Combination of percutaneous thermal ablation and adoptive Th9 cell transfer therapy against non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the predominant malignancies globally. Percutaneous thermal ablation (PTA) has gained widespread use among NSCLC patients, with the potential to elicit immune responses but limited therapeutic efficacies for advanced-stage disease. T-helper type 9 (Th9) cells are a subset of CD4+ effector T cells with robust and persistent anti-tumor effects. This study proposes to develop PTA-Th9 cell integrated therapy as a potential strategy for NSCLC treatment. METHODS: The therapeutic efficacies were measured in mice models with subcutaneously transplanted, recurrence, or lung metastatic tumors. The tumor microenvironments (TMEs) were evaluated by flow cytometry. The cytokine levels were assessed by ELISA. The signaling molecules were determined by quantitative PCR and Western blotting. The translational potential was tested in the humanized NSCLC patient-derived xenograft (PDX) model. RESULTS: We find that PTA combined with adoptive Th9 cell transfer therapy substantially suppresses tumor growth, recurrence, and lung metastasis, ultimately extending the survival of mice with NSCLC grafts, outperforming both PTA and Th9 cell transfer monotherapy. Analysis of TMEs indicates that combinatorial therapy significantly augments tumor-infiltrating Th9 cells, boosts anti-tumor effects of CD8+ T cells, and remodels tumor immunosuppressive microenvironments. Moreover, combinatorial therapy significantly strengthens the regional and circulation immune response of CD8+ T cells in mice with tumor lung metastasis and induces peripheral CD8+ T effector memory cells in mice with tumor recurrence. Mechanically, PTA reinforces the anti-tumor ability of Th9 cells primarily through upregulating interleukin (IL)-1ß and subsequently activating the downstream STAT1/IRF1 pathway, which could be effectively blocked by intercepting IL-1ß signaling. Finally, the enhanced therapeutic effect of combinatorial therapy is validated in humanized NSCLC PDX models. CONCLUSIONS: Collectively, this study demonstrates that combinatorial therapy displays robust and durable anti-tumor efficacy and excellent translational potential, offering excellent prospects for translation and emerging as a promising approach for NSCLC treatment.

Mechanical Control of Polar Patterns in Wrinkled Thin Films via Flexoelectricity.

Intriguing topological polar structures in oxide nanofilms have drawn growing attention owing to their immense potential applications in nanoscale electronic devices. Here, we report a novel route to mechanically manipulate polar structures via flexoelectricity in wrinkled thin films. Our results present a flexoelectric polar transition from a nonpolar state to uniaxial polar stripes, biaxial meronlike or antimeronlike polar structures, and polar labyrinths by varying wrinkle morphologies. The evolution mechanisms and the outstanding mechanical tunability of these flexoelectric polar patterns were investigated theoretically and numerically. This strategy based on flexoelectricity for generating nontrivial polar structures will no longer rely on the superlattice structure and can be widely applicable to all centrosymmetric or noncentrosymmetric materials, providing a broader range of material and structure candidates for polar topologies.

Oxygen Impurity-Tuned Structure and Adhesion Properties of the Cu/SiO2 Interface.

The properties of the Cu/SiO2 interface usually deteriorate in the complex atmospheric environment, which may limit its performance and application in the engineering. Using the reactive molecular dynamics method, we investigate how the mechanical behaviors of the Cu/SiO2 interface change as it interacts with oxygen impurities. The interfacial oxidation degree could be enhanced as O2 penetrates into the interface area. This makes the interfacial structure disordered and is not conducive to the survival of Cu-O-Si bondings, which reduces the tensile and shear strengths of the interface. To improve the abrupt bonding property change at the interface and modify the interfacial adhesion properties, O impurities are introduced at the Cu interstitial sites near the interface. By doing so, the interface strength can be significantly enhanced due to the production of typical O-Cu-O bondings while the regular interfacial structure is retained. Meanwhile, the interfacial oxidation also changes the tensile failure site and shearing sliding mode of the interface, i.e., from inside the oxide to between oxide and Cu. The findings of this work may not only advance the understanding of interaction mechanism between oxygen impurities and the Cu/SiO2 interface but also provide new insights into optimizing the bonding properties of the metal/oxide interface.

A superstable, flexible, and scalable nanofluidic ion regulation composite membrane.

