ICAM1-Targeting Theranostic Nanoparticles for Magnetic Resonance Imaging and Therapy of Triple-Negative Breast Cancer.

Purpose: Owing to the lack of effective biomarkers, triple-negative breast cancer (TNBC) has the worst prognosis among all subtypes of breast cancer. Meanwhile, tremendous progress has been made to identify biomarkers for TNBC. However, limited number of biomarkers still restrain the specifically targeting outcomes against TNBC. Here, to solve the obstacle, we designed and synthesized a new type of biocompatible nanoparticles to amplify the targeting effects for TNBC theranostics. Methods: To identify the biomarker of TNBC, the expression of intercellular adhesion molecule-1 (ICAM1) was assessed by real-time polymerase chain reaction and western blot among all subtypes of breast cancer and normal breast epithelium. Then, vesicular nanoparticles based on poly(ethylene glycol)-poly(ε-caprolactone) copolymers were prepared by the double emulsion method and modified with anti-ICAM1 antibodies through click chemistry to conjugate with related antigens on TNBC cell membranes and then loaded with magnetic resonance imaging (MRI) contrast agent gadolinium and chemotherapeutic drug doxorubicin. The targeting capability, diagnostic and therapeutic efficacy of this nanoparticle were validated through cell-based and tumor model-based experiments. Results: ICAM1 was expressed significantly higher on TNBC than on other subtypes of breast cancer and normal breast epithelium in both mRNA and protein level. Theranostic nanoparticle modified with anti-ICAM1 was proved to be able to specifically target to TNBC in vitro experiments. Such theranostic nanoparticle also displayed enhanced diagnostic and therapeutic efficacy by specifically targeting capability and extending circulation time in tumor models. The biocompatibility and biosafety of this nanoparticle was also confirmed in vitro and in vivo. Conclusion: Overall, this new nanoparticle has been demonstrated with effective therapeutic outcomes against TNBC, providing a promising theranostic approach for MRI-guided therapy of TNBC.

Preliminary study on the assessment of early cartilage degeneration by quantitative ultrashort echo time magnetic resonance imaging in vivo.

Background: To investigate the feasibility of quantitative ultrashort echo time magnetic resonance imaging (UTE-MRI) techniques for assessing early cartilage degeneration in vivo. Methods: A total of 46 patients with knee pain due to osteoarthritis (OA) as the main complaint were recruited into the study. We performed MRI examinations with different quantitative UTE-MRI techniques, including UTE-based magnetization transfer (MT), UTE-adiabaticT1ρ, and UTE-T2* mapping on a 3.0T clinical magnetic resonance (MR) scanner (MR750; GE Healthcare, Milwaukee, WI, USA). Three regions of interest (ROIs) were manually drawn on the medial and lateral femoral condyles and the corresponding medial and lateral tibial plateaus, respectively. A total of 561 ROIs (12 ROIs for each knee) were finally included and divided into 3 groups according to the MRI Osteoarthritis Knee Score (MOAKS): normal (MOAKS 0, n=175), mild degeneration (MOAKS 1, n=283), and moderate degeneration (MOAKS 2, n=103). One-way analysis of variance (ANOVA) and Tamhane's T2 test were used to compare the differences of quantitative UTE-biomarkers among different groups. The analysis of Spearman's correlation was used to assess the correlation between the UTE-biomarkers and MOAKS grading. The diagnostic efficacy of different quantitative UTE-MRI techniques for detecting mild cartilage degeneration was evaluated using the receiver operating characteristic (ROC) curve. Results: The UTE-MT ratio (UTE-MTR) and the UTE-adiabatic T1ρ values had a moderate correlation with the MOAKS grading (r=-0.523, P<0.001; r=0.531, P<0.001, respectively), while the UTE-T2* was weakly correlated with the MOAKS grading (r=-0.396, P<0.001). For the normal group (MOAKS 0) and the mild group (MOAKS 1), the UTE-MTR values were 21.09%±3.03% and 17.30%±3.22%, respectively. The UTE-adiabatic T1ρ values were 30.43±6.26 ms and 35.05±8.78 ms for the normal group (MOAKS 0) and the mild group (MOAKS 1), respectively. With respect to the UTE-T2* values, the normal group (MOAKS 0) values were 21.49±3.96 ms and the mild group (MOAKS 1) values were 19.86±3.08 ms. All the differences between the 2 groups of the 3 UTE-MRI values were significant. The AUCs of the UTE-MTR, UTE-adiabatic T1ρ, and UTE-T2* mapping were 0.794, 0.732, and 0.651, respectively. Conclusions: The quantitative UTE-MRI techniques (UTE-MT, UTE-adiabatic T1ρ, and UTE-T2* mapping) show great promise for assessing the early degeneration of articular cartilage in vivo, and the UTE-MT and UTE-adiabatic T1ρ values show better diagnostic efficacy than UTE-T2* mapping.

Evaluation of cartilage degeneration using multiparametric quantitative ultrashort echo time-based MRI: an ex vivo study.

Background: The quantitative MR techniques developed rapidly, vary MR-biomarkers have shown the ability to assess the quality of articular cartilage. This study aimed to investigate the diagnostic efficacy of multi-parametric quantitative ultrashort echo time (UTE)-based MRI for evaluating human cartilage degeneration. Methods: Twenty fresh anterolateral femoral condyle samples were obtained from 20 patients (age, 58.8±6.6 years; 6 females) who underwent total knee arthroplasty due to primary osteoarthritis (OA). The samples were imaged using UTE-based magnetization transfer (UTE-MT), UTE-based adiabatic T1ρ (UTE-AdiabT1ρ), UTE-based T2* (UTE-T2*), and CubeQuant-T2 sequences. Cartilage degeneration was classified based on the OA Research Society International grade and polarized light microscopy (PLM) collagen organization score. Spearman's correlation analysis was used to determine the relationships between quantitative MRI biomarkers [UTE-MT ratio (UTE-MTR), UTE-AdiabT1ρ, UTE-T2*, and CubeQuant-T2], OA Research Society International grade, and PLM collagen organization score. The diagnostic efficacy of each MRI biomarker for the detection of mild cartilage degeneration was assessed using the area under the receiver operating characteristic (ROC) curve (AUC). Results: Of the quantitative MRI biomarkers, UTE-MTR had the strongest correlation with both OA Research Society International grade (r=-0.709, P<0.001) and PLM collagen organization score (r=0.579, P<0.001). The UTE-MTR and UTE-AdiabT1ρ values showed significant differences between the normal group and the mild degeneration group (P=0.047 and 0.015, respectively), while UTE-T2* and CubeQuant-T2 did not. The UTE-MTR values were 15.90%±1.06% and 14.59%±1.35% for normal and mildly degenerated cartilage, respectively. The UTE-AdiabT1ρ values were 40.19±2.87 and 42.6±2.26 ms for normal and mildly degenerated cartilage, respectively. ROC analysis showed that UTE-MTR (AUC =0.805, P=0.001, sensitivity =73.7%, specificity =89.5%) had the highest diagnostic efficacy for mild cartilage degeneration, while UTE-AdiabT1ρ (AUC =0.727, P=0.017) and CubeQuant-T2 (AUC =0.712, P=0.026) showed lower diagnostic efficacy. Conclusions: Quantitative UTE-MT and UTE-AdiabT1ρ biomarkers may potentially be used in the evaluation of early cartilage degeneration.

Impact of genetic status on the survival outcomes of patients with clinical stage I non-small cell lung cancer with a radiological pure-solid appearance.

