Nonspecific intraventricular conduction delay predicts the prognosis of dilated cardiomyopathy.

PURPOSE: Left bundle branch block (LBBB) has been confirmed to be independently associated with adverse outcomes in dilated cardiomyopathy (DCM). However, prognostic data on nonspecific intraventricular conduction delay (NSIVCD) are still limited and conflicting. We aimed to evaluate the prognosis of DCM with NSIVCD. METHODS: A total of 548 DCM patients who underwent cardiovascular magnetic resonance imaging (CMR) from January 2016 to December 2017 were consecutively enrolled. The cohort was divided into four groups: 87 with LBBB, 27 with RBBB, 61 with NSIVCD, and 373 without intraventricular conduction delay (IVCD). After a median follow-up of 58 months (interquartile range: 47-65), 123 patients reached the composite endpoints, which included cardiovascular death, heart transplantation, and malignant arrhythmias. The associations between different patterns of IVCD and the outcomes of DCM were analysed by Kaplan‒Meier analysis and Cox proportional hazards regression analysis. RESULTS: Of 548 DCM patients, there were 398 males (72.6%), and the average age was 46 ± 15 years, ranging from 18 to 76 years. In Kaplan‒Meier analysis, patients with NSIVCD and LBBB showed higher event rates than patients without IVCD, while RBBB patients did not. By multivariate Cox regression analysis, LBBB, NSIVCD, NYHA class, left ventricular ejection fraction (LVEF), indexed left ventricular end-diastolic diameter (LVEDDI), percentage of late gadolinium enhancement mass (LGE%), and global longitudinal strain (GLS) were found to be independently associated with the outcomes of DCM. CONCLUSIONS: In addition to LBBB, NSIVCD was an unfavourable prognostic marker in patients with DCM, independent of LVEDDI, NYHA class, LVEF, LGE%, and GLS.

A systematic analysis of the global and regional burden of colon and rectum cancer and the difference between early- and late-onset CRC from 1990 to 2019.

The burden of colorectal cancer (CRC) varies substantially across different geographical locations. However, there was no further quantitative analysis of regional social development and the disease burden of CRC. In addition, the incidence of early- and late-onset CRC has increased rapidly in developed and developing regions. The main purpose of this study was to investigate the trends in CRC burden across different regions, in addition to the epidemiological differences between early and late-onset CRC and their risk factors. In this study, estimated annual percentage change (EAPC) was employed to quantify trends in age-standardized incidence rate (ASIR), mortality rate, and disability-adjusted life-years. Restricted cubic spline models were fitted to quantitatively analyze the relationship between trends in ASIR and Human Development Index (HDI). In addition, the epidemiological characteristics of early- and late-onset CRC were investigated using analyses stratified by age groups and regions. Specifically, meat consumption and antibiotic use were included to explore the differences in the risk factors for early- and late-onset CRC. The quantitative analysis showed that the ASIR of CRC was exponentially and positively correlated with the 2019 HDI in different regions. In addition, the growing trend of ASIR in recent years varied substantially across HDI regions. Specifically, the ASIR of CRC showed a significant increase in developing countries, while it remained stable or decreased in developed countries. Moreover, a linear correlation was found between the ASIR of CRC and meat consumption in different regions, especially in developing countries. Furthermore, a similar correlation was found between the ASIR and antibiotic use in all age groups, with different correlation coefficients for early-onset and late-onset CRC. It is worth mentioning that the early onset of CRC could be attributable to the unrestrained use of antibiotics among young people in developed countries. In summary, for better prevention and control of CRC, governments should pay attention to advocate self-testing and hospital visits among all age groups, especially among young people at high risk of CRC, and strictly control meat consumption and the usage of antibiotics.

Magnetic Nanodroplets for Enhanced Deep Penetration of Solid Tumors and Simultaneous Magnetothermal-Sensitized Immunotherapy against Tumor Proliferation and Metastasis.

