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Chemotherapy is important in the systemic therapy for breast cancer. However, after chemotherapy, the left living tumour cells are more progressive. There is an urgent need to study the underlying mechanism which is still unclear to further improve the therapeutic efficacy of chemotherapy in breast cancer. Here we find a pro-tumour effect of the apoptotic cells induced by the chemotherapy, which is mediated by a new subset of macrophages undergoing LC3-associated phagocytosis (LAP). By transferring exosomal S100A11 into the living tumour cells after chemotherapy, the macrophage exhibits a more pro-tumour phenotype than classic M2-type macrophages. Moreover, S100A11 binds to IFITM3, inducing Akt phosphorylation of living tumour cells after chemotherapy, which promotes tumour progression. Of note, Akt inhibitor can enhance the therapeutic effcicay of chemotherapy in breast cancer. This study provides a novel mechanistic link between tumour-associated macrophages and breast cancer, uncovering Akt as a potential therapeutic target to improve chemotherapy efficacy.

Objective: The purpose of this study was to determine the analgesic effect of a flurbiprofen ester injection via continuous intravenous drip during transvaginal 4-dimensional hysterosalpingography (TVS 4D-HyCoSy). Methods: Two hundred thirty patients who underwent TVS 4D-HyCoSy for infertility from May 2018 to August 2021 at our hospital were selected. The participants were grouped based on tubal patency, flurbiprofen ester use, and uterine cannula diameter, as follows: bilateral tubal patency group; non-bilateral tubal patency group; atropine group; atropine + flurbiprofen ester group; coarse tube group; and fine tube group. The analgesic effect during TVS 4D-HyCoSy and pain relief were compared between groups using visual analog scoring (NRS). Additionally, the incidence of adverse effects was recorded and factors related to the influence of pain were analyzed. Results: 1. Tubal patency reduced pain during ultrasound tubal examination, flurbiprofenate provided significant analgesia after ultrasound tubalography and reduced adverse effects (P < 0.001). 2. The tube diameter thickness had no effect on tubal ultrasonography procedure-related pain. 3. Multivariable analysis of pain relief during imaging suggested that the use of flurbiprofen for bilateral tubal patency had a significant positive effect on pain relief within 30 min after the examination with an AUC of 0.732 (95% CI: 0.665–0.798). Conclusion: A flurbiprofen ester continuous intravenous drip had a good analgesic effect in patients with TVS 4D-HyCoSy. Specifically, the pain relief effect after examination was significant and reduced the incidence of adverse reactions during the contrast examination. Flurbiprofen ester can be administered independently and is worthy of clinical promotion and application.

Abstract Metabolic reprogramming in cancer significantly impacts immune responses within the tumor microenvironment, but its influence on cancer immunotherapy effectiveness remains uncertain. This study aims to elucidate the prognostic significance of metabolic genes in cancer immunotherapy through a comprehensive analytical approach. Utilizing data from the IMvigor210 trial (n = 348) and validated by retrospective datasets, we performed patient clustering using non‐negative matrix factorization based on metabolism‐related genes. A metabiotic score was developed using a “DeepSurv” neural network to assess correlations with overall survival (OS), progression‐free survival, and immunotherapy response. Validation of the metabolic score and key genes was achieved via comparative gene expression analysis using qPCR. Our analysis identified four distinct metabolic classes with significant variations in OS. Notably, the metabolism‐inactive and hypoxia‐low class demonstrated the most pronounced benefit in terms of OS. The metabolic score predicted immunotherapeutic benefits with high accuracy (AUC: 0.93 at 12 months). SETD3 emerged as a crucial gene, showing strong correlations with improved OS outcomes. This study underscores the importance of metabolic profiling in predicting cancer immunotherapy success. Specifically, patients classified as metabolism‐inactive and hypoxia‐low appear to derive substantial benefits. SETD3 is established as a promising prognostic marker, linking metabolic activity with patient outcomes, advocating for the integration of metabolic profiling into immunotherapy strategies to enhance treatment precision and efficacy.

T cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy. Emerging evidence has shown that interferon-gamma (IFNγ) could enhance CXCL9 secretion from macrophages to recruit T cells, but Siglec15 expressed on TAMs can attenuate T cell proliferation. Therefore, targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues. We herein developed reduction-responsive nanoparticles (NPs) made with poly (disulfide amide) (PDSA) and lipid-poly (ethylene glycol) (lipid-PEG) for systemic delivery of Siglec15 siRNA (siSiglec15) and IFNγ for enhanced cancer immunotherapy. After intravenous administration, these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages (TAMs). With the highly concentrated glutathione (GSH) in the cytoplasm to destroy the nanostructure, the loaded IFNγ and siSiglec15 could be rapidly released, which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation, leading to significant inhibition of hepatocellular carcinoma (HCC) growth when combining with the immune checkpoint inhibitor. The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.

