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Obesity is a global pandemic that is causally linked to many life-threatening diseases. Apart from some rare genetic conditions, the biological drivers of overeating and reduced activity are unclear. Here, we show that neurotensin-expressing neurons in the mouse IPAC, a nucleus of the central extended amygdala, encode dietary preference for unhealthy energy-dense foods. Optogenetic activation of IPAC(Nts) neurons promotes obesogenic behaviors, such as hedonic eating, and modulates food preference. Conversely, acute inhibition of IPAC(Nts) neurons reduces feeding and decreases hedonic eating. Chronic inactivation of IPAC(Nts) neurons recapitulates these effects, reduces preference for sweet, non-caloric tastants, and, furthermore, enhances locomotion and energy expenditure. As a result, mice display long-term weight loss, improved metabolic health, and are protected from obesity. Thus, the activity of a single neuronal population bidirectionally regulates energy homeostasis. Our findings could lead to new therapeutic strategies to prevent and treat obesity.

Purpose To compare the diagnostic performance of morphologic criteria for detection of cirrhosis in patients with alcoholic liver disease (ALD), hepatitis C (HCV), and non-alcoholic steatohepatitis (NASH). Methods One hundred patients (53 male) with different etiologies of chronic liver disease (NASH,n = 41; HCV,n = 39; and ALD,n = 20) and with different degrees of fibrosis on histopathologic examination (74 with cirrhosis) were retrospectively evaluated. Four readers (R1: fellowship-trained abdominal radiologist, R2: community attending radiologist, R3: senior radiology resident/research fellow, R4: junior radiology resident) analyzed the contrast-enhanced CTs for presence of commonly accepted morphologic changes of cirrhosis and portal hypertension. Each reader assigned an overall score (using a 5-point scale) for possibility of cirrhosis based on liver morphology and features of portal hypertension. Diagnostic performance, sensitivity, and specificity for the diagnosis of cirrhosis were calculated and compared between different etiologies of chronic liver disease. Results Performance of readers was affected by their level of training. Less experienced readers had overall lower sensitivity for diagnosis of cirrhosis in NASH group (R3: 81.5%, R4: 63.0% compared to 96.3% for both R1 and R2). Sensitivities for detection of NASH cirrhosis significantly decreased for less experienced readers in the absence of ascites (R3: 75.0%, R4: 62.0%) or other features of portal hypertension (R3: 50.0%; R4: 0%). The specificity was consistently high among different etiologies and for all readers (85.7-100%). Inter-reader agreement for morphologic features ranged widely from fair to almost perfect (k: 0.23-0.85). Conclusion Cirrhotic changes in NASH are subtler and can be underestimated by less experienced readers.

International audience; Control of cell death/survival balance is an important feature to maintain tissue homeostasis. Dependence receptors are able to induce either survival or cell death in presence or absence of their ligand, respectively. However, their precise mechanism of action and their physiological importance are still elusive for most of them including the MET receptor. We evidence that pro-apoptotic fragment generated by caspase cleavage of MET localizes to the mitochondria-associated membrane region. This fragment triggers a calcium transfer from endoplasmic reticulum to mitochondria, which is instrumental for the apoptotic action of the receptor. Knock-in mice bearing a mutation of MET caspase cleavage site highlighted that p40MET production is important for FAS-driven hepatocyte apoptosis, and demonstrate that MET acts as a dependence receptor in vivo. Our data shed light on new signaling mechanisms for dependence receptors' control of cell survival/death balance, which may offer new clues for the pathophysiology of epithelial structures.

Simple Summary Despite many therapeutic approaches attempted over the last years, the prognosis of children with high-grade glioma or diffuse intrinsic pontine glioma remains dismal. Hypoxia-activated prodrugs (HAPs) were developed to target hypoxic areas within solid tumors as gliomas. Evofosfamide (Evo) is a 2nd generation HAP exhibiting significant preclinical and clinical activities against adult glioblastoma. We thus investigated the potential of Evo in six pediatric glioma cell lines. Interestingly, we showed that the growth of all cell lines was inhibited by Evo, mainly under hypoxia as expected. We also evidenced a significant synergism between Evo and three drugs widely used in pediatric oncology. Finally, Evo appeared able to potentiate the effect of ionizing radiations. Since these tumors are highly hypoxic and Evo appears effective in hypoxic glioma cells as a single drug and in combination with radio- and chemotherapy, hypoxia-activated prodrugs could represent a promising therapeutic option for children with brain tumors. Abstract Hypoxia is a hallmark of many solid tumors and is associated with resistance to anticancer treatments. Hypoxia-activated prodrugs (HAPs) were developed to target the hypoxic regions of these tumors. Among 2nd generation HAPs, Evofosfamide (Evo, also known as TH-302) exhibits preclinical and clinical activities against adult glioblastoma. In this study, we evaluated its potential in the field of pediatric neuro-oncology. We assessed the efficacy of Evo in vitro as a single drug, or in combination with SN38, doxorubicin, and etoposide, against three pediatric high-grade glioma (pHGG) and three diffuse intrinsic pontine glioma (DIPG) cell lines under hypoxic conditions. We also investigated radio-sensitizing effects using clonogenic assays. Evo inhibited the growth of all cell lines, mainly under hypoxia. We also highlighted a significant synergism between Evo and doxorubicin, SN38, or etoposide. Finally, Evo radio-sensitized the pHGG cell line tested, both with fractionated and single-dose irradiation schedules. Altogether, we report here the first preclinical proof of evidence about Evofosfamide efficiency against hypoxic pHGG and DIPG cells. Since such tumors are highly hypoxic, and Evo potentiates the effect of ionizing radiation and chemotherapy, it appears as a promising therapeutic strategy for children with brain tumors.