The central cells of solid tumors are more proliferative and metastatic than the marginal cells. Therefore, more intelligent strategies for targeting cells with deep spatial distributions in solid tumors remain to be explored. In this work, a biocompatible nanotheranostic agent with a lipid membrane-coated, Fe3 O4 and perfluoropentane (PFP)-loaded, cRGD peptide (specifically targeting the integrin αvß3 receptor)-grafted, magnetic nanodroplets (MNDs) is developed. The MNDs exhibit excellent magnetothermal conversion and controllable magnetic hyperthermia (MHT) through alternating magnetic field regulation. Furthermore, MHT-mediated magnetic droplet vaporization (MDV) induces the expansion of the MNDs to transform them into ultrasonic microbubbles, increasing the permeability of tissue and the cell membrane via the ultrasound-targeted microbubble destruction (UTMD) technique and thereby promoting the deep penetration of MNDs in solid tumors. More importantly, MHT not only causes apoptotic damage by downregulating the expression of the HSP70, cyclin D1, and Bcl-2 proteins in tumor cells but also improves the response rate to T-cell-related immunotherapy by upregulating PD-L1 expression in tumor cells, thus inhibiting the growth of both primary and metastatic tumors. Overall, this work introduces a distinct application of nanoultrasonic biomedicine in cancer therapy and provides an attractive immunotherapy strategy for preventing the proliferation and metastasis of deeply distributed cells in solid tumors.

Tumor-self-targeted "thermoferroptosis-sensitization" magnetic nanodroplets for multimodal imaging-guided tumor-specific therapy.

Ferroptosis-based nanomedicine has drawn increasing attention in antitumor therapy because of the advantages of this unconventional mode of apoptosis, but the difficulties of delivery to the tumor site and surface-to-core penetration after arrival seriously hinder further clinical transformation and application. Herein, we propose an unprecedented strategy of injecting magnetic nanodroplets (MNDs) to solve these two longstanding problems. MNDs are nanocarriers that can carry multifunctional drugs and imaging materials. MNDs can effectively accumulate in the tumor site by active tumor targeting (multifunctional drugs) and passive tumor targeting (enhanced permeability and retention effect), allowing diffusion of the MNDs from the surface to the core through mild-temperature magnetic fluid hyperthermia (MHT) under multimodal imaging guidance. Finally, the ferroptosis pathway is activated deep within the tumor site through the drug release. This approach was inspired by the ability of mild-temperature MHT to allow MNDs to quickly pass through the blood vessel-tumor barrier and deeply penetrate the tumor tissue from the surface to the core to amplify the antitumor efficacy of ferroptosis. This strategy is termed as "thermoferroptosis sensitization". Importantly, this behavior can be performed under the guidance of multimodal imaging, making the design of MNDs for cancer therapy safer and more reasonable.

PLZF suppresses differentiation of mouse spermatogonial progenitor cells via binding of differentiation associated genes.

Promyelocytic leukaemia zinc finger (PLZF) is a key factor in inhibiting differentiation of spermatogonial progenitor cells (SPCs), but the underlying mechanisms are still largely unknown. In this study, the regulation of PLZF on Kit, Stra8, Sohlh2, and Dmrt1 (SPCs differentiation related genes) was investigated. We found some PLZF potential binding sites existed in the promoters of Kit, Stra8, Sohlh2, and Dmrt1. Additionally, the expressions of KIT, STRA8, SOHLH2, and DMRT1 were upregulated when PLZF was knockdown in SPCs. Furthermore, chromatin immunoprecipitation quantitative polymerase chain reaction revealed PLZF directly bound to the promoters of Kit, Stra8, Sohlh2, and Dmrt1. Besides, dual luciferase assay verified PLZF repressed those gene expressions. Collectively, our finding indicate that PLZF binds to the promoter regions of Kit, Stra8, Sohlh2, and Dmrt1 to regulate SPCs differentiation, which facilitate us to further understand the regulatory mechanism of PLZF in SPCs fates.

Androgen Indirectly Regulates Gap Junction Component Connexin 43 Through Wilms Tumor-1 in Sertoli Cells.

In mammals, spermatogenesis is closely related to intercellular interactions of germ cells and surrounding Sertoli cells, that is, blood-testis barrier and gap junction, which are subjected to hormone signals in testicular seminiferous tubules. Androgen signal plays pivotal role in regulating spermatogenesis, but the underlying mechanism is largely unknown. Our recent study demonstrated a novel regulatory pattern of androgen in regulation of spermatogonia differentiation, in which androgen indirectly regulates the expression of ITGB1 on Sertoli Cells through intermediate molecule Wilms tumor-1 (Wt-1) during spermatogenesis. In this study, we identified that Connexin 43 (Cx43), the key component for gap junction distributed between spermatogonia and Sertoli cells, was also regulated by androgen signal. Chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) demonstrated that WT1 occupied Cx43 promoter in Sertoli cells, suggesting WT1 as an intermediate molecule in regulation of Cx43. Finally, we revealed a regulatory pattern of Cx43 by androgen in Sertoli cells, and the Sertoli cells in germ cell depleted microenvironment were sensitive to androgen signal, which enhances the understanding of the mechanism of spermatogenesis.

