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Chemotherapy plays an important role in treating cancers in clinic. Hypoxia-mediated chemoresistance remains a major hurdle for effective tumor chemotherapy. Herein, a new class of tLyP-1-modified dopamine (DOPA)-β-cyclodextrin (CD)-coated paclitaxel (PTX)- and manganese dioxide (MnO

This article presents a split time-interleaved (TI) successive-approximation register (SAR) analog-to-digital converter (ADC) with digital background timing-skew mismatch calibration. It divides a TI-SAR ADC into two split parts with the same overall sampling rate but different numbers of TI channels. Benefitting from the proposed split TI topology, the timing-skew calibration convergence speed is fast without any extra analog circuits. The input impedance of the overall TI-ADC remains unchanged, which is essential for the preceding driving stage in a high-speed application. We designed a prototype seven-/eight-way split TI-ADC implemented in 28-nm CMOS. After a digital background timing-skew calibration, it reaches a 54.2-dB signal-to-noise-and-distortion ratio (SNDR) and 67.1-dB spurious free dynamic range (SFDR) with a near Nyquist rate input signal and a 2.5-GHz effective resolution bandwidth (ERBW). Furthermore, the power consumption of ADC core (mismatch calibration off-chip) is 12.2-mW running at 1.6 GS/s, leading to a Walden figure-of-merit (FOM) of 18.2 fJ/conv.-step and a Schreier FOM of 162.4 dB, respectively.

This article presents a 16-channel 5 GS/s time-interleaved (TI) SAR ADC for a direct-sampling receiver that employs a digital-mixing background timing mismatch calibration to compensate for timing-skew errors. It uses a first-order approximation to obtain the derivative of the autocorrelation of the input signal, subsequently used to evaluate the explicit amount of the timing-skew. Therefore, this allows a digital background calibration of the timing-skew, avoiding extra analog circuits. The proposed 16-channel TI ADC uses a splitting-combined monotonic DAC switching method for the individual SAR channel to achieve a trade-off of simple switching and small common-mode voltage variation of the comparator. The prototype, implemented in 28 nm CMOS, reaches a 48.5/47.8 dB SNDR with an input signal of 2.38/4.0 GHz after the proposed background timing mismatch calibration, respectively. Furthermore, the ADC core's power consumption is 29 mW sampling at 5 GS/s, with a Walden FoM of 26.7 fJ/conv.-step and a Schreier FoM of 157.9 dB.

BackgroundOvertreatment of axillary lymph node dissection (ALND) may occur in patients with axillary positive sentinel lymph node (SLN) but negative non-SLN (NSLN). Developing a magnetic resonance imaging (MRI)-based radiomics nomogram to predict axillary NSLN metastasis in patients with SLN-positive breast cancer could effectively decrease the probability of overtreatment and optimize a personalized axillary surgical strategy.MethodsThis retrospective study included 285 patients with positive SLN breast cancer. Fifty five of them had metastatic NSLNs and 230 had non-metastatic NSLNs. MRI-based radiomic features of primary tumors were extracted and MRI morphologic findings of the primary tumor and axillary lymph nodes were assessed. Four models, namely, a radiomics signature, an MRI-clinical nomogram, and two MRI-clinical-radiomics nomograms were established based on MRI morphologic findings, clinicopathologic characteristics, and MRI-based radiomic features to predict the NSLN status. The optimal predictors in each model were selected using the 5-fold cross-validation (CV) method. Their predictive performances were determined by the receiver operating characteristic (ROC) curves analysis. The area under the curves (AUCs) of different models was compared by the Delong test. Their discrimination capability, calibration curve, and clinical usefulness were also assessed.ResultsThe 5-fold CV analysis showed that the AUCs ranged from 0.770 to 0.847 for the radiomics signature, from 0.720 to 0.824 for the MRI-clinical nomogram, from 0.843 to 0.932 for the MRI-clinical-radiomics nomogram. The optimal predictive factors in the radiomics signature, MRI-clinical nomogram, and MRI-clinical-radiomics nomogram were one texture feature of diffusion-weighted imaging (DWI), two clinicopathologic features together with one MRI morphologic finding, and the DWI-based texture feature together with the two clinicopathologic features plus the one MRI morphologic finding, respectively. The MRI-clinical-radiomics nomogram with CA 15-3 included achieved the highest AUC compared with the radiomics signature (0.868 vs. 0.806, P <0.001) and MRI-clinical nomogram (0.868 vs. 0.761; P <0.001). In addition, the MRI-clinical-radiomics nomogram without CA 15-3 showed a higher performance than that of the radiomics signature (AUC, 0.852 vs. 0.806, P = 0.016) and the MRI-clinical nomogram (AUC, 0.852 vs. 0.761, P = 0.007). The MRI-clinical-radiomics nomograms showed good discrimination and good calibration. Decision curve analysis demonstrated that the MRI-clinical-radiomics nomograms were clinically useful.ConclusionThe MRI-clinical-radiomics nomograms developed in our study showed high predictive performance, which can be used to predict the axillary NSLN status in SLN-positive breast cancer patients before surgery.

Duan X, Lu L, Wang Y, et al. Int J Nanomedicine. 2017;12:6705–6719. The authors have advised that Figures 6, 8 and 9 on pages 6713, 6715 and 6716, respectively, of the published paper are incorrect. The errors were introduced by the Editorial staff during the publication process. The correct figures are shown in Download Article. Read the original article

Objectives To determine the predictive value of pretreatment MRI texture analysis for progression-free survival (PFS) in patients with primary nasopharyngeal carcinoma (NPC). Methods Ethical approval by the institutional review board was obtained for this retrospective analysis. In 79 patients with primary NPC, texture analysis of the primary tumour was performed on pretreatment T2 and contrast-enhanced T1-weighted images (T2WIs and CE-T1WIs). The Cox proportional hazards model was used to determine the association of texture features, tumour volume and the tumour-node-metastasis (TNM) stage with PFS. Survival curves were plotted using the Kaplan-Meier method. The prognostic performance was evaluated with the receiver operating characteristic (ROC) analyses and C-index. Results Tumour volume (hazard ratio, 1.054; 95% confidence interval [CI], 1.016–1.093) and CE-T1WI-based uniformity (hazard ratio, 0; 95% CI, 0–0.001) were identified as independent predictors for PFS (p

Purpose To evaluate the diagnostic performance of quantitative parameters derived from dual-energy CT for the preoperative diagnosis of metastatic sentinel lymph nodes (SLNs) in participants with breast cancer. Materials and Methods For this prospective study, dual-phase contrast agent-enhanced CT was performed in female participants with breast cancer from June 2015 to December 2017. Quantitative dual-energy CT parameters and morphologic parameters were compared between metastatic and nonmetastatic SLNs. The quantitative parameters were fitted to univariable and multivariable logistic regression models. The diagnostic role of morphologic and quantitative parameters was analyzed by receiver operating characteristic curves and compared by using the McNemar test. Results This study included 193 female participants (mean age, 47.6 years ± 10.1; age range, 22-79 years). Quantitative dual-energy CT parameters including slope of the spectral Hounsfield unit curve (λHu) measured at both arterial and venous phases, normalized iodine concentration at both arterial and venous phase, and normalized effective atomic number at the venous phase were higher in metastatic than in nonmetastatic SLNs (P value range, ≤.001 to .031). Univariable and multivariable logistic regression analyses showed that venous phase λHu (in Hounsfield units per kiloelectron-volt) was the best single parameter for the detection of metastatic SLNs. The accuracy of the venous phase λHu for detecting metastatic SLNs was 90.5% on a per-lymph node basis and 87.0% on a per-patient basis. The accuracy and specificity at venous phase λHu was higher than their counterparts in the morphologic parameters (P < .001). Conclusion Dual-energy CT is a complementary means for the preoperative identification of sentinel lymph nodes metastases in participants with breast cancer. © RSNA, 2018 Online supplemental material is available for this article.

To develop and validate a multiparametric MRI-based radiomics nomogram for pretreatment predicting the axillary sentinel lymph node (SLN) burden in early-stage breast cancer. A total of 230 women with early-stage invasive breast cancer were retrospectively analyzed. A radiomics signature was constructed based on preoperative multiparametric MRI from the training dataset (n = 126) of center 1, then tested in the validation cohort (n = 42) from center 1 and an external test cohort (n = 62) from center 2. Multivariable logistic regression was applied to develop a radiomics nomogram incorporating radiomics signature and predictive clinical and radiological features. The radiomics nomogram’s performance was evaluated by its discrimination, calibration, and clinical use and was compared with MRI-based descriptors of primary breast tumor. The constructed radiomics nomogram incorporating radiomics signature and MRI-determined axillary lymph node (ALN) burden showed a good calibration and outperformed the MRI-determined ALN burden alone for predicting SLN burden (area under the curve [AUC]: 0.82 vs. 0.68 [p < 0.001] in training cohort; 0.81 vs. 0.68 in validation cohort [p = 0.04]; and 0.81 vs. 0.58 [p = 0.001] in test cohort). Compared with the MRI-based breast tumor combined descriptors, the radiomics nomogram achieved a higher AUC in test cohort (0.81 vs. 0.58, p = 0.005) and a comparable AUC in training (0.82 vs. 0.73, p = 0.15) and validation (0.81 vs. 0.65, p = 0.31) cohorts. A multiparametric MRI-based radiomics nomogram can be used for preoperative prediction of the SLN burden in early-stage breast cancer. • Radiomics nomogram incorporating radiomics signature and MRI-determined ALN burden outperforms the MRI-determined ALN burden alone for predicting SLN burden in early-stage breast cancer. • Radiomics nomogram might have a better predictive ability than the MRI-based breast tumor combined descriptors. • Multiparametric MRI-based radiomics nomogram can be used as a non-invasive tool for preoperative predicting of SLN burden in patients with early-stage breast cancer.