PURPOSE: To investigate whether genetic status is associated with the prognosis of patients with clinical stage (c-stage) I non-small cell lung cancer (NSCLC) with radiological pure-solid manifestations. MATERIALS AND METHODS: We included 340 patients with pure-solid c-stage I NSCLC and evaluated their clinicopathological and genetic information. Disease recurrence and death were also observed at the end of the 5-year follow-up period. A Cox proportional hazards model was performed to identify the effect of clinicopathological variables, including genetic status, on oncological outcomes. Recurrence-free survival (RFS) and overall survival (OS) were calculated by Kaplan-Meier curves and were compared using log-rank tests. RESULTS: The gene-mutation rate of c-stage I NSCLC with a radiological pure-solid appearance was 55.9% (190/340), and the frequencies of EGFR, KRAS, ALK, ROS1 and fused genes were 69.5% (132/190), 16.8% (32/190), 8.9% (17/190), 1.6% (3/190) and 3.2% (6/190), respectively. The 5-year RFS and OS rates of eligible patients were 57.1% and 76.5%, respectively. A multivariable analysis revealed that genetic status was an independent significant prognostic factor associated with RFS (hazard ratio [HR] = 1.416, 95% confidence interval [CI]: 1.020-1.964, p = 0.038) but not with OS. RFS was lower in the genetic mutation group compared with the wild-type group (p = 0.027), with 5-year RFS rate (65.7 vs. 51.6%), but the difference in OS (mutated group vs. wild-type group: 78.0% vs. 75.3%) was not statistically significant (p = 0.602). Additionally, we found that pathological nodal involvement (HR = 2.455, 95% CI: 1.745-3.454, p < 0.001 for RFS; HR = 2.204, 95% CI: 1.409-3.447, p = 0.001 for OS) was also a valuable prognostic factor in patients with pure-solid c-stage I NSCLC. CONCLUSION: Our study provides a comprehensive description of the mutational landscape of c-stage I NSCLC, and indicates that genetic status has an impact on disease recurrence in patients with c-stage I NSCLC with pure-solid appearance.

Stratification of axillary lymph node metastasis risk with breast magnetic resonance imaging in breast cancer.

Aims: To develop a model based on breast MRI to stratify axillary lymph node metastasis (ALNM) in breast cancer. Patients & methods: A total of 134 eligible patients were used to build a predicting model, which was validated with an independent group of 57 patients and evaluated for accuracy and sensitivity. Results: A model based on breast MRI was developed and yielded total accuracy of 82.5% and sensitivities of 94.3, 64.3 and 62.5% to predict patients with no, low and heavy ALNM burden, respectively, in the validation group. Conclusion: A noninvasive model based on breast MRI was developed to preoperatively stratify ALNM in breast cancer; its performance needs to be validated and improved in future research.

Plain language summary Assessment of axillary lymph node metastasis burden before surgery in breast cancer patients is warranted for axillary management. This study tried to develop a simple model based on breast MRI to differentiate patients with no, low or heavy axillary metastasis burden. By providing the probability of different axillary metastasis burdens, this model would help patients and clinicians to make more rational decisions when choosing to omit intervention, undergo sentinel lymph node biopsy or axillary lymph node dissection for axilla management.

[Development and Application of Permanent Magnet Motor and Its Control in the Field of Artificial Blood Pump].

Permanent magnet motor has been widely used in the field of artificial heart pump due to its high power density, high stability and easy control. In this paper, the development history and research progress of permanent magnet motor for blood pump were described. Firstly, the motors were classified according to their structures and application scenarios. And then, the measures taken by different types of motors to meet the corresponding performance requirements were introduced, and the specific application cases were given. After that, commonly used control algorithms of these motors were enumerated. What's more, the advantages and disadvantages of the control algorithms and their application emphasis were carefully explained. Finally, the paper was summarized in short.

Myeloid-derived suppressor cells and myeloid regulatory cells in cancer and autoimmune disorders.

Myeloid-derived suppressor cells (MDSCs) were originally described as a heterogeneous population of immature cells derived from myeloid progenitors with immune-suppressive functions in tumor-bearing hosts. In recent years, increasing number of studies have described various populations of myeloid cells with MDSC-like properties in murine models of cancer and autoimmune diseases. These studies have observed that the populations of MDSCs are increased during inflammation and autoimmune conditions. In addition, MDSCs can effectively suppress T cell responses and modulate the activity of natural killer cells and other myeloid cells. MDSCs have also been implicated in the induction of regulatory T cell production. Furthermore, these cells have the potential to suppress the autoimmune response, thereby limiting tissue injury. Myeloid regulatory cells (Mregs) are recently attracting increasing attention, since they function in proinflammatory and immune suppression in autoimmune diseases, as well as in various types of cancer. Currently, research focus is directed from MDSCs to Mregs in cancer and autoimmune diseases. The present study reviewed the suppressive roles of MDSCs in various autoimmune murine models, the immune modulation of MDSCs to T helper 17 lymphocytes, as well as the proinflammatory and immunosuppressive roles of Mregs in various types of cancer and autoimmune diseases.