Breast cancer is a highly heterogeneous disease lacking prognostic markers. Tumor-associated macrophages (TAMs) in the tumor microenvironment are associated with distant metastasis as well as poorer outcomes in breast cancer. Therefore, monitoring TAMs may guide prognostic assessment. This study explores an imaging modality based on a two-step click chemistry procedure for detecting TAMs in breast cancer. Mannose-targeted liposomes (MAN-lipo-AAG) and non-targeted liposomes (lipo-AAG) encapsulating Ac4GalNAz were prepared and comprehensively characterized. The sizes of the prepared MAN-lipo-AAG and lipo-AAG were 126 ± 0.22 and 93 ± 0.23 nm, respectively. In vitro studies demonstrated higher uptake of MAN-lipo-AAG than lipo-AAG by RAW264.7 cells. Moreover, flow cytometry and confocal microscopy confirmed that bright, homogeneous fluorescence labeling was present on RAW264.7 cell membranes in the MAN-lipo-AAG group. Furthermore, in vivo analysis indicated that MAN-lipo-AAG, compared with lipo-AAG, had higher accumulation in a 4T1 xenograft model and higher uptake by mannose-overexpressing TAMs. This study describes a promising approach for specific and non-invasive TAM-targeted imaging via metabolic glycoengineering.

Abstract Background Circular RNAs (circRNAs) circularized by back-splicing of pre-mRNA are widely expressed and affected the proliferation, invasion and metastasis of bladder cancer (BCa). However, the mechanism underlying circRNA biogenesis in mediating the distant metastasis of BCa still unexplored. Methods RNA sequencing data between BCa and normal adjacent tissues was applied to identify the differentially expressed circRNAs. The functions of circNIPBL in BCa were investigated via a series of biochemical experiments. The Clinical significance of circNIPBL was examined in a cohort of larger BCa tissues. Results In the present study, we identified a novel circRNA (hsa_circ_0001472), circNIPBL, which was significantly upregulated and had great influence on the poor prognosis of patients with BCa. Functionally, circNIPBL promotes BCa metastasis in vitro and in vivo. Mechanistically, circNIPBL upregulate the expression of Wnt5a and activated the Wnt/β-catenin signaling pathway via directly sponged miR-16-2-3p, leading to the upregulation of ZEB1, which triggers the EMT of BCa. Moreover, we revealed that ZEB1 interacted with the flanking introns of exons 2–9 on NIPBL pre-mRNA to trigger circNIPBL biogenesis, thus forming a positive feedback loop. Importantly, circNIPBL overexpression significantly facilitated the distant metastasis of BCa in the orthotopic bladder cancer model, while silencing ZEB1 remarkably blocked the effects of metastasis induced by circNIPBL overexpression. Conclusions Our study highlights that circNIPBL-induced Wnt signaling pathway activation triggers ZEB1-mediated circNIPBL biogenesis, which forms a positive feedback loop via the circNIPBL/miR-16-2-3p/Wnt5a/ZEB1 axis, supporting circNIPBL as a novel therapeutic target and potential biomarker for BCa patients. Graphical Abstract

AbstractBackground Radiofrequency ablation (RFA) is a first-line treatment for early-stage hepatocellular carcinoma (HCC). However, the recurrence after RFA remains an urgent challenge. Current studies have shown that residual tumor after RFA is an important cause of recurrence.Objective We hypothesized that the products of dead tumor cells after RFA have direct effects on the development of residual tumors. Further, we investigated the underlying mechanisms.Methods The proliferation and invasion ability of HepG2 and Huh7 cells were assessed using CCK-8, colony formation, EdU, transwell invasion and migration assay. Immunofluorescence and western blotting were used to show HMGB1 released from dead tumor cells. The levels of MMP2, MMP9, CyclinE1 and pERK1/2 were determined using western blotting. Finally, in vivo validation was performed in BALB/c nude mice xenograft tumor models.Results The products of dead tumor cells after thermal treatment can promote the proliferation and invasion of residual HCC cells. Dead tumor cells could release high-mobility group box 1 (HMGB1) after thermal treatment. Similar to the products of dead tumor cells, the recombinant protein of HMGB1 can promote the proliferation and invasion of residual HCC cells. Moreover, HMGB1 could bind to receptor of advanced glycation end-products. Then, it activated the ERK1/2 pathway and significantly upregulated the expressions of MMP2, MMP9, and CyclinE1.Conclusion Our study reveals that HMGB1 released by dead tumor cells after thermal treatment can promote the proliferation and invasion of residual HCC cells. Hence, the HMGB1/RAGE/ERK1/2 pathway is a potential target for improving the prognosis of HCC after radiofrequency ablation.