Background To compare the diagnostic performance of neurite orientation dispersion and density imaging (NODDI), mean apparent propagator magnetic resonance imaging (MAP-MRI), diffusion kurtosis imaging (DKI), diffusion tensor imaging (DTI) and diffusion-weighted imaging (DWI) in distinguishing high-grade gliomas (HGGs) from solitary brain metastases (SBMs). Methods Patients with previously untreated, histopathologically confirmed HGGs (n = 20) or SBMs (n = 21) appearing as a solitary and contrast-enhancing lesion on structural MRI were prospectively recruited to undergo diffusion-weighted MRI. DWI data were obtained using a q-space Cartesian grid sampling procedure and were processed to generate parametric maps by fitting the NODDI, MAP-MRI, DKI, DTI and DWI models. The diffusion metrics of the contrast-enhancing tumor and peritumoral edema were measured. Differences in the diffusion metrics were compared between HGGs and SBMs, followed by receiver operating characteristic (ROC) analysis and the Hanley and McNeill test to determine their diagnostic performances. Results NODDI-based isotropic volume fraction (Viso) and orientation dispersion index (ODI); MAP-MRI-based mean-squared displacement (MSD) and q-space inverse variance (QIV); DKI-generated radial, mean diffusivity and fractional anisotropy (RDk, MDk and FAk); and DTI-generated radial, mean diffusivity and fractional anisotropy (RD, MD and FA) of the contrast-enhancing tumor were significantly different between HGGs and SBMs (p iso, MSD, RDk and RD for NODDI, MAP-MRI, DKI and DTI, respectively. The AUC of Viso (0.871) was significantly higher than that of MSD (0.736), RDk (0.760) and RD (0.733) (p Conclusion NODDI outperforms MAP-MRI, DKI, DTI and DWI in differentiating between HGGs and SBMs. NODDI-based Viso has the highest performance.

Glioma is a common primary brain malignancy with a poor prognosis. Chemotherapy is the first‐line treatment for brain tumors but low efficiency of drugs in crossing the blood–brain barrier (BBB) and drug resistance related to tumor hypoxia thwart its efficacy. Herein, a theranostic nanodrug (iRPPA@TMZ/MnO) is developed by incorporating oleic acid‐modified manganese oxide (MnO) and temozolomide (TMZ) into a polyethylene glycol‐poly(2‐(diisopropylamino)ethyl methacrylate‐based polymeric micelle containing internalizing arginine‐glycine‐aspartic acid (iRGD). The presence of iRGD provides the nanodrug with a high capacity of crossing the BBB and penetrating the tumor tissue. After accumulation in glioma, the nanodrug responds to the tumor microenvironment to simultaneously release TMZ, Mn2+, and O2. The released TMZ induces tumor cell apoptosis and the released Mn2+ causes intracellular oxidative stress that kill tumor cells via a Fenton‐like reaction. The O2 produced in situ alleviates tumor hypoxia and enhances the chemotherapy/chemodynamic therapeutic effects against glioma. The Mn2+ can also serve as a magnetic resonance imaging (MRI) contrast agent for tumor imaging during therapy. The study demonstrates the great potential of this multifunctional nanodrug for MRI‐visible therapy of brain glioma., A theranostic nanodrug (iRPPA@TMZ/MnO) exhibiting a high capability of crossing the blood–brain barrier and accumulating in glioma is developed. This nanodrug can respond to the tumor microenvironment to alleviate tumor hypoxia, exert synergistic chemotherapy/chemodynamic therapy, and enable site‐specific magnetic resonance imaging for effective treatment of orthotopic brain glioma.

Objectives:To determine the performance of pretreatment structural and arterial spin labelling (ASL) MRI in predicting p53 mutation in patients with high-grade gliomas (HGGs).Methods:Pre-treatment structural and ASL MRI were performed in 57 patients with histologically confirmed HGGs and information of p53 status. Whole-lesion histogram analysis of cerebral blood flow (CBF) images of the enhancing tumour and the peritumoral oedema in the HGGs were performed. Visually AcceSAble Rembrandt Images features were used as qualitative analysis. The differences of ASL histogram parameters and Visually AcceSAble Rembrandt Images features between HGGs with or without p53 mutation were analyzed with post hoc correction for multiple comparisons. LASSO regression was performed to select the optimal features that could predict p53 mutation, followed by receiver operating characteristic analysis to determine the predictive efficacy.Results:A total of 33 HGGs with p53 mutation and 24 without p53 mutation were included. HGGs with mutant p53 showed lower CBFpercentile5and CBFuniformityof the enhancing tumour (p < 0.05) and higher prevalence of the qualitative MRI feature of enhancing tumour crossing midline (ETCM) (p < 0.05) as compared with HGGs with wild-type p53. LASSO regression showed that the CBFuniformityof the enhancing tumour and ETCM were predictive features for p53 mutation. CBFuniformityshowed an acceptable performance in predicting p53 mutation (area under the curve = 0.721), when combined with the feature of ETCM, its predictive efficacy was significantly improved (area under the curve = 0.814, p = 0.012).Conclusion:An integrated pre-treatment structural and ASL MRI can help to predict p53 mutation in HGGs.

