Natural Fat Nanoemulsions for Enhanced Optical Coherence Tomography Neuroimaging and Tumor Imaging in the Second Near-Infrared Window.

Optical coherence tomography (OCT) imaging mainly uses backscattered light to visualize the structural and functional information on biological tissues. In particular, OCT angiography can not only map the capillary networks but also capture the blood flow in the tissue microenvironment, making it a good candidate for neuroimaging and tumor imaging in vivo and in real time. To further improve the detection accuracy of cancer or brain disorders, it is essential to develop a natural and nontoxic contrast agent for enhanced OCT imaging in the second near-infrared (NIR-II) window. In this study, a superior biocompatible and highly scattering NIR-II fat nanoemulsion was constructed to improve OCT imaging contrast and depth for monitoring the vascular network changes of the cerebral cortex or tumor. In vivo experimental results demonstrated that a natural fat nanoemulsion can serve as an excellent probe for enhanced OCT neuroimaging and tumor imaging.

Downregulation of PDIA3 inhibits gastric cancer cell growth through cell cycle regulation.

OBJECTIVE: Protein disulfide isomerase A3 (PDIA3) promotes the correct folding of newly synthesized glycoproteins in the endoplasmic reticulum. PDIA3 is overexpressed in most tumors, and it may become a biomarker of cancer prognosis and immunotherapy. Our study aims to detect the expression level of PDIA3 in gastric cancer (GC) and its association with GC development as wells as the underlying mechanisms. METHODS: GC cell lines with PDIA3 knockdown by siRNA, CRISPR-cas9 sgRNAs or a pharmacological inhibitor of LOC14 were prepared and used. PDIA3 knockout GC cells were established by CRISPR-cas9-PDIA3 system. The proliferation, migration, invasion and cell cycle of GC cells were analyzed by cell counting kit-8 assay, wound healing assay, transwell assay and flow cytometry, respectively. Immunodeficient nude mice was used to evaluate the role of PDIA3 in tumor formation. Quantitative PCR and western blot were used for examining gene and protein expressions. RNA sequencing was performed to see the altered gene expression. RESULTS: The expressions of PDIA3 in GC tissues and cells were increased significantly, and its expression was negatively correlated with the three-year survival rate of GC patients. Down-regulation of PDIA3 by siRNA, LOC14 or CRISPR-cas9 significantly inhibited proliferation, invasion and migration of GC cells TMK1 and AGS, with cell cycle arrested at G2/M phase. Meanwhile, decreased PDIA3 significantly inhibited growth of tumor xenograft in vivo. It was found that cyclin G1 (encoded by CCNG1 gene) expression was decreased by downregulation of PDIA3 in GC cells both in vitro and in vivo. In addition, protein levels of other cell cycle related factors including cyclin D1, CDK2, and CDK6 were also significantly decreased. Further study showed that STAT3 was associated with PDIA3-mediated cyclin G1 regulation. CONCLUSION: PDIA3 plays an oncogenic role in GC. Our findings unfolded the functional role of PDIA3 in GC development and highlighted a novel target for cancer therapeutic strategy.

Anti-oxidative activities and anti-ferroptosis of conditioned medium from umbilical cord mesenchymal stem cells.

The therapeutic effect of MSC is closely related to its antioxidant capacity. There is no uniform standard for evaluating the antioxidant capacity of MSC. In this study, we compared the antioxidant capacity of control medium (CON) and conditioned medium (CM) from umbilical cord mesenchymal stem cells cultured for 48 h, about total antioxidant capacity, DPPH scavenging capacity, O2- and hydroxyl radical inhibiting capacity, and the detection of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, and catalase, and resistance to cellular oxidative damage caused by H2O2, SNAP, erastin, and RSL3. The results showed that CM had better DPPH scavenging capacity than CON. No significant differences were observed in antioxidant enzymes. CM did not resist the oxidative damage induced by H2O2 and SNAP, but it had a strong resistance to ferroptosis induced by erastin and RSL3, indicating that CM had excellent resistance to cell lipid peroxidation. CM could improve the cell shrinkage morphology induced by ferroptosis and reduce the production of lipid ROS. qPCR experiments proved that CM improved and regulated multiple pathways of ferroptosis, including genes related to iron metabolism such as FPN, FTH1, TFRC, and IREB2, and redox regulatory genes such as GPX4, AIFM2, DHODH, and TP53, and increased the antioxidant-related transcription factors NRF2 and ATF4.

