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Multiple arterial-phase magnetic resonance imaging (MA-MRI) was introduced to overcome the limitations of gadoxetic acid-enhanced MRI, but its clinical impacts on hepatocellular carcinoma (HCC) diagnosis have not been well assessed. We investigated whether MA-MRI with gadoxetic acid could improve the diagnosis of HCC ≤3.0 cm in comparison with single arterial-phase MRI (SA-MRI).This retrospective study included 397 patients from two tertiary institutions who underwent gadoxetic acid-enhanced MRI (243 patients with 271 lesions in cohort-1 underwent SA-MRI, and 154 patients with 166 lesions in cohort-2 underwent MA-MRI). The patients had 437 hepatic lesions ≤3.0 cm with pathologic confirmation. The arterial-phase image quality and diagnostic performance of SA-MRI and MA-MRI were analysed and compared. To minimize the effects of selection bias because of potential confounding between the two groups, propensity score-matching was additionally performed.MA-MRI showed a significantly higher percentage of optimal arterial-phase timing (94.2% vs. 74.5%, p .001) and lower incidence of inadequate examinations (1.3% vs. 5.8%, p = .034) than SA-MRI. MA-MRI had a significantly higher non-rim arterial-phase hyperenhancement (APHE) detection rate (94.9% vs. 85.5%, p = .005) and sensitivity for diagnosing HCC (87.4% vs. 70.0%, p .001) than SA-MRI, but no significant difference in specificity (92.9% vs. 93.1%, p = .966). In 123 pairs of propensity score-matched patients, MA-MRI had significantly higher sensitivity (89.1% vs. 74.5%, p = .006) than SA-MRI with equal specificity (92.3% vs. 92.3%, p .999).Compared with SA-MRI, MA-MRI with gadoxetic acid can detect more non-rim APHE and significantly improve sensitivity for diagnosing HCC ≤3.0 cm, without a significant decrease in specificity.

Colorectal cancer (CRC) is a very common and deadly cancer worldwide, and oxaliplatin is used as first-line chemotherapy. However, resistance usually develops, limiting treatment. Echinatin (Ech) is the main component of licorice and exhibits various therapeutic effects on inflammation-mediated diseases and cancer, ischemia/reperfusion, and liver injuries. The present study elucidated the underlying molecular mechanism of Ech-induced apoptosis in both oxaliplatin-sensitive (HT116 and HT29) and -resistant (HCT116-OxR and HT29-OxR) CRC cells. To evaluate the antiproliferative activities of Ech, we performed MTT and soft agar assays. Ech reduced viability, colony size, and numbers of CRC cells. The underlying molecular mechanisms were explored by various flow cytometry analyses. Ech-induced annexin-V stained cells, reactive oxygen species (ROS) generation, cell cycle arrest, JNK/p38 MAPK activation, endoplasmic reticulum (ER) stress, mitochondrial membrane potential depolarization, and multi-caspase activity. In addition apoptosis-, cell cycle-, and ER stress-related protein levels were confirmed by western blotting. Moreover, we verified ROS-mediated cell death by treatment with inhibitors such as N-acetyl-L-cysteine, SP600125, and SB203580. Taken together, Ech exhibits anticancer activity in oxaliplatin-sensitive and -resistant CRCs by inducing ROS-mediated apoptosis through the JNK/p38 MAPK signaling pathway. This is the first study to show that Ech has the potential to treat drug-resistant CRC, providing new directions for therapeutic strategies targeting drug-resistant CRC.

Many defined approaches (DAs) for skin sensitization assessment based on the adverse outcome pathway (AOP) have been developed to replace animal testing because the European Union has banned animal testing for cosmetic ingredients. Several DAs have demonstrated that machine learning models are beneficial. In this study, we have developed an ensemble prediction model utilizing the graph convolutional network (GCN) and machine learning approach to assess skin sensitization. The model integrates in silico parameters and data from alternatives to animal testing of well-defined AOP to improve DA predictivity. Multiple ensemble models were created using the probability produced by the GCN with six physicochemical properties, direct peptide reactivity assay, KeratinoSens™, and human cell line activation test (h-CLAT), using a multilayer perceptron approach. Models were evaluated by predicting the testing set's human hazard class and three potency classes (strong, weak, and non-sensitizer). When the GCN feature was used, 11 models out of 16 candidates showed the same or improved accuracy in the testing set. The ensemble model with the feature set of GCN, KeratinoSens™, and h-CLAT produced the best results with an accuracy of 88% for assessing human hazards. The best three-class potency model was created with the feature set of GCN and all three assays, resulting in 64% accuracy. These results from the ensemble approach indicate that the addition of the GCN feature could provide an improved predictivity of skin sensitization hazard and potency assessment.