Summary: Background: Ultrasonography is the most widely used technique to diagnose echinococcosis; however, challenges in using this technique and the demand on medical resources, especially in low-income or remote areas, can delay diagnosis. We aimed to develop a deep convolutional neural network (DCNN) model based on ultrasonography to identify echinococcosis and its types, especially alveolar echinococcosis. Methods: This retrospective, large-scale, multicentre study used ultrasound images from patients assessed at 84 hospitals in China, obtained between Jan 1, 2002, and Dec 31, 2021. Patients with a diagnosis of cystic echinococcosis, alveolar echinococcosis, or seven other types of focal liver lesions were included. We tested ResNet-50, ResNext-50, and VGG-16 as the backbone network architecture for a classification DCNN model and input the perinodular information from the ultrasound images. We trained and validated the DCNN model to diagnose and classify echinococcosis using still greyscale ultrasound images of focal liver lesions in four stages: differentiating between echinococcosis and other focal liver lesions (stage one); differentiating cystic echinococcosis, alveolar echinococcosis, and other focal liver lesions (stage two); differentiating cystic echinococcosis, alveolar echinococcosis, benign other focal liver lesions, and malignant focal liver lesions (stage three); and differentiating between active and transitional cystic echinococcosis and inactive cystic echinococcosis (stage four). We then tested the algorithm on internal, external, and prospective test datasets. The performance of DCNN was also compared with that of 12 radiologists recruited between Jan 15, 2022, and Jan 28, 2022, from Qinghai, Xinjiang, Anhui, Henan, Xizang, and Beijing, China, with different levels of diagnostic experience for echinococcosis and other focal liver lesions in a subset of ultrasound data that were randomly chosen from the prospective test dataset. The study is registered at ClinicalTrials.gov (NCT03871140). Findings: The study took place between Jan 1, 2002, and Dec 31, 2021. In total, to train and test the DCNN model, we used 9631 liver ultrasound images from 6784 patients (2819 [41·7%] female patients and 3943 [58·3%] male patients) from 87 Chinese hospitals. The DCNN model was trained with 6328 images, internally validated with 984 images, and tested with 2319 images. The ResNet-50 network architecture outperformed VGG-16 and ResNext-50 and was generalisable, with areas under the receiver operating characteristic curve (AUCs) of 0·982 (95% CI 0·960–0·994), 0·984 (0·972–0·992), and 0·913 (0·886–0·935) in distinguishing echinococcosis from other focal liver lesions; 0·986 (0·966–0·996), 0·962 (0·946–0·975), and 0·900 (0·872–0·924) in distinguishing alveolar echinococcosis from cystic echinococcosis and other focal liver lesions; and 0·974 (0·818–1·000), 0·956 (0·875–0·991), and 0·944 (0·844–0·988) in distinguishing active and transitional cystic echinococcosis from inactive echinococcosis in the three test datasets. Specifically, in patients with the hepatitis B or hepatitis C virus, the model could distinguish alveolar echinococcosis from hepatocellular carcinoma with an AUC of 0·892 (0·812–0·946). In identifying echinococcosis, the model showed significantly better performance compared with senior radiologists from a high-endemicity area (AUC 0·942 [0·904–0·967] vs 0·844 [0·820–0·866]; p=0·027) and improved the diagnostic ability of junior, attending, and senior radiologists before and after assistance with AI with comparison of AUCs of 0·743 (0·714–0·770) versus 0·850 (0·826–0·871); p

Abstract Background Studies on deep learning (DL)-based models in breast ultrasound (US) remain at the early stage due to a lack of large datasets for training and independent test sets for verification. We aimed to develop a DL model for differentiating benign from malignant breast lesions on US using a large multicenter dataset and explore the model’s ability to assist the radiologists. Methods A total of 14,043 US images from 5012 women were prospectively collected from 32 hospitals. To develop the DL model, the patients from 30 hospitals were randomly divided into a training cohort (n = 4149) and an internal test cohort (n = 466). The remaining 2 hospitals (n = 397) were used as the external test cohorts (ETC). We compared the model with the prospective Breast Imaging Reporting and Data System assessment and five radiologists. We also explored the model’s ability to assist the radiologists using two different methods. Results The model demonstrated excellent diagnostic performance with the ETC, with a high area under the receiver operating characteristic curve (AUC, 0.913), sensitivity (88.84%), specificity (83.77%), and accuracy (86.40%). In the comparison set, the AUC was similar to that of the expert (p = 0.5629) and one experienced radiologist (p = 0.2112) and significantly higher than that of three inexperienced radiologists (p

