Nonmetallic graphite for tumor magnetic hyperthermia therapy.

Magnetic hyperthermia therapy (MHT) has garnered immense interest due to its exceptional spatiotemporal specificity, minimal invasiveness and remarkable tissue penetration depth. Nevertheless, the limited magnetothermal heating capability and the potential toxicity of metal ions in magnetic materials based on metallic elements significantly impede the advancement of MHT. Herein, we introduce the concept of nonmetallic materials, with graphite (Gra) as a proof of concept, as a highly efficient and biocompatible option for MHT of tumors in vivo for the first time. The Gra exhibits outstanding magnetothermal heating efficacy owing to the robust eddy thermal effect driven by its excellent electrical conductivity. Furthermore, being composed of carbon, Gra offers superior biocompatibility as carbon is an essential element for all living organisms. Additionally, the Gra boasts customizable shapes and sizes, low cost, and large-scale production capability, facilitating reproducible and straightforward manufacturing of various Gra implants. In a mouse tumor model, Gra-based MHT successfully eliminates the tumors at an extremely low magnetic field intensity, which is less than one-third of the established biosafety threshold. This study paves the way for the development of high-performance magnetocaloric materials by utilizing nonmetallic materials in place of metallic ones burdened with inherent limitations.

One-Minute Preparation of Iron Foam-Drug Implant for Ultralow-Power Magnetic Hyperthermia-Based Combination Therapy of Tumors in Vivo.

The magnetic hyperthermia-based combination therapy (MHCT) is a powerful tumor treatment approach due to its unlimited tissue penetration depth and synergistic therapeutic effect. However, strong magnetic hyperthermia and facile drug loading are incompatible with current MHCT platforms. Herein, an iron foam (IF)-drug implant is established in an ultra-facile and universal way for ultralow-power MHCT of tumors in vivo for the first time. The IF-drug implant is fabricated by simply immersing IF in a drug solution at an adjustable concentration for 1 min. Continuous metal structure of IF enables ultra-high efficient magnetic hyperthermia based on eddy current thermal effect, and its porous feature provides great space for loading various hydrophilic and hydrophobic drugs via "capillary action". In addition, the IF has the merits of low cost, customizable size and shape, and good biocompatibility and biodegradability, benefiting reproducible and large-scale preparation of IF-drug implants for biological application. As a proof of concept, IF-doxorubicin (IF-DOX) is used for combined tumor treatment in vivo and achieves excellent therapeutic efficacy at a magnetic field intensity an order of magnitude lower than the threshold for biosafety application. The proposed IF-drug implant provides a handy and universal method for the fabrication of MHCT platforms for ultralow-power combination therapy.

Butyrate mitigates metabolic dysfunctions via the ERα-AMPK pathway in muscle in OVX mice with diet-induced obesity.

The higher prevalence of metabolic syndrome (MetS) in women after menopause is associated with a decrease in circulating 17ß-oestradiol. To explore novel treatments for MetS in women with oestrogen deficiency, we studied the effect of exogenous butyrate on diet-induced obesity and metabolic dysfunctions using ovariectomized (OVX) mice as a menopause model. Oral administration of sodium butyrate (NaB) reduced the body fat content and blood lipids, increased whole-body energy expenditure, and improved insulin sensitivity. Additionally, NaB induced oestrogen receptor alpha (ERα) expression, activated the phosphorylation of AMPK and PGC1α, and improved mitochondrial aerobic respiration in cultured skeletal muscle cells. In conclusion, oral NaB improves metabolic parameters in OVX mice with diet-induced obesity. Oral supplementation with NaB might provide a novel therapeutic approach to treating MetS in women with menopause. Video Abstract.

Hypothalamic subregion abnormalities are related to body mass index in patients with sporadic amyotrophic lateral sclerosis.

