Ginsenoside modified lipid-coated perfluorocarbon nanodroplets: A novel approach to reduce complement protein adsorption and prolong in vivo circulation.

Lipid-coated perfluorocarbon nanodroplets (lp-NDs) hold great promise in bio-medicine as vehicles for drug delivery, molecular imaging and vaccine agents. However, their clinical utility is restricted by limited targeted accumulation, attributed to the innate immune system (IIS), which acts as the initial defense mechanism in humans. This study aimed to optimize lp-ND formulations to minimize non-specific clearance by the IIS. Ginsenosides (Gs), the principal components of Panax ginseng, possessing complement inhibition ability, structural similarity to cholesterol, and comparable fat solubility to phospholipids, were used as promising candidate IIS inhibitors. Two different types of ginsenoside-based lp-NDs (Gs lp-NDs) were created, and their efficacy in reducing IIS recognition was examined. The Gs lp-NDs were observed to inhibit the adsorption of C3 in the protein corona (PC) and the generation of SC5b-9. Adding Gs to lp-NDs reduced complement adsorption and phagocytosis, resulting in a longer blood circulation time in vivo compared to lp-NDs that did not contain Gs. These results suggest that Gs can act as anti-complement and anti-phagocytosis adjuvants, potentially reducing non-specific clearance by the IIS and improving lifespan.

Efficient wastewater disinfection by raised 1O2 yield through enhanced electron transfer and intersystem crossing via photocatalysis of peroxymonosulfate with CuS quantum dots modified MIL-101(Fe).

Peroxymonosulfate (PMS)-based photocatalysis is a promising alternative approach for wastewater disinfection. Singlet oxygen (1O2) is sensitive and efficient for bacterial inactivation. This study developed a 1O2-predominated PMS disinfection technique under visible light with CuS quantum dots (QDs) modified MIL-101(Fe) (CSQDs@MF). CuS QDs modification greatly enhanced the 1O2 quantum yield by 80% than that of MIL-101(Fe). Photoelectricity and photoluminescence tests demonstrated that both the enhanced electron transfer and energy transfer were responsible for improved 1O2 generation in Vis/PMS/CSQDs@MF system. The system took 60 min to inactivate 7.5-log E. coli, and it could be applied in a broad pH and dissolve oxygen range. Bacterial inactivation mechanism suggested that 1O2 attacked cell membrane first, then induced oxidative stress, up-regulated intracellular ROS level, eventually broke DNA strand. The system showed good disinfection performance on Gram-positive B. subtilis and fecal coliforms in practical wastewater, implying it is a promising alternative disinfection technology for wastewater treatment.

Role of Surface Charge of Nanoscale Ultrasound Contrast Agents in Complement Activation and Phagocytosis.

Purpose: To prepare nanoscale ultrasound contrast agents (Nano-UCAs) and examine the role of their surface charge in complement activation and phagocytosis. Materials and Methods: We analyzed serum proteins present in the corona formed on Nano-UCAs and evaluated two important protein markers of complement activation (C3 and SC5b-9). The effect of surface charge on phagocytosis was further assessed using THP-1 macrophages. Results: When Nano-UCAs were incubated with human serum, they were opsonized by various blood proteins, especially C3. Highly charged Nano-UCAs, whether positive or negative, were favorably opsonized by complement proteins and phagocytized by macrophages. Conclusion: Charged Nano-UCAs show a higher tendency to activated complement system, and are efficiently engulfed by macrophages. The present results provide meaningful insights into the role of the surface charge of nanoparticles in the activation of the innate immune system, which is important not only for the design of targeted Nano-UCAs, but also for the effectiveness and safety of other theranostic agents.

An Oxygen-Sufficient Nanoplatform for Enhanced Imaging-Guided Microwave Dynamic Therapy Against Hypoxic Tumors.

Background: Microwave dynamic therapy (MDT) as a novel reactive oxygen species (ROS)-based therapeutic modality has been explored as a promising modality for cancer treatment. However, the intrinsic hypoxic tumor microenvironment (TME) restricted the effectiveness of the MDT. The aim of this study is to develop an oxygen-sufficient nanoplatform with multi-modal imaging capability for enhanced MDT against hypoxic tumors. Methods and Materials: The liquid perfluorocarbon-based nanoplatform PFP@IR780@O2 was constructed by the phospholipid hydration and sonication method. Then, the characteristics, intracellular uptake process, and subcellular localization of PFP@IR780@O2 were verified. Additionally, the abilities of ROS generation, the anti-hypoxia capability, multi-mode imaging capabilities, and MDT efficacy of the nanoplatform were evaluated via in vitro and in vivo experiments. Finally, the in vivo biocompatibility and toxicity were also evaluated. Results: The prepared nanoparticles PFP@IR780@O2 exhibited suitable size, improved stability, elevated dissolved oxygen level, enhanced cellular uptake, and mitochondria targeting capacity. Additionally, PFP@IR780@O2 demonstrated in vitro and in vivo multimodal imaging capabilities involving ultrasound, fluorescence, and photoacoustic imaging. In vivo studies also indicated that nanoparticles were safe and capable of accumulating in the tumor site after intravenous injection. Furthermore, the PFP@IR780@O2 nanoplatform mediated MDT could effectively alleviate the hypoxic TME, and elevate ROS concentration, thereby resulting in significant tumor growth inhibition. Conclusion: Overall, the oxygen-sufficient nanoplatform with multi-bimodal imaging capability demonstrated improved MDT efficiency, indicating a promising strategy for treating hypoxic tumors.

