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Dan Xu,1 Shu-Ting Lu,2 Yu-Shuang Li,2 Aju Baidya,2 Hao Mei,2 Yong He,1 Bo Wu2 1Department of Nuclear Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, PR China; 2Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, PR China Background: Gliomas are one of the most common types of primary brain tumors. It is usually evaluated by gadolinium(III)-based contrast agents by magnetic resonance imaging (MRI) in the clinic. Methotrexate (MTX), as a type of folate analog that inhibits the enzyme dihydrofolate reductase, is widely used as a chemotherapeutic agent to treat gliomas in the experiment.Purpose: In this study, a novel theranostic agent MTX-DOTA-Gd (MTX-Gd) was synthesized, which integrates magnetic resonance imaging (MRI) with anticancer treatment.Methods: MTX-Gd was synthesized by connecting MTX and Gd through 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The characterization of MTX-Gd was detected by ultraviolet (UV) and infrared spectroscopy (IR). To confirm the antitumor effect of MTX-Gd, the cytotoxicity of MTX-Gd was examined by the MTT assay. The contrast enhancement of the MTX-Gd was measured through MRI in vitro. Then, nude mice bearing C6 tumor xenografts were used to study in vivo imaging capabilities.Results: The ultraviolet-visible-near infrared radiation (UV-NIR) absorption curve indicated that MTX-Gd had a broad absorption in the region of 500-700 nm. The formation of MTX-Gd was confirmed from the characteristic bands of MTX-DOTA-Gd in the 1413 cm-1 (C-N), 1577 cm-1 (-NH2), and 3429 cm-1 (N-H), in the fourier-transform infrared (FTIR) spectra. MTX-Gd showed little difference in the cell viability compared with MTX, except for the highest concentration (270 μM). In vitro, the imaging of MTX-Gd was significantly brighter than Gd-DOTA at the same concentration, and the brightness and signal intensity of MRI were increased followed by the increased concentration of MTX-Gd. And it also showed that MTX was not visualized on MRI. The other images revealed that the concentration of 4 mM MTX-Gd had the same imaging effect with the concentration of 10 mM Gd-DOTA. Then, MTX-Gd was injected in nude mice bearing C6 tumor xenografts through the tail vein. Significant contrast enhancement was observed at the tumor site from 0.5 h to 3 h. The signal of tumor area was strongest at 3 h due to accumulation by size effect of macromolecules.Conclusion: A novel stable and unique theranostic agent(MTX-Gd) was successfully synthesized, and it has good stability, strong anticancer ability and excellent magnetic capacity. The methotrexate component of MTX-Gd, as a chemotherapeutic agent, played an important role in targeted therapies of cancer. The DOTA-Gd component of MTX-Gd performed as the MRI contrast agent. The superior MRI imaging performance and synergetic chemical antineoplastic ability of MTX-Gd was revealed, and it has great potential in the diagnosis and treatment of glioma and potentially other cancers, with prospects of clinical application in the near future. Keywords: methotrexate, gadolinium, glioma, theranostics

Bo Wu,1,* Bing Wan,2,* Shu-Ting Lu,1 Kai Deng,3 Xiao-Qi Li,1 Bao-Lin Wu,1 Yu-Shuang Li,1 Ru-Fang Liao,1 Shi-Wen Huang,3 Hai-Bo Xu1,2 1Department of Radiology, Zhongnan Hospital of Wuhan University, 2Department of Radiology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, 3Department of Chemistry, Key Laboratory of Biomedical Polymers, Ministry of Education, Wuhan University, Wuhan, People’s Republic of China *These authors contributed equally to this work Abstract: The major challenge in current clinic contrast agents (CAs) and chemotherapy is the poor tumor selectivity and response. Based on the self-quench property of IR820 at high concentrations, and different contrast effect ability of Gd-DOTA between inner and outer of liposome, we developed “bomb-like” light-triggered CAs (LTCAs) for enhanced CT/MRI/FI multimodal imaging, which can improve the signal-to-noise ratio of tumor tissue specifically. IR820, Iohexol and Gd-chelates were firstly encapsulated into the thermal-sensitive nanocarrier with a high concentration. This will result in protection and fluorescence quenching. Then, the release of CAs was triggered by near-infrared (NIR) light laser irradiation, which will lead to fluorescence and MRI activation and enable imaging of inflammation. In vitro and in vivo experiments demonstrated that LTCAs with 808 nm laser irradiation have shorter T1 relaxation time in MRI and stronger intensity in FI compared to those without irradiation. Additionally, due to the high photothermal conversion efficiency of IR820, the injection of LTCAs was demonstrated to completely inhibit C6 tumor growth in nude mice up to 17 days after NIR laser irradiation. The results indicate that the LTCAs can serve as a promising platform for NIR-activated multimodal imaging and photothermal therapy. Keywords: light triggered, near-infrared light, tumor-specific, multimodal imaging, photothermal therapy, contrast agents

Because parametric values are unknown during initial concept generation, the Axiomatic Design Theory uses the binary design matrix (DM) to represent the coupling relationship between functional requirements and design parameters. However, given an existing product, it would be possible to employ the numerical DM that has more detailed information than the binary DM to help improve the design concept. This paper proposed a two-phase method to create a numerical DM in phase I and manage the functional couplings in phase II for concept improvement of existing product. A decomposition-definition-levelling framework and the Puritan-Bennett’s 0-1-3-9 level rating are employed to evaluate the system impact of each functional coupling to create the numerical DM of an existing design concept. The Design Coupling Sequence (DCS) approach was extended to use the numerical DM to improve this design concept. Compared with other numerical matrices for product development and the structured approach by Su et al., our method is more generic and faster, providing useful details yet still able to maintain the dominance of the high-level couplings.