Dysregulation of immunity by cigarette smoking promotes inflammation and cancer: A review.

Smoking is a serious global health issue. Cigarette smoking contains over 7000 different chemicals. The main harmful components include nicotine, acrolein, aromatic hydrocarbons and heavy metals, which play the key role for cigarette-induced inflammation and carcinogenesis. Growing evidences show that cigarette smoking and its components exert a remarkable impact on regulation of immunity and dysregulated immunity promotes inflammation and cancer. Therefore, this comprehensive and up-to-date review covers four interrelated topics, including cigarette smoking, inflammation, cancer and immune system. The known harmful chemicals from cigarette smoking were summarized. Importantly, we discussed in depth the impact of cigarette smoking on the formation of inflammatory or tumor microenvironment, primarily by affecting immune effector cells, such as macrophages, neutrophils, and T lymphocytes. Furthermore, the main molecular mechanisms by which cigarette smoking induces inflammation and cancer, including changes in epigenetics, DNA damage and others were further summarized. This article will contribute to a better understanding of the impact of cigarette smoking on inducing inflammation and cancer.

The association of the serum levels of aldehydes with diabetes-related eye diseases: a cross-sectional population-based study.

Diabetes could impact many ocular tissues. However, the association of the serum aldehydes with diabetes-related eye diseases (DED) remains unclear. Thus, we aimed to examine the above relationship from the general US population of 2013-2014 National Health and Nutrition Examination Survey (NHANES). The multivariable logistic regression and Bayesian kernel machine regression (BKMR) were used to analyze the effect of serum aldehydes on the risk of DED. Pearson's correlation analysis, the restricted cubic spline (RCS) model, and the linear regression were performed to explore the association between the serum aldehydes and other parameters. The multivariable linear regression was conducted to further underlie the relationship between the serum aldehydes and the glycohemoglobin A1c (HbA1c) in DED participants. Although no significant association was observed between the serum aldehydes and the risk of DED by the multivariable logistic regression and BKMR, the Pearson correlation revealed a positive association between the HbA1c level and the serum level of heptanaldehyde and isopentanaldehyde in DED participants. The RCS model confirmed the above linear correlation. After adjusting for the cofounding factor of smoking, the multivariable linear regression revealed a significant association between the serum level of heptanaldehyde and the HbA1c level in DED participants. Our results suggest that aldehyde exposure did not significantly increase the risk of DED, while heptanaldehyde was the risk factor for increased HbA1c in DED population.

Recombinant Neorudin for the Prevention of Deep-Vein Thrombosis After Spinal-Cord Injury.

Background: Whether anticoagulant therapy should be used after spinal-cord injury (SCI) surgery was controversial. The anticoagulation characteristics of a newly developed anticoagulant, recombinant neorudin (EPR-hirudin (EH)), were explored using a rat model of SCI to provide a basis for clinical anticoagulation therapy of SCI. Methods: A rat model of SCI was developed by Allen's method. Then, thrombosis in the inferior vena cava was induced by ligation. The low-bleeding characteristics of EH were explored by investigating dose-response and time-effect relationships, as well as multiple administration of EH, on thrombus formation complicated with SCI. Results: EH inhibited thrombosis in a dose-dependent manner by reducing the wet weight and dry weight of the thrombus. An inhibiting action of EH on thrombosis was most evident in the group given EH 2 h after SCI. After multiple intravenous doses of EH, thrombosis inhibition was improved to that observed with low molecular weight heparin (LMWH) (87% vs 90%). EH administration after SCI neither increased bleeding in the injured spine nor damaged to nerve function. Bleeding duration and activated partial thromboplastin time were increased in the high-dose EH group compared with that in the normal-saline group, but were lower than those in the LMWH group. Conclusion: EH can reduce thrombus formation in a rat model of SCI, and bleeding is decreased significantly compared with that using LMWH. EH may prevent thrombosis after SCI or spinal surgery.

CircFOXK2 promotes hepatocellular carcinoma progression and leads to a poor clinical prognosis via regulating the Warburg effect.

