MR Assessment of Acute Pathologic Process after Myocardial Infarction in a Permanent Ligation Mouse Model: Role of Magnetic Nanoparticle-Contrasted MRI.

We evaluated the relationship between myocardial infarct size and inflammatory response using cardiac magnetic resonance imaging (CMR) in an acute myocardial infarction (AMI) mouse model. Myocardial infarction (MI) was induced in 14 mice by permanent ligation of the left anterior descending artery. Late gadolinium enhancement (LGE), manganese-enhanced MRI (MEMRI), and magnetofluorescent nanoparticle MRI (MNP-MRI) were performed 1, 2, and 3 days after MI, respectively. The size of the enhanced lesion was quantitatively determined using Otsu's thresholding method in area-based and sector-based approaches and was compared statistically. Linear correlation between the enhanced lesion sizes was evaluated by Pearson's correlation coefficients. Differences were compared using Bland-Altman analysis. The size of the inflammatory area determined by MNP-MRI (57.1 ± 10.1%) was significantly larger than that of the infarct area measured by LGE (40.8 ± 11.7%, P < 0.0001) and MEMRI (44.1 ± 14.9%, P < 0.0001). There were significant correlations between the sizes of the infarct and inflammatory lesions (MNP-MRI versus LGE: r = 0.3418, P = 0.0099; MNP-MRI versus MEMRI: r = 0.4764, P = 0.0002). MNP-MRI provides information about inflammatory responses in a mouse model of AMI. Thus, MNP-MRI associated with LGE and MEMRI may play an important role in monitoring the disease progression in MI.

Infarcted Myocardium-Primed Dendritic Cells Improve Remodeling and Cardiac Function After Myocardial Infarction by Modulating the Regulatory T Cell and Macrophage Polarization.

BACKGROUND: Inflammatory responses play a critical role in left ventricular remodeling after myocardial infarction (MI). Tolerogenic dendritic cells (tDCs) can modulate immune responses, inducing regulatory T cells in a number of inflammatory diseases. METHODS: We generated tDCs by treating bone marrow-derived dendritic cells with tumor necrosis factor-α and cardiac lysate from MI mice. We injected MI mice, induced by a ligation of the left anterior descending coronary artery in C57BL/6 mice, twice with tDCs within 24 hours and at 7 days after the ligation. RESULTS: In vivo cardiac magnetic resonance imaging and ex vivo histology confirmed the beneficial effect on postinfarct left ventricular remodeling in MI mice treated with tDCs. Subcutaneously administered infarct lysate-primed tDCs near the inguinal lymph node migrated to the regional lymph node and induced infarct tissue-specific regulatory T-cell populations in the inguinal and mediastinal lymph nodes, spleen, and infarcted myocardium, indicating that a local injection of tDCs induces a systemic activation of MI-specific regulatory T cells. These events elicited an inflammatory-to-reparative macrophage shift. The altered immune environment in the infarcted heart resulted in a better wound remodeling, preserved left ventricular systolic function after myocardial tissue damage, and improved survival. CONCLUSIONS: This study showed that tDC therapy in a preclinical model of MI was potentially translatable into an antiremodeling therapy for ischemic tissue repair.

Combining vasculature disrupting agent and Toll-like receptor 7/8 agonist for cancer therapy.