Conceptual design is the stage where the upstream objectives and downstream constraints meet, so both the ideality and practicality are important in conceptual design. Modularity supports designing complex system while the design can take advantages from the downstream resources. According to Axiomatic Design Theory (ADT), the design with the least complexity is the ideal design, and managing functional coupling sequence can lead to the minimal complexity of design concepts. In this paper, Design Coupling Sequence (DCS) was introduced to bridge the ADT and the modular design. The ‘precedence’ and ‘functional sets’ were defined in DCS to manage the coupled design concepts in order to support the modularity of the design concepts. The ‘precedence’ identified by the level of functional coupling helps realize the sequencing order. The two ‘functional sets’ were defined as the independent U-set: the collection of functionally dependent concepts, and the coupled C-set: the collection of the strongly coupled concepts. The faucet design case study shows how the DCS method and its strategy to decrease relative complexity and increase modularity, and the results between design by extra coupling elimination and design by the existing modules are compared. The DCS method bridges the design theory to design practice.

Abstract Background Signal peptide peptidase (SPP), a member of the presenilin-like intra-membrane cleaving aspartyl protease family, migrates on Blue Native (BN) gels as 100 kDa, 200 kDa and 450 kDa species. SPP has recently been implicated in other non-proteolytic functions such as retro-translocation of MHC Class I molecules and binding of misfolded proteins in the endoplasmic reticulum (ER). These high molecular weight SPP complexes might contain additional proteins that regulate the proteolytic activity of SPP or support its non-catalytic functions. Results In this study, an unbiased iTRAQ-labeling mass spectrometry approach was used to identify SPP-interacting proteins. We found that vigilin, a ubiquitous multi-KH domain containing cytoplasmic protein involved in RNA binding and protein translation control, selectively enriched with SPP. Vigilin interacted with SPP and both proteins co-localized in restricted intracellular domains near the ER, biochemically co-fractionated and were part of the same 450 kDa complex on BN gels. However, vigilin does not alter the protease activity of SPP, suggesting that the SPP-vigilin interaction might be involved in the non-proteolytic functions of SPP. Conclusions We have identified and validated vigilin as a novel interacting partner of SPP that could play an important role in the non-proteolytic functions of SPP. This data adds further weight to the idea that intramembrane-cleaving aspartyl proteases, such as presenilin and SPPs, could have other functions besides the proteolysis of short membrane stubs.

Background: Dysfunction of the glymphatic system in the brain in different stages of altered glucose metabolism and its influencing factors are not well characterized., Aim: To investigate the function of the glymphatic system and its clinical correlates in patients with different glucose metabolism states, the present study employed diffusion tensor imaging along the perivascular space (DTI-ALPS) index., Methods: Sample size was calculated using the pwr package in R software. This cross-sectional study enrolled 22 patients with normal glucose metabolism (NGM), 20 patients with prediabetes, and 22 patients with type 2 diabetes mellitus (T2DM). A 3.0T magnetic resonance imaging was used to evaluate the function of the glymphatic system. The mini-mental state examination (MMSE ) was used to assess general cognitive function. The DTI-ALPS index of bilateral basal ganglia and the mean DTI-ALPS index was calculated. Further, the correlation between DTI-ALPS and clinical features was assessed., Results: The left-side, right-side, and mean DTI-ALPS index in the T2DM group were significantly lower than that in the NGM group. The right-side DTI-ALPS and mean DTI-ALPS index in the T2DM group were significantly lower than those in the prediabetes group. DTI-ALPS index lateralization was not observed. The MMSE score in the T2DM group was significantly lower than that in the NGM and prediabetes group. After controlling for sex, the left-side DTI-ALPS and mean DTI-ALPS index in the prediabetes group were positively correlated with 2-hour postprandial blood glucose level; the left-side DTI-ALPS index was negatively correlated with total cholesterol and low-density lipoprotein level. The right-side DTI-ALPS and mean DTI-ALPS index were negatively correlated with the glycosylated hemoglobin level and waist-to-hip ratio in the prediabetes group. The left-side, right-side, and mean DTI-ALPS index in the T2DM group were positively correlated with height. The left-side and mean DTI-ALPS index in the T2DM group were negatively correlated with high-density lipoprotein levels., Conclusion: Cerebral glymphatic system dysfunction may mainly occur in the T2DM stage. Various clinical variables were found to affect the DTI-ALPS index in different glucose metabolism states. This study enhances our understanding of the pathophysiology of diabetic brain damage and provides some potential biological evidence for its early diagnosis., Competing Interests: Conflict-of-interest statement: The authors declare that this study was conducted without any business or financial relationship that could be interpreted as a potential conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: To introduce a case of a uterus "hernia-like" myoma within the uterine cavity that was successfully treated with hysteroscopy., Design: Step-by-step explanation of the case and surgical procedure using a video and slides. The Medical Ethics Committee of Women and Children's Hospital of Chongqing Medical University approved the study and decided for this video to be exempt from formal approval, and informed consent was obtained from the patient., Setting: Hospital., Patient(s): A 37-year-old woman, gravida 1, para 1, with a history of secondary infertility for 2 years and heavy menstrual bleeding for 7 months, which eventually resulted in anemia, was diagnosed with a type 1 (International Federation of Gynecology and Obstetrics leiomyoma subclassification system) myoma approximately 4 cm in diameter using ultrasonography. Her hemoglobin level was 8.6 g/dL (11.5-15.0 g/dL), red blood cell count was 3.6 ×10-12/L (3.8-5.1 ×10-12/L), and hematocrit was 26.7% (35%-45%)., Intervention(s): Hysteroscopic myomectomy with bipolar resectoscope and transabdominal ultrasound guidance was used to resect the hernia-like myoma. Blunt dissection combined with oxytocin (20 U I.V.) and uterine dilation pressure reduction was used to induce the hernial content (myoma) protrusion into the uterine cavity., Main Outcome Measure(s): The hernia-like myoma was completely resected by hysteroscopy, and all symptoms disappeared., Result(s): The hernia-like myoma was successfully and completely resected by hysteroscopy. The operative time was 37 minutes. No surgical-related or anesthesia-related complications occurred. During the follow-up period, the patient had regular menstrual cycles without hypermenorrhea, and her anemia had improved. The 5-month follow-up ultrasound examination and hysteroscopy revealed that the uterine cavity had recovered well. The patient conceived 7 months after the procedure and delivered at term (39 weeks 1 day) via cesarean section., Conclusion(s): A hernia-like myoma covered with endometrium is a degenerative myoma that herniates into the myometrium and forms a hernia sac-like defect. Hysteroscopy is an effective and feasible method for treating hernia-like myoma., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Large area skin trauma has always been a great challenge for both patients and clinicians. Exosomes originating from human adipose-derived mesenchymal stem cells (hADSCs) have been a novel promising cell-free treatment in cutaneous damage repair. Nevertheless, the low retention rate of exosomes post-transplantation in vivo remains a significant challenge in clinical applications. Herein, we purposed to explore the potential clinical application roles of hADSCs-Exos encapsulated in functional PF-127 hydrogel in wound healing., Methods: hADSCs-Exos were isolated from human hADSCs by ultracentrifugation. An injectable, biocompatible, and thermo-sensitive hydrogel Pluronic F-127 hydrogel was employed to encapsulate allogeneic hADSCs-Exos, and this complex was topically applied to a full-thickness cutaneous wound in mice. On different days post-transplantation, the mice were sacrificed, and the skin tissue was excised for histological and immunohistochemical analysis., Results: Compared with hADSCs-Exos or PF-127 only, PF-127/hADSCs-Exos complexes enhanced skin wound healing, promoted re-epithelialization, increased expression of Ki67, α-SMA, and CD31, facilitated collagen synthesis (Collagen I, Collagen III), up-regulated expression of skin barrier proteins (KRT1, AQP3), and reduced inflammation (IL-6, TNF-α, CD68, CD206). By using PF-127/hADSCs-Exos complexes, hADSCs-Exos can be administrated at lower doses frequency while maintaining the same therapeutic effects., Conclusion: Administration of hADSCs-Exos in PF-127 improves the efficiency of exosome delivery, maintains the bioactivity of hADSCs-Exos, and optimizes the performance of hADSCs-Exos. Thus, this biomaterial-based exosome will be a promising treatment approach for the cutaneous rejuvenation of skin wounds., (© 2022. The Author(s).)