The visualization score of hepatobiliary-phase (HBP) images has been introduced as an image quality index for gadoxetic acid-enhanced MRI. It may be associated with hepatic function and could have an implication on the diagnostic accuracy for hepatocellular carcinoma (HCC).To investigate the association between the visualization score of gadoxetic acid-enhanced MRI and clinical factors and to evaluate its effect on the diagnostic accuracy for HCC ≤ 3.0 cm.Retrospective.A total of 493 focal lesions from 397 patients.A 5-T or 3.0 -T with pre/postcontrast T1-weighted 3D gradient echo sequence, and T2-weighted fast spin-echo sequence ASSESSMENT: Child-Pugh classification and albumin-bilirubin (ALBI) score were assessed. Three readers evaluated the visualization score of each MRI examination (A, no or minimal; B, moderate; and C, severe limitations), and major features (arterial-phase hyperenhancement, washout, enhancing capsule, threshold growth) and ancillary features of each focal lesion.Univariable and multivariable logistic regression analyses were performed to determine significant clinical factors associated with a suboptimal visualization score (B or C). Generalized estimating equations were used to compare the sensitivity and specificity for diagnosing HCC between the two group (visualization score A vs. B or C). A P value 0.05 was considered statistically significant.Of the 397 MRI examinations, the incidence of suboptimal visualization score was 13%. A suboptimal visualization score was significantly associated with Child-Pugh classification B or C (adjusted odds ratio [OR] = 15.2) and ALBI grade 2 or 3 (OR = 4.7). Compared with the visualization score A group, the suboptimal visualization score group showed significantly lower sensitivity (56.8% vs. 75.2%) and less frequent washout in HCC (62.2% vs. 84.0%).The visualization score on gadoxetic acid-enhanced MRI can be an important image quality index and the diagnostic accuracy for HCC ≤ 3.0 cm may not be sufficient in the suboptimal visualization score group.3 TECHNICAL EFFICACY STAGE: 3.

We assessed the imaging outcomes of Liver Imaging Reporting and Data System (LI-RADS) v2018 categories in prospective hepatocellular carcinoma (HCC) surveillance cohort and determined imaging features significantly predictive of progression to a malignant LI-RADS category.The imaging outcomes of 120 patients (162 observations) prospectively enrolled between November 2011 and August 2012 were analysed according to LI-RADS v2018. Cumulative incidences for progression to a malignant category (LR-5 or LR-M) and LR-4 or higher were calculated for each baseline category and compared using log-rank tests. Clinical variables and imaging features significantly predictive of progression to a malignant category were evaluated using Cox proportional hazards modelling.The 162 observations were initially categorized into 60 LR-2, 75 LR-3 and 27 LR-4. For LR-4 observations, the 1-year, 3-year and 5-year cumulative incidences of progression to a malignant category were 18.5% (95% confidence interval, 6.6-35.2%), 43.0% (23.1-61.5%) and 52.5% (25.9-73.5%), which were significantly higher than those of LR-2 and LR-3 (p .001). For LR-3, the 1-year, 3-year and 5-year cumulative incidences of progression to LR-4 or higher were 4.1% (1.1-10.4%), 13.9% (6.7-23.6%) and 23.1% (12.7-35.4%), which were significantly higher than that of LR-2 (p = .009). In multivariable analysis, size ≥1.0 cm (hazard ratio [HR] = 2.58, 1.04-6.40) and nonrim arterial-phase hyperenhancement (HR = 2.45, 1.11-5.42) were significantly independently associated with progression to a malignant category.Long-term imaging outcomes differed significantly according to LI-RADS category. Size ≥1.0 cm and nonrim arterial-phase hyperenhancement were imaging features significantly predictive of progression to a malignant category.

Background & aims Aspirin and statins have been suggested to prevent hepatocellular carcinoma (HCC). However, the combined effects of aspirin and statins on HCC risk in patients with chronic hepatitis B (CHB) is not clear. Methods A nationwide nested case-control study was performed with data from the National Health Insurance Service gathered between 2005 and 2015 in Korea. In a cohort of 538,135 treatment-naive, non-cirrhotic patients with CHB, 6,539 HCC cases were matched to 26,156 controls and were analyzed by conditional logistic regression. Separate historical cohort studies for each drug were analyzed by time-dependent Cox regression as a sensitivity analysis. Results In the nested case-control study, statins (OR 0.34; 95% CI 0.32-0.37) and aspirin (OR 0.92; 95% CI 0.85-0.99) were significantly associated with a HCC risk reduction. However, dose-dependent risk reduction was observed only with statins. By sensitivity analysis in the historical cohorts, statin users (n = 244,455; HR 0.67; 95% CI 0.66-0.68) and aspirin users (n = 288,777; HR 0.81; 95% CI 0.80-0.82) had significantly lower HCC risk. In the drug-stratified analyses, statins were associated with significantly reduced risk of HCC regardless of aspirin, whereas aspirin did not show such associations. Conclusions In this nationwide population-based study of patients with CHB, statin use was consistently associated with a significant and dose-dependent reduction in HCC risk. In contrast, the association between aspirin use and HCC risk reduction was not dose-dependent and was suggested to be confounded by statins.