HMGB1 Facilitated Macrophage Reprogramming towards a Proinflammatory M1-like Phenotype in Experimental Autoimmune Myocarditis Development.

Macrophages can be reprogramming, such as the classical activated macrophage, M1 or alternative activated macrophages, M2 phenotype following the milieu danger signals, especially inflammatory factors. Macrophage reprogramming is now considered as a key determinant of disease development and/or regression. Experimental autoimmune myocarditis (EAM) is characterized by monocytes/macrophage infiltration, Th17 cells activation and inflammatory factors producing such as high mobility group box 1 (HMGB1). Whether infiltrated macrophages could be reprogramming in EAM? HMGB1 was associated with macrophage reprogramming? Our results clearly demonstrated that infiltrated macrophage was reprogrammed towards a proinflammatory M1-like phenotype and cardiac protection by monocytes/macrophages depletion or HMGB1 blockade in EAM; in vitro, HMGB1 facilitated macrophage reprogramming towards M1-like phenotype dependent on TLR4-PI3Kγ-Erk1/2 pathway; furthermore, the reprogramming M1-like macrophage promoted Th17 expansion. Therefore, we speculated that HMGB1 contributed EAM development via facilitating macrophage reprogramming towards M1-like phenotype except for directly modulating Th17 cells expansion.

Ultrastructural Changes and Corneal Wound Healing After SMILE and PRK Procedures.

PURPOSE: To compare keratocyte activation, cellular morphologic changes and wound healing after SMILE and PRK procedures using transmission electron microscope (TEM). METHODS: In this study, 22 New Zealand white rabbits (10- to 15-week old) were used. The right eyes of all animals underwent SMILE procedure and the left eyes underwent PRK procedure. Cornea samples taken 1 day and 1 week postoperatively were examined using TEM. RESULTS: Using TEM 1 day after SMILE procedure, the organization of collagen fibers seemed to have been preserved without thermal alterations. Keratocyte activation was observed in the anterior stroma. Disrupted collagen arrangement and debris of cells are visible in the area of damage, and some phagocytic cells and a large number of secondary lysosomes are visible in those cells. At the perimeter zone of the interface, many coenocytes and collagen fragments could be found within the phagocytic cell. One week after SMILE procedure, potential lacuna could be discerned. A large part of the interface of the lenticule extracted had an appearance of clearly being adhered to some mucus secretions. One day after PRK procedure, an irregular epithelial surface was visible using TEM. Keratocytes had been activated and the rough endoplasmic reticulum in those cells had expanded. One week after PRK procedure, the epithelial surface still was irregular and keratinization of the epithelium was still visible in some areas. Corneal endothelium cells were mildly damaged and some vacuoles within the cytoplasm could be discerned. In the anterior stroma, some unhealthy activated keratocytes could still be observed. New collagen fibrils were found present near the activated keratocytes. CONCLUSION: Using TEM, keratocyte activation could still be observed after SMILE compared to after PRK procedure. Fewer cellular ultrastructural changes were seen after SMILE procedure. Unlike in PRK procedure, no damaged epithelium and endothelium were found after SMILE.

HMGB1 silence could promote MCF-7 cell apoptosis and inhibit invasion and metastasis.