Herceptin-decorated paclitaxel-loaded poly(lactide-co-glycolide) nanobubbles: ultrasound-facilitated release and targeted accumulation in breast cancers.

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.

Radiomics Analysis of Dynamic Contrast-Enhanced Magnetic Resonance Imaging for the Prediction of Sentinel Lymph Node Metastasis in Breast Cancer.

Purpose: To investigate whether a combination of radiomics and automatic machine learning applied to dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of primary breast cancer can non-invasively predict axillary sentinel lymph node (SLN) metastasis. Methods: 62 patients who received a DCE-MRI breast scan were enrolled. Tumor resection and sentinel lymph node (SLN) biopsy were performed within 1 week after the DCE-MRI examination. According to the time signal intensity curve, the volumes of interest (VOIs) were delineated on the whole tumor in the images with the strongest enhanced phase. Datasets were randomly divided into two sets including a training set (~80%) and a validation set (~20%). A total of 1,409 quantitative imaging features were extracted from each VOI. The select K best and least absolute shrinkage and selection operator (Lasso) were used to obtain the optimal features. Three classification models based on the logistic regression (LR), XGboost, and support vector machine (SVM) classifiers were constructed. Receiver Operating Curve (ROC) analysis was used to analyze the prediction performance of the models. Both feature selection and models construction were firstly performed in the training set, then were further tested in the validation set by the same thresholds. Results: There is no significant difference between all clinical and pathological variables in breast cancer patients with and without SLN metastasis (P > 0.05), except histological grade (P = 0.03). Six features were obtained as optimal features for models construction. In the validation set, with respect to the accuracy and MSE, the SVM demonstrated the highest performance, with an accuracy, AUC, sensitivity (for positive SLN), specificity (for positive SLN) and Mean Squared Error (MSE) of 0.85, 0.83, 0.71, 1, 0.26, respectively. Conclusions: We demonstrated the feasibility of combining artificial intelligence and radiomics from DCE-MRI of primary tumors to predict axillary SLN metastasis in breast cancer. This non-invasive approach could be very promising in application.

Androgen promotes differentiation of PLZF+ spermatogonia pool via indirect regulatory pattern.

BACKGROUND: Androgen plays a pivotal role in spermatogenesis, accompanying a question how androgen acts on germ cells in testis since germ cells lack of androgen receptors (AR). Promyelocytic leukemia zinc-finger (PLZF) is essential for maintenance of undifferentiated spermatogonia population which is terminologically called spermatogonia progenitor cells (SPCs). AIMS: We aim to figure out the molecular connections between androgen and fates of PLZF+ SPCs population. METHOD: Immunohistochemistry was conducted to confirm that postnatal testicular germ cells lacked endogenous AR. Subsequently, total cells were isolated from 5 dpp (day post partum) mouse testes, and dihydrotestosterone (DHT) and/or bicalutamide treatment manifested that Plzf was indirectly regulated by androgen. Then, Sertoli cells were purified to screen downstream targets of AR using ChIP-seq, and gene silence and overexpression were used to attest these interactions in Sertoli cells or SPCs-Sertoli cells co-culture system. Finally, these connections were further verified in vivo using androgen pharmacological deprivation mouse model. RESULTS: Gata2 is identified as a target of AR, and ß1-integrin is a target of Wilms' tumor 1 (WT1) in Sertoli cells. Androgen signal negatively regulate ß1-integrin on Sertoli cells via Gata2 and WT1, and ß1-integrin on Sertoli cells interacts with E-cadherin on SPCs to regulate SPCs fates. CONCLUSION: Androgen promotes differentiation of PLZF+ spermatogonia pool via indirect regulatory pattern.

Magnetic nanobubbles with potential for targeted drug delivery and trimodal imaging in breast cancer: an in vitro study.

AIM: The aim of this study was to improve tumor-targeted therapy for breast cancer by designing magnetic nanobubbles with the potential for targeted drug delivery and multimodal imaging. MATERIALS & METHODS: Herceptin-decorated and ultrasmall superparamagnetic iron oxide (USPIO)/paclitaxel (PTX)-embedded nanobubbles (PTX-USPIO-HER-NBs) were manufactured by combining a modified double-emulsion evaporation process with carbodiimide technique. PTX-USPIO-HER-NBs were examined for characterization, specific cell-targeting ability and multimodal imaging. RESULTS: PTX-USPIO-HER-NBs exhibited excellent entrapment efficiency of Herceptin/PTX/USPIO and showed greater cytotoxic effects than other delivery platforms. Low-frequency ultrasound triggered accelerated PTX release. Moreover, the magnetic nanobubbles were able to enhance ultrasound, magnetic resonance and photoacoustics trimodal imaging. CONCLUSION: These results suggest that PTX-USPIO-HER-NBs have potential as a multimodal contrast agent and as a system for ultrasound-triggered drug release in breast cancer.