In order to comprehensively explore multitarget mechanism and key active compounds of Artemisia argyi essential oil (AAEO) in the treatment of pressure injuries (PIs), we analyzed the biological functions and pathways involved in the intersection targets of AAEO and PIs based on network pharmacology, and the affinity of AAEO active compounds and core targets was verified by molecular docking finally. In our study, we first screened 54 effective components according to the relative content and biological activity. In total, 103 targets related to active compounds of AAEO and 2760 targets associated with PIs were obtained, respectively, and 50 key targets were overlapped by Venny 2.1.0. The construction of key targets-compounds network was achieved by the STRING database and Cytoscape 3.7.2 software. GO analysis from Matespace shows that GO results are mainly enriched in biological processes, including adrenergic receptor activity, neurotransmitter clearance, and neurotransmitter metabolic process. KEGG analysis by the David and Kobas website shows that the key targets can achieve the treatment on PIs through a pathway in cancer, PI3K-Akt signaling pathway, human immunodeficiency virus 1 infection, MAPK signaling pathway, Wnt signaling pathway, etc. In addition, molecular docking results from the CB-Dock server indicated that active compounds of AAEO had good activity docking with the first 10 key targets. In conclusion, the potential targets and regulatory molecular mechanisms of AAEO in the treatment of PIs were analyzed by network pharmacology and molecular docking. AAEO can cure PIs through the synergistic effect of multicomponent, multitarget, and multipathway, providing a theoretical basis and new direction for further study., Competing Interests: All authors declare that they have no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Shu-ting Lu et al.)

Background: Endometriosis of the uterine body can be manifested as diffuse solid lesions or cystic lesions. The former is common, while the latter is rare, especially for cystic adenomyosis larger than 5 cm., Case Presentation: A 30-year-old woman was admitted for severe and worsening dysmenorrhea. Ultrasound examination revealed a rare well-circumscribed cystic lesion about 5.5 × 4 × 5.0 cm. CA-125 level was slightly elevated. She accepted laparoscopic surgery and the adenomyotic tissues were excised. The histopathology of the specimen demonstrated the endometrial glands in the walls of cysts and an area of extensive hemorrhage can be seen in the inner wall of cyst. The patient made a good recovery after surgery and her symptoms complete resoluted., Conclusions: This is a rare case of a cystic adenomyotic lesion that was treated by laparoscopic surgery.

Background: Cutaneous wound healing and regeneration have become a recognized health challenge in the world, which causes severe damage to the mental and physical health of patients. Human adipose-derived mesenchymal stem cells (hADSC) play an essential role in wound healing via their paracrine function. Exosomes secreted by hADSC may contribute to this progress. In this study, we investigated the potential clinical application roles of hADSC and hADSC-derived exosomes (hADSC-Exo) in cutaneous wound healing., Methods: hADSC-Exo was isolated from human hADSC by ultracentrifugation. Mice were subjected to a full-thickness skin biopsy experiment and treated with either control vehicle or hADSC or hADSC-Exo by smearing administration (sm) or subcutaneous administration (sc) or intravenous administration (iv). The efficacy of hADSC and hADSC-Exo on wound healing was evaluated by measuring wound closure rates, histological analysis., Results: Combined application of local hADSC-Exo smearing and hADSC/hADSC-Exo intravenous administration offered the additional benefit of promoting wound healing, accelerating re-epithelialization, reducing scar widths, and enhancing angiogenesis and collagen synthesis. Either topical application of hADSC-Exo or systemic administration with hADSC/hADSC-Exo appeared more effective in stimulating cell proliferation, inhibiting cell apoptosis and inflammation, and promoting skin elasticity and barrier integrity, with increased genes expression of PCNA, VEGF, collagen III, Filaggrin, Loricrin, and AQP3, with decreased genes expression of TNF-alpha., Conclusion: Our findings suggest that the combined administration of hADSC/hADSC-Exo can facilitate cutaneous wound healing and reduce scar formation. These data provide the first evidence for the feasibility of smearing of hADSC-Exo as a cell-free therapy in treating cutaneous wounds, and the potential clinical value of combined administration of hADSC/hADSC-Exo.

