Imaging-Guided Photoacoustic Immunotherapy Based on the Polydopamine-Functionalized Black Phosphorus Nanocomposites.

Phototherapy has great application prospects in superficial tumors, such as melanoma, esophageal cancer, and breast carcinoma, owing to the advantages of noninvasiveness, high spatiotemporal selectivity, and less side effects. However, classical phototherapies including photodynamic and photothermal therapy still need to settle the bottleneck problems of poor efficacy, inevitable thermal damage, and a high rate of postoperative recurrence. In this study, we developed a nanocomposite with excellent optical properties and immune-stimulating properties, termed PBP@CpG, which was obtained by functionalizing black phosphorus (BP) with polydopamine and further adsorbing CpG. Benefiting from the protection of polydopamine against BP, ideal light absorption, and photoacoustic conversion properties, PBP@CpG not only enables precisely delineation of the tumor region with photoacoustic imaging but also powerfully disrupts the plasma membrane and cytoskeleton of tumor cells with a photoacoustic cavitation effect. In addition, we found that the photoacoustic cavitation effect was also capable of inducing immunogenic cell death and remarkably strengthening the antitumor immune response upon cooperating with immune adjuvant CpG. Therefore, PBP@CpG was expected to provide a promising nanoplatform for optical theranostics and herald a new strategy of photoimmunotherapy based on the photoacoustic cavitation effects and immunostimulatory effect.

Cu3P/1-MT Nanocomposites Potentiated Photothermal-Immunotherapy.

Purpose: Photothermal therapy (PTT) is a promising anticancer treatment that involves inducing thermal ablation and enhancing antitumor immune responses. However, it is difficult to completely eradicate tumor foci through thermal ablation alone. Additionally, the PTT elicited antitumor immune responses are often insufficient to prevent tumor recurrence or metastasis, due to the presence of an immunosuppressive microenvironment. Therefore, combining photothermal and immunotherapy is believed to be a more effective treatment approach as it can modulate the immune microenvironment and amplify the post-ablation immune response. Methods: Herein, the indoleamine 2, 3-dioxygenase-1 inhibitors (1-MT) loaded copper (I) phosphide nanocomposites (Cu3P/1-MT NPs) are prepared for PTT and immunotherapy. The thermal variations of the Cu3P/1-MT NPs solution under different conditions were measured. The cellular cytotoxicity and immunogenic cell death (ICD) induction efficiency of Cu3P/1-MT NPs were analyzed by cell counting kit-8 assay and flow cytometry in 4T1 cells. And the immune response and antitumor therapeutic efficacy of Cu3P/1-MT NPs were evaluated in 4T1-tumor bearing mice. Results: Even at low energy of laser irradiation, Cu3P/1-MT NPs remarkably enhanced PTT efficacy and induced immunogenic tumor cell death. Particularly, the tumor-associated antigens (TAAs) could help promote the maturation of dendritic cells (DCs) and antigen presentation, which further activates infiltration of CD8+ T cells through synergistically inhibiting the indoleamine 2, 3-dioxygenase-1. Additionally, Cu3P/1-MT NPs decreased the suppressive immune cells such as regulatory T cells (Tregs) and M2 macrophages, indicating an immune suppression modulation effect. Conclusion: Cu3P/1-MT nanocomposites with excellent photothermal conversion efficiency and immunomodulatory properties were prepared. In addition to enhanced the PTT efficacy and induced immunogenic tumor cell death, it also modulated the immunosuppressive microenvironment. Thereby, this study is expected to offer a practical and convenient approach to amplify the antitumor therapeutic efficiency with photothermal-immunotherapy.

miR-181a targets PTEN to mediate the neuronal injury caused by oxygen-glucose deprivation and reoxygenation.

Evidence suggests that the microRNA-181 (miR-181) family performs various roles in the pathophysiology of cerebral ischemia and reperfusion injury (CIRI). MiR-181a has been identified as a critical determinant of neuronal survival. Moreover, the significance of miR-181a in controlling neuronal death after CIRI has received little attention. The objective of this study was to assess the role of miR-181a in neuronal cell injury after CIRI. To mimic the in-vitro and in-vivo CIRI, we developed an oxygen-glucose deficiency/reoxygenation (OGD/R) model in SH-SY5Y cells and a transient middle cerebral artery occlusion model in rats. MiR-181a expression was significantly higher in both in-vivo and in-vitro CIRI models. The overexpression of miR-181a increased cell damage and oxidative stress caused by OGD/R, whereas inhibition of miR-181a reduced both. PTEN has also been found to be a direct miR-181a target. PTEN overexpression reduced cell apoptosis and oxidative stress induced by miR-181a upregulation under an OGD/R condition. Furthermore, we found that the rs322931 A allele was related to increased miR-181a levels in IS peripheral blood and higher susceptibility to IS. The current results offer new insights into the understanding of the molecular pathophysiology of CIRI, as well as possible new treatment candidates.

Direct targeting of DOCK4 by miRNA-181d in oxygen-glucose deprivation/reoxygenation-mediated neuronal injury.

