Structural Basis of Transcription Inhibition by Fidaxomicin (Lipiarmycin A3).

Fidaxomicin is an antibacterial drug in clinical use for treatment of Clostridium difficile diarrhea. The active ingredient of fidaxomicin, lipiarmycin A3 (Lpm), functions by inhibiting bacterial RNA polymerase (RNAP). Here we report a cryo-EM structure of Mycobacterium tuberculosis RNAP holoenzyme in complex with Lpm at 3.5-Å resolution. The structure shows that Lpm binds at the base of the RNAP "clamp." The structure exhibits an open conformation of the RNAP clamp, suggesting that Lpm traps an open-clamp state. Single-molecule fluorescence resonance energy transfer experiments confirm that Lpm traps an open-clamp state and define effects of Lpm on clamp dynamics. We suggest that Lpm inhibits transcription by trapping an open-clamp state, preventing simultaneous interaction with promoter -10 and -35 elements. The results account for the absence of cross-resistance between Lpm and other RNAP inhibitors, account for structure-activity relationships of Lpm derivatives, and enable structure-based design of improved Lpm derivatives.

Discrimination between human epidermal growth factor receptor 2 (HER2)-low-expressing and HER2-overexpressing breast cancers: a comparative study of four MRI diffusion models.

OBJECTIVES: To determine the value of conventional DWI, continuous-time random walk (CTRW), fractional order calculus (FROC), and stretched exponential model (SEM) in discriminating human epidermal growth factor receptor 2 (HER2) status of breast cancer (BC). METHODS: This prospective study included 158 women who underwent DWI, CTRW, FROC, and SEM and were pathologically categorized into the HER2-zero-expressing group (n = 10), HER2-low-expressing group (n = 86), and HER2-overexpressing group (n = 62). Nine diffusion parameters, namely ADC, αCTRW, ßCTRW, DCTRW, ßFROC, DFROC, µFROC, αSEM, and DDCSEM of the primary tumor, were derived from four diffusion models. These diffusion metrics and clinicopathologic features were compared between groups. Logistic regression was used to determine the optimal diffusion metrics and clinicopathologic variables for classifying the HER2-expressing statuses. Receiver operating characteristic (ROC) curves were used to evaluate their discriminative ability. RESULTS: The estrogen receptor (ER) status, progesterone receptor (PR) status, and tumor size differed between HER2-low-expressing and HER2-overexpressing groups (p < 0.001 to p = 0.009). The αCTRW, DCTRW, ßFROC, DFROC, µFROC, αSEM, and DDCSEM were significantly lower in HER2-low-expressing BCs than those in HER2-overexpressing BCs (p < 0.001 to p = 0.01). Further multivariable logistic regression analysis showed that the αCTRW was the single best discriminative metric, with an area under the curve (AUC) being higher than that of ADC (0.802 vs. 0.610, p < 0.05); the addition of ER status, PR status, and tumor size to the αCTRW improved the AUC to 0.877. CONCLUSIONS: The αCTRW could help discriminate the HER2-low-expressing and HER2-overexpressing BCs. CLINICAL RELEVANCE STATEMENT: Human epidermal growth factor receptor 2 (HER2)-low-expressing breast cancer (BC) might also benefit from the HER2-targeted therapy. Prediction of HER2-low-expressing BC or HER2-overexpressing BC is crucial for appropriate management. Advanced continuous-time random walk diffusion MRI offers a solution to this clinical issue. KEY POINTS: • Human epidermal receptor 2 (HER2)-low-expressing BC had lower αCTRW, DCTRW, ßFROC, DFROC, µFROC, αSEM, and DDCSEM values compared with HER2-overexpressing breast cancer. • The αCTRW was the single best diffusion metric (AUC = 0.802) for discrimination between the HER2-low-expressing and HER2-overexpressing breast cancers. • The addition of αCTRW to the clinicopathologic features (estrogen receptor status, progesterone receptor status, and tumor size) further improved the discriminative ability.

Diagnostic value of an enhanced MRI combined with serum CEA, CA19-9, CA125 and CA72-4 in the liver metastasis of colorectal cancer.

