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Fig. S7. The effect of HSP2 on oxygenation of subcutaneous NSCLC A549-luc tumor xenografts after 3 weeks of treatment (same tumors as shown in Fig. S1). (A) Representative tumor images of spatial distribution of oxygen saturation [sO2 (O2)] after the oxygen challenge and the amplitude of signal change (Î"sO2) for each treatment group from breathing air to breathing 100% oxygen. The change in sO2 (Î"sO2) is calculated by subtracting the average tumor sO2 while breathing air from the average tumor sO2 while breathing oxygen. The sizes of the shown tumors were: Control: 111 mm3; HSP2: 51.9 mm3. (B & C) Quantification of sO2 (O2) and Î"sO2 for each treatment group. For statistical analysis, the levels in treated tumors were compared to the levels in control tumors with a Welch 2-sample t-test. ***, P < 0.001. Box is between 25th and 75th percentile, line at median.

Multispectral optoacoustic tomography (MSOT) is an emerging noninvasive imaging modality that can detect real-time dynamic information about the tumor microenvironment in humans and animals. Oxygen enhanced (OE)-MSOT can monitor tumor vasculature and oxygenation during disease development or therapy. Here, we used MSOT and OE-MSOT to examine in mice the response of human non–small cell lung cancer (NSCLC) xenografts to a new class of antitumor drugs, heme-targeting agents heme-sequestering peptide 2 (HSP2) and cyclopamine tartrate (CycT). HSP2 inhibits heme uptake, while CycT inhibits heme synthesis in NSCLC cells, where heme is essential for ATP generation via oxidative phosphorylation. HSP2 and CycT can inhibit ATP generation and thereby suppress NSCLC cell tumorigenic functions. MSOT showed that treatment of NSCLC tumors with HSP2 or CycT reduced total hemoglobin, increased oxygen saturation, and enhanced the amplitude of response to oxygen gas breathing challenge. HSP2 and CycT normalized tumor vasculature and improved tumor oxygenation, where levels of several hypoxia markers in NSCLC tumors were reduced by treatment with HSP2 or CycT. Furthermore, treatment with HSP2 or CycT reduced levels of angiogenic factor VEGFA, its receptor VEGFR1, and vascular marker CD34. Together, our data show that heme-targeting drugs HSP2 and CycT elicit multiple tumor-suppressing functions, such as inhibiting angiogenic function, normalizing tumor vasculature, alleviating tumor hypoxia, and inhibiting oxygen consumption and ATP generation.Significance:Heme-targeting agents HSP2 and CycT effectively normalize tumor vasculature and alleviate tumor hypoxia, raising the possibility of their combination with chemo-, radio-, and immunotherapies to improve antitumor efficacy.See related commentary by Tomaszewski, p. 3461

Objective. Ultrasound is a practical imaging modality for screening and identification of anomalies in the organs. This study used ultrasonography to examine the association between body parameters and dimensions of the normal liver, spleen, and kidney in adolescents based on ultrasound examination results. Methods. A total of 300 junior and senior high school teenagers receiving routine health check-ups in our hospital from January 2020 to January 2021 were included. Their height and weight were measured, and their body surface area (BSA) and body mass index (BMI) were calculated. Ultrasound imaging was employed to obtain information such as the length and volume of the liver, gallbladder, spleen, and kidney. Besides, the correlation of body parameters such as gender, age, height, weight, BSA, and BMI with visceral dimension was investigated using the Pearson test and multiple regression analysis, respectively. Results. We observed that the abdominal organs of adolescents were enlarged with age. The span and volume of the liver and the length and volume of the right kidney were significantly larger in boys than in girls. The age, BSA, and BMI were positively correlated with the liver span and spleen length, as well as the left and right kidney lengths. Additionally, age, BSA, and BMI were identified as important predictors for dimensions of the spleen, liver, and kidney. Conclusions. Body parameters are notably associated with the dimensions of the liver, spleen, and kidney and could be utilized as predicting factors for the liver, spleen, and kidney dimensions.