We extend the Rosen–Roback spatial equilibrium model to show that increasing city‐level college share affects welfare distribution by changing both wages and housing costs heterogeneously across individuals with different education levels. Using the Panel Study of Income Dynamics (PSID) from 1980 to 2013, we confirm that high‐skilled workers gain greater benefits from living in cities with a rising college share, as the increase in their wage premiums outweighs their rent growth. However, the increased earnings of the unskilled are completely offset by higher housing rents. In response to the college graduate influx, housing wealth also increases significantly more for college graduates, further widening the welfare gap. The increased welfare gap is greater in cities where housing supply is inelastic.

We report an autopsy case of a 56-year-old male patient with the coexistence of dentatorubral-pallidoluysian atrophy (DRPLA) and Parkinson's disease (PD). He presented with gait instability and dysarthria for 10 years. The removed brain showed general atrophy (988 g) with depigmentation of the substantia nigra. The neocortex and deep gray matter, including the red nucleus, subthalamic nuclei, and globus pallidus, were atrophic, and grumose degeneration of the cerebellar dentate nucleus was observed. Polyglutamine- and p62-positive neuronal inclusions were present and widespread in the areas mentioned above. Interestingly, this case also had brainstem-predominant PD pathology with α-synuclein-positive Lewy bodies and Lewy neurites. Generalized white matter atrophy with patchy loss of astrocytes in the white matter suggested glial dysfunction by elongated CAG repeats in the atrophin 1 gene (atrophin 1). Polymerase chain reaction (PCR) fragment analysis revealed increased CAG repeats (61) on atrophin 1 encoding atrophin 1. The patient had a family history of DRPLA, including his daughter, who was confirmed positive on genetic testing (CAG repeat: 65). His father, brother, and niece were suspected of having the disease. Clinicopathologically, all of the above findings are consistent with the coexistence of DRPLA and PD. So far, various overlapping neurodegenerative disorders have been reported, but the coexistence of DRPLA and PD has never been demonstrated in the published literature. Even though the exact time of PD development is unknown in this case, PD might develop after DRPLA, and the overwhelming symptoms of DRPLA might mask those of PD. Here, we report a clinicopathologically definite case of the coexistence of DRPLA and PD. White matter degeneration with patchy loss of astrocytes was another remarkable finding of this case.

Funding Information: The project was conducted within the framework of a "Multidisciplinary Survey and Monitoring of the Gareja Rock Cut Complex, the Monument of National Value" funded by the National Agency for Cultural Heritage Preservation of Georgia and managed by the Ilia State University, Georgia, together with the Italian Institute for Environmental Protection and Research, Italy, and the support of the University of Milano-Bicocca, Italy. Data used in this work was jointly acquired and, accordingly, belongs to all three institutions. Background: Atherosclerosis-related adverse events are commonly observed even in conditions with low cardiovascular (CV) risk. Longitudinal data regarding the association of normal systolic blood pressure maintenance (SBPmaintain) with coronary plaque volume changes (PVC) has been limited in adults without traditional CV disease. Hypothesis: Normal SBPmaintain is important to attenuate coronary atherosclerosis progression in adults without baseline CV disease. Methods: We analyzed 95 adults (56.7 ± 8.5 years; 40.0% men) without baseline CV disease who underwent serial coronary computed tomographic angiography with mean 3.5 years of follow-up. All participants were divided into two groups of normal SBPmaintain (follow-up SBP < 120 mm Hg) and ≥elevated SBPmaintain (follow-up SBP ≥ 120 mm Hg). Annualized PVC was defined as PVC divided by the interscan period. Results: Compared to participants with normal SBPmaintain, those with ≥elevated SBPmaintain had higher annualized total PVC (mm3/year) (0.0 [0.0–2.2] vs. 4.1 [0.0–13.0]; p

The objective of this study was to compare the diagnostic accuracy of office blood pressure (BP) threshold of 140/90 and 130/80 mmHg for correctly identifying uncontrolled out‐of‐office BP in apparent treatment‐resistant hypertension (aTRH). We analyzed 468 subjects from a prospectively enrolled cohort of patients with resistant hypertension in South Korea (clinicaltrials.gov: NCT03540992). Resistant hypertension was defined as office BP ≥ 130/80 mmHg with three different classes of antihypertensive medications including thiazide‐type/like diuretics, or treated hypertension with four or more different classes of antihypertensive medications. We conducted different types of BP measurements including office BP, automated office BP (AOBP), home BP, and ambulatory BP. We defined uncontrolled out‐of‐office BP as daytime BP ≥ 135/85 mmHg and/or home BP ≥ 135/85 mmHg. Among subjects with office BP

