Engineering liquid metal-based nanozyme for enhancing microwave dynamic therapy in breast cancer PDX model.

BACKGROUNDS: The novel concept of microwave dynamic therapy (MDT) solves the problem of incomplete tumor eradication caused by non-selective heating and uneven temperature distribution of microwave thermal therapy (MWTT) in clinic, but the poor delivery of microwave sensitizer and the obstacle of tumor hypoxic microenvironment limit the effectiveness of MDT. RESULTS: Herein, we engineer a liquid metal-based nanozyme LM@ZIF@HA (LZH) with eutectic Gallium Indium (EGaIn) as the core, which is coated with CoNi-bimetallic zeolite imidazole framework (ZIF) and hyaluronic acid (HA). The flexibility of the liquid metal and the targeting of HA enable the nanozyme to be effectively endocytosed by tumor cells, solving the problem of poor delivery of microwave sensitizers. Due to the catalase-like activity, the nanozyme catalyze excess H2O2 in the tumor microenvironment to generate O2, alleviating the restriction of the tumor hypoxic microenvironment and promoting the production of ROS under microwave irradiation. In vitro cell experiments, the nanozyme has remarkable targeting effect, oxygen production capacity, and microwave dynamic effect, which effectively solves the defects of MDT. In the constructed patient-derived xenograft (PDX) model, the nanozyme achieves excellent MDT effect, despite the heterogeneity and complexity of the tumor model that is similar to the histological and pathological features of the patient. The tumor volume in the LZH + MW group is only about 1/20 of that in the control group, and the tumor inhibition rate is as high as 95%. CONCLUSION: The synthesized nanozyme effectively solves the defects of MDT, improves the targeted delivery of microwave sensitizers while regulating the hypoxic microenvironment of tumors, and achieves excellent MDT effect in the constructed PDX model, providing a new strategy for clinical cancer treatment.

Aliskiren-attenuated myocardium apoptosis via regulation of autophagy and connexin-43 in aged spontaneously hypertensive rats.

There are controversies about the mechanism of myocardium apoptosis in hypertensive heart disease. The aim of this study was to investigate the relationship among autophagy, Cx43 and apoptosis in aged spontaneously hypertensive rats (SHRs) and establish whether Aliskiren is effective or not for the treatment of myocardium apoptosis. Twenty-one SHRs aged 52 weeks were randomly divided into three groups, the first two receiving Aliskiren at a dose of 10 and 25 mg/kg/day respectively; the third, placebo for comparison with seven Wistar-Kyoto (WKY) as controls. After a 2-month treatment, systolic blood pressure (SBP), heart to bw ratios (HW/BW%) and angiotensin II (AngII) concentration were significantly enhanced in SHRs respectively. Apoptotic cardiomyocytes detected with TUNEL and immunofluorescent labelling for active caspase-3 increased nearly fourfolds in SHRs, with a decline in the expression of survivin and AKT activation, and an increase in caspase-3 activation and the ratio of Bax/Bcl-2. Myocardium autophagy, detected with immunofluorescent labelling for LC3-II, increased nearly threefolds in SHRs, with the up-regulation of Atg5, Atg16L1, Beclin-1 and LC3-II. The expression of Cx43 plaque was found to be down-regulated in SHRs. Aliskiren significantly reduced SBP, HW/BW%, AngII concentration and the expression of AT(1)R. Thus, Aliskiren protects myocardium against apoptosis by decreasing autophagy, up-regulating Cx43. These effects showed a dose-dependent tendency, but no significance. In conclusion, the myocardium apoptosis developed during the hypertensive end-stage of SHRs could be ameliorated by Aliskiren via the regulation of myocardium autophagy and maladaptive remodelling of Cx43.

Stabilized four-electron aqueous zinc-iodine batteries by quaternary ammonium complexation.

Four-electron aqueous zinc-iodine batteries (4eZIBs) leveraging the I-/I0/I+ redox couple have garnered attention for their potential high voltage, capacity, and energy density. However, the electrophilic I+ species is highly susceptible to hydrolysis due to the nucleophilic attack by water. Previous endeavors to develop 4eZIBs primarily relied on highly concentrated aqueous electrolytes to mitigate the hydrolysis issue, nonetheless, it introduced challenges associated with dissolution, high electrolyte viscosity, and sluggish electrode kinetics. In this work, we present a novel complexation strategy that capitalizes on quaternary ammonium salts to form solidified compounds with I+ species, rendering them impervious to solubilization and hydrolysis in aqueous environments. The robust interaction in this complexation chemistry facilitates a highly reversible I-/I0/I+ redox process, significantly improving reaction kinetics within a conventional ZnSO4 aqueous electrolyte. The proposed 4eZIB exhibits a superior rate capability and an extended lifespan of up to 2000 cycles. This complexation chemistry offers a promising pathway for the development of advanced 4eZIBs.