Two-dimensional layered membranes with high and stable ion transport properties have various applications in nanofluidic devices; however, their construction remains a considerable challenge. Herein, we develop a superstable aramid nanofiber/graphite composite membrane with numerous one-dimensional and two-dimensional nano-confined interspaces for ultrafast ion transport. The fabricated flexible and scalable membrane exhibits high tensile strength (∼115.3 MPa) even after immersion in water for 90 days. Further, the aramid nanofiber/graphite conductor features the surface-charge-governed ion transport behavior. The ionic conductivity of the membrane at a low potassium chloride concentration of 10-4 mol/L can be enhanced by 16 times that of the bulk counterpart. More importantly, its structure and ionic conductivity remain unchanged even after immersion in different harsh solutions (e.g., acid, base, and ethanol) for over 30 days. Molecular dynamics simulations reveal that the superstability of the membrane is attributable to the robust interchain interactions within the aramid nanofibers and the strong interfacial interactions between the aramid nanofibers and graphite nanosheets. This study highlights the superior structural stability of the proposed flexible and scalable aramid nanofiber/graphite composite membrane, which could be employed in advanced nanofluidic devices for application under extreme working environments.

Neoadjuvant Chemoimmunotherapy Increases Tumor Immune Lymphocytes Infiltration in Resectable Non-small Cell Lung Cancer.

BACKGROUND: Neoadjuvant chemoimmunotherapy treatment (NCIT) has achieved great success for non-small cell lung cancer (NSCLC); however, the intrinsic mechanism underlying this treatment remains unclear. METHODS: Thirty-two patients with stage IIA-IIIC NSCLC who underwent surgery after NCIT were included in this retrospective study. Multiplex immunofluorescence (mIF) staining and image analysis assays were performed on the samples collected before and after NCIT for each patient. RNA analyses was applied to confirm the mIF results. RESULTS: Among the enrolled patients, 14 achieved major pathological response or pathological complete response (pCR) and were defined as the 'response' group, whereas 18 patients did not respond well to NCIT and were defined as the 'nonresponse' group. The results of the mIF assays revealed an overall increase in tumor immune lymphocytes (TILs) after NCIT in the stroma area (p = 0.03) rather than the tumor area (p = 0.86). The percentage of CD8+ T cells and tertiary lymphoid structure counts in both the response and nonresponse groups increased significantly after NCIT compared with before NCIT. CD3+ T cells and FOXP3+ cells decreased significantly in the response group but remained unchanged or increased in the nonresponse group. A comparison of the response and nonresponse groups showed that CD3, FOXP3+ and CD8+/PD-1+ cells before NCIT may serve as predictors of the response to neoadjuvant immunotherapy. The RNA analyses confirmed the mIF results that TILs were elevated after NCIT. CONCLUSIONS: The infiltration of immune cells before NCIT was correlated with pathologic complete response, which enhanced the TILs as a promising predictor for selecting patients who were more likely to benefit from NCIT.

Directly Observing the Evolution of Flexoelectricity at the Tip of Nanocracks.

As an electromechanical coupling between strain gradients and polarization, flexoelectricity is largely enhanced at the nanoscale. However, directly observing the evolution of flexoelectric fields at the nanoscale usually suffers from the difficulty of producing strain gradients and probing electrical responses simultaneously. Here, we introduce nanocracks in SrTiO3, Ba0.67Sr0.33TiO3, and TiO2 samples and apply continuously varying mechanical loading to them, and as a result, huge strain gradients appear at the crack tip and result in a significant flexoelectric effect. Then, using atomic force microscopy, we successfully measure the evolution of flexoelectricity around the crack tips. For the case of SrTiO3, the maximum induced electric field reaches 11 kV/m due to the tensile load increasing. The proposed method provides a reliable way to identify the significance of the flexoelectric effect. It may also open a new avenue for the study of flexoelectricity involving multiple physics phenomena including flexoelectronics, the flexo-photovoltaic effect, and others.

High-frequency and rapid response tungsten sulfide nano onion-based electrochemical actuators.

Poor rate capability, the biggest barrier to potential applications of electrochemical actuators (ECAs), is primarily resulted from symmetric electrochemical reactions. This makes it extremely difficult for ECAs to actuate above 1 Hz while maintaining sufficient displacement retainability compared with their actuations at relatively low frequencies, particularly when working in liquids. Here, tungsten trisulfide (WS3) assisted tungsten disulfide nano onions are synthesized through a one-step laser-assisted strategy. Using the irreversibility of WS3 in adsorbing hydrogen in an acidic solution, the electrochemical reaction of tungsten sulfide nano onions is tailored to realize an asymmetric redox reaction for breaking the symmetry of the electrical double layer and battery-like process. Experiments demonstrate that the ECA's response rate (0.24 mm-1 s-1) is at least 10 times faster than that of the previously reported ECAs. Moreover, this ECA can actuate at 30 Hz and reaches top performance in liquids at 4 Hz with long-term durability (>90% after 23 000 cycles), which is comparable to that of electromagnetic and electrothermal actuators. To understand the electrochemical actuation of tungsten sulfide from the atomic scale to the macroscopic scale, density functional theory calculations are conducted and an electrochemomechanical coupling model is proposed. A new generation of subvolt electric-driven actuators used in underwater robotics can be developed by modulating the electrochemical response and chemomechanical coupling effect.

Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients.

BACKGROUND: Neoadjuvant immunotherapy is emerging as novel effective intervention in lung cancer, but study to unearth effective surrogates indicating its therapeutic outcomes is limited. We investigated the genetic changes between non-small cell lung cancer (NSCLC) patients with varied response to neoadjuvant immunotherapy and discovered highly potential biomarkers with indicative capability in predicting outcomes. METHODS: In this study, 3 adenocarcinoma and 11 squamous cell carcinoma NSCLC patients were treated by neoadjuvant immunotherapy with variated regimens followed by surgical resection. Treatment-naive FFPE or fresh tissues and blood samples were subjected to whole-exome sequencing (WES). Genetic alternations were compared between differently-responded patients. Findings were further validated in multiple public cohorts. RESULTS: DNA damage repair (DDR)-related InDel signatures and DDR-related gene mutations were enriched in better-responded patients, i.e., major pathological response (MPR) group. Besides, MPR patients exhibited provoked genome instability and unique homologous recombination deficiency (HRD) events. By further inspecting alternation status of homology-dependent recombination (HR) pathway genes, the clonal alternations were exclusively enriched in MPR group. Additionally, associations between HR gene alternations, percentage of viable tumor cells and HRD event were identified, which orchestrated tumor mutational burden (TMB), mutational intratumor heterogeneity (ITH), somatic copy number alteration (SCNA) ITH and clonal neoantigen load in patients. Validations in public cohorts further supported the generality of our findings. CONCLUSIONS: We reported for the first time the association between HRD event and enhanced neoadjuvant immunotherapy response in lung cancer. The power of HRD event in patient therapeutic stratification persisted in multifaceted public cohorts. We propose that HR pathway gene status could serve as novel and additional indicators guiding immune-neoadjuvant and immunotherapy treatment decisions for NSCLC patients.

The relationship between different subtypes of KRAS and PD-L1 & tumor mutation burden (TMB) based on next-generation sequencing (NGS) detection in Chinese lung cancer patients.

Background: KRAS gene mutations are the most common driver oncogenes in non-small cell lung cancer (NSCLC). We conducted an analysis of the immunological characteristics including tumor mutation burden and programmed death-ligand 1 (PD-L1) expression of different subtypes of KRAS in 2880 KRAS-mutant NSCLC patients. Methods: A total of 2,880 patients with NSCLC were included in the study. Somatic mutation data were provided by Berry Oncology (Fujian, China), Geneplus BioTech (Beijing, China), Nanjing Geneseeq Technology Inc (Nanjing, China), and Burning Rock Biotech (Guangzhou, China). Z-scores were used to unify all data. SPSS 20.0 (SPSS, Chicago, IL, USA) software was used for statistical analyses. All scatter plots and boxplot maps were drawn using GraphPad Prism 8. Tumor mutation burden (TMB) expression was defined by the number of somatic mutations. The PD-L1 clone 22C3 pharmDx kit was used to measure the expression level of PD-L1. Mann-Whitney U test was used for statistical analysis. P value <0.05 was considered statistically significant. Results: We identified 2,880 patients with KRAS-mutant NSCLC. The percentage level of TMB and expression of PD-L1 was significantly decreased in KRAS Q61X-mutant lung cancer tissue and blood samples (n=162). The percentage level of TMB and expression of PD-L1 in KRAS G13X-mutant lung cancer specimens was significantly increased (n=190). Conclusions: The findings demonstrate a decreased level of TMB and expression of PD-L1 in KRAS Q61X-mutant lung cancer and the increased level of TMB and expression of PD-L1 in KRAS G13X-mutant lung cancer. Further work is needed to identify if the subtype of KRAS mutation could be a potential therapeutic biomarker in lung cancer patients with KRAS mutation. TMB data was consistently verified in tissue and blood samples and confirmed the feasibility of next-generation sequencing (NGS) verification in plasma samples. Our research may help to provide more individualized treatment options for NSCLC patients.

Tailoring the nanostructures of electrochemical actuators for fast response and large deformation.