OBJECTIVE Genetic variants of the cytoplasmic FMR1-interacting protein 2 (CYFIP2) encoding an actin-regulatory protein are associated with brain disorders, including intellectual disability and epilepsy. However, specific in vivo neuronal defects and potential treatments for CYFIP2-associated brain disorders remain largely unknown. Here, we characterized Cyfip2 heterozygous (Cyfip2+/- ) mice to understand their neurobehavioral phenotypes and the underlying pathological mechanisms. Furthermore, we examined a potential treatment for such phenotypes of the Cyfip2+/- mice and specified a neuronal function mediating its efficacy. METHODS We performed behavioral analyses of Cyfip2+/- mice. We combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses of Cyfip2+/- prefrontal neurons. We also selectively reduced CYFIP2 in the prefrontal cortex (PFC) of mice with virus injections. RESULTS Adult Cyfip2+/- mice exhibited lithium-responsive abnormal behaviors. We found increased filamentous actin, enlarged dendritic spines, and enhanced excitatory synaptic transmission and excitability in the adult Cyfip2+/- PFC that was restricted to layer 5 (L5) neurons. Consistently, adult Cyfip2+/- mice showed increased seizure susceptibility and auditory steady-state responses from the cortical electroencephalographic recordings. Among the identified prefrontal defects, lithium selectively normalized the hyperexcitability of Cyfip2+/- L5 neurons. RNA sequencing revealed reduced expression of potassium channel genes in the adult Cyfip2+/- PFC. Virus-mediated reduction of CYFIP2 in the PFC was sufficient to induce L5 hyperexcitability and lithium-responsive abnormal behavior. INTERPRETATION These results suggest that L5-specific prefrontal dysfunction, especially hyperexcitability, underlies both the pathophysiology and the lithium-mediated amelioration of neurobehavioral phenotypes in adult Cyfip2+/- mice, which can be implicated in CYFIP2-associated brain disorders. ANN NEUROL 2020;88:526-543.

Tumor-associated macrophages (TAMs) promote tumor growth and metastasis, and are closely related with poor prognosis of cancers. Therefore, TAMs have been an attractive target in cancer therapy. This study investigated whether the root bark of Morus alba L. (MA) regulates TAMs. Methylene chloride extract of MA (MEMA) decreased the migration of RAW264.7 cells and THP-1 macrophages toward cancer cells via inhibition of focal adhesion kinase and Src activity. In addition, MEMA inhibited the phorbol myristate acetate-stimulated secretion of plasminogen activator inhibitor-1 from cancer cells, leading to the decreased chemotaxis of macrophages. Finally, MEMA-suppressed M2 macrophage polarization induced by interleukin (IL)-4/IL-13 or IL-6. MEMA downregulated the mRNA expression of M2 macrophage markers and decreased the phosphorylation of signal transducer and activator of transcription (STAT) 6 and STAT3 in RAW264.7 cells. Suppression of M2 polarization of macrophages by MEMA resulted in the reduced migration of Lewis lung carcinoma cells when the conditioned media from RAW264.7 cells was used as a chemoattractant. Taken together, our results demonstrate that MEMA regulates TAMs by blocking the recruitment of macrophages into tumor microenvironments and by inhibiting M2 polarization of macrophages.

Background and aims The Liver Imaging Reporting and Data System (LI-RADS) category M (LR-M) was introduced to preserve the high specificity of LI-RADS algorithm for diagnosing hepatocellular carcinoma (HCC). We aimed to systematically determine the probability of the LR-M for HCC and non-HCC malignancy, and to determine the sources of heterogeneity between reported results. Methods Original studies reporting the probability of LR-M for HCC and non-HCC malignancy on magnetic resonance imaging (MRI) were identified in MEDLINE and EMBASE. The meta-analytic pooled percentages of HCC and non-HCC in LR-M were calculated. Meta-regression analysis was performed to explore study heterogeneity. The meta-analytic frequency of each LR-M imaging feature was determined. Results We found 10 studies reporting the diagnostic performance of LR-M (1819 lesions in 1631 patients), and six reporting the frequency of LR-M imaging features. The pooled percentages of HCC and non-HCC malignancy for LR-M were 28.2% (95% confidence interval [CI], 23.8%-33.1%; I2 = 83%) and 69.6% (95% CI, 64.6%-74.1%; I2 = 83%) respectively. The study type and MRI scanner field strength were significantly associated with study heterogeneity (P ≤ .04). Of the seven imaging features, rim arterial phase hyperenhancement showed the highest frequency in both non-HCC (48.9%; 95% CI, 43.0%-54.8%) and HCC groups (9.8%; 95% CI, 6.9%-13.6%). Conclusions The LR-M category most commonly included non-HCC malignancy but also included 28.2% of HCC. Substantial study heterogeneity was noted, and it was significantly associated with study type and MRI scanner field strength. In addition, the frequency of LR-M imaging features was variable.