This study evaluates the effect of combination of two different treatment regimens for solid tumor therapy: vasculature targeting agent and immune-stimulation. Poly lactide-co-glycolide (PLGA) nanoparticles were synthesized for intracellular delivery of Toll-like receptor (TLR) 7/8 agonist-gardiquimod. Spherical and mono-disperse gardiquimod encapsulated PLGA nanoparticles (Gardi-PLGA), approximately 194 nm in size were formulated. Gardi-PLGA induced immune-stimulation, and vasculature disrupting agent (VDA)-5,6-Dimethylxanthenone-4-acetic acid (DMXAA) was used in combination to assessing the influence on bone marrow derived dendritic cells (BMDCs) and B16-F10 melanoma cells. The combination treatment significantly increased the levels of pro-inflammatory cytokines, indicating their activation in BMDCs, while melanoma cells remained viable. Further, mice melanoma model was established, and DMXAA was administered intraperitoneally and Gardi-PLGA was administered via an intra-tumoral injection. The combination treatments strategy significantly inhibited tumor growth as shown by tumor volume analysis, and the survival rate of the mice was found to be 63.6% (n = 11), after 54 days of tumor inoculation. Immunohistochemical findings of tumor sections treated with DMXAA confirmed the in vivo vasculature disruption. Thus, the inhibition of tumor growth can be attributed to the synergistic effect of immune stimulation caused by DC activation and vasculature disruption.

Sector-Based Assessment of Infarct Size on Late-Gadolinium-Enhancement MRI in a Mouse Model of Acute Myocardial Infarction.

Scoring of myocardial infarction (MI) disease extent in cardiac magnetic resonance (CMR) images has been generally presented in terms of area-based infarct size. However, gradual thinning of the infarcted wall and compensatory hypertrophy of the noninfarcted remote wall during left ventricular (LV) remodeling after MI complicate the accuracy of infarct size measurement. In this study, we measured and compared infarct sizes in mice on late gadolinium enhancement (LGE) images using area-, length-, and radial sector-based methods.MI was induced by permanent ligation of the left coronary artery (n = 6). LGE images were acquired 30 minutes after intravenous injection of Gd-DTPA-BMA. Percentages of infarct size (%Area, %Length, and %Sector) on the LGE images were calculated and compared with histological findings.Infarct sizes obtained by an area-based approach were smaller than those obtained by other measurements. The area-based approach underestimated infarct size compared with the length-based approach. Most infarct sizes measured by each method demonstrated a similar trend, with maximum values determined by sector-based measurements using a mean + SD threshold. Spearman's rank correlation coefficients indicated that the 3 measurements were strongly correlated (P < 0.05) to each other. Significant differences and trends were observed between sector-based infarct sizes with different thresholds when 16 or more sectors were used.In conclusion, our study demonstrated that methods used for the histological calculation of infarct size could be applied to CMR analysis. Moreover, our results showed a similar trend to histological assessment. Sector-based CMR approaches can be useful for infarct size measurement.

Potential anti-cancer effect of N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), a novel histone deacetylase inhibitor, for the treatment of thyroid cancer.

BACKGROUND: Thyroid cancer has been indicated to have a higher global proportion of DNA methylation and a decreased level of histone acetylation. Previous studies showed that histone gene reviser and epigenetic changes role significant parts in papillary and anaplastic thyroid cancer tumorigenesis. The goal of this research was to study the endoplasmic reticulum (ER) stress-mediated actions of the dominant histone deacetylase (HDAC) inhibitor, N-hydroxy-7-(2-naphthylthio) hepatonomide (HNHA), in thyroid cancer and to explore its effects on apoptotic cell death pathways. METHODS: Experiments were achieved to conclude the effects of HNHA in papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) cell lines and xenografts, as compared with two other established HDAC inhibitors (SAHA; suberoylanilide hydroxamic acid and TSA; trichostatin A). RESULTS: Apoptosis, which was induced by all HDAC inhibitors, was particularly significant in HNHA-treated cells, where noticeable B-cell lymphoma-2 (Bcl-2) suppression and caspase activation were observed both in vitro and in vivo. HNHA increased Ca(2+) release from the ER to the cytoplasm. ER stress-dependent apoptosis was induced by HNHA, suggesting that it induced caspase-dependent apoptotic cell death in PTC and ATC. PTC and ATC xenograft studies demonstrated that the antitumor and pro-apoptotic effects of HNHA were greater than those of the established HDAC inhibitors. These HNHA activities reflected its induction of caspase-dependent and ER stress-dependent apoptosis on thyroid cancer cells. CONCLUSIONS: The present study indicated that HNHA possibly provide a new clinical approach to thyroid cancers, including ATC.