OBJECTIVE: This paper aims to explore the diagnostic value of enhanced magnetic resonance imaging (MRI) combined with a carcinoembryonic antigen (CEA) and carbohydrate antigen in terms of the liver metastasis of colorectal cancer. METHODS: A total of 167 colorectal cancer patients with liver metastasis and 167 colorectal cancer patients without liver metastasis were selected as the subjects. An automatic electrochemiluminescence analyser was then used to detect the tumour markers CEA, CA19-9, CA125 and CA72-4. The consistency between the MRI examination and clinical pathological examination was also analysed, and the sensitivity, specificity and positive and negative predictive values of various combined detection methods were compared. RESULTS: The abnormal rates of CEA, CA19-9, CA125 and CA72-4 in the two groups were statistically significant (P < 0.05), while the results of the enhanced MRI and clinicopathological examination for liver metastasis in patients with colon cancer were largely consistent (Kappa coefficient = 0.788, P < 0.000). However, the two methods were inconsistent. The false positive rate of the enhanced MRI examination was 15.3%, while the false negative rate was 6.0%. The specificity (94.61%), positive predictive value (92.68%) and positive likelihood ratio (12.67%) were the highest for the MRI combined with serial CEA, while the sensitivity (98.80%) and negative predictive value (97.22%) were the highest with the MRI combined with parallel CEA, and this combination returned the lowest negative likelihood ratio (0.03). CONCLUSION: The combination of MRI and CEA excludes non-metastatic patients and identifies colorectal liver metastasis cancer patients. Overall, it has a higher diagnostic value.

Capturing the interactome of newly transcribed RNA.

We combine the labeling of newly transcribed RNAs with 5-ethynyluridine with the characterization of bound proteins. This approach, named capture of the newly transcribed RNA interactome using click chemistry (RICK), systematically captures proteins bound to a wide range of RNAs, including nascent RNAs and traditionally neglected nonpolyadenylated RNAs. RICK has identified mitotic regulators amongst other novel RNA-binding proteins with preferential affinity for nonpolyadenylated RNAs, revealed a link between metabolic enzymes/factors and nascent RNAs, and expanded the known RNA-bound proteome of mouse embryonic stem cells. RICK will facilitate an in-depth interrogation of the total RNA-bound proteome in different cells and systems.

Assessment of Cardiac Lead Perforation: Comparison Among Chest Radiography, Transthoracic Echocardiography and Electrocardiography-gated Contrast-enhanced Cardiac CT.

OBJECTIVES: Cardiac lead perforation is a rare but potentially life-threatening event. The purpose of this study was to investigate the diagnostic performances of chest radiography, transthoracic echocardiography (TTE) and electrocardiography (ECG)-gated contrast-enhanced cardiac CT in the assessment of cardiac lead perforation. METHODS: This retrospective study was approved by the ethics review board of Sun Yat-Sen Memorial Hospital at Sun Yat-Sen University (Guangzhou, China), and the need to obtain informed consent was waived. Between May 2010 and Oct 2017, 52 patients were clinically suspected to have a cardiac lead perforation and received chest radiography, TTE and ECG-gated contrast-enhanced cardiac CT. Among them, 13 patients were identified as having cardiac lead perforation. The diagnostic performances of these three modalities were evaluated by receiver-operating characteristic (ROC) curves using a composite reference standard of surgical and electrophysiological results and clinical follow-up. The areas under ROCs (AUROCs) were compared with the McNemar test. RESULTS: The accuracies of chest radiography, TTE and ECG-gated contrast-enhanced cardiac CT imaging for the diagnosis of cardiac lead perforation were 73.1%, 82.7% and 98.1%, respectively. ECG-gated contrast-enhanced cardiac CT had a higher AUROC than chest radiography (p < 0.001) and TTE (p < 0.001). CONCLUSIONS: ECG-gated contrast-enhanced cardiac CT is superior to both chest radiography and TTE imaging for the assessment of cardiac lead perforation. KEY POINTS: • ECG-gated contrast-enhanced cardiac CT has an accuracy of 98.1% in the diagnosis of cardiac lead perforation. • The AUROC of ECG-gated contrast-enhanced cardiac CT is higher than those of chest radiography and TTE imaging. • ECG-gated contrast-enhanced cardiac CT imaging has better diagnostic performance than both chest radiography and TTE imaging for the assessment of cardiac lead perforation.