Electrochemical actuators (EAs) can effectively convert electric energy to mechanical energy through chemical reactions. However, the response rate and deformability, two of the crucial and antithetic factors in EA studies, can both hardly be improved just by developing or hybridizing different kinds of materials. In this work, this challenge is overcome through tailoring the nanostructures of EAs. A 3D nanoporous structure formed by aggregating spherical MoS2 nanoparticles (NPs) is reported. The NP-aggregated nanoporous structure not only provides a fast ion-migration process but also ensures strong mechanical strength. Experiments show that the voltage-dependent response rate and curvature amplitude respectively approach 0.015 mm-1·s-1·V-1 and 0.244 mm-1·V-1, which simultaneously exceed those of most EAs. A continuous energy density of 14 kJ·m-3, almost double that of mammalian muscle, enables the EA to rotate a stainless-steel weight which is over 550 times heavier than itself. By opening a new way to improve EAs' comprehensive performance, this research propels their potential applications in microrobotics and mini-medical devices.

Nonlinear electrochemomechanical modelling of electrochemical strain microscopy imaging.

Electrochemical strain microscopy (ESM) is a powerful tool to resolve ionic transport and electrochemical processes with a nanoscale resolution. To ascertain the underlying mechanism that governs the signal generation of ESM imaging, a fully coupled nonlinear electrochemomechanical model based on the finite element method is developed and applied to LiMn2O4 particles. The frequency dependence of the ESM response, in particular the response at high frequencies used in the detection regime, is investigated in detail. The performed analysis demonstrates that the error induced by the decoupling approximation increases with decreasing bias frequency due to the relatively large variation in ion concentration. In the high frequency regime, the results reveal that the stress effect is negligible and local electroneutrality holds, providing the simplification of numerical simulation for ESM imaging. By applying an alternative current voltage, we suggest that the detectable signal observed in ESM imaging can be attributed to the Vegard effect, which was controversial in previous linear models. The local distribution of ion concentration shows that the ionic reorganization only takes place near the tip-surface junction, the spatial extent of which can be described by two relevant lengths, the contact radius and ion drift length, which determine the spatial lateral resolution and depth resolution, respectively, in ESM imaging. Through a parametric study, the electromigration is proved to be dominant at high frequencies and the relationship between ESM amplitude and some parameters may offer a strategy to measure local electrochemical reactivity. The impact of contact force is evaluated and the results indicate that the local compression reduces ion concentration and the resultant ESM signal in the detection regime. Thus attention must be paid to the contact force when a comparison between different measurements is conducted. The combination of the numerical model and experiment holds the promise of quantitative probing of local electrochemical parameters in solids.

Athermal Shape Memory Effect in Magnetoactive Elastomers.

Shape memory materials (SMMs) are usually referred to as materials with the ability to recover the original shape via certain thermal stimulations, such as temperature increase. Such shape memory behaviors achieved thermally usually exhibit slow response due to the constraint of thermal conductivity, leaving a big challenge for situations with temperature and speed requirements. In this work, different from previous shape memory mechanisms, an athermal fast-response shape memory effect (SME) based on the manipulation of magnetization profiles is introduced both experimentally and theoretically. Through the new mechanism, the shape information of a hard magnetic-particle-embedded magnetoactive elastomer (H-MAE) can be accurately converted into the distribution of magnetic domains and recorded/memorized in the material. Then, upon the application of an external magnetic field, due to the interactions between magnetic domains and the magnetic field, the recorded shape information can be immediately displayed. To exploit this mechanism, the magnetic actuating properties are analyzed and a new way for information writing and repeatable reading is also realized.

Rayleigh wave propagation in a homogeneous centrosymmetric flexoelectric half-space.

Although Rayleigh waves are a research topic of constant interest, research on Rayleigh waves in flexoelectric materials is still lacking. This study reports the influences of flexoelectricity, strain gradient elasticity, micro-inertia effect and surface effect on Rayleigh waves in a homogeneous centrosymmetric flexoelectric material half-space. The nonclassical governing equations and boundary conditions are deduced with Hamilton's principle. Our findings suggest that the influence of flexoelectricity on the phase velocity depends on the flexoelectric coefficients. Strain gradient elasticity and surface elasticity can increase the phase velocity, while micro-inertia effect can decrease the phase velocity. Besides, these influences become significant for Rayleigh waves with high frequencies and short wavelengths. A mathematical foundation may be established to measure the material properties on the basis of the relationships among the material parameters, the phase velocity and the wave number. Moreover, the current work might provide guidance in developing small-scale acoustic wave devices operating at high frequencies.

