to engineered favorable interfaces. This work offers an innovative and sustainable strategy for creating bio-based multifunctional additives by using industrial lignin waste and further the application of PLA in the areas of packaging, fabrics, electronics, automobiles, etc.

Quartz Crystal Microbalance Detection of Poly(ADP-ribose) Polymerase-1 Based on Gold Nanorods Signal Amplification.

Recent findings have thrust poly(ADP-ribose) polymerase-1 (PARP-1) into the limelight as a potential biomarker and chemotherapeutic target for cancer. Thus, a sensitive method for detection of PARP-1 is necessary for early diagnosis of cancer and drug development. However, the poor electrochemical and optical activity of PARP-1 and its product poly(ADP-ribose) (PAR) prompted researchers to develop more methods. Here, we developed an efficient method for the determination of PARP-1 by using quartz crystal microbalance (QCM) because it is mass-sensitive. Once activated by the specific DNA, PARP-1 cleaves nicotinamideadenine dinucleotide (NAD+) into nicotinamide and ADP-ribose to synthesize a hyperbranched poly(ADP-ribose) polymer. Although QCM is mass-sensitive, it is not sensitive enough to discern PAR effectively. So, positively charged cetyltrimethylammonium bromide (CTAB)-coated gold nanorods (GNRs) were introduced to increase the frequency change significantly because of the strong electrostatic interaction between them with negatively charged PAR. PARP-1 ranging from 0.06 to 3 nM can be facilely detected with a low detection limit of 0.04 nM. The strategy has been used to evaluate PARP-1 inhibitors and to detect PARP-1 activity in real cancer cells lysate with satisfactory results, indicating that it was a promising candidate for clinical diagnosis and drug screening in the future.

Increased sensitivity to apoptosis upon endoplasmic reticulum stress-induced activation of the unfolded protein response in chemotherapy-resistant malignant pleural mesothelioma.

BACKGROUND: Standard treatment for advanced malignant pleural mesothelioma (MPM) is a cisplatin/pemetrexed (MTA) regimen; however, this is confronted by drug resistance. Proteotoxic stress in the endoplasmic reticulum (ER) is a hallmark of cancer and some rely on this stress signalling in response to cytotoxic chemotherapeutics. We hypothesise that ER stress and the adaptive unfolded protein response (UPR) play a role in chemotherapy resistance of MPM. METHODS: In vitro three-dimensional (3D) and ex vivo organotypic culture were used to enrich a chemotherapy-resistant population and recapitulate an in vivo MPM microenvironment, respectively. Markers of ER stress, the UPR and apoptosis were assessed at mRNA and protein levels. Cell viability was determined based on acid phosphatase activity. RESULTS: MPM cells with de novo and/or acquired chemotherapy resistance displayed low ER stress, which rendered the cells hypersensitive to agents that induce ER stress and alter the UPR. Bortezomib, an FDA-approved proteasome inhibitor, selectively impairs chemotherapy-resistant MPM cells by activating the PERK/eIF2α/ATF4-mediated UPR and augmenting apoptosis. CONCLUSIONS: We provide the first evidence for ER stress and the adaptive UPR signalling in chemotherapy resistance of MPM, which suggests that perturbation of the UPR by altering ER stress is a novel strategy to treat chemotherapy-refractory MPM.

Analysis of poly(ADP-ribose) polymerase-1 by enzyme-initiated auto-PARylation-controlled aggregation of hemin-graphene nanocomposites.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a highly conserved nuclear enzyme, which binds tightly to damaged DNA and plays a key role in DNA repair, recombination, proliferation, and genomic stability. However, due to the poor electrochemical and optical activity of PARP-1 and its product PAR, only a few studies on its activity detection method have been reported. Herein, we report a simple and sensitive colorimetric strategy to monitor PARP-1 activity based on enzyme-initiated auto-PARylation-controlled aggregation of hemin-graphene nanocomposites (H-GNs). PARP, activated by dsDNA, catalyzed its substrate nicotinamide adenine dinucleotide (NAD+) to polymerize as a poly(ADP-ribose) polymer (PAR). PAR possesses several negative charges, and its charge density is twice that of a single-stranded DNA, which greatly impacts the dispersibility of H-GNs; due to their peroxidase-like catalytic activities, H-GNs can catalyze the chromogenic reaction of TMB and H2O2. As a result, in the presence of different PARP-1 activities, the supernatant of the corresponding solution contained different amounts of dispersed H-GNs and showed different colors after the chromogenic reaction that could be discerned easily by the absorbance or the color changes of the solution. The method was simple, sensitive, and reliable. The proposed method displays a linear range from 0.05 to 1 U with a detection limit of 0.03 U. In addition, this new method has been successfully applied to detect PARP-1 activity in human serum and different cancer cells and evaluate PARP-1 inhibitors.

Sensitive Detection of Rifampicin Based on Au-Carbon Nanocomposite.

Gold nanoparticles-supported Cabot Vulcan XC72R (Au/VXC72R) nanocomposite was synthesized by chemical reduction of gold (III) chloride with VXC72R. A novel electrochemical sensor based on the Au/VXC72R nanocomposite has been fabricated for the sensitive detection of rifampicin (RIF). Field-emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), X-ray powder diffractometer (XRD) and X-ray photoelectron spectroscopy (XPS) were used to characterize the morphology, structure and compositions of the nanocomposite. Under the optimal conditions, the Au/VXC72R-chitosan/GCE can be used to determine RIF concentration in a linear range from 5 × 10-7 mol/L to 1 × 10-5 mol/L with the detection limit of 1.1 × 107 M (S/N = 3). The proposed approach exhibits good stability, acceptable reproducibility and applicability, which will probably bring widespread applications in quality monitoring in real samples.

Sensitive Determination of Dopamine and Paracetamol Based on Carbon Nanotubes-Supported Pd Nanoparticles.

A novel chemically modified electrode was constructed in this study based on the carbon nanotubes-supported Pd nanoparticles (Pd/CNTs). It was demonstrated that the sensor could be used for the determination of dopamine (DA) and paracetamol (PA). The measurements were carried out through application of cyclic voltammetry (CV), differential pulse voltammetry (DPV) and amperometric i-t curve. Under optimum conditions and using the amperometric i-t curve method, the modified electrode provided linear response versus dopamine concentrations in the range of 0.3 × 10-6-5.0 × 10-5 M and PA concentrations in the range of 0.2 × 10-6-6.0 × 10-5 M, respectively. The detection limits for the DA and PA were 9.1 × 10-8 M and 8.9 × 10-8 M (S/N = 3), respectively. The sensitivities for of the electrode were 0.928 and 1.532 µA µM-1 cm-1, respectively.

Visual, Label-Free Telomerase Activity Monitor via Enzymatic Etching of Gold Nanorods.

Early diagnosis and life-long surveillance are clinically important to improve the long-term survival of cancer patients. Telomerase activity is a valuable biomarker for cancer diagnosis, but its measurement often used complex label procedures. Herein, we designed a novel, simple, visual and label-free method for telomerase detection by using enzymatic etching of gold nanorods (GNRs). First, repeating (TTAGGG)x sequences were extented on telomerase substrate (TS) primer. It formed G-quadruplex under the help of Hemin and K+. Second, the obtained horseradish peroxidase mimicking hemin/G-quadruplex catalyzed the H2O2-mediated etching of GNRs to the short GNRs, even to gold nanoparticles (GNPs), generating a series of distinct color changes due to their plasmon-related optical response. Thus, this enzymatic reaction can be easily coupled to telomerase activity, allowing for the detection of telomerase activity based on vivid colors. This can be differentiated sensitively by naked eyes because human eyes are more sensitive to color variations rather than the optical density variations. As a result, telomerase activity can be quantitatively detected ranging from 200 to 15000 HeLa cells mL-1. The detection limit was 90 HeLa cells mL-1 (S/N = 3). Importantly, the application of this method in bladder cancer samples was in agreement with the clinical results. Thus, this method was considerably suitable for point-of-care diagnostics in resource-constrained regions because of the easy readout of results without the use of sophisticated apparatus.

The acetylcholinesterase (AChE) inhibition analysis of medaka (Oryzias latipes) in the exposure of three insecticides.

