Is dynamic occlusal design necessary for anterior guidance recