Filamentous-Actin-Mimicking Nanoplatform for Enhanced Cytosolic Protein Delivery.

Despite the potential of protein therapeutics, the cytosolic delivery of proteins with high efficiency and bioactivity remains a significant challenge owing to exocytosis and lysosomal degradation after endocytosis. Therefore, it is important to develop a safe and efficient strategy to bypass endocytosis. Inspired by the extraordinary capability of filamentous-actin (F-actin) to promote cell membrane fusion, a cyanine dye assembly-containing nanoplatform mimicking the structure of natural F-actin is developed. The nanoplatform exhibits fast membrane fusion to cell membrane mimics and thus enters live cells through membrane fusion and bypasses endocytosis. Moreover, it is found to efficiently deliver protein cargos into live cells and quickly release them into the cytosol, leading to high protein cargo transfection efficiency and bioactivity. The nanoplatform also results in the superior inhibition of tumor cells when loaded with anti-tumor proteins. These results demonstrate that this fusogenic nanoplatform can be valuable for cytosolic protein delivery and tumor treatment.

Differentiation of malignant and benign pulmonary nodules with first-pass dual-input perfusion CT.

OBJECTIVE: To assess diagnostic performance of dual-input CT perfusion for distinguishing malignant from benign solitary pulmonary nodules (SPNs). METHODS: Fifty-six consecutive subjects with SPNs underwent contrast-enhanced 320-row multidetector dynamic volume CT. The dual-input maximum slope CT perfusion analysis was employed to calculate the pulmonary flow (PF), bronchial flow (BF), and perfusion index [Formula: see text]. Differences in perfusion parameters between malignant and benign tumours were assessed with histopathological diagnosis as the gold standard. Diagnostic value of the perfusion parameters was calculated using the receiver-operating characteristic (ROC) curve analysis. RESULTS: Amongst 56 SPNs, statistically significant differences in all three perfusion parameters were revealed between malignant and benign tumours. The PI demonstrated the biggest difference between malignancy and benignancy: 0.30 ± 0.07 vs. 0.51 ± 0.13 , P < 0.001. The area under the PI ROC curve was 0.92, the largest of the three perfusion parameters, producing a sensitivity of 0.95, specificity of 0.83, positive likelihood ratio (+LR) of 5.59, and negative likelihood ratio (-LR) of 0.06 in identifying malignancy. CONCLUSIONS: The PI derived from the dual-input maximum slope CT perfusion analysis is a valuable biomarker for identifying malignancy in SPNs. PI may be potentially useful for lung cancer treatment planning and forecasting the therapeutic effect of radiotherapy treatment. KEY POINTS: • Modern CT equipment offers assessment of vascular parameters of solitary pulmonary nodules (SPNs) • Dual vascular supply was investigated to differentiate malignant from benign SPNs. • Different dual vascular supply patterns were found in malignant and benign SPNs. • The perfusion index is a useful biomarker for differentiate malignancy from benignancy.

The ultra-early protective effect of ulinastatin on rabbit acute lung injury induced by paraquat.

OBJECTIVE: To study ultra-early pathophysiological changes of rabbit acute lung injury (ALI) caused by paraquat (PQ) and discuss the ultra-early protective effect of ulinastatin on rabbit ALI due to PQ. METHODS: 30 New Zealand white rabbits were randomly divided into a control group, a paraquat group and an ulinastatin intervention group with 10 rabbits in each group. For paraquat group and intervention group a single dose of paraquat (35 mg/kg) was injected intraperitoneally to establish rabbit models of ALI. The control group was injected an equal volume of saline. The intervention group was treated with 100 Ku/kg ulinastatin immediately after the establishment of the ALI model. The respective experimental groups underwent 320-slice CT perfusion scan of pleural at 2h, 4h and 6h time point after modeling to get CTP (CT Perfusion) images and related parameters. 2 mL blood was collected in the marginal ear vein to determine the mass concentration of the vascular endothelial growth factor (VEGF). The animals were killed by air embolism after 6h and lung tissue was taken for pathology observation. RESULTS: The reginal blood flow (rBF) and reginal blood volume (rBV) of paraquat group at 2,4,6 h time point were significantly (P <0.05) lower than those of control group. The intervention group rBF and rBV at 2, 4 and 6 h time points were significantly higher (P <0.05) compared to paraquat group. The permeability surface (rPS) and VEGF mass concentration of paraquat group at 2,4,6 h time point were significantly higher than the control group (P <0.05), and the intervention group rPS and VEGF mass concentrations at 2,4,6h time point were significantly lower (P <0.05) than those of paraquat group. Pathological detection indicators of paraquat group (congestive capillary percentage, the number of red blood cells outside of capillaries, percentage of capillaries with basement membrane damage) were significantly higher (P <0.05) at 6h time point compared with the control group, while significantly lower (P <0.05) in intervention group than in paraquat groups. Pathological observation under light microscope showed in paraquat group obvious inflammatory cell infiltration, alveolar epithelial cell hyperplasia, widened alveolar septum, visible focal hemorrhage, visible acute and chronic inflammatory cell infiltration in bronchioles cavity; under electron microscopy alveolar epithelial cell degeneration and necrosis, vascular welling of the endothelial cells, basement membrane rupture, a lot of exudates in alveolar space. In the intervention group, the above the symptoms were mitigated. CONCLUSION: In the ultra-early stage of rabbit ALI induced by PQ, pulmonary vascular endothelial cell is damaged and serum VEGF mass concentration and pulmonary vascular permeability increase. Early ulinastatin intervention can reduce serum VEGF level and PQ-induced vascular permeability amplitude, indicating that ulinastatin has a protective effect on pulmonary vascular endothelial cells.