Intercalated combination of chemotherapy and erlotinib for stage IIIA non-small-cell lung cancer: a multicenter, open-label, single-arm, phase II study.

OBJECTIVE: This multicenter, open-label, single-arm, phase II trial evaluated the efficacy and safety of an intercalated combination of erlotinib and gemcitabine/cisplatin or carboplatin in patients with stage IIIA non-small-cell lung cancer (NSCLC). REGISTRATION: This trial is registered with ClinicalTrials.gov, number NCT01297101. METHODS: The primary endpoint was the objective response rate (ORR), which includes complete response (CR) and partial response (PR), assessed using RECIST version 1.0 in the intention-to-treat population. Adverse events (AEs) were graded by the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Secondary endpoints included the disease control rate, disease-free survival (DFS), overall survival (OS), and safety. Between April 1, 2011, and July 31, 2014, 39 patients with stage IIIA NSCLC received two cycles of intercalated use of erlotinib with gemcitabine/cisplatin or carboplatin. RESULTS: Eighteen patients (46.15%) achieved a PR and no patient achieved a pathologic CR, resulting in an ORR of 46.15% (95% CI 30-63%). Median DFS was 20 months (95% CI 5.26-50.61) and median OS was 25 months (95% CI 15.57-33.39). Patients with EGFR mutations (n=7) had a higher ORR than those with wild-type EGFR (n=9) (85.71% vs 55.56%, P=0.00). Most AEs were CTCAE grade 1 or 2; there were no cases of increased hematologic toxicity or erlotinib-emergent interstitial lung disease observed. CONCLUSION: Two cycles of intercalated neoadjuvant therapy with erlotinib and gemcitabine/cisplatin or carboplatin were effective and safe for patients with stage IIIA NSCLC. This approach should be further explored in larger randomized controlled trials given the lack of a consensus about the best treatment for stage IIIA NSCLC.

Flexoelectret: An Electret with a Tunable Flexoelectriclike Response.

Because of the flexoelectric effect, dielectric materials usually polarize in response to a strain gradient. Soft materials are good candidates for developing a large strain gradient because of their good deformability. However, they always suffer from lower flexoelectric coefficients compared to ceramics. In this work, a flexoelectriclike effect is introduced to enhance the effective flexoelectricity of a polydimethylsiloxane bar. The flexoelectriclike effect is realized by depositing a layer of net charges on the middle plane of the bar to form an electret. Experiments show that the enhancement of flexoelectricity depends on the density of inserted net charges. It is found that a charged layer with surface potential of -5723 V results in a 100 times increase of the material's flexoelectric coefficient. We also show that the enhancement is proportional to the thickness of electrets. This work provides a new way of enhancing flexoelectricity in soft materials and further prompts the application of soft materials in electromechanical transducers.

Comparison of genomic landscapes of large cell neuroendocrine carcinoma, small cell lung carcinoma, and large cell carcinoma.

BACKGROUND: The classification of large cell neuroendocrine carcinoma (LCNEC) has generated considerable debate and has been revised since its recognition as a separate entity. Although it shares clinical features with small cell lung carcinoma (SCLC) and was classified with SCLC in the 2015 World Health Organization classification system, numerous studies have revealed inferior treatment outcomes of LCNEC when it was treated as SCLC. Because the incidence of LCNEC is rare, its mutational landscape has not been comprehensively interrogated. METHODS: We performed capture-based ultra-deep targeted sequencing on tumor samples of LCNEC, large cell carcinoma (LCC), and SCLC to elucidate its biological relationship with these subtypes and to identify potentially targetable molecular alterations. RESULTS: Our data revealed a molecular signature, consisting of RUNX1, ERBB4, BRCA1, and EPHA3, that is distinctively mutated in LCNEC. A majority (60%) of LCNEC patients harbored copy number variations (CNVs). Interestingly, there were no common CNVs shared among the three subtypes: NFкBIA amplification was shared between LCNEC and LCC, while AKT2 amplification was shared between LCNEC and SCLC. Furthermore, genetic alterations in the PI3K/AKT/mTOR pathway were enriched in all three subtypes. CONCLUSION: Despite the histological and/or morphological similarities among LCNEC, LCC, and SCLC, our data revealed a molecular signature, consisting of RUNX1, ERBB4, BRCA1, and EPHA3, that is distinctively mutated in LCNEC, which has the potential to be used as a panel of biomarkers to distinguish LCNEC from a molecular perspective. Furthermore, the molecular distinction among the three subtypes can also be reflected from CNV events.