Benign Pancreatic Neurofibroma with Malignant Imaging Features: A Case Report and Literature Review.

Pancreatic neurofibroma is a very rare benign neurogenic tumor unrelated to neurofibromatosis type 1 (NF-1). As the volume increases, it has the risk of malignant transformation. The surgical prognosis of pancreatic neurofibroma is good, but its preoperative imaging features are very similar to those of malignant tumors, which may affect the formulation of treatment plans. This article reports a case of giant neurofibroma of the pancreas with contrast-enhanced ultrasound (CEUS) as one of the diagnostic methods and discusses the tumor's preoperative clinical features, laboratory examinations, and imaging features.

The value of ultrasound for the preoperative assessment of carotid body tumors.

OBJECTIVES: To evaluate the value of ultrasound (US) examination for the preoperative assessment of carotid body tumors (CBTs) and to predict surgical outcomes. METHODS: A total of 15 CBT lesions in 15 patients were included in this study. CBT measurements determined using US, and included maximal diameter, volume, tumor distance to base of skull (DTBOS), and carotid wall infiltration. A correlation analysis was conducted to determine the correlation between US measurements and surgical outcomes, including estimated blood loss (EBL), cranial nerve injury, surgical time, and hospital length of stay (HLOS). RESULTS: EBL showed a high level of correlation with the maximal dimeter (r = 0.596, p < .05) and the volume of the tumor (r = 0.864, p < .05). Surgical time was positively correlated with tumor volume (r = 0.592, p < .05) and negatively correlated with DTBOS (r = -0.554, p < .05). There was no significant correlation (p > .05) shown between cranial nerve injury and US variables. HLOS showed the high degree of correlation with the maximal dimeter (r = 0.658, p < .05), and was also negatively correlated with DTBOS (r = -0.620, p < .00). CONCLUSIONS: US examination allows for the visualization of features of CBTs, which is a useful and safe tool to be used to predict surgical outcomes. Further research is necessary to validate this exploration method for the preoperative assessment of CBTs.

Diagnosis of steatohepatitis and fibrosis in biopsy-proven nonalcoholic fatty liver diseases: including two-dimension real-time shear wave elastography and noninvasive fibrotic biomarker scores.

Background: The aim of this retrospective study was to evaluate the accuracy of two-dimension real-time shear wave elastography (2D-SWE) for the diagnosis of steatohepatitis and fibrosis in a cohort patients confirmed nonalcoholic fatty liver diseases (NAFLD) by liver biopsy, and compare with four noninvasive fibrotic biomarker scores (NFS, FIB-4, BARD and APRI). Methods: 116 NAFLD patients and 23 normal control group were enrolled. The diagnostic performance of 2D-SWE and four noninvasive fibrotic biomarker scores was evaluated based on histopathological inflammation grades and fibrosis stages (F) according to Kleiner/Brunt et al.'s criteria classification. 5-fold cross validation and receiver operating characteristics curve (ROC) analyses were used to obtain an assessment of 2D-SWE and four noninvasive fibrotic biomarker scores; then cross validated area under the curves (AUCs) were compared using the test of Delong. Meanwhile, influence of steatosis on liver stiffness measurement (LSM) of 2D-SWE was also studied. Results: Liver stiffness measured by 2D-SWE proved to be an excellent diagnostic indicator for detecting steatohepatitis (AUROC =0.88), and fibrosis: ≥F2 stage (AUROC =0.86), ≥F3 stage (AUROC =0.89) and =F4 stage (AUROC =0.90) with the cutoff values were 7.3, 10.0, 11.6 and 12.6 kPa, respectively. Compared with fibrotic scores, 2D-SWE had the highest AUROC for predicting ≥F2, ≥F3, =F4 by Delong test (all P<0.05). No statistic differences of LSM were found among different steatosis levels (P=0.97). Conclusions: The stiffness measured by 2D-SWE could be used to noninvasively identify steatohepatitis and stage fibrosis in NAFLD patients. Moreover, the diagnosis efficiency of the stiffness measured by 2D-SWE could not be influenced by steatosis.

