Design, concise synthesis and evaluation of novel amide-based combretastatin A-4 analogues as potent tubulin inhibitors.

As our ongoing work, a novel series of the amide-based CA-4 analogues were successfully designed, synthesized, and explored for their biological evaluation. Among these compounds, 7d and 8a illustrated most potent antiproliferative activity toward A549, HeLa, HCT116, and HT-29 cell lines. Most importantly, these two compounds didn't display noticeable cytotoxic activity on the non-tumoural cell line HEK-293. Further mechanism studies revealed that analogue 8a was identified as a novel tubulin polymerization inhibitor with an IC50 value of 6.90 µM, which is comparable with CA-4. The subsequent investigations unveiled that analogue 8a not only effectively caused cell cycle arrest at the G2/M phase but also induced apoptosis in A549 cells via a concentration-dependent manner. The molecular docking revealed that 8a could occupy well the colchicine-binding site of tubulin. Collectively, these findings indicate that amide-based CA-4 scaffold could be worthy of further evaluation for development of novel tubulin inhibitors with improved safety profile.

One-day examination of triple nuclear medicine imaging and application in evaluating transarterial embolization.

A diagnosis based on multiple nuclear medicine imaging (NMI) was more comprehensive in approaching the nature of pathological changes. In this research, a method to realize triple NMIs within one day was developed based on the reasonable arrangements of 68Ga-RGD PET/CT specialized on neovascularization, 99mTc-HL-91 SPECT/CT specialized on hypoxia and 18F-FDG PET/CT specialized on tumor metabolism. Feasibility was verified in evaluating the therapeutic effects of transarterial embolization (TAE) performed on rabbit models with VX2 tumor. Radiation dosimetry was carried out to record the radiation exposure from multiple injections of radiopharmaceuticals. In results, the one-day examination of triple NMIs manifested the diversity of the postoperative histological changes, including the local neovascularization induced by embolization, hypoxic state of embolized tissues, and suppression of tumor metabolism. More importantly, radiation dosage from radiopharmaceuticals was limited below 5.70 ± 0.90 mSv. In conclusion, the strong timeliness and complementarity of one-day examination of triple nuclear medicine imaging made it clinically operative and worthy of popularizing. There was flexibility in combining distinct NMIs according to the clinical demands, so as to provide comprehensive information for diagnosis.

[99mTc]Tc-labeled cyc-DX600-HYNIC as a SPECT probe for ACE2-specific pancreatic cancer imaging.

As a regulator in renin-angiotensin-aldosterone system, angiotensin-converting enzyme 2 (ACE2) closely correlated with tumor progression of pancreatic cancer, meantime, was easily affected by a variety of factors. [99mTc]Tc-cyc-DX600 SPECT was established as an ACE2-specific imaging protocol to figure out the ACE2 status in pancreatic tumor. BALB/C-NU mice were used to prepare the subcutaneous cell derived xenograft (CDX) models with HEK-293T or HEK-293T/hACE2 cells to validate ACE2 specificity of [99mTc]Tc-cyc-DX600 SPECT and establish SPECT imaging protocol. On the basis of [99mTc]Tc-cyc-DX600 SPECT and [18F]F-FDG PET/CT, ACE2-dependence on tumor size and tumor metabolism were further verified on orthotopic pancreatic cancer model with KPC cells. Immunohistochemical analysis was used to demonstrate the findings on ACE2 SPECT. [99mTc]Tc-cyc-DX600 was of superior tumor uptake in HEK-293T/hACE2 CDX than wild type (6.74 ± 0.31 %ID/mL vs 1.83 ± 0.26 %ID/mL at 1.5 h post injection (p.i.); 3.14 ± 0.31 %ID/mL vs 1.16 ± 0.15 %ID/mL at 4.5 h p.i.). For the CDX models with PANC-1 cells, a significant negative correlation between the slope of tumor volume and tumor uptake was observed (r = -0.382 for the 1-4th day; r = -0.146 for the 1-5th day; r = -0.114 for the 1-6th day; r = -0.152 for the 1-7th day; but P > 0.05 for all). For orthotopic pancreatic cancer model, the linear correlation between FDG PET and ACE2 SPECT of the pancreatic lesions was negative (r = -0.878), the quantitative values of ACE2 SPCET was positively correlated with the volume of primary lesions (r = 0.752) and also positively correlated with the quantitative values of ACE2 immunohistochemical analysis (r = 0.991). Conclusively, [99mTc]Tc-cyc-DX600 SPECT is an ACE2-specific imaging protocol with clinical translational potential, adding multidimensional information on the disease progression of pancreatic cancer.

Adverse effects of cigarette filter silica on lungs: Comparison with natural crystalline silica particles.

As a common additive in cigarette filters, nanosilica has been implemented to reduce the release of harmful substances in cigarette smoke. However, the potential risk of occupational exposure for cigarette factory workers is unknown. We collected physical examination data from 710 cigarette factory workers to evaluate the adverse effects of cigarette filter silica exposure. We also established mouse models induced by cigarette filter silica and crystalline silica separately to compare the lung inflammation, pulmonary function, apoptosis, and fibrosis of the two models. Workers in the rolling and packing workshop exposed to cigarette filter silica had a higher rate of abnormal lung function (17.75%) than those in the cutting workshop (0.87%). Animal experiments showed that compared with the same dose of crystalline silica, cigarette filter silica resulted in higher levels of inflammatory factors in the bronchoalveolar lavage fluid (BALF) of mice at day 7, and lower levels of total lung capacity (TLC), inspiratory capacity (IC), vital capacity (VC), and forced vital capacity (FVC) in mice at day 28. Additionally, both exposed groups of mice showed increased levels of caspase 3, collagen I (Col-Ⅰ), α-smooth muscle actin (α-SMA) and hydroxyproline (HYP) in the lungs, as well as collagen accumulation and fibrous nodules at day 28, with no significant difference between the two groups. The results suggested that cigarette filter silica caused more severe early lung inflammation and late ventilation impairment than the same dose of crystalline silica. In the future, we need to pay more attention to nanosilica protection in cigarette factories to prevent pulmonary dysfunction in workers.

Design, synthesis, and biological evaluation of N-(pyridin-3-yl)pyrimidin-4-amine analogues as novel cyclin-dependent kinase 2 inhibitors for cancer therapy.

The discovery and development of CDK2 inhibitors has currently been validated as a hot topic in cancer therapy. Herein, a series of novel N-(pyridin-3-yl)pyrimidin-4-amine derivatives were designed and synthesized as potent CDK2 inhibitors. Among them, the most promising compound 7l presented a broad antiproliferative efficacy toward diverse cancer cells MV4-11, HT-29, MCF-7, and HeLa with IC50 values of 0.83, 2.12, 3.12, and 8.61 µM, respectively, which were comparable to that of Palbociclib and AZD5438. Interestingly, these compounds were less toxic on normal embryonic kidney cells HEK293 with high selectivity index. Further mechanistic studies indicated 7l caused cell cycle arrest and apoptosis on HeLa cells in a concentration-dependent manner. Moreover, 7l manifested potent and similar CDK2/cyclin A2 nhibitory activity to AZD5438 with an IC50 of 64.42 nM. These findings revealed that 7l could serve as ahighly promisingscaffoldfor CDK2 inhibitors as potential anticancer agents and functional probes.

HMGB1/RAGE Signaling Regulates Th17/IL-17 and Its Role in Bronchial Epithelial-Mesenchymal Transformation.