Background: Benign or malignant breast lesions with typical ultrasonic characteristics could be easily and correctly diagnosed with two-dimensional ultrasound (2D US). However, diagnosis of atypical lesions remains a challenge. Most atypical lesions have different ultrasonographic features with probe direction variation. Thus, the interpretation of ultrasonographic features based on static images empirically collected by sonographers might be inaccurate. We aimed to investigate the section discrepancy and diagnostic performance of breast lesions in 2D US by dynamic videos versus static images. Methods: Static images and dynamic videos based on two perpendicular planes of 468 breast lesions were collected and evaluated. The Breast Imaging and Reporting Data System (BI-RADS®) US lexicon was used. Category 3 was used as the cut-off point, and section discrepancy was defined as two perpendicular planes showing different BI-RADS categories (3 versus 4A, 4B, 4C, and 5). Results: This retrospective study included 315 benign and 153 malignant lesions. There were 53 and 50 lesions with section discrepancy during static and dynamic observations, respectively. The proportion of benign lesions with section discrepancy was significantly higher than that of malignant lesions (P < 0.05) either in dynamic or static observation, and the contingency coefficient was 0.2 between section discrepancy and histopathology. Duct changes were more clearly depicted in dynamic videos than in static images (P < 0.05) both in malignant and benign lesions. Calcification and architectural distortion were more sensitively detected by dynamic videos than with static images (P < 0.05) in malignant lesions. The interpretation of “margin” significantly differed in benign lesions between static images and dynamic videos (P < 0.05). The areas under the curve of static image-horizontal, static image-sagittal, dynamic video-horizontal, and dynamic video-sagittal were 0.807, 0.820, 0.837, and 0.846, respectively. The specificities of dynamic videos were higher than those of static images (P < 0.05). Conclusion: Breast lesions have section discrepancy in 2D US. Observations based on dynamic videos could more accurately reflect lesion features and increase the specificity of US in the differentiation of atypical breast lesions.

The issue of freezing often occurs when using all-glass vacuum tube solar water heaters during cold winter seasons, leading to problems such as pipe ruptures and tank leakage. In order to further study the nocturnal heat dissipation and freezing characteristics of these heaters, a three-dimensional transient numerical model of their nocturnal heat dissipation was established. The model simulated the nocturnal heat dissipation process, and experimental validations were conducted through nocturnal temperature drops of the collector and temperature drops of individual tubes without a storage tank. Experimental and simulation results revealed that in clear weather conditions during cold winters in Luoyang, the all-glass vacuum tube solar water heaters experienced freezing issues during the night, with freezing predominantly starting from the bottom surface of the vacuum tubes. The frozen length along the tube wall and the thickness of ice at the bottom section reached up to 1180 mm and 5 mm, respectively. In the absence of a storage tank, the freezing situation was severe, with approximately 4/5 of the individual tubes completely frozen. Under specified operating conditions, different storage tank volumes exhibited varying degrees of freezing in the all-glass vacuum tube solar water heaters. When the volume was increased to 15 L, the temperature drop in the storage tank and the vacuum tubes decreased by 12.1% and 7.6%, respectively. Larger storage tank volumes resulted in reduced freezing risks in all-glass vacuum tube solar collectors. This study provides valuable guidance for the design and application of solar collectors and serves as a reference for the development and application of solar energy utilization technologies.

Aims: Hepatocellular carcinoma (HCC) remains a major tumoral burden globally, and its heterogeneity encumbers prognostic prediction. The lymphangiogenesis-related long non-coding RNAs (lrlncRNAs) reported to be implicated in immune response regulation show potential importance in predicting the prognostic and therapeutic outcome. Hence, this study aims to establish a lrlncRNA pairs-based signature not requiring specific expression levels of transcripts, which displays promising clinical practicality and satisfactory predictive capability. Main methods: Transcriptomic and clinical information of the Liver Hepatocellular Carcinoma (LIHC) project retrieved from the TCGA portal were used to find differently expressed lrlncRNA (DElrlncRNA) via analysis performed between lymphangiogenesis-related genes (lr-genes) and lncRNAs(lrlncRNA), and to ultimately construct the signature based on lrlncRNA pairs screened out via Lasso and Cox regression analyses. Akaike information criterion (AIC) values were computed to find the cut-off point optimum for high-risk and low-risk group allocation. The signature then underwent trials in terms of its predictive value for survival, clinicopathological features, immune cells infiltration in tumoral microenvironment, selected checkpoint biomarkers and chemosensitivity. Key findings: A novel lymphangiogenesis-related lncRNA pair signature was established using nine lrlncRNA pairs identified and significantly related to overall survival, clinicopathological features, immune cells infiltration and susceptibility to chemotherapy. Moreover, the signature efficacy was verified in acknowledged clinicopathological subgroups and partially validated by qRT-PCR assay in various human HCC cell lines. Significance: The novel lrlncRNA-pairs based signature was shown to effectively and independently estimate HCC prognosis and help screen patients suitable for anti-tumor immunotherapy and chemotherapy.

Abstract Residual tumors after insufficient radiofrequency ablation (IRFA) shows accelerated progression and anti‐PD‐1 resistance. It is also reported that macrophages infiltrating into residual tumors leads to anti‐PD‐1 resistance. Elements of autophagy have been detected to conjugate LC3 to be increasingly expressed in residual tumors. The underlying mechanisms between LC3 and macrophages are aimed to be investigated, and explore further ways to enhance immunotherapy in treating residual tumors. In mice models and patients, macrophages demonstrate increased infiltration into residual tumors, especially surrounding the ablated zone. Single‐cell transcriptome demonstrates enhancement of immunosuppression function in macrophages after IRFA. It is shown that macrophages engulf heat‐treated cells through LC3‐associated phagocytosis (LAP), enhance IL‐4 mediated macrophage programming through the PI3Kγ/AKT pathway, and suppress T cell proliferation. Blockade of the PI3Kγ/AKT pathway enhances the antitumor activity of PD‐1 blockades, inhibits malignant growth, and enhances survival in post‐IRFA models. In conclusion, in mice models and patients, macrophages demonstrate increased infiltration around ablated zones in residual tumors. Blockade of the PI3Kγ/AKT pathway suppresses the growth of residual tumors in subcutaneous and orthotopic models. The results illustrate the translational potential of PI3Kγ inhibitors to enhance anti‐PD‐1 therapy for the treatment of residual tumors after IRFA.