Fumarylacetoacetate Hydrolase Knock-out Rabbit Model for Hereditary Tyrosinemia Type 1.

Hereditary tyrosinemia type 1 (HT1) is a severe human autosomal recessive disorder caused by the deficiency of fumarylacetoacetate hydroxylase (FAH), an enzyme catalyzing the last step in the tyrosine degradation pathway. Lack of FAH causes accumulation of toxic metabolites (fumarylacetoacetate and succinylacetone) in blood and tissues, ultimately resulting in severe liver and kidney damage with onset that ranges from infancy to adolescence. This tissue damage is lethal but can be controlled by administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), which inhibits tyrosine catabolism upstream of the generation of fumarylacetoacetate and succinylacetone. Notably, in animals lacking FAH, transient withdrawal of NTBC can be used to induce liver damage and a concomitant regenerative response that stimulates the growth of healthy hepatocytes. Among other things, this model has raised tremendous interest for the in vivo expansion of human primary hepatocytes inside these animals and for exploring experimental gene therapy and cell-based therapies. Here, we report the generation of FAH knock-out rabbits via pronuclear stage embryo microinjection of transcription activator-like effector nucleases. FAH-/- rabbits exhibit phenotypic features of HT1 including liver and kidney abnormalities but additionally develop frequent ocular manifestations likely caused by local accumulation of tyrosine upon NTBC administration. We also show that allogeneic transplantation of wild-type rabbit primary hepatocytes into FAH-/- rabbits enables highly efficient liver repopulation and prevents liver insufficiency and death. Because of significant advantages over rodents and their ease of breeding, maintenance, and manipulation compared with larger animals including pigs, FAH-/- rabbits are an attractive alternative for modeling the consequences of HT1.

MR T2 value of the tibial nerve can be used as a potential non-invasive and quantitative biomarker for the diagnosis of diabetic peripheral neuropathy.

OBJECTIVE: To determine the role of quantitative tibial nerve T2 value in the diagnosis of diabetic peripheral neuropathy (DPN). METHODS: MR imaging and T2 mapping of the tibial nerve were performed in 22 diabetic patients with DPN, 20 diabetic patients without DPN and 20 healthy controls. Nerve T2 values were measured, and compared using the Mann-Whitney U test. Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic ability of T2 value to identify DPN. RESULTS: Nerve T2 value was 55.06 ± 4.05 ms, 48.91 ± 3.06 ms and 45.61 ± 1.86 ms in patients with DPN, patients without DPN and controls, respectively. Patients with DPN had significantly higher nerve T2 values than patients without DPN (P < 0.001). Nerve T2 values in patients without DPN were higher than in controls (P < 0.001). ROC analysis showed that T2 values had a diagnostic sensitivity of 81.8 %, specificity of 89.2 % and area under the curve of 0.922 for identifying patients with DPN from patients without DPN plus controls when the cutoff point was 51.34 ms. CONCLUSION: T2 value of the tibial nerve can be used as an alternative, non-invasive quantitative parameter to assess DPN in diabetic patients. KEY POINTS: • Tibial nerves in patients with DPN showed T2 hyperintensity and enlargement. • Tibial nerves in patients with DPN had an increased T2 value. • T2 value might be used as a quantitative biomarker for DPN.

A case of Cardiobacterium valvarum endocarditis with cerebral hemorrhage after MVR, TVP and vegetation removal operation.

BACKGROUND: Cardiobacterium is a fastidious Gram-negative bacillus, and is a rare human pathogen in clinical settings. Herein, we describe a case of Cardiobacterium valvarum (C. valvarum) endocarditis with a rare complication of cerebral hemorrhage after mitral valve replacement (MVR), tricuspid valve prosthesis (TVP) and vegetation removal operation. CASE PRESENTATION: A 41-year-old woman who had a history of gingivitis developed into infective endocarditis due to the infection of C. valvarum. Then, she was hospitalized to receive MVR, TVP and vegetation removal operation. The indicators of patient tended to be normal until the abrupt cerebral hemorrhage occurred on day 15 after operation. This is the first well-described case of C. valvarum infection in China, and the first report of C. valvarum endocarditis with cerebral hemorrhage after MVR, TVP and vegetation removal operation worldwide. CONCLUSIONS: We reported the first case of C. valvarum infection in China clinically, with a rare complication of cerebral hemorrhage after MVR, TVP and vegetation removal operation.

