Intra-individual comparison of Sonazoid contrast-enhanced ultrasound and SonoVue contrast-enhanced ultrasound in diagnosing hepatocellular carcinoma.

PURPOSE: To assess whether the diagnostic performance of Sonazoid contrast-enhanced ultrasound (SZUS) is non-inferior to that of SonoVue contrast-enhanced ultrasound (SVUS) in diagnosing hepatocellular carcinoma (HCC) in individuals with high risk. MATERIALS AND METHODS: This prospective study was conducted from October 2020 to May 2022 and included participants with a high risk of HCC who underwent SZUS and SVUS. All lesions were confirmed by clinical or pathological diagnosis. Each nodule was classified according to the Contrast-Enhanced Ultrasound Liver Imaging Reporting and Data System version 2017 (CEUS LI-RADS v2017) for SVUS and SZUS and the modified CEUS LI-RADS (using Kupffer phase defect instead of late and mild washout) for SZUS. The diagnostic performance of both two modalities for all observations was compared. Analysis of the vascular phase and Kupffer phase imaging characteristics of CEUS was performed. RESULTS: One hundred and fifteen focal liver lesions from 113 patients (94 HCCs, 12 non-HCC malignancies, and 9 benign lesions) were analysed. According to CEUS LI-RADS (v2017), SVUS and SZUS showed similar sensitivity (71.3% vs. 72.3%) and specificity (85.7% vs. 81.0%) in HCC diagnosis. However, the modified CEUS LI-RADS did not significantly improve the diagnostic efficacy of Sonazoid compared to CEUS LI-RADS v2017, having equivalent sensitivity (73.4% vs. 72.3%) and specificity (81.0% vs. 81.0%). The agreement between SVUS and SZUS for all observations was 0.610 (95% CI 0.475, 0.745), while for HCCs it was 0.452 (95% CI 0.257, 0.647). CONCLUSION: Using LI-RADS v2017, SZUS and SVUS showed non-inferior efficacy in evaluating HCC lesions. In addition, adding Kupffer phase defects to SZUS does not notably improve its diagnostic efficacy.

Multi-Scale-Denoising Residual Convolutional Network for Retinal Disease Classification Using OCT.

Macular pathologies can cause significant vision loss. Optical coherence tomography (OCT) images of the retina can assist ophthalmologists in diagnosing macular diseases. Traditional deep learning networks for retinal disease classification cannot extract discriminative features under strong noise conditions in OCT images. To address this issue, we propose a multi-scale-denoising residual convolutional network (MS-DRCN) for classifying retinal diseases. Specifically, the MS-DRCN includes a soft-denoising block (SDB), a multi-scale context block (MCB), and a feature fusion block (FFB). The SDB can determine the threshold for soft thresholding automatically, which removes speckle noise features efficiently. The MCB is designed to capture multi-scale context information and strengthen extracted features. The FFB is dedicated to integrating high-resolution and low-resolution features to precisely identify variable lesion areas. Our approach achieved classification accuracies of 96.4% and 96.5% on the OCT2017 and OCT-C4 public datasets, respectively, outperforming other classification methods. To evaluate the robustness of our method, we introduced Gaussian noise and speckle noise with varying PSNRs into the test set of the OCT2017 dataset. The results of our anti-noise experiments demonstrate that our approach exhibits superior robustness compared with other methods, yielding accuracy improvements ranging from 0.6% to 2.9% when compared with ResNet under various PSNR noise conditions.

Diagnostic performance and interreader agreement of CEUS LI-RADS in ≤ 30 mm liver nodules with different experienced radiologists.

