Apoptotic metabolites ameliorate bone aging phenotypes via TCOF1/FLVCR1-mediated mitochondrial homeostasis.

Over 50 billion cells undergo apoptosis each day in an adult human to maintain tissue homeostasis by eliminating damaged or unwanted cells. Apoptotic deficiency can lead to age-related diseases with reduced apoptotic metabolites. However, whether apoptotic metabolism regulates aging is unclear. Here, we show that aging mice and apoptosis-deficient MRL/lpr (B6.MRL-Faslpr/J) mice exhibit decreased apoptotic levels along with increased aging phenotypes in the skeletal bones, which can be rescued by the treatment with apoptosis inducer staurosporine (STS) and stem cell-derived apoptotic vesicles (apoVs). Moreover, embryonic stem cells (ESC)-apoVs can significantly reduce senescent hallmarks and mtDNA leakage to rejuvenate aging bone marrow mesenchymal stem cells (MSCs) and ameliorate senile osteoporosis when compared to MSC-apoVs. Mechanistically, ESC-apoVs use TCOF1 to upregulate mitochondrial protein transcription, resulting in FLVCR1-mediated mitochondrial functional homeostasis. Taken together, this study reveals a previously unknown role of apoptotic metabolites in ameliorating bone aging phenotypes and the unique role of TCOF1/FLVCR1 in maintaining mitochondrial homeostasis.

Imaging and monitoring of granzyme B in the immune response.

Significant progress has been made in tumor immunotherapy that uses the human immune response to kill and remove tumor cells. However, overreactive immune response could lead to various autoimmune diseases and acute rejection. Accurate and specific monitoring of immune responses in these processes could help select appropriate therapies and regimens for the patient and could reduce the risk of side effects. Granzyme B (GzmB) is an ideal biomarker for immune response, and its peptide substrate could be coupled with fluorescent dyes or contrast agents for the synthesis of imaging probes activated by GzmB. These small molecules and nanoprobes based on PET, bioluminescence imaging, or fluorescence imaging have proved to be highly GzmB specific and accuracy. This review summarizes the design of different GzmB-responsive imaging probes and their applications in monitoring of tumor immunotherapy and overreactive immune response. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

Chemotherapy-Induced Neoantigen Nanovaccines Enhance Checkpoint Blockade Cancer Immunotherapy.

Chemotherapeutics have the potential to increase the efficacy of cancer immunotherapies by stimulating the production of damage-associated molecular patterns (DAMPs) and eliciting mutations that result in the production of neoantigens, thereby increasing the immunogenicity of cancerous lesions. However, the dose-limiting toxicity and limited immunogenicity of chemotherapeutics are not sufficient to induce a robust antitumor response. We hypothesized that cancer cells in vitro treated with ultrahigh doses of various chemotherapeutics artificially increased the abundance, variety, and specificity of DAMPs and neoantigens, thereby improving chemoimmunotherapy. The in vitro chemotherapy-induced (IVCI) nanovaccines manufactured from cell lysates comprised multiple neoantigens and DAMPs, thereby exhibiting comprehensive antigenicity and adjuvanticity. Our IVCI nanovaccines exhibited enhanced immune responses in CT26 tumor-bearing mice, with a significant increase in CD4+/CD8+ T cells in tumors in combination with immune checkpoint inhibitors. The concept of IVCI nanovaccines provides an idea for manufacturing and artificial enhancement of immunogenicity vaccines to improve chemoimmunotherapy.

Utilizing chemotherapy-induced tumor RNA nanoparticles to improve cancer chemoimmunotherapy.

Chemotherapy has become a popular combination strategy to improve the response rate of immunotherapy since certain chemotherapeutic drugs kill tumor cells by an immunogenic cell death (ICD) pathway, which activates antitumor immune responses. Unfortunately, the synergistic effect of chemoimmunotherapy can be impaired due to the toxicities of chemotherapeutic agent-induced lymphatic depletion and immunosuppression. In this study, we present an approach to improve immunotherapy by using tumor RNA nanoparticles (RNA-NPs) where RNA is directly extracted from chemotherapy-treated cancer cells and then condensed by protamine via electrostatic interactions to form complexes. Such RNA-NPs can be effectively taken up by dendritic cells (DCs) in the draining lymph nodes after subcutaneous injection. Compared with noninduced tumor RNA nanoparticles (N-RNA-NPs), chemotherapy-induced tumor RNA nanoparticles (C-RNA-NPs) can significantly promote DC maturation and stimulate a stronger immune response against established CT-26 colon carcinoma. Besides, C-RNA-NPs can improve the efficacy of immune checkpoint blockade (ICB) therapy by facilitating the infiltration of intratumoral T cells and increasing the ratio of CD8+ T cells to regulatory T cells (Tregs). More importantly, the synergistic effect of chemoimmunotherapy is also enhanced by treatment with C-RNA-NPs. STATEMENT OF SIGNIFICANCE: Although immune checkpoint blockade therapy has been demonstrated to be effective in some advanced cancers, the low response rate has significantly limited its clinical application. To address this issue, a new strategy for improving cancer immunotherapy using chemotherapy-induced tumor RNA nanoparticles (C-RNA-NPs) is developed in this work. The proposed C-RNA-NPs could be captured by dendritic cells, which were then stimulated to the maturation status to initiate an anticancer immune response. Furthermore, the response rate to immunotherapy was significantly increased by promoting intratumoral T-cell infiltration and elevating the intratumoral ratio of CD8+ T cells to regulatory T cells after treatment with C-RNA-NPs. Therefore, C-RNA-NPs have the potential to improve cancer immunotherapy.

An Automatic Random Walker Algorithm for Segmentation of Ground Glass Opacity Pulmonary Nodules.

Automatic and accurate segmentation of ground glass opacity (GGO) nodules still remains challenging due to inhomogeneous interiors, irregular shapes, and blurred boundaries from different patients. Despite successful applications in the image processing domains, the random walk has some limitations for segmentation of GGO pulmonary nodules. In this paper, an improved random walker method is proposed for the segmentation of GGO nodules. To calculate a new affinity matrix, intensity, spatial, and texture features are incorporated. It strengthens discriminative power between two adjacent nodes on the graph. To address the problem of robustness in seed acquisition, the geodesic distance is introduced and a novel local search strategy is presented to automatically acquire reliable seeds. For segmentation, a label constraint term is introduced to the energy function of original random walker, which alleviates the accumulation of errors caused by the initial seeds acquisition. Massive experiments conducted on Lung Images Dataset Consortium (LIDC) demonstrate that the proposed method achieves visually satisfactory results without user interactions. Both qualitative and quantitative evaluations also demonstrate that the proposed method obtains better performance compared with conventional random walker method and state-of-the-art segmentation methods in terms of the overlap score and F-measure.

Ultrasensitive Photochromic Iodocuprate(I) Hybrid.

By employing in situ methylnicotinohydrazide dication (MNH(2+)) as an electron acceptor, we have constructed an iodocuprate(I) hybrid {[MNH][Cu2I3]2}n (1), which exhibits charge transfer (CT) thermochromism due to the intense absorption of CT and electron transfer (ET) photochromism with high photocoloration contrast and fast response to UV irradiation due to the synergetic effect of valence change of copper ions.

[Study on biomimetic mineralization of lipopolysaccharide-amine nanopolymersomes/hyaluronic acid polyelectrolyte films on titanium surface].

OBJECTIVE: To explore biomimetic mineralization of polyelectrolyte multilayer films (PEM) of gene-loaded lipopolysaccharide-amine nanopolymersomes/hyaluronic acid self assembled on titanium surface. METHODS: Via lay-by-layer self assembly technology, PEM were constructed on titanium or quartz surface using bone morphogenetic protein-2(BMP-2) plasmid-loaded lipopolysaccharide-amine nanopolymersomes(pLNP) as a polycation, and hyaluronic acid(HA) as a polyanion. The constructed PEM were defined as substrate-pLNP-(HA-pLNP)n, where a successive deposition of HA and pLNP on substrate surface was defined as one assembly cycle, and n was the cycle number. Biomimetic mineralization on surfaces of Ti-pLNP-(HA-pLNP)4(Group A, with outermost layer of pLNP), Ti-pLNP-(HA-pLNP)4.5(Group B, with outermost layer of HA), blank control(polished titanium, Ti) and alkaline-heat treated titanium(Ti-OH) were investigated. The biomimetic mineralization was analyzed by observing the topography under field-emisssion electron microscopy(FE-SEM), characterizing the surface chemical structure and components via X-ray diffractometer(XRD) and X-ray energy disperse spectroscopy(EDS). RESULTS: For experiment groups, XRD analysis showed that the diffraction peak of hydroxyapatite appeared, and its intensity was higher than that for Ti group. FE-SEM images showed that its surface was homogeneously covered by discrete agglomerate of big particles. EDS spectra showed that the percentage of Ca and P were 77.24% and 64.23%, and these were much higher than those in Ti group. CONCLUSIONS: The surface of Ti-pLNP-(HA-pLNP)n is favorable for in vitro biomimetic mineralization.