BackgroundImmunotherapy with IFNβ is a promising strategy for treating malignant glioma. However, systemic administration of IFNβ is inadequate because of low intratumoral concentration and major adverse effects. This study aimed to determine whether mesenchymal stem cells (MSCs) can be used as cellular vehicles to locally deliver IFNβ for glioma therapy by using in vivo MRI tracking.MethodsA recombinant lentiviral vector encoding IFNβ and ferritin heavy chain (FTH) reporter genes was constructed to transduce MSCs. The effectiveness and safety of transduction were assessed. After the IFNβ and FTH overexpressed MSCs (IFNβ-FTH-MSCs) were transplanted into intracranial orthotopic rat F98 gliomas via peritumoral, intracerebral, intratumoral or intra-arterial injection, MRI was performed to track IFNβ-FTH-MSCs and to evaluate their therapeutic effect on glioma in vivo, as validated by histologic analysis, quantitative PCR and ELISA assays.ResultsMSCs were efficiently and safely transduced to upregulate their IFNβ secretion and FTH expression by the constructed lentivirus. After peritumoral injection, IFNβ-FTH-MSCs appeared as hypointense signals on MRI, which gradually diminished but remained visible until 11 days. Compared with other administration routes, only peritumoral injection of IFNβ-FTH-MSCs showed a remarkable inhibition on the glioma growth. Nearly 30% of IFNβ-FTH-MSCs survived up to 11 days after peritumoral injection, while most of IFNβ-FTH-MSCs injected via other routes died within 11 days. IFNβ-FTH-MSCs grafted peritumorally secreted IFNβ persistently, leading to pronounced Batf3+dendritic cells and CD8+T lymphocyte infiltration within the glioma.ConclusionsMSCs can be used as cellular vehicles of IFNβ to treat malignant glioma effectively via peritumoral injection.

Aseptic loosening (AL) caused by wear particles released from implant surfaces is one of the main causes for the failure of artificial joints, which is initiated by macrophage inflammatory responses. Emerging evidence suggests that the member of a broad-complex, tramtrack, bric-a-brac/poxvirus and zinc finger (BTB/POZ) family as well as zinc finger and BTB domain-containing protein 20 (ZBTB20) can inhibit IκBα gene transcription, promote NF-κB activation, and initiate innate immune responses. The molecular mechanism(s) by which ZBTB20 contributes to titanium particle (TiP)-induced macrophage inflammatory responses and osteolysis has not been fully elucidated. Here, we showed that ZBTB20 increased either in the AL group's synovial membranes or in TiP-stimulated bone-marrow-derived macrophages (BMDMs) as compared to that in the control groups. Moreover, the knockdown of ZBTB20 led to the inhibition of proinflammatory factors induced by TiPs in BMDMs, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-β (IFN-β). Here, we also reported that the knockdown of ZBTB20 suppressed TiP-induced NF-κB activation and M1 polarization as well as stabilized the trans Golgi network (TGN) in BMDMs. The dual-luciferase reporter assay identified the binding between the IκBα promoter and ZBTB20, and IκBα knockdown could rescue the antiinflammatory effects induced by the ZBTB20 knockdown in BMDMs. Finally, we found that sh-ZBTB20 lentivirus injection could reduce TiP-induced osteolysis in mouse calvaria, inhibiting TiP-induced proinflammatory factors and loss of bone volume/total volume (BV/TV) as well as bone mineral density (BMD). These results suggest that ZBTB20 positively regulated NF-κB activation and M1 polarization as well as the production of TGN-derived tubular carriers in BMDMs, playing a positive role in macrophage activation and mouse cranial osteolysis induced by TiPs. It may be a potential therapeutic target for the prevention of aseptic loosening of prostheses.

Triple-negative breast cancer shows resistance to conventional radiotherapies and chemotherapies, and few molecular targeted therapies are currently available for this malignancy in clinical settings. In this work, a theranostic nanosystem with a core–shell structure was synthesized through self-assembly of amphiphilic macromolecules, which can be used in effective catalysis therapy and phototherapy. Herein, we report that superparamagnetic iron oxide nanocrystals and IR780 dye were effectively loaded into the hydrophobic core of the nanosystem, which enabled dual-modality magnetic resonance imaging and near-infrared fluorescence imaging. Furthermore, on the hydrophilic crown, the neighboring carboxylic acid-based amide linkage showed charge conversion properties in the tumor acidic microenvironment and endowed the system with targeted diagnosis and delivery. Upon light excitation, this theranostic system exerted synergistic anti-cancer activity through the nano-enzyme catalysis effect enhanced phototherapy in a triple-negative 4T1 breast cancer model. Furthermore, there were no obvious side-effects. The results of our study demonstrate the great potential of this theranostic nanosystem in cancer diagnosis and therapy.