PURPOSE: To explore the diagnostic performance and interreader agreement of CEUS LI-RADS in diagnosing ≤ 30 mm liver nodules with different experienced radiologists. METHODS: Between January 2018 and October 2020, 244 patients at high-risk for HCC who underwent CEUS were enrolled. Two novice radiologists and two expert radiologists independently evaluated LI-RADS categories and main features. Kappa (κ) and Kendall's tests were employed to evaluate the interreader agreement of CEUS LI-RADS. The diagnostic performance was determined based on sensitivity, specificity, accuracy, PPV and NPV. RESULTS: The interreader agreement for arterial phase hyperenhancement, late and mild washout, early washout, and rim hyperenhancement was moderate to almost perfect (κ, 0.44-0.93) among the different levels of radiologists. The interreader agreement for the LI-RADS categories was substantial to almost perfect (κ, 0.78-0.88). However, the interreader agreement for marked washout was fair to moderate (κ, 0.28-0.50). When CEUS LR-5 was used as a diagnostic criterion for HCC, there were no statistical differences in sensitivity, specificity, accuracy, PPV and NPV among the radiologists (p > 0.05), except for the differences between Reader 4 and the remaining three radiologists in terms of accuracy and sensitivity (p < 0.05). CONCLUSION: CEUS LI-RADS has good diagnostic agreement for ≤ 30 mm liver nodules among experienced radiologists.

Atomically resolved single-molecule triplet quenching.

The nonequilibrium triplet state of molecules plays an important role in photocatalysis, organic photovoltaics, and photodynamic therapy. We report the direct measurement of the triplet lifetime of an individual pentacene molecule on an insulating surface with atomic resolution by introducing an electronic pump-probe method in atomic force microscopy. Strong quenching of the triplet lifetime is observed if oxygen molecules are coadsorbed in close proximity. By means of single-molecule manipulation techniques, different arrangements with oxygen molecules were created and characterized with atomic precision, allowing for the direct correlation of molecular arrangements with the lifetime of the quenched triplet. Such electrical addressing of long-lived triplets of single molecules, combined with atomic-scale manipulation, offers previously unexplored routes to control and study local spin-spin interactions.

Pan-cancer analysis of clinical significance and associated molecular features of glycolysis.

Tumor glycolysis is a major promoter of carcinogenesis and cancer progression. Given its complex mechanisms and interactions, comprehensive analysis is needed to reveal its clinical significance and molecular features. On the basis of a well-established glycolysis gene expression signature, we quantified 8633 patients with different cancer types from the Cancer Genome Atlas (TCGA) and evaluated their prognostic associations. High tumor glycolytic activity correlated with inferior overall survival in the pan-cancer patients (hazard ratio: 1.70, 95% confidence interval: 1.20-2.40, P = 0.003). The prognostic value of glycolysis correlated with the molecular subtypes and was stable regardless of clinical parameters. The prognostic significance of glycolysis was validated using three independent datasets. In addition, genome, transcriptome, and proteome profiles were utilized to characterize the distinctive molecular features associated with glycolysis. Mechanistically, glycolysis fulfilled the fundamental needs of tumor proliferation in multiple ways. Exploration of the relationships between glycolysis and tumor-infiltrating immune cells showed that glycolysis enabled the immune evasion of tumor cells. Mammalian target of rapamycin (mTOR) inhibitors and dopamine receptor antagonists can effectively reverse the glycolytic status of cancers. Overall, our study provides an in-depth molecular understanding of tumor glycolysis and may have practical implications for clinical cancer therapy.

Using ultrasound features and radiomics analysis to predict lymph node metastasis in patients with thyroid cancer.

BACKGROUND: Lymph node metastasis (LNM) is an important factor for thyroid cancer patients' treatment and prognosis. The aim of this study was to explore the clinical value of ultrasound features and radiomics analysis in predicting LNM in thyroid cancer patients before surgery. METHODS: The characteristics of ultrasound images of 150 thyroid nodules were retrospectively analysed. All nodules were confirmed as thyroid cancer. Among the assessed patients, only one hundred and twenty-six patients underwent lymph node dissection. All patients underwent an ultrasound examination before surgery. In the radiomic analysis, the area of interest was identified from selected ultrasound images by using ITK-SNAP software. The radiomic features were extracted by using Ultrosomics software. Then, the data were classified into a training set and a validation set. Hypothetical tests and bagging were used to build the model. The diagnostic performance of different ultrasound features was assessed, a radiomic analysis was conducted, and a receiver operating characteristic (ROC) curve analysis was performed to explore the diagnostic accuracy. RESULTS: Regarding the prediction of LNM, the ROC curves showed that the area under the curve (AUC) values of an irregular shape and microcalcification were 0.591 (P = 0.059) and 0.629 (P = 0.007), respectively. In the radiomics analysis, in the training set, the AUC value of LNM was 0.759, with a sensitivity of 0.90 and a specificity of 0.860. In the verification set, the AUC was 0.803, with a sensitivity of 0.727 and a specificity of 0.800. CONCLUSIONS: Microcalcification and an irregular shape are predictors of LNM in thyroid carcinoma patients. In addition, radiomics analysis has promising value in screening meaningful ultrasound features in thyroid cancer patients with LNM. Therefore, the prediction of LNM based on ultrasound features and radiomic features is useful for making appropriate decisions regarding surgery and interventions before thyroid carcinoma surgery.

Clinical significance of CCNE2 protein and mRNA expression in thyroid cancer tissues.

PURPOSE: Thyroid carcinoma (TC) is the most common endocrinal malignancy worldwide. Cyclin E2 (CCNE2), a member of the cyclin family, acts as a regulatory subunit of cyclin-dependent kinases (CDKs). It controls the transition of quiescent cells into the cell cycle, regulates the G1/S transition, promotes DNA replication, and activates CDK2. This study explored the role and potential molecular mechanisms of CCNE2 expression in TC tissues. MATERIAL/METHODS: Immunohistochemistry was used to evaluate the CCNE2 protein expression levels in TC. High-throughput data on CCNE2 in TC were obtained from RNA sequencing (RNA-seq), microarray, and literature data. The CCNE2 expression levels in TC were comprehensively assessed through an integrated analysis. Analyses of Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPIs) data facilitated the investigation of the relative molecular mechanisms of CCNE2 in TC. RESULTS: The immunohistochemical experiment showed a significant increase in the expression of CCNE2 in the TC tissues. For 505 TC and 59 non-cancerous samples from RNA-seq data, the area under the curve (AUC) was 0.8016 (95% confidence interval [CI] 0.742-0.8612; p<0.001). With another 14 microarrays, the pool standard mean difference [SMD] was 1.01 (95% CI [0.82-1.19]). The pooled SMD of CCNE2 was 1.12 (95% CI [0.60-1.64]), and the AUC was 0.87 (95% CI [0.84-0.90]) for 1157 TC samples and 366 non-cancerous thyroid samples from all possible sources. Nine hub genes were upregulated in TC. CONCLUSIONS: A high expression of CCNE2 may lead to carcinogenesis and the development of TC.

Probing Nonequilibrium Dynamics of Photoexcited Polarons on a Metal-Oxide Surface with Atomic Precision.

Understanding the nonequilibrium dynamics of photoexcited polarons at the atomic scale is of great importance for improving the performance of photocatalytic and solar-energy materials. Using a pulsed-laser-combined scanning tunneling microscopy and spectroscopy, here we succeeded in resolving the relaxation dynamics of single polarons bound to oxygen vacancies on the surface of a prototypical photocatalyst, rutile TiO_{2}(110). The visible-light excitation of the defect-derived polarons depletes the polaron states and leads to delocalized free electrons in the conduction band, which is further corroborated by ab initio calculations. We found that the trapping time of polarons becomes considerably shorter when the polaron is bound to two surface oxygen vacancies than that to one. In contrast, the lifetime of photogenerated free electrons is insensitive to the atomic-scale distribution of the defects but correlated with the averaged defect density within a nanometer-sized area. Those results shed new light on the photocatalytically active sites at the metal-oxide surface.

Potential therapies for residual hepatoblastoma following incomplete ablation treatment in a nude mouse subcutaneous xenograft model based on lncRNA and mRNA expression profiles.

Tumor recurrence following radiofrequency ablation (RFA) treatment in liver cancer is an important factor affecting patient prognosis. Furthermore, the biological role of long non­coding RNAs (lncRNAs) in residual hepatoblastoma (HB) tissues after RFA remains largely unknown. By using microarray technology, this study investigated the expression of lncRNAs and mRNAs among four pairs of HB tissues (incomplete ablation treatment and no treatment) in a nude mouse subcutaneous xenograft model. Subsequently, bioinformatics analysis was used to understand the functions and pathways of the identified mRNAs. Finally, a connectivity map (CMap) analysis was conducted to identify potential therapeutic strategies for residual HB tissues. Compared with the untreated nude mouse subcutaneous xenograft model, in the experimental group, a significant difference in the expression of 740 lncRNAs and 663 mRNAs was detected. Subsequently, bioinformatics analysis revealed that the differentially expressed mRNAs were significantly enriched in pathways associated with antigen processing, the presentation of endogenous antigens, the regulation of cellular metabolic processes, MAPK signaling and cell cycle regulation. Additionally, six compounds (valproic acid, metformin, tanespimycin, wortmannin, fulvestrant and MK­886) were identified by CMap analysis as potential therapeutic agents for the treatment of residual HB tissues. These findings provide a novel insight into the pathogenesis of residual HB and potential therapeutic strategies for aggressive tumor recurrence following RFA treatment in patients with HB.