PurposeTo validate the feasibility of S-Detect, an ultrasound computer-aided diagnosis (CAD) system using deep learning, in enhancing the diagnostic performance of breast ultrasound (US) for patients with opportunistic screening-detected breast lesions.MethodsNine medical centers throughout China participated in this prospective study. Asymptomatic patients with US-detected breast masses were enrolled and received conventional US, S-Detect, and strain elastography subsequently. The final pathological results are referred to as the gold standard for classifying breast mass. The diagnostic performances of the three methods and the combination of S-Detect and elastography were evaluated and compared, including sensitivity, specificity, and area under the receiver operating characteristics (AUC) curve. We also compared the diagnostic performances of S-Detect among different study sites.ResultsA total of 757 patients were enrolled, including 460 benign and 297 malignant cases. S-Detect exhibited significantly higher AUC and specificity than conventional US (AUC, S-Detect 0.83 [0.80–0.85] vs. US 0.74 [0.70–0.77], p < 0.0001; specificity, S-Detect 74.35% [70.10%–78.28%] vs. US 54.13% [51.42%–60.29%], p < 0.0001), with no decrease in sensitivity. In comparison to that of S-Detect alone, the AUC value significantly was enhanced after combining elastography and S-Detect (0.87 [0.84–0.90]), without compromising specificity (73.93% [68.60%–78.78%]). Significant differences in the S-Detect’s performance were also observed across different study sites (AUC of S-Detect in Groups 1–4: 0.89 [0.84–0.93], 0.84 [0.77–0.89], 0.85 [0.76–0.92], 0.75 [0.69–0.80]; p [1 vs. 4] < 0.0001, p [2 vs. 4] = 0.0165, p [3 vs. 4] = 0.0157).ConclusionsCompared with the conventional US, S-Detect presented higher overall accuracy and specificity. After S-Detect and strain elastography were combined, the performance could be further enhanced. The performances of S-Detect also varied among different centers.

BackgroundHigh-volume lymph node metastasis (HVLNM, equal to or more than 5 lymph nodes) is one of the adverse features indicating high recurrence risk in papillary thyroid carcinoma (PTC) and is recommended as one of the indications of completion thyroidectomy for patients undergoing thyroid lobectomy at first. In this study, we aim to develop a preoperative nomogram for the prediction of HVLNMs in the central compartment in PTC (cT1-2N0M0), where preoperative imaging techniques perform poor.MethodsFrom October 2016 to April 2021, 423 patients were included, who were diagnosed as PTC (cT1-2N0M0) and underwent total thyroidectomy and prophylactic central compartment neck dissection in our center. Demographic and clinicopathological features were recorded and analyzed using univariate and multivariate logistic regression analysis. A nomogram was developed based on multivariate logistic regression analysis.ResultsAmong the included patients, 13.4% (57 cases) were found to have HVLNMs in the central compartment. Univariate and multivariate logistic regression analysis showed that age (35 years), BRAF with V600E mutated, nodule diameter, and calcification independently predicted HVLNMs in the central compartment. The nomogram showed good discrimination with an AUC of 0.821 (95% CI, 0.768–0.875).ConclusionThe preoperative nomogram can be used to quantify the probability of HVLNMs in the central compartment and may reduce the reoperation rate after thyroid lobectomy.

Introduction: The present study aimed to evaluate the influence of biological characteristics of hepatocellular carcinoma (HCC) on the Liver Imaging Reporting and Data System (LI-RADS) v2017 category of contrast-enhanced ultrasound (CEUS) in patients with high risk and compare the outcomes among different categories after radical resection. Methods: Between June 2017 and December 2020, standardized CEUS data of liver nodules were prospectively collected from multiple centers across China. We conducted a retrospective analysis of the prospectively collected data on HCCs measuring no more than 5 cm as diagnosed by pathology. LI-RADS categories were assigned after thorough evaluation of CEUS features. Then, CEUS LI-RADS categories and major features were compared in different differentiation, Ki-67 and microvascular invasion (MVI) statuses. Differences in recurrence-free survival (RFS) among different LI- RADS categories were further analyzed. Results: A total of 293 HCC nodules in 293 patients were included. This study revealed significant differences in the CEUS LI-RADS category of HCCs among differentiation (p 0.05). With a median follow-up of 23 months, HCCs assigned to different CEUS LI-RADS classes showed no significant differences in RFS after resection. Conclusions: Biological characteristics of HCC, including differentiation and level of Ki-67 expression could influence major features of CEUS and impact the CEUS LI-RADS category. HCCs in different CEUS LI-RADS categories showed no significant differences in RFS after resection.