Periostin contributes to arsenic trioxide resistance in hepatocellular carcinoma cells under hypoxia.

Hypoxia has been suggested to induce chemoresistance in tumor cells. In this study, we aimed to test the hypothesis that hypoxia-inducible factor-1alpha (HIF-1α)/periostin axis might promote arsenic trioxide resistance in hepatocellular carcinoma (HCC) cells under hypoxia. HCC cells were exposed to hypoxia and measured for periostin expression. Loss-of-function studies were done to assess the role of periostin in arsenic trioxide resistance. In vivo xenograft mouse studies were performed to determine the effect of periostin silencing on HCC susceptibility to arsenic trioxide. It was found that periostin expression was significantly increased in SMMC7721 and Hep3B HCC cells after hypoxic treatment. Depletion of HIF-1α blocked the upregulation of periostin induced by hypoxia. HCC cells under hypoxia displayed more resistant to arsenic trioxide than those under normoxia. Interestingly, downregulation of periostin re-sensitized hypoxic SMMC7721 and Hep3B cells to arsenic trioxide, which was accompanied by increased apoptosis. Luciferase reporter assay revealed that periostin overexpression enhanced HIF-1α-dependent transcriptional activity and induced the expression of vascular endothelial growth factor, Mcl-1, and Bcl-xL in SMMC7721 cells. Administration of arsenic trioxide resulted in a significant inhibition of SMMC7721 tumor growth. Notably, downregulation of periostin significantly enhanced the anticancer effect of arsenic trioxide against SMMC7721 tumors and reduced the percentage of Ki-67-positive proliferating cells. Taken together, periostin contributes to arsenic trioxide resistance in HCC under hypoxic microenvironment, which is likely associated with promotion of HIF-1α-dependent activation of survival genes. Targeting periostin may represent a promising strategy to improve arsenic trioxide-based anticancer therapy against HCC.

Monoclonal Antibodies Against Porcine sIgA and Their Use in Immunohistochemistry.

Secretory IgA (sIgA) is known as the predominant immunoglobulin in the mucosal system. It prevents pathogens from invading an animal's body through mucosa, making homeostasis. However, few studies examining the secretion of sIgA in mucosal-associated tissues of porcines based on immunohistochemistry methods have been done. In this study, BALB/c mice were immunized with porcine sIgA and the splenocytes were then fused with myeloma cells. Finally, three hybridoma cell lines secreting monoclonal antibody (MAb) against porcine sIgA were obtained. All three MAbs had no cross-reaction with porcine IgG confirmed by Western blot analysis. Furthermore, lungs, tracheas, and intestines were collected from healthy porcines to prepare tissue slices, followed by incubation with the MAb produced in this study. The results showed that sIgA existing in respiratory and digestive systems could be detected by this newly produced MAb. These generated MAbs against porcine sIgA might have a potential use in mucosal research of porcines.

Synthesis and evaluation of perfluorooctylbromide nanoparticles modified with a folate receptor for targeting ovarian cancer: in vitro and in vivo experiments.

