High b-Value and Ultra-High b-Value Diffusion Weighted MRI in Stroke.

PURPOSE: To explore the application value of high-b-value and ultra-high b-value DWI in noninvasive evaluation of ischemic infarctions. STUDY TYPE: Prospective. SUBJECTS: Sixty-four patients with clinically diagnosed ischemic lesions based on symptoms and DWI. FIELD STRENGTH/SEQUENCE: 3.0 T/T2-weighted fast spin-echo, fluid-attenuated inversion recovery, pre-contrast T1-weighted magnetization prepared rapid gradient echo sequence, multi-b-value trace DWI and q-space sampling sequences. ASSESSMENT: Lesions were segmented on standard b-value DWI (SB-DWI, 1000 s/mm2), high b-value DWI (HB-DWI, 4000 s/mm2) and ultra-high b-value DWI (UB-DWI, 10,000 s/mm2), and cumulative segmented areas were the final abnormality volumes. Normal white matter (WM) areas were obtained after binarization of segmented brain. In 47 patients, fractional anisotropy (FA) and apparent diffusion coefficients (ADCs) at b values of 1000, 4000, and 10,000 s/mm2 were extracted from symmetrical WM masks and lesion masks of contralateral WM (CWM) and lesion-side WM (LWM). STATISTICAL TESTS: Wilcoxon matched-pairs signed-rank test and Pearson correlation analysis. Two-tailed P-values <0.05 were considered statistically significant. RESULTS: Various signals of HB-/UB-DWI (hypo-, iso- or hyper-intensity) were observed in strokes compared with SB-DWI, and some areas with iso-intensity of SB-DWI manifested with hyper-intensity on HB-/UB-DWI. Abnormality volumes from SB-DWI were significantly smaller than those from HB-DWI and UB-DWI (10.32 ± 16.45 cm3, vs. 12.25 ± 19.71 cm3 and 11.83 ± 19.41 cm3), while no significant difference exist in volume between HB-DWI and UB-DWI (P = 0.32). In CWM, FA significantly correlated with ADC4000 and ADC10,000 (maximum r = -0.51 and -0.64), but did not significantly correlate with ADC1000 (maximum r = -0.20, P = 0.17). ADC1000 or ADC4000 of LWM not significant correlated with FA of CWM (maximum r = -0.28, P = 0.06), while ADC10,000 of LWM significantly correlated with FA of CWM (maximum r = -0.46). DATA CONCLUSION: HB- and UB-DWI have potential to be supplementary tools for the noninvasive evaluation of stroke lesions in clinics. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Anomalous diffusion in cerebral glioma assessed using a fractional motion model.

PURPOSE: To demonstrate the capability of the fractional motion (FM) model for describing anomalous diffusion in cerebral gliomas and to assess the potential feasibility of FM for grading these tumors. METHODS: Diffusion MRI images were acquired from brain tumor patients using a special Stejskal-Tanner diffusion sequence with variable diffusion gradient amplitudes and separation times. Patients with histopathologically confirmed gliomas, including astrocytic and oligoastrocytic tumors, were selected. The FM-related parameters, including the Noah exponent ( α), the Hurst exponent ( H), and the memory parameter ( µ=H-1/α), were calculated and compared between low- and high-grade gliomas using a two-sample t-test. The grading performance was evaluated using the receiver operating characteristic analysis. RESULTS: Twenty-two patients were included in the present study. The calculated α, H, and µ permitted the separation of tumor lesions from surrounding normal tissues in parameter maps and helped differentiate glioma grades. Moreover, α showed greater sensitivity and specificity in distinguishing low- and high-grade gliomas compared with the apparent diffusion coefficient. CONCLUSION: The FM model could improve the diagnostic accuracy in differentiating low- and high-grade gliomas. This improved diffusion model may facilitate future studies of neuro-pathological changes in clinical populations. Magn Reson Med 78:1944-1949, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Many-Body Function Corrected Neural Network with Atomic Attention (MBNN-att) for Molecular Property Prediction.