ABSTRACT Objective: Nonalcoholic fatty liver disease is the commonest diffuse liver disease, of which women with polycystic ovary syndrome are at an increased risk. The aim of the present study was to assess the diagnostic value of the semiquantitative strain parameters of real-time ultrasound elastography for nonalcoholic fatty liver disease in patients with polycystic ovary syndrome. Subjects and methods: Thirty-five polycystic ovary syndrome patients with nonalcoholic fatty liver disease, 70 polycystic ovary syndrome patients without nonalcoholic fatty liver disease, and 70 healthy female controls of reproductive age were included. All participants underwent ultrasonic examination and semiquantitative analysis of real-time ultrasound elastography of the liver. Results: Main semi quantitative strain parameters, such as average strain value, differed significantly among groups polycystic ovary syndrome with nonalcoholic fatty liver disease, polycystic ovary syndrome without nonalcoholic fatty liver disease, and control (87.02 ± 10.16 vs. 96.31 ± 11.44 vs. 104.49 ± 7.28, p < 0.001). Clinical and laboratory parameters differed significantly between the two subgroups with low or high average strain value. For diagnostic value of average strain value for elevated aminotransferase, the area under the curve was 0.808 (range 0.721-0.895). In multiple linear regression analysis, polycystic ovary syndrome, waist circumference, and metabolic syndrome were stand-alone independent factors associated with average strain value among subjects without nonalcoholic fatty liver disease. Conclusion: Semiquantitative real-time ultrasound elastography analysis could distinguish liver parenchyma alterations in patients with polycystic ovary syndrome more sensitively. The diagnostic value of the proposed method for nonalcoholic fatty liver disease need further research.

Insufficient recommendations do not support the clinical use of carotid ultrasonography for further risk stratification in moderate-to-high risk patients with cardiovascular disease (CVD). A literature review was performed to assess six aspects of the research progress and limitations of carotid ultrasonography and carotid atherosclerosis-related risk factors: (1) structures of the carotid intima and media; (2) plaques; (3) inflammation; (4) dynamics of carotid blood flow; (5) early detection and intervention; and (6) risk factors for CVD. Although carotid intima-media thickness and carotid plaques are well-acknowledged independent predictors of CVD risk, normative and cut-off values are difficult to define due to the heterogeneous measurements reported in previous studies. Plaque properties, including location, number, density, and size, become more important risk predictors for cardiovascular disease, but a better approach for clinical use needs to be further established. Three-dimensional ultrasound and contrast-enhanced ultrasound are promising for promoting risk stratification with more details on plaque morphology. Moreover, inflammatory diseases and biomarkers should be evaluated for a full assessment of the inflammatory burden for atherosclerosis. Carotid flow velocity is not only an indicator for stenosis but also a potential risk predictor. Carotid atherosclerosis should be detected and treated early, and additional clinical trials are needed to determine the efficacy of these measures in reducing CVD risk. Cardiovascular risk factors tend to affect carotid plaques, and early treat-to-target therapy might yield clinical benefits. Based on the aforementioned six aspects, we consider that these six important factors act like a “SPIDER” spinning the web of atherosclerosis; a timely comprehensive assessment and intervention may halt the progression to CVD. Carotid ultrasound results should be combined with other atherosclerotic factors, and a comprehensive risk assessment may help to guide cardiovascular prevention decisions.

ObjectiveShear-wave elastography (SWE) can improve the diagnostic specificity of the B-model ultrasonography (US) in breast cancer. However, whether deep learning-based radiomics signatures based on the B-mode US (B-US-RS) or SWE (SWE-RS) could further improve the diagnostic performance remains to be investigated. We aimed to develop the B-US-RS and SWE-RS and determine their performances in classifying breast masses.Materials and MethodsThis retrospective study included 291 women (mean age ± standard deviation, 40.9 ± 12.3 years) from two centers who had US-visible solid breast masses and underwent biopsy and/or surgical resection between June 2015 and July 2017. B-mode US and SWE images of the 198 masses in 198 patients (training cohort) from center 1 were segmented, respectively, to construct B-US-RS and SWE-RS using the least absolute shrinkage and selection operator regression and tested in an independent validation cohort of 65 masses in 65 patients from center 1 and in an external validation cohort of 28 masses in 28 patients from center 2. The performances of B-US-RS and SWE-RS were assessed using receiver operating characteristic (ROC) analysis and compared with that of radiologist assessment [Breast Imaging Reporting and Data System (BI-RADS)] and quantitative SWE parameters [maximum elasticity (Emax), mean elasticity (Emean), elasticity ratio (Eratio), and elastic modulus standard deviation (ESD)] by using the McNemar test.ResultsThe single best-performing quantitative SWE parameter, Emax, had a higher specificity than BI-RADS assessment in the training and independent validation cohorts (P < 0.001 for both). The areas under the ROC curves (AUCs) of B-US-RS and SWE-RS both were 0.99 (95% CI = 0.99–1.00) in the training cohort, 1.00 (95% CI = 1.00–1.00) in the independent validation cohort, and 1.00 (95% CI = 1.00–1.00) in the external validation cohort. The specificities of B-US-RS and SWE-RS were higher than that of Emax in the training (P < 0.001 for both) and independent validation cohorts (P = 0.02 for both).ConclusionThe B-US-RS and SWE-RS outperformed the quantitative SWE parameters and BI-RADS assessment for classifying breast masses. The integration of the deep learning-based radiomics approach would help improve the classification ability of B-mode US and SWE for breast masses.