The diagnosis of hepatocellular carcinoma (HCC) can be reached noninvasively on imaging in patients at high risk as discussed in chapter “Hepatocellular carcinoma: Diagnostic Guidelines.” In this chapter, we describe the CT and MR imaging criteria more commonly used in the guidelines for the diagnosis and management of patients with HCC, including arterial phase hyperenhancement, washout, capsule, growth, and hypointensity on hepatobiliary phase MR imaging. The provided definitions are based on the latest version (v2018) of the liver imaging reporting and data system (LI-RADS) document (American College of Radiology 2018, https://www.acr.org/Clinical-Resources/Reporting-and-Data-Systems/LI-RADS).

Hybrid imaging with F-18 fludeoxyglucose positron emission tomography/magnetic resonance imaging (FDG PET/MRI) has increasing clinical applications supplementing conventional ultrasound, CT, and MRI imaging as well as hybrid PET/CT imaging in assessing cervical, endometrial, and ovarian cancer. This article summarizes the existing literature and discusses the emerging role of hybrid PET/MRI in gynecologic malignancies. Thus, far, the published literature on the applications of FDG PET/MRI shows that it can have a significant impact on patient management by improving the staging of the cancers compared with PET/CT, influencing clinical decision and treatment strategy. For disease restaging, current literature indicates that PET/MRI performs equivalently to PET/CT. There appears to be a mild-moderate inverse correlation between standard-uptake-value (SUV) and apparent-diffusion-coefficient (ADC) values, which could be used to predict tumor grading and risk stratification. It remains to be seen as to whether multi-parametric PET/MRI imaging could prove valuable for prognostication and outcome. PET/MRI provides the opportunity for reduced radiation exposure, which is particularly relevant for a young female in need of multiple scans for treatment monitoring and follow-up. Fast acquisition protocols and optimized methods for attenuation correction are still evolving. Major limitations of PET/MRI remains such as suboptimal detection of small pulmonary nodules and lack of utility for radiation treatment planning, which pose an impediment in making PET/MRI a viable one-stop-shop imaging option to compete with PET/CT.

Purpose: To compare the level of parenchymal and portal venous enhancement in the portal venous phase (PVP) in cirrhotic patients undergoing gadoxetate disodium- and gadobenate dimeglumine-enhanced MRI. Methods: In this retrospective study, 84 cirrhotic patients (mean age ± SD: 66 ± 13years) who underwent contrast-enhanced MRI with both gadoxetate disodium and gadobenate dimeglumine between 2012 and 2018 were included. Two readers measured signal intensities of hepatic parenchyma, portal vein and psoas muscle on precontrast and PVP. Relative enhancement (RE), image contrast, and portal vein-to-liver contrast difference were calculated. Intraindividual differences were compared with the Wilcoxon signed rank-sum test and inter-reader differences with the intraclass correlation coefficient (ICC). Results: In PVP, gadoxetate disodium provided lower RE than gadobenate dimeglumine (Reader 1: 42.4 ± 44.6 vs. 56.1 ± 58.8, p = 0.044; Reader 2: 42.4 ± 42.9 vs. 57.7 ± 60.5, p = 0.027;), lower image contrast (Reader 1: 0.27 ± 0.11 vs. 0.35 ± 0.11, respectively; p < 0.001; Reader 2: 0.29 ± 0.10 vs. 0.37 ± 0.07, respectively; p < 0.001), and lower portal vein-to-liver contrast difference (Reader 1: 0.89 ± 0.39 vs. 1.42 ± 0.90, p < 0.001; Reader 2: 0.95 ± 0.40 vs. 1.28 ± 0.37, p < 0.001). ICC was 0.94, 0.79, and 0.69 for RE, image contrast, and portal vein-to-liver contrast difference, respectively. Conclusion: In cirrhotic patients, gadoxetate disodium yielded lower enhancement of the hepatic parenchyma and lower contrast of the portal vein than gadobenate dimeglumine in PVP.

Background Radiomic texture analysis quantifies tumor heterogeneity. The aim of this study is to determine if radiomics can predict biologic aggressiveness in HCC and identify tumors with MVI. Methods Single-center, retrospective review of HCC patients undergoing resection/ablation with curative intent from 2009 to 2017. DICOM images from preoperative MRIs were analyzed with texture analysis software. Texture analysis parameters extracted on T1, T2, hepatic arterial phase (HAP) and portal venous phase (PVP) images. Multivariate logistic regression analysis evaluated factors associated with MVI. Results MVI was present in 52.2% (n = 133) of HCCs. On multivariate analysis only T1 mean (OR = 0.97, 95%CI 0.95–0.99, p = 0.043) and PVP entropy (OR = 4.7, 95%CI 1.37–16.3, p = 0.014) were associated with tumor MVI. Area under ROC curve was 0.83 for this final model. Empirical optimal cutpoint for PVP tumor entropy and T1 tumor mean were 5.73 and 23.41, respectively. At these cutpoint values, sensitivity was 0.68 and 0.5, respectively and specificity was 0.64 and 0.86. When both criteria were met, the probability of MVI in the tumor was 87%. Conclusion Tumor entropy and mean are both associated with MVI. Texture analysis on preoperative imaging correlates with microscopic features of HCC and can be used to predict patients with high-risk tumors.

Purpose To investigate the accuracy of rapid kV-switching single-source dual-energy computed tomography (rsDECT) for prediction of classes of non-uric-acid stones. Materials and methods Non-uric-acid renal stones retrieved via percutaneous nephrolithotomy were prospectively collected between January 2017 and February 2018 in a single institution. Only stones >= 5 mm and with pure composition (i.e., >= 80% composed of one component) were included. Stone composition was determined using Fourier Transform Infrared Spectroscopy. The stones were scanned in 32-cm-wide anthropomorphic whole-body phantom using rsDECT. The effective atomic number (Zeff), the attenuation at 40 keV (HU40), 70 keV (HU70), and 140 keV (HU140) virtual monochromatic sets of images as well as the ratios between the attenuations were calculated. Values of stone classes were compared using ANOVA and Mann-Whitney U test. Receiver operating curves and area under curve (AUC) were calculated. A p value < 0.05 was considered statistically significant. Results The final study sample included 31 stones from 31 patients consisting of 25 (81%) calcium-based, 4 (13%) cystine, and 2 (6%) struvite pure stones. The mean size of the stones was 9.9 +/- 2.4 mm. The mean Zeff of the stones was 12.01 +/- 0.54 for calcium-based, 11.10 +/- 0.68 for struvite, and 10.23 +/- 0.75 for cystine stones (p < 0.001). Zeff had the best efficacy to separate different classes of stones. The calculated AUC was 0.947 for Zeff; 0.833 for HU40; 0.880 for HU70; and 0.893 for HU140. Conclusion Zeff derived from rsDECT has superior performance to HU and attenuation ratios for separation of different classes of non-uric-acid stones.