Evaluating hypertrophic thyroidectomy scar outcomes after treatment with triamcinolone injections and copper bromide laser therapy.

BACKGROUND AND OBJECTIVES: Postoperative hypertrophic scar following thyroidectomy can be a major concern due to its disfiguring appearance. Recently, copper bromide laser (CBL) and intralesional triamcinolone injection (TA ILI) have been used to treat hypertrophic thyroidectomy scars. Data regarding the number of treatment sessions needed to reach a certain endpoint and the prognostic factors that affect treatment duration are unknown. The aim of this study was to evaluate the number of treatment sessions required to reduce VSS score by 50%, which was regarded as the treatment endpoint, and to investigate the factors that influence treatment duration when using CBL and TA ILI. MATERIALS AND METHODS: A total of 67 patients were enrolled in this study. Baseline characteristics of the patients including age, sex, body mass index (BMI), distance of the scar from the sternal notch, time of development of the hypertrophic scar, sternocleidomastoid (SCM) muscle prominence, and date of operation were collected on the first visit. They were treated with CBL and TA. The concentration of triamcinolone used was 2.5 mg/ml or 5 mg/ml according to the pliability score of each scar. RESULTS: The mean number of treatment sessions required to achieve the endpoint was 3.85 ± 1.25. Among the variables assessed, location of the scar near the sternal notch (P = 0.020) and patient BMI (P = 0.001) were associated with the increasing number of treatment sessions. CONCLUSION: In our study cohort, four treatments were required to reduce the VSS of thyroidectomy scars by 50% when using a combination treatment of CBL and low concentration TA ILI. Also, scar location and patient BMI are factors that affect treatment outcome.

Robot-assisted posterior retroperitoneoscopic adrenalectomy: single port access.

Laparoscopic adrenalectomy has become a gold standard in adrenal gland surgery. More recently, some minimally invasive trials have been conducted on single access surgery on the adrenal gland. In this study, we introduce our first experiences of robot-assisted posterior retroperitoneoscopic adrenalectomy using single-port access and the da Vinci system.

Cetuximab-conjugated magneto-fluorescent silica nanoparticles for in vivo colon cancer targeting and imaging.

Magneto-fluorescent silica nanoparticles were conjugated with cetuximab for the targeting and imaging of colon cancer. In this study, cetuximab-conjugated magneto-fluorescent nanoparticles (MFSN-Ctx) could specifically target colon cancer cells that expressed EGFR on their cell membranes, and specific fluorescence was detected. MFSN-Ctx produced significant MRI signal changes in a human colon cancer xenograft mouse model. Intravenous injection of MFSN-Ctx resulted in faster uptake as compared to intraperitoneal injection, indicating that MFSN-Ctx had different kinetic properties in tumors based on the method of injection. The local concentration of MFSN-Ctx in a tumor was amplified by the use of an external magnetic field. These results demonstrate the potential application of MFSN-Ctx for the detection of EGFR-expressing colon cancer using in vivo imaging approaches.

Visually discernible [18F]fluorodeoxyglucose uptake in papillary thyroid microcarcinoma: a potential new risk factor.