Volumetric Modulated Arc Therapy for High-Risk and Very High-Risk Locoregional Prostate Cancer in the Modern Era: Real-World Experience from an Asian Cohort.

This study retrospectively evaluates the clinical outcomes of definitive volumetric modulated arc therapy (VMAT) for high-risk or very high-risk locoregional prostate cancer patients from an Asian institution. Consecutive patients who received VMAT (76 Gy in 38 fractions) between January 2017 and June 2022 were included. Whole pelvic radiotherapy (WPRT) (46 Gy in 23 fractions) was employed for clinically node-negative disease (cN0) and a Roach estimated risk of ≥15%, as well as simultaneous integrated boost (SIB) of 55-57.5 Gy to node-positive (cN1) disease. The primary endpoint was biochemical relapse-free survival (BRFS). Secondary endpoints included radiographic relapse-free survival (RRFS), metastasis-free survival (MFS) and prostate cancer-specific survival (PCSS). A total of 209 patients were identified. After a median follow-up of 47.5 months, the 4-year actuarial BRFS, RRFS, MFS and PCSS were 85.2%, 96.8%, 96.8% and 100%, respectively. The incidence of late grade ≥ 2 genitourinary (GU) and gastrointestinal (GI) toxicity were 15.8% and 11.0%, respectively. No significant difference in cancer outcomes or toxicity was observed between WPRT and prostate-only radiotherapy for cN0 patients. SIB to the involved nodes did not result in increased toxicity. International Society of Urological Pathology (ISUP) group 5 and cN1 stage were associated with worse RRFS (p < 0.05). PSMA PET-CT compared to conventional imaging staging was associated with better BRFS in patients with ISUP grade group 5 (p = 0.039). Five-year local experience demonstrates excellent clinical outcomes. PSMA PET-CT staging for high-grade disease and tailored pelvic irradiation based on nodal risk should be considered to maximize clinical benefit.

Metronidazole-modified Au@BSA nanocomposites for dual sensitization of radiotherapy in solid tumors.

The hypoxic microenvironment of solid tumors can lead to reduced therapeutic DNA damage to the tumor cells, thus diminishing tumor sensitivity to radiotherapy. Although hypoxic radiosensitizers can improve radiotherapy efficacy by enhancing the role of oxygen, their effects are limited by the uneven distribution of oxygen within solid tumor tissues. In this study, a novel radiosensitizer via leveraging gold complexes and metronidazole (MN) was synthesized to improve radiotherapeutic efficacy. The gold atoms incorporated in the radiosensitizer enabled efficient deposition of high-energy radiation; the hydrophobic metronidazole was reduced to hydrophilic aminoimidazole under hypoxia conditions and further promoted radiotherapy sensitization. The results of CCK-8 assays, Live/Dead assays, γ-H2AX immunofluorescence indicated that metronidazole-modified Au@BSA nanocomposites (NCs) exhibited excellent antitumor effects. The in vivo antitumor tests further showed an inhibition rate of 100%. These results demonstrated that the NCs successfully enhanced radiotherapy efficacy by the dual sensitization strategy. Overall, we believe this multimodal radiosensitizing nanocomplex can significantly inhibit tumor growth and metastasis, with their hypoxia-oriented characteristics ensuring a higher efficacy and safety.

DLM-GelMA/tumor slice sandwich structured tumor on a chip for drug efficacy testing.

The in vitro recapitulation of tumor microenvironment is of great interest to preclinical screening of drugs. Compared with culture of cell lines, tumor organ slices can better preserve the complex tumor architecture and phenotypic activity of native cells, but are limited by their exposure to fluid shear and gradual degradation under perfusion culture. Here, we established a decellularized liver matrix (DLM)-GelMA "sandwich" structure and a perfusion-based microfluidic platform to support long-term culture of tumor slices with excellent structural integrity and cell viability over 7 days. The DLM-GelMA was able to secrete cytokines and growth factors while providing shear protection to the tumor slice via the sandwich structure, leading to the preservation of the tumor microenvironment where immune cells (CD3, CD8, CD68), tumor-associated fibroblasts (α-SMA), and extracellular matrix components (collagen I, fibronectin) were well maintained. Furthermore, this chip presented anti-tumor efficacy at cisplatin (20 µM) on tumor patients, demonstrating our platform's efficacy to design patient-specific treatment regimens. Taken together, the successful development of this DLM-GelMA sandwich structure on the chip could faithfully reflect the tumor microenvironment and immune response, accelerating the screening process of drug molecules and providing insights for practical medicine.

