Preoperative prediction of macrotrabecular-massive hepatocellular carcinoma based on B-Mode US and CEUS.

OBJECTIVES: To develop a preoperative prediction model to identify macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) and evaluate the model's diagnostic performance in differentiating MTM-HCC from HCC. METHODS: We conducted a mono-center retrospective study in a grade A tertiary hospital in China. Consecutive patients with suspected HCC from February 2019 to December 2020 were eligible for inclusion. All consenting patients underwent CEUS examination and were histologically diagnosed. Based on the clinical and US features between the two groups, we developed a binary logistic regression model and a nomogram for predicting MTM-HCC. RESULTS: A total of 161 patients (median age, 57 years; interquartile range, 48-64 years; 129 men) were included in the analysis. Twenty-seven of the HCCs (16.8%) were of the MTM subtype. Binary logistic regression analysis indicated that PVP hypoenhancement (OR = 15.497; 95% CI: 1.369, 175.451; p = 0.027), AFP > 454.6 ng/mL (OR = 8.658; 95% CI: 3.030, 24.741; p < 0.001), ALB ≤ 29.9 g/L (OR = 3.937; 95% CI: 1.017, 15.234; p = 0.047), halo sign (OR = 3.868; 95% CI: 1.314, 11.391; p = 0.016), and intratumoral artery (OR = 2.928; 95% CI: 1.039, 8.255; p = 0.042) were predictors for MTM subtype. Combining any two criteria showed a high sensitivity (100.0%); combining all five criteria showed a high specificity (99.2%); and the AUC value of the logistic regression model was 0.88 (95% CI: 0.81, 0.92). CONCLUSIONS: BMUS and CEUS could be used for identifying patients suspected of having MTM-HCC. Combining clinical information, BMUS, and CEUS features could achieve a noninvasive diagnosis of MTM-HCC. KEY POINTS: • Contrast-enhanced ultrasound examination helps clinicians to identify MTM-HCCs preoperatively. • PVP hypoenhancement, high AFP levels, low ALB levels, halo signs, and intratumoral arteries could be used to predict MTM-HCCs. • A logistic regression model and nomogram were built to noninvasively diagnose MTM-HCCs with an AUC value of 0.88 (95% CI: 0.81, 0.92).

Combination of ruthenium (II) polypyridyl complex Δ-Ru1 and Taxol enhances the anti-cancer effect on Taxol-resistant cancer cells through Caspase-1/GSDMD-mediated pyroptosis.

Taxol is the first-line drug for cancer treatment. However, tumor resistance to Taxol is still a significant challenge in clinical practice. Here, we studied the synergistic effect of a ruthenium (II) polypyridyl complex, Δ-[Ru(bpy)2(HPIP)](ClO4)2(Δ-Ru1, where bpy = 2,2'-bipyridine, HPIP = 2-(2-hydroxyphenyl) imidazo[4,5-f] [1, 10] phenanthroline) combined with Taxol (Δ-Ru1 & Taxol) on Taxol resistant cervical cancer HeLa cell line (HeLa/Taxol). The results of the Chou-Talalay and Synergyfinder analytical test show that the Δ-Ru1 & Taxol combination has a synergistic effect in HeLa/Taxol cells. Especially, vesicles structures were observed on the membranes of HeLa/Taxol cells treated with Δ-Ru1 & Taxol, accompanied by cell swelling, which characterizes pyroptosis. Furthermore, the release of Interleukin-1ß (IL-1ß) and Lactate Dehydrogenase (LDH) were increased. At the same time, the activation and cleavage of Caspase-1 and Gasdermin D (GSDMD), the key molecules of the pyroptosis pathway, were detected. In addition, the Δ-Ru1 & Taxol combination had a synergistic anti-tumor effect in the mice model and could effectively inhibit tumor growth and significantly reduce the side effects on the lungs and the neuroethology of Taxol. Taken together, the Δ-Ru1 & Taxol combination can induce cell death through Caspase-1/GSDMD-mediated pyroptosis to enhance the therapeutic effect on HeLa/Taxol cells. This study provides a novel idea for the combined application of ruthenium complexes and other drugs, which may be utilized to overcome cancer drug resistance.

Reduction BACE1 expression via suppressing NF-κB mediated signaling by Tamibarotene in a mouse model of Alzheimer's disease.