Transplantation of neural stem cells (NSCs) is emerging as a new therapeutic approach for stroke. Real-time imaging of transplanted NSCs is essential for successful cell delivery, safety monitoring, tracking cell fate and function, and understanding the interactions of transplanted cells with the host environment. Magnetic resonance imaging (MRI) of magnetic nanoparticle-labeled cells has been the most widely used means to track stem cells in vivo. Nevertheless, it does not allow for the reliable discrimination between live and dead cells. Reporter gene-based MRI was considered as an alternative strategy to overcome this shortcoming. In this work, a class of lentiviral vector-encoding ferritin heavy chain (FTH) and enhanced green fluorescent protein (EGFP) was constructed to deliver reporter genes into NSCs. After these transgenic NSCs were transplanted into the contralateral hemisphere of rats with acute ischemic stroke, MRI and fluorescence imaging (FLI) were performed in vivo for tracking the fate of transplanted cells over a long period of 6 wk. The results demonstrated that the FTH and EGFP can be effectively and safely delivered to NSCs via the designed lentiviral vector. The distribution and migration of grafted stem cells could be monitored by bimodal MRI and FLI. FTH can be used as a robust MRI reporter for reliable reporting of the short-term viability of cell grafts, whereas its capacity for tracking the long-term viability of stem cells remains dependent on several confounding factors such as cell death and the concomitant reactive inflammation.

Xiaohui Duan,1,* Liejing Lu,1,* Yong Wang,2 Fang Zhang,1 Jiaji Mao,1 Minghui Cao,1 Bingling Lin,1 Xiang Zhang,1 Xintao Shuai,2,3 Jun Shen1 1Department of Radiology, Sun Yat-Sen Memorial Hospital, 2PCFM Lab of Ministry of Education, School of Materials Science and Engineering, 3BME Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Understanding the long-term fate and potential mechanisms of mesenchymal stem cells (MSCs) after transplantation is essential for improving functional benefits of stem cell-based stroke treatment. Magnetic resonance imaging (MRI) is considered an attractive and clinically translatable tool for longitudinal tracking of stem cells, but certain controversies have arisen in this regard. In this study, we used SPION-loaded cationic polymersomes to label green fluorescent protein (GFP)-expressing MSCs to determine whether MRI can accurately reflect survival, long-term fate, and potential mechanisms of MSCs in ischemic stroke therapy. Our results showed that MSCs could improve the functional outcome and reduce the infarct volume of stroke in the brain. In vivo MRI can verify the biodistribution and migration of grafted cells when pre-labeled with SPION-loaded polymersome. The dynamic change of low signal volume on MRI can reflect the tendency of cell survival and apoptosis, but may overestimate long-term survival owing to the presence of iron-laden macrophages around cell graft. Only a small fraction of grafted cells survived up to 8 weeks after transplantation. A minority of these surviving cells were differentiated into astrocytes, but not into neurons. MSCs might exert their therapeutic effect via secreting paracrine factors rather than directing cell replacement through differentiation into neuronal and/or glial phenotypes. Keywords: mesenchymal stem cells, magnetic resonance imaging, superparamagnetic iron oxide nanoparticles, polymersome, ischemic stroke, green fluorescence protein

Transplantation of neural stem cells (NSCs) is a promising treatment strategy for acute ischemic stroke. In vivo tracking of the therapeutic stem cells in the host brain after transplantation is essential not only to ensure the safety and efficacy of the treatment, but also to better understand their migrational dynamics and regeneration potential. Many polymeric nanoparticles have been developed to label stem cells for in vivo tracking by magnetic resonance imaging (MRI), optical imaging (OI) or other imaging modalities. However, the non-degradability and presence of cellular toxicity of the nanoparticles restrict their clinical applications. In this study, we developed a novel cationic polymeric micelles based on amphipathic polymer of biodegradable hydrophilic poly(aspartic acid-dimethylethanediamine) (PAsp(DMA)) that were conjugated with two molecules of hydrophobic cholic acid (CA) by lysine. Image labels, superparamagnetic iron oxide nanoparticles (SPIONs) and fluorescent nile red were simultaneously loaded into the micelles to label NSCs. The labeling capacity, efficiency and cytotoxicity of the cationic micelles were determined. The in vivo MRI tracking of the therapeutic NSCs in acute ischemic stroke was also explored. Our results showed that this type of cationic polymeric micelles achieved a high efficient and safe labeling of NSCs and resulted in reliable in vivo MRI tracking of therapeutic stem cells in acute ischemic stroke, but without detrimental effect. The cationic, biodegradable polymeric micelles are highly translatable for clinical application and can be used as a versatile nanoplatform for stem cell labeling and subsequently in vivo tracking in regenerative medicine.

