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SummaryDysfunction of natural killer (NK) cells is associated with poor prognosis in hepatocellular carcinoma (HCC). We explored the phenotypic and functional characteristics of peripheral blood NK cells in HCC patients following sorafenib treatment.Peripheral blood samples were collected from 60 HCC patients in a single centre (2015~2017) and 45 healthy donors. The percentage and cytoplasmic granule production of NK cells were analysed. Subset proportions were evaluated for their associations with the modified Response Evaluation Criteria in Solid Tumors (mRECIST), time to progression, and median overall survival (OS).Compared with baseline, the percentages of total and CD56dimCD16+ NK cells increased after two months of treatment, while the percentage of CD56brightCD16− NK cells decreased, leading to a dramatically reduced ratio of CD56bright and CD56dim NK cells (ratiobri/dim). Patients with low ratiobri/dim exhibited better mRECIST responses and longer median OS than those with high ratiobri/dim. The expression levels of granzyme B and perforin in total NK cells and in both subsets of cells were increased after treatment.This study showed that sorafenib could affect the proportions and functions of peripheral CD56brightCD16− and CD56dimCD16+ NK cells, which was associated with the outcomes including OS of HCC patients.

The Clear Sky Radiance (CSR) product has been widely used instead of Level 1 (L1) geostationary imager data in data assimilation for numerical weather prediction due to its many advantages concerning superobservation methodology. In this study, CSR was produced in two water vapor channels (channels 9 and channel 10, with wavelengths at 5.8–6.7 μm and 6.9–7.3 μm) of the Advanced Geostationary Radiation Imager aboard Fengyun 4A. The root mean square error (RMSE) between CSR observations and backgrounds was used as a quality flag and was predicted by cloud cover, standard deviation (STD), surface type, and elevation of a CSR field of view (FOV). Then, a centesimal scoring system based on the predicted RMSE was set to a CSR FOV that indicates its percentile point in the quality distribution of the whole FOV. Validations of the scoring system demonstrated that the biases of the predicted RMSE were small for all FOVs and that the score was consistent with the predicted RMSE, especially for FOVs with high scores. We suggest using this score for quality control (QC) to replace the QC of cloud cover, STD, and elevation of CSR, and we propose 40 points as the QC threshold for the two channels, above which the predicted RMSE of a CSR is superior to the RMSE of averaged clear-sky L1 data.

To make better use of microwave radiance observations for data assimilation, removal of radiances contaminated by hydrometeor particles is one of the most important steps. Generally, all observations below the middle troposphere are eliminated before the analysis when precipitation is present. However, the altitude of the cloud top varies; when the weighting function peak height of a channel is higher than the altitude of the cloud top, observations are not affected by the absorption or scattering of cloud particles. Thus, the radiative transfer calculation can be performed under a clear sky scenario. In this paper, a dynamic channel selection (DCS) method was developed to determine the radiance observations unaffected by clouds under cloudy conditions in assimilation. First, the sensitivity of cloud liquid water (CLW) profiles to radiance from the microwave temperature sounding frequencies was analyzed. It was found that the impact of CLW on transmittance can be neglected where the cloud top height is below the weighting function peak height. Second, three lookup tables were devised through analysis of the impact of cloud fraction and cloud top height on radiance, which is the basis of the DCS method. The unified cloud top height of the Microwave Temperature Sounder (MWTS)-2 fields of view (FOVs) can be calculated by remapping the cloud mask and cloud top height data from the Medium Resolution Spectral Imager-2 (MERSI-2). Observations from various channels may be removed or retained based on real-time dynamic unified cloud top height data. Twelve-hour and long-term time-series brightness temperature simulation experiments both showed that an increase in the amount of observations used for data assimilation of more than 300% can be achieved by application of DCS, but this had no effect on the amount of error. Through DCS, areas of strong precipitation can be accurately identified and removed, and more observations above cloud top height can be included in the data assimilation. The application of DCS to data assimilation will greatly improve the data utilization rate, and therefore allow for more accurate characterization of upper atmospheric circulation.