Ultrasound can promote the drug release from drug-loaded substances and alter the tumor local microenvironment to facilitate the transport of drug carriers into the tumor tissues. Based on the altered tumor microenvironment, nanobubbles (NBs) as drug carriers with surfaces functionalized with targeting ligands can reach the tumor sites, thereby increasing the efficacy of chemotherapy. Herein, paclitaxel (PTX)-loaded poly(lactide-co-glycolide) (PLGA) NBs are prepared as drug carriers with covalently conjugated herceptin (anti-HER2 monoclonal antibody) on the surface to guide the target. The effect of ultrasound on the drug release and targeting of the herceptin-conjugated drug-loaded nanobubbles (PTX-NBs-HER) on the cancerous cells is determined. The use of ultrasound significantly improves the cell targeting capability in vitro, and efficiency of enhanced permeability and retention in vivo. The combination of PTX-NBs-HER and ultrasound facilitates the release of PTX, as well as the uptake and cell apoptosis in vitro. The in vivo application of both PTX-NBs-HER and ultrasound enhances the PTX targeting and accumulation in breast cancers while reducing the transmission and distribution of PTX in healthy organs. The combination of ultrasound with PTX-NBs-HER as contrast agents and drug carriers affords an image-guided drug delivery system for the precise targeted therapy of tumors.

Gold nanorods exhibit a wide variety of applications such as tumor molecular imaging and photothermal therapy (PTT) due to their tunable optical properties. Several studies have demonstrated that the combination of other therapeutic strategies may improve PTT efficiency. A method called optical droplet vaporization (ODV) was considered as another noninvasive imaging and therapy strategy. Via the ODV method, superheated perfluorocarbon droplets can be vaporized to a gas phase for enhancing ultrasound imaging; meanwhile, this violent process can cause damage to cells and tissue. In addition, active targeting through the functionalization with targeting ligands can effectively increase nanoprobe accumulation in the tumor area, improving the sensitivity and specificity of imaging and therapy. Our study prepared a nanoparticle loaded with gold nanorods and perfluorinated hexane and conjugated to a monoclonal antibody (MAGE-1 antibody) to melanoma-associated antigens (MAGE) targeting melanoma, investigated the synergistic effect of PTT/ODV therapy, and monitored the therapeutic effect using ultrasound. The prepared MAGE-Au-PFH-NPs achieved complete eradication of tumors. Meanwhile, the MAGE-Au-PFH-NPs also possess significant ultrasound imaging signal enhancement, which shows the potential for imaging-guided tumor therapy in the future.

Ultrasound can promote the drug release from drug-loaded substances and alter the tumor local microenvironment to facilitate the transport of drug carriers into the tumor tissues. Based on the altered tumor microenvironment, nanobubbles (NBs) as drug carriers with surfaces functionalized with targeting ligands can reach the tumor sites, thereby increasing the efficacy of chemotherapy. Herein, paclitaxel (PTX)-loaded poly(lactide