Efficacy and safety of neoadjuvant immunotherapy in resectable esophageal or gastroesophageal junction carcinoma: A pooled analysis of prospective clinical trials.

Neoadjuvant chemoradiotherapy (NCRT) plus radical esophagectomy is currently the standard treatment for resectable esophageal or gastroesophageal junction (GEJ) carcinoma. The aim of this study is to evaluate the efficacy and safety of neoadjuvant immunotherapy in resectable esophageal or GEJ carcinoma. Prospective clinical trials investigating efficacy and/or safety of neoadjuvant immunotherapy with immune checkpoint inhibitors (ICIs) followed by radical esophagectomy in patients with newly diagnosed resectable esophageal or GEJ carcinoma were identified through literature search. Quality assessment was performed by using the Newcastle-Ottawa scale. Preliminary treatment outcomes of pathologically complete response (pCR, ypT0N0) and grade 3-4 adverse effects (AEs) were pooled together and then compared with standard NCRT of the historical control CROSS study by Chi-square (χ2) test. A two-sided P value < 0.05 was considered statistically significant. A total of 17 eligible non-randomized trials with 455 participants were included into analysis. The most common primary endpoint was pCR (n = 7, 41%), and the median sample size and follow-up period was 23 patients and 7.9 months, respectively. For patients receiving neoadjuvant immunotherapy, the overall pCR, R0 resection, and grade 3-4 AE rates were 33.2%, 95.5%, and 35.1%, respectively. For esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC), neoadjuvant immunochemoradiotherapy showed no significant improvement in pCR rate than NCRT (ESCC, 50% vs 48.7%, P = 0.9; EAC, 32.6% vs 23.1%, P = 0.22). Grade 3-4 AEs were the most common in patients with neoadjuvant immunochemoradiotherapy, significantly higher than immunochemotherapy (46.7% vs 32.8%, P = 0.04) and NCRT (46.7% vs 18.1%, P < 0.0001). In conclusion, for patients with resectable esophageal or GEJ carcinoma, the addition of ICIs to standard NCRT could not improve pCR rate in both ESCC and EAC, but significantly increased the risk of severe AEs. Large-scale phase 3 randomized trials were urgently needed to further confirm the survival benefit and safety profile of neoadjuvant immunotherapy.

Synergistic Cascade Strategy Based on Modifying Tumor Microenvironment for Enhanced Breast Cancer Therapy.

Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with very few treatment options. Although tumor-targeted nanomedicines hold great promise for the treatment of TNBC, the tumor microenvironment (TME) continues to be a major cause of failure in nanotherapy and immunotherapy. To overcome this barrier, we designed a new synergistic cascade strategy (SCS) that uses mild hyperthermia and smart drug delivery system (SDDS) to alter TME resistance in order to improve drug delivery and therapeutic efficacy of TNBC. Methods: Mild hyperthermia was produced by microwave (MW) irradiation. SDDS were formulated with thermosensitive polymer-lipid nanoparticles (HA-BNPs@Ptx), composed of polymer PLGA, phospholipid DPPC, hyaluronic acid (HA, a differentiation-44-targeted molecule, also known as CD44), 1-butyl-3-methylimidazolium-L-lactate (BML, a MW sensitizer), and paclitaxel (Ptx, chemotherapy drug). 4T1 breast tumor-bearing mice were treated with two-step MW combined with HA-BNPs@Ptx. Tumors in mice were pretreated with first MW irradiation prior to nanoparticle injection to modify and promote TME and promoting nanoparticle uptake and retention. The second MW irradiation was performed on the tumor 24 h after the injection of HA-BNPs@Ptx to produce a synergistic cascade effect through activating BML, thus, enhancing a hyperthermia effect, and instantly releasing Ptx at the tumor site. Results: Multifunctional CD44-targeted nanoparticles HA-BNPs@Ptx were successfully prepared and validated in vitro. After the first MW irradiation of tumors in mice, the intratumoral perfusion increased by two times, and the nanoparticle uptake was augmented by seven times. With the second MW irradiation, remarkable antitumor effects were obtained with the inhibition rate up to 88%. In addition, immunohistochemical analysis showed that SCS therapy could not only promote tumor cell apoptosis but also significantly reduce lung metastasis. Conclusion: The SCS using mild hyperthermia combined with SDDS can significantly improve the efficacy of TNBC treatment in mice by modifying TME and hyperthermia-mediated EPR effects.

Carotid sheath xanthoma: A rare manifestation of lipid disorders.