Recent years have seen a surge of machine learning (ML) in chemistry for predicting chemical properties, but a low-cost, general-purpose, and high-performance model, desirable to be accessible on central processing unit (CPU) devices, remains not available. For this purpose, here we introduce an atomic attention mechanism into many-body function corrected neural network (MBNN), namely, MBNN-att ML model, to predict both the extensive and intensive properties of molecules and materials. The MBNN-att uses explicit function descriptors as the inputs for the atom-based feed-forward neural network (NN). The output of the NN is designed to be a vector to implement the multihead self-attention mechanism. This vector is split into two parts: the atomic attention weight part and the many-body-function part. The final property is obtained by summing the products of each atomic attention weight and the corresponding many-body function. We show that MBNN-att performs well on all QM9 properties, i.e., errors on all properties, below chemical accuracy, and, in particular, achieves the top performance for the energy-related extensive properties. By systematically comparing with other explicit-function-type descriptor ML models and the graph representation ML models, we demonstrate that the many-body-function framework and atomic attention mechanism are key ingredients for the high performance and the good transferability of MBNN-att in molecular property prediction.

Glass-Forming Ability, Mechanical Properties, and Energetic Characteristics of ZrCuNiAlNbHfY Bulk Metallic Glasses.

The effects of partially substituting Al for Cu in Zr59.62Cu18.4-xNi12Al6+xNb3Hf0.78Y0.2 (x = 0, 2, 4, 6, 8 at.%) bulk metallic glasses (BMGs) on their glass-forming ability (GFA), quasi-static and dynamic mechanical properties, and energy characteristics were investigated. The results showed that an appropriate substitution of Al for Cu can improve GFA and reach a critical casting size up to 10 mm. Additionally, with Al replacement of Cu, the change in the distribution and content of free volume inside the BMGs was the main reason for the quasi-static compression plasticity. In contrast, the BMGs exhibited no plasticity during dynamic compression and high-speed impact, owing to the short loading time and thermal softening effect. In terms of energy characteristics, all alloys have a high combustion enthalpy. And on the surface of the fragments collected from impact, the active elements Zr, Al, and Nb reacted because of the adiabatic temperature rise. Further, x = 4 at.% Zr-based BMG with its superior overall performance could penetrate a 6 mm Q235 plate at a speed of 1038 m/s, combining excellent mechanical properties and energy characteristics. This study contributes to the development of Zr-based BMGs as novel energetic structural materials.

SAR and evaluation of novel 5H-benzo[c][1,8]naphthyridin-6-one analogs as Aurora kinase inhibitors.

Several potent Aurora kinase inhibitors derived from 5H-benzo[c][1,8]naphthyridin-6-one scaffold were identified. A crystal structure of Aurora kinase A in complex with an initial hit revealed a binding mode of the inhibitor within the ATP binding site and provided insight for structure-guided compound optimization. Subsequent SAR campaign provided a potent and selective pan Aurora inhibitor, which demonstrated potent target modulation and antiproliferative effects in the pancreatic cell line, MIAPaCa-2. Furthermore, this compound inhibited phosphorylation of histone H3 (pHH3) in mouse bone morrow upon oral administration, which is consistent with inhibition of Aurora kinase B activity.

Noninvasive Characterization of Metabolic Changes in Ischemic Stroke Using Z-spectrum-fitted Multiparametric Chemical Exchange Saturation Transfer-weighted Magnetic Resonance Imaging.

OBJECTIVE: This study aimed to noninvasively characterize the metabolic alterations in ischemic brain tissues using Z-spectrum-fitted multiparametric chemical exchange saturation transfer-weighted magnetic resonance imaging (CEST-MRI). METHODS: Three sets of Z-spectrum data with saturation power (B1) values of 1.5, 2.5, and 3.5 µT, respectively, were acquired from 17 patients with ischemic stroke. Multiple contrasts contributing to the Z-spectrum, including fitted amide proton transfer (APTfitted), +2 ppm peak (CEST@2ppm), concomitantly fitted APTfitted and CEST@2ppm (APT&CEST@2ppm), semisolid magnetization transfer contrast (MT), aliphatic nuclear Overhauser effect (NOE), and direct saturation of water (DSW), were fitted with 4 and 5 Lorentzian functions, respectively. The CEST metrics were compared between ischemic lesions and contralateral normal white matter (CNWM), and the correlation between the CEST metrics and the apparent diffusion coefficient (ADC) was assessed. The differences in the Z-spectrum metrics under varied B1 values were also investigated. RESULTS: Ischemic lesions showed increased APTfitted, CEST@2ppm, APT&CEST@2ppm, NOE, and DSW as well as decreased MT. APT&CEST@2ppm, MT, and DSW showed a significant correlation with ADC [APT&CEST@2ppm at the 3 B1 values: R=0.584/0.467/0.551; MT at the 3 B1 values: R=-0.717/-0.695/-0.762 (4-parameter fitting), R=-0.734/-0.711/-0.785 (5-parameter fitting); DSW of 4-/5-parameter fitting: R=0.794/0.811 (2.5 µT), R=0.800/0.790 (3.5 µT)]. However, the asymmetric analysis of amide proton transfer (APTasym) could not differentiate the lesions from CNWM and showed no correlation with ADC. Furthermore, the Z-spectrum contrasts varied with B1. CONCLUSION: The Z-spectrum-fitted multiparametric CEST-MRI can comprehensively detect metabolic alterations in ischemic brain tissues.

Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer.

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer. Transcriptional and epigenetic profiling studies show reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc and stem cell pathways associated with CTx-648 anti-tumor activity in ER-positive (ER+) breast cancer. CTx-648 treatment leads to potent tumor growth inhibition in ER+ breast cancer in vivo models, including models refractory to endocrine therapy, highlighting the potential for targeting KAT6A in ER+ breast cancer.

Bone metastasis of hepatocellular carcinoma: facts and hopes from clinical and translational perspectives.

Patients with hepatocellular carcinoma (HCC) and bone metastasis (BM) suffer from greatly reduced life quality and a dismal prognosis. However, BM in HCC has long been overlooked possibly due to its relatively low prevalence in previous decades. To date, no consensus or guidelines have been reached or formulated for the prevention and management of HCC BM. Our narrative review manifests the increasing incidence of HCC BM to sound the alarm for additional attention. The risk factors, diagnosis, prognosis, and therapeutic approaches of HCC BM are detailed to provide a panoramic view of this disease to clinicians and specialists. We further delineate an informative cancer bone metastatic cascade based on evidence from recent studies and point out the main factors responsible for the tumor-associated disruption of bone homeostasis and the formation of skeletal cancer lesions. We also present the advances in the pathological and molecular mechanisms of HCC BM to shed light on translational opportunities. Dilemmas and challenges in the treatment and investigation of HCC BM are outlined and discussed to encourage further endeavors in the exploration of underlying pathogenic and molecular mechanisms, as well as the development of novel effective therapies for HCC patients with BM.

Proton exchange rate of chemical exchange saturation transfer MRI constructed from direct saturation-removed omega plots to improve the assessment of patients with ischemic stroke.