BACKGROUND: Epithelial ovarian cancer is the leading cause of death among gynecologic malignancies. However, detecting ovarian cancer at an early stage remains challenging. In this work, we aimed to synthesize a folate-receptor-targeting perfluorooctylbromide nanoparticle (FR-TPNP) as a targeted computed tomography (CT) contrast agent for the early detection of ovarian cancer. METHODS: Perfluorooctylbromide (PFOB) was encapsulated in Poly (lactic-co-glycolic acid) (PLGA) by a two-step emulsion technique to construct the nanoparticles. Folate-poly (ethylene glycol)-carboxylic acid (Fol-PEG-COOH) was introduced to modify the surface of the nanoparticles through attachment to the PLGA. The effects of different volume ratios of PFOB to PLGA on the characteristics of the FR-TPNP emulsions were compared. The size distribution and potential of the FR-TPNPs were assessed with a laser particle size analyzer system. The in vitro targeting ability of the FR-TPNPs was observed with a confocal laser scanning microscope (CLSM), and the in vivo transportation of the FR-TPNPs was evaluated with CT. RESULTS: The sizes of the FR-TPNP emulsion with different volume ratios varied from 302.67 ± 27.83 nm to 563.68 ± 47.29 nm, and the mean CT value ranged from 233 ± 20.59 HU to 587.66 ± 159.51 HU. Both the size and mean CT value increased with the volume ratio. The FR-TPNPs showed greater cell affinity and targeting efficiency to SKOV3 cells than the control group and folic acid interference group in vitro, as observed by CLSM. A significant CT enhancement of ovarian cancer xenografts in the targeted group of a nude mice model was observed 2 h post-injection; it increased to a peak at 12 h and had a duration of 48 h. The mean CT value of the tumor in the targeted group was considerably higher than those in the non-targeted and other groups 6 h post-injection. CONCLUSION: The synthesized FR-TPNP emulsion was an effective CT contrast agent with highly efficient targeting ability and a long circulation time, thus representing a potential strategy for the earlier detection of ovarian cancer.

Phase-Shifted PFH@PLGA/Fe3O4 Nanocapsules for MRI/US Imaging and Photothermal Therapy with near-Infrared Irradiation.

Photothermal therapy (PTT) utilizes photothermal conversion reagents to generate heat energy from absorbed light to effectively treat various malignant diseases. This approach has attracted broad and increasing interest in cancer treatment. Near-infrared (NIR)-induced PTT is particularly attractive because of its minimal absorbance by normal tissue and relatively deep tissue penetration. To improve the efficacy of PTT, we have developed nanocapsules encapsulating superparamagnetic iron oxide (Fe3O4) as synergistic agents for NIR-induced PTT. In this study, phase-shift and NIR photoabsorbing poly(lactic-co-glycolic acid) (PLGA) nanocapsules (perfluorohexane (PFH)@PLGA/Fe3O4) were fabricated for MRI/US dual-modal imaging-guided PTT. The multifunctional nanocapsules can be used not only to increase the local tumor temperature by absorbing the NIR energy but also as bimodal contrast agents for both MRI and US imaging. Such nanocapsules can be converted into microbubbles under NIR irradiation, which produces excellent contrast for US imaging and enhanced cancer ablation. We refer to the nanocapsule phase transition process induced by the infrared lamp as NIR radiation droplet vaporization (NIRDV).

Targeted antiangiogenesis gene therapy using targeted cationic microbubbles conjugated with CD105 antibody compared with untargeted cationic and neutral microbubbles.

OBJECTIVE: This study aimed to develop targeted cationic microbubbles conjugated with a CD105 antibody (CMB105) for use in targeted vascular endothelial cell gene therapy and ultrasound imaging. We compared the results with untargeted cationic microbubbles (CMB) and neutral microbubbles (NMB). METHODS: CMB105 were prepared and compared with untargeted CMB and NMB. First, the microbubbles were characterized in terms of size, zeta-potential, antibody binding ability and plasmid DNA loading capacity. A tumor model of subcutaneous breast cancer in nude mice was used for our experiments. The ability of different types of microbubbles to target HUVECs in vitro and tumor neovascularization in vivo was measured. The endostatin gene was selected for its outstanding antiangiogenesis effect. For in vitro experiments, the transfection efficiency and cell cycle were analyzed using flow cytometry, and the transcription and expression of endostatin were measured by qPCR and Western blotting, respectively. Vascular tube cavity formation and tumor cell invasion were used to evaluate the antiangiogenesis gene therapy efficiency in vitro. Tumors were exposed to ultrasound irradiation with different types of microbubbles, and the gene therapy effects were investigated by detecting apoptosis induction and changes in tumor volume. RESULTS: CMB105 and CMB differed significantly from NMB in terms of zeta-potential, and the DNA loading capacities were 16.76±1.75 µg, 18.21±1.22 µg, and 0.48±0.04 µg per 5×10(8) microbubbles, respectively. The charge coupling of plasmid DNA to CMB105 was not affected by the presence of the CD105 antibody. Both CMB105 and CMB could target to HUVECs in vitro, whereas only CMB105 could target to tumor neovascularization in vivo. In in vitro experiments, the transfection efficiency of CMB105 was 24.7-fold higher than the transfection efficiency of NMB and 1.47-fold higher than the transfection efficiency of CMB (P<0.05). With ultrasound-targeted microbubble destruction (UTMD)-mediated gene therapy, the transcription and expression of endostatin were the highest in the CMB105 group (P<0.001); the antiangiogenesis effect and inhibition of tumor cells invasion was better with CMB105 than CMB or NMB in vitro (P<0.01). After gene therapy, the tumor volumes of CMB105 group were significantly smaller than that of CMB and NMB, and many tumor cells had begun apoptosis in the CMB105 group, which had the highest apoptosis index (P<0.001). CONCLUSIONS: As a contrast agent and plasmid carrier, CMB105 can be used not only for targeted ultrasound imaging but also for targeted gene therapy both in vitro and in vivo. The plasmid DNA binding ability of the CMB was not affected by conjugation of the CMB with the CD105 antibody, and because of its targeting ability, the gene transfection efficiency and therapeutic effect were better compared with the untargeted CMB and NMB. The advantages of targeted gene therapy with CMB105 in vivo were more prominent than with CMB or NMB because neither can target the endothelia in vivo.