BACKGROUND: The Warburg effect is well-established to be essential for tumor progression and accounts for the poor clinical outcomes of hepatocellular carcinoma (HCC) patients. An increasing body of literature suggests that circular RNAs (circRNAs) are important regulators for HCC. However, few circRNAs involved in the Warburg effect of HCC have hitherto been investigated. Herein, we aimed to explore the contribution of circFOXK2 to glucose metabolism reprogramming in HCC. METHODS: In the present study, different primers were designed to identify 14 circRNAs originating from the FOXK2 gene, and their differential expression between HCC and adjacent liver tissues was screened. Ultimately, circFOXK2 (hsa_circ_0000817) was selected for further research. Next, the clinical significance of circFOXK2 was evaluated. We then assessed the pro-oncogenic activity of circFOXK2 and its impact on the Warburg effect in both HCC cell lines and animal xenografts. Finally, the molecular mechanisms of how circFOXK2 regulates the Warburg effect of HCC were explored. RESULTS: CircFOXK2 was aberrantly upregulated in HCC tissues and positively correlated with poor clinical outcomes in patients that underwent radical hepatectomy. Silencing of circFOXK2 significantly suppressed HCC progression both in vitro and in vivo. Mechanistically, circFOXK2 upregulated the expression of protein FOXK2-142aa to promote LDHA phosphorylation and led to mitochondrial fission by regulating the miR-484/Fis1 pathway, ultimately activating the Warburg effect in HCC. CONCLUSIONS: CircFOXK2 is a prognostic biomarker of HCC that promotes the Warburg effect by promoting the expression of proteins and miRNA sponges that lead to tumor progression. Overall, circFOXK2 has huge prospects as a potential therapeutic target for patients with HCC.

Molecular phenotypic linkage between N6-methyladenosine methylation and tumor immune microenvironment in hepatocellular carcinoma.

PURPOSE: The crucial role of N6-methyladenosine (m6A) methylation in anti-tumor immunity and immunotherapy has been broadly depicted. However, the molecular phenotypic linkages between m6A modification pattern and immunological ecosystem are expected to be disentangled in hepatocellular carcinoma (HCC), for immunotherapeutic unresponsiveness circumvention and combination with promising drug agents. METHODS: Modification patterns of m6A methylation were qualitatively dissected according to the large-scale HCC samples profiling. We then determined the immune phenotypic linkages by systematically evaluating their tumor microenvironment composition, immune/stromal-relevant signature, immune checkpoints correlation, and prognostic value. Individual quantification of m6A methylation pattern was achieved by m6Ascore construction, intensified by longitudinal single-cell analysis of immunotherapy cohort and validated by the transcriptomic profiles of our in-hospital GDPH-HCC cohort. Candidate therapeutic agents were also screened out. RESULTS: Three distinct m6A methylation patterns were determined in high accordance with inflamed-, excluded-, and desert-immunophenotype. To be precise, Immune-inflamed high-m6Ascore group was characterized by activated immunity with favorable prognosis. Stromal activation and absence of immune cell infiltration were observed in low-m6Ascore phenotype, linked to impaired outcome. Patients with low-m6Ascore demonstrated diminished responses and clinical benefits for cohorts receiving immunotherapy. The above credible linkage between m6A methylation pattern and tumor immune microenvironment was robustly validated in our GDPH-HCC cohort. Single-cell dynamic change of m6A methylation level in exhausted CD8 T cell and fibroblast was depicted in immunotherapy cohort fore and art. Derived from m6A methylation pattern, seven potential frontline drug agents were recognized as promising choice for high-m6Ascore patients. CONCLUSION: Our work bridged the credible linkage between epigenetics and anti-tumor immunity in HCC, unraveling m6A modification pattern as immunological indicator and predictor for immunotherapy. Individualized m6Ascore facilitated strategic choices to maximize therapy-responsive possibility.

LncRNA DUXAP8 as a prognostic biomarker for various cancers: A meta-analysis and bioinformatics analysis.