Background: Proton exchange rate (k ex) magnetic resonance imaging (MRI) has recently been developed, with preliminary results demonstrating its potential for evaluating reactive oxygen species. This prospective cohort study investigated the k ex in different stroke stages and its correlation with stroke severity and prognosis. Methods: In all, 96 ischemic stroke patients were included in the study. Patients were divided into 3 groups based on stroke phase (acute, subacute, and chronic). A spin echo-echo planar imaging sequence with presaturation powers of 1.5, 2.5, and 3.5 µT was implemented to obtain Z-spectra, and k ex maps were constructed from direct saturation-removed omega plots. Relative k ex (rk ex) and the relative apparent diffusion coefficient (rADC) were calculated as the ratio of k ex or ADC in the infarcts to values in contralateral tissue, respectively. Correlations between both k ex and rk ex and National Institute of Health Stroke Scale (NIHSS) scores were evaluated. Receiver operating characteristic (ROC) analysis was used to evaluate the performance of k ex, rk ex, rADC, and lesion volume for predicting acute stroke outcome. Results: The k ex was significantly higher in ischemic lesions than in contralateral tissue at all stages. In addition, the k ex of acute lesions was higher than that of subacute and chronic lesions [mean (± SD) 935.1±81.5 vs. 881.4±55.7 and 866.9±76.7 s-1, respectively; P<0.05 and P<0.01, respectively]. The difference in k ex between subacute and chronic lesions was not significant. In acute stroke, there was a limited correlation between a lesion's k ex and NIHSS score (R2=0.16; P=0.01) and between rk ex and NIHSS score (R2=0.28; P=0.001). Acute stroke patients with poor prognosis had significantly higher lesion k ex and rk ex than did those with good prognosis (k ex: 991.1±78.2 vs. 893.1±55.1 s-1, P<0.001; rk ex: 1.28±0.09 vs. 1.15±0.06, P<0.001). In ROC analyses, k ex and rk ex showed favorable predictive performance for acute stroke outcome, with areas under the curve (AUC) of 0.837 and 0.880, respectively, which were slightly but not significantly higher than the AUCs for lesion volume (0.730) and rADC (0.673). Conclusions: This study indicates that k ex MRI is promising for the diagnosis and management of ischemic stroke because it can reflect the oxidative stress of lesions and predict prognosis.

Neurite Orientation Dispersion and Density Imaging of Rat Brain Microstructural Changes due to Middle Cerebral Artery Occlusion at a 3T MRI.

The purpose of this work was to demonstrate the feasibility of neurite orientation dispersion and density imaging (NODDI) in characterizing the brain tissue microstructural changes of middle cerebral artery occlusion (MCAO) in rats at 3T MRI, and to validate NODDI metrics with histology. A multi-shell diffusion MRI protocol was performed on 11 MCAO rats and 10 control rats at different post-operation time points of 0.5, 2, 6, 12, 24 and 72 h. NODDI orientation dispersion index (ODI) and intracellular volume fraction (Vic) metrics were compared between MCAO group and control group. The evolution of NODDI metrics was characterized and validated by histology. Infarction was consistent with significantly increased ODI and Vic in comparison to control tissues at all time points (P<0.001). Lesion ODI increased gradually from 0.5 to 72 h, while its Vic showed a more complicated and fluctuated evolution. ODI and Vic were significantly different between hyperacute and acute stroke periods (P<0.001). The NODDI metrics were found to be consistent with the histological findings. In conclusion, NODDI can reflect microstructural changes of brain tissues in MCAO rats at 3T MRI and the metrics are consistent with histology. This study helps to prepare NODDI for the diagnosis and management of ischemic stroke in translational research and clinical practice.

Structure-Based Drug Design and Synthesis of PI3Kα-Selective Inhibitor (PF-06843195).

The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3S)-3-{[2'-amino-5-fluoro-2-(morpholin-4-yl)-4,5'-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1) (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of 1.

Associations Between Diffusion Dynamics and Functional Outcome in Acute and Early Subacute Ischemic Stroke.