Stabilizing Zinc Anodes by a Uniform Nucleation Process with Cysteine Additive.

Zinc anodes in aqueous batteries face challenges such as dendrite growth and interfacial instability. This study investigates the use of cysteine as an electrolyte additive to address these issues. By establishing the correlation between the size of zinc nuclei and the surface tensions/contact angle at the electrolyte-anode interface, it is demonstrated that the addition of cysteine in the electrolyte alters the surface tensions/contact angle at the electrolyte-anode interface and the nucleation process of zinc. This alteration results in the formation of smaller and more dispersed nuclei, as opposed to the formation of larger island grains. This has a profound impact on the subsequent deposition growth process, enabling smooth and uniform zinc electrodeposition without the formation of dendrites. Additionally, cysteine molecules create a stable interface during zinc plating and stripping, effectively preventing corrosion from side reactions. The incorporation of cysteine in the electrolyte significantly enhances cycling stability and extends the lifespan of zinc anodes in aqueous batteries.

Establishment and Characterization of Patient-Derived Xenograft Models of Anaplastic Thyroid Carcinoma and Head and Neck Squamous Cell Carcinoma.

Patient-derived xenograft (PDX) models faithfully preserve the histological and genetic characteristics of the primary tumor and maintain its heterogeneity. Pharmacodynamic results based on PDX models are highly correlated with clinical practice. Anaplastic thyroid carcinoma (ATC) is the most malignant subtype of thyroid cancer, with strong invasiveness, poor prognosis, and limited treatment. Although the incidence rate of ATC accounts for only 2%-5% of thyroid cancer, its mortality rate is as high as 15%-50%. Head and neck squamous cell carcinoma (HNSCC) is one of the most common head and neck malignancies, with over 600,000 new cases worldwide each year. Herein, detailed protocols are presented to establish PDX models of ATC and HNSCC. In this work, the key factors influencing the success rate of model construction were analyzed, and the histopathological features were compared between the PDX model and the primary tumor. Furthermore, the clinical relevance of the model was validated by evaluating the in vivo therapeutic efficacy of representative clinically used drugs in the successfully constructed PDX models.

Audible Acoustic Wave Promotes EV Formation and Secretion from Adherent Cancer Cells via Mechanical Stimulation.

Cancer-derived extracellular vesicles (EVs) have shown great potential in the field of cancer metastasis research. However, inefficient EV biofabrication has become a barrier to large-scale research on cancer-derived EVs. Here, we presented a novel method to enhance the biofabrication of cancer-derived EVs via audible acoustic wave (AAW), which yielded mechanical stimuli, including surface acoustic pressure and surface stress. Compared to EV yield in conventional static culture, AAW increased the number of cancer-derived EVs by up to 2.5-folds within 3 days. Furthermore, cancer-derived EVs under AAW stimulation exhibited morphology, size, and zeta potential comparable to EVs generated in conventional static culture, and more importantly, they showed the capability to promote cancer cell migration and invasion under both 2D and 3D culture conditions. Additionally, the elevation in EV biofabrication correlated with the activation of the ESCRT pathway and upregulation of membrane fusion-associated proteins (RAB family, SNARE family, RHO family) in response to AAW stimulation. We believe that AAW represents an attractive approach to achieving high-quantity and high-quality production of EVs and that it has the potential to enhance EV biofabrication from other cell types, thereby facilitating EV-based scientific and translational research.

Rosuvastatin-attenuated heart failure in aged spontaneously hypertensive rats via PKCα/ß2 signal pathway.