BACKGROUND: Airway remodeling is one of the reasons for severe steroidresistant asthma related to HMGB1/RAGE signaling or Th17 immunity. OBJECTIVE: Our study aims to investigate the relationship between the HMGB1/RAGE signaling and the Th17/IL-17 signaling in epithelial-mesenchymal transformation (EMT) of airway remodeling. METHODS: CD4+ T lymphocytes were collected from C57 mice. CD4+ T cell and Th17 cell ratio was analyzed by flow cytometry. IL-17 level was detected by ELISA. The Ecadherin and α-SMA were analyzed by RT-qPCR and immunohistochemistry. The Ecadherin, α-SMA, and p-Smad3 expression were analyzed by western blot. RESULTS: The HMGB1/RAGE signaling promoted the differentiation and maturation of Th17 cells in a dose-dependent manner in vitro. The HMGB1/RAGE signaling also promoted the occurrence of bronchial EMT. The EMT of bronchial epithelial cells was promoted by Th17/IL-17 and the HMGB1 treatment in a synergic manner. Silencing of RAGE reduced the signaling transduction of HMGB1 and progression of bronchial EMT. CONCLUSION: HMGB1/RAGE signaling synergistically enhanced TGF-ß1-induced bronchial EMT by promoting the differentiation of Th17 cells and the secretion of IL-17.

Radioiodine-131-Labeled Theranostic Nanoparticles for Transarterial Radioembolization and Chemoembolization Combination Therapy of VX2 Liver Tumor.

In interventional treatment, materials are administered into the blood supply artery and directly delivered to tumors, offering proper scenarios for nanomedicine potential clinical applications. Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) are effective treatment methods for hepatocellular carcinoma (HCC), but postoperative residual tumor may result in intrahepatic recurrence and distant metastasis. The combination therapy of TACE and TARE based on multifunctional nanoparticles (NPs) is expected to overcome the drug resistance in hypoxic tumors and improve the therapeutic effect. Herein, BaGdF5 NPs are synthesized and then coated with polydopamine (PDA), conjugated with the chemotherapeutic drug cis-diamminedichloride platinum (CDDP), radio-labeled with therapeutic radionuclide 131 I, yielding 131 I-BaGdF5 @PDA-CDDP NPs. The in vitro anti-cancer effects of 131 I-BaGdF5 @PDA-CDDP NPs are confirmed using CCK-8 and γ-H2AX assays in Huh7 cells. Mixed with Lipiodol, 131 I-BaGdF5 @PDA-CDDP NPs are injected into the hepatic artery via a microcatheter to realize the TACE and TARE combination therapy in a rabbit VX2 liver tumor model. The results indicate that glucose metabolism is clearly decreased based on 18 F-FDG PET imaging and the apoptosis of tumor cells is increased. Furthermore, 131 I and BaGdF5 NPs can be used for SPECT imaging and CT/MR imaging respectively, facilitating real-time monitoring of the in vivo biodistribution of 131 I-BaGdF5 @PDA-CDDP NPs.

Silk fibroin-based embolic agent for transhepatic artery embolization with multiple therapeutic potentials.

BACKGROUND: The excellent physicochemical and biomedical properties make silk fibroin (SF) suitable for the development of biomedical materials. In this research, the silk fibroin microspheres (SFMS) were customized in two size ranges, and then carried gold nanoparticles or doxorubicin to evaluate the performance of drug loading and releasing. Embolization efficiency was evaluated in rat caudal artery and rabbit auricular artery, and the in vivo distribution of iodinated SFMS (125I/131I-SFMS) after embolization of rat hepatic artery was dynamically recorded by SPECT. Transhepatic arterial radioembolization (TARE) with 131I-SFMS was performed on rat models with liver cancer. The whole procedure of selective internal radiation was recorded with SPECT/CT, and the therapeutic effects were evaluated with 18 F-FDG PET/CT. Lastly, the enzymatic degradation was recorded and followed with the evaluation of particle size on clearance of sub-micron silk fibroin. RESULTS: SFMS were of smooth surface and regular shape with pervasive pores on the surface and inside the microspheres, and of suitable size range for TAE. Drug-loading functionalized SFMS with chemotherapy or radio-sensitization, and the enhanced therapeutic effects were proved in treating HUH-7 cells as lasting doxorubicin release or more lethal radiation. For artery embolization, SFMS effectively blocked the blood supply; when 131I-SFMS serving as the embolic agent, the good labeling stability and embolization performance guaranteed the favorable therapeutic effects in treating in situ liver tumor. At the 5th day post TARE with 37 MBq/3 mg 131I-SFMS per mice, tumor activity was quickly inhibited to a comparable glucose metabolism level with surrounding normal liver. More importantly, for the fragments of biodegradable SFMS, smaller sized SF (< 800 nm) metabolized in gastrointestinal tract and excreted by the urinary system, while SF (> 800 nm) entered the liver within 72 h for further metabolism. CONCLUSION: The feasibility of SFMS as degradable TARE agent for liver cancer was primarily proved as providing multiple therapeutic potentials.