PURPOSE: The current study aimed to investigate the associations between diffusion dynamics of ischemic lesions and clinical functional outcome of acute and early subacute stroke. MATERIAL AND METHODS: A total of 80 patients with first ever infarcts in the territory of the middle cerebral artery underwent multi-b-values diffusion-weighted imaging and diffusion kurtosis imaging. Multiple diffusion parameters were generated in postprocessing using different diffusion models. Long-term functional outcome was evaluated with modified Rankin scale (mRS) at 6 months post-stroke. Good functional outcome was defined as mRS score ≤ 2 and poor functional outcome was defined as mRS score ≥ 3. Univariate analysis was used to compare the diffusion parameters and clinical features between patients with poor and good functional outcome. Significant parameters were further analyzed for correlations with functional outcome using partial correlation. RESULTS: In univariate analyses, standard-b-values apparent diffusion coefficient (ADCst) ratio and fractional anisotropy (FA) ratio of acute stroke, ADCst ratio and mean kurtosis (MK) ratio of early subacute stroke were statistically different between patients with poor outcome and good outcome (P < 0.05). When the potential confounding factor of lesion volume was controlled, only FA ratio of acute stroke, ADCst ratio and MK ratio of early subacute stroke remained correlated with the functional outcome (P < 0.05). CONCLUSION: Diffusion dynamics are correlated with the clinical functional outcome of ischemic stroke. This correlation is independent of the effect of lesion volume and is specific to the time period between symptom onset and imaging. More effort is needed to further investigate the predictive value of diffusion-weighted imaging.

Joint construction of micro-vibration stimulation and BCP scaffolds for enhanced bioactivity and self-adaptability tissue engineered bone grafts.

The bone defects caused by trauma and disease have become a major difficulty in the treatment of clinical bone defects, and bone tissue engineering has become a promising treatment strategy. It was found that mechanical stimulation regulated the development of bone constructs by affecting the distribution and differentiation of cells on them. In this study, tissue-engineered bone grafts with enhanced bioactivity and self-adaptability were constructed by BMSCs and biphasic calcium phosphate (BCP) scaffolds under periodic micro-vibration stimulation (MVS) with a frequency of 40 Hz and a magnitude of 0.3 g. The results of the material characterization indicated that the BCP scaffolds created a more favourable osteogenic micro-environment with promoted calcium ion release, protein adsorption and mineralization deposition under the micro-vibration stimulation. The in vitro results showed that the apoptosis of BMSCs increased significantly on day 1, but from day 3 on, the proliferation increased and apoptosis decreased. Cells were evenly distributed on the scaffolds, exhibiting tight adhesion in a flat-shape and distinct matrix mineralization. F-actin and ALP expression significantly increased and meanwhile osteogenesis-related genes including Runx2, Col-I, ALP, and OCN were significantly up-regulated. Western blotting results suggested that the ERK1/2 and Wnt/ß-catenin signalling pathways were involved in the osteogenic behaviour of BMSCs induced by MVS. In vivo experiments showed that grafts had stronger osteoinduction and mechanical adaptability. Taken together, this study suggested that micro-vibration stimulation combined with BCP scaffolds with good osteoinduction could be a promising approach for constructing tissue engineered bone grafts with enhanced bioactivity, mechanical adaptability, and bone regeneration repair capability.

Novel proton exchange rate MRI presents unique contrast in brains of ischemic stroke patients.

BACKGROUND: To map and quantify the proton exchange rate (kex) of brain tissues using improved omega plots in ischemic stroke patients and to investigate whether kex can serve as a potential endogenous surrogate imaging biomarker for detecting the metabolic state and the pathologic changes due to ischemic stroke. NEW METHOD: Three sets of Z-spectra were acquired from seventeen ischemic stroke patients using a spin echo-echo planar imaging sequence with pre-saturation chemical exchange saturation transfer (CEST) pulse at B1 of 1.5, 2.5, and 3.5 µT, respectively. Pixel-wise kex was calculated from improved omega plot of water direct saturation (DS)-removed Z-spectral signals. RESULTS: The derived kex maps can differentiate infarcts from contralateral normal brain tissues with significantly increased signal (893 ±â€¯52 s-1vs. 739 ±â€¯34 s-1, P < 0.001). COMPARISON WITH EXISTING METHOD(S): The kex maps were found to be different from conventional contrasts from diffusion-weighted imaging (DWI), CEST, and semi-solid magnetization transfer (MT) MRI. In brief, kex MRI showed larger lesion areas than DWI with different degrees and different lesion contrast compared to CEST and MT. CONCLUSIONS: In this preliminary translational research, the kex MRI based on DS-removed omega plots has been demonstrated for in vivo imaging of clinical ischemic stroke patients. As a noninvasive and unique MRI contrast, kex MRI at 3 T may serve as a potential surrogate imaging biomarker for the metabolic changes of stroke and help for monitoring the evolution and the treatment of stroke.