This present study examined the effect of Tamibarotene (AM80) in APP/PS1 mice, a well-established AD mouse model. AM80 was intraperitoneal administered to 3-month-old APP/PS1 mice at a dose of 5 mg/kg/day for 16 weeks. The results clearly showed that AM80 could reduce amyloid-ß peptides through impact on APP processing and reduce microglia and astrocyte activation in APP/PS1 mice. The most notable finding in the present study was that inhibitory effect on BACE1 mediated by NF-κB pathway underlies the anti-inflammatory action of AM80. Moreover, AM80 could significantly decrease synaptic loss and enhance the expressions of Synapsin and Drebrin. Therefore, AM80 treatment may have the preclinical prevention of AD with new therapeutic strategies.

Two-photon photodynamic ablation of tumour cells using an RGD peptide-conjugated ruthenium(ii) photosensitiser.

An RGD-peptide conjugated ruthenium(ii) complex has been developed, which functions as a two-photon absorption (TPA) photodynamic therapy (PDT) agent for ablating tumours by selectively targeting the mitochondria of integrin αvß3-rich tumour cells. This approach offers a new and effective design and application for tumour-targeting metallo-anticancer drugs via two-photon PDT.

An Ultrasmall RuO2 Nanozyme Exhibiting Multienzyme-like Activity for the Prevention of Acute Kidney Injury.

Oxidative stress induced by reactive oxygen species (ROS) is one of the major pathological mechanisms of acute kidney injury (AKI). Inorganic nanomaterial-mediated antioxidant therapy is considered a promising method for the prevention of AKI; however, currently available antioxidants for AKI exhibit limited clinical efficacy due to the glomerular filtration threshold (∼6 nm). To address this issue, we developed ultrasmall RuO2 nanoparticles (RuO2NPs) (average size ≈ 2 nm). The NPs show excellent antioxidant activity and low biological toxicity. In addition, they can pass through the glomerulus to be excreted. These properties in combination make the ultrasmall RuO2NPs promising as a nanozyme for the prevention of AKI. The NP catalytic properties mimic the activity of catalase, peroxidase, superoxide dismutase, and glutathione peroxidase. The nanozyme can be efficiently and rapidly absorbed by human embryonic kidney cells while significantly reducing ROS-induced apoptosis by eliminating excess ROS. After intravenous injection, the ultrasmall RuO2NPs significantly inhibit the development of AKI in mice. In vivo toxicity experiments demonstrate the biosafety of the NPs after long-term preventing. The multienzyme-like activity and biocompatibility of the ultrasmall RuO2NPs makes them of great interest for applications in the fields of biomedicine and biocatalysis.

Combination of Ruthenium Complex and Doxorubicin Synergistically Inhibits Cancer Cell Growth by Down-Regulating PI3K/AKT Signaling Pathway.

Combinational use of drugs has been a common strategy in cancer treatment because of synergistic advantages in reducing dose and toxicity, minimizing or delaying drug resistance. To improve the efficacy of chemotherapy, various potential combinations have been investigated. Ruthenium complex is considered a potential alternative of the platinum-based drugs due to its significant efficacy and safety. Previously, we reported that ruthenium(II) complex (Δ-Ru1) has great anticancer potential and minor toxicity toward normal tissues. However, the therapeutic efficacy and mechanism of action of ruthenium(II) complex combined with other anticancer drugs is still unknown. Here, we investigated the combinational effect of Δ-Ru1 and doxorubicin in different cancer cells. The data assessed by Chou-Talalay method showed significant synergism in MCF-7 cells. Furthermore, the results in antiproliferation efficacy indicated that the combination showed strong cytotoxicity and increasing apoptosis of MCF-7 cells in 2D and 3D multicellular tumor spheroids (MCTSs). Significant inhibition of MCF-7 cells accompanied with increased ROS generation was observed. Furthermore, the expression of PI3K/AKT was significantly down-regulated, while the expression of PTEN was strongly up-regulated in cells treated with combination of Δ-Ru1 and doxorubicin. The expression of NF-κB and XIAP decreased while the expression of P53 increased and associated with apoptosis. These findings suggest that the combination of ruthenium complex and doxorubicin has a significant synergistic effect by down-regulating the PI3K/AKT signaling pathway in MCF-7 cells. This study may trigger more research in ruthenium complex and combination therapy that will be able to provide opportunities for developing better therapeutics for cancer treatment.

Correction: Mitochondria-targeted Ir@AuNRs as bifunctional therapeutic agents for hypoxia imaging and photothermal therapy.