Objectives: To evaluate the safety of low-dose tanezumab in the treatment of knee or hip osteoarthritis (OA)., Methods: Databases were searched up to September 2019 for phase III randomized controlled trials (RCTs). Eleven phase III RCTs comprising 11,455 patients were eligible. The pooled estimates of safety outcomes were assessed and expressed using relative risks (RRs) and 95% confidence intervals with a random-effects model., Results: Tanezumab significantly increased the incidence of rapidly progressive OA (RPOA; RR = 9.07, 95% CI = 1.21-67.90, P = 0.03) and abnormal peripheral sensation (APS; RR = 2.68, 95% CI = 1.64-4.37, P < 0.00001) compared with placebo. No significant difference was found in terms of incidence of total joint replacement (TJR; RR = 1.13, 95% CI = 0.76-1.68, P = 0.55) or withdrawal due to adverse effects (AEs; RR = 1.26, 95% CI = 0.79-2.00, P = 0.33). The tanezumab group showed a statistically higher incidence of RPOA (RR = 3.96, 95% CI = 2.23-7.04, P < 0.00001) and APS (RR = 1.2, 95% CI = 1.44-2.56, P < 0.00001) compared with the nonsteroidal anti-inflammatory drugs and opioids group. No significant difference was found in terms of TJR (RR = 1.51, 95% CI = 0.65-3.47, P = 0.33) and withdrawal (RR = 0.54, 95% CI = 0.20-1.40, P = 0.20). Subgroup analysis revealed that 2.5 mg of tanezumab did not show an advantage over 5 mg of tanezumab in reducing AEs., Conclusions: These results demonstrate that RPOA and APS should be the most concerning AEs when using tanezumab in OA patients. Additional data are needed to define the optimal dose to minimize risk and to determine the optimal subjects to receive this treatment., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Shunt infection is a common complication while treating hydrocephalus. The antibiotic-impregnated shunt catheter (AISC) was designed to reduce shunt infection rate. A meta-analysis was conducted to study the effectiveness of AISCs in reduction of shunt infection in terms of age, follow-up time and high-risk patient population., Methods: This study reviewed literature from three databases including PubMed, EMBASE, and Cochrane Library (from 2000 to March 2019). Clinical studies from controlled trials for shunt operation were included in this analysis. A subgroup analysis was performed based on the patient's age, follow-up time and high-risk population. The fixed effect in RevMan 5.3 software (Cochrane Collaboration) was used for this meta-analysis., Results: This study included 19 controlled clinical trials including 10105 operations. The analysis demonstrated that AISC could reduce the infection rate in shunt surgery compared to standard shunt catheter (non-AISC) from 8.13% to 4.09% (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.40-0.58; p=0.01; I2=46%). Subgroup analysis of different age groups showed that AISC had significant antimicrobial effects in all three groups (adult, infant, and adolescent). Follow-up time analysis showed that AISC was effective in preventing early shunt infections (within 6 months after implant). AISC is more effective in high-risk population (OR, 0.24; 95% CI, 0.14-0.40; p=0.60; I2=0%) than in general patient population., Conclusion: The results of meta-analysis indicated that AISC is an effective method for reducing shunt infection. We recommend that AISC should be considered for use in infants and high-risk groups. For adult patients, the choice for AISC could be determined based on the treatment cost.

Differential diagnosis between inflammatory mass and malignant glioma is of great significance to patients, which is the basis for developing accurate individualized treatment. Due to the lack of non-invasive imaging characterization methods in the clinical application, the current diagnosis grading of glioma mainly depended on the pathological biopsy, which is complicated and risky. This study aims to develop a non-invasive imaging differential diagnosis method of glioma based on the reduction activated strategy of intracellular aggregation of sensitive superparamagnetic Fe 3 O 4 nanoparticles (SIONPs). In vitro and in vivo magnetic resonance imaging results indicated that SIONPs could specifically increase the T 2 relaxation rate and enhance MR imaging in tumor with redox microenvironment by the response-aggregation in the tumorous site. In vivo experiments also demonstrate that the substantial improvement of T2-weighted imaging contrast could be used to differentiate inflammatory mass and malignant glioma. The reduction-active MR imaging contrast agent offers a new paradigm for designing "smart" MR imaging probes of differential diagnosis of the tumor., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Neuronal GABAergic responses switch from excitatory to inhibitory at an early postnatal period in rodents. The timing of this switch is controlled by intracellular Cl- concentrations, but factors determining local levels of cation-chloride cotransporters remain elusive. Here, we report that local abundance of the chloride importer NKCC1 and timely emergence of GABAergic inhibition are modulated by proteasome distribution, which is mediated through interactions of proteasomes with the adaptor Ecm29 and the axon initial segment (AIS) scaffold protein ankyrin G. Mechanistically, both the Ecm29 N-terminal domain and an intact AIS structure are required for transport and tethering of proteasomes in the AIS region. In mice, Ecm29 knockout (KO) in neurons increases the density of NKCC1 protein in the AIS region, a change that positively correlates with a delay in the GABAergic response switch. Phenotypically, Ecm29 KO mice showed increased firing frequency of action potentials at early postnatal ages and were hypersusceptible to chemically induced convulsive seizures. Finally, Ecm29 KO neurons exhibited accelerated AIS developmental positioning, reflecting a perturbed AIS morphological plastic response to hyperexcitability arising from proteasome inhibition, a phenotype rescued by ectopic Ecm29 expression or NKCC1 inhibition. Together, our findings support the idea that neuronal maturation requires regulation of proteasomal distribution controlled by Ecm29., (© 2020 Lee et al.)