CONTEXT: A significant number of papillary thyroid microcarcinomas (PTMCs), despite excellent prognosis, show aggressive features such as extrathyroidal extension (EE) and lymph node metastasis (LNM) that may not always be detected preoperatively or intraoperatively. The relapse rate appears also substantial. OBJECTIVE: To assess the value of [(18)F]fluorodeoxyglucose (FDG) uptake in PTMC as a potential risk factor for preoperative risk stratification. METHODS: This retrospective study included 87 patients (17 males and 70 females; mean age = 51.2 yr, range 29-74 yr) with a unifocal PTMC who underwent preoperative FDG-positron emission tomography (PET)/computed tomography (CT)and total thyroidectomy and central lymph node dissection. Statistical analyses were performed to compare the gender, age, tumor size, and FDG uptake in PTMC with the presence of histopathologically proven EE and central LNM (cLNM). RESULTS: Of the 87 patients, 44 (51%) had EE, and 27 (31%) had cLNM. PET/CT showed visually discernible FDG uptake in 46 PTMCs (53%). FDG positivity of PTMCs was the only significant variable correlated with both EE and cLNM; there was a significant difference in the prevalence of both EE (70 vs. 29%) and cLNM (41 vs. 19.5%) between the FDG-positive and FDG-negative groups. In contrast, other already known risk factors, i.e. gender, age, and size, showed a correlation with only one or neither of EE and cLNM. CONCLUSION: The results indicate that visual FDG positivity in PTMCs is a potential risk factor that can be useful for preoperative risk stratification. Prospective studies would be warranted to assess the long-term benefit and cost effectiveness of preoperative FDG-PET/CT.

In vivo tracking of human mesenchymal stem cells in experimental stroke.

To understand the fates of human mesenchymal stem cells (hMSCs) following transplantation into a rodent model of middle cerebral artery occlusion (MCAo), magnetic resonance imaging (MRI) techniques were employed, hMSCs were labeled with ferumoxides (Feridex)--protamine sulfate complexes, which were visualized and examined by MRI up to 10 weeks following transplantation. Migration of the transplanted cells to the infarcted area was further confirmed by histological methods. We found that the hMSCs transplanted in MCAo models possess the capacity to migrate to the infarcted area extensively in both ipsilateral and contralateral injections, exhibiting a pathotropism. We also analyzed the detailed migration patterns of transplanted hMSCs. We speculate that the extensive migratory ability of hMSCs may represent a therapeutic potential for developing efficient cell transplantation strategies in stroke.

Variation of the choline signal intensity in the dorsolateral prefrontal cortex of rats exposed to the forced swimming test as detected by in vivo 1H MR spectroscopy.

BACKGROUND: (1)H magnetic resonance spectroscopy (MRS) has documented an increased Cho/Cr ratio in the dorsolateral prefrontal cortex (DLPFC) in major depressive disorder (MDD). The aim of this study was to investigate neurochemical alterations in the left DLPFC, considered a main area of pathogenesis in depression, using rats exposed to the forced swimming test (FST). MATERIALS AND METHODS: Twenty-four male rats were used for the MRI and in vivo(1)H MRS studies. Rats exposed to the FST to induce a depressed mental status. Using in vivo(1)H MRS, the metabolite ratios of the rats with a depressed mental status and the controls, were measured and the values of the two groups were compared. RESULTS: The Cho/Cr and Cho/NAA ratios in the DLPFC of the rats with a depressed mental status were significantly higher than that in the controls. CONCLUSIONS: The present study demonstrates a significantly increased Cho/Cr ratio in the DLPFC of rats with depression compared with controls. This result may suggest an accelerated turnover of membrane without neuronal loss is occurring in the DLPFC of the rats with depression.

In Vivo Tracking of Human Mesenchymal Stem Cells in Experimental Stroke.

To understand the fates of human mesenchymal stem cells (hMSCs) following transplantation into a rodent model of middle cerebral artery occlusion (MCAo), magnetic resonance imaging (MRI) techniques were employed. hMSCs were labeled with ferumoxides (Feridex®)-protamine sulfate complexes, which were visualized and examined by MRI up to 10 weeks following transplantation. Migration of the transplanted cells to the infarcted area was further confirmed by histological methods. We found that the hMSCs transplanted in MCAo models possess the capacity to migrate to the infarcted area extensively in both ipsilateral and contralateral injections, exhibiting a pathotropism. We also analyzed the detailed migration patterns of transplanted hMSCs. We speculate that the extensive migratory ability of hMSCs may represent a therapeutic potential for developing efficient cell transplantation strategies in stroke.