Correction for 'Mitochondria-targeted Ir@AuNRs as bifunctional therapeutic agents for hypoxia imaging and photothermal therapy' by Libing Ke et al., Chem. Commun., 2019, 55, 10273-10276.

Nucleus-targeting ultrasmall ruthenium(iv) oxide nanoparticles for photoacoustic imaging and low-temperature photothermal therapy in the NIR-II window.

Nucleus-targeting NPs based on RuO2 (RuO2NPs) were developed by controlling the size and the surface charge of nanoparticles (NPs). This study not only demonstrates a facile approach for the fabrication of ultrasmall CS-RuO2NPs with good biocompatibility and excellent photothermal properties but also their unique potential for the nucleus-targeted low-temperature PTT.

Mitochondria-targeted Ir@AuNRs as bifunctional therapeutic agents for hypoxia imaging and photothermal therapy.

Ir(iii) complex modified gold nanorods, Ir@AuNRs, were developed as mitochondria-targeted theranostic nanoagents. Their hypoxia imaging and photothermal therapeutic properties were demonstrated in vitro and in vivo.

Computer-Aided Diagnosis of Solid Breast Lesions With Ultrasound: Factors Associated With False-negative and False-positive Results.

OBJECTIVES: To investigate factors that may lead to false-positive or false-negative results in a computer-aided diagnostic system (S-Detect; Samsung Medison Co, Ltd, Seoul, Korea) for ultrasound (US) examinations of solid breast lesions. METHODS: This prospective study was approved by the Institutional Review Board of Sun Yat-sen Memorial Hospital. All patients signed and provided written informed consent before biopsy or surgery. From September 2017 to May 2018, 269 consecutive women with 338 solid breast lesions were included. All lesions were examined with US and S-Detect before biopsy or surgical excision. The final US assessments made by radiologists and S-Detect were matched to the pathologic results. Patient and lesion factors in the "true" and "false" S-Detect groups were compared, and multivariate logistic regression analyses were used to identify the factors associated with false S-Detect results. RESULTS: The mean age of the patients ± SD was 42.6 ± 12.9 years (range, 18-77 years). Of the 338 lesions, 209 (61.8%) were benign, and 129 (38.2%) were malignant. Larger lesions, the presence of lesion calcifications detected by B-mode US, and grades of 2 and 3 according to Adler et al (Ultrasound Med Biol 1990; 16:553-559) were significantly associated with false-positive S-Detect results (odds ratio [OR], 1.071; P = .006; OR, 5.851; P = .001; OR, 1.726; P = .009, respectively). Smaller lesions and the absence of calcifications detected by B-mode US in malignant solid breast lesions were significantly associated with false-negative S-Detect results (OR, 1.141; P = .015; OR, 7.434; P = .016). CONCLUSIONS: Larger benign lesions, the presence of lesion calcifications, and high degrees of vascularity are likely to show false-positive S-Detect results. Smaller malignant lesions and the absence of calcifications are likely to show false-negative S-Detect results.

Applications of Ruthenium Complex in Tumor Diagnosis and Therapy.

Ruthenium complexes are a new generation of metal antitumor drugs that are currently of great interest in multidisciplinary research. In this review article, we introduce the applications of ruthenium complexes in the diagnosis and therapy of tumors. We focus on the actions of ruthenium complexes on DNA, mitochondria, and endoplasmic reticulum of cells, as well as signaling pathways that induce tumor cell apoptosis, autophagy, and inhibition of angiogenesis. Furthermore, we highlight the use of ruthenium complexes as specific tumor cell probes to dynamically monitor the active biological component of the microenvironment and as excellent photosensitizer, catalyst, and bioimaging agents for phototherapies that significantly enhance the diagnosis and therapeutic effect on tumors. Finally, the combinational use of ruthenium complexes with existing clinical antitumor drugs to synergistically treat tumors is discussed.

Insufficient radiofrequency ablation promotes proliferation of residual hepatocellular carcinoma via autophagy.

Radiofrequency ablation (RFA) is considered to be a potentially curative therapy for hepatocellular carcinoma (HCC). However, insufficient RFA (IRFA) can promote rapid progression of the residual tumor. The mechanisms underlying IRFA-induced tumor promotion remain poorly understood. In the present study, we have established a subcutaneous xenograft mouse model and monitored the location and extent of IRFA by dual monitoring with ultrasonography and a thermal imager. For the first time, we provide evidence of the activation of autophagic pathways in mice exposed to IRFA. We show that autophagy plays an important role in relapse and proliferation after IRFA and that hydroxychloroquine (HCQ) can suppress these effects. Our findings indicate that autophagy is involved in experimental IRFA and that inhibition of autophagy may be a novel approach in the treatment of local recurrences of HCC after IRFA in the clinic.