Background: Dual homeoboxes A pseudogene 8 (DUXAP8) is a newly discovered long noncoding RNA that has been shown to function as an oncogene in a variety of human malignant cancers. By integrating available data, this meta-analysis sought to determine the relationship between clinical prognosis and DUXAP8 expression levels in diverse malignancies. Materials and methods: A systematic search was performed to identify eligible studies from several electronic databases from their inception to 25 October 2021. Pooled odds ratios and hazard ratios with 95% CI were used to estimate the association between DUXAP8 expression and survival. For survival analysis, the Kaplan-Meier method and COX analysis were used. Furthermore, we utilized Spearman's correlation analysis to explore the correlation between DUXAP8 and tumor mutational burden (TMB), microsatellite instability (MSI), the related genes of mismatch repair (MMR), DNA methyltransferases (DNMTs), and immune checkpoint biomarkers. Results: Our findings indicated that overexpression of DUXAP8 was related to poor overall survival (OS) (HR = 1.63, 95% CI, 1.49-1.77, p < 0.001). In addition, elevated DUXAP8 expression was closely related to poor OS in several cancers in the TCGA database. Moreover, DUXAP8 expression has been associated with TMB, MSI, and MMR in a variety of malignancies. Conclusion: This study revealed that DUXAP8 might serve as a prognostic biomarker and potential therapeutic target for cancer. It can be used to improve cancer diagnosis, discover potential treatment targets, and improve prognosis.

Comparison of CD146 +/- mesenchymal stem cells in improving premature ovarian failure.

BACKGROUND: Mesenchymal stem cells (MSCs) are a heterogeneous group of subpopulations with differentially expressed surface markers. CD146 + MSCs correlate with high therapeutic and secretory potency. However, their therapeutic efficacy and mechanisms in premature ovarian failure (POF) have not been explored. METHODS: The umbilical cord (UC)-derived CD146 +/- MSCs were sorted using magnetic beads. The proliferation of MSCs was assayed by dye670 staining and flow cytometry. A mouse POF model was established by injection of cyclophosphamide and busulfan, followed by treatment with CD146 +/- MSCs. The therapeutic effect of CD146 +/- MSCs was evaluated based on body weight, hormone levels, follicle count and reproductive ability. Differential gene expression was identified by mRNA sequencing and validated by RT-PCR. The lymphocyte percentage was detected by flow cytometry. RESULTS: CD146 +/- MSCs had similar morphology and surface marker expression. However, CD146 + MSCs exhibited a significantly stronger proliferation ability. Gene profiles revealed that CD146 + MSCs had a lower levels of immunoregulatory factor expression. CD146 + MSCs exhibited a stronger ability to inhibit T cell proliferation. CD146 +/- MSCs treatment markedly restored FSH and E2 hormone secretion level, reduced follicular atresia, and increased sinus follicle numbers in a mouse POF model. The recovery function of CD146 + MSCs in a reproductive assay was slightly improved than that of CD146 - MSCs. Ovary mRNA sequencing data indicated that UC-MSCs therapy improved ovarian endocrine locally, which was through PPAR and cholesterol metabolism pathways. The percentages of CD3, CD4, and CD8 lymphocytes were significantly reduced in the POF group compared to the control group. CD146 + MSCs treatment significantly reversed the changes in lymphocyte percentages. Meanwhile, CD146 - MSCs could not improve the decrease in CD4/8 ratio induced by chemotherapy. CONCLUSION: UC-MSCs therapy improved premature ovarian failure significantly. CD146 +/- MSCs both had similar therapeutic effects in repairing reproductive ability. CD146 + MSCs had advantages in modulating immunology and cell proliferation characteristics.

Integrative Analysis of Metallothioneins Identifies MT1H as Candidate Prognostic Biomarker in Hepatocellular Carcinoma.