The continuous effects on Acetylcholinesterase (AChE) activity of medaka (Oryzias latipes) caused by dichlorvos, methomyl and deltamethrin in vivo were investigated, and the trends of AChE activity inhibition due to the influence of these insecticides were discussed. The LC50-24h of dichlorvos, methomyl and deltamethrin on medaka were 2.3 mg/L, 0.2 mg/L, and 2.9×10(-3) mg/L respectively. The result suggested that at the beginning of the exposure, the AChE activity might increase, and the AChE activity in dead individuals was obviously lower than the live individuals. Though the de novo synthesis of AChE in medaka might help the AChE activity recover, the trends during the exposure in different treatments were downward, and it showed both exposure time and concentration dependent. Meanwhile, higher temperature might cause the AChE inhibition earlier due to the higher metabolic rate. Therefore, as a specific biomarker for organophosphate, carbamate pesticides and pyrethroids, the degree of the AChE inhibition with in vivo conditions is a good tool in continuous monitoring of insecticides, which may induce the nerve conduction disorders.

Minimally invasive surgery role in central squamous lung cancer after neoadjuvant chemoimmunotherapy.

Background: The present body of literature provides restricted evidence concerning the application of video-assisted thoracoscopic surgery (VATS) in individuals diagnosed with centrally located, locally advanced, and initially surgically challenging squamous cell lung carcinoma (SqCLC) following neoadjuvant chemoimmunotherapy (CIT). Further research is warranted to elucidate the role and potential benefits of VATS in this particular patient population. Methods: We performed a retrospective analysis on individuals diagnosed with centrally located and locally advanced SqCLC who received preoperative CIT at a single institution. The study evaluated the percentage of VATS performed, conversion rates, and perioperative outcomes. Furthermore, survival outcomes related to the resection extent were compared between patients who underwent standard lobectomy (SL) and extended lobectomy (EL, e.g., sleeve, bilobectomy or pneumonectomy) after neoadjuvant CIT. Results: A total of 27 cases of centrally located SqCLC underwent neoadjuvant CIT followed by VATS, with one case requiring conversion to thoracotomy due to adhesions. Comparison of perioperative outcomes and long-term cancer-specific mortality between the VATS group (N=24) and the thoracotomy group (N=13) did not yield any statistically significant differences. However, the VATS group exhibited a significantly higher frequency of SL (66.7% vs. 30.8%, P=0.046). Notably, within the VATS group, all three patients who experienced tumor relapse or died due to tumor recurrence were from the SL subgroup. Conclusions: This study contributes valuable real-world evidence demonstrating the feasibility and safety of utilizing VATS in the management of patients with centrally located and locally advanced SqCLC following neoadjuvant CIT. However, careful consideration might be given to the extent of resection to optimize patient long-term outcomes.

Photoactive Poly-L-Lysine gel with resveratrol-magnesium metal polyphenol network: A promising strategy for preventing tracheal anastomotic complications following surgery.

Postoperative complications at the anastomosis site following tracheal resection are a prevalent and substantial concern. However, most existing solutions primarily focus on managing symptoms, with limited attention given to proactively preventing the underlying pathological processes. To address this challenge, we conducted a drug screening focusing on clinically-relevant polyphenolic compounds, given the growing interest in polyphenolic compounds for their potential role in tissue repair during wound healing. This screening led to the identification of resveratrol as the most promising candidate for mitigating tracheal complications, as it exhibited the most significant efficacy in enhancing the expression of vascular endothelial growth factor (VEGF) while concurrently suppressing the pivotal fibrosis factor: transforming growth factor-beta 1 (TGF-ß1), showcasing its robust potential in addressing these issues. Building upon this discovery, we further developed an innovative photosensitive poly-L-lysine gel integrated with a resveratrol-magnesium metal polyphenol network (MPN), named Res-Mg/PL-MA. This design allows for the enables sustained release of resveratrol and synergistically enhances the expression of VEGF and also promotes resistance to tensile forces, aided by magnesium ions, in an anastomotic tracheal fistula animal models. Moreover, the combination of resveratrol and poly-L-lysine hydrogel effectively inhibits bacteria, reduces local expression of key inflammatory factors, and induces polarization of macrophages toward an anti-inflammatory phenotype, as well as inhibits TGF-ß1, consequently decreasing collagen production levels in an animal model of post-tracheal resection. In summary, our novel Res-Mg/PL-MA hydrogel, through antibacterial, anti-inflammatory, and pro-vascularization mechanisms, effectively prevents complications at tracheal anastomosis, offering significant promise for translational applications in patients undergoing tracheal surgeries.

