Asymmetric-backed multi-frequency ultrasonic transducer for conformal tumor ablation.

OBJECTIVE: Minimally invasive ultrasound ablation transducers have been widely studied. However, conventional designs are limited by the single working frequency, restricting their conformal ablation ability (i.e. ablation size and shape controllability). METHODS: New multi-frequency ultrasonic transducer design method is proposed based on the asymmetric backing layer, which divides the transducer into non-backing-layer region (i.e. front-piezoelectric region) and backing-layer region (i.e. front-piezoelectric-backing region) with multiple local thickness mode resonant frequencies. Ablation zone can be controlled by exciting the local resonance within or between the regions, and its control flexibility is further enhanced by driven under a multi-frequency modulation signal. Experiments and calculations are combined for verifying the proposal. RESULTS: The fabricated transducer with a Y-direction asymmetric backing layer shows five resonances, with two in each region and one resonance excited in both regions. Spatial ultrasound emission is demonstrated by acoustic measurements. Tissue ablation experiments verified spatial ablation zone control, and frequency modulation driving method enables the spatial transition of ablation zone from one region to the other, generating different ablation sizes and shapes. Finally, patient-specific simulations verified the effectiveness of conformal ablation. CONCLUSION: The proposed transducer enables flexible control of ablation zone. SIGNIFICANCE: This study demonstrates a new method for conformal tumor ablation.

Wind-Speed-Adaptive Resonant Piezoelectric Energy Harvester for Offshore Wind Energy Collection.

This paper proposes a wind-speed-adaptive resonant piezoelectric energy harvester for offshore wind energy collection (A-PEH). The device incorporates a coil spring structure, which sets the maximum threshold of the output rotational frequency, allowing the A-PEH to maintain a stable output rotational frequency over a broader range of wind speeds. When the maximum output excitation frequency of the A-PEH falls within the sub-resonant range of the piezoelectric beam, the device becomes wind-speed-adaptive, enabling it to operate in a sub-resonant state over a wider range of wind speeds. Offshore winds exhibit an annual average speed exceeding 5.5 m/s with significant variability. Drawing from the characteristics of offshore winds, a prototype of the A-PEH was fabricated. The experimental findings reveal that in wind speed environments, the device has a startup wind speed of 4 m/s, and operates in a sub-resonant state when the wind speed exceeds 6 m/s. At this point, the A-PEH achieves a maximum open-circuit voltage of 40 V and an average power of 0.64 mW. The wind-speed-adaptive capability of the A-PEH enhances its ability to harness offshore wind energy, showcasing its potential applications in offshore wind environments.

Preparation, characterization and cytotoxicity assessment of a novel selenized polysaccharide from Morchella sextelata.

Selenylation modification has been widely developed to improve the biological effects of natural polysaccharides. In this study, a purified new polysaccharide (MSP-4) was isolated from Morchella Sextelata, and selenized into SeMSP-4 using the HNO3-Na2SeO3 method. The selenium (Se) content of SeMSP-4 was 101.81 ± 9.90 mg/kg, and the molecular weight of SeMSP-4 was 1.23 × 105 Da. The FT-IR, XRD and AFM results showed that MSP-4 was successfully combined with the Se element. The structure characters of SeMSP-4 were analyzed by methylation analysis combined with 1D and 2D NMR spectroscopy. And, the radical scavenging test revealed that SeMSP-4 exhibited higher antioxidant capacities in vitro than MSP-4. The cytotoxicity analysis indicated that SeMSP-4 could dose-dependently inhibit the proliferation of HepG2 and HeLa cells, but did not show a cytotoxic effect on normal cells (HEK293). Furthermore, SeMSP-4 stimulation significantly increased the macrophage viability and enhanced NO production in macrophage cells. This study suggested that SeMSP-4 could be utilized as a potential selenium source with antioxidant, antitumor, and immunostimulatory activities.

Wind-Wave Synergistic Triboelectric Nanogenerator: Performance Evaluation Test and Potential Applications in Offshore Areas.