Background: Metallothioneins (MTs) play crucial roles in the modulation of zinc/copper homeostasis, regulation of neoplastic growth and proliferation, and protection against apoptosis. The present study attempted to visualize the prognostic landscape of MT functional isoforms and identify potential prognostic biomarkers in hepatocellular carcinoma (HCC). Methods: The transcriptional expression, comprehensive prognostic performances, and gene-gene interaction network of MT isoforms in HCC were evaluated via Oncomine, GEPIA, Kaplan-Meier plotter, and GeneMANIA databases. Characterized by good prognostic value in three external cohorts, MT1H was specifically selected as a potential prognostic biomarker in HCC with various clinicopathological features. Functional and pathway enrichment analyses of MT1H status were performed using cBioPortal, the Database for Annotation, Visualization, and Integrated Discovery (DAVID), and ssGSVA method. Results: MT1E/1F/1G/1H/1M/1X/2A was greatly downregulated in HCC. Prognostic analyses elucidated the essential correlations between MT1A/1B/1H/1X/2A/4 attenuation and poor overall survival, between MT1B/1H/4 downregulation and worse relapse-free survival, and between MT1A/1B/1E/1H/1M/2A/4 downregulation and diminished progression-free survival in HCC. Taken together, these results indicated the powerful prognostic value of MT1H among MTs in HCC. In-depth analyses suggested that MT1H may be more applicable to alcohol-derived HCC and involved in the downregulation of the inflammatory pathway, Jak-STAT pathway, TNF pathway, and Wnt signaling pathway. Conclusion: MT-specific isoforms displayed aberrant expression and varying prognostic value in HCC. MT1H repression in HCC was multi-dimensionally detrimental to patient outcomes. Therefore, MT1H was possibly associated with carcinogenesis and exploited as a novel prognostic biomarker and candidate therapeutic target for HCC.

Development and Validation of a Nomogram Based on Noninvasive Liver Reserve and Fibrosis (PALBI and FIB-4) Model to Predict Posthepatectomy Liver Failure Grade B-C in Patients with Hepatocellular Carcinoma.

Hepatectomy is currently one of the most effective treatments for hepatocellular carcinoma (HCC). However, postoperative liver failure (PHLF) is a serious complication and the leading cause of mortality in patients with HCC after hepatectomy. This study attempted to develop a novel nomogram based on noninvasive liver reserve and fibrosis models, platelet-albumin-bilirubin grade (PALBI) and fibrosis-4 index (FIB-4), able to predict PHLF grade B-C. This was a single-centre retrospective study of 574 patients with HCC undergoing hepatectomy between 2014 and 2018. The independent risk factors of PHLF were screened using univariate and multivariate logistic regression analyses. Multivariate logistic regression was performed using the training set, and the nomogram was developed and visualised. The utility of the model was evaluated in a validation set using the receiver operating characteristic (ROC) curve. A total of 574 HCC patients were included (383 in the training set and 191 for the validation set) and included PHLF grade B-C complications of 14.8, 15.4, and 13.6%, respectively. Overall, cirrhosis (P < 0.026, OR = 2.296, 95% confidence interval (CI) 1.1.02-4.786), major hepatectomy (P=0.031, OR = 2.211, 95% CI 1.077-4.542), ascites (P=0.014, OR = 3.588, 95% 1.299-9.913), intraoperative blood loss (P < 0.001, OR = 4.683, 95% CI 2.281-9.616), PALBI score >-2.53 (, OR = 3.609, 95% CI 1.486-8.764), and FIB-4 score ≥1.45 (P < 0.001, OR = 5.267, 95% CI 2.077-13.351) were identified as independent risk factors associated with PHLF grade B-C in the training set. The areas under the ROC curves for the nomogram model in predicting PHLF grade B-C were significant for both the training and validation sets (0.832 vs 0.803). The proposed nomogram predicted PHLF grade B-C among patients with HCC with a better prognostic accuracy than other currently available fibrosis and noninvasive liver reserve models.

TP53 Mutational Status-Based Genomic Signature for Prognosis and Predicting Therapeutic Response in Pancreatic Cancer.

TP53 mutation is a critical driver mutation that affects the carcinogenesis and prognosis of patients with pancreatic cancer (PC). Currently, there is no driver mutation-derived signature based on TP53 mutational status for prognosis and predicting therapeutic response in PC. In the present study, we characterized the TP53 mutational phenotypes in multiple patient cohorts and developed a prognostic TP53-associated signature based on differentially expressed genes between PC samples with mutated TP53 and wild-type TP53. Comprehensive investigations were carried out in prognostic stratification, genetic variation, immune cell infiltration, and efficacy prediction of chemotherapy and targeted therapy. We found that TP53 mutation commonly occurred as a survival-related driver mutation in PC. In total, 1,154 differentially expressed genes were found between two distinct TP53 mutational phenotypes. A five-gene TP53-associated signature was constructed in The Cancer Genome Atlas (TCGA) cohort by least absolute shrinkage and selection operator (LASSO)-Cox analysis and proven to be a robust prognostic predictor, which performed well in three independent Gene Expression Omnibus (GEO) validating cohorts. Remarkably, patients in the low-risk group were characterized with decreased tumor mutation burden and activity of immunity, with favorable prognosis. Higher fractions of macrophages M0 and impaired CD8 + T cells were observed in patients in the high-risk group, suggesting immunosuppression with poor survival. Patients in the high-risk group also demonstrated enhanced response to specific chemotherapeutic agents, including gemcitabine and paclitaxel. Several targeted inhibitors, like histamine receptor inhibitor, were screened out as promising drugs for PC treatment. Collectively, the TP53-associated signature is a novel prognostic biomarker and predictive indicator of PC. The signature could contribute to optimizing prognostic stratification and guide effective PC treatments.