Fiber Connectivity Density in Cerebral Small-Vessel Disease Patients With Mild Cognitive Impairment and Cerebral Small-Vessel Disease Patients With Normal Cognition.

Abnormal structural connectivity of cerebral small-vessel disease (CSVD) is associated with cognitive impairment. But the different characteristics of structural connectivity have not been elucidated in early CSVD patients. The current study aimed to investigate the potential differences of structural connectivity in CSVD patients with mild cognitive impairment (MCI) and CSVD patients with normal cognition. Twenty-two CSVD patients with MCI, 34 CSVD patients with normal cognition, and 35 controls, who were age, sex, and education matched underwent diffusion tensor imaging and high resolution T1-weighted imaging. Clinical characteristics, lacunar infarct volume, white matter hyperintensity (WMH) volume, and global atrophy were quantitatively evaluated. Maps of fiber connectivity density (FiCD) were constructed and compared across groups in vertex levels. Pearson correlation was used to estimate the imaging-clinical relationships with control of general characteristics. CSVD patients with MCI had higher lesion load of WMH and lacunar infarcts, and correspondingly lower global FiCD value than CSVD patients with normal cognition (P < 0.01). Lacunar infarct (r = -0.318, P < 0.01) and WMH (r = -0.400, P < 0.01), but not global atrophy, age, or sex, were significantly correlated with the global FiCD value. CSVD patients with normal cognition showed decreased FiCD value mainly in the prefrontal areas (P < 0.01 with Monte Carlo correction). Compared with CSVD patients with normal cognition, CSVD patients with MCI showed significantly decreased FiCD value in enlarged frontal and parietal areas (P < 0.01 with Monte Carlo correction). Inter-group comparisons showed regional enhanced impairment of connectivity density in CSVD patients with MCI in the left superior frontal gyrus, the left precuneus, and the orbital part of the right inferior frontal gyrus (P < 0.01 with Monte Carlo correction). Regional FiCD value of frontal and parietal areas was associated with the cognitive function (P < 0.01). In conclusion, cognitively normal CSVD patients already have disruptions of structural connectivity. The extent and intensity of connectivity disruptions in frontal and parietal areas may underlie the mechanism of cognitive impairment in CSVD. Fiber connectivity density measurements may be helpful for quantitative description of structural cortical connectivity.

Age and anatomical location related hemodynamic changes assessed by 4D flow MRI in the carotid arteries of healthy adults.