SummaryBackground & Aims Sorafenib-related adverse events have been reported as clinical surrogates for treatment response in hepatocellular carcinoma (HCC); however, no consensus has been reached regarding the definition of responders. We evaluated the predictive abilities of different definitions for sorafenib response based on treatment-emergent adverse events, aiming to identify the most discriminatory one as a clinical marker. Methods From January 2010 to December 2014, 435 consecutive HCC patients treated with sorafenib were enrolled. Considering the type, severity and timing of adverse events, twelve different categories of sorafenib response were defined. By comparing their discriminatory abilities for survival, an indicative criterion was defined, the prognostic value of which was evaluated by time-dependent multivariate analysis, validated in various subsets and confirmed by landmark analysis. Results Using concordance (C)-index analysis and time-dependent receiver operating characteristic curves, the development of a hand-foot-skin reaction ≥ grade 2 within 60 days of sorafenib initiation (2HFSR60) showed the highest discriminating value. Based on this criterion, 161 (37.0%) sorafenib responders achieved decreased risk of death by 47% (adjusted HR 0.53, 95%CI 0.43–0.67, P < 0.001) and likelihood of progression by 26% (adjusted HR 0.74, 95%CI 0.58–0.96, P = 0.020) compared with non-responders. Notably, 2HFSR60 remained an effective discriminator among most subgroups and had superior predictive ability to previous definitions, even according to the landmark analysis. Conclusions Our study demonstrated that 2HFSR60, with the best discriminatory ability compared to currently available definitions of sorafenib-related adverse events, could be the optimal clinical marker to identify sorafenib responders with decreased risk of death by half.

ObjectivesEarly placement of transjugular intrahepatic portosystemic shunt (TIPS) has been shown to improve survival in high-risk patients (Child-Pugh B plus active bleeding at endoscopy or Child-Pugh C 10–13) with cirrhosis and acute variceal bleeding (AVB). However, early TIPS criteria may overestimate the mortality risk in a significant proportion of patients, and the survival benefit conferred by early TIPS in such patients has been questioned. Alternative criteria have been proposed to refine the criteria used to identify candidates for early TIPS. Nevertheless, the true survival benefit provided (or not) by early TIPS compared with standard treatment in the different risk categories has not been investigated in specifically designed comparative studies.DesignWe collected data on 1425 consecutive patients with cirrhosis and AVB who were admitted to 12 university hospitals in China between December 2010 and June 2016. Of these, 206 patients received early TIPS, and 1219 patients received standard treatment. The Fine and Gray competing risk regression model was used to compare the outcomes between the two groups that were stratified based on the currently available risk stratification systems after adjusting for liver disease severity and other potential confounders.ResultsOverall, early TIPS was associated with an 80% relative risk reduction (RRR) in mortality at 6 weeks (adjusted HR=0.20; 95% CI: 0.10 to 044; p<0.001) and 51% RRR at 1 year (adjusted HR=0.49, 95% CI: 0.32 to 0.73; p<0.001) compared with standard treatment. In stratification analyses, the RRRs in mortality did not significantly differ among the risk categories. However, the absolute risk reductions (ARRs) of mortality were more pronounced in high-risk patients. The ARRs at 6 weeks were −2.1%, −10.2% and −32.4% in Model for End-stage Liver Disease (MELD) ≤11, 12–18 and ≥19 patients and were −1.5%, −9.1% and −23.2% in Child-Pugh A, B and C patients, respectively (interaction tests, p<0.001 for both criteria). The ARRs for mortality at 1 year were −1.7%, −5.4% and −32.7% in MELD ≤11, 12–18 and ≥19 patients, respectively, and −3.6%, −5.2% and −20.3% in Child-Pugh A, B and C patients, respectively (interaction tests, p<0.001 for both criteria). After adjusting for liver disease severity and other potential confounders, a survival benefit was observed in MELD ≥19 or Child-Pugh C patients but not in MELD ≤11 or Child-Pugh A patients. In MELD 12–18 patients, a survival benefit was observed within 6 weeks but not at 1 year. In Child-Pugh B patients, a survival benefit was observed in those with active bleeding but not those without active bleeding. However, the evaluation of active bleeding was associated with a high interobserver variability. Furthermore, early TIPS was associated with a significantly reduced incidence of failure to control bleeding or rebleeding and new or worsening ascites, without increasing the risk of overt hepatic encephalopathy.ConclusionsEarly TIPS was associated with improved survival in patients with MELD ≥19 or Child-Pugh C cirrhosis but not in patients with MELD ≤11 or Child-Pugh A cirrhosis. For MELD 12–18 or Child-Pugh B patients, future studies addressing optimal selection criteria for early TIPS remain highly warranted.