From Basic Research to Clinical Practice: Considerations for Treatment Drugs for Silicosis.

Silicosis, characterized by irreversible pulmonary fibrosis, remains a major global public health problem. Nowadays, cumulative studies are focusing on elucidating the pathogenesis of silicosis in order to identify preventive or therapeutic antifibrotic agents. However, the existing research on the mechanism of silica-dust-induced pulmonary fibrosis is only the tip of the iceberg and lags far behind clinical needs. Idiopathic pulmonary fibrosis (IPF), as a pulmonary fibrosis disease, also has the same problem. In this study, we examined the relationship between silicosis and IPF from the perspective of their pathogenesis and fibrotic characteristics, further discussing current drug research and limitations of clinical application in silicosis. Overall, this review provided novel insights for clinical treatment of silicosis with the hope of bridging the gap between research and practice in silicosis.

Nephrotoxicity of immune checkpoint inhibitor combination therapy in patients with advanced renal cell carcinoma: a meta-analysis.

PURPOSE: Few data are available regarding the nephrotoxicity of immune checkpoint inhibitor (ICI) combination therapy in advanced renal cell carcinoma (RCC). This study aimed to investigate the nephrotoxicity of ICI-based combination therapy versus standard of care sunitinib in patients with advanced RCC. METHODS: We searched Embase/PubMed/Cochrane Library for relevant randomized controlled trials (RCTs). Treatment-related nephrotoxicities including increase of creatinine and proteinuria were analyzed by Review Manager 5.4 software. RESULTS: Seven RCTs involving 5239 patients were included. The analysis showed that ICI combination therapy had similar risks of any grade (RR = 1.03, 95% CI: 0.77-1.37, P = 0.87) and grade 3-5 (RR = 1.48, 95% CI: 0.19-11.66, P = 0.71) increased creatinine compared with sunitinib monotherapy. However, ICI combination therapy was associated with significantly higher risks of any grade (RR = 2.33, 95% CI: 1.54-3.51, P < 0.0001) and grade 3-5 proteinuria (RR = 2.25, 95% CI: 1.21-4.17, P = 0.01). CONCLUSIONS: This meta-analysis suggests that ICI combination therapy shows more nephrotoxicity of proteinuria than sunitinib in advanced RCC, which deserves a high attention in the clinic.

Factors affecting perception of laypeople and dental professionals toward different smile esthetics.

Abstract Background: /purpose: Several factors such as identity, income, and age potentially associated with smile perceptions. This study aimed to identify the factors affecting the smile esthetic perception in different identities (layperson, general dentist and orthodontist) and to detect the extent of their association with smile perception. Materials and methods: Extraoral photographs in frontal, lateral, and three-quarter views were shot and adjusted on Adobe Photoshop into 95 smile photographs with different smile patterns. Based on these photographs, the investigators were asked to fill the online questionnaire. Pearson chi-square test and logistic regression were used for statistical analyses. Results: Identity, gender, age, and treatment experience were noted to affect smile esthetic perception. In addition, the perception of smile esthetics was significantly different among frontal, lateral, and three-quarters views regarding the arc ratio, most posterior teeth exposure, upper teeth exposure, and lower teeth exposure. Conclusion: Identity, gender, age, and treatment experience influence the smile esthetics perception, with a significant difference in the results of the esthetic perception based on the 3 smile views. Of all demographic factors, identity had a strong relation to the perception of smile attractiveness. Nevertheless, additional studies are needed to realize how the demographic factors influence people's perception of smile esthetics, particularly in the three-quarter and lateral views.