Microbubbles from gas-generating perfluorohexane nanoemulsions for targeted temperature-sensitive ultrasonography and synergistic HIFU ablation of tumors.

A special "small to big" temperature-responsive phase-transformation strategy based on the "acoustic droplet vaporization (ADV)" mechanism is developed for efficient targeted ultrasonography and synergistic high intensity focused ultrasound (HIFU) cancer surgery by engineering targeted nanoemulsions, which is systematically evaluated and successfully demonstrated in vitro, ex vivo, and in vivo.

Doxorubicin loaded superparamagnetic PLGA-iron oxide multifunctional microbubbles for dual-mode US/MR imaging and therapy of metastasis in lymph nodes.

Current strategies for tumor-induced sentinel lymph node detection and metastasis therapy have limitations. In this work, we co-encapsulated iron oxide nanoparticles and chemotherapeutic drug into poly(lactic-co-glycolic acid) (PLGA) microbubbles to form multifunctional polymer microbubbles (MPMBs) for both tumor lymph node imaging and therapy. Fe(3)O(4) nanoparticles and doxorubicin (DOX) co-encapsulated PLGA microbubbles were prepared and filled with perfluorocarbon gas. Enhancement of ultrasound (US)/magnetic resonance (MR) imaging and US triggered drug delivery were evaluated both in vitro and in vivo. The MPMBs exhibited characters like narrow size distribution and smooth surface with a mean diameter of 868.0 ± 68.73 nm. In addition, varying the concentration of Fe(3)O(4) nanoparticles in the bubbles did not significantly influence the DOX encapsulation efficiency or drug loading efficiency. Our in vitro results demonstrated that these MPMBs could enhance both US and MR imaging which was further validated in vivo showing that these MPMBs enhanced tumor lymph nodes signals. The anti-tumor effect of MPMBs mediated chemotherapy was assessed in vivo using end markers like tumor proliferation index, micro blood vessel density and micro lymphatic vessel density, which were shown consistently the lowest after the MPMBs plus sonication treatment compared to controls. In line with these findings, the tumor cell apoptotic index was found the largest after the MPMBs plus sonication treatment. In conclusion, we have successfully developed a doxorubicin loaded superparamagnetic PLGA-Iron Oxide multifunctional theranostic agent for dual-mode US/MR Imaging of lymph node, and for low frequency US triggered therapy of metastasis in lymph nodes, which might provide a strategy for the imaging and chemotherapy of primary tumor and their metastases.

[Effects of ethanol extracts of Panax notoginseng on liver metastasis of B16 melanoma grafted in mice].

OBJECTIVE: To observe the effects of ethanol extracts of Panax notoginseng on the tumor and the liver metastasis in experimental mice grafted with B16 melanoma. METHODS: B16 melanoma was transplanted in the spleen of C57BL/6 mice. The effects of different doses of ethanol extracts of Panax notoginseng on the inhibition rate of spleen tumors and the liver metastasis were observed respectively. RESULTS: The high-, medium-, and low-doses of the extracts and the interferon-alpha (IFN-alpha) can improve the quality of life of the experimental mice. The weights of spleen tumor were lower in the low- and medium-dose extracts-treated groups and the IFN-alpha-treated group than that in the normal saline (NS)-treated group (P<0.05 or P<0.01). The liver metastasis was less in the low- and medium-dose extracts-treated groups and the IFN-alpha-treated group than that in the NS-treated group (P<0.01). CONCLUSION: The ethanol extracts of Panax notoginseng can improve the quality of life of the experimental mice and inhibit the growth of tumor and the liver metastasis.