High mobility group box 1 (HMGB1), a non-histone nuclear protein, was associated with a variety of biological important processes, such as transcription, differentiation, extracellular signaling. As a cytokine or inflammatory mediator, more and more data showed that HMGB1 was involved in inflammatory diseases, cancers or autoimmune disease. However, few data focused on nucleic or cytoplasmic function of HMGB1. Therefore, the present study focused on cancer cells biological characteristics following HMGB1 silence. HMGB1 siRNAs were designed and chemically synthesized, and then transfected into the breast cancer cell line MCF-7 with lipofectamine 2000. The transcription and translation level of HMGB1 expression, proliferation, apoptosis, migration of MCF-7 were determined. The results demonstrated that HMGB1 silence inhibit invasion and migration and promote apoptosis of human breast cells; which indicated that HMGB1 silence might be a potential therapy targets.

[Distribution of corneal densitometry and its correlation with ocular stray light in healthy eyes].

OBJECTIVE: To evaluate and investigate the distribution of corneal density and its Correlation with stray-light value in adult and healthy eyes. METHODS: A prospective study. Human corneal specimens ranging in age between 20 and 49 years, 116 patients (232 eyes) in total, divided into three groups: 20-29, 30-39, 40-49. Pentacam was used to evaluate total corneal average density and corneal thickness at different diameter around the corneal apex, for corneal density were ≤ 2 mm, >2 mm and ≤ 6 mm, >6 mm and ≤ 10 mm, for corneal thickness were 2 mm, 6 mm and 10 mm, C-quant was used for the stray-light value. Software SPSS 17.0 was used for statistical analysis. Independent samples t testing method was applied to compare the corneal densitometry in different gender and between left eyes and right ones, One-way ANOVA was applied to analyze the differences of corneal density in different age groups and diameters. Pearson correlation analysis was applied to assess the correlation in corneal densitometry values of different diameters, between corneal density of different diameters and age, corneal density of different diameters and corneal thickness of different diameters, corneal density of different diameters and stray-light values. RESULTS: Corneal density for ≤ 2 mm, >2 mm and ≤ 6 mm, >6 mm and ≤ 10 mm diameter are 10.1 ± 1.5(8.2-16.7), 9.3 ± 1.3(7.9-14.2), 9.6 ± 1.7(7.3-16.2). Corneal density of >6 mm and ≤ 10 mm diameter in different age groups were 8.9 ± 1.1, 9.3 ± 1.2, 10.7 ± 2.1, there was a statistical difference in these values (F = 28.939, P = 0.000), and there was a positive correlation between corneal density of >6 mm and ≤ 10 mm diameter and age (r = 0.417, P = 0.000), There were no statistical differences in corneal density values of ≤ 2 mm and >2 mm and ≤ 6 mm in different age groups (F = 1.575, 1.436; P > 0.05), and they had no correlation with age (r = 0.002, 0.048; P > 0.05). There was no statistical difference in corneal density in different gender (t = 1.744, 1.647, -1.181; P > 0.05). Corneal density values of left eyes and right ones had positive relationships at the same diameter (r = 0.977, P = 0.000; r = 0.992, P = 0.000; r = 0.933, P = 0.000), and there were no statistical differences (t = 0.124, 0.199, -0.020;P > 0.05). Between corneal density values of different diameter, there are also some positive relationships, >6 mm and ≤ 10 mm and ≤ 2 mm (r = 0.710, P = 0.000), >6 mm and ≤ 10 mm and >2 mm and ≤ 6 mm (r = 0.748, P = 0.000), ≤ 2 mm and >2 mm and ≤ 6 mm (r = 0.973, P = 0.000), relationship between ≤ 2 mm and >2 mm and ≤ 6 mm, >2 mm and ≤ 6 mm and >6 mm and ≤ 10 mm was obvious, and there was statistical difference in them (F = 17.057, P = 0.000) . The ocular stray light value was 0.95 ± 0.19(0.48-1.38), Corneal density values of ≤ 2 mm, >2 mm and ≤ 6 mm and >6 mm and ≤ 10 mm diameter had positive relationships with the stray light value (r = 0.134,0.146,0.159, P = 0.042,0.026,0.016). CONCLUSIONS: Corneal density can be influenced by age, the influence from age infected the corneal density of peripheral more. There was no correlation between corneal density and corneal thickness. There were some influences of corneal density of healthy eyes to the ocular stray light.