Methyl-cpg-binding Domain Protein 2 Silencing Inhibits Th17 Differentiation of CD4+T cells Induced by Ovalbumin.

Background: Little is known about MBD2's epigenetic regulation in the immune pathogenesis of CD4+T cell differentiation. Objective: This study attempted to explore the mechanism of methyl-cpg-binding domain protein 2 (MBD2) in CD4+T cell differentiation stimulated by environmental allergen ovalbumin (OVA). Methods: Mononuclear cells were separated from the spleen tissues of male C57BL/6 mice. The OVA interfered with the differentiation of splenic mononuclear cells and CD4+T cells. The CD4+T cells were obtained by magnetic beads and identified by CD4 labeled antibody. CD4+T cells were transfected with lentivirus to silence MBD2 gene. A methylation quantification kit was used to detect 5-mC levels. Results: The purity of CD4+T cells reached 95.99% after magnetic beads sorting. Treatment with 200 µg/mL OVA stimulated the CD4+T cells differentiation to Th17 cells and promoted the secretion of IL-17. After being induced, the Th17 cell ratio increased. 5-Aza inhibited the Th17 cell differentiation and the IL-17 level in a dose-dependent manner. Under the intervention of the Th17 induction and 5-Aza, MBD2 silencing inhibited the differentiation of Th17 cell, and decreased the IL-17 and 5-mC levels in the cell supernatants. MBD2 silencing reduced the scale of the Th17 cell and IL-17 levels in the OVA-treated CD4+T cells. Conclusion: MBD2 affected IL-17 and 5-mC levels by mediating the Th17 cell differentiation in splenic CD4+T cells that were interfered with 5-Aza. OVA induced Th17 differentiation and increased IL-17 levels, inhibited by MBD2 silencing.

SPECT Imaging with Tc-99m-Labeled HYNIC-FAPI-04 to Extend the Differential Time Window in Evaluating Tumor Fibrosis.

The so-far used Ga-68- or F-18-labelled tracers are of a relative short time window in differentiating tumor fibrosis. SPECT applicable imaging probe, 99mTc-HYNIC-FAPI-04, was synthesized and evaluated in tumor cells and animal models of FAP-positive glioma and FAP-negative hepatoma, and then compared with 18F-FDG or 68Ga-FAPI-04 PET/CT. The radio-labeling rate of 99mTc-HYNIC-FAPI-04 was greater than 90%, and the radiochemical purity was >99% after purification with sep-pak C18 column. In vitro cell uptake experiments of 99mTc-HYNIC-FAPI-04 showed good FAP binding specificity, and the cellular uptake significantly decreased when blocked by DOTA-FAPI-04, reflecting the similar targeting mechanism of HYNIC-FAPI-04 and DOTA-FAPI-04. SPECT/CT imaging showed that U87MG tumor was distinguishable and of a high uptake of 99mTc-HYNIC-FAPI-04 (2.67 ± 0.35 %ID/mL at 1.5 h post injection (h P.I.), while tumor signal of FAP-negative HUH-7 was as low as 0.34 ± 0.06 %ID/mL. At 5 h P.I., U87MG tumor was still distinguishable (1.81 ± 0.20 %ID/mL). In comparison, although U87MG tumor was of obvious 68Ga-FAPI-04 uptake and clearly visible at 1 h P.I., the tumorous radioactive signals were fuzzy at 1.5 h P.I. 99mTc-HYNIC-FAPI-04 specifically bound to FAP-positive tumors and qualified with the ability of evaluating tumor fibrosis over longer time windows.

The functional views on response of host rabbit post coronavirus vaccination via ACE2 PET.