Triboelectric nanogenerators (TENGs) can effectively collect low-frequency, disordered mechanical energy and are therefore widely studied in the field of ocean energy collection. Most of the rotary TENGs studied so far tend to have insufficient rotation, resulting in slow charge transfer rates in low-frequency ocean environments. For this reason, in this paper, we propose a wind-wave synergistic triboelectric nanogenerator (WWS-TENG). It is different from the traditional rotary TENGs based on free-standing mode in that its power generation unit has two types of rotors, and the two rotors rotate in opposite directions under the action of wind energy and wave energy, respectively. This type of exercise can more effectively collect energy. The WWS-TENG has demonstrated excellent performance in sea wind and wave energy harvesting. In the simulated ocean environment, the peak power can reach 13.5 mW under simulated wind-wave superposition excitation; the output of the WWS-TENG increased by 49% compared to single-wave power generation. The WWS-TENG proposal provides a novel means of developing marine renewable energy, and it also demonstrates broad application potential in the field of the self-powered marine Internet of Things (IoT).

A novel CPT1A covalent inhibitor modulates fatty acid oxidation and CPT1A-VDAC1 axis with therapeutic potential for colorectal cancer.

Colorectal cancer (CRC) is a common and deadly disease of the digestive system, but its targeted therapy is hampered by the lack of reliable and specific biomarkers. Hence, discovering new therapeutic targets and agents for CRC is an urgent and challenging task. Here we report that carnitine palmitoyltransferase 1A (CPT1A), a mitochondrial enzyme that catalyzes fatty acid oxidation (FAO), is a potential target for CRC treatment. We show that CPT1A is overexpressed in CRC cells and that its inhibition by a secolignan-type compound, 2,6-dihydroxypeperomin B (DHP-B), isolated from the plant Peperomia dindygulensis, suppresses tumor cell growth and induces apoptosis. We demonstrate that DHP-B covalently binds to Cys96 of CPT1A, blocks FAO, and disrupts the mitochondrial CPT1A-VDAC1 interaction, leading to increased mitochondrial permeability and reduced oxygen consumption and energy metabolism in CRC cells. We also reveal that CPT1A expression correlates with the survival of tumor-bearing animals and that DHP-B exhibits anti-CRC activity in vitro and in vivo. Our study uncovers the molecular mechanism of DHP-B as a novel CPT1A inhibitor and provides a rationale for its preclinical development as well as a new strategy for CRC targeted therapy.

Interpretable Machine Learning Model to Predict Bone Cement Leakage in Percutaneous Vertebral Augmentation for Osteoporotic Vertebral Compression Fracture Based on SHapley Additive exPlanations.

STUDY DESIGN: Retrospective study. OBJECTIVES: Our objective is to create comprehensible machine learning (ML) models that can forecast bone cement leakage in percutaneous vertebral augmentation (PVA) for individuals with osteoporotic vertebral compression fracture (OVCF) while also identifying the associated risk factors. METHODS: We incorporated data from patients (n = 425) which underwent PVA. To predict cement leakage, we devised six models based on a variety of parameters. Evaluate and juxtapose the predictive performances relied on measures of discrimination, calibration, and clinical utility. SHapley Additive exPlanations (SHAP) methodology was used to interpret model and evaluate the risk factors associated with cement leakage. RESULTS: The occurrence rate of cement leakage was established at 50.4%. A binary logistic regression analysis identified cortical disruption (OR 6.880, 95% CI 4.209-11.246), the basivertebral foramen sign (OR 2.142, 95% CI 1.303-3.521), the fracture type (OR 1.683, 95% CI 1.083-2.617), and the volume of bone cement (OR 1.198, 95% CI 1.070-1.341) as independent predictors of cement leakage. The XGBoost model outperformed all others in predicting cement leakage in the testing set, with AUC of .8819, accuracy of .8025, recall score of .7872, F1 score of .8315, and a precision score of .881. Several important factors related to cement leakage were drawn based on the analysis of SHAP values and their clinical significance. CONCLUSION: The ML based predictive model demonstrated significant accuracy in forecasting bone cement leakage for patients with OVCF undergoing PVA. When combined with SHAP, ML facilitated a personalized prediction and offered a visual interpretation of feature importance.

Heliangin acts as a covalent ligand of RPS2 that disrupts pre-rRNA metabolic processes in NPM1-mutated acute myeloid leukemia.