In the present study, a novel biodegradable Zn-0.8Cu coronary artery stent was fabricated and implanted into porcine coronary arteries for up to 24 months. Micro-CT analysis showed that the implanted stent was able to maintain structural integrity after 6 months, while its disintegration occurred after 9 months of implantation. After 24 months of implantation, approximately 28 ± 13 vol% of the stent remained. Optical coherence tomography and histological analysis showed that the endothelialization process could be completed within the first month after implantation, and no inflammation responses or thrombosis formation was observed within 24 months. Cross-section analysis indicated that the subsequent degradation products had been removed in the abluminal direction, guaranteeing that the strut could be replaced by normal tissue without the risk of contaminating the circulatory system, causing neither thrombosis nor inflammation response. The present work demonstrates that the Zn-0.8Cu stent has provided sufficient structural supporting and exhibited an appropriate degradation rate during 24 months of implantation without degradation product accumulation, thrombosis, or inflammation response. The results indicate that the Zn-0.8Cu coronary artery stent is promising for further clinical applications. STATEMENT OF SIGNIFICANCE: Although Zn and its alloys have been considered to be potential candidates of biodegradable metals for vascular stent use, by far, no Zn-based stent with appropriate medical device performance has been reported because of the low mechanical properties of zinc. The present work presents promising results of a Zn-Cu biodegradable vascular stent in porcine coronary arteries. The Zn-Cu stent fabricated in this work demonstrated adequate medical device performance both in vitro and in vivo and degraded at a proper rate without safety problems induced. Furthermore, large animal models have more cardiovascular similarities as humans. Results of this study may provide further information of the Zn-based stents for translational medicine research., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Single-component nanomaterials such as bismuth (Bi) based on nanoparticles (NPs) intrinsically having both diagnostic and therapeutic capabilities are widely needed in biomedical fields. However, their design and fabrication still face enormous challenges. Here, a kind of pure Bi NPs with ultrahigh X-ray attenuation coeffcient was developed and evaluated as a simple but powerful theranostic nanomaterals and potent light-to-heat conversion efficiency for photoacuostic imaging (PAI)/photothermal therapy (PTT) in this study. The prepared pure Bi NPs showed excellent photothermal performance and the temperature of NPs solution (1 mg/mL) increased to 70 °C under near-infrared light irradiation within 4 min. The pure Bi NPs showed obvious enhancement effect both in X-ray computed tomography (CT) and PA imaging modalities in vivo . In addition, the glioma growth was efficiently suppressed by the pure Bi NPs after 808 nm laser irradiation, while maintained the biosafety and low toxicity. Thus, it is notable that this type of Bi nanomaterial has great potential in multi-imaging guided cancer treatment.

Effective hemostasis is vital to reduce the pain and mortality of patients, and the research and development of hemostatic materials are prerequisite for effective hemostasis. Chitosan (CS), with good biodegradability, biocompatibility and non-toxicity, has been widely applied in bio-medicine, the chemical industry, the food industry and cosmetics. The excellent hemostatic properties of CS have been extensively studied. As a result, chitosan-based composite hemostatic materials have been emerging. In this review, the hemostatic mechanism of chitosan is briefly discussed, and then the progress of research on chitosan-based composite hemostatic materials with multiple forms such as films, sponges, hydrogels, particles and fibers are introduced. Finally, future perspectives of chitosan-based composite hemostatic materials are given. The objective of this review is to provide a reference for further research and development of effective hemostatic materials.

Multifunctional nanomaterials with simple structure and good biosafety, integrating multimodal imaging and therapeutic functions, can facilitate the development of clinical cancer treatments. Here, a simple but powerful pure bismuth based nanoparticle (Gd-PEG-Bi NPs) was developed from pure Bi NPs and gadolinium-diethylenetriaminepentaacetic acid-bis-tetradecylamide, which not only shows high quality MRI/CT/PAI triple-modal imaging, but can also be a potent photothermal therapy agent under the guidance of the triple-modal imaging. The Gd-PEG-Bi NPs showed good stability and excellent biocompatibility. In vitro and in vivo study demonstrated that Gd-PEG-Bi NPs have ultrahigh X-ray attenuation coefficient, short T1 relaxation time in MRI, and strong PAI signal. Following the imaging diagnosis, the excellent light-to-heat conversion efficiency of Gd-PEG-Bi NPs was capable of suppressing the tumor growth effectively under near-infrared laser radiation in vivo. Such multifunctional nanoparticles were ideal candidates for cancer diagnosis and treatment., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Neurite initiation is the first step in neuronal development and occurs spontaneously in soft tissue environments. Although the mechanisms regulating the morphology of migratory cells on rigid substrates in cell culture are widely known, how soft environments modulate neurite initiation remains elusive. Using hydrogel cultures, pharmacologic inhibition, and genetic approaches, we reveal that paxillin-linked endocytosis and adhesion are components of a bistable switch controlling neurite initiation in a substrate modulus-dependent manner. On soft substrates, most paxillin binds to endocytic factors and facilitates vesicle invagination, elevating neuritogenic Rac1 activity and expression of genes encoding the endocytic machinery. By contrast, on rigid substrates, cells develop extensive adhesions, increase RhoA activity and sequester paxillin from the endocytic machinery, thereby delaying neurite initiation. Our results highlight paxillin as a core molecule in substrate modulus-controlled morphogenesis and define a mechanism whereby neuronal cells respond to environments exhibiting varying mechanical properties.