Multispectral optoacoustic tomography (MSOT) is an emerging noninvasive imaging modality that can detect real-time dynamic information about the tumor microenvironment in humans and animals. Oxygen enhanced (OE)-MSOT can monitor tumor vasculature and oxygenation during disease development or therapy. Here, we used MSOT and OE-MSOT to examine in mice the response of human non–small cell lung cancer (NSCLC) xenografts to a new class of antitumor drugs, heme-targeting agents heme-sequestering peptide 2 (HSP2) and cyclopamine tartrate (CycT). HSP2 inhibits heme uptake, while CycT inhibits heme synthesis in NSCLC cells, where heme is essential for ATP generation via oxidative phosphorylation. HSP2 and CycT can inhibit ATP generation and thereby suppress NSCLC cell tumorigenic functions. MSOT showed that treatment of NSCLC tumors with HSP2 or CycT reduced total hemoglobin, increased oxygen saturation, and enhanced the amplitude of response to oxygen gas breathing challenge. HSP2 and CycT normalized tumor vasculature and improved tumor oxygenation, where levels of several hypoxia markers in NSCLC tumors were reduced by treatment with HSP2 or CycT. Furthermore, treatment with HSP2 or CycT reduced levels of angiogenic factor VEGFA, its receptor VEGFR1, and vascular marker CD34. Together, our data show that heme-targeting drugs HSP2 and CycT elicit multiple tumor-suppressing functions, such as inhibiting angiogenic function, normalizing tumor vasculature, alleviating tumor hypoxia, and inhibiting oxygen consumption and ATP generation. Significance: Heme-targeting agents HSP2 and CycT effectively normalize tumor vasculature and alleviate tumor hypoxia, raising the possibility of their combination with chemo-, radio-, and immunotherapies to improve antitumor efficacy. See related commentary by Tomaszewski, p. 3461

Myocardial fibrosis plays an important role in the development of heart failure and malignant arrhythmia, which potentially increases the incidence of sudden cardiac death. Therefore, early detection of myocardial fibrosis is of great significance for evaluating the prognosis of patients and formulating appropriate treatment strategies. Late gadolinium enhanced magnetic resonance imaging is considered as the currently effective strategy for noninvasive detection of myocardial fibrosis, but it still suffers from some critical issues. In this work, multifunctional CNA35-labeled perfluoropentane nanoparticles (CNA35-PFP NPs) have been elaborately designed and constructed for molecular imaging of fibrotic myocardium based on ultrasound imaging. These as-constructed CNA35-PFP NPs are intravenously infused into rabbit circulation with an animal model of myocardial infarction. Especially, these targeted CNA35-PFP NPs with nanoscale size could efficiently pass through the endothelial cell gap and adhere to the surface of fibroblasts in the fibrotic myocardium. Importantly, followed by low-intensity focused ultrasound irradiation on the myocardium, these intriguing CNA35-PFP NPs could transform from liquid into gaseous microbubbles, which further significantly enhanced the ultrasound contrast in the fibrotic area, facilitating the detection by diagnostic ultrasound imaging. Therefore, this work provides a desirable noninvasive, economical, and real-time imaging technique for the assessment of cardiac fibrosis with diagnostic ultrasound based on the rational design of liquid-to-gas phase-changeable nanoplatforms.

People are more and more concerned about the health of modern life. Diabetes is the enemy of health. Forecast to 2030, diabetes will become the seventh largest cause of death. Diabetes is an important public health problem; it is one of the top four non communicable diseases in the world. So, how to detect blood sugar effectively is a question, how to prevent and treat diabetes is particularly important. In this paper, we used Internet of Things, big data, CGM, recommendation algorithms and other technologies to build a diet-based, drugs supplemented diabetes health management platform. Patients wear CGM device to detect blood sugar and other data, upload to the mobile app. Then mobile app uploads combined data to the diabetes health management platform. The platform through big data analysis to provide recommended diet and early warning, and relatives of the patients can understand the state of their parents anytime and anywhere.

The myocardial microenvironment plays a decisive role in the survival, migration and differentiation of stem cells. We studied myocardial micro-environmental changes induced by ultrasound-targeted microbubble destruction (UTMD) and their influence on the transplantation of mesenchymal stem cells (MSCs). Various intensities of ultrasound were applied to the anterior chest in canines with myocardial infarction after intravenous injection of microbubbles. The expression of cytokines and adhesion molecules in the infarcted area of the myocardium was detected after three sessions of UTMD in 1 wk. Real-time quantitative reverse transcription polymerase chain reaction (RTQ-PCR) showed that the expression of vascular cell adhesion molecule-1 (VCAM-1), stromal cell-derived factor-1 (SDF-1) and vascular endothelial growth factor (VEGF) in the 1.5 W/cm(2) and 1 W/cm(2) groups was markedly increased compared with the 0.5 W/cm(2) or the control groups (3.8- to 4.7-fold, p