Although NPM1 mutations are frequently found in acute myeloid leukemia patients, therapeutic strategies are scarce and unsuitable for those who cannot tolerate intensive chemotherapy. Here we demonstrated that heliangin, a natural sesquiterpene lactone, exerts favorable therapeutic responses in NPM1 mutant acute myeloid leukemia cells, with no apparent toxicity to normal hematogenous cells, by inhibiting their proliferation, inducing apoptosis, causing cell cycle arrest, and promoting differentiation. In-depth studies on its mode of action using quantitative thiol reactivity platform screening and subsequent molecular biology validation showed that the ribosomal protein S2 (RPS2) is the main target of heliangin in treating NPM1 mutant AML. Upon covalent binding to the C222 site of RPS2, the electrophilic moieties of heliangin disrupt pre-rRNA metabolic processes, leading to nucleolar stress, which in turn regulates the ribosomal proteins-MDM2-p53 pathway and stabilizes p53. Clinical data shows that the pre-rRNA metabolic pathway is dysregulated in acute myeloid leukemia patients with the NPM1 mutation, leading to a poor prognosis. We found that RPS2 plays a critical role in regulating this pathway and may be a novel treatment target. Our findings suggest a novel treatment strategy and lead compound for acute myeloid leukemia patients, especially those with NPM1 mutations.

Covalent targeting the LAS1-NOL9 axis for selective treatment in NPM1 mutant acute myeloid leukemia.

Patients with NPM1 gene mutation-associated acute myeloid leukemia (AML), particularly those over the age of 60, have no viable targeted therapeutic choices. In this study, we identified HEN-463, a sesquiterpene lactone derivative specific targets AML with this gene mutation. This compound inhibits the interaction of LAS1-NOL9 by covalently binding to the C264 site of the ribosomal biogenesis-related protein LAS1, which translocates the LAS1 to the cytoplasm, thereby inhibiting the maturation of 28 S rRNA. This has a profound effect on the NPM1-MDM2-p53 pathway and ultimately results in the stabilization of p53. Combining this treatment with the XPO1 inhibitor Selinexor (Sel) can ideally preserve the stabilized p53 in the nucleus, considerably enhancing the efficacy of HEN-463 and addressing Sel's drug resistance. Patients with AML over the age of 60 who possess the NPM1 mutation have an unusually elevated level of LAS1, which has a significant impact on their prognosis. In NPM1-mutant AML cells, decreased LAS1 expression promotes proliferation inhibition, apoptosis, cell differentiation, and cell cycle arrest. This suggests that it may be a therapeutic target for this kind of blood cancer, especially in patients over the age of 60.

Revealing the Phenolic Acids in Cardamine violifolia Leaves by Transcriptome and Metabolome Analyses.

Cardamine violifolia, a species belonging to the Brassicaceae family, is a selenium hyperaccumulator and a nutritious leafy vegetable. Our previous study showed that C. violifolia leaves are rich in total phenolic acids, but the composition and corresponding genes remain unknown. In this study, we investigated the phenolic acid compounds and potential gene regulation network in the outer leaves (OL) and central leaves (CL) of C. violifolia using transcriptome and metabolome analyses. Results showed that the OL contained a higher total phenolic acid content than the CL. Metabolome analysis revealed a total of 115 phenolic acids, 62 of which (e.g., arbutin, rosmarinic acid, hydroxytyrosol acetate, and sinapic acid) were differentially accumulated between the CL and OL of C. violifolia. Transcriptome analysis showed that the differentially expressed genes were significantly enriched in the pathways of secondary metabolite biosynthesis and phenylpropanoid biosynthesis. Conjoint analysis of the transcriptome and metabolome indicated that seven genes (CYP84A1, CYP84A4, CADH9, SGT1, UGT72E1, OMT1, and CCR2) and eight phenolic acids (sinapic acid, sinapyl alcohol, 5-O-caffeoylshikimic acid, sinapoyl malate, coniferin, coniferyl alcohol, L-phenylalanine, and ferulic acid) constituted a possible regulatory network. This study revealed the phenolic acid compounds and possible regulatory network of C. violifolia leaves and deepened our understanding of its nutrient value.

Systematic Study of the Sensory Quality, Metabolomics, and Microbial Community of Fresh-Cut Watermelon Provides New Clues for Its Quality Control and Preservation.

As a popular form of fruit consumption, fresh-cut watermelon is of great convenience for its consumers. Owing to the lack of comprehensive knowledge about the quality changes of fresh-cut watermelon during its shelf life, guidelines and standards are unavailable currently. To clarify the deterioration process and its underlying mechanism in fresh-cut watermelon, the sensory parameters, metabolomics, and microbial community of fresh-cut watermelon during a three-day storage at both room temperature (RT) and refrigerator temperature were systematically studied in this work. Results revealed that the whole property of the watermelon stored at refrigerator temperature kept stable, while pulps stored at RT had substantially deteriorated after 36 h. The decay was reflected in the significant decrease in soluble solid contents, firmness, pH, and color parameters in the sensory perspective. At the metabolic level, significantly declined malate, citrate, uridine, uridine 5-monophosphate, and amino acids, and increased ethanol and lactate contents, were observed as deterioration markers, which partially resulted from the activities of pyruvate dehydrogenase and alcohol dehydrogenase and the burst of genera Enterobacteriaceae and Leuconostocaceae. This study unveiled the underlying mechanisms of quality changes in fresh-cut watermelon under its primary storage conditions to provide fundamental information and potential clues for its quality control and preservation.