This paper presents a 5GS/s 16-way Time-Interleaved SAR ADC in 28nm CMOS, proposing a fully-digital background timing-skew calibration based on digital mixing, without adding any extra analog circuits. We implement the sub-channel SAR with a splitting-combined monotonic switching procedure. The prototype ADC achieves 48.5dB SNDR at Nyquist rate, while the power consumption is 29mW leading to a Walden FOM of 26.7fJ/conv-step.

For patients undergoing total joint replacement (TJR), one of the complications, aseptic loosening, could cause serious consequences, such as revision surgery. In early research, pattern recognition receptors (PRRs) were reported to play vital roles in recognizing wear particles from the prosthesis and initiating an inflammation response. In this research, we aimed to clarify the role of nucleotide-binding and oligomerization domain containing protein 2 (NOD2), one of the PRRs, in macrophage-induced aseptic loosening in vivo and in vitro. High expressions of NOD2 and TNFα were observed from twenty patients who underwent primary or revision total hip replacements (THR). The effect of NOD2 on the activation of inflammation pathways was observed in RAW264.7 cells and CRISPR-Cas9 NOD2-knockout mice. The expressions of NOD2, the NF-κB pathway, the MAPK pathway and proinflammatory cytokine TNF-α in macrophages stimulated by wear particles were up-regulated. Otherwise, inhibition of NOD2 further up-regulated the expressions of NOD2, the NF-κB pathway, the MAPK pathway and TNF-α. Knockdown of the NOD2 gene enhanced the cranial osteolysis induced by titanium particles in a mouse model. In conclusion, our study demonstrated that NOD2 plays a negative role in osteolysis induced by titanium particles in vitro and in vivo.

OBJECTIVE. The purpose of this study was to investigate the performance of quantitative parameters derived from dual-energy CT (DECT) in the preoperative diagnosis of regional metastatic lymph nodes (LNs) in patients with colorectal cancer. SUBJECTS AND METHODS. Triphasic contrast-enhanced DECT was performed for 178 patients with colon or high rectal cancer. The morphologic criteria, short-axis diameter, and quantitative DECT parameters of the largest regional LN were measured and compared between pathologically metastatic and nonmetastatic LNs. Univariate and multivariable logistic regression analyses were used to determine the independent DECT parameters for predicting LN metastasis. Diagnostic performance measures were assessed by ROC curve analysis and compared by McNemar test. RESULTS. A total of 178 largest LNs (72 metastatic, 106 nonmetastatic) were identified in 178 patients. The best single DECT parameter for differentiation between metastatic and nonmetastatic LNs was normalized effective atomic number (Zeff) in the portal venous phase (AUC, 0.871; accuracy, 84.8%). These values were higher than those of morphologic criteria (AUC, 0.505-0.624; accuracy, 47.8-62.4%) and short-axis diameter (AUC, 0.647; accuracy, 66.3%) (p < 0.05). The diagnostic accuracy of combined normalized iodine concentration in the arterial phase and normalized effective atomic number in the portal venous phase was further improved to 87.1% (AUC, 0.916). CONCLUSION. Quantitative parameters derived from DECT can be used to improve preoperative diagnostic accuracy in evaluation for regional metastatic LNs in patients with colorectal cancer.

This paper presents a split time-interleaved (TI) successive-approximation register (SAR) analog-to-digital converter (ADC) with digital background mismatch calibration. Benefitting from the proposed split TI topology, the mismatch calibration convergence speed is fast without any extra analog circuits. A prototype 10-b 1.6-GS/s 7/8-way split TI-SAR ADC in 28-nm CMOS achieves 54.2dB SNDR at Nyquist rate with a 2.5GHz 3-dB bandwidth, while the power consumption is 12.2mW leading to a Walden FOM of 18.2 fJ per conversion step.

Manganese dioxide (MnO

PURPOSE To determine the capacity of intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) in differential diagnosis between recurrent carcinoma and postchemoradiation fibrosis of skull base in patients with nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS Eleven patients with recurrent NPC and 21 patients with postchemoradiation fibrosis in the skull base were enrolled. All the diagnoses were proved by endoscopic biopsy or imaging follow-up. IVIM MRI was performed to obtain quantitative parameters including D (pure diffusion), f (perfusion fraction), and D* (pseudodiffusion). D, f, and D* were compared between two groups; the diagnostic performances of D and f were evaluated using the receiver operating characteristic (ROC) analysis. RESULTS D and f values were significantly lower in recurrent carcinoma than that in fibrosis (P < 0.001; P = 0.001). No significant difference was found in D* values between recurrent carcinoma and fibrosis (P = 0.229). ROC curve analysis showed that the area under the curve of D and f values were 0.996 and 0.838, respectively. Respective cutoff values with sensitivity, specificity, and accuracy were: D = 1.161 × 10-3 mm2 /s (sensitivity 100.0%, specificity 95.2%, accuracy 96.9%), f = 0.109 (sensitivity 81.8%, specificity 71.4%, accuracy 75.0%). CONCLUSION Recurrent NPC and postchemoradiation fibrosis in the skull base have distinctive D and f values. IVIM MRI could be used to differentiate between recurrent carcinoma and postchemoradiation fibrosis in patients with NPC. J. Magn. Reson. Imaging 2016;44:1556-1564.