Purpose: To determine whether hepatobiliary phase hypointensity, enhancing “capsule” and size provide prognostic information regarding the risk of progression to hepatocellular carcinoma (HCC), as well as the time to progression, of intermediate to high risk observations ≥ 10 mm with arterial phase hyperenhancement (APHE). Method: This retrospective dual-institution study included 160 LR-3 and 26 LR-4 observations measuring more than 10 mm and having APHE in 136 patients (mean age [SD], 57 [11] years old). A composite reference standard of pathologic analysis and imaging follow-up was used. The prognostic performance of hepatobiliary phase hypointensity, enhancing “capsule” and size (cut-off: 20 mm) for the prediction of probability of progression to HCC and median time to progression to HCC was assessed and compared by means of Log-rank test, Cox-regression and Kaplan-Meier curves. Results: 110 (59%) of 186 of observations progressed to HCC, 29.1% (32) progressed within 6 months, 60% (66) within 1 year and 84.5% (93) within 2 years. Hepatobiliary phase hypointensity was a significant predictor of progression to HCC (p < 0.0001, odds ratio: 20.62) but not of time to progression (p = 0.17). Median time to progression to HCC was 284 days [IQR: 266–363] and was shorter – though not significantly - for observations with enhancing “capsule” (118 days vs 301 days; p = 0.19). Conclusions: Hepatobiliary phase hypointensity is an independent predictor of progression to HCC in intermediate to high risk APHE observations ≥ 10 mm.

To determine whether the LI-RADS imaging features of primary liver carcinomas (PLCs) other than hepatocellular carcinoma (non-HCC PLCs) differ between patients considered high risk (RF+) versus not high risk (RF−) for HCC and to compare rates of miscategorization as probable or definite HCC between the RF+ and RF− populations. This retrospective study included all pathology-proven non-HCC PLCs imaged with liver-protocol CT or MRI from 2007 to 2017 at two liver transplant centers. Patients were defined per LI-RADS v2018 criteria as RF+ or RF−. Two independent, blinded readers (R1, R2) categorized 265 lesions using LI-RADS v2018. Logistic regression was utilized to assess for differences in imaging feature frequencies between RF+ and RF− patients. Fisher’s exact test was used to assess for differences in miscategorization rates. Non-HCC PLCs were significantly more likely to exhibit nonrim arterial phase hyperenhancement (R1: OR = 2.94; R2: OR = 7.09) and nonperipheral “washout” (R1: OR = 3.65; R2: OR = 7.69) but significantly less likely to exhibit peripheral “washout” (R1: OR = 0.30; R2: OR = 0.10) and delayed central enhancement (R1: OR = 0.18; R2: OR = 0.25) in RF+ patients relative to RF− patients. Consequently, non-HCC PLCs were more often miscategorized as probable or definite HCC in RF+ versus RF− patients (R1: 23.3% vs. 3.6%, p

BACKGROUND & AIMS: Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas and bile duct contain epithelial cells with numerous, large mitochondria and are cystic precursors to pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA), respectively. However, IOPNs do not have the genomic alterations found in other pancreatobiliary neoplasms. In fact, no recurrent genomic alterations have been described in IOPNs. PDACs without activating mutations in KRAS contain gene rearrangements, so we investigated whether IOPNs have recurrent fusions in genes. METHODS: We analyzed 20 resected pancreatic IOPNs and 3 resected biliary IOPNs using a broad RNA-based targeted sequencing panel to detect cancer-related fusion genes. Four invasive PDACs and 2 intrahepatic cholangiocarcinomas from the same patients as the IOPNs, were also available for analysis. Samples of pancreatic cyst fluid (n=5, collected before surgery) and bile duct brushings (n=2) were analyzed for translocations. For comparison, we analyzed pancreatobiliary lesions from 126 patients without IOPN (controls). RESULTS: All IOPNs evaluated were found to have recurring fusions of ATP1B1-PRKACB (n = 13), DNAJB1–PRKACA (n = 6), or ATP1B1–PRKACA (n = 4). These fusions were also found in corresponding invasive PDACs and intrahepatic cholangiocarcinomas, as well as in matched pancreatic cyst fluid and bile duct brushings. These gene rearrangements were absent from all 126 control pancreatobiliary lesions. CONCLUSIONS: We identified fusions in PRKACA and PRKACB genes in pancreatic and biliary IOPNs, as well as in PDACs and pancreatic cyst fluid and bile duct cells from the same patients. We did not identify these gene fusions in 126 control pancreatobiliary lesions. These fusions might be used to identify patients at risk for IOPNs and their associated invasive carcinomas.

International audience; How nuclear proteins diffuse and find their targets remains a key question in the transcription field. Dynamic proteins in the nucleus are classically subdiffusive and undergo anomalous diffusion, yet the underlying physical mechanisms are still debated. In this study, we explore the contribution of interactions to the generation of anomalous diffusion by the means of fluorescence spectroscopy and simulation. Using interaction-deficient mutants, our study indicates that HEXIM1 interactions with both 7SK RNA and positive transcription elongation factor b are critical for HEXIM1 subdiffusion and thus provides evidence of the effects of protein-RNA interaction on molecular diffusion. Numerical simulations allowed us to establish that the proportions of distinct oligomeric HEXIM1 subpopulations define the apparent anomaly parameter of the whole population. Slight changes in the proportions of these oligomers can lead to significant shifts in the diffusive features and recapitulate the modifications observed in cells with the various interaction-deficient mutants. By combining simulations and experiments, our work opens new prospects in which the anomaly a coefficient in diffusion becomes a helpful tool to infer alterations in molecular interactions.

A 39-year-old man was referred to our clinic for liver diseases for a liver mass incidentally found on CT done to rule out kidney stones (figure 1A). In our clinic, he was asymptomatic with regular bowel habits. He denied episodes of jaundice, did not have skin tattoos, never smoked or used illicit drugs and rarely consumed alcohol. His lifestyle was sedentary, and his diet consisted predominantly of fast food. His medical history included arterial hypertension and hyperlipidaemia. Several years prior, he had undergone a laparoscopic cholecystectomy. His obese abdomen (body mass index 36 kg/m2) was non-tender to palpation. On laboratory analysis, white blood cell count, haemoglobin, platelet count, bilirubin, liver transaminases and international normalised ratio (INR) were within …

International audience; How the mammalian circadian clock interacts with metabolism and its possible implications in metabolic diseases are actively studied. In PNAS, Foteinou et al. (1) propose a mathematical model of the circadian clock that incorporates the metabolic sensor SIRT1 and validate it with cell experiments. Their findings shed light on conflicting reports by Asher et al. (2) and Nakahata et al. (3) about the effect of SIRT1 deficiency on clock function and SIRT1 targets. The authors conclude that SIRT1 acts on the clock not only via the well-known clock protein PER2, but also through PGC-1α, a transcriptional co-activator of the BMAL1 clock gene with key metabolic functions. Interestingly, the Foteinou model is comparable to the model designed by Woller et al. (4) to understand the mechanisms of liver clock disruption observed upon high-fat diet (HFD) consumption. The two models describe the dynamics of the same molecular network, except that Woller et al. additionally consider clock regulation by the energy sensor AMPK. Remarkably, both models point to a key role of PGC-1α in the circadian clock from different perspectives. The Woller model takes into account the NAMPT-NAD+-SIRT1-PGC1α-ROR-BMAL1 metabolic loop and show its requirement to reproduce the dampened oscillations in clock gene expression observed by Hatori et al. (5) and Eckel-Mahan et al. (6) upon HFD feeding, a condition mimicked by altered AMPK activity. On the other hand, Foteinou et al. (1) report that inclusion of PGC-1α in their model is needed to reproduce correctly the altered reporter expression levels upon combined SIRT1 and BMAL1 silencing. These findings confirm the role of PGC-1α linking SIRT1 and AMPK activities: PGC-1α needs to be phosphorylated by AMPK before it can be deacetylated by SIRT1 (7). The key role of PGC-1α

PURPOSE: The Liver Imaging Reporting and Data System (LI-RADS) was created to standardize the diagnostic criteria for hepatocellular carcinoma (HCC), and has undergone multiple revisions including a recent update in 2018 (v2018). The primary aim of this study was to determine the diagnostic performance and interrater reliability (IRR) of LI-RADS v2018 for distinguishing HCC from non-HCC primary hepatic malignancy in patients ‘at-risk’ for HCC. A secondary aim was to assess the impact of changes introduced in the v2018 diagnostic algorithm. METHODS: This retrospective study combined a 10-year experience of pathologically-proven primary liver malignancies from two large liver transplant centers. Two blinded readers independently evaluated each lesion and assigned a LI-RADS diagnostic category, additionally scoring all relevant imaging features. Changes in category based on the reader-provided features and the new v2018 criteria were assessed by a study coordinator. RESULTS: The final study cohort comprised 105 HCCs and 73 non-HCC primarily liver malignancies. LI-RADS had a high specificity for distinguishing HCC from non-HCC (89% and 90% for reader 1 and reader 2, respectively), and IRR was moderate to substantial for final LI-RADS category and most features. Revision of the LI-RADS v2018 diagnostic algorithm resulted in very few changes (5 [2.8%] and 3 [1.7%] for reader 1 and reader 2, respectively) in overall lesion classification. CONCLUSION: LI-RADS diagnostic categories and features had moderate to substantial IRR and high specificity for distinguishing HCC from non-HCC primary liver malignancy. Revision of LI-RADS v2018 diagnostic algorithm resulted in reclassification of very few lesions.

OBJECTIVE. The objective of our study was to assess the diagnostic performance of texture analysis (TA) on gadoxetic acid-enhanced MR images for differentiation of hepatocellular adenoma (HCA) from focal nodular hyperplasia (FNH).MATERIALS AND METHODS. This study included 40 patients (39 women and one man) with 51 HCAs and 28 patients (27 women and one man) with 32 FNH lesions. All lesions were histologically proven with preoperative MRI performed with gadoxetic acid. Two readers reviewed all the imaging sequences to assess the qualitative MRI characteristics. The T2-weighted fast spin-echo, hepatic arterial phase (HAP), and hepatobiliary phase (HBP) sequences were used for TA. Textural features were extracted using commercially available software (TexRAD). The differences in distributions of TA parameters of FNHs and HCAs were assessed using the Mann-Whitney U test. Area under the ROC curve (AUROC) values were calculated for statistically significant features. A logistic regression analysis was conducted to explore the added value of TA. A p value < 0.002 was considered statistically significant after Bonferroni correction for multiple comparisons.RESULTS. Multiple TA parameters showed a statistically different distribution in HCA and FNH including skewness on T2-weighted imaging, skewness on HAP imaging, skewness on HBP imaging, and entropy on HBP imaging (p < 0.001). Skewness on HBP imaging showed the largest AUROC (0.869; 95% CI, 0.777-0.933). A skewness value on HBP imaging of greater than -0.06 had a sensitivity of 72.5% and a specificity of 90.6% for the diagnosis of HCA. Six of 51 (11.8%) HCAs lacked hypointensity on HBP imaging. A binary logistic regression analysis including hypointensity on HBP imaging and the statistically significant TA parameters yielded an AUROC of 0.979 for the diagnosis of HCA and correctly predicted 96.4% of the lesions.CONCLUSION. TA may be of added value for the diagnosis of atypical HCA presenting without hypointensity on HBP imaging.