OBJECTIVE: To investigate atrophy patterns in hypothalamic subunits at different stages of ALS and examine correlations between hypothalamic subunit volume and clinical information. METHODS: We used the King's clinical staging system to divide 91 consecutive ALS patients into the different disease stages. We investigated patterns of hypothalamic atrophy using a recently published automated segmentation method in ALS patients and in 97 healthy controls. We recorded all subjects' demographic and clinical information. RESULTS: Compared with healthy controls, we found significant atrophy in the bilateral anterior-superior subunit and the superior tubular subunit, as well as a reduction in global hypothalamic volume in ALS patients. When we used the King's clinical staging system to divide patients into the different disease stages, we found neither global nor specific subunit atrophy until King's stage 3 in the hypothalamus. Moreover, specific subunit volumes were significantly associated with body mass index. CONCLUSIONS: In a relatively large sample of Chinese patients with ALS, using a recently published automated segmentation method for the hypothalamus, we found the pattern of hypothalamic atrophy in ALS patients differed greatly across King's clinical disease stages. Moreover, specific hypothalamic subunit atrophy may play an important role in energy metabolism in ALS patients. Thus, our findings suggest that hypothalamic atrophy may have potential phenotypic associations, and improved energy metabolism may become an important component of individualised therapy for ALS.

Clinical, pathological and genetic features and follow-up of 110 patients with late-onset MADD: a single-center retrospective study.

To observe a long-term prognosis in late-onset multiple acyl-coenzyme-A dehydrogenation deficiency (MADD) patients and to determine whether riboflavin should be administrated in the long-term and high-dosage manner, we studied the clinical, pathological and genetic features of 110 patients with late-onset MADD in a single neuromuscular center. The plasma riboflavin levels and a long-term follow-up study were performed. We showed that fluctuating proximal muscle weakness, exercise intolerance and dramatic responsiveness to riboflavin treatment were essential clinical features for all 110 MADD patients. Among them, we identified 106 cases with ETFDH variants, 1 case with FLAD1 variants and 3 cases without causal variants. On muscle pathology, fibers with cracks, atypical ragged red fibers (aRRFs) and diffuse decrease of SDH activity were the distinctive features of these MADD patients. The plasma riboflavin levels before treatment were significantly decreased in these patients as compared to healthy controls. Among 48 MADD patients with a follow-up of 6.1 years on average, 31 patients were free of muscle weakness recurrence, while 17 patients had episodes of slight muscle weakness upon riboflavin withdrawal, but recovered after retaking a small-dose of riboflavin for a short-term. Multivariate Cox regression analysis showed vegetarian diet and masseter weakness were independent risk factors for muscle weakness recurrence. In conclusion, fibers with cracks, aRRFs and diffuse decreased SDH activity could distinguish MADD from other genotypes of lipid storage myopathy. For late-onset MADD, increased fatty acid oxidation and reduced riboflavin levels can induce episodes of muscle symptoms, which can be treated by short-term and small-dose of riboflavin therapy.

Gram-scale synthesis of a neodymium chelate as a spectral CT and second near-infrared window imaging agent for visualizing the gastrointestinal tract in vivo.

The diagnosis of gastrointestinal (GI) tract diseases is frequently performed in the clinic, so it is crucial to develop high-performance contrast agents for real-time and non-invasive imaging examination of the GI tract. Herein, we show a novel method to synthesize a neodymium (Nd) chelate, Nd-diethylenetriaminepentaacetic acid (Nd-DTPA), on a large scale without byproducts for spectral computed tomography (CT) and second near-infrared window imaging of the GI tract in vivo. The Nd-DTPA was simply generated by heating the mixture of Nd2O3 and DTPA in water at 85 °C for 2 h. This dual-modal imaging agent has the advantages of a simple and green synthesis route, no need of purification process, high yield (86.24%), large-scale production capability (>10 g in lab synthesis), good chemical stability and excellent water solubility (≈2 g mL-1). Moreover, the Nd-DTPA emitted strong near-infrared fluorescence at 1308 nm, and exhibited superior X-ray attenuation ability compared to clinical iohexol. The proposed Nd-DTPA can integrate the complementary merits of dual-modal imaging to realize spatial-temporal and highly sensitive imaging of the GI tract in vivo, and accurate diagnosis of the location of intestinal obstruction and monitor its recovery after surgery. The developed highly efficient method for the gram-scale synthesis of Nd-DTPA and the proposed spectral CT and second near-infrared window dual-modal imaging strategy provide a promising route for accurate visualization of the GI tract in vivo.

Automated coronary artery tree segmentation in coronary CTA using a multiobjective clustering and toroidal model-guided tracking method.