Molecular imaging can dynamically and quantitatively record the biochemical changes in a systemic view. In this research, SARS-CoV-2 pseudovirus was intramuscularly injected to simulate the vaccination with inactivated virus. New Zealand white rabbits were evaluated with 18F-FDG PET for inflammation and 68Ga-cyc-DX600 PET for ACE2 fluctuation, which were performed before and at 3, 7 and 14 days post injection (d P.I.); furthermore, one rabbit was vaccinated with two cycles with interval of 14 days for a longer period evaluation. Different with the vaccination-induced inflammatory response that was random and individual, ACE2 regulation was systemic and organ-specific: the liver and spleen were of a moderate decrease post injection but rebound at 14 d P.I., while there were a downward trend in heart, testis and bone marrow; besides, similar pattern of ACE2 regulation were recorded after the second injection with a relatively greater volatility. In conclusion, ACE2 PET gave a more comprehensive view on host response post vaccination, hold substantial promise in continuous monitoring of coronavirus vaccine administration and effectiveness.

ACE2 PET to reveal the dynamic patterns of ACE2 recovery in an infection model with pseudocorona virus.

Due to the COVID-19 pandemic, a series of sequelae, such as fatigue, tachypnea, and ageusia, appeared in long COVID patients, but the pathological basis was still uncertain. The targeted radiopharmaceuticals were of potential to systemically and dynamically trace the pathological changes. For the key ACE2 protein in the virus-host interaction, 68 Ga-cyc-DX600 was developed on the basis of DX600 as a PET tracer of ACE2 fluctuation and maintained the ability in differentiating ACE and ACE2. In the temporary infection model inhaled with the radio-traceable pseudovirus in the upper respiratory tract of male humanized ACE2 (hACE2) mice, organ-specific ACE2 dysfunction in acute period and the following ACE2 recovery in a relatively long period was visualized and quantified by ACE2 PET, revealing a complex pattern of virus concentration-dependent degree and time period-dependent tendency of ACE2 recovery, mainly a sudden decrease of apparent ACE2 in the heart, liver, kidneys, lungs, and so on, but the liver was of a quick functional compensation on ACE2 expression after a temporary decrease. ACE2 expression of most organs has recovered to a normal level at 15 days post inhalation, with brain and genitals still of a decreased SUVACE2 ;  meanwhile, kidneys were of an increased SUVACE2 . These findings on ACE2 PET were further verified by western blot. When compared with high-resolution computed tomography on structural changes and FDG PET on glycometabolism, ACE2 PET was superior in an earlier diagnostic window during infection and more comprehensive understanding of functional dysfunction post-infection. In the respective ACE2 PET/CT and ACE2 PET/MR scans of a volunteer, the repeatability of SUVACE2 and the ACE2 specificity were further confirmed. In conclusion, 68 Ga-cyc-DX600 was developed as an ACE2-specific tracer, and the corresponding ACE2 PET revealed the dynamic patterns of functional ACE2 recovery and provided a reference and approach to explore the ACE2-related pathological basis of sequelae in long COVID.

Application of 3-Dimensional Technology for Evaluating Muscular Type and Muscle-Fat Pad Mixed-Type Nasolabial Folds With Botulinum Toxin-A Treatment.

BACKGROUND: Botulinum toxin-A (BTX-A) is used in the treatment of nasolabial folds (NLFs). However, lighting and clinician subjectivity play a major role in evaluating the efficacy of this treatment. OBJECTIVES: By applying 3-dimensional (3D) technology, this study aimed to quantitatively evaluate the effects of BTX-A injection on muscular (M) and muscle-fat pad mixed-type (MF) NLFs. METHODS: BTX-A was injected into bilateral marked points on the NLFs, where the levator labii alaeque nasi, zygomaticus minor, and zygomaticus major pull the skin to form the NLF (2 U at each injection site). Pretreatment and posttreatment 3D facial images were captured with static and laughing expressions. The curvature, width, depth, and lateral fat volume of the NLFs were measured to compare the therapeutic efficacy for type M and MF NLFs. RESULTS: Thirty-nine patients with type M and 37 with type MF NLFs completed the follow-up data. In these patients, the curvature, width, and depth of the NLF showed a significant reduction at 1 month and gradually recovered at 3 and 6 months after treatment, with more significant improvement when laughing than when static. Variations compared to the pretreatment values of type MF were greater than those of type M at each time point. The lateral fat volume of the type MF NLF was significantly reduced (P < .05). CONCLUSIONS: 3D technology can quantitatively evaluate the effects BTX-A injection for treating type M and type MF NLFs. BTX-A is more effective on type MF than on type M NLFs.