The goal of the Liver Imaging Reporting and Data System (LI-RADS) is to standardize the interpretation and reporting of liver observations on contrast-enhanced CT and MR imaging of patients at risk for hepatocellular carcinoma. Although LI-RADS represents a significant achievement in standardization of the diagnosis and management of cirrhotic patients, complexity and caveats to the algorithm may challenge correct application in clinical practice. The purpose of this paper is to discuss common pitfalls and potential solutions when applying LI-RADS in practice. Knowledge of the most common pitfalls may improve the diagnostic confidence and performance when using the LI-RADS system for the interpretation of CT and MR imaging of the liver.

OBJECTIVE. The purpose of this study was to determine the diagnostic performance of hepatobiliary phase hypointensity and Liver Imaging Reporting and Data System (LI-RADS) major imaging features in the diagnosis of hepatocellular carcinoma (HCC) in hepatic lesions with arterial phase hyperenhancement (APHE) measuring 10-19 mm in patients at high risk of HCC. MATERIALS AND METHODS. A composite reference standard of pathologic analysis and imaging follow-up was used. The diagnostic performance (sensitivity and specificity) of hepatobiliary phase hypointensity and LI-RADS major imaging features other than APHE for the diagnosis of HCC was assessed and compared by means of a logistic regression model. RESULTS. This retrospective dual-institution study included 189 LI-RADS LR-3 and LR-4 lesions measuring 10-19 mm and having APHE in 144 consecutively registered patients (96 men, 48 women; mean age, 58 years). Hepatobiliary phase hypointensity had significantly higher sensitivity (84% [92/109], p < 0.00001) than major imaging features in the diagnosis of HCC but lower specificity (84% [67/80]; p = 0.01). However, hepatobiliary phase hypointensity in LR-3 observations measuring 10-19 mm and having APHE had moderately elevated sensitivity (73% [44/60]) and specificity (85%, 64/75). All three major imaging features had high specificity for the diagnosis of HCC, including 95% (76/80) for washout, 100% (80/80) for enhancing capsule, and 99% (79/80) for threshold growth. CONCLUSION. Major imaging features have high specificity for the diagnosis of HCC in lesions measuring 10-19 mm that have APHE. The finding of hepatobiliary phase hypointensity significantly improves sensitivity while moderately high specificity is maintained for the diagnosis of HCC in LR-3 lesions measuring 10-19 mm that exhibit APHE.

Background Hepatocellular carcinoma (HCC) can be diagnosed using imaging criteria in patients at high-risk for HCC, according to Liver Imaging Reporting and Data System (LI-RADS) guidelines. The aim of this study was to determine the diagnostic performance and inter-rater reliability (IRR) of LI-RADS v2018 for differentiating HCC from non-HCC primary liver carcinoma (PLC), in patients who are at increased risk for HCC but not included in the LI-RADS ‘high-risk’ population. Methods This retrospective HIPAA-compliant study included a 10-year experience of pathologically-proven PLC at two liver transplant centers, and included patients with non-cirrhotic hepatitis C infection, non-cirrhotic non-alcoholic fatty liver disease, and fibrosis. Two readers evaluated each lesion and assigned an overall LI-RADS diagnostic category, additionally scoring all major, LR-M, and ancillary features. Results The final study cohort consisted of 27 HCCs and 104 non-HCC PLC in 131 patients. The specificity of a ‘definite HCC’ designation was 97% for reader 1 and 100% for reader 2. The IRR was fair for overall LI-RADS category and substantial for most major features. Conclusion In a population at increased risk for HCC but not currently included in the LI-RADS ‘high-risk’ population, LI-RADS v2018 demonstrated very high specificity for distinguishing pathologically-proven HCC from non-HCC PLC.

Purpose: To conduct an intraindividual comparison of the enhancement pattern of hepatocellular adenoma (HCA) on dynamic MRI study obtained following the injection of Gadoxetic acid (Gd-EOB-DTPA) and other gadolinium-based contrast agents (GBCAs).Method: This is a retrospective, Institutional Review Board-approved study conducted in a single institution. A search of medical records between 2008 and 2017 revealed 17 patients (all females) with at least one pathologically-proven HCA who underwent liver MRI with Gd-EOB-DTPA and another GBCA within 1 year. Enhancement of each lesion on hepatic arterial (HAP), portal venous (PVP), 2 min and 4-5 minutes phases was subjectively evaluated by two abdominal radiologists. Lesions were categorized as hyper-, iso- or hypointense compared to the surrounding liver parenchyma. The presence of a peripheral pseudocapsule was also recorded. The differences in lesion enhancement were assessed using the McNemar Test. A p-value

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. The Liver Imaging and Reporting Data System (LI-RADS) is a comprehensive system for standardizing the terminology, technique, interpretation, reporting, and data collection of liver imaging with the overarching goal of improving communication, clinical care, education, and research relating to patients at risk for or diagnosed with hepatocellular carcinoma (HCC). In 2018, the American Association for the Study of Liver Diseases (AASLD) integrated LI-RADS into its clinical practice guidance for the imaging-based diagnosis of HCC. The harmonization between the AASLD and LI-RADS diagnostic imaging criteria required minor modifications to the recently released LI-RADS v2017 guidelines, necessitating a LI-RADS v2018 update. This article provides an overview of the key changes included in LI-RADS v2018 as well as a look at the LI-RADS v2018 diagnostic algorithm and criteria, technical recommendations, and management suggestions. Substantive changes in LI-RADS v2018 are the removal of the requirement for visibility on antecedent surveillance ultrasound for LI-RADS 5 (LR-5) categorization of 10-19 mm observations with nonrim arterial phase hyper-enhancement and nonperipheral “washout”, and adoption of the Organ Procurement and Transplantation Network definition of threshold growth (≥ 50% size increase of a mass in ≤ 6 months). Nomenclatural changes in LI-RADS v2018 are the removal of -us and -g as LR-5 qualifiers.