Atomic imaging of the edge structure and growth of a two-dimensional hexagonal ice.

The formation and growth of water-ice layers on surfaces and of low-dimensional ice under confinement are frequent occurrences1-4. This is exemplified by the extensive reporting of two-dimensional (2D) ice on metals5-11, insulating surfaces12-16, graphite and graphene17,18 and under strong confinement14,19-22. Although structured water adlayers and 2D ice have been imaged, capturing the metastable or intermediate edge structures involved in the 2D ice growth, which could reveal the underlying growth mechanisms, is extremely challenging, owing to the fragility and short lifetime of those edge structures. Here we show that noncontact atomic-force microscopy with a CO-terminated tip (used previously to image interfacial water with minimal perturbation)12, enables real-space imaging of the edge structures of 2D bilayer hexagonal ice grown on a Au(111) surface. We find that armchair-type edges coexist with the zigzag edges usually observed in 2D hexagonal crystals, and freeze these samples during growth to identify the intermediate edge structures. Combined with simulations, these experiments enable us to reconstruct the growth processes that, in the case of the zigzag edge, involve the addition of water molecules to the existing edge and a collective bridging mechanism. Armchair edge growth, by contrast, involves local seeding and edge reconstruction and thus contrasts with conventional views regarding the growth of bilayer hexagonal ices and 2D hexagonal matter in general.

Advances in Atomic Force Microscopy: Weakly Perturbative Imaging of the Interfacial Water.

The structure and dynamics of interfacial water, determined by the water-interface interactions, are important for a wide range of applied fields and natural processes, such as water diffusion (Kim et al., 2013), electrochemistry (Markovic, 2013), heterogeneous catalysis (Over et al., 2000), and lubrication (Zilibotti et al., 2013). The precise understanding of water-interface interactions largely relies on the development of atomic-scale experimental techniques (Guo et al., 2014) and computational methods (Hapala et al., 2014b). Scanning probe microscopy has been extensively applied to probe interfacial water in many interdisciplinary fields (Ichii et al., 2012; Shiotari and Sugimoto, 2017; Peng et al., 2018a). In this perspective, we review the recent progress in the noncontact atomic force microscopy (nc-AFM) imaging and AFM simulation techniques and discuss how the newly developed techniques are applied to study the properties of interfacial water. The nc-AFM with the quadrupole-like CO-terminated tip can achieve ultrahigh-resolution imaging of the interfacial water on different surfaces, trace the reconstruction of H-bonding network and determine the intrinsic structures of the weakly bonded water clusters and even their metastable states. In the end, we present an outlook on the directions of future AFM studies of interfacial water as well as the challenges faced by this field.

Ultrasound characteristics of thyroid nodules facilitate interpretation of the malignant risk of Bethesda system III/IV thyroid nodules and inform therapeutic schedule.