The Retention-Rate Improvement of Stromal Vascular Fraction Gel in Prefrontal Filling With Botulinum Toxin-A Injection: A Retrospective Analysis.

BACKGROUND: As a derivative of adipose tissues, stromal vascular fraction gel has been widely utilized in facial soft tissue filling, but it still does not achieve the expected effect in forehead filling. The reason may be related to the corrugator muscles movements. OBJECTIVES: The authors aimed to evaluate the effect of botulinum toxin-A (BTX-A) on the retention rate of stromal vascular fraction gel by limiting the corrugator muscles movements and to provide a theoretical basis that short-term inhibition of movement in the affected area could improve the effects of the fat graft. METHODS: From January 2019 to June 2021, patients with stromal vascular fraction gel facial filling (including frontal and temporal parts) were selected. According to whether or not BTX-A treatment was received, patients were divided into injected and the noninjected groups. A questionnaire and the Global Aesthetic Improvement Scale (GAIS) were administered to evaluate 2-dimensional photos. The retention rate and curvature were calculated with 3-dimensional images utilizing Artec Studio 13 Professional and MATLAB software. RESULTS: The graft retention, forehead curvature, and GAIS scores were all higher in the injected group than the noninjected group (P < .01). On the questionnaire, the injected group also showed more satisfaction with the treatment effect and were more willing to recommend the treatment to their friends. CONCLUSIONS: BTX-A injection can improve the retention rate of prefrontal stromal vascular fraction gel filling, with higher patient satisfaction and better postoperative effects.

DPP4 Regulates the Th17/IL-17 Axis and Accelerates Epithelial Mesenchymal Transition to Promote Ovalbumin-Induced Asthma in Female C57BL/6J Mice.

BACKGROUND: Dipeptidyl peptidase-4 (DPP4) is a transmembrane glycoprotein, prevalent across a variety of tissues and cells and can be foundin a solubilised in peripheral blood. This paper aims at determining the role of sCD26/sDPP4 in Th17 cell polarization and airway epithelial cell to epithelial mesenchymal transition (EMT) in asthma. METHODS: Female C57BL/6J mice were treated with ovalbumin to constructed asthma mice. The CD4+ T cell, and bronchial epithelial cells (BECs) were purified from the spleens and bronchus of mice. The KRT8 expression in BECs were identified by immunofluorescence (IF). Th17 cells were differentiated from a CD4+ T cell. Flow cytometry was usewd to identify and calculate the Th17 and Treg cells. Mice woth asthma were treated by DPP4 overexpressing lentivirus or DPP4 inhibitor. Histopathological modifications were assessed by hematoxylin-eosin (HE), periodic acid Schiff (PAS), and Masson staining. The total number of leucocytes was detected using a hemocytometer. For detection, quantitative Real-time PCR (qRT-PCR), western blotting (WB), and IF were used to evaluate the expression of E-cadherin and alpha-smooth muscle actin (α-SMA). Enzyme-linked immunosorbent assay (ELISA) was performed to analyze the DPP4, IL-4, IL-5, IL-13 and IL-17 levels. RESULTS: The findings suggest that sCD26/sDPP4 promote CD4+ T cells differentiation into Th17 cells in a depending on the applied dose. sCD26/sDPP4 up-regulated the expression of α-SMA and down-regulated the expression of E-cadherin in TGF-ß1-induced mouse BECs, which was reversed by DPP4 inhibitor. Co-culture induced a synergic effect between Th17 cells and sCD26/sDPP4 on the formation of airway EMT in BECs. Furthermore, DPP4 inhibitor prevented lung-bronchial inflammatory infiltration, mucus secretion, goblet cell hyperplasia and collagen deposition in asthma mice. Meanwhile, DPP4 inhibitor decreased the levels of DPP4, IL-4, IL-5, IL-13, IL-17 and increased the total number of leukocytes in bronchoalveolar lavage fluid of asthma mice. In addition, DPP4 inhibitor also inhibited airway EMT and Th17 cell polarization in asthma mice. CONCLUSIONS: The results in this paper show that up-regulation of DPP4 enabled airway inflammation and airway remodeling in asthmatic mice by modulating the Th17/IL-17 axis and accelerating the airway EMT, which isa therapeutic target in asthma.