RNA abundance is a powerful indicator of the state of individual cells. Single-cell RNA sequencing can reveal RNA abundance with high quantitative accuracy, sensitivity and throughput 1 . However, this approach captures only a static snapshot at a point in time, posing a challenge for the analysis of time-resolved phenomena such as embryogenesis or tissue regeneration. Here we show that RNA velocity—the time derivative of the gene expression state—can be directly estimated by distinguishing between unspliced and spliced mRNAs in common single-cell RNA sequencing protocols. RNA velocity is a high-dimensional vector that predicts the future state of individual cells on a timescale of hours. We validate its accuracy in the neural crest lineage, demonstrate its use on multiple published datasets and technical platforms, reveal the branching lineage tree of the developing mouse hippocampus, and examine the kinetics of transcription in human embryonic brain. We expect RNA velocity to greatly aid the analysis of developmental lineages and cellular dynamics, particularly in humans.

The mammalian nervous system executes complex behaviors controlled by specialised, precisely positioned and interacting cell types. Here, we used RNA sequencing of half a million single cells to create a detailed census of cell types in the mouse nervous system. We mapped cell types spatially and derived a hierarchical, data-driven taxonomy. Neurons were the most diverse, and were grouped by developmental anatomical units, and by the expression of neurotransmitters and neuropeptides. Neuronal diversity was driven by genes encoding cell identity, synaptic connectivity, neurotransmission and membrane conductance. We discovered several distinct, regionally restricted, astrocytes types, which obeyed developmental boundaries and correlated with the spatial distribution of key glutamate and glycine neurotransmitters. In contrast, oligodendrocytes showed a loss of regional identity, followed by a secondary diversification. The resource presented here lays a solid foundation for understanding the molecular architecture of the mammalian nervous system, and enables genetic manipulation of specific cell types.

Biochemical studies have revealed that the RNA Polymerase II (RNAPII) pause release is triggered by phosphorylation of the transcription machinery by the positive transcription elongation factor b (P-TEFb). However, there are no direct report that P-TEFb and RNA polymerase II interact in single living cells and the biophysical mechanisms mediating this association are still unclear. Forster resonance energy transfer (FRET) detects molecular interactions at the subcellular level. Time domain fluorescence lifetime imaging provides an accurate quantification of FRET efficiency, E FRET , because it is fluorochrome concentration-independent and insensitive to fluorescence bleed-through. However, the way FRET signal is usually analyzed does not provide information about the areas where protein-protein interactions take place. In this work, we developed a method, dubbed FRET image correlation spectroscopy (FICS), which relied on FRET fluorescence lifetime imaging image acquisition and image correlation spectroscopy of E FRET clusters to quantify the spatial distribution of interaction clusters in the nucleus. The combination of high content FRET microscopy with batch image analysis allowed a robust statistical analysis. By applying FICS, we characterized the area and density of interaction clusters between P-TEFb and RNAPII or histone H2A in single living cells. The FICS method applied to cells expressing genetically engineered mutated proteins confirmed that the histidine-rich domain of P-TEFb is required for its interaction with RNAPII. Furthermore, it demonstrated that P-TEFb was also located in close vicinity to histone H2A, independently of its interactions with RNAPII. These results support the hypothesis that P-TEFb dynamics on chromatin regulate its recruitment on RNAPII.

RNA abundance is a powerful indicator of the state of individual cells, but does not directly reveal dynamic processes such as cellular differentiation. Here we show that RNA velocity—the time derivative of RNA abundance—can be estimated by distinguishing unspliced and spliced mRNAs in standard single-cell RNA sequencing protocols. We show that RNA velocity is a vector that predicts the future state of individual cells on a timescale of hours. We validate the accuracy of RNA velocity in the neural crest lineage, demonstrate its use on multiple technical platforms, reconstruct the branching lineage tree of the mouse hippocampus, and measure RNA kinetics in human embryonic brain. We expect RNA velocity to greatly aid the analysis of developmental lineages and cellular dynamics, particularly in humans.

INTRODUCTION Circulating adrenaline can have profound effects on the body’s “inner world,” adjusting levels depending on demand to maintain organ and bodily homeostasis during daily living. In the more extreme fight-or-flight response, the surge of adrenaline is “energizing” through effects on organs and tissues, including increased heart rate and blood glucose levels, and redirecting oxygen and glucose to limb muscles. Chromaffin cells located in the adrenal medulla constitute the main hormonal component of the autonomic nervous system and are the principal source for release of catecholamines, including adrenaline, in the systemic circulation. Understanding the cellular origin and biological processes by which the adrenal medulla is formed during development is needed for mechanistic insights into how the hormonal component of the autonomic nervous system is formed and its relation to the rest of the autonomic nervous system. RATIONALE Adrenergic chromaffin cells in the adrenal medulla are thought to originate from a common sympathoadrenal lineage close to the dorsal aorta, where these cells split in a dorsoventral direction, forming the sympathetic chain and adrenal medulla, respectively. Revisiting this dogma, we examined the cell type origin of chromaffin cells, lineage segregation of sympathoblasts and chromaffin cells, the gene programs driving specification of chromaffin cells from progenitors, and the proliferative dynamics by which the adrenal medulla is formed. RESULTS We found that chromaffin cells of the adrenal medulla are formed from peripheral glia stem cells, termed Schwann cell precursors. Genetic cell lineage tracing revealed that most chromaffin cells arise from Schwann cell precursors, and consistently, genetic ablation of Schwann cell precursors results in marked depletion of chromaffin cells. Genetic ablation of the preganglionic nerve, on which Schwann cell precursors migrate, similarly leads to marked deficiencies of chromaffin cells, and fate-tracing cells unable to differentiate into chromaffin cells reveal an accumulation of glia cells in the region of the adrenal medulla. Experiments reveal that sympathetic and adrenergic lineages diverge at an unexpectedly early stage during embryonic development. Embryonic development of the adrenal medulla relies on recruitment of numerous Schwann cell precursors with limited cell expansion. Thus, the large majority of chromaffin cells arise from Schwann cell precursors migrating on preganglionic nerves innervating the adrenal medulla. Unexpectedly, single-cell RNA sequencing revealed a complex gene-regulatory mechanism during differentiation of Schwann cell precursors to chromaffin cells, whereby Schwann cell precursors enter into a gene expression program unique for a transient cellular state. Subsequently, this gene program and chromaffin cell gene networks suppress glial gene programs, advancing cells into the chromaffin cell identity. CONCLUSION By revisiting development of the adrenergic sympathetic system, we discovered a new cellular origin of this nervous system component. The adrenergic medulla is built from both neural crest cells and Schwann cell precursors, with a major contribution from Schwann cell precursors in rodents. A cellular origin from Schwann cell precursors highlights the importance of peripheral nerves as a stem cell niche and transportation routes for progenitors essential for neuroendocrine development. These results and mechanisms of differentiation through a transient intermediate cell type may also be helpful in advancing our knowledge on neuroblastoma and pheochromocytoma, because these most often arise from the adrenal gland region.