BACKGROUND: We aimed to investigate if left ventricular electromechanical delay (LVEMD) prolongation predicts trastuzumab‐induced cardiotoxicity (TIC) in breast cancer patients. HYPOTHESIS: LVEMD prolongation on serial echocardiograms could be an indicator of subclinical TIC. METHODS: We included 237 breast cancer patients receiving trastuzumab chemotherapy, who underwent echocardiography at baseline and at 6 and 12 months after trastuzumab initiation. LVEMD was defined as the time from electrical activation to myocardial contraction. TIC was defined as left ventricular ejection fraction (LVEF) worsening to

BACKGROUND Use of the Liver Imaging Reporting and Data System (LI-RADS) is increasing, but the reported results for interreader agreement seem quite variable. PURPOSE To systematically determine the interreader agreement of LI-RADS on magnetic resonance imaging (MRI) and to determine the sources of heterogeneity between the reported results. STUDY TYPE Systematic review and meta-analysis. SUBJECTS Fifteen original articles with 2968 lesions. FIELD STRENGTH 1.5T and 3.0T. ASSESSMENT Two reviewers independently performed the data extraction. The reviewers identified and reviewed the original articles reporting the interreader agreement of LI-RADS using MRI. STATISTICAL TESTS The meta-analytic pooled intraclass correlation coefficient (ICC) for lesion size and kappa value (κ) for major features (arterial-phase hyperenhancement [APHE], nonperipheral washout [WO], enhancing capsule [EC]) and LI-RADS categorization (LR) were calculated using the random-effects model. Sensitivity analysis and meta-regression analysis were performed to explore the cause of study heterogeneity. RESULTS The meta-analytic pooled ICC of lesion size was 0.97 (95% confidence interval [CI], 0.94-1.00). Meta-analytic pooled κ of APHE, WO, EC, and LR were 0.72 (95% CI, 0.62-0.82), 0.69 (95% CI, 0.60-0.78), 0.66 (95% CI, 0.58-0.74), and 0.70 (95% CI, 0.56-0.85), respectively. Substantial study heterogeneity was noted in all five variables (I2 ≥ 89.1%, P

Network-attached storage (NAS) is a system that uses a redundant array of disks (RAID) to create virtual disks comprising multiple disks and provide network services such as FTP, SSH, and WebDAV. Using these services, the NAS's virtual disks store data about individuals or groups, making them a critical analysis target for digital forensics. Well-known storage manufacturers like Seagate, Synology, and NETGEAR use Linux-based software RAID, and they usually support Berkeley RAID (e.g., RAID 0, 1, 5, 6, and 10) as well as self-developed hybrid RAID. Those manufacturers have published data on the introduction and features of hybrid RAID, but there is not enough information to reassemble RAID from a digital forensic perspective. Besides, digital forensic tools (such as EnCase, FTK, X-ways, and RAID Reconstructor) do not support automatic RAID reassembly for hybrid RAID, so research on hybrid RAID reassembly methods is necessary. This paper analyzes the disk array composed of hybrid RAID and explains the layout of disk array, partition layout in hybrid RAID, and hybrid RAID configuration strategy. Furthermore, it suggests parameters that are required for RAID reassembly and then propose a hybrid RAID reassembly procedure using them. Finally, we propose a proof-of-concept tool (Hybrid RAID Reconstructor) that identifies hybrid RAID from disk array and parse RAID parameters.

Dysregulation of the adipo-osteogenic differentiation balance of mesenchymal stem cells (MSCs), which are common progenitor cells of adipocytes and osteoblasts, has been associated with many pathophysiologic diseases, such as obesity, osteopenia, and osteoporosis. Growing evidence suggests that lipid metabolism is crucial for maintaining stem cell homeostasis and cell differentiation; however, the detailed underlying mechanisms are largely unknown. Here, we demonstrate that glucosylceramide (GlcCer) and its synthase, glucosylceramide synthase (GCS), are key determinants of MSC differentiation into adipocytes or osteoblasts. GCS expression was increased during adipogenesis and decreased during osteogenesis. Targeting GCS using RNA interference or a chemical inhibitor enhanced osteogenesis and inhibited adipogenesis by controlling the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ). Treatment with GlcCer sufficiently rescued adipogenesis and inhibited osteogenesis in GCS knockdown MSCs. Mechanistically, GlcCer interacted directly with PPARγ through A/B domain and synergistically enhanced rosiglitazone-induced PPARγ activation without changing PPARγ expression, thereby treatment with exogenous GlcCer increased adipogenesis and inhibited osteogenesis. Animal studies demonstrated that inhibiting GCS reduced adipocyte formation in white adipose tissues under normal chow diet and high-fat diet feeding and accelerated bone repair in a calvarial defect model. Taken together, our findings identify a novel lipid metabolic regulator for the control of MSC differentiation and may have important therapeutic implications.