The miRNA-181 (miR-181) family regulates neuronal persistence during cerebral ischemia/reperfusion injury (CI/RI). Since the effect of miR-181d on CI/RI has never been studied, the current work sought to determine the involvement of miR-181d in neuronal apoptosis after brain I/R injury. To replicate in vivo and in vitro CI/RI, a transient middle cerebral artery occlusion (tMCAO) model in rats and an oxygen-glucose deficiency/reoxygenation (OGD/R) model in neuro 2A cells were developed. In both in vivo and in vitro stroke models, the expression of miR-181d was considerably higher. miR-181d suppression reduced apoptosis and oxidative stress in OGD/R-treated neuroblastoma cells, but miR-181d overexpression increased both. Furthermore, it was observed that miR-181d has a direct target in dedicator of cytokinesis 4 (DOCK4). The overexpression of DOCK4 partially overcame cell apoptosis and oxidative stress induced by miR-181d upregulation and OGD/R injury. Furthermore, the DOCK4 rs2074130 mutation was related to lower DOCK4 levels in ischemic stroke (IS) peripheral blood and higher susceptibility to IS. These findings suggest that downregulating miR-181d protects neurons from ischemic damage by targeting DOCK4, implying that the miR-181d/DOCK4 axis might be a novel therapeutic target for IS.

KFWC: A Knowledge-Driven Deep Learning Model for Fine-grained Classification of Wet-AMD.

BACKGROUND AND OBJECTIVES: Automated diagnosis using deep neural networks can help ophthalmologists detect the blinding eye disease wet Age-related Macular Degeneration (AMD). Wet-AMD has two similar subtypes, Neovascular AMD and Polypoidal Choroidal Vasculopathy (PCV). However, due to the difficulty in data collection and the similarity between images, most studies have only achieved the coarse-grained classification of wet-AMD rather than a fine-grained one of wet-AMD subtypes. Therefore, designing and building a deep learning model to diagnose neovascular AMD and PCV is a great challenge. METHODS: To solve this issue, in this paper, we propose a Knowledge-driven Fine-grained Wet-AMD Classification Model (KFWC) to enhance the model's accuracy in the fine-grained disease classification with insufficient data. We innovatively introduced a two-stage method. In the first stage, we present prior knowledge of 10 lesion signs through pre-training; in the second stage, the model implements the classification task with the help of human knowledge. With the pre-training of priori knowledge of 10 lesion signs from input images, KFWC locates the powerful image features in the fine-grained disease classification task and therefore achieves better classification. RESULTS: To demonstrate the effectiveness of KFWC, we conduct a series of experiments on a clinical dataset collected in cooperation with a Grade III Level A ophthalmology hospital in China. The AUC score of KFWC reaches 99.71%, with 6.69% over the best baseline and 4.14% over ophthalmologists. KFWC can also provide good interpretability and effectively alleviate the pressure of data collection and annotation in the field of fine-grained disease classification for wet-AMD. CONCLUSIONS: The model proposed in this paper effectively solves the difficulties of small data volume and high image similarity in the wet-AMD fine-grained classification task through a knowledge-driven approach. Besides, this method effectively relieves the pressure of data collection and annotation in the field of fine-grained classification. In the diagnosis of wet-AMD, KFWC is superior to previous work and human ophthalmologists.

Hydrogen sulfide activatable metal-organic frameworks for Fluorescence Imaging-Guided Photodynamic Therapy of colorectal cancer.

Photodynamic therapy (PDT) is a promising alternative and palliative therapeutic strategy for colorectal cancer (CRC). A novel photosensitizer with higher selectivity for CRC and fewer side effects is vital for clinical application. Given that the overexpression of hydrogen sulfide (H2S) in CRC, it is expected to provide a selective stimulus for activatable photosensitizers that in respond to the specific microenvironment. Herein, we report a novel development of metal-organic frameworks (MOFs) composed of meso-Tetra (4-carboxyphenyl) porphine (TCPP) and ferric ion (Fe3+) through a facile one-pot process. Experiments both in vitro and in vivo reveal that the MOF is capable of depredating in response to the high content of H2S in tumor microenvironment of CRC. Accompanying with the degradation and release of TCPP, the fluorescence and photosensitivity effect is switched from "off" to "on", enabling the MOF to serve as a H2S activatable nano-photosensitizer for real-time fluorescence imaging-guided and targeted PDT of CRC.

A sandwich-type electrochemical immunosensor for CYFRA 21-1 based on probe-confined in PtPd/polydopamine/hollow carbon spheres coupled with dendritic Au@Rh nanocrystals.

A signal-on sandwich-like electrochemical immunosensor was built for determination of cytokeratin 19 fragments 21-1 (CYFRA 21-1) in non-small cell lung cancer (NSCLC) by confining electroactive dye (e.g., methylene blue, MB) as a probe for amplifying signals. Specifically, core-shell gold@rhodium dendritic nanocrystals (Au@Rh DNCs) behaved as a substrate for primary antibody and accelerate interfacial electron transfer. Besides, hollow carbon spheres (HCSs) were subsequently modified with polydopamine (PDA) and PtPd nanoparticles for sequential integration of the secondary antibody and confinement of MB as a label, termed as MB/PtPd/PDA/HCSs for clarity. The built sensors showed a broad linear range (100 fg mL-1 ~ 100 ng mL-1) for detection of CYFRA 21-1 with an ultra-low detection limit (31.72 fg mL-1, S/N = 3), coupled with satisfactory performance in human serum samples. This work can be explored for assays of other proteins and provides some constructive insights for early and accurate diagnosis of NSCLC.