BACKGROUND: This study was designed to explore whether ultrasound of thyroid nodules facilitates the interpretation of the malignant risk of Bethesda III/IV thyroid nodules to inform further therapies. METHODS: We reviewed patient records in which the results of ultrasound-guided fine-needle aspiration (US-FNA) were classified by the Bethesda III/IV in our institution between January 2016 and June 2018. Studies were retrieved from PubMed, Cochrane Central Register of Controlled Trials, ISI Web of Science, Science Direct, Wiley Online Library, EMBASE, China National Knowledge Infrastructure, WanFang, and Chinese VIP. The odds ratio (OR) was used to measure associations between risk factors and thyroid nodule malignancy. RESULTS: Fifty-nine cases of Bethesda III/IV with corresponding surgeries were included, and the malignancy risk was 54.2%. Meta-analysis revealed irregular borders, solitary nodules, hypoechogenicity, microcalcifications, and being taller than wide, all of which increased the malignancy risk of thyroid nodules. Combined ORs for these factors were 4.08 (95% CI: 2.34-7.14, P < .001), 2.18 (95% CI: 1.39-3.42, P = .001), 2.02 (95% CI: 1.35-3.01, P = .001), 3.21 (95% CI: 2.26-4.56, P < .001), and 4.35 (95% CI: 3.07-6.15, P < .001), respectively. CONCLUSION: As the risk of malignancy for papillary thyroid carcinoma (PTC) is high, when any one of the five ultrasound features of malignancy were confirmed, repeated FNA is recommended to confirm PTC-type malignancy, even though nodules were Bethesda III/IV classification. However, repeated FNA should be avoided when none of these ultrasound features are identified because repeated FNA does not contribute to identifying non-PTC type malignancies, such as follicular thyroid carcinoma and poorly differentiated thyroid carcinoma.

A Loop-Mediated Isothermal Amplification Assay for Rapid Detection of Pectobacterium aroidearum that Causes Soft Rot in Konjac.

Bacterial soft rot caused by Pectobacterium species is a serious disease in konjac (Amorphophallus konjac), a healthy source of starch particularly in East Asia. An effective diagnostic method is crucial to control the disease and reduce losses in konjac production. In this study, we evaluated a loop-mediated isothermal amplification (LAMP) assay with a specific primer set for the rapid and accurate detection of P. aroidearum. A comparative genomics approach was used to identify the specific genes suitable for the design of LAMP primers. The candidate target genes were determined through a first-round comparison with a 50-genome nucleotide database, and subjected to a second-round screening with the GenBank NR database. As a result, nine specific genes of P. aroidearum were selected for LAMP primer design. After screening of the primers, the primer set 1675-1 was chosen for LAMP detection owing to its high specificity and sensitivity. The LAMP assay could detect the presence of P. aroidearum genomic DNA at a concentration as low as 50 fg and 1.2 × 104 CFU/g artificially infected soil within 40 min at 65 °C. Subsequently, this primer set was successfully used to specifically detect P. aroidearum in naturally infected and non-symptomatic plant samples or soil samples from the field. This study indicates that a comparative genomic approach may facilitate the development of highly specific primers for LAMP assays, and a LAMP diagnostic assay with the specific primer set 1675-1 should contribute to the rapid and accurate detection of soft-rot disease in konjac at an early stage.

Publisher Correction: The effect of hydration number on the interfacial transport of sodium ions.

In this Letter, the links to Supplementary Videos 5, 7, 9 and 10 were incorrect, and there were some formatting errors in the Supplementary Video legends. These errors have been corrected online.

Probing the Structure and Dynamics of Interfacial Water with Scanning Tunneling Microscopy and Spectroscopy.

Water/solid interfaces are ubiquitous and play a key role in many environmental, biophysical, and technological processes. Resolving the internal structure and probing the hydrogen-bond (H-bond) dynamics of the water molecules adsorbed on solid surfaces are fundamental issues of water science, which remains a great challenge owing to the light mass and small size of hydrogen. Scanning tunneling microscopy (STM) is a promising tool for attacking these problems, thanks to its capabilities of sub-Ångström spatial resolution, single-bond vibrational sensitivity, and atomic/molecular manipulation. The designed experimental system consists of a Cl-terminated tip and a sample fabricated by dosing water molecules in situ onto the Au(111)-supported NaCl(001) surfaces. The insulating NaCl films electronically decouple the water from the metal substrates, so the intrinsic frontier orbitals of water molecules are preserved. The Cl-tip facilitates the manipulation of the single water molecules, as well as gating the orbitals of water to the proximity of Fermi level (EF) via tip-water coupling. This paper outlines the detailed methods of submolecular resolution imaging, molecular/atomic manipulation, and single-bond vibrational spectroscopy of interfacial water. These studies open up a new route for investigating the H-bonded systems at the atomic scale.

The effect of hydration number on the interfacial transport of sodium ions.