Clinical performance of anterior resin-bonded fixed dental prostheses with different framework designs: A systematic review and meta-analysis.

OBJECTIVES: To systematically review the failure rate and complications of different framework designs of resin-bonded fixed dental prostheses (RBFDPs) in the anterior region. METHODS: A systematic search for clinical studies on RBFDPs published prior to December 2014 in Medline/PubMed, EMBASE, and Cochrane Library databases was conducted and complemented by a manual search. Randomized controlled trials (RCTs) as well as prospective and retrospective cohort studies that compared at least two RBFDP framework designs with a minimum of 2 years follow up were included in this review. The quality of the included studies were assessed using the Newcastle-Ottawa scale for cohort studies and Cochrane Handbook for RCT. Prostheses-based data on reported failure rate/survival rate, debonding, and fractures were analyzed by meta-analysis. RESULTS: Of 1010 screened articles, one RCT and 4 cohort studies fit the inclusion criteria and were included in the meta-analysis. All included articles have a high risk of bias. Failure rates of single-retainer cantilever RBFDPs were lower than two-retainer fixed-fixed RBFDPs (OR 0.42, 95% CI 0.19-0.94, P=0.04). Metal-ceramic RBFDPs showed no difference of failure rates between cantilever RBFDPs and two-retainer fixed-fixed RBFDPs (OR 0.93, 95% CI 0.33-2.63, P=0.89). Debonding was not significantly different between cantilever RBFDPs and two-retainer fixed-fixed RBFDPs (OR 0.61, 95% CI 0.23-1.60, P=0.32). Metal-ceramic RBFDPs showed no difference of debonding between cantilever RBFDPs and two-retainer fixed-fixed RBFDPs (OR 0.81, 95% CI 0.28-2.34, P=0.70,). CONCLUSIONS: Within the limitations of the present study, cantilever RBFDPs demonstrate lower clinical failure than two-retainer RBFDPs in the anterior region. The failure of metal-ceramic RBFDPs is independent of the framework design, while the failure of all-ceramic RBFDPs with different designs has not been clear yet. CLINICAL SIGNIFICANCE: Based on the principle of minimally invasive treatment, less number of retainers is recommended for RBFDPs.

Topology adaptive vessel network skeleton extraction with novel medialness measuring function.

Vessel tree skeleton extraction is widely applied in vascular structure segmentation, however, conventional approaches often suffer from the adjacent interferences and poor topological adaptability. To avoid these problems, a robust, topology adaptive tree-like structure skeleton extraction framework is proposed in this paper. Specifically, to avoid the adjacent interferences, a local message passing procedure called Gaussian affinity voting (GAV) is proposed to realize adaptive scale-growing of vessel voxels. Then the medialness measuring function (MMF) based on GAV, namely GAV-MMF, is constructed to extract medialness patterns robustly. In order to improve topological adaptability, a level-set graph embedded with GAV-MMF is employed to build initial curve skeletons without any user interaction. Furthermore, the GAV-MMF is embedded in stretching open active contours (SOAC) to drive the initial curves to the expected location, maintaining smoothness and continuity. In addition, to provide an accurate and smooth final skeleton tree topology, topological checks and skeleton network reconfiguration is proposed. The continuity and scalability of this method is validated experimentally on synthetic and clinical images for multi-scale vessels. Experimental results show that the proposed method achieves acceptable topological adaptability for skeleton extraction of vessel trees.

[Investigation on relationship between wedge-shaped defects and occlusal interference].