BAP1 Deficiency Inflames the Tumor Immune Microenvironment and Is a Candidate Biomarker for Immunotherapy Response in Malignant Pleural Mesothelioma.

Introduction: Malignant pleural mesothelioma (MPM) is a rare and universally lethal malignancy with limited treatment options. Immunotherapy with immune checkpoint inhibitors (ICIs) has recently been approved for unresectable MPM, but response to ICIs is heterogeneous, and reliable biomarkers for prospective selection of appropriate subpopulations likely to benefit from ICIs remain elusive. Methods: We performed multiscale integrative analyses of published primary tumor data set from The Cancer Genome Atlas (TCGA) and the French cohort E-MTAB-1719 to unravel the tumor immune microenvironment of MPM deficient in BAP1, one of the most frequently mutated tumor suppressor genes (TSGs) in the disease. The molecular profiling results were validated in independent cohorts of patients with MPM using immunohistochemistry and multiplex immunohistochemistry. Results: We revealed that BAP1 deficiency enriches immune-associated pathways in MPM, leading to increased mRNA signatures of interferon alfa/gamma response, activating dendritic cells, immune checkpoint receptors, and T-cell inflammation. This finding was confirmed in independent patient cohorts, where MPM tumors with low BAP1 levels are associated with an inflammatory tumor immune microenvironment characterized by increased exhausted precursor T-cells and macrophages but decreased myeloid-derived suppressor cells (MDSCs). In addition, BAP1low MPM cells are in close proximity to T cells and therefore can potentially be targeted with ICIs. Finally, we revealed that BAP1-proficient MPM is associated with a hyperactive mitogen-activated protein kinase (MAPK) pathway and may benefit from treatment with MEK inhibitors (MEKis). Conclusion: Our results suggest that BAP1 plays an immunomodulatory role in MPM and that BAP1-deficient MPM may benefit from immunotherapy, which merits further clinical investigation.

Treatment patterns and clinical outcomes of patients with resectable non-small cell lung cancer receiving neoadjuvant immunochemotherapy: A large-scale, multicenter, real-world study (NeoR-World).

BACKGROUND: Neoadjuvant immunotherapy has ushered in a new era of perioperative treatment for resectable non-small cell lung cancer (NSCLC). However, large-scale data for verifying the efficacy and optimizing the therapeutic strategies of neoadjuvant immunochemotherapy in routine clinical practice are scarce. METHODS: NeoR-World (NCT05974007) was a multicenter, retrospective cohort study involving patients who received neoadjuvant immunotherapy plus chemotherapy or chemotherapy alone in routine clinical practice from 11 medical centers in China between January 2010 and March 2022. Propensity score matching was performed to address indication bias. RESULTS: A total of 408 patients receiving neoadjuvant immunochemotherapy and 684 patients receiving neoadjuvant chemotherapy were included. The pathologic complete response (pCR) and major pathologic response (MPR) rates of the real-world neoadjuvant immunochemotherapy cohort were 32.8% and 58.1%, respectively. Notably, patients with squamous cell carcinoma exhibited significantly higher pCR and MPR rates than those with adenocarcinoma (pCR, 39.2% vs 16.5% [P < .001]; MPR, 66.6% vs 36.5% [P < .001]), whereas pCR and MPR rates were comparable among patients receiving different neoadjuvant cycles. In addition, the 2-year rates of disease-free survival (DFS) and overall survival (OS) rate were 82.0% and 93.1%, respectively. Multivariate analyses identified adjuvant therapy as an independent prognostic factor for DFS (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.29-0.89; P = .018) and OS (HR, 0.28; 95% CI, 0.13-0.58; P < .001). A significantly longer DFS with adjuvant therapy was observed in patients with non-pCR or 2 neoadjuvant cycles. We observed significant benefits in pCR rate (32.4% vs 6.4%; P < .001), DFS (HR, 0.50; 95% CI, 0.38-0.68; P < .001) and OS (HR, 0.61; 95% CI, 0.40-0.94; P = .024) with immunotherapy plus chemotherapy compared to chemotherapy alone both in the primary propensity-matched cohort and across most key subgroups. CONCLUSIONS: The study validates the superior efficacy of neoadjuvant immunochemotherapy over chemotherapy alone for NSCLC. Adjuvant therapy could prolong DFS in patients receiving neoadjuvant immunochemotherapy, and patients with non-pCR or those who underwent 2 neoadjuvant cycles were identified as potential beneficiaries of adjuvant therapy.

Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks.

The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stress and xenobiotics under physiological circumstances. Cancer cells often hijack this pathway during initiation and progression, with aberrant KEAP1-NRF2 activity predominantly observed in non-small cell lung cancer (NSCLC), suggesting that cell/tissue-of-origin is likely to influence the genetic selection during malignant transformation. Hyperactivation of NRF2 confers a multi-faceted role, and recently, increasing evidence shows that a close interplay between metabolic reprogramming and tumor immunity remodelling contributes to its aggressiveness, treatment resistance (radio-/chemo-/immune-therapy) and susceptibility to metastases. Here, we discuss in detail the special metabolic and immune fitness enabled by KEAP1-NRF2 aberration in NSCLC. Furthermore, we summarize the similarities and differences in the dysregulated KEAP1-NRF2 pathway between two major histo-subtypes of NSCLC, provide mechanistic insights on the poor response to immunotherapy despite their high immunogenicity, and outline evolving strategies to treat this recalcitrant cancer subset. Finally, we integrate bioinformatic analysis of publicly available datasets to illustrate the new partners/effectors in NRF2-addicted cancer cells, which may provide new insights into context-directed treatment.

Phosphorylation by IKKß Promotes the Degradation of HMGCL via NEDD4 in Lung Cancer.

Inflammation and metabolic reprogramming are hallmarks of cancer. How inflammation regulates cancer metabolism remains poorly understood. In this study, we found that 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL), the enzyme that catalyzes the catabolism of leucine and promotes the synthesis of ketone bodies, was downregulated in lung cancer. Downregulation of HMGCL was associated with a larger tumor size and a shorter overall survival time. In a functional study, overexpression of HMGCL increased the content of ß-hydroxybutyrate (ß-HB) and inhibited the tumorigenicity of lung cancer cells, and deletion of HMGCL promoted de novo tumorigenesis in KP (KrasG12D;P53f/f) mice. Mechanistically, tumor necrosis factor α (TNFα) treatment decreased the HMGCL protein level, and IKKß interacted with HMGCL and phosphorylated it at Ser258, which destabilized HMGCL. Moreover, NEDD4 was identified as the E3 ligase for HMGCL and promoted its degradation. In addition, mutation of Ser258 to alanine inhibited the ubiquitination of HMGCL by NEDD4 and thus inhibited the anchorage-independent growth of lung cancer cells more efficiently than did wild-type HMGCL. In summary, this study demonstrated a link between TNFα-mediated inflammation and cancer metabolism.

Effectiveness comparison of third-generation EGFR-TKI as initial and sequential therapy in adjuvant treatment for EGFR mutation-sensitive stage IIIA non-small cell lung cancer after surgery.