In recent years, ultrasound-targeted microbubble destruction (UTMD) has been utilised for the targeted delivery of stem cells. We tested the effects of the myocardial micro-environment changes induced by UTMD on promoting the homing of mesenchymal stem cells (MSCs) to the ischemic myocardium. Dogs were randomly divided into two groups and treated with or without UTMD after the establishment of myocardial infarction models. 4,6-diamino-2-phenyl indole (DAPI) labelled MSCs were transplanted via coronary injections 2 weeks after myocardial infarction in both groups. The results from real-time PCR and western blot analyses indicated that the expression of various cytokines in UTMD-treated dogs was much higher than that observed in non-treated dogs. Histopathological findings demonstrate that ultrasound at a frequency of 1MHz and an intensity of 1.0W/cm(2) provoked inflammatory reactions with mild myocardial damage. Myocardial microenvironment changes caused by UTMD may promote the homing of MSCs to the ischemic myocardium. This non-invasive technique may be a promising method for cardiac cell transplantation therapy.

Objectives The transplantation of bone-marrow derived mesenchymal stem cells (MSCs) to ischaemic myocardium is considered to be a useful therapeutic approach to ischaemic heart disease, but the MSCs delivery efficacy still can9t meet the needs for therapy. Recently, ultrasound-targeted microbubble destruction (UTMD) has been utilised in the targeted delivery of stem cells. In this study, we tested the effects of myocardial micro-environment changes induced by ultrasound target microbubble destruction on promoting the MSCs homing to the ischaemic myocardium. Methods In order to optimise the ultrasonic parameters and to explore the biological effects of different intensities of ultrasound mediated microbubble destruction to the myocardium of canine, 9 mongrel dogs were randomly divided into three groups. Three groups were treated with frequency of 1 MHz ultrasonic irradiation, but the intensity of ultrasonic irradiation was different in each group. Group 1 was treated with intensity of 0.5 W/cm 2 , group 2 was treated with intensity of 1.0 W/cm 2 and group 3 was treated with intensity of 1.5 W/cm 2 . The myocardium was harvested for hematoxylcne & eosin (HE) staining and Transmission electron microscope (TEM) detection to observe the tissue microstructures. The ultrasound parameters were optimised according to the results of TEM and HE staining results. Then, ultrasound with optimised parameters was used to investigate the cardiac micro-environment change induced by ultrasound mediated microbubble destruction. Twenty mongrel dogs were randomly divided into a treatment group and a control group after the establishment of animal models of myocardial infarction. One-week later, dogs in treatment group were treated by ultrasonic microbubble destruction for three times in 1 week, no treatment for the dogs in the control group. Vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1), vascular cell adhesion molecule-1 (VCAM-1) and interleckin-1β (IL-1β) levels of the myocardium were measured by Real time PCR and western blot analyses in half of the dogs in each group after 2 weeks. The other half of the remaining dogs (n=10) in each group were transplanted with 5 ml DAPI labelled MSCs (2.45×10 7 cells/ml) with via coronary ostium by intervention technique under digital subtraction arteriography (DSA) monitor. Five-days later, the myocardium was harvested from the margin of the infarcted area. Laser scanning confocal microscope (LSCM) was used to observe the distribution of the stem cells. Results The 1 MHz ultrasound at the intensity of 1.0 W/cm 2 provoked pertinent inflammatory reaction with mild myocardial damage. Real time PCR and western blot analyses showed that the expression of VEGF, SDF-1, VCAM-1 and IL-1β in the treatment group were much higher than that in the control group. By laser scanning confocal microscope, we found that the distribution of MSCs in pretreatment myocardium was significantly wider than that in the control group. Conclusions Ultrasound targeted microbubble destruction improved myocardial microenviroment changes might promote MSCs homing to the ischaemic myocardium. This noninvasive technique might be a promising method for the cardiac cell transplantation therapy.