Xanthomas are visibly deformed cholesterol deposits that are commonly associated with lipid disorders, such as familial hypercholesterolemia (FH) or rare sitosterolemia. We present the first report of two cases of carotid sheath xanthomas in patients with lipid disorders. Case 1 involved a 26-year-old woman presenting with two heterogeneous mutations on the ABCG5 gene-as noted on genetic testing-who was finally diagnosed with sitosterolemia. Ultrasonography (US) revealed hypoechoic masses centered in the bilateral carotid sheath, which gradually reduced in size after diet control and the use of ezetimibe. Case 2 involved a 27-year-old man who was diagnosed with possible FH and had recurrent bilateral buttock xanthomas, as well as bilateral carotid sheath masses detected by US. Postoperative pathological examination of the resected right neck mass confirmed a xanthoma with proliferation of multinucleated giant cells and deposition of cholesterol clefts.

Multifunctional pathology-mapping theranostic nanoplatforms for US/MR imaging and ultrasound therapy of atherosclerosis.

Atherosclerotic thrombosis is the leading cause of most life-threatening cardiovascular diseases (CVDs), particularly as a result of rupture or erosion of vulnerable plaques. Rupture or erosion-prone plaques are quite different in cellular composition and immunopathology, requiring different treatment strategies. The current imaging technology cannot distinguish the types of vulnerable plaques, and thus empirical treatment is still applied to all without a tailored and precise treatment. Herein, we propose a novel strategy called "Multifunctional Pathology-mapping Theranostic Nanoplatform (MPmTN)" for the tailored treatment of plaques based on the pathological classification. MPmTNs are made up of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), containing contrast imaging materials Fe3O4 and perfluoropentane (PFP), and coated with specific plaque-targeted peptides PP1 and cyclic RGD. The PFP encapsulated inside the MPmTN can undergo a phase change from nanodroplets to gas microbubbles under therapeutic ultrasound (TUS) exposure. The acoustic and biological effects induced by TUS and disruption of microbubbles may further promote therapeutic effects. Hypothetically, MPmTN NPs can target the rupture-prone plaque via the binding of PP1 to class A scavenger receptors (SR-A) on macrophages, induce the apoptosis due to TUS exposure and thus reduce the chronic soakage of inflammatory cells. The MPmTN NPs can also target the erosion-prone plaque through the binding of cRGD to glycoprotein (GP) IIb/IIIa on activated platelets and promote platelet disaggregation under TUS exposure. Therefore, MPmTNs may work as a multifunctional pathology-mapping therapeutic agent. Our in vitro results show that the MPmTN with PP1 and cRGD peptides had a high binding affinity both for activated macrophages and blood clots. Under TUS exposure, the MPmTN could effectively induce macrophage apoptosis, destroy thrombus and exhibit good imaging properties for ultrasound (US) and MRI. In apoE-/- mice, MPmTNs can selectively accumulate at the plaque site and reduce the T2-weighted signal. The apoptosis of macrophages and disaggregation of activated platelets on the plaques were also confirmed in vivo. In summary, this study provides a potential strategy for a tailored treatment of vulnerable plaques based on their pathological nature and a multimodal imaging tool for the risk stratification and assessment of therapeutic efficacy.

Value of Contrast-Enhanced Ultrasound in the Differential Diagnosis of Focal Splenic Lesions.

PURPOSE: To identify and validate contrast-enhanced ultrasound (CEUS) features for differentiating malignant from benign splenic lesions. PATIENTS AND METHODS: Splenic lesions in 123 patients who underwent conventional ultrasound (B-mode US) and CEUS were included in this study. Two radiologists evaluated the sonograms of B-mode and CEUS. Statistical analysis was performed to identify significant imaging predictors for splenic malignant lesions. Two other radiologists independently reviewed B-mode and CEUS sonograms and diagnosed the lesions based on proposed criteria as 1) benign, 2) probably benign, 3) probably malignant or 4) malignant. The diagnostic efficiency between B-mode US and CEUS was compared. RESULTS: Common imaging findings of malignant lesions included hypoechoic, ill-defined margin, absence of cystic/necrotic portion, presence of splenomegaly on B-mode US, and hypoenhancement, rapid washout and presence of intralesional vessels on CEUS (P < 0.05). Among them, three independent features were identified using multivariate logistic regression analysis: hypoechoic pattern, hypoenhancement pattern and intralesional vessels. When three of these findings were combined as a predictor for splenic malignant lesions, 22 (55.0%) of 40 malignant splenic lesions were identified with a specificity of 100%. The diagnostic performance of two readers using receiver operating characteristic curve analysis was 0.622 and 0.533, respectively, for B-mode US, which was significantly improved to 0.908 and 0.906 for CEUS (P < 0.001). The degree of other diagnostic efficiency and inter-reader agreement also increased with CEUS compared to B-mode US. CONCLUSION: CEUS may provide more useful information than B-mode US and improve the diagnosis efficiency for distinguishing malignant from benign splenic lesions.