Does Methionine Status Influence the Outcome of Selenomethinione Supplementation? A Comparative Study of Metabolic and Selenium Levels in HepG2 Cells.

Methionine restriction and selenium supplementation are recommended because of their health benefits. As a major nutrient form in selenium supplementation, selenomethionine shares a similar biological process to its analog methionine. However, the outcome of selenomethionine supplementation under different methionine statuses and the interplay between these two nutrients remain unclear. Therefore, this study explored the metabolic effects and selenium utilization in HepG2 cells supplemented with selenomethionine under deprived, adequate, and abundant methionine supply conditions by using nuclear magnetic resonance-based metabolomic and molecular biological approaches. Results revealed that selenomethionine promoted the proliferation of HepG2 cells, the transcription of selenoproteins, and the production of most amino acids while decreasing the levels of creatine, aspartate, and nucleoside diphosphate sugar regardless of methionine supply. Selenomethionine substantially disturbed the tricarboxylic acid cycle and choline metabolism in cells under a methionine shortage. With increasing methionine supply, the metabolic disturbance was alleviated, except for changes in lactate, glycine, citrate, and hypoxanthine. The markable selenium accumulation and choline decrease in the cells under methionine shortage imply the potential risk of selenomethionine supplementation. This work revealed the biological effects of selenomethionine under different methionine supply conditions. This study may serve as a guide for controlling methionine and selenomethionine levels in dietary intake.

An Air Velocity Monitor for Coal Mine Ventilation Based on Vortex-Induced Triboelectric Nanogenerator.

Air velocity of coal mine ventilation is an important consideration that may cause serious damage. This paper proposes a simple, low cost and effective air velocity monitor (AVM) for coal mine ventilation. The AVM uses the lock-in characteristic of vortex-induced vibration (VIV) to sense the air velocity. Amplitude of the VIV is converted into frequency signal of a vortex-induced triboelectric nanogenerator (VI-TENG) to improve the durability. Structure of the AVM are designed, and parameters of the AVM are optimized with experiments. For the upper and lower air velocity thresholds of 3.1 and 3.6 m/s, the optimized flexible beam length, slider weight, electrode space and electrode width are 42.5 mm, 0.4 g, 0.2 mm and 0.5 mm, respectively. Experiments also show that the output frequency of the VI-TENG could represent the amplitude of VIV well with the correlation coefficient of 0.93. Durability test demonstrates that the AVM generates stable output frequency in 120,000 cycles. A prototype and its controller are fabricated. Wind tunnel tests of this prototype show that it can give alarm when the gas velocity goes above the upper threshold or below the lower threshold. The proposed AVM could be a good solution for simple and effective coal mine ventilation alarm.

Selenium Nanoparticles Synergistically Stabilized by Starch Microgel and EGCG: Synthesis, Characterization, and Bioactivity.

Selenium (Se) is a chemical element essential to human health because of its bioactive properties, including antioxidative, anticancer, and immunomodulating activities. Despite the high therapeutic potential of Se, its intrinsic properties of poor stability, a narrow therapeutic window, and low bioavailability and bioactivity have limited its clinical applications. Selenium nanoparticles (SeNPs) exhibit lower toxicity and higher bioactivity than other Se forms. Herein, we report a green method for the preparation of monodisperse SeNPs with starch microgel (SM) and epigallocatechin gallate (EGCG) through Se-O bonds and polysaccharide-polyphenol interactions (namely, SM-EGCG-SeNPs). SM-EGCG-SeNPs showed higher stability, bioactivities, and cytotoxicity than SeNPs and SM-SeNPs at the equivalent dose. SM-EGCG-SeNPs induced the apoptosis of cancer cells via the activation of several caspases and reactive oxygen species overproduction. This work proposes a facile method for the design and potentiation of structure-bioactive SeNPs via polysaccharide-polyphenol interactions.

Study on the water state, migration, and microstructure modification during the process of salt-reduced stewed duck.