Though radiofrequency ablation (RFA) is considered to be an effective treatment for hepatocellular carcinoma (HCC), but more than 30% of patients may suffer insufficient RFA (IRFA), which can promote more aggressive of the residual tumor. One possible method to counter this is to accurately identify the margin of the HCC. Colony-stimulating factor 1 receptor (CSF-1R) has been found to be restrictively expressed by tumor associated macrophages (TAMs) and monocytes which more prefer to locate at the boundary of HCC. Using biotinylation method, we developed a CSF-1R-conjugated nanobubble CSF-1R (NBCSF–1R) using a thin-film hydration method for margin detection of HCC. CSF-1R expression was higher in macrophages than in HCC cell lines. Furthermore, immunofluorescence showed that CSF-1R were largely located in the margin of xenograft tumor and IFRA models. In vitro, NBCSF–1R was stable and provided a clear ultrasound image even after being stored for 6 months. In co-culture, NBCSF–1R adhered to macrophages significantly better than HCC cells (p = 0.05). In in vivo contrast-enhanced ultrasound imaging, the washout half-time of the NBCSF–1R was significantly greater than that of NBCTRL and Sonovue® (p = 0.05). The signal intensity of the tumor periphery was higher than the tumor center or non-tumor region after NBCSF–1R injection. Taken together, NBCSF–1R may potentially be used as a non-invasive diagnostic modality in the margin detection of HCC, thereby improving the efficiency of RFA. This platform may also serve as a complement method to detect residual HCC after RFA; and may also be used for targeted delivery of therapeutic drugs or genes.

Macrophages are mainly divided into two phenotypes: M1-like (anti-tumoral, pro-inflammatory) and M2-like (pro-tumoral, anti-inflammatory). The more abundant M2-like phenotype of tumor associated macrophages (TAMs) has been associated with poor prognosis in various cancers, therefore, many studies have been carried out to modulate TAMs to change from an M2 to M1-like phenotype as an effective way to suppress tumor growth. Previous study indicated that the FDA-approved Ferumoxytol is an iron oxide nanoparticle that has intrinsic tumor inhibiting properties and is accompanied by the increased presence of the pro-inflammatory, anti-tumoral M1-like phenotype. Intrigued by this finding, we hypothesize that differently charged super-paramagnetic iron oxide nanoparticles (SPIONs) would have preferential differences in polarizing macrophages. Herein, we report that differently charged SPIONs have distinct preferences in the modulation of TAM phenotypes. Positively charged SPION (S+) had the highest cellular uptake and highest macrophage polarization effect. Interestingly, although negatively charged SPION (S−) should present charge–charge repulsion with cell membranes, they showed considerably high uptake in vitro, nevertheless presenting the highest cellular toxicity. Neutrally charged SPION (SN) showed minimal uptake and cellular toxicity in vitro. Both S+ and S− could effectively re-polarize M2-like macrophages toward M1-like macrophages in vitro, and significantly increased the Fenton effect and chemotaxis of macrophages. When macrophages pre-treated with these SPIONs were co-injected with tumor cells to obtain a tumor xenograft, S+ and S− treated macrophages significantly induced tumor retardation, indicating the successful repolarization of tumor macrophages by these SPIONs. Taken together, we provide an insight on the importance of SPION charge in immunomodulation of macrophages.