BACKGROUND AND OBJECTIVE: Accurate coronary artery tree segmentation can now be developed to assist radiologists in detecting coronary artery disease. In clinical medicine, the noise, low contrast, and uneven intensity of medical images along with complex shapes and vessel bifurcation structures make coronary artery segmentation challenging. In this work, we propose a multiobjective clustering and toroidal model-guided tracking method that can accurately extract coronary arteries from computed tomography angiography (CTA) imagery. METHODS: Utilizing integrated noise reduction, candidate region detection, geometric feature extraction, and coronary artery tracking techniques, a new segmentation framework for 3D coronary artery trees is presented. The candidate regions are extracted using a multiobjective clustering method, and the coronary arteries are tracked by a toroidal model-guided tracking method. RESULTS: The qualitative and quantitative results demonstrate the effectiveness of the presented framework, which achieves better performance than the compared segmentation methods in three widely used evaluation indices: the Dice similarity coefficient (DSC), Jaccard index and Recall across the CTA data. The proposed method can accurately identify the coronary artery tree with a mean DSC of 84%, a Jaccard index of 74%, and a Recall of 93%. CONCLUSIONS: The proposed segmentation framework effectively segments the coronary tree from the CTA volume, which improves the accuracy of 3D vascular tree segmentation.

[Application of nerve trunk stimulation therapy in functional rehabilitation of the lower limbs in the patients with cerebral apoplexy at convalescence stage].

OBJECTIVE: To explore the value of nerve trunk stimulation in the rehabilitation of lower limb function in the patients with cerebral apoplexy at convalescence stage. METHODS: According the random number table, the patients with the lower limb dysfunction of cerebral apoplexy at convalescence stage were divided into a control group and a treatment group, 42 cases in each group. The drug therapy and the routine rehabilitation training were provided in the two groups. Additionally, in the treatment group, the nerve trunk stimulation therapy was adopted， in which, Chize (LU5，stimulating point of radial nerve), Neiguan (PC6, stimulating point of median nerve), Xiaohai (SI8, stimulating point of ulnar nerve) were selected. In the control group, acupuncture intervention was supplemented. Before and after treatment, the peak torque (PT) of the lower flexor-extensor muscle of the knee joint, gait parameters，the score of the modified Ashworth spasm scale (MAS), the score of Fugl-Meyer motor assessment (FMA) and the score of Fugl-Meyer balance scale (FBS) were recorded. RESULTS: After the treatment, the PT of the lower flexor-extensor muscle of the knee joint，the scores of FMA and FBS，the step speed and frequency were all increased, the score of MAS and the difference in the stride between the left and the right were decreased as compared with those before treatment (P<0.01). After the treatment, The PT of the lower flexor-extensor muscle of the knee joint，the scores of FMA and FBS，the step speed and frequency in the treatment group were higher than those in the control group (P<0.01). The score of MAS and the difference in the stride between the left and the right in the treatment group were lower than those in the control group (P<0.01). CONCLUSION: Nerve trunk stimulation therapy quite effectively increases the muscle strength and relieves the muscle tension as well as improves the motor function, the balance and the walking pattern of the lower limbs. This therapy is significantly valuable in the rehabilitation of the lower limbs in the patients with cerebral apoplexy at convalescence stage.

Rhenium Sulfide Nanoparticles as a Biosafe Spectral CT Contrast Agent for Gastrointestinal Tract Imaging and Tumor Theranostics in Vivo.

Spectral computed tomography (CT) imaging as a novel imaging technique shows promising prospects in the accurate diagnosis of various diseases. However, clinically iodinated contrast agents suffer from poor signal-to-noise ratio, and emerging heavy-metal-based CT contrast agents arouse great biosafety concern. Herein, we show the fabrication of rhenium sulfide (ReS2) nanoparticles, a clinic radiotherapy sensitizer, as a biosafe spectral CT contrast agent for the gastrointestinal tract imaging and tumor theranostics in vivo by teaching old drugs new tricks. The ReS2 nanoparticles were fabricated in a one-pot facile method at room temperature, and exhibited sub-10 nm size, favorable monodispersity, admirable aqueous solubility, and strong X-ray attenuation capability. More importantly, the proposed nanoparticles possess an outstanding spectral CT imaging ability and undoubted biosafety as a clinic therapeutic agent. Besides, the ReS2 nanoparticles possess appealing photothermal performance due to their intense near-infrared absorption. The proposed nano-agent not only guarantees obvious contrast enhancement in gastrointestinal tract spectral CT imaging in vivo, but also allows effective CT imaging-guided tumor photothermal therapy. The proposed "teaching old drugs new tricks" strategy shortens the time and cuts the cost required for clinical application of nano-agents based on existing clinical toxicology testing and trial results, and lays down a low-cost, time-saving, and energy-saving method for the development of multifunctional nano-agents toward clinical applications.