High salt content is one of the major problems for stewed products. To help address this issue, the effect of salt reduction on water migration in stewed ducks was investigated through diverse approaches, including water activity (Aw) and water-holding capacity (WHC) assay, as well as low-field nuclear magnetic resonance (LF-NMR) and scanning electron microscopy (SEM) observation. Our results showed that Aw value remained stable, while centrifugal loss decreased, and cooking loss increased significantly (p < 0.05). The analysis of NMR indicated that, during the marinating stage, the proportion of immobilized water increased from 86.86%-89.66% (sodium chloride group) and 90.51% (salt-reduced group), respectively. After 2 h, the free water content became 0, and then became stable until the end of marinating. In the stewing stage, at the beginning 20 min, relaxation time of immobilized water decreased to about 35 ms and the ratio of immobilized water significantly reduced (p < 0.05) by 5.38% (sodium chloride group) and 5.95% (salt-reduced group), respectively. Free water peak was detected upon stewing of 10 min, and 20 min later, there was no significant difference in the proportion of free water (p > 0.05). In general, no significance was observed in water behavior and microstructure of stewed duck meat between the salt reduction group and sodium chloride group. In addition, SEM analysis revealed that marinating could expand the muscle fiber gap to accommodate more immobilized water. However, the fiber was looser at the initial stage of stewing and then became more compact. PRACTICAL APPLICATION: This work demonstrates potentially feasible to produce salt-reduced duck products.

Quantitative Evaluation of Burn Injuries Based on Electrical Impedance Spectroscopy of Blood with a Seven-Parameter Equivalent Circuit.

A quantitative and rapid burn injury detection method has been proposed based on the electrical impedance spectroscopy (EIS) of blood with a seven-parameter equivalent circuit. The degree of burn injury is estimated from the electrical impedance characteristics of blood with different volume proportions of red blood cells (RBCs) and heated red blood cells (HRBCs). A quantitative relationship between the volume portion HHCT of HRBCs and the electrical impedance characteristics of blood has been demonstrated. A seven -parameter equivalent circuit is employed to quantify the relationship from the perspective of electricity. Additionally, the traditional Hanai equation has been modified to verify the experimental results. Results show that the imaginary part of impedance ZImt under the characteristic frequency (fc) has a linear relationship with HHCT which could be described by ZImt = -2.56HHCT - 2.01 with a correlation coefficient of 0.96. Moreover, the relationship between the plasma resistance Rp and HHCT is obtained as Rp = -7.2HHCT + 3.91 with a correlation coefficient of 0.96 from the seven -parameter equivalent circuit. This study shows the feasibility of EIS in the quantitative detection of burn injury by the quantitative parameters ZImt and Rp, which might be meaningful for the follow-up clinical treatment for burn injury.

MiR-218-5p Suppresses the Killing Effect of Natural Killer Cell to Lung Adenocarcinoma by Targeting SHMT1.

PURPOSE: Lung adenocarcinoma (LA) is one of the major types of lung cancer. MicroRNAs (miRNAs) play an essential role in regulating responses of natural killer (NK) cells to cancer malignancy. However, the mechanism of miR-218-5p involved in the killing effect of NK cells to LA cells remains poorly understood. MATERIALS AND METHODS: The expression of miR-218-5p was examined by quantitative real-time polymerase chain reaction (qRT-PCR). Serine hydroxymethyl transferase 1 (SHMT1) level was detected by qRT-PCR or western blots. Cytokines production of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) were detected by ELISA. The killing effect of NK cells to LA cells was investigated using lactate dehydrogenase cytotoxicity assay kit. The interaction of miR-218-5p and SHMT1 was probed by luciferase activity assay. Xenograft model was established to investigate the killing effect of NK cells in vivo. RESULTS: miR-218-5p was enhanced and SHMT1 was inhibited in NK cells of LA patients, whereas stimulation of interleukin-2 (IL-2) reversed their abundances. Addition of miR-218-5p reduced IL-2-induced cytokines expression and cytotoxicity in NK-92 against LA cells. Moreover, SHMT1 was negatively regulated by miR-218-5p and attenuated miR-218-5p-mediated effect on cytotoxicity, IFN-γ and TNF-α secretion in IL-2-activated NK cells. In addition, miR-218-5p exhaustion inhibited tumor growth by promoting killing effect of NK cells. CONCLUSION: miR-218-5p suppresses the killing effect of NK cells to LA cells by targeting SHMT1, providing a potential target for LA treatment by ameliorating NK cells function.

Tailor-made PL-UC-C3 nanoparticles for fluorescence/computed tomography imaging-guided cascade amplified photothermal therapy.