International audience; Inhibitors of the receptor tyrosine kinase (RTK) MET have been ineffective at treating cancer, possibly because of lack of knowledge that would allow selection of tumors likely to respond to this treatment. In contrast, specific epidermal growth factor receptor (EGFR) inhibitors have been used successfully against lung tumors displaying activating mutations in the kinase domain of EGFR. Recent publications describe a set of mutations causing MET exon 14 skipping, and importantly, several case reports describe objective responses to MET-targeting tyrosine kinase inhibitors in patients with such mutations. These observations suggest a novel therapeutic strategy for fighting cancer, especially in the lung. Exon 14 encodes the MET juxtamembrane domain targeted by mechanisms that negatively regulate receptor stability and activity. In this review, we describe the molecular mechanisms leading first to exon 14 skipping and then to activation of the MET receptor and how this process differs from that triggered by classical RTK-activating mutations in the kinase domain. We detail the clinical characteristics of patients carrying these mutations and the sensitivity of their tumors to MET inhibitors. Lastly, we discuss future challenges related to MET mutations in cancers, including patient screening and anticipating resistance to MET inhibitors.

GOALS To explore the diagnostic challenges, management, and clinical outcomes of patients with isolated peripancreatic necrosis (PPN), with emphasis on the extent of involvement, and compare them to pancreatic necrosis (PN). BACKGROUND PPN, a relatively new term, has been included as a separate entity in the Revised Atlanta Classification. STUDY Clinical data of recruited acute pancreatitis patients were recorded prospectively. Contrast-enhanced computed tomographic scans were reviewed by expert radiologists blinded to clinical outcomes. RESULTS In total, 271 of the 400 acute pancreatitis patients underwent contrast-enhanced computed tomography, of which 29 (11%) had PPN (14: limited; 15: extensive) and 124 (46%) PN (40: 50% of parenchyma). Patients with PPN were similar to PN in age (56 y), gender (55% male), and body mass index (29 kg/m(2)). Nutritional support was provided in 18 (62%) patients with PPN and 97 (78%) with PN (P=0.12). Drainage/debridement was required in 2 patients (7%) with PPN and 64 (53%) with parenchymal necrosis (P

Vascular torsion is a rare renal transplant complication which requires prompt diagnosis and surgery to salvage allograft function. We report here a case of renal allograft torsion with interesting imaging findings on unenhanced CT and color Doppler ultrasound. A 60-year-old woman with a history of pancreas and kidney transplant presented to the emergency room with nausea, vomiting, abdominal pain, and minimal urine output. Unenhanced CT of the abdomen demonstrated an enlarged and malrotated renal allograft with moderate hydronephrosis. Color Doppler ultrasound demonstrated lack of vascularity within the allograft. The patient was taken urgently to the operating room where the renal allograft was found twisted 360 degrees around the vascular pedicle. After the allograft was detorsed, the color of the kidney returned and the Doppler signals for arterial flow improved. Intraoperative biopsy showed no evidence of infarct or acute cellular rejection. The detorsed kidney was surgically fixed in position in its upper and lower poles. Follow-up ultrasound 1 day later demonstrated normal blood flow to the renal allograft and the serum level of creatinine returned to normal.

In this short review, we put emphasis on the importance of ETS transcription factor family, and more especially of its founder Ets-1, in the control of epithelium-mesenchyme dialogues. In the context of tumor progression, Ets-1 expression can be induced by various stromal instructive signals. Reciprocally, integration of these various microenvironmental influences via Ets-1 will result in the remodeling of the extracellular matrix by tumor cells. We sum up the current knowledge about the balance between cell growth and invasion orchestrated by EMT drivers, among which Ets-1, and the growing evidence that EMT needs to be spatio-temporally regulated along tumor progression and metastasis. We eventually discuss the impact these data have on our understanding of tumorigenesis, and the consideration they should be given when elaborating therapeutic anticancer strategies.