Background Determining if a given patient with primary pancreatic adenocarcinoma (PDA) has hepatic metastasis is important for treatment planning. Several previous studies reported on the diagnostic performance of MRI for liver metastasis in patients with PDA. But the reported data are quite variable. Purpose To systematically determine the diagnostic performance of MRI for liver metastasis in patients with PDA, including comparing it with computed tomography (CT). Study type Systemic review and meta-analysis. Subjects In all, 457 patients from five eligible articles. Field strength/sequence Conventional MR sequences with or without contrast enhancement at 1.5T and 3T. Assessment Two reviewers independently performed the data extraction. The reviewers identified and reviewed the original articles reporting the diagnostic performance of MRI for liver metastases in patients with PDA, including those articles making comparisons with CT. Statistical tests Meta-analytic summary sensitivity and specificity were calculated on a per-patient basis using a bivariate random effects model. We compared the meta-analytic summary sensitivity and specificity between MRI and CT. Results The meta-analytic summary sensitivity and specificity were 85% (95% confidence interval [CI], 74-92%; I2 = 0%) and 98% (95% CI, 78-100%; I2 = 85%), respectively. In comparison with CT, MRI showed a higher sensitivity (85% vs. 75%) but similar specificity (98% vs. 94%). Data conclusion MRI had good overall diagnostic performance for liver metastasis in patients with PDA, with a higher sensitivity than CT. Level of evidence 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:1737-1744.

The peel of Citrus unshiu Marcow. fruits (CU) has long been used as a traditional medicine that has therapeutic effects against pathogenic diseases, including asthma, vomiting, dyspepsia, blood circulation disorders, and various types of cancer. In this study, we investigated the effect of CU peel on metastatic melanoma, a highly aggressive skin cancer, in B16F10 melanoma cells, and in B16F10 cells inoculated‐C57BL/6 mice. Our results show that ethanol extracts of CU (EECU) inhibited cell growth and increased the apoptotic cells in B16F10 cells. EECU also stimulated the induction of mitochondria‐mediated intrinsic pathway, with reduced mitochondrial membrane potential and increased generation of intracellular reactive oxygen species. Furthermore, EECU suppressed the migration, invasion, and colony formation of B16F10 cells. In addition, the oral administration of EECU reduced serum lactate dehydrogenase activity without weight loss, hepatotoxicity, nor nephrotoxicity in B16F10 cell‐inoculated mice. Moreover, EECU markedly suppressed lung hypertrophy, the number and expression of metastatic tumor nodules, and the expression of inflammatory tumor necrosis factor‐alpha in lung tissue. In conclusion, our findings suggest that the inhibitory effect of EECU on the metastasis of melanoma indicates that it may be regarded as a potential therapeutic herbal drug for melanoma.

To evaluate the effect of local parathyroid hormone (PTH) administration on rotator cuff tendon-to-bone healing in a rat model compared with systemic PTH injection and untreated controls. PTH-alginate scaffold was prepared and sustained release of PTH was confirmed. Bilateral supraspinatus tendon repairs were performed in 39 rats (group 1, supraspinatus repair only; group 2, supraspinatus repair with systemic PTH injection; group 3, supraspinatus repair with local PTH administration via an absorbable scaffold; n = 13 each). Biomechanical (cross-sectional area, mode of failure, load to failure, and ultimate stress: right side) and histological analyses (hematoxylin and eosin stain, Masson's Trichrome stain Picrosirius red stain, Immunohistochemistry for BMP2, PTH1R, ColI, and ColIII: Left side) were performed to evaluate tendon-to-bone healing quality at 8 weeks after repair, and blood test (osteocalcin and procollagen type I N-terminal pro-peptide [PINP] levels) was performed in all rats. There was no intergroup difference in the healing failure rate (p = 0.910) or failure mode (p = 0.585). Biomechanically, subjects in groups 2 and 3 exhibited significantly larger cross-sectional areas and higher ultimate failure loads and ultimate stress than those in group 1 (all p 0.05); however, no differences were noted between groups 2 and 3 (all p 0.05). Histologically, groups 2 and 3 exhibited more organized tendon-to-bone interface structures with higher density, parallel orientation, and collagen fiber continuity than group 1 (all p 0.05 except collagen fiber continuity in group 1 vs. 2); however, no differences in histological parameters between groups 2 and 3 (all p 0.05). The protein levels of bone morphogenic protein 2, PTH 1 receptor, and collagen I and III and the serum level of PINP were increased in groups 2 and 3 versus group 1 (all p 0.05) without showing differences between groups 2 and 3 (all p 0.05). Local PTH administration using an absorbable scaffold improved the biomechanical and histological outcomes of rotator cuff tendon-to-bone healing comparable with systemic PTH injection at 8 weeks after repair in a rat model. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:82-91, 2020.