Introduction: Although third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) Osimertinib has been approved as adjuvant therapy for resected stage IIIA non-small cell lung cancer (NSCLC) with EGFR-sensitive mutations, the optimal treatment sequencing of EGFR-TKIs, particularly whether Osimertinib should be the initial or sequential therapy following the first-generation EGFR-TKIs remains uncertain. Methods: A retrospective analysis was conducted on a cohort of patients with EGFR-mutated stage IIIA NSCLC who received treatment with either first-generation EGFR-TKIs or Osimertinib (third-generation) alone, or in sequential combination, at a single institution. The data analysis involved using the Kaplan-Meier method, log-rank test, and Cox regression. Results: Out of the total 148 patients with stage IIIA NSCLC included in the study, 76 individuals underwent treatment with either first-generation EGFR-TKIs (referred to as subgroup "1″) or exclusively Osimertinib (subgroup "0 + 3″), or a sequential combination of the two (subgroup "1 + 3″) following surgery. Both univariate and multivariate analyses demonstrated that there were no discernible disparities in terms of disease-free survival and overall survival between subgroup " 1″ and " 1 + 3," nor between subgroup " 0 + 3″ and "1 + 3". Conclusion: The findings from this study indicate that the introduction of third-generation EGFR-TKI Osimertinib did not yield enhanced survival benefits when compared to the first-generation drug in patients with stage IIIA completely resected NSCLC who were administered EGFR-TKIs as part of their postoperative adjuvant treatment. Additionally, within the observed sample size of this cohort, the sequential use of Osimertinib alongside first-generation EGFR-TKI did not demonstrate superiority over using either the first-generation EGFR-TKI or Osimertinib alone in terms of postoperative survival.

Multienzyme-Mimicking LaCoO3 Nanotrigger for Programming Cancer-Cell Pyroptosis.

Pyroptosis, a distinct paradigm of programmed cell death, is an efficient strategy against cancer by overcoming resistance to apoptosis. In this study, LaCoO3 (LCO) lanthanide-based nanocrystals with multienzyme characteristics are rationally designed and engineered to trigger the generation of cytotoxic reactive oxygen species (ROS) and the release of lanthanum ions, ultimately inducing lung cancer cell pyroptosis. The peroxidase- and oxidase-mimicking activities of LCO nanocrystals endow LCO with ROS production capacity in tumor tissues with an acidic pH and high hydrogen peroxide content. Concurrently, the LCO nanoenzyme exhibits catalase- and glutathione peroxidase-like activities, reversing the hypoxic microenvironment, destroying the activated antioxidant system of tumor cells, and amplifying the sensitivity of tumor cells to ROS. The use of ultrasound further accelerates the enzymatic kinetic rate. Most importantly, the La3+ ions released by LCO robustly destroy the lysosomal membrane, finally inducing canonical pyroptotic cell death, together with ROS. LCO-nanocrystal-triggered programmed cell pyroptosis amplifies the therapeutic effects both in vitro and in vivo, effectively restraining lung cancer growth and metastasis. This study paves a new avenue for the efficient treatment of lung cancer and metastasis through US-enhanced lanthanum-based nanoenzyme platforms and pyroptotic cell death.

One-Pot Synthesis of Tumor-Microenvironment Responsive Degradable Nanoflower-Medicine for Multimodal Cancer Therapy with Reinvigorating Antitumor Immunity.

Multimodal cancer therapies show great promise in synergistically enhancing anticancer efficacy through different mechanisms. However, most current multimodal therapies either rely on complex assemblies of multiple functional nanomaterials and drug molecules or involve the use of nanomedicines with poor in vivo degradability/metabolizability, thus restricting their clinical translatability. Herein, a nanoflower-medicine using iron ions, thioguanine (TG), and tetracarboxylic porphyrin (TCPP) are synthesized as building blocks through a one-step hydrothermal method for combined chemo/chemodynamic/photodynamic cancer therapy. The resulting nanoflowers, consisting of low-density Fe2 O3 core and iron complex (Fe-TG and Fe-TCPP compounds) shell, exhibit high accumulation at the tumor site, desirable degradability in the tumor microenvironment (TME), robust suppression of tumor growth and metastasis, as well as effective reinvigoration of host antitumor immunity. Triggered by the low pH in tumor microenvironment, the nanoflowers gradually degrade after internalization, contributing to the effective drug release and initiation of high-efficiency catalytic reactions precisely in tumor sites. Moreover, iron ions can be eliminated from the body through renal clearance after fulfilling their mission. Strikingly, it is also found that the multimodal synergistic therapy effectively elicits the host antitumor immunity without inducing additional toxicity. This easy-manufactured and degradable multimodal therapeutic nanomedicine is promising for clinical precision oncology.