A phase I, single and continuous dose administration study on the safety, tolerability, and pharmacokinetics of neorudin, a novel recombinant anticoagulant protein, in healthy subjects.

The aim of this study was to evaluate the tolerability, safety, and pharmacokinetics of single and continuous dose administration of recombinant neorudin (EPR-hirudin, EH) by intravenous administration in healthy subjects, and to provide a safe dosage range for phase II clinical research. Forty-four subjects received EH as a single dose of between 0.2 and 2.0 mg/kg by intravenous bolus and drip infusion. In addition, 18 healthy subjects were randomly divided into three dose groups (0.15, 0.30, and 0.45 mg/kg/h) with 6 subjects in each group for the continuous administration trial. Single or continuous doses of neorudin were generally well tolerated by healthy adult subjects. There were no serious adverse events (SAEs), and all adverse events (AEs) were mild to moderate. Moreover, no subjects withdrew from the trial because of AEs. There were no clinically relevant changes in physical examination results, clinical chemistry, urinalysis, or vital signs. The incidence of adverse events was not significantly related to drug dose or systemic exposure. After single-dose and continuous administration, the serum EH concentration reached its peak at 5 min, and the exposure increased with the increase in the administered dose. The mean half-life (T1/2 ), clearance (Cl), and apparent volume of distribution (Vd) of EH ranged from 1.7 to 2.5 h, 123.9 to 179.7 ml/h/kg, and 402.7 to 615.2 ml/kg, respectively. The demonstrated safety, tolerability, and pharmacokinetic characteristics of EH can be used to guide rational drug dosing and choose therapeutic regimens in subsequent clinical studies. Clinical trial registration: Chinadrugtrials.org identifier: CTR20160444.

HBO1 overexpression is important for hepatocellular carcinoma cell growth.

Hepatocellular carcinoma (HCC) is a common primary liver malignancy lacking effective molecularly-targeted therapies. HBO1 (lysine acetyltransferase 7/KAT7) is a member of MYST histone acetyltransferase family. Its expression and potential function in HCC are studied. We show that HBO1 mRNA and protein expression is elevated in human HCC tissues and HCC cells. HBO1 expression is however low in cancer-surrounding normal liver tissues and hepatocytes. In HepG2 and primary human HCC cells, shRNA-induced HBO1 silencing or CRISPR/Cas9-induced HBO1 knockout potently inhibited cell viability, proliferation, migration, and invasion, while provoking mitochondrial depolarization and apoptosis induction. Conversely, ectopic overexpression of HBO1 by a lentiviral construct augmented HCC cell proliferation, migration and invasion. In vivo, xenografts-bearing HBO1-KO HCC cells grew significantly slower than xenografts with control HCC cells in severe combined immunodeficient mice. These results suggest HBO1 overexpression is important for HCC cell progression.

Thermosensitive Polymer Dot Nanocomposites for Trimodal Computed Tomography/Photoacoustic/Fluorescence Imaging-Guided Synergistic Chemo-Photothermal Therapy.