In recent years, there has been increasing interest in developing a multifunctional nanoscale platform for cancer monitoring and chemotherapy. However, there is still a big challenge for current clinic contrast agents to improve their poor tumor selectivity and response. Herein, we report a new kind of Gd complex and folate-coated redox-sensitive lipid-polymer hybrid nanoparticle (Gd-FLPNP) for tumor-targeted magnetic resonance imaging and therapy. Gd-FLPNPs can simultaneously accomplish diagnostic imaging, and specific targeting and controlled release of doxorubicin (DOX). They exhibit good monodispersity, excellent size stability, and a well-defined core-shell structure. Paramagnetic nanoparticles based on gadolinium-diethylenetriaminepentaacetic acid-bis-cetylamine have paramagnetic properties with an approximately two-fold enhancement in the longitudinal relaxivity compared to clinical used Magnevist. For targeted and reduction-sensitive drug delivery, Gd-FLPNPs released DOX faster and enhanced cell uptake in vitro, and exhibited better antitumor effect both in vitro and in vivo., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Codelivery is a promising strategy to overcome the limitations of single chemotherapeutic agents in cancer treatment. Despite progress, codelivery of two or more different functional drugs to increase anticancer efficiency still remains a challenge. Here, reduction-sensitive lipid-polymer hybrid nanoparticles (LPNPs) drug delivery system composed of monomethoxy-poly(ethylene glycol)- S - S -hexadecyl (mPEG- S - S -C 16 ), soybean lecithin, and poly(D,L-lactide-co-glycolide) (PLGA) was used for codelivery of doxorubicin (DOX) and a Chinese herb extract triptolide (TPL). Hydrophobic DOX and TPL could be successfully loaded in LPNPs by self-assembly. More importantly, drug release and cellular uptake experiments demonstrated that the two drugs were reduction sensitive, released simultaneously from LPNPs, and taken up effectively by the tumor cells. DOX/TPL-coloaded LPNPs (DOX/TPL-LPNPs) exhibited a high level of synergistic activation with low combination index (CI) in vitro and in vivo. Moreover, the highest synergistic therapeutic effect was achieved at the ratio of 1:0.2 DOX/TPL. Further experiments showed that TPL enhanced the uptake of DOX by human oral cavity squamous cell carcinoma cells (KB cells). Overall, DOX/TPL-coencapsulated reduction-sensitive nanoparticles will be a promising strategy for cancer treatment., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The aim of the present study was to investigate the effects of phosphorylated osteopontin (p-OPN) on apoptosis and pro-inflammatory cytokine expression in human knee osteoarthritis (OA) chondrocytes. Human knee OA chondrocytes obtained from patients who underwent total knee arthroplasty were treated with p-OPN, OPN or buffer. Reverse transcription quantitative-polymerase chain reaction (RT-qPCR) and western blot analysis were used to assess the expression levels of proinflammatory factors, including interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6 and nuclear factor (NF)-κB. Apoptosis of human knee OA chondrocytes was detected by Annexin V-fluorescein isothiocyanate/propidium iodide flow cytometry. Compared with the controls, chondrocytes treated with OPN exhibited higher mRNA and protein expression levels of proinflammatory factors (IL-1β, TNF-α, IL-6 and NF-κB), and a higher percentage of apoptotic chondrocytes. Furthermore, chondrocytes treated with p-OPN exhibited the highest mRNA and protein expression levels of proinflammatory factors (IL-1β, TNF-α, IL-6, NF-κB) and the highest percentage of apoptotic chondrocytes. p-OPN induces chondrocyte apoptosis and proinflammatory factor release, which suggests that p-OPN may contribute to OA pathogenesis, and inhibition of p-OPN may provide a novel effective strategy to slow or halt OA progression.

This study investigates the risk factors in railway reconstruction project through complete literature reviews on construction project risks and scrutinizing experiences and challenges of railway reconstructions in Taiwan. Based on the identified risk factors, an assessing framework based on the fuzzy multicriteria decision-making (fuzzy MCDM) approach to help construction agencies build awareness of the critical risk factors on the execution of railway reconstruction project, measure the impact and occurrence likelihood for these risk factors. Subjectivity, uncertainty and vagueness within the assessment process are dealt with using linguistic variables parameterized by trapezoid fuzzy numbers. By multiplying the degree of impact and the occurrence likelihood of risk factors, estimated severity values of each identified risk factor are determined. Based on the assessment results, the construction agencies were informed of what risks should be noticed and what they should do to avoid the risks. That is, it enables construction agencies of railway reconstruction to plan the appropriate risk responses/strategies to increase the opportunity of project success and effectiveness.

The microbial activity in soils was a critical factor governing the degradation of organic micro-pollutants. The present study was conducted to analyze the effects of soil organic matter on the development of degradation potentials for polycyclic aromatic hydrocarbons (PAHs). Most of the degradation kinetics for PAHs by the indigenous microorganisms developed in soils can be fitted with the Logistic growth models. The microbial activities were relatively lower in the soils with the lowest and highest organic matter content, which were likely due to the nutrition limit and PAH sequestration. The microbial activities developed in humic acid (HA) were much higher than those developed in humin, which was demonstrated to be able to sequester organic pollutants stronger. The results suggested that the nutrition support and sequestration were the two major mechanisms, that soil organic matter influenced the development of microbial PAHs degradation potentials., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

A hypothesis of microwave-induced circulatory under perfusion was tested in ketamine anesthetized rats whose heart rate, mean arterial pressure, pulse pressure, respiration rate, and body temperatures were monitored continuously. Fifty-eight ventral head and neck exposures in a waveguide consisted of sham-exposure and exposure to continuous wave (CW) and pulsed 1.25 GHz microwaves for 5 min. The 0.5 Hz (10 microseconds, 2 W average) and 16 Hz (1 microsecond, 6.4 W average) pulse-modulated microwaves were delivered at 400 kW peak power. The CW microwaves were 2 and 6.4 W. The average specific absorption rate was 4.75 W/kg per watt transmitted in the brain and 17.15 W/kg per watt transmitted in the neck. Respiration rate and mean arterial pressure were not altered. Changes in heart rate and pulse pressure were observed in rats exposed to higher power (16 Hz pulses and 6.4 W CW) but not to the lower average power microwaves (0.5 Hz pulses and 2 W CW). Depression of pulse pressure, an indication of a decrease in stroke volume, and increased (tachycardia) or decreased (bradycardia) heart rate were noted in presence of whole-body hyperthermia. The cardiac output of those animals exposed to higher average power microwaves was considered to be below normal as hypothesized. Decreased cardiac output and normal mean arterial pressure resulted in an increase in the total peripheral resistance which was contrary to the anticipated thermal response of animals.

The pharmacological properties and mechanism of the action of protopine on isolated rat thoracic aorta were examined. It inhibited norepinephrine (NE, 3 microM)-induced tonic contraction in rat thoracic aorta in a concentration-dependent manner (25-100 micrograms/ml). The phasic contraction caused by NE was inhibited only by a high concentration of protopine (100 micrograms/ml). At the plateau of NE-induced tonic contraction, the addition of protopine also caused relaxation. This relaxing effect of protopine was not antagonized by indomethacin (20 microM) or methylene blue (50 microM), and it still existed in denuded rat aorta or in the presence of nifedipine (2-100 microM). Protopine also inhibited high potassium (60 mM)-induced, calcium-dependent (0.03-3 mM) contraction of rat aorta in a concentration-dependent manner. Neither cAMP nor cGMP level was changed by protopine. Both the formation of inositol monophosphate caused by NE and the phasic contraction induced by caffeine were also not affected by protopine. 45Ca2+ influx caused by either NE or K+ was inhibited by protopine concentration-dependently. It is concluded that protopine relaxed the rat thoracic aorta mainly by suppressing the Ca2+ influx through both voltage- and receptor-operated calcium channels.