BACKGROUND: Development of the burgeoning number of photothermal therapy (PTT) agents has drawn a huge amount of interest, since PTT treatment is a powerful and effective alternative to traditional treatments. Optimal PTT agents should integrate some essential preconditions including negligible systemic toxicity, deep penetration into tumor tissues, and maximum laser energy absorbance. Unfortunately, only few of the PTT agents reported could meet all of the above mentioned conditions. METHODS: Here, we report a brand new PTT agent through the encapsulation of NaGdF4:Yb,Tm@ NaGdF4:Yb (UCNPs) and an organic compound (C3) into poly-e-caprolactone-polyethylene-polyglycol (PCL-PEG) (PL-UC-C3 NPs). RESULTS: UCNPs as an up-conversion material and C3 as a PTT agent both feature low cytotoxicity, and most importantly, UCNPs with superior conversion efficiency could efficiently absorb the energy of a 980 nm laser, transform the near-infrared laser light into visible light, and translate the palingenetic visible light to C3. The usage of a 980 nm laser ensures a deeper penetration and lower energy, while the highly efficient absorption and transformation process confers a cascade amplified hyperthermia for tumor treatment. CONCLUSION: In this regard, our research provides a powerful and robust breakthrough for florescence/computed tomography imaging-guided PTT treatment, lighting up the clinical application in cancer treatment.

Doxorubicin and paclitaxel carried by methoxy poly(ethylene glycol)-poly(lactide-co-glycolide) is superior than traditional drug-delivery methods.

AIM: To evaluate the advantages of nanomaterial methoxy poly(ethylene glycol)-poly(lactide-co-glycolide) (mPEG-PLGA) encapsulated doxorubicin (D/DOX) and paclitaxel (T/TAX; mPEG-PLGA-DT) over free form of DOX and TAX (DOX/TAX). MATERIALS & METHODS: Metabonomics was conducted to characterize the systemic metabolic response of allograft breast cancer model mice to mPEG-PLGA-DT and DOX/TAX treatments. RESULTS: Breast tumor growth induced metabolic reprogram in serum and multiple organs. DOX/TAX treatment could ameliorate the elevated energy and nucleotides demands in some organs while mPEG-PLGA-DT treatment showed outstanding therapeutic outcomes in restoring the metabolic phenotypes of serum and kidney from tumor-bearing mice to the healthy state. CONCLUSION: This investigation proved the biological advantages of mPEG-PLGA-DT over DOX/TAX in molecular level through the comparison between their metabolic responses in vivo.

A targeted biocompatible organic nanoprobe for photoacoustic and near-infrared-II fluorescence imaging in living mice.

Multimodal molecular imaging probes have attracted much attention, and they possess great potential to accurately diagnose diseases due to the synergistic superiorities of multiple complementary imaging. Herein, a targeted biocompatible organic nanoplatform (IR-PEG-FA) with a strong optical absorption in the near-infrared window (NIR-I) for photoacoustic imaging (PAI) and excellent second near-infrared (NIR-II) fluorescence imaging property for NIR-II imaging is fabricated. The dual-modal nanoprobe is composed of the small organic dye molecule IR-1061, water-soluble poly(ethylene glycol) (PEG) and folic acid (FA) as the targeted ligands. Depending on the strength of high temporal resolution and preeminent spatial resolution, the targeted biocompatible dual-mode nanoprobe for PAI and NIR-II imaging can provide more detailed date of cancers and diseases, and enables us to specifically diagnose them through quite a precise way.

Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) inhibitors such as erlotinib are novel effective agents in the treatment of EGFR-driven lung cancer, but their clinical impact is often impaired by acquired drug resistance through the secondary T790M EGFR mutation. To overcome this problem, we analysed the metabonomic differences between two independent pairs of erlotinib-sensitive/resistant cells and discovered that glutathione (GSH) levels were significantly reduced in T790M EGFR cells. We also found that increasing GSH levels in erlotinib-resistant cells re-sensitised them, whereas reducing GSH levels in erlotinib-sensitive cells made them resistant. Decreased transcription of the GSH-synthesising enzymes (GCLC and GSS) due to the inhibition of NRF2 was responsible for low GSH levels in resistant cells that was directly linked to the T790M mutation. T790M EGFR clinical samples also showed decreased expression of these key enzymes; increasing intra-tumoural GSH levels with a small-molecule GST inhibitor re-sensitised resistant tumours to erlotinib in mice. Thus, we identified a new resistance pathway controlled by EGFR T790M and a therapeutic strategy to tackle this problem in the clinic.