Precision delivery of theranostic agents to the tumor site is essential to improve their diagnostic and therapeutic efficacy and concurrently minimize adverse effects during treatment. In this study, a novel concept of near-infrared (NIR) light activation of conjugated polymer dots (Pdots) at thermosensitive hydrogel nanostructures is introduced for multimodal imaging-guided synergistic chemo-photothermal therapy. Interestingly, owing to the attractive photothermal conversion efficiency of Pdots, the Pdots@hydrogel as theranostic agents is able to undergo a controllable softening or melting state under the irradiation of NIR laser, resulting in light-triggered drug release in a controlled way and concurrently hydrogel degradation. Besides, the novel Pdots@hydrogel nanoplatform can serve as the theranostic agent for enhanced trimodal photoacoustic (PA)/computed tomography (CT)/fluorescence (FL) imaging-guided synergistic chemo-photothermal therapy of tumors. More importantly, the constructed intelligent nanocomposite Pdots@hydrogel exhibits excellent biodegradability, strong NIR absorption, bright PA/CT/FL signals, and superior tumor ablation effect. Therefore, the concept of a light-controlled multifunctional Pdots@hydrogel that integrates multiple diagnostic/therapeutic modalities into one nanoplatform can potentially be applied as a smart nanotheranostic agent to various perspectives of personalized nanomedicine.

Effect of Achilles tendon on kinematic coupling relationship between tarsal bones: a pilot finite element study.

BACKGROUND: The procedure of percutaneous Achilles tenotomy (PAT) is an important component of the Ponseti method. However, few studies reported the influence of Achilles tendon on kinematic coupling relationship between tarsal bones. The purpose of present study was to demonstrate the effect of Achilles tendon on the kinematic coupling relationship between tarsal bones, and to illustrate how kinematic coupling relationship between tarsal bones works in term of finite element analysis. METHODS: A three-dimensional finite element model of foot and ankle was constructed based on the Chinese digital human girl No.1 (CDH-G1) image database using the software of mimics, Geomagic studio, HyperMesh, and Abaqus. The last manipulation of the Ponseti method before the procedure of PAT was simulated. The talus head and the proximal tibia and fibula bone were fixed in all six degrees of freedom, and the outward pressure was added on the first metatarsal head to investigate the kinematic coupling relationship between tarsal bones. RESULTS: The least relationship of kinematic coupling between tarsal bones was found in calcaneus. Stress concentration was mainly observed at the navicular, talus and the medial malleolus. The difference in displacement of the navicular was only found with the Achilles tendon stiffness of 0 N/mm and others. No difference in the navicular displacement was found in the stiffness of Achilles tendon between 40, 80, 200, 400, and 1000 N/mm. The maximum displacement of navicular was observed at the ankle position of PF-20° (plantar flexion-20°). The difference in displacement of the navicular was greater at the ankle position of PF-20° with the Achilles tendon stiffness of 0 N/mm than that at the ankle position of PF-40° with the Achilles tendon stiffness of 40 N/mm. CONCLUSIONS: Based on the findings from this study, it was demonstrated that the Achilles tendon existence or not and ankle position had great influence, while increased stiffness of Achilles tendon had no influence on kinematic coupling relationship between tarsal bones. For the cases with severe equinus, earlier implementation of PAT procedure (with the purpose of release the Achilles tendon and reduce the degree of ankle plantar flexion) may be beneficial to the deformity correction.

Inhibiting tumor oxygen metabolism and simultaneously generating oxygen by intelligent upconversion nanotherapeutics for enhanced photodynamic therapy.

Hypoxia is one of the hallmarks of solid tumor, which heavily restricts the clinical cancer therapy treatments, especially for the oxygen (O2) -dependent photodynamic therapy (PDT). Herein, an intelligent multi-layer nanostructure was developed for decreasing the O2-consumption and elevating the O2-supply simultaneously. The cell respiration inhibitor -atovaquone (ATO) molecules were reserved in the middle mesoporous silicon layer, and thus were intelligently released at the tumor site after the degradation of gatekeeper of MnO2 layer, which effectively inhibit tumor respiration metabolism to elevate oxygen content. Meanwhile, the degradation of MnO2 layer can generate O2, further boosting oxygen content. Moreover, the inner upconversion nanostructures as the near infrared (NIR) light-transducers enable to activate photosensitizers for deep-tissue PDT. Systematic experiments demonstrate that this suppressing O2-consumption and O2-generation strategy improved oxygen supply to boost the singlet oxygen generation to eradicate cancer cells under NIR light excitation. Better still, superior trimodality imaging capabilities (computed tomography (CT), NIR-II window fluorescence, and tumor microenvironment-responsive T1-weighted magnetic resonance (MR) imaging) of the nanoplatform were evaluated. Our findings offer a promising aproach to conquer the serious hypoxia problem in cancer therapy by turning down the O2 metabolism aveneue and simultaneously generating O2.