Liposomal Glucose Oxidase for Enhanced Photothermal Therapy and Photodynamic Therapy against Breast Tumors.

Organic near-infrared fluorescent dye mediated photothermal therapy (PTT) and photodynamic therapy (PDT) suffer from heat shock response, since, heat shock proteins (HSPs) are overexpressed and can repair the proteins damaged by PTT and PDT. Starvation therapy by glucose oxide (GOx) can inhibit the heat shock response by limiting the energy supply. However, the delivery of sufficient and active GOx remains a challenge. To solve this problem, we utilize liposomes as drug carriers and prepare GOx loaded liposome (GOx@Lipo) with a high drug loading content (12.0%) and high enzymatic activity. The successful delivery of GOx shows excellent inhibition of HSPs and enhances PTT and PDT. Additionally, we apply the same liposome formulation to load near-infrared dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbo cyanine iodide (DiR) and prepare DiR contained liposomes (DiR@Lipo) for PTT and PDT. The liposomal formulation substantially enhances the PTT and PDT properties of DiR as well as the cellular uptake and tumor accumulation. Finally, the combination therapy shows excellent tumor inhibition on 4T1 tumor-bearing mice. Interestingly, we also find that the starvation therapy can efficiently inhibit tumor metastasis, which is probably due to the immunogenic effect. Our work presents a biocompatible and effective carrier for the combination of starvation therapy and phototherapy, emphasizing the importance of auxiliary starvation therapy against tumor metastasis and offering important guidance for clinical PTT and PDT.

Liposome-templated gold nanoparticles for precisely temperature-controlled photothermal therapy based on heat shock protein expression.

Mild temperature photothermal therapy is gaining more and more attention due to high safety, high specificity and moderate efficacy. However, the therapeutical outcome of mild photothermal therapy is limited due to the overexpression of heat shock proteins (HSPs). Therefore, the precise management of HSP expression is the key to improvement of mild temperature photothermal therapy. However, the correlation between HSP expression and photothermal temperature in vivo is still unclear. To precisely control the photothermal temperature by managing the HSP expression, we quantified the HSP expression at different photothermal temperatures after irradiation on liposome-templated gold nanoparticles, which have high photostability, high photothermal conversion efficiency and low temperature fluctuation (smaller than 1 â„ƒ). We found that the expression of HSP70 was least at 47 â„ƒ, which was the optimal temperature for HSP management. We chose to co-administrate HSP70 inhibitor during 47 â„ƒ photothermal therapy, leading to greatly enhanced tumor inhibition. Our precise temperature-controlled photothermal therapy based on HSP expression offers a new strategy for clinical tumor photothermal therapy.

Differentiation between pancreatic metastases from clear cell renal cell carcinoma and pancreatic neuroendocrine tumor using double-echo chemical shift imaging.

PURPOSE: The purpose of the study was to retrospectively analyze whether double-echo gradient-echo (GRE) chemical shift imaging (CSI) can differentiate between pancreatic metastases from clear cell renal cell carcinoma (PM-ccRCC) and pancreatic neuroendocrine tumor (pNET). METHODS: Institutional review board approval and informed consent were waived. CSI, T2WI, DWI, and DCE magnetic resonance imaging (MRI) were performed in patients with PM-ccRCC and pNET. Eleven patients with PM-ccRCC and 24 patients with pNET were enrolled into this retrospective study. The signal intensity was measured in the pancreatic tumor and spleen on in-phase and opposed-phase images. The signal intensity index (SII) and tumor-to-spleen ratio (TSR) in PM-ccRCC and pNET were calculated and compared. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic accuracy of SII and TSR in the differentiation between PM-ccRCC and pNET. RESULTS: The SII between PM-ccRCC and pNET (20.3% ± 16.8% vs. - 3.2% ± 11.4%) was significantly different (P < 0.001), as was the TSR (- 19.2% ± 16.6% vs. 6.0% ± 13.8%) (P < 0.001). The area under the ROC curve was 0.917 for the SII and 0.902 for the TSR. Additionally, an SII threshold value of 8.1% permitted the differentiation of PM-ccRCC from pNET with a sensitivity of 90.9%, a specificity of 91.7%, a positive predictive value of 90.1%, a negative predictive value of 91.7%, and an accuracy of 91.4%. A TSR cut-off value of - 4.7% enabled the differentiation of the two groups with a sensitivity of 79.2%, a specificity of 90.9%, a positive predictive value of 90.9%, a negative predictive value of 79.2% and an accuracy of 82.9%. CONCLUSION: Double-echo GRE chemical shift MR imaging can accurately differentiate between PM-ccRCC and pNET.