Previous studies show a close relationship between the East Asian Summer Monsoon (EASM) and Southern Hemisphere (SH) circulation on interannual timescales. In this study, we investigate whether this close relationship will change under intensive greenhouse-gas effect by analyzing simulations under two different climate background states: preindustrial era and Representative Concentration Pathway (RCP) 8.5 stabilization from the Community Climate System Model Version 4 (CCSM4). Results show a significantly reduced relationship under stabilized RCP8.5 climate state, such a less correlated EASM with the sea level pressure in the southern Indian Ocean and the SH branch of local Hadley Cell. Further analysis suggests that the collapse of the Atlantic Meridional Overturning Circulation (AMOC) due to this warming leads to a less vigorous northward meridional heat transport, a decreased intertropical temperature contrast in boreal summer, which produces a weaker cross-equatorial Hadley Cell in the monsoonal region and a reduced Interhemispheric Mass Exchange (IME). Since the monsoonal IME acts as a bridge connecting EASM and SH circulation, the reduced IME weakens this connection. By performing freshwater hosing experiment using the Flexible Global Ocean—Atmosphere—Land System model, Grid-point Version 2 (FGOALS-g2), we show a weakened relationship between the EASM and SH circulation as in CCSM4 when AMOC collapses. Our results suggest that a substantially weakened AMOC is the main driver leading to the EASM, which is less affected by SH circulation in the future warmer climate.

Establishing a long-term vascular access in patients exhibiting vascular access exhaustion is challenging. In this study, we reported a case of a direct catheterization in the superior vena cava of a hemodialysis patient with vascular access exhaustion and original dysfunctional catheter inserted via the left internal jugular vein. The direct catheterization was performed with cuffed tunnel catheter （CUFF） and guided by digital subtraction angiography （DSA） and multidetector computedtomography venography （MDCTV）. The DSA and MDCTV results revealed an occlusion in the right innominate vein and thromboses in the left innominate, right internal jugular, subclavian, and femoral veins. The distal end of the superior vena cava was localized clearly by the original CUFF under DSA. Directed at the distal end of the superior vena cava, a 0.5-cm secondary puncture was introduced below the lateral head of the sternocleidomastoid muscle via the right neck area. This study is one of the few reports regarding direct catheterization of CUFF via the superior vena cava of a patient with vascular access exhaustion and CUFF dysfunction on the left internal jugular vein. We believe that our study can provide a new alternative for inserting central venous catheter for such patient.

Lymphatic metastases are closely associated with tumor relapse and reduced survival in colorectal cancer (CRC). How tumor cells disseminate within the lymphatic network remains largely unknown. Here, we analyze the subclonal structure of 94 tumor samples, covering the primary tumors, lymph node metastases (LNMs), and liver metastases from 10 CRC patients. We portray a high-resolution lymphatic metastatic map for CRC by dividing LNMs into paracolic, intermediate, and central subgroups. Among the 61 metastatic routes identified, 38 (62.3%) are initiated from the primary tumors, 22 (36.1%) from LNMs, and 1 from liver metastasis (1.6%). In 5 patients, we find 6 LNMs that reseed 2 or more LNMs. We summarize 3 diverse modes of metastasis in CRC and show that skip spreading of tumor cells within the lymphatic network is common. Our study sheds light on the complicated metastatic pattern in CRC and has great clinical implications. Lymphatic metastases are closely associated with tumor relapse and reduced survival in colorectal cancer (CRC). Here, the authors analysed the primary tumours, lymph node metastasis and liver metastasis of ten CRC patients and reveal co-existence of diverse modes of metastasis in the same patient.

Non-invasive assessment of the risk of lymph node metastasis (LNM) in patients with papillary thyroid carcinoma (PTC) is of great value for the treatment option selection. The purpose of this paper is to develop a transfer learning radiomics (TLR) model for preoperative prediction of LNM in PTC patients in a multicenter, cross-machine, multi-operator scenario. Here we report the TLR model produces a stable LNM prediction. In the experiments of cross-validation and independent testing of the main cohort according to diagnostic time, machine, and operator, the TLR achieves an average area under the curve (AUC) of 0.90. In the other two independent cohorts, TLR also achieves 0.93 AUC, and this performance is statistically better than the other three methods according to Delong test. Decision curve analysis also proves that the TLR model brings more benefit to PTC patients than other methods. A non-destructive and efficient method for predicting the risk of lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC) patients is highly needed. Here, the authors develop a transfer learning radiomics model for preoperative prediction of LNM in patients with PTC in a multicenter scenario.

A detailed understanding of the function of neural networks and how they are supported by a dynamic vascular system requires fast three-dimensional imaging in thick tissues. Here we present confocal light field microscopy, a method that enables fast volumetric imaging in the brain at depths of hundreds of micrometers. It uses a generalized confocal detection scheme that selectively collects fluorescent signals from the in-focus volume and provides optical sectioning capability to improve imaging resolution and sensitivity in thick tissues. We demonstrate recording of whole-brain calcium transients in freely swimming zebrafish larvae and observe behaviorally correlated activities in single neurons during prey capture. Furthermore, in the mouse brain, we detect neural activities at depths of up to 370 μm and track blood cells at 70 Hz over a volume of diameter 800 μm × thickness 150 μm and depth of up to 600 μm. A new imaging method enables deep imaging of neural networks.