PURPOSE: To evaluate hemodynamic changes (volume, velocity, wall shear stress, pressure gradient, and energy loss) in the common carotid artery (CCA) and internal carotid artery (ICA) of healthy adults among different ages and anatomical locations using 4D flow MRI. METHODS: Sixty-two healthy volunteers aged 20-75 years were enrolled in this study. 4D flow MRI examinations were performed for each subject and were analyzed using the CVI42 platform to generate hemodynamic parameters. Hemodynamic parameters were compared among different age groups and anatomical locations (proximal CCA, distal CCA, proximal ICA and distal CCA) using one-way ANOVA. The paired t-test was used to estimate the differences between left and right vessels. The relationship between age and hemodynamic parameters was quantified by Pearson's correlation coefficient. RESULTS: There were no differences between the left and right carotid arteries for any of the hemodynamic parameters (all p values > 0.05), so we set each vessel as an independent sample. The proximal ICA had significantly lower volume, velocity, wall shear stress, and pressure gradient values than the values determined for other locations (p < 0.05), and energy loss was similar among different locations. Wall shear stress (except in the distal ICA), velocity, pressure gradient, and energy loss decreased with age (p < 0.05). CONCLUSIONS: The multiparameter analysis of 4D flow MRI can identify age and anatomical location changes in hemodynamic parameters in the carotid arteries of healthy adults. The lower velocity, wall shear stress, and pressure gradient in the proximal ICA and the reduced trend with age may be associated with disease occurrence.

Mutations in BRAF and KRAS converge on activation of the mitogen-activated protein kinase pathway in lung cancer mouse models.

Mutations in the BRAF and KRAS genes occur in approximately 1% to 2% and 20% to 30% of non-small-cell lung cancer patients, respectively, suggesting that the mitogen-activated protein kinase (MAPK) pathway is preferentially activated in lung cancers. Here, we show that lung-specific expression of the BRAF V600E mutant induces the activation of extracellular signal-regulated kinase (ERK)-1/2 (MAPK) pathway and the development of lung adenocarcinoma with bronchioloalveolar carcinoma features in vivo. Deinduction of transgene expression led to dramatic tumor regression, paralleled by dramatic dephosphorylation of ERK1/2, implying a dependency of BRAF-mutant lung tumors on the MAPK pathway. Accordingly, in vivo pharmacologic inhibition of MAPK/ERK kinase (MEK; MAPKK) using a specific MEK inhibitor, CI-1040, induced tumor regression associated with inhibition of cell proliferation and induction of apoptosis in these de novo lung tumors. CI-1040 treatment also led to dramatic tumor shrinkage in murine lung tumors driven by a mutant KRas allele. Thus, somatic mutations in different signaling intermediates of the same pathway induce exquisite dependency on a shared downstream effector. These results unveil a potential common vulnerability of BRAF and KRas mutant lung tumors that potentially affects rational deployment of MEK targeted therapies to non-small-cell lung cancer patients.

Functional brain connectome and its relation to mild cognitive impairment in cerebral small vessel disease patients with thalamus lacunes: A cross-sectional study.

To investigate the functional connectome alterations in cerebral small-vessel disease (CSVD) patients with thalamus lacunes and its relation to cognitive impairment.This case-control study was approved by the local research ethics committee, and all participants provided informed consent. There were 14 CSVD patients with thalamus lacunes (CSVDw.), 27 without (CSVDwo.), and 34 healthy controls (HC) recruited matched for age, sex, and education to undergo a 3T resting-state functional MR examination. The whole-brain functional connectome was constructed by thresholding the Pearson correlation matrices of 90 brain regions, and the topologic properties were analyzed by using graph theory approaches. Networks were compared between CSVD patients and HC, and associations between network measures and cognitive function were tested.Compared with HC, the functional connectome in CSVDw. patients showed abnormalities at the global level and at the nodal level (P < .05, false discovery rate corrected). The network-based statistics method identified a significantly altered network consisting 6 nodes and 13 connections. Among all the 13 connections, only two connections had significant correlation with episodic memory (EM) and processing speed (PS) respectively (P < .05). The CSVDwo. patients showed no significant network alterations relative to controls (P > .05).The configurations of brain functional connectome in CSVDw. patients were perturbed but not obvious for those without, and correlated with the mild cognitive impairment, especially for EM and PS. This study suggested that lacunes on thalamus played a vital role in mediating the neural functional changes of CSVD patients.

A study of neurite orientation dispersion and density imaging in ischemic stroke.