DTI metrics can be used as biomarkers to determine the therapeutic effect of stem cells in acute peripheral nerve injury.

PURPOSE: To determine the role of diffusion tensor imaging (DTI) metrics as biomarkers for the therapeutic effects of mesenchymal stem cells (MSCs) in acute peripheral nerve injury. MATERIALS AND METHODS: Forty-four adult rats received subepineurial microinjection of MSCs (n = 22) or phosphate buffered saline (PBS, n = 22) 1 week after the sciatic nerve trunk crush injury. Sequential fat-suppressed T2-weighted imaging, T2 measurement, DTI and sciatic nerve functional assessment were performed at a 3.0 Tesla MR unit over an 8-week follow-up, with histological assessments performed at regular intervals. The sciatic nerve function index, T2 value, and DTI metrics, including fractional anisotropy (FA), axial diffusivity, radial diffusivity (RD), and mean diffusivity values of the distal stumps of crushed nerves were measured and compared between the two groups. RESULTS: Nerves treated with MSCs showed better functional recovery and exhibited more pronounced nerve regeneration compared with nerves treated with PBS. T2 values in nerves treated with MSCs or PBS showed a similar change pattern (P = 0.174), while FA and RD values in nerves treated with MSCs showed more rapid return (one week earlier) to baseline level than nerves treated with PBS (P = 0.045; 0.035). Nerves treated with MSCs had higher FA and lower RD values than nerves treated with PBS during the period from 2 to 3 weeks after surgery (P ≤ 0.0001, 0.004; P = 0.004, 0.006). CONCLUSION: FA and RD values derived from DTI might be used as sensitive biomarkers for detecting the therapeutic effect of stem cells in acute peripheral nerve crush injuries. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:855-862.

Predictive features of CT for risk stratifications in patients with primary gastrointestinal stromal tumour.

PURPOSE: To determine the predictive CT imaging features for risk stratifications in patients with primary gastrointestinal stromal tumours (GISTs). MATERIALS AND METHODS: One hundred and twenty-nine patients with histologically confirmed primary GISTs (diameter >2 cm) were enrolled. CT imaging features were reviewed. Tumour risk stratifications were determined according to the 2008 NIH criteria where GISTs were classified into four categories according to the tumour size, location, mitosis count, and tumour rupture. The association between risk stratifications and CT features was analyzed using univariate analysis, followed by multinomial logistic regression and receiver operating characteristic (ROC) curve analysis. RESULTS: CT imaging features including tumour margin, size, shape, tumour growth pattern, direct organ invasion, necrosis, enlarged vessels feeding or draining the mass (EVFDM), lymphadenopathy, and contrast enhancement pattern were associated with the risk stratifications, as determined by univariate analysis (P < 0.05). Only lesion size, growth pattern and EVFDM remained independent risk factors in multinomial logistic regression analysis (OR = 3.480-100.384). ROC curve analysis showed that the area under curve of the obtained multinomial logistic regression model was 0.806 (95 % CI: 0.727-0.885). CONCLUSION: CT features including lesion size, tumour growth pattern, and EVFDM were predictors of the risk stratifications for GIST. KEY POINTS: • CT features were of predictive value for risk stratification of GISTs. • Tumour size, growth patterns, and EVFDM were risk predictors of GISTs. • Large size, mixed growth pattern, or EVFDM indicated high risk GIST.

MR imaging features and staging of neuroendocrine carcinomas of the uterine cervix with pathological correlations.