Deterioration of Mechanical Properties and the Damage Constitutive Model of Corroded Steel in an Industrial Environment.

To investigate the degradation law of the mechanical properties of corroded steel, the standard specimens from machining steel members in service for 9 years in an industrial environment were subjected to tensile tests. The influences of different degrees and types of corrosion on the fracture path, stress-strain curve, and mechanical properties of specimens were discussed. Finally, the damage constitutive model of corroded steel was established based on the damage mechanics theory. The results showed that the failure modes of corroded specimens were related to the degrees and types of corrosion. The fracture morphology of specimens with general corrosion were step-like and the fractures of steel were uneven. However, those with local corrosion were mainly flat-like, and the fracture path was along the cross section where the larger corrosion pits were located. The fracture path of the specimen was related to the interaction of the corroded surface and internal material defects (holes). Meanwhile, with the increase of corrosion degree, the yield platform of stress-strain curve gradually became shorter, or even disappeared, and the ultimate strain and elongation at break decreased, implying that the ductility of steel became worse. Ultimately, the good agreement between the curves of the model and test indicated that the damage model could reflect the damage development process of corroded steel in the tensile process better. Corrosion damage resulted in the decrease in the damage threshold, and the damage variable D decreased by the time fracture occurred and the maximum reduction rate was up to 62.5%.

The inhibiting effect of alpha-based TARE on embolized vessels and neovascularization.

Transarterial embolization (TAE) is a personalized technology that offers precise delivery of chemotherapeutic drugs or selective internal radiation therapy for hepatocellular carcinoma (HCC). Beta-emitting radionuclide embolisms for TAE (ß-based TARE) are commonly used in the clinic via inducing biochemical lethality on tumor cells, while alpha-emitting radionuclides-based embolisms for TAE (α-based TARE) are still under study. The feeding artery plays a key role in tumor growth, metastasis, and recurrence. In this research, the auricular central arteries (ACAs) of rabbits were embolized with silk fibroin-based microspheres (SFMs) or SFMs integrated with α (Ra-223) or ß (I-131) radionuclides to investigate the influence on vessels. TARE-induced tissue necrosis and the following neovascularization were measured by pathological analysis and 68Ga-DOTA-RGD PET/CT. The results showed that, compared to I-131, Ra-223 enhanced the growth inhibition of human hepatoma cells Huh-7 and induced more DNA double-strand breaks in vascular smooth muscle cells. Unlike ß-based TARE, which mainly led to extensive necrosis of surrounding tissues, α-based TARE induced irreversible necrosis of a limited area adjacent to the embolized vessels. RGD PET revealed the inhibition on neovascularization in α-based TARE (SUVmax = 0.053 ± 0.004) when compared with normal group (SUVmax = 0.099 ± 0.036), the SFMs-lipiodol group (SUVmax = 0.240 ± 0.040), and ß-based TARE (SUVmax = 0.141 ± 0.026), owing to the avoidance of the embolism-induced neovascularization. In conclusion, α-based TARE provided a promising strategy for HCC treatments via destroying the embolized vessels and inhibiting neovascularization.