Although decreased serum thyrotropin (TSH) concentration has been found to be part of the endocrine response pattern in rats exposed to microwaves and other stimuli, the response of individual endocrine organs was not activated simultaneously by a given irradiance. Therefore, analytical evaluation of the function of endocrine organs individually as well as collectively is required to characterize the extent of biological involvement in microwave exposure. We have studied the changes in TSH concentration in unanesthetized rats exposed to 2.45 GHz amplitude modulated (120 Hz) microwaves in the far field for 2 and 4 h, between 0 and 55 mW/cm2, and from 1 to 10 times to demonstrate any possible cumulation, acclimation, or sensitization process. Ether inhalation was administered to test the responsiveness of TSH in groups of rats that failed to respond to microwave exposure by lowering TSH concentration. In addition, groups of rats were sampled 24 h after microwave exposure to test the persistency of the microwave effect on serum TSH concentration. Results showed that TSH concentration decreased in rats after microwave exposure. Influence of microwave exposure on serum TSH concentration was independent of the number of exposures indicating absence of cumulation, acclimation, or sensitization. The microwave effect on serum TSH could be dependent on duration of exposure. Decreased TSH concentration was usually accompanied by increased colonic temperature. For 4-h exposure, the lowest irradiance was 20 mW/cm2 or a 0.3 degree C increase in colonic temperature independent of the number of exposures. For 2-h exposure, the lowest irradiance was 30 mW/cm2 or a 1.1 degree C increase in colonic temperature regardless of the number of exposures. All the rats exposed at 10 mW/cm2 for 2 h had a lower TSH concentration than those of sham-exposed rats. Occasionally, significant reduction in TSH concentration could not be found in rats exposed to 20 or 25 mW/cm2 for 2 h. None of the rats exposed at an irradiance lower than 10 mW/cm2 had any change in TSH concentration. Failure of change in TSH concentration in response to microwave exposure was not a reflection of a deficiency since these rats responded to ether inhalation by lowering their TSH concentration. The effect of microwave exposure on TSH concentration was not persistent after exposure. The relation between TSH concentration and colonic temperature was curvilinear (exponential). From these results, two mechanisms and their implications for man were discussed.(ABSTRACT TRUNCATED AT 400 WORDS)

Confounding factors influencing the sensitivity of biological indicators of microwave exposure--lethality, colonic temperature (Tco), decreased body mass (dW), corticosterone (CS), thyrotropin (TSH), thyroxine (T4), free thyroxine (FT4), and prolactin (PRL) concentration--were studied in Long-Evans (LE), Wistar-Kyoto (WKY), and spontaneous hypertensive (SHR) rats. The microwave signal was 2.45 GHz amplitude modulated at 120 Hz. Test power density ranged from 1 to 50 mW/cm2 for 2 h. In contrast to the LE and WKY rats, the SHR rats were characterized by intolerance (death) between 40 and 50 mW/cm2 (9.2 to 11.5 W/kg). The lowest lethal Tco was 41.1 degrees C. Survivors including all the LE and WKY rats were capable of maintaining Tco lower than 41.0 degrees C. In general, strain of rat seemed to influence other bioindicators and to interact with power density on these bioindicators. Except for Tco and PRL, baseline for the various bioindicators varied among the different strains of rats. Responses of T4 and FT4 were limited in magnitude and inconsistent among strains of rats. In general, the magnitude of Tco increase was more pronounced in SHR than in WKY. Differences between SHR and LE, however, could be noted only at 1, 10, and 50 mW/cm2. Increased Tco, increased magnitude of Dw, increased CS, decreased TSH, and increased PRL (stress reactions) could be noted in rats exposed to 30 mW/cm2 (approximately 6 W/kg) or higher, irrespective of strain. At least two of three strains of rats (WKY and SHR) exposed to 20 mW/cm2 (approximately 4 W/kg) showed changes in Tco, CS, TSH, and PRL. At 10 mW/cm2 (2 W/kg), increased Tco could be found in all three strains of rats accompanied by changes in dW and TSH in LE, TSH in WKY, and dW and CS in SHR. At 1 mW/cm2 (0.2 W/kg), increased Tco could be noted in two of three strains (LE and SHR) and increased PRL in LE only. The smallest Tco increases for a consistent response (increased magnitude of response with power density) were 1.59 degrees C for dW, 0.70 degrees C for CS, 0.24 degrees C for TSH, and 0.97 degrees C for PRL. Tentatively, the threshold intensity for response to microwave exposure for rats could be considered as 2 W/kg or a 0.24 degrees C increase at 24 degrees C ambient temperature.

Human mononuclear leukocytes were exposed to microwaves at energies relevant to current public safety recommendations. No detectable effects on viability or function of the leukocytes resulted from exposure to microwaves at specific absorption rates up to 4 milliwatts per milliliter. The results were highly reproducible and provided no evidence that current safety standard recommendations are inappropriate insofar as leukocyte function is concerned.

Data are available regarding interactions of radiofrequency radiation (RFR) with normal human mononuclear leukocytes. However, no data have emerged regarding effects of RFR on human leukocytes already challenged by a commonly encountered alternate agent, such as a virus. Therefore, in these studies, uninfected (control) and in vitro influenza virus-infected human mononuclear leukocytes were exposed to 2450 MHz RFR as continuous waves or pulse-modulated at 60 or 16 Hz, at a specific absorption rate of 4 mW/ml. Such exposures produced no significant effects on leukocyte viability or on mitogen-stimulated DNA synthesis by either uninfected or influenza virus-infected leukocytes when compared to sham-RFR-exposed of cells.

Hyperthermia is being used clinically in the treatment of neoplasms, and mononuclear leukocytes are commonly present in a heated tumor or in surrounding tissues. Therefore, we examined the effects of exposure of human mononuclear leukocytes to less than 41 degrees or greater than 42.5 degrees hyperthermia for 2 h. The ability of the cells to exclude dyes, used as a measurement of leukocyte viability, was not altered by such exposures. Exposure of the cells to less than 41 degrees hyperthermia generally did not alter unstimulated or mitogen-stimulated DNA, RNA, or total protein synthesis. In contrast, exposure to greater than 42.5 degrees hyperthermia resulted in decreased unstimulated RNA and total protein synthesis, as well as delayed synthesis of DNA, RNA, and total protein in response to stimulation with the optimal concentration of mitogen and decreased synthesis in response to suboptimal concentrations of mitogen.