OBJECTIVES: To demonstrate the feasibility of the neurite orientation dispersion and density imaging (NODDI) technique in characterizing the microstructural changes in brain tissues during ischemic stroke and to compare its sensitivity with diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI). METHODS: Seventy-one patients with hyperacute/acute/subacute ischemic stroke were enrolled in the study. A multishell diffusion magnetic resonance imaging (dMRI) protocol was performed for each subject. Diffusion data were analyzed using the NODDI and diffusional kurtosis estimator toolboxes. Then, NODDI metrics between the lesions and the contralateral tissues were compared to evaluate their values in ischemic stroke. NODDI metrics among different stroke periods and the correlations between NODDI and the duration since stroke onset were analyzed as well. To compare the NODDI's sensitivity with established diffusion techniques, paired t-tests were performed to determine the absolute percentage changes of diffusion metrics between NODDI and DTI/DKI. RESULTS: Compared with the contralateral tissues, lesions showed significantly increased values of intracellular volume fraction (Vic) and orientation dispersion index (ODI) and decreased values of isotropic volume fraction (Viso). ODI value was significantly different among three periods and showed fair to good positive correlation with the duration since stroke onset (R = 0.450). NODDI metrics showed significantly larger absolute percentage changes than that of DTI and DKI (P < 0.05, respectively). CONCLUSION: NODDI allowed efficient evaluation of microstructural changes in brain tissues during ischemic stroke and showed increased sensitivity compared with DTI and DKI. The possible biophysical mechanisms underlying ischemia could be further elucidated using this advanced diffusion technique.

Grading and proliferation assessment of diffuse astrocytic tumors with monoexponential, biexponential, and stretched-exponential diffusion-weighted imaging and diffusion kurtosis imaging.

PURPOSE: To compare the main parameters derived from monoexponential, biexponential and stretched-exponential diffusion-weighted imaging (DWI) and diffusion kurtosis imaging (DKI) with respect to diagnostic performance for tumor grading and proliferation assessment in diffuse astrocytic tumors (DATs). MATERIALS AND METHODS: Fifty-eight pathologically confirmed DAT patients who underwent DWI and DKI on a 3-T scanner were prospectively collected and retrospectively reviewed. Measurements including the apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudodiffusion coefficient (D*), perfusion fraction (f), distributed diffusion coefficient (DDC), heterogeneity index (α), mean diffusivity (MD), fractional anisotropy (FA), and mean kurtosis (MK) were compared between tumor grades (Ⅱ, Ⅲ, and Ⅳ) by using a Jonckheere-Terpstra test. Receiver operating characteristic (ROC) curves were used to assess the diagnostic efficacy of these parameters. Spearman's rho with the Ki-67 labeling index (LI) was calculated for each parameter. RESULTS: MK values differed significantly between all DAT subtypes and increased with grade. The ADC, D, f, DDC, α and MD values were significantly higher in grade Ⅱ tumors than in grade Ⅲ/Ⅳ tumors. D* values were significantly lower in grade Ⅱ tumors than in grade Ⅳ tumors (all P < 0.05). In discriminating between grade Ⅱ and Ⅲ tumors, α, MK, MD, D and f had significantly greater area under the ROC curve (AUC) values than D* and FA (0.927, 0.901, 0.896, 0.895, and 0.889, respectively vs 0.659 and 0.598, respectively, P < 0.05). In discriminating between grade Ⅲ and Ⅳ tumors, only MK demonstrated acceptable discrimination (AUC = 0.711). MK and D showed a strong correlation with the Ki-67 LI (ρ = 0.791 and -0.789, respectively, P < 0.001). D*, f, MD, ADC, DDC and α showed a moderate correlation (|ρ| ranged from 0.415 to 0.698, P < 0.05). CONCLUSION: MK and D have considerable potential to predict the degree of proliferation of DATs. MK could effectively characterize microstructural changes throughout the malignant transformation of DATs and provided useful complementary information for grading.