The research of lipid nanoparticles (LNPs) has been ongoing for more than three decades, and more research are still being carried out today. Being the first Food and Drug Administration (FDA)-approved nanomedicine, LNPs not only provide various advantages, but also display some unique properties. The unique lipid bilayer structure of LNPs allows it to encapsulate both fat-soluble and water-soluble molecules, hence enabling a wide range of possibilities for the delivery of therapeutic agents with different physical and chemical properties. The ultra-small size of some LNPs confers them the ability to cross the blood brain barrier (BBB), thus obtaining superiority in the treatment of diseases of the central nervous system (CNS). The ability of tumor targeting is one of the basic requirements to be an excellent delivery system, where the LNPs have to reach the interior of the tumor. Factors that influence tumor extravasation and the permeability of LNPs are size, surface charge, lipid composition, and shape. The effect of size, surface charge, and lipid composition on the cellular uptake of LNPs is no longer recent news, while increasing numbers of researchers are interested in the effect of shape on the uptake of LNPs and its consequential effects. In our study, we prepared three lipid nanostars (LNSs) by mixing phosphatidylcholine (PC) with different backbone lengths (C14:C4 or C16:C6 or C18:C8) at a 3:1 ratio. Although several star-shaped nanocarriers have been reported, these are the first reported star-shaped LNPs. These LNSs were proven to be safe, similar in size with their spherical controls (~100 nm), and stable at 37°C. The release rate of these LNSs are inversely related to the length of the lipid backbone. Most importantly, these LNSs exhibited greatly enhanced cellular uptake and in vivo tumor extravasation compared with their spherical controls. Based on the different uptake and pharmacokinetic characteristics displayed by these LNSs, numerous route formulations could be taken into consideration, such as via injection or transdermal patch. Due to their excellent cellular uptake and in vivo tumor accumulation, these LNSs show exciting potential for application in cancer therapy.

Background. RNA helicases have various essential functions in basically all aspects of RNA metabolism, not only unwinding RNA but also disturbing the interaction of RNA with proteins. Recently, RNA helicases have been considered potential targets in cancers. So far, there has been no detailed investigation of the biological functions of RNA helicase DHX37 in cancers. Objective. We aim to identify the prognostic value of DHX37 associated with tumor microenvironments in cancers. Methods. DHX37 expression was examined via the Oncomine database and Tumor Immune Estimation Resource (TIMER). We explored the prognostic role of DHX37 in cancers across various databases. Coexpression genes, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), and fundamental regulators were performed via LinkedOmics. Confirming the prognostic value of DHX37 in liver hepatocellular carcinoma (LIHC) and lung adenocarcinoma (LUAD), we explored the role of DHX37 in infiltrated lymphocytes in cancers using the Gene Expression Profiling Interactive Analysis (GEPIA) and TIMER databases. Results. Through GO and KEGG analyses, expression of DHX37 was also correlated with complex function-specific networks involving the ribosome and RNA metabolic signaling pathways. In LIHC and LUAD, DHX37 expression showed significant positive correlations with markers of Tregs, myeloid-derived suppressor cells (MDSCs), and T cell exhaustion, contributing to immune tolerance. Conclusion. These results indicate that DHX37 can serve as a prognostic biomarker in LIHC and LUAD while having an important role in immune tolerance by activating the function of Tregs, MDSC, and T cell exhaustion.

Although many studies about breast contrast-enhanced ultrasound had been conducted, clear diagnostic criteria for evaluating enhancement patterns are still lacking. This study aims to identify significant indicators for breast contrast-enhanced ultrasound and to establish an initial scoring system.Totally 839 patients were included in the study. This study was divided into two parts. 364 patients were included in part 1 while 475 in part 2. Conventional ultrasound and contrast-enhanced ultrasound were used to examine each lesion. Only the cases in part 2 were also examined by elastography. In part 1, Logistic regression analysis was performed to predict significant variables. A 5-point scoring system was developed based on the results. In part 2, the scoring system was used to evaluate all the breast lesions. To evaluate the diagnostic efficacy of the new scoring system, it was compared with the system established for elastography and conventional ultrasound (BI-RADS).Three independent variables, namely, lesion scope, margin, and shape were selected in the final step of the logistic regression analysis in part 1. In part 2, the area under the ROC (receiver operating characteristic) curve for the contrast-enhanced scoring system was 0.912. The difference in the diagnostic capabilities of the contrast-enhanced scoring system and elastography was not statistically significant (P = 0.17). The difference in the diagnostic capabilities of the contrast-enhanced scoring system and BI-RADS was statistically significant (P

Ultrasound-measured inferior vena cava (IVC) and abdominal aorta (Ao)-associated parameters have been used to predict volume status for decades, yet research focusing on the impact of individual physical characteristics, including gender, height/weight, body surface area (BSA), and age, assessed simultaneously on those parameters in Chinese children is lacking. The aim of the present study was to explore the impact of individual characteristics on maximum IVC diameter (IVCmax), Ao, and IVCmax/Ao in healthy Chinese children. From September to December 2015, 200 healthy children from 1 to 13 years of age were enrolled. IVCmax and Ao diameters were measured by 2D ultrasound. We found that age (years), height (cm), weight (kg), waist circumference (cm), and BSA (m2) were positively correlated with IVCmax and Ao. Multivariate linear regression showed that age was the only independent variable for IVCmax (mm) in female children, height was the only independent variable for IVCmax in male children, and age was the only independent variable for Ao in both females and males. IVCmax/Ao was not significantly influenced by the subjects’ characteristics. In conclusion, IVCmax and Ao were more susceptible to subjects’ characteristics than IVCmax/Ao. IVCmax/Ao could be a reliable and practical parameter in Chinese children as it was independent of age, height, and weight.