OBJECTIVE: To investigate the relationship between wedge-shaped defects and occlusal interference. METHODS: Following examination from 46 patients, a total of 157 teeth were identified to have the criteria set for wedge-shaped defects and regarded as the experiment group. Also, 157 adjacent teeth exhibiting no such noncarious cervical lesions were randomly selected from the same group of patients and regarded as the control group. The distribution of occlusal force and time were examined with T-Scan II system in 46 patients with wedge-shaped defects in intercuspal occlusion position, protrusive movement and lateral movement. Occlusal interference and premature contact were evaluated and compared between the two groups. RESULTS: The proportion of the teeth with premature contact in experiment group was 6.37%, while the control group was 2.55%, there was no significant difference between the two groups (P > 0.05). The total proportion with occlusal interferences in experiment group was 23.57%, which was significantly higher than that of the control group (10.19%, P < 0.05), in experiment group the proportion with working side interferences was 15.92%, and in control group, the proportion was 3.82%, there was significant difference between the two groups (P < 0.01). At the same time, the teeth with occlusal interferences had more serious degree of the wedge-shape defects than those with no occlusal interference. CONCLUSION: The increased occlusal force has relation to the formation as well as severity of wedge-shaped defects.

[Effect of zirconia content on flexural strength and fracture toughness of dental zirconia toughened composite alumina ceramic].

OBJECTIVE: To evaluate mechanical properties of zirconia toughened composite alumina (ZTCA) ceramic used for dental application, characterize the effect of different zirconia contents on mechanical properties of ZTCA. METHODS: Dental alumina ceramic powder was prepared by sol-gel method, and four groups of ZTCA powders with different zirconia contents were prepared via surface-induced precipitation method. All five groups of powders were dry-pressed and then sintered to make standard specimens for mechanical tests. The flexural strength and fracture toughness of these specimens were evaluated, and the fractography was characterized by scanning electronic microscope (SEM). Phases of ZTCA were also determined using X-ray diffraction (XRD). RESULTS: It was found that the flexural strength of ZTCA ceramics increases with ZrO2 content up to 30%, and decreases thereafter. ZTCA specimens containing 30% ZrO2 show the highest flexural strength, and the corresponding fracture toughness was 1.85 MPa x m(1/2). The XRD results of ZTCA ceramics showed the phase constituents of alpha-Al2O3, t-ZrO2 and a small amount of m-ZrO2. CONCLUSION: The strengthening and toughening mechanisms of ZTCA depend on ZrO2 content. In the range of 15%-30% ZrO2, the stress-induced phase transformation toughening mechanism is dominant, while microcrack and deflection exist as the additional toughening mechanism when ZrO2 addition amount is above 30%.

[Effects of soil fertility and nitrogen application rate on nitrogen absorption and translocation, grain yield, and grain protein content of wheat].

The results of this study showed that nitrogen application improved the nitrogen uptake by wheat, especially during its late growth stage. Although a higher nitrogen application rate could increase the amount of absorbed nitrogen, an excess of nitrogen would remain in vegetative organs at the stage after flowering, owing to the low translocation rate of nitrogen from these organs to the grain, and hence, the nitrogen use efficiency and nitrogen harvest index were decreased. Compared with that on high fertility soil, the ratio of nitrogen absorbed from fertilizer to total absorbed nitrogen was higher when the wheat was grown on low fertility soil. On high fertility soil, wheat plant absorbed more nitrogen from top-dressed fertilizer than from basis fertilizer, and top-dressed fertilizer contributed more nitrogen to the grain. It was reversed on low fertility soil.

[Effect of jaw shape on stresses at implant-bone interface: a three-dimensional finite element analysis].

OBJECTIVE: To study the influence of different shape of lower jaw on stress distribution at bone interface in the mandibular molar region of implant restoration models. METHODS: Six models with different lower jaw shapes were constructed by using three-dimensional finite element method. Implant-bone interface stresses in these models were studied under vertical and lateral loads. RESULTS: No matter in the condition of vertical loading of lateral loading, stress distribution patterns were similar in variant models and differences of stress values were not statistically significant. The maximal differences in Von-Mises stress, compressive stress and tensile stress among the six models were 6.4%, 2.8% and 6.2%respectively. CONCLUSION: It is rational to simplify the lower jaw shape in finite element analysis.