Indirubin regulates MPL and TNF expression in peripheral blood mononuclear cells from patients with primary immune thrombocytopenia.

Indirubin, a traditional Chinese medicine, is currently used to treat certain autoimmune diseases such as primary immune thrombocytopenia (ITP) in clinics. However, the effects of indirubin on expression of related genes in peripheral blood mononuclear cells (PBMCs) from ITP patients have not been investigated. In the present study, PBMCs were isolated from 19 adult patients with well-characterized active ITP and 20 healthy controls (HCs) and then treated with increasing concentrations of indirubin. The mRNA expression levels of thrombopoietin receptor (MPL), GATA binding protein 3 (GATA3), DNA methyltransferase 3B (DNMT3B), interleukin-6 (IL6), tumor necrosis factor (TNF), and interferon gamma (IFN-γ) were determined by quantitative real-time polymerase chain reaction (PCR). We found that indirubin had no cytotoxic effect on PBMC viability. Significantly lower MPL (p < 0.05) and GATA3 (p < 0.05) expression together with markedly higher IL6 (p < 0.05), TNF (p < 0.0001), and IFN-γ (p < 0.001) mRNA levels were observed in ITP patients compared with HCs. Notably, indirubin significantly enhanced MPL expression and inhibited TNF expression in PBMCs from ITP patients (p < 0.05). In summary, indirubin may play a direct role in thrombopoiesis by activating cellular MPL and normalizing TNF expression to suppress inflammation in ITP. This study may thus improve our understanding of indirubin and provide important information for optimizing therapeutic strategies for ITP patients.

In Situ Fabrication of Intelligent Photothermal Indocyanine Green-Alginate Hydrogel for Localized Tumor Ablation.

Simplifying synthesis and administration process, improving photothermal agents' accumulation in tumors, and ensuring excellent biocompatibility and biodegradability are keys to promoting the clinical application of photothermal therapy. However, current photothermal agents have great difficulties in meeting the requirements of clinic drugs from synthesis to administration. Herein, we reported the in situ formation of a Ca2+/Mg2+ stimuli-responsive ICG-alginate hydrogel in vivo for localized tumor photothermal therapy. An ICG-alginate hydrogel can form by the simple introduction of Ca2+/Mg2+ into ICG-alginate solution in vitro, and the widely distributed divalent cations in organization in vivo enabled the in situ fabrication of the ICG-alginate hydrogel without the leakage of any agents by simple injection of ICG-alginate solution into the body of mice. The as-prepared ICG-alginate hydrogel not only owns good photothermal therapy efficacy and excellent biocompatibility but also exhibits strong ICG fixation ability, greatly benefiting the high photothermal agents' accumulation and minimizing the potential side effects induced by the diffusion of ICG to surrounding tissues. The in situ-fabricated ICG-alginate hydrogel was applied successfully in highly efficient PTT in vivo without obvious side effects. Besides, the precursor of the hydrogel, ICG and alginate, can be stored in a stable solid form, and only simple mixing and noninvasive injection are needed to achieve PTT in vivo. The proposed in situ gelation strategy using biocompatible components lays down a simple and mild way for the fabrication of high-performance PTT agents with the superiors in the aspects of synthesis, storage, transportation, and clinic administration.

Microwave-assisted ultrafast fabrication of high-performance polypyrrole nanoparticles for photothermal therapy of tumors in vivo.