OBJECTIVE: To determine MR imaging features and staging accuracy of neuroendocrine carcinomas (NECs) of the uterine cervix with pathological correlations. METHODS: Twenty-six patients with histologically proven NECs, 60 patients with squamous cell carcinomas (SCCs), and 30 patients with adenocarcinomas of the uterine cervix were included. The clinical data, pathological findings, and MRI findings were reviewed retrospectively. MRI features of cervical NECs, SCCs, and adenocarcinomas were compared, and MRI staging of cervical NECs was compared with the pathological staging. RESULTS: Cervical NECs showed a higher tendency toward a homogeneous signal intensity on T2-weighted imaging and a homogeneous enhancement pattern, as well as a lower ADC value of tumour and a higher incidence of lymphadenopathy, compared with SCCs and adenocarcinomas (P < 0.05). An ADC value cutoff of 0.90 × 10-3 mm2/s was robust for differentiation between cervical NECs and other cervical cancers, with a sensitivity of 63.3 % and a specificity of 95 %. In 21 patients who underwent radical hysterectomy and lymphadenectomy, the overall accuracy of tumour staging by MR imaging was 85.7 % with reference to pathology staging. CONCLUSION: Homogeneous lesion texture and low ADC value are likely suggestive features of cervical NECs and MR imaging is reliable for the staging of cervical NECs. KEY POINTS: • Cervical NECs show a tendency of lesion homogeneity and lymphadenopathy • Low ADC values are found in cervical NECs • MRI is an accurate imaging modality for the cervical NEC staging.

Assessment of diabetic peripheral neuropathy in streptozotocin-induced diabetic rats with magnetic resonance imaging.

OBJECTIVE: To determine the role of magnetic resonance (MR) imaging and quantitative T2 value measurements in the assessment of diabetic peripheral neuropathy (DPN). METHODS: Sequential MR imaging, T2 measurement, and quantitative sensory testing of sciatic nerves were performed in streptozotocin-induced diabetic rats (n = 6) and normal control rats (n = 6) over a 7-week follow-up period. Histological assessment was obtained from 48 diabetic rats and 48 control rats once weekly for 7 weeks (n = 6 for each group at each time point). Nerve signal abnormalities were observed, and the T2 values, mechanical withdrawal threshold (MWT), and histological changes were measured and compared between diabetic and control animals. RESULTS: Sciatic nerves in the diabetic rats showed a gradual increase in T2 values beginning at 2 weeks after the induction (P = 0.014), while a decrease in MWT started at 3 weeks after the induction (P = 0.001). Nerve T2 values had a similar time course to sensory functional deficit in diabetic rats. Histologically, sciatic nerves of diabetic rats demonstrated obvious endoneural oedema from 2 to 3 weeks after the induction, followed by progressive axonal degeneration, Schwann cell proliferation, and coexistent disarranged nerve regeneration. CONCLUSION: Nerve T2 measurement is potentially useful in detecting and monitoring diabetic neuropathy. KEY POINTS: • Sciatic nerves in diabetic rats showed a gradual increase in T2 values • Nerve T2 values were negatively correlated with sensory function impairment • Longitudinal T2 values can be used to monitor the disease progress • Nerve degeneration contributed mainly to progressive prolongation of nerve T2 values.

The Effects of Metakaolin on the Properties of Magnesium Sulphoaluminate Cement.

Magnesium sulphoaluminate (MSA) cement has good bonding properties and is suitable as an inorganic adhesive for repairing materials in civil engineering. However, there are still some problems with its use, such as its insufficient 1 day (d) strength and poor volumetric stability. This paper aims to investigate the influences of metakaolin (MK) on the physical and mechanical properties of magnesium sulphoaluminate (MSA) cement. The hydration products and microstructures of typical MSA cement samples were also analysed using X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDS). The results showed that the addition of metakaolin reduces the fluidity and shortens the setting time of the MSA cement. The initial setting time and final setting time shortened maximally by 15-27 min and 25-48 min, respectively, with the addition of 10-30% metakaolin. Moreover, the compressive strength and flexural strength of the MSA cement improved significantly with the addition of 10-30% metakaolin at a curing age of 1 d. Compared with the compressive and flexural strengths of the control sample at 1 d, the compressive strengths of the modified samples showed obvious increases of 98%, 101%, and 109%, and the flexural strengths increased by 39%, 31%, and 26%, respectively, although they decreased slightly when the curing ages were 7 d, 14 d, and 28 d. The addition of 10% metakaolin improved the water resistance of the MSA cement immersed in water for 7 d and resulted in even higher water resistance at 28 d. The addition of 10-30% metakaolin improved the volumetric stability of the MSA cement with increasing dosages before 28 d of ageing. XRD and SEM-EDS analyses showed that the metakaolin accelerated the early hydration reaction and optimised the phase composition of the MSA cement. The results indicate that the addition of 10-20% metakaolin improved the strength after 1 d of ageing, water resistance, and volumetric stability of the MSA cement, providing theoretical support for the application of MAS cement as an inorganic bonding agent for repairing materials.