BACKGROUND To evaluate correlation between growth rate of left portal vein (LPV) and future liver remnant (FLR) after right portal vein embolization (PVE), and to design models predicting FLR growth rate and volume using LPV area measurements on computed tomography (CT). METHODS A total of 134 patients (59.6 ± 10.2 years; 103 men) who underwent right PVE with contrast-enhanced CT before and 3-5 weeks after PVE were retrospectively identified. Kinetic hypertrophy ratio (KHR) and kinetic degree of hypertrophy (KDH) served as growth rate parameters. Correlations between LPV growth rate and FLR growth rate and volume change were evaluated by linear regression analysis. The agreements between actual volumetrically determined growth rates and volume of FLR and those estimated from regression equation using LPV measurements were assessed by Bland-Altman plots. RESULTS Growth rates of LPV and FLR correlated significantly (P

In vitro gliding assay, microtubule translocation by kinesin motor proteins on a surface, has been used as an engineering tool in analyte detection, molecular cargo transport, and other applications. Although controlling the moving direction is often necessary to realize these applications, current direction control methods focus largely on lithographic microfabrication of tracks or external fields on the microtubules. These methods are effective, but are relatively complicated. In addition, they cannot target particular microtubules without affecting others. In this study, we propose a facile approach that can make local direction changes for selected microtubules using a polystyrene particle as a circular motion center and a DNA double helix with streptavidin as a capture arm. The DNA arm captures a microtubule in the close proximity of the immobilized particle via biotin-streptavidin interaction and changes the moving direction ~10° on average. In contrast, no significant direction changes are observed other than random variations with streptavidin-less DNA arms (normal distribution centered at 0°), similar to regular motility assay. The particle-assisted local direction change scheme is compared with a flow field-based ensemble method. The combination of flow and kinesin interactions with each microtubule exerts a force to change the direction, ultimately aligning it to the flow field, regardless of its initial direction. A simple model based on the force balance predicts the time needed for such an alignment. Overall, the particle-based local scheme is distinct and different from ensemble methods such as crossflow that changes directions of all microtubules in the field, thus offering unique utility in engineering applications.

Background Rapid coronary plaque progression (RPP) is associated with incident cardiovascular events. To date, no method exists for the identification of individuals at risk of RPP at a single point in time. This study integrated coronary computed tomography angiography–determined qualitative and quantitative plaque features within a machine learning (ML) framework to determine its performance for predicting RPP. Methods and Results Qualitative and quantitative coronary computed tomography angiography plaque characterization was performed in 1083 patients who underwent serial coronary computed tomography angiography from the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) registry. RPP was defined as an annual progression of percentage atheroma volume ≥1.0%. We employed the following ML models: model 1, clinical variables; model 2, model 1 plus qualitative plaque features; model 3, model 2 plus quantitative plaque features. ML models were compared with the atherosclerotic cardiovascular disease risk score, Duke coronary artery disease score, and a logistic regression statistical model. 224 patients (21%) were identified as RPP. Feature selection in ML identifies that quantitative computed tomography variables were higher‐ranking features, followed by qualitative computed tomography variables and clinical/laboratory variables. ML model 3 exhibited the highest discriminatory performance to identify individuals who would experience RPP when compared with atherosclerotic cardiovascular disease risk score, the other ML models, and the statistical model (area under the receiver operating characteristic curve in ML model 3, 0.83 [95% CI 0.78–0.89], versus atherosclerotic cardiovascular disease risk score, 0.60 [0.52–0.67]; Duke coronary artery disease score, 0.74 [0.68–0.79]; ML model 1, 0.62 [0.55–0.69]; ML model 2, 0.73 [0.67–0.80]; all P P =0.128). Conclusions Based on a ML framework, quantitative atherosclerosis characterization has been shown to be the most important feature when compared with clinical, laboratory, and qualitative measures in identifying patients at risk of RPP.

Extracellular matrix dysregulation is associated with chronic liver disease. CollagenVI-alpha3 chain (COL6A3) is a biomarker for hepatic fibrosis and poor prognosis of hepatocellular carcinoma (HCC), but its function in liver pathology remains unknown. High levels of COL6A3 and its cleaved product, endotrophin (ETP) in tumor-neighboring regions are strongly associated with poor prognosis in HCC patients. Here, we report that the high levels of ETP in injured hepatocytes induce JNK-dependent hepatocyte apoptosis and activate nonparenchymal cells to lead further activation of hepatic inflammation, fibrosis, and apoptosis. Nevertheless ETP per se showed limited phenotypic changes in normal liver tissues. Furthermore, inhibition of ETP activity by utilizing neutralizing antibodies efficiently suppressed the pathological consequences in chronic liver diseases. Our results implicate ETP mechanistically as a crucial mediator in reciprocal interactions among various hepatic cell populations in the pathogenesis of chronic liver disease, and it could be a promising therapeutic target particularly in individuals with high local levels of COL6A3. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The most common symptom of bladder cancer (BC) is hematuria. However, not all patients with hematuria are diagnosed with BC. Here, we explored a novel method to discriminate BC from hematuria under nonmalignant conditions by measuring differences in urinary cell-free microRNA (miRNA) expression between patients with BC and those with hematuria. A multicenter study was performed using 543 urine samples obtained from the National Biobank of Korea, including 326 BC, 174 hematuria and 43 pyuria without cancer. The urinary miR-6124 to miR-4511 ratio was considerably higher in BC than in hematuria or pyuria, and enabled the discrimination of BC from patients with hematuria at a sensitivity of >90% (p < 0.001). Conclusively, the proposed noninvasive diagnostic tool based on the expression ratio of urinary cell-free miR-6124 to miR-4511 can reduce unnecessary cystoscopies in patients with hematuria undergoing evaluation for BC, with a minimal loss in sensitivity for detecting cancer.