Photothermal therapy with minimal invasiveness and high selectivity has been regarded as a powerful technique for tumor therapy to overcome the risks of toxic side effects and limited therapeutic efficacy of clinic cancer treatments. Among various photothermal therapeutic agents, polypyrrole (PPy) nanoparticles show a promising prospect in tumor ablation in vivo due to their admirable biocompatibility and outstanding photothermal performance. Besides, polypyrrole nanoparticles are extensively applied in biosensors, electrochemical sensors, tissue engineering, flexible microelectronics, and so on. However, the available synthesis methods of PPy nanoparticles are all time-consuming and seriously hindered their highly efficient production for diverse applications. Here we present a microwave-assisted strategy for the fabrication of PPy nanoparticles in 2 min, and the required synthesis time is shortened by 120-720 times compared to that in traditional ways. The prepared PPy nanoparticles possess uniform size, favorable aqueous solubility, and enhanced photothermal performance derived from the stronger near-infrared absorbance. Low cytotoxicity and in vivo toxicity of the nanoparticles were confirmed via comprehensive assessments. The PPy nanoparticle-based photothermal therapy in vitro led to a remarkable death of tumor cells, and in vivo tumor ablation using the nanoparticles was achieved under mild laser irradiation with a FDA-approved safe power. The proposed microwave-assisted synthesis strategy opens up a facile and ultrafast way for the construction of organic nanoparticles and facilitates a wide range of applications of them in biomedicine and other fields.

Green and facile synthesis of a theranostic nanoprobe with intrinsic biosafety and targeting abilities.

Traditional targeting nanoprobes suffer from the risks of partial loss of targeting activity and nanoparticle aggregation induced by post-synthetic modifications, ambiguous toxicity, tedious synthesis procedures and environmentally hazardous processes. Herein, we report a green and facile strategy to fabricate transferrin-indocyanine green nanoparticles as a smart theranostic agent with intrinsic biosafety and active targeting abilities for near-infrared fluorescent imaging and photothermal therapy of tumors. Simple mixing of transferrin and indocyanine green enables their self-assembly in aqueous solution to form nanoparticles with excellent water solubility, colloidal stability, favorable biocompatibility and impressive active targeting theranostic effects in vitro and in vivo. The transferrin-indocyanine green nanoparticles show great potential in theranostic applications of tumors in clinical therapy.

Biomineralization of Versatile CuS/Gd2 O3 Hybrid Nanoparticles for MR Imaging and Antitumor Photothermal Chemotherapy.

The versatile application of nanoparticles in integrating imaging and therapy has aroused extensive research interest in precision medicine. Of the various nanoparticles that have been studied, CuS has shown great potential in the construction of multifunctional agents, owing to its excellent photothermal heating properties. Herein, we report a facile one-pot biomineralization approach for the preparation of versatile bovine-serum-albumin-conjugated CuS/Gd2 O3 hybrid nanoparticles (BSA-CuS/Gd2 O3 HNPs), which simultaneously possessed strong longitudinal relaxivity, an outstanding photothermal effect, high drug-loading capacity, and pH/temperature-responsive drug release. The versatile nanoparticles were used for magnetic resonance imaging (MRI) and antitumor photothermal chemotherapy, both in vitro and in vivo. In vivo MRI showed that the BSA-CuS/Gd2 O3 HNPs had a long circulation time and effective passive tumor-uptake ability. More importantly, combined in vitro and in vivo therapy demonstrated that drug-loaded BSA-CuS/Gd2 O3 HNPs offered outstanding synergistic therapeutic efficacy for tumor inhibition.

BSA-directed synthesis of CuS nanoparticles as a biocompatible photothermal agent for tumor ablation in vivo.

Photothermal therapy as a physical therapeutic approach has greatly attracted research interest due to its negligible systemic effects. Among the various photothermal agents, CuS nanoparticles have been widely used due to their easy preparation, low cost, high stability and strong absorption in the NIR region. However, the ambiguous biotoxicity of CuS nanoparticles limited their bio-application. So it is highly desirable to develop biocompatible CuS photothermal agents with the potential of clinical translation. Herein, we report a novel method to synthesize biocompatible CuS nanoparticles for photothermal therapy using bovine serum albumin (BSA) as a template via mimicking biomaterialization processes. Owing to the inherent biocompatibility of BSA, the toxicity assays in vitro and in vivo showed that BSA-CuS nanoparticles possessed good biocompatibility. In vitro and in vivo photothermal therapies were performed and good results were obtained. The bulk of the HeLa cells treated with BSA-CuS nanoparticles under laser irradiation (808 nm) were killed, and the tumor tissues of mice were also successfully eliminated without causing any obvious systemic damage. In summary, a novel strategy for the synthesis of CuS nanoparticles was developed using BSA as the template, and the excellent biocompatibility and efficient photothermal therapy effects of BSA-CuS nanoparticles show great potential as an ideal photothermal agent for cancer treatment.