Objectives To assess the effects of acupuncture and dry-needling for the treatment of nonspecific low back pain. Background Low back pain is usually a self-limiting condition that tends to improve spontaneously over time. However, for many people, back pain becomes a chronic or recurrent problem for which a large variety of therapeutic interventions are employed. Search strategy We updated the searches from 1996 to February 2003 in CENTRAL, MEDLINE, and EMBASE. We also searched the Chinese Cochrane Centre database of clinical trials and Japanese databases to February 2003. Selection criteria Randomized controlled trials of acupuncture (that involved needling) or dry-needling for adults with nonspecific acute/subacute or chronic low back pain. Data collection and analysis Two reviewers independently assessed methodologic quality (using the criteria recommended by the Cochrane Back Review Group) and extracted data. The trials were combined using meta-analysis methods or levels of evidence when the data reported did not allow statistical pooling. Results Thirty-five randomized clinical trials were included: 20 were published in English, 7 in Japanese, 5 in Chinese, and 1 each in Norwegian, Polish, and German. There were only 3 trials of acupuncture for acute low back pain. These studies did not justify firm conclusions because of their small sample sizes and low methodologic quality. For chronic low back pain, there is evidence of pain relief and functional improvement for acupuncture compared to no treatment or sham therapy. These effects were only observed immediately after the end of the sessions and in short-term follow-up. There is also evidence that acupuncture, added to other conventional therapies, relieves pain and improves function better than the conventional therapies alone. However, the effects are only small. Dry-needling appears to be a useful adjunct to other therapies for chronic low back pain. No clear recommendations could be made about the most effective acupuncture technique. Conclusions The data do not allow firm conclusions regarding the effectiveness of acupuncture for acute low back pain. For chronic low back pain, acupuncture is more effective for pain relief and functional improvement than no treatment or sham treatment immediately after treatment and in the short-term only. Acupuncture is not more effective than other conventional and "alternative" treatments. The data suggest that acupuncture and dry-needling may be useful adjuncts to other therapies for chronic low back pain. Because most of the studies were of lower methodologic quality, there is a clear need for higher quality trials in this area.

Detection and characterization of focal lesions in the cirrhotic liver may pose a diagnostic dilemma. Several benign and malignant lesions may be found in a cirrhotic liver along with hepatocellular carcinoma (HCC), and may exhibit typical or atypical imaging features. In this pictorial essay, we illustrate computed tomography and magnetic resonance imaging findings of lesions such as simple bile duct cysts, hemangioma, focal nodular hyperplasia-like nodules, peribiliary cysts, intrahepatic cholangiocarcinoma, lymphoma, and metastases, all of which occur in cirrhotic livers with varying prevalences. Pseudolesions, such as perfusion anomalies, focal confluent fibrosis, and segmental hyperplasia, will also be discussed. Imaging characterization of non-HCC lesions in cirrhosis is important in formulating an accurate diagnosis and triaging the patient towards the most appropriate management.

The sympathetic nervous system relies on distinct populations of neurons that use noradrenaline or acetylcholine as neurotransmitter. We show that fating of the sympathetic lineage at early stages results in hybrid precursors from which, genetic cell-lineage tracing reveals, all types progressively emerge by principal mechanisms of maintenance, repression and induction of phenotypes. The homeobox transcription factor HMX1 represses Tlx3 and Ret, induces TrkA and maintains tyrosine hydroxylase (Th) expression in precursors, thus driving segregation of the noradrenergic sympathetic fate. Cholinergic sympathetic neurons develop through cross-regulatory interactions between TRKC and RET in precursors, which lead to Hmx1 repression and sustained Tlx3 expression, thereby resulting in failure of TrkA induction and loss of maintenance of Th expression. Our results provide direct evidence for a model in which diversification of noradrenergic and cholinergic sympathetic neurons is based on a principle of cross-repressive functions in which the specific cell fates are directed by an active suppression of the expression of transcription factors and receptors that direct the alternative fate.

Background & Aims: Genetic studies indicate that distinct signaling modulators are each necessary but not individually sufficient for embryonic hepatocyte survival in vivo. Nevertheless, how signaling players are interconnected into functional circuits and how they coordinate the balance of cell survival and death in developing livers are still major unresolved issues. In the present study, we examined the modulation of the p53 pathway by HGF/ Met in embryonic livers. Methods: We combined pharmacological and genetic approaches to biochemically and functionally evaluate p53 pathway modulation in primary embryonic hepatocytes and in developing livers. RT-PCR arrays were applied to investigate the selectivity of p53 transcriptional response triggered by Met. Results: Met recruits p53 to regulate the liver developmental program, by qualitatively modulating its transcriptional properties: turning on the Mdm2 survival gene, while keeping death and cell-cycle arrest genes Pmaip1 and p21 silent. We investigated the mechanism leading to p53 regulation by Met and found that Abl and p38MAPK are required for p53 phosphorylation on S 389 , Mdm2 upregulation, and hepatocyte survival. Alteration of this signaling mechanism switches p53 properties, leading to p53-dependent cell death in embryonic livers. RT-PCR array studies affirmed the ability of the Met-Abl-p53 axis to modulate the expression of distinct genes that can be regulated by p53. Conclusions: A signaling circuit involving Abl and p38MAPK is required downstream of Met for the survival of embryonic hepatocytes, via qualitative regulation of the p53 transcriptional response, by switching its proapoptotic into survival properties. 2012 European Association for the Study of the Liver. Published

OBJECTIVE:To evaluate agreement between contrast-enhanced ultrasound (CEUS), multi-detector row computed tomography (MDCT) and magnetic resonance imaging (MRI) for the assessment of typical and atypical enhancement patterns of small hepatocellular carcinoma (HCC); and to compare diagnostic sensitivity of 2005 and 2010 American Association for the Study of Liver Diseases (AASLD) guidelines. MATERIALS AND METHODS: Between January 2008 and December 2009, we included cirrhotic patients with newly diagnosed 10-20 mm HCC imaged at two contrast-enhanced imaging techniques among CEUS, MDCT, and MRI. Dynamic studies were reviewed by two radiologists to assess enhancement pattern. Percentage of cases with concordant findings and Cohen coefficient (k) were calculated. McNemar's test was used to compare sensitivity between 2005 and 2010 AASLD guidelines. RESULTS: There were 91 patients (69 M; 22 F; mean age, 68 years) with 96 HCCs, studied with a combination of CEUS and MDCT (n=59), CEUS and MRI (n=26), or MDCT and MRI (n=11). Intermodality agreement for assessment of tumor enhancement pattern was 67% (k=0.294, P=0.001). Typical enhancement pattern was detected coincidentally at two imaging modalities in 50 (52%) HCCs. Sensitivity for the diagnosis of HCC increased significantly using the 2010 AASLD (81/96 (84%) vs. 50/96 (52%), P