LncRNA GAS5 rs145204276 Polymorphism Reduces Renal Cell Carcinoma Susceptibility in Southern Chinese Population.

OBJECTIVE: Recent studies have demonstrated that the long non-coding RNA (lncRNA) GAS5 is closely associated with the onset and progression of several tumor types, including renal cell carcinoma (RCC). This study sought to evaluate the relationship between two functional GAS5 polymorphisms (rs145204276 and rs55829688) and the risk for RCC in the Han Chinese population. METHODS: The rs145204276 and rs55829688 polymorphisms in the GAS5 promoter region were genotyped in 624 RCC patients and 655 age/sex-matched healthy participants. The association between these polymorphisms and RCC risk was then evaluated using odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Additionally, quantitative RT-PCR was used to determine whether these polymorphisms were associated with changes in the levels of expression of GAS5 in 58 RCC patients. RESULTS: There were significant differences in the GAS5 rs145204276 polymorphism genotype and allele frequencies between the RCC patients and controls (adjusted OR = 0.73, 95% CI = 0.61- 0.87, P = 1.8×10-3). When the study participants were stratified based on age, sex, BMI index, and smoking and drinking history, we found that the rs145204276 del allele was associated with a reduced risk for RCC in nondrinkers (P = 3.3×10-3), nonsmokers (P = 3.3×10-3), females (P = 3.8×10-3), and those who were less than 60 years old (P = 3.3×10-3). There was also a significant association between the rs145204276 del allele and elevated expression of GAS5 in RCC patients (P = 0.030). CONCLUSIONS: The results of this study revealed an association between the rs145204276 polymorphism in the GAS5 lncRNA and the risk for the development of RCC, thus representing a potentially viable biomarker for identifying individuals at risk of developing this form of cancer.

SP1-mediated upregulation of lncRNA LMCD1-AS1 functions a ceRNA for miR-106b-5p to facilitate osteosarcoma progression.

Growing studies have indicated the involvements of long noncoding RNAs (lncRNAs) in the initiation and progression of various tumors. We aimed to investigated the role of lncRNA LMCD1 antisense RNA 1 (LMCD1-AS1) in osteosarcoma development. We found that LMCD1-AS1 and SP1 were highly expressed in osteosarcoma tissues and cell lines. High levels of LMCD1-AS1 were correlated with positively metastasis and poor clinical prognosis. Moreover, we showed that SP1 can bind to the promoter region of LMCD1-AS1, resulting in its overexpression in osteosarcoma. Functionally, silencing of LMCD1-AS1 suppressed the proliferation, migration, invasion and EMT progress of osteosarcoma cells. Mechanistic studies revealed that LMCD1-AS1 was a sponge of miR-106b-5p activity. LMCD1-AS1 modulated survival of osteosarcoma via targeting miR-106b-5p. Overall, we firstly indicated that LMCD1-AS1 overexpression contributes to osteosarcoma development and poor clinical outcome, suggesting that LMCD1-AS1 may be a novel diagnostic and prognostic biomarker for osteosarcoma and a target for osteosarcoma therapy.

Meta-analysis on the efficacy of tourniquet on ankle trauma surgery.

BACKGROUND: In our study, we used meta-analysis to study the efficacy of the tourniquet on ankle trauma surgery. Postoperative infection rate, deep venous thrombosis incidence, hospital stay, and joint range of motion were studied to compare the tourniquet and non-tourniquet groups and provide certain references for clinical decision. METHODS: We searched PubMed, MEDLINE, EMBASE, and the Cochrane controlled trials register for all publications about the efficacy of tourniquet published before November 2012. The quality of included studies was evaluated by two estimators. I2-test and Q-statistic were used for heterogeneity analysis. When there was heterogeneity between studies, the random effects model analysis was applied or else the fixed effects model analysis was used. RESULTS: Three studies were included with 166 patients suffering from ankle trauma surgery. There was no statistical difference (P >0.05) between the tourniquet and non-tourniquet groups on operation time (mean difference (MD) -5.45, 95% confidence intervals (CI): (-13.98, 3.09)), postoperative infection rate (relative risk (RR) 1.83, 95% CI: (0.65, 5.12)), and deep venous thrombosis incidence (RR 4.13, 95% CI: (0.47, 36.17)). But statistical significances were observed on hospital stays (MD 3.17, 95% CI: (1.39, 4.95)) and joint range of motion (MD - 5.25, 95% CI: (-9.61, -0.89)). CONCLUSIONS: In general, the efficacy of the tourniquet group is comparable to that of the non-tourniquet group. The non-tourniquet group achieved greater benefits for the joint range of motion and reduced the hospital stay. However, a larger number of primary studies is still required for future evaluation of tourniquet efficacy on ankle trauma surgery.