PURPOSE The relationship between severe liver iron overload (LIO) and heart iron overload (HIO) in transfusion-dependent patients with thalassemia major (TM) is uncertain. Whether severe LIO can serve as an index for assessing heart iron deposition has vital clinical significance. Therefore, our aim is to determine if a close relationship exists between severe LIO and HIO. MATERIALS AND METHODS We examined 110 TM patients who underwent T2* measurement in the liver and heart on a 1.5 Tesla MRI scanner. Various statistical analysis methods were used to assess the relationship. RESULTS Most of these patients suffered from severe LIO (58.18%, liver T2* < 1.4 ms). Both Pearson's and Spearman's tests showed a significant correlation between liver T2* and heart T2* values (with a correlation coefficient of 0.408 and 0.550, respectively, both P < 0.0001). A nonlinear model, with the equation of Heart T2* = 37.974-17.684 / Liver T2*, was found to be the best model to indicate the relationship between liver T2* and heart T2*. Receiver operating characteristic (ROC) analysis showed the area under the ROC curve of liver T2* and serum ferritin for predicting HIO was 0.812 (95% confidence interval [CI]: 0.731-0.892; P < 0.0001) and 0.69 (95% CI: 0.585-0.795; P = 0.001), respectively. CONCLUSION Our preliminary data suggest the existence of a close relationship between severe LIO and HIO. High liver iron levels appear to increase the risk of heart iron deposition. This further supports the concept of critical liver iron concentration, above which elevated heart iron is present. J. MAGN. RESON. IMAGING 2016;44:880-889.

Cell-free DNA (cfDNA) released from damaged or dead cells can activate DNA sensors that exacerbate the pathogenesis of rheumatoid arthritis (RA). Here we show that ~40 nm cationic nanoparticles (cNP) can scavenge cfDNA derived from RA patients and inhibit the activation of primary synovial fluid monocytes and fibroblast-like synoviocytes. Using clinical scoring, micro-CT images, MRI, and histology, we show that intravenous injection of cNP into a CpG-induced mouse model or collagen-induced arthritis rat model can relieve RA symptoms including ankle and tissue swelling, and bone and cartilage damage. This culminates in the manifestation of partial mobility recovery of the treated rats in a rotational cage test. Mechanistic studies on intracellular trafficking and biodistribution of cNP, as well as measurement of cytokine expression in the joints and cfDNA levels in systemic circulation and inflamed joints also correlate with therapeutic outcomes. This work suggests a new direction of nanomedicine in treating inflammatory diseases., Cell-free DNA (cfDNA) released from damaged or dead cells can activate DNA sensors that exacerbate the pathogenesis of rheumatoid arthritis (RA). Here the authors use ~40 nm cationic nanoparticles to scavenge cfDNA, and demonstrate the potential for nanomedicine to relieve debilitating RA symptoms.

Cell-based therapy with mesenchymal stem cells (MSCs) is a promising strategy for acute ischemic stroke. In vivo tracking of therapeutic stem cells with magnetic resonance imaging (MRI) is imperative for better understanding cellular survival and migrational dynamics over time. In this study, we develop a novel biocompatible nanocomplex (ASP-SPIONs) based on cationic amylose, by introducing spermine and the image label, ultrasmall superparamagnetic iron oxide nanoparticles (SPIONs), to label MSCs. The capacity, efficiency, and cytotoxicity of the nanocomplex in transferring SPIONs into green fluorescence protein-modified MSCs were tested; and the performance of in vivo MRI tracking of the transplanted cells in acute ischemic stroke was determined. The results demonstrated that the new class of SPIONs-complexed nanoparticles based on biodegradable amylose can serve as a highly effective and safe carrier to transfer magnetic label into stem cells. A reliable tracking of transplanted stem cells in stroke was achieved by MRI up to 6 weeks, with the desirable therapeutic benefit of stem cells on stroke retained. With the advantages of a relatively low SPIONs concentration and a short labeling period, the biocompatible complex of cationic amylose with SPIONs is highly translatable for clinical application. It holds great promise in efficient, rapid, and safe labeling of stem cells for subsequent cellular MRI tracking in regenerative medicine.

Mesenchymal stem cells (MSCs) have emerged as a promising cellular vehicle for gene therapy of malignant gliomas due to their property of tumor tropism. However, MSCs may show bidirectional and divergent effects on tumor growth. Therefore, a robust surveillance system with a capacity for noninvasive monitoring of the homing, distribution and fate of stem cells in vivo is highly desired for developing stem cell-based gene therapies for tumors. In this study, we used ferritin gene-based magnetic resonance imaging (MRI) to track the tumor tropism of MSCs in a rat orthotopic xenograft model of malignant glioma. MSCs were transduced with lentiviral vectors expressing ferritin heavy chain (FTH) and enhanced green fluorescent protein (eGFP). Intra-arterial, intravenous and intertumoral injections of these FTH transgenic MSCs (FTH-MSCs) were performed in rats bearing intracranial orthotopic C6 gliomas. The FTH-MSCs were detected as hypointense signals on T2- and T2*-weighted images on a 3.0 T clinical MRI. After intra-arterial injection, 17% of FTH-MSCs migrated toward the tumor and gradually diffused throughout the orthotopic glioma. This dynamic process could be tracked in vivo by MRI up to 10 days of follow-up, as confirmed by histology. Moreover, the tumor tropism of MSCs showed no appreciable impact on the progression of the tumor. These results suggest that FTH reporter gene-based MRI can be used to reliably track the tropism and fate of MSCs after their systemic transplantation in orthotopic gliomas. This real-time in vivo tracking system will facilitate the future development of stem cell-based therapies for malignant gliomas.

Manganese dioxide (MnO2 )-based nanoparticles are a promising tumor microenvironment-responsive nanotheranostic carrier for targeted magnetic resonance imaging (MRI) and for alleviating tumor hypoxia. However, the complexity and potential toxicity of the present common synthesis methods limit their clinical application. Herein, multifunctional hyaluronic acid-MnO2 nanoparticles (HA-MnO2 NPs) are synthesized in a simple way by directly mixing sodium permanganate with HA aqueous solutions, which serve as both a reducing agent and a surface-coating material. The obtained HA-MnO2 NPs show an improved water-dispersibility, fine colloidal stability, low toxicity, and responsiveness to the tumor microenvironment (high H2 O2 and high glutathione, low pH). After intravenous injection, HA-MnO2 NPs exhibit a high imaging sensitivity for detecting rat intracranial glioma with MRI for a prolonged period of up to 3 d. These nanoparticles also effectively alleviate the tumor hypoxia in a rat model of intracranial glioma. The downregulation of VEGF and HIF-1α expression in intracranial glioma validates the sustained attenuation effect of HA-MnO2 NPs on tumor hypoxia. These results show that HA-MnO2 NPs can be used for sensitive, targeted MRI detection of gliomas and simultaneous attenuation of tumor hypoxia.

Acute ischemic stroke remains a leading cause of death and disability. Endogenous neurogenesis enhanced via activation of neural stem cells (NSCs) could be a promising method for stroke treatment. In vivo targeted tracking is highly desirable for monitoring the dynamics of endogenous NSCs in stroke. Previously, we have successfully realized in vivo targeted MR imaging of endogenous NSCs in normal adult mice brains by using anti-CD15 antibody-conjugated superparamagnetic iron oxide nanoparticles (anti-CD15-SPIONs) as the molecular probe. Herein, we explore the performance of this molecular probe in targeted in vivo tracking of activated endogenous NSCs in ischemic stroke. Our study showed that intraventricular injection of anti-CD15-SPIONs could label activated endogenous NSCs in situ seven days after ischemic stroke, which were detected as enlarged areas of hypo-intense signals on MR imaging at 7.0 T. The treatment of cytosine arabinosine could inhibit the activation of endogenous NSCs, which was featured by the disappearance of areas of hypo-intense signals on MR imaging. Using anti-CD15-SPIONs as imaging probes, the dynamic process of activation of endogenous NSCs could be readily monitored by in vivo MR imaging. This targeted imaging strategy would be of great benefit to develop a new therapeutic strategy utilizing endogenous NSCs for ischemic stroke.

The relationship between severe liver iron overload (LIO) and heart iron overload (HIO) in transfusion-dependent patients with thalassemia major (TM) is uncertain. Whether severe LIO can serve as an index for assessing heart iron deposition has vital clinical significance. Therefore, our aim is to determine if a close relationship exists between severe LIO and HIO.We examined 110 TM patients who underwent T2* measurement in the liver and heart on a 1.5 Tesla MRI scanner. Various statistical analysis methods were used to assess the relationship.Most of these patients suffered from severe LIO (58.18%, liver T2*1.4 ms). Both Pearson's and Spearman's tests showed a significant correlation between liver T2* and heart T2* values (with a correlation coefficient of 0.408 and 0.550, respectively, both P0.0001). A nonlinear model, with the equation of Heart T2* = 37.974-17.684 / Liver T2*, was found to be the best model to indicate the relationship between liver T2* and heart T2*. Receiver operating characteristic (ROC) analysis showed the area under the ROC curve of liver T2* and serum ferritin for predicting HIO was 0.812 (95% confidence interval [CI]: 0.731-0.892; P0.0001) and 0.69 (95% CI: 0.585-0.795; P = 0.001), respectively.Our preliminary data suggest the existence of a close relationship between severe LIO and HIO. High liver iron levels appear to increase the risk of heart iron deposition. This further supports the concept of critical liver iron concentration, above which elevated heart iron is present. J. MAGN. RESON. IMAGING 2016;44:880-889.