Production and characterization of a novel long-acting Herceptin-targeted nanobubble contrast agent specific for Her-2-positive breast cancers.

BACKGROUND: There is an unmet need for specific and sensitive imaging techniques to assess the efficacy of breast cancer therapy, particularly Her-2-expressing cancers. Ultrasonic microbubbles are being developed for use as diagnostic and therapeutic tools. However, nanobubbles circulate longer, are smaller, and diffuse into extravascular tissue to specifically bind target molecules. Here, we characterize a novel Herceptin-conjugated nanobubble for use against Her-2-expressing tumors. METHODS: Phospholipid-shelled nanobubbles conjugated with Herceptin (NBs-Her) were fabricated using a thin-film hydration method and characterized in vitro in breast cancer cell lines and in vivo in a mouse model. RESULTS: The average size of the unconjugated nanobubbles (NBs-Blank) and NBs-Her was 447.1 ± 18.4 and 613.0 ± 25.4 nm, respectively. In cell culture, the NBs-Her adhered to Her-2-positive cells significantly better than to Her-2-negative cells (p < 0.05). In vivo, the peak intensity and the half-time to washout of the NBs-Her were significantly greater than those of the NBs-Blank (p < 0.05). In addition, contrast-enhanced ultrasound imaging quality was improved through the use of the NBs-Her. The nanobubbles were able to penetrate into tumor tissue to allow extravascular imaging, but did not penetrate normal skeletal muscle. CONCLUSIONS: The Herceptin-conjugated nanobubble had many properties that made it useful for in vivo imaging, including longer circulation time and better tumor selectivity. This platform may be able to provide targeted delivery of therapeutic drugs or genes.

Ultrasonic elastography features of phyllodes tumors of the breast: a clinical research.

The purpose of this study was to analyze the ultrasonic elastography features of phyllodes tumors of the breast comparing with fibroadenomas. A retrospective database was queried for the patients diagnosed as phyllodes tumors and fibroadenomas at Sun Yat-sen Memorial Hospital from January 2008 to August 2012. Three hundred and fifty lesions from 323 consecutive patients were included in the study. All the cases were examined by conventional ultrasonography and ultrasound elastography. Ultrasound elastography was used to calculate strain ratio of the lesions with bilateral breast tissue at the same depth as reference. There were 36 phyllodes tumors (27 benign, 8 borderline, 1 malignant) and 314 fibroadenomas (158 the pericanalicular type, 103 the intracanalicular type, 53 other special types). The strain ratio for phyllodes tumors (3.19 ± 2.33) was significantly higher than for fibroadenomas (1.69 ± 0.88) (p<0.05). The Spearman(.)s correlation coefficient between strain ratio of ultrasound elastography and pathological groups was significant, with a value of 0.17 (p<0.05). Ultrasound elastography could provide additional information to differentiate phyllodes tumors from fibroadenoma in breast.

Could ultrasonic elastography help the diagnosis of small (≤2 cm) breast cancer with the usage of sonographic BI-RADS classification?

OBJECTIVES: To evaluate the additive value of ultrasound strain elastography (USE) to BI-RADS for the differentiation of benign and malignant breast small lesions. METHODS: Breast masses (≤2 cm) with histological diagnosis examined by ultrasonography and USE in our department from April 2004 to December 2009 were reviewed. Conventional B-mode ultrasound findings were classified according to the BI-RADS classification. USE findings were classified according to the 5-point scale. Histological diagnosis was used as the reference standard. RESULTS: 401 (246 benign (61.3%), 155 malignant (38.7%)) from 370 consecutive patients were included in the study. Sensitivity and specificity were 90.3%, 68.3% for BI-RADS; 72.3%, 91.9% for USE. The sensitivity of BI-RADS was better than that of USE (P<0.05), while the specificity of USE was better than that of BI-RADS (P<0.05). A revised BI-RADS combined with USE results was proposed in this study. Sensitivity and specificity were 83.9% and 87.8% for revised BI-RADS. The diagnostic performance of revised BI-RADS was better than BI-RADS (P<0.05). CONCLUSIONS: USE could give BI-RADS some help in the differentiation of benign and malignant breast small lesions. The addition of elastography to BI-RADS could improve the diagnostic performance in <2 cm lesions.