Heat stable serum enzymes were studied in rats exposed to microwaves (2.45 GHz, 120 Hz amplitude modulated) 24 hr after a single 4-hr exposure or immediately after 3 and 10 exposures to 0.1 to 55 mW/cm2. In addition, stable colonic temperature at 41.5 degrees C for 30 min was maintained by microwave exposure in a group of five rats under barbiturate anesthesia. Alkaline phosphatase and lactic dehydrogenase did not increase as a result of microwave exposure. Increased serum glutamic pyruvic transaminase (GPT) and glutamic oxaloacetic transaminase (GOT) were noted in the 41.5 degrees C group 24 hr after exposure. A threshold body temperature for acute cellular injury after microwave exposure was demonstrated. The acute cellular injury could be in the liver. These mild elevations in the serum enzyme levels (mean +/- SE, GOT = 167 +/- 40 U/liter: GPT = 74 +/- 26 U/liter) indicated that the injuries were not accompanied by any significant sequelae in the rat. From this threshold and colonic temperature (41.5 degrees C for 30 min) in barbiturate-anesthetized, microwave-exposed rats, we derived a tentative threshold for the whole-body average absorption rate at 14 W/kg (70 mW/cm2 at 2.45 GHz for adult rats) for 4 hr. This tentative threshold is subject to changes by duration of exposure and by compounding variables influencing maintenance of body temperature.

The nature of the response of the thyroid gland in animals exposed to microwave irradiation is controversial. An enlarged thyroid and an increase of radioiodine uptake in microwave workers have been reported. Absence of thyroid disorders has also been reported in other exposed populations. Animal experimentation has contributed to the controversy because both increased and decreased thyroid functions have been reported. The thyroxine concentration in rats as representative of thyroid function in animals exposed to 2.45-GHz, 120-Hz amplitude-modulated microwaves has been studied. Comparison was made between thyroxine concentrations in microwave- and sham-exposed rats by Student's t test. After a 1-hr exposure, an increased thyroxine concentration was found in rats exposed at 40 and 70 mW/cm2, but not at 1, 5, 10, 20, 50, or 60 mW/cm2. After a 2-hr exposure, increased thyroxine concentration was noted in rats exposed at 25, 30, and 40 mW/cm2, but not at 1, 5, 10, and 20 mW/cm2. After a 4-hr exposure, thyroxine concentration increased in rats exposed at 1 mW/cm2 and decreased in rats exposed at 20 mW/cm2; but changes were not noted at 5 or 10 mW/cm2. Other experiments included animals that were exposed once for 4 hr (0.1, 1, 10, 25, and 40 mW/cm2), sampled 24 hr after a 4-hr exposure (0.1, 1, 10, 25, and 40 mW/cm2), or exposed for 4 hr 3 times (1, 10, 20, 30, 40, and 55 mW/cm2) and 10 times (1, 10, 20, 25, 30, and 40 mW/cm2), to evaluate the consistency of the thyroxine response. None of the rats in these experiments displayed any alteration of thyroxine concentration, except that decreased thyroxine was noted in rats exposed at 40 mW/cm2 for the third time. These studies covered a long time span; rats from two commercial sources (BS and CR) were used and subjected to different numbers of exposures, and therefore these data were evaluated for their stability. Two factors could influence the result significantly, i.e., source of animal and number of sham exposures. Rats used in the 2-hr exposures were from two different commercial sources; rats from CR had a higher (but normal) thyroxine concentration than did rats from BS. Therefore the data of these animals were separated by commercial source for reevaluation. Instead of increased thyroxine concentration in rats exposed at 25, 30, and 40 mW/cm2, changes were not noted in any microwave-exposed rats. The influence of sham exposure revealed that appropriate concurrent control and specification of animal source are needed in longitudinal studies.(ABSTRACT TRUNCATED AT 400 WORDS)

Six-hundred-and-one male Long-Evans rats were used to study the effect of microwaves on adrenocortical secretion. Power density ranged from 0.1 to 55 mW/cm2 (SAR 0.02 to 11 W/kg). The microwave signal was 2.45 GHz amplitude modulated at 120 Hz. Serum corticosterone (CS) concentration was used as an index of adrenocortical function. Ten different exposure protocols were used to identify confounding factors influencing the sensitivity of adrenal cortex to microwave exposure. Increases in CS concentration were proportional to power density or colonic temperature and inversely proportional to the baseline CS. Increased CS concentration was never observed without increased colonic temperature and was not persistent 24 h after exposure. Acclimation (reduction in magnitude of response) could be noted after the tenth exposure. Facilitated heat loss attenuated the magnitude of CS increases by limiting the degree of hyperthermia. Ethanol enhanced the hyperthermic response and desensitized the adrenal response to microwave hyperthermia by increased baseline CS. Ether stimulated adrenal secretion irrespective of previous microwave exposure or adrenal stimulation induced by microwaves. Minor inhibition was also noted occasionally as decreased CS concentration at lower intensity (less than 20 mW/cm2) and decreased postexposure urinary CS excretion at 40 mW/cm2. Adrenal stimulation required minimally a 20 mW/cm2 (4 W/kg) or 0.7 degrees C increase in colonic temperature. An SAR lower than 4 W/kg may stimulate adrenal secretion by potentiating the hyperthermic effect if the ambient temperature is well above 24 degrees C.

Rats, with their fur clipped, pressed a lever to turn on an infrared lamp while in a cold chamber. When they were exposed to continuous-wave microwaves at 2450 megahertz for 15-minute periods, the rate at which they turned on the infrared lamp decreased as a function of the microwave power density, which ranged between 5 and 20 milliwatts per square centimeter. This result indicates that behaviorally significant levels of heating may occur at an exposure duration and intensities that do not produce measurable changes in many other behavioral measures or in colonic temperature. Further study of how microwaves affect thermoregulatory behavior may help us understand such phenomena as the reported "nonthermal" behavioral effects of microwaves.