Ion hydration and transport at interfaces are relevant to a wide range of applied fields and natural processes1-5. Interfacial effects are particularly profound in confined geometries such as nanometre-sized channels6-8, where the mechanisms of ion transport in bulk solutions may not apply9,10. To correlate atomic structure with the transport properties of hydrated ions, both the interfacial inhomogeneity and the complex competing interactions among ions, water and surfaces require detailed molecular-level characterization. Here we constructed individual sodium ion (Na+) hydrates on a NaCl(001) surface by progressively attaching single water molecules (one to five) to the Na+ ion using a combined scanning tunnelling microscopy and noncontact atomic force microscopy system. We found that the Na+ ion hydrated with three water molecules diffuses orders of magnitude more quickly than other ion hydrates. Ab initio calculations revealed that such high ion mobility arises from the existence of a metastable state, in which the three water molecules around the Na+ ion can rotate collectively with a rather small energy barrier. This scenario would apply even at room temperature according to our classical molecular dynamics simulations. Our work suggests that anomalously high diffusion rates for specific hydration numbers of ions are generally determined by the degree of symmetry match between the hydrates and the surface lattice.

Comprehensive analysis of the clinical significance and prospective molecular mechanisms of differentially expressed autophagy-related genes in thyroid cancer.

Thyroid cancer (TC) is the most common endocrine malignancy, accounting for approximately 90% of all malignancies of the endocrine system. Despite the fact that patients with TC tend to have good prognoses, the high incidence rate and lymph node metastases remain unresolved issues. Autophagy is an indispensable process that maintains intracellular homeostasis; however, the role of autophagy in several steps of the initiation and progression of TC has not yet been elucidated. In this study, we first identified several autophagy-related genes (ARGs) that were provoked in the onset of TC. Subsequently, a bioinformatics analysis hinted that these genes were markedly disturbed in several proliferative signaling pathways. Moreover, we demonstrated that the differentially expressed ARGs were closely related to several aggressive clinical manifestations, including an advanced tumor stage and lymph node metastasis. Our study further selected prognostic ARGs and developed a prognostic signature based on three key genes (ATG9B, BID and B1DNAJB1), which displayed a moderate ability to predict the prognosis of TC. On the whole, the findings of this study demonstrate that ARGs disrupt proliferation-related pathways and consequently lead to aggressive clinical manifestations. These findings provide insight into the potential molecular mechanisms of action of ARGs and their clinical significance, and also provide classification information of potential therapeutic significance.

Weakly perturbative imaging of interfacial water with submolecular resolution by atomic force microscopy.

Scanning probe microscopy has been extensively applied to probe interfacial water in many interdisciplinary fields but the disturbance of the probes on the hydrogen-bonding structure of water has remained an intractable problem. Here, we report submolecular-resolution imaging of the water clusters on a NaCl(001) surface within the nearly noninvasive region by a qPlus-based noncontact atomic force microscopy. Comparison with theoretical simulations reveals that the key lies in probing the weak high-order electrostatic force between the quadrupole-like CO-terminated tip and the polar water molecules at large tip-water distances. This interaction allows the imaging and structural determination of the weakly bonded water clusters and even of their metastable states with negligible disturbance. This work may open an avenue for studying the intrinsic structure and dynamics of ice or water on surfaces, ion hydration, and biological water with atomic precision.

Atomic-scale imaging of the dissolution of NaCl islands by water at low temperature.

The dissolution of sodium chloride (NaCl) in water is a frequently encountered process in our daily lives. While the NaCl dissolution process in liquid water has been extensively studied, whether and how the dissolution occurs below the freezing point is still not clear. Using a low-temperature scanning tunneling microscope (STM), here we were able to directly visualize the dissolution of Au-supported NaCl (0 0 1) bilayer islands by water at atomic level. We found that the single water molecule on the STM tip can assist the extraction of single Na+ from the NaCl surface even at 5 K, while leaving the Cl- intact. When covered with a full water monolayer, the NaCl islands started to dissolve from the step edges and also showed evidence of dissolution inside the terraces as the temperature was raised up to 145 K. At 155 K, the water molecules completely desorbed from the surface, which was accompanied with the decomposition and restructuring of the bilayer NaCl islands. Those results suggest that the dissolution of NaCl may occur well below the freezing point at the ice/NaCl interfaces and is mainly driven by the interaction between the water molecules and the Na+, which is in clear contrast with the NaCl dissolution in liquid water.