Vaccinia-related kinase 2 (VRK2) is a serine/threonine kinase that belongs to the casein kinase 1 family. VRK2 has long been known for its relationship with neurodegenerative disorders such as schizophrenia. However, the role of VRK2 and the substrates associated with it are unknown. Dysbindin is known as one of the strong risk factors for schizophrenia. The expression of dysbindin is indeed significantly reduced in schizophrenia patients. Moreover, dysbindin is involved in neurite outgrowth and regulation of NMDA receptor signaling. Here, we first identified dysbindin as a novel interacting protein of VRK2 through immunoprecipitation. We hypothesized that dysbindin is phosphorylated by VRK2 and further that this phosphorylation plays an important role in the function of dysbindin. We show that VRK2 phosphorylates Ser 297 and Ser 299 of dysbindin using in vitro kinase assay. In addition, we found that VRK2-mediated phosphorylation of dysbindin enhanced ubiquitination of dysbindin and consequently resulted in the decrease in its protein stability through western blotting. Over-expression of VRK2 in human neuroblastoma (SH-SY5Y) cells reduced neurite outgrowth induced by retinoic acid. Furthermore, a phosphomimetic mutant of dysbindin alleviated neurite outgrowth and affected surface expression of N-methyl-d-aspartate 2A, a subunit of NMDA receptor in mouse hippocampal neurons. Together, our work reveals the regulation of dysbindin by VRK2, providing the association of these two proteins, which are commonly implicated in schizophrenia. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Sepsis is a systemic inflammatory response syndrome due to microbial infection. Growth arrest and DNA-damage-inducible 45 beta (GADD45β) are induced by genotoxic stress and inflammatory cytokines. However, the role of GADD45β during bacterial infection remains unclear. This study was aimed at investigating the role of GADD45β in sepsis. We used GADD45β-knockout (KO) mice and C57BL/6J wild-type (WT) mice. Experimental sepsis was induced by lipopolysaccharide (LPS) administration or cecal ligation and puncture (CLP). Sepsis-induced mortality was higher in GADD45β-KO mice than in WT mice. Histopathological data demonstrated LPS treatment markedly increased lung injury in GADD45β-KO mice as compared to that in WT mice; however, no significant difference was observed in the liver and kidney. Further, mRNA levels of inflammatory cytokines, such as Il-1β, Il-6, Il-10, and Tnf-α, were higher in the lungs of LPS-treated GADD45β-KO mice than in WT mice. Interestingly, plasma levels of these inflammatory cytokines were decreased in LPS-administered GADD45β-KO mice. A significant increase in lung cell apoptosis was observed at early time points in GADD45β-KO mice after administration of LPS as compared to that in WT mice. In line with LPS-induced apoptosis, JNK, and p38 activity was higher in the lung of GADD45β-KO mice at 3 hr after LPS treatment than that in WT mice. In summary, this study is the first to demonstrate the protective role of GADD45β in sepsis and the results suggest that GADD45β could be used as a novel therapeutic target to cure sepsis.

Chimeric antigen receptor-T (CAR-T) cell immunotherapy has shown impressive clinical outcomes for hematologic malignancies. However, its broader applications are challenged due to its complex ex vivo cell-manufacturing procedures and low therapeutic efficacy against solid tumors. The limited therapeutic effects are partially due to limited CAR-T cell infiltration to solid tumors and inactivation of CAR-T cells by the immunosuppressive tumor microenvironment. Here, a facile approach is presented to in vivo program macrophages, which can intrinsically penetrate solid tumors, into CAR-M1 macrophages displaying enhanced cancer-directed phagocytosis and anti-tumor activity. In vivo injected nanocomplexes of macrophage-targeting nanocarriers and CAR-interferon-γ-encoding plasmid DNA induce CAR-M1 macrophages that are capable of CAR-mediated cancer phagocytosis, anti-tumor immunomodulation, and inhibition of solid tumor growth. Together, this study describes an off-the-shelf CAR-macrophage therapy that is effective for solid tumors and avoids the complex and costly processes of ex vivo CAR-cell manufacturing.