Theoretical Analysis of Thermophysical Properties of 3D Carbon/Epoxy Braided Composites with Varying Temperature.

A three-dimensional helix geometry unit cell is established to simulate the complex spatial configuration of 3D braided composites. Initially, different types of yarn factors, such as yarn path, cross-sectional shape, properties, and braid direction, are explained. Then, the multiphase finite element method is used to develop a new theoretical calculation procedure based on the unit cell for predicting the impacts of environmental temperature on the thermophysical properties of 3D four-direction carbon/epoxy braided composites. The changing rule and distribution characteristics of the thermophysical properties for 3D four-direction carbon/epoxy braided composites are obtained at temperatures ranging from room temperature to 200 °C. The influences of environmental temperature on the coefficients of thermal expansion (CTE) and the coefficients of thermal conduction (CTC) are evaluated, by which some important conclusions are drawn. A comparison is conducted between theoretical and experimental results, revealing that variations in temperature exert a notable influence on the thermophysical characteristics of 3D four-directional carbon/epoxy braided composites. The theoretical calculation procedure is an effective tool for the mechanical property analysis of composite materials with complex geometries.

Cell atlas of CCl 4-induced progressive liver fibrosis reveals stage-specific responses.

Chronic liver injury leads to progressive liver fibrosis and ultimately cirrhosis, a major cause of morbidity and mortality worldwide. However, there are currently no effective anti-fibrotic therapies available, especially for late-stage patients, which is partly attributed to the major knowledge gap regarding liver cell heterogeneity and cell-specific responses in different fibrosis stages. To reveal the multicellular networks regulating mammalian liver fibrosis from mild to severe phenotypes, we generated a single-nucleus transcriptomic atlas encompassing 49 919 nuclei corresponding to all main liver cell types at different stages of murine carbon tetrachloride (CCl 4)-induced progressive liver fibrosis. Integrative analysis distinguished the sequential responses to injury of hepatocytes, hepatic stellate cells and endothelial cells. Moreover, we reconstructed cell-cell interactions and gene regulatory networks implicated in these processes. These integrative analyses uncovered previously overlooked aspects of hepatocyte proliferation exhaustion and disrupted pericentral metabolic functions, dysfunction for clearance by apoptosis of activated hepatic stellate cells, accumulation of pro-fibrotic signals, and the switch from an anti-angiogenic to a pro-angiogenic program during CCl 4-induced progressive liver fibrosis. Our dataset thus constitutes a useful resource for understanding the molecular basis of progressive liver fibrosis using a relevant animal model.

Structure and activity alteration in adult highland residents' cerebrum: Voxel-based morphometry and amplitude of low-frequency fluctuation study.

Introduction: People living in highland areas may have factors that allow them to adapt to chronic hypoxia, but these physiological mechanisms remain unclear. This study aimed to investigate the brain mechanism in a cohort of adult residents of Tibet, a well-known plateau section in China, by observing differences in brain structure and function in non-plateau populations. Methods: The study included 27 Tibetan and 27 non-plateau region residents who were matched in age, sex, and education. All participants underwent high-resolution three-dimensional T1 weighted imaging (3D-T1WI) and resting-state functional magnetic resonance imaging (rs-fMRI) scans on a 1.5 Tesla MR. Gray matter volumes and regional spontaneous neuronal activity (SNA) were calculated and compared between the two groups. Results: When comparing gray matter in people living in high altitudes to those living in the flatlands, the results showed positive activation of gray matter in local brain regions (p < 0.05, false discovery rate (FDR) corrected), in the right postcentral [automated atomic labeling (aal)], left postcentral (aal), and right lingual (aal) regions. Comparing the people of high altitude vs. flat land in the brain function study (p < 0.05, FDR corrected), positive activation was found in the right superior motor area (aal) and left superior frontal (aal), and negative activation was found in the right precuneus (aal). Conclusion: In high-altitude individuals, larger regional gray matter volumes and higher SNA may represent a compensatory mechanism to adapt to chronic hypoxia.