Antitumoural hydroxyapatite nanoparticles-mediated hepatoma-targeted trans-arterial embolization gene therapy: in vitro and in vivo studies.

BACKGROUND/AIMS: Absence of curative treatment creates urgent need for new strategies for unresectable hepatoma. Based on former discoveries of good liver cell compatibility, safety and tumour-specific inhibition of hydroxyapatite nanoparticles (nHAP), this work tries to make nHAP serve as gene vector in the hepatoma-targeted trans-arterial embolization (TAE) gene therapy to elevate and synergize the therapeutic efficacy of TAE and target gene therapy. METHOD: Following dosage and ratio optimization, polypolex formed by surface modified nHAP and p53 expressing plasmid was applied in vitro for human hepatoma HePG2 cell, and then in vivo for rabbit hepatic VX2 tumour by injection of polypolex/lipodoil emulsion to the hepatic artery in a tumour-target manner. RESULTS: In vitro, the polypolex transfected only about 5% HepG2 cells, but can elevate the inhibition of its growth and apoptosis in a much more degree while keeping safe to the normal hepatocyte line, L02. In vivo, the emulsion, with better dispersion than the polypolex and more specific tumour-target than lipiodol, mediated specific 4% p53 expression and antitumoural nanoparticle retention in the target tumour site, also significantly reduced tumour growth and prolonged the animal survival times more than the lipiodol (P < 0.05). CONCLUSIONS: In all, this new treatment based on nHAP can enhance therapeutic effect of HCC safely both in vitro and in vivo.

Hepatic and biliary damage after transarterial chemoembolization for malignant hepatic tumors: incidence, diagnosis, treatment, outcome and mechanism.

OBJECTIVE: To provide an overview of recent studies on transarterial chemoembolization-related hepatic and biliary damage (TRHBD) in patients with malignant hepatic tumors (MHT) and to explore the reasons for TRHBD. METHODS: Literature on the treatments for MHT by TACE was sought in PubMed and the related information was summarized. RESULTS: TRHBD is found to occur in the hepatic parenchymal cells, biliary tree and blood-vascular system. The damage is mainly due to ischemia resulting from embolic materials such as gelatin sponge and lipiodol. In addition, clinicians' skill levels in non-superselective catheterization, the health condition of the patients, and the chemical agents used may also be related to the damage. Most of the deterioration can be reversed if the patients are diagnosed and treated properly and promptly. CONCLUSIONS: Understanding the mechanisms of TRHBD more comprehensively is helpful in developing effective methods for prevention and treatment.

Relevance of two genes in the multidrug resistance of hepatocellular carcinoma: in vivo and clinical studies.

AIMS AND BACKGROUND: A former study evaluated the roles of four multidrug resistance-related proteins, namely multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), multidrug resistance-related protein (MRP1), and lung resistance-related protein (LRP), in the MDR mechanism of the multidrug resistant hepatoma HepG2/ADM cell line and proposed that up-regulated MDR1 and BCRP are responsible for the MDR of hepatocellular carcinoma. This work aims to confirm that assumption in vivo and in clinical specimens. METHODS: First, the chemotherapeutic resistance of subcutaneous HepG2/ADM tumor and hepatocellular carcinoma samples post-transarterial chemoembolization (TACE) was determined by MTT, contrary to subcutaneous HepG2 tumor and hepatocellular carcinoma samples without TACE, respectively. Then, the mRNA and protein differential expression of the four genes between the MDR tissues and drug-sensitive tissues were quantitatively investigated by real-time RT-PCR and enhanced chemiluminescence western blot analysis, respectively. RESULTS: 1) mRNA expression of BCRP and MDR1 was respectively amplified 38.3 and 20.1 fold in tumors of HepG2/ADM mice compared to those of HepG2 mice, whereas they were respectively augmented for 14.6 and 9.3 times in TACE samples, contrary to the tumor tissues without TACE. 2) The protein presence of MDR1 and BCRP in MDR tumors was also significantly higher than those in the control group in vivo and in clinical specimens. 3) The mRNA expressions of MDR1 and BCRP were correlated to their protein levels. CONCLUSIONS: The study showed that MDR1 and BCRP may be the most important factors for drug resistance in hepatocellular carcinoma. Moreover, the positive correlation between their mRNA and protein expression indicates the easy prediction of HCC MDR and possible inhibitive target of drug resistance at multi-levels.