There are controversies concerning the capacity of Rosuvastatin to attenuate heart failure in end-stage hypertension. The aim of the study was to show whether the Rosuvastatin might be effective or not for the heart failure treatment. Twenty-one spontaneously hypertensive rats (SHRs) aged 52 weeks with heart failure were randomly divided into three groups: two receiving Rosuvastatin at 20 and 40 mg/kg/day, respectively, and the third, placebo for comparison with seven Wistar-Kyoto rats (WKYs) as controls. After an 8-week treatment, the systolic blood pressure (SBP) and echocardiographic features were evaluated; mRNA level of B-type natriuretic peptide (BNP) and plasma NT-proBNP concentration were measured; the heart tissues were observed under electron microscope (EM); myocardial sarcoplasmic reticulum Ca(2+) pump (SERCA-2) activity and mitochondria cytochrome C oxidase (CCO) activity were measured; the expressions of SERCA-2a, phospholamban (PLB), ryanodine receptor2 (RyR2), sodium-calcium exchanger 1 (NCX1), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and protein phosphatase inhibitor-1 (PPI-1) were detected by Western blot and RT-qPCR; and the total and phosphorylation of protein kinase Cα/ß (PKCα/ß) were measured. Aged SHRs with heart failure was characterized by significantly decreased left ventricular ejection fraction and left ventricular fraction shortening, enhanced left ventricular end-diastolic diameter and LV Volume, accompanied by increased plasma NT-proBNP and elevated BNP gene expression. Damaged myofibrils, vacuolated mitochondria and swollen sarcoplasmic reticulum were observed by EM. Myocardium mitochondria CCO and SERCA-2 activity decreased. The expressions of PLB and NCX1 increased significantly with up-regulation of PPI-1 and down-regulation of CaMKII, whereas that of RyR2 decreased. Rosuvastatin was found to ameliorate the heart failure in aged SHRs and to improve changes in SERCA-2a, PLB, RyR2, NCX1, CaMKII and PPI-1; PKCα/ß2 signal pathway to be suppressed; the protective effect of Rosuvastatin to be dose dependent. In conclusion, the heart failure of aged SHRs that was developed during the end stage of hypertension could be ameliorated by Rosuvastatin.

A four-electron Zn-I2 aqueous battery enabled by reversible I-/I2/I+ conversion.

Electrochemically reversible redox couples that embrace more electron transfer at a higher potential are the eternal target for energy storage batteries. Here, we report a four-electron aqueous zinc-iodine battery by activating the highly reversible I2/I+ couple (1.83 V vs. Zn/Zn2+) in addition to the typical I-/I2 couple (1.29 V). This is achieved by intensive solvation of the aqueous electrolyte to yield ICl inter-halogens and to suspend its hydrolysis. Experimental characterization and modelling reveal that limited water activity and sufficient free chloride ions in the electrolyte are crucial for the four-electron process. The merits of the electrolyte also afford to stabilize Zn anode, leading to a reliable Zn-I2 aqueous battery of 6000 cycles. Owing to high operational voltage and capacity, energy density up to 750 Wh kg-1 based on iodine mass was achieved (15-20 wt% iodine in electrode). It pushes the Zn-I2 battery to a superior level among these available aqueous batteries.

In Vivo Magnetic Resonance Imaging and Microwave Thermotherapy of Cancer Using Novel Chitosan Microcapsules.

Herein, we develop a novel integrated strategy for the preparation of theranostic chitosan microcapsules by encapsulating ion liquids (ILs) and Fe3O4 nanoparticles. The as-prepared chitosan/Fe3O4@IL microcapsules exhibit not only significant heating efficacy in vitro under microwave (MW) irradiation but also obvious enhancement of T2-weighted magnetic resonance (MR) imaging, besides the excellent biocompatibility in physiological environments. The chitosan/Fe3O4@IL microcapsules show ideal temperature rise and therapeutic efficiency when applied to microwave thermal therapy in vivo. Complete tumor elimination is realizing after MW irradiation at an ultralow power density (1.8 W/cm(2)), while neither the MW group nor the chitosan microcapsule group has significant influence on the tumor development. The applicability of the chitosan/Fe3O4@IL microcapsules as an efficient contrast agent for MR imaging is proved in vivo. Moreover, the result of in vivo systematic toxicity shows that chitosan/Fe3O4@IL microcapsules have no acute fatal toxicity. Our study presents an interesting type of multifunctional platform developed by chitosan microcapsule promising for imaging-guided MW thermotherapy.

Acid-sensing ion channels are expressed in the ventrolateral medulla and contribute to central chemoreception.

The role of acid-sensing ion channels (ASICs) in the ventrolateral medulla (VLM) remains uncertain. Here, we found that ASIC1a and ASIC2 are widely expressed in rat medulla, and the expression level is higher at neonatal stage as compared to adult stage. The two ASIC subunits co-localized in medualla neurons. Furthermore, pH reduction triggered typical ASIC-type currents in the medulla, including the VLM. These currents showed a pH50 value of 6.6 and were blocked by amiloride. Based on their sensitivity to psalmotoxin 1 (PcTx1) and zinc, homomeric ASIC1a and heteromeric ASIC1a/2 channels were likely responsible for acid-mediated currents in the mouse medulla. ASIC currents triggered by pH 5 disappeared in the VLM neurons from ASIC1-/-, but not ASIC2-/- mice. Activation of ASICs in the medulla also triggered neuronal excitation. Moreover, microinjection of artificial cerebrospinal fluid at a pH of 6.5 into the VLM increased integrated phrenic nerve discharge, inspiratory time and respiratory drive in rats. Both amiloride and PcTx1 inhibited the acid-induced stimulating effect on respiration. Collectively, our data suggest that ASICs are highly expressed in the medulla including the VLM, and activation of ASICs in the VLM contributes to central chemoreception.

Facile preparation and bifunctional imaging of Eu-doped GdPO4 nanorods with MRI and cellular luminescence.

The biocompatibility of multifunctional nanomaterials is very important for their clinical applications. Herein, the hexagonal crystal Eu-doped GdPO4 nanorods (NRs) in the template of silk fibroin (SF) peptides are successfully synthesized via a mineralization process. The sizes of the Eu-doped GdPO4 NRs with SF peptides (SF-NRs) are ∼150 nm in length and ∼10 nm in diameter. The Eu-doped SF-NRs have strong pink luminescence and a mass magnetic susceptibility value of 1.27 emu g(-1) in 20,000 G of magnetic field due to Eu ion doping. The cell test indicates that the Eu-doped SF-NRs obviously promote the viability of cells at an NR concentration of 25-200 µg mL(-1). A growth mechanism of Eu-doped GdPO4 SF-NRs is proposed to explain their strong cellular luminescence, magnetic resonance (MR) imaging and good cyto-compatibility. Compared to NRs without SF, the Eu-doped SF-NRs not only exhibit a higher effective positive signal-enhancement ability (the longitudinal relaxivity r1 value is 1.38 (Gd mM s)(-1)) and in vivo T1 weighted MR imaging enhancement under a 7.0 T MRI system, but also show the better luminescence imaging of living cells under the fluorescence microscope. This indicates that the Eu-doped SF-NRs have potential as T1 MRI contrast agents and optical imaging probes.

Encapsulating Ionic Liquid and Fe3O4 Nanoparticles in Gelatin Microcapsules as Microwave Susceptible Agent for MR Imaging-guided Tumor Thermotherapy.

The combination of therapies and monitoring the treatment process has become a new concept in cancer therapy. Herein, gelatin-based microcapsules have been first reported to be used as microwave (MW) susceptible agent and magnetic resonance (MR) imaging contrast agent for cancer MW thermotherapy. Using the simple coacervation methods, ionic liquid (IL) and Fe3O4 nanoparticles (NPs) were wrapped in microcapsules, and these microcapsules showed good heating efficacy in vitro under MW irradiation. The results of cell tests indicated that gelatin/IL@Fe3O4 microcapsules possessed excellent compatibility in physiological environments, and they could effectively kill cancer cells with exposure to MW. The ICR mice bearing H22 tumors treated with gelatin/IL@Fe3O4 microcapsules were obtained an outstanding MW thermotherapy efficacy with 100% tumor elimination under ultralow density irradiation (1.8 W/cm(2), 450 MHz). In addition, the applicability of the microcapsules as an efficient contrast agent for MR imaging in vivo was evident. Therefore, these multifunctional microcapsules have a great potential for MR imaging-guided MW thermotherapy.

Gelatin microcapsules for enhanced microwave tumor hyperthermia.

Local and rapid heating by microwave (MW) irradiation is important in the clinical treatment of tumors using hyperthermia. We report here a new thermo-seed technique for the highly efficient MW irradiation ablation of tumors in vivo based on gelatin microcapsules. We achieved 100% tumor elimination in a mouse model at an ultralow power of 1.8 W without any side-effects. The results of MTT assays, a hemolysis test and the histological staining of organs indicated that the gelatin microcapsules showed excellent compatibility with the physiological environment. A possible mechanism is proposed for MW hyperthermia using gelatin microcapsules. We also used gelatin microcapsules capped with CdTe quantum dots for in vivo optical imaging. Our study suggests that these microcapsules may have potential applications in imaging-guided cancer treatment.

Green synthesis of Fe3O4 nanoparticles with controlled morphologies using urease and their application in dye adsorption.

This paper describes a simple and environmentally friendly method for the preparation of highly stable dispersions of Fe3O4 nanoparticles with controlled morphologies, in the same synthesis system for the first time. During the process, the Fe3O4 nanoparticles are formed using urease as a multifunctional reagent, including catalyst, template and dispersant, due to its enzymatic activity and special enzymatic steric structure. A possible formation mechanism for these Fe3O4 nanoparticles, which have various morphologies including nanospheres, nanosheets and nanorods, is proposed. The as-prepared nanoparticles show a larger specific surface area and a stronger magnetism, which enhances their dye adsorption capacity and increases their potential for application in wastewater treatment.