Quantitative Parameters of Diffusion Spectrum Imaging: HER2 Status Prediction in Patients With Breast Cancer.

OBJECTIVE: To explore the value of quantitative parameters derived from diffusion spectrum imaging (DSI) in preoperatively predicting human epidermal growth factor receptor 2 (HER2) status in patients with breast cancer. METHODS: In this prospective study, 114 and 56 female patients with invasive ductal carcinoma were consecutively included in a derivation cohort and an independent validation cohort, respectively. Each patient was categorized into HER2-positive or HER2-negative groups based on the pathologic result. All patients underwent DSI and conventional MRI including dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI). The tumor size, type of the time-signal intensity curve (TIC) from DCE-MRI, apparent diffusion coefficient (ADC) from DWI, and quantitative parameters derived from DSI, including diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), mean apparent propagator (MAP), and neurite orientation dispersion and density imaging (NODDI) of primary tumors, were measured and compared between the HER2-positive and HER2-negative groups in the derivation cohort. Univariable and multivariable logistic regression analyses were used to determine the potential independent predictors of HER2 status. The discriminative ability of quantitative parameters was assessed by receiver operating characteristic (ROC) curve analyses and validated in the independent cohort. RESULTS: In the derivation cohort, the tumor size, TIC type, and ADC values did not differ between the HER2-positive and HER2-negative groups (p = 0.126-0.961). DSI quantitative parameters including axial kurtosis of DKI (DKI_AK), non-Gaussianity (MAP_NG), axial non-Gaussianity (MAP_NGAx), radial non-Gaussianity (MAP_NGRad), return-to-origin probability (MAP_RTOP), return-to-axis probability of MAP (MAP_RTAP), and intracellular volume fraction of NODDI (NODDI_ICVF) were lower in the HER2-positive group than in the HER2-negative group (p ≤ 0.001-0.035). DSI quantitative parameters including radial diffusivity (DTI_RD), mean diffusivity of DTI (DTI_MD), mean squared diffusion (MAP_MSD), and q-space inverse variance of MAP (MAP_QIV) were higher in the HER2-positive group than in the HER2-negative group (p = 0.016-0.049). The ROC analysis showed that the area under the curve (AUC) of ADC was 0.632 and 0.568, respectively, in the derivation and validation cohorts. The AUC values of DSI quantitative parameters ranged from 0.628 to 0.700 and from 0.673 to 0.721, respectively, in the derivation and validation cohorts. Logistic regression analysis showed that only NODDI_ICVF was an independent predictor of HER2 status (p = 0.001), with an AUC of 0.700 and 0.721, respectively, in the derivation and validation cohorts. CONCLUSIONS: DSI could be helpful for preoperative prediction of HER2, but DSI alone may not be sufficient in predicting HER2 status preoperatively in patients with breast cancer.

MRI-Based Radiomics Nomogram: Prediction of Axillary Non-Sentinel Lymph Node Metastasis in Patients With Sentinel Lymph Node-Positive Breast Cancer.

Background: Overtreatment 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. Methods: This 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. Results: The 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. Conclusion: The 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.

New aromatic substituted pyrazoles as selective inhibitors of human adipocyte fatty acid-binding protein.

a-FABP is indespensible in inflammation and may serve as a new potential drug target for inflammation related diseases. We have successfully designed and synthesized a series of aromatic substituted pyrazoles as new human a-FABP inhibitors. The compounds strongly bound to the hydrophobic binding pocket of a-FABP, while showed significantly lower binding affinities to the closely related homologue protein h-FABP. The most potent and selective compound 5 g bound to a-FABP with an apparent K(i) value below 1.0 nM, while did not inhibit h-FABP at 50 µM and thus represents one of the most potent and selective a-FABP inhibitors to date. The strong binding capacity of these inhibitors was further validated by their effective blockade of inflammatory responses as determined by the production of pro-inflammatory cytokines upon LPS stimulation. Compound 5 g may serve as a lead compound for developing new effective therapeutic agent for prevention and treatment of atherosclerosis, type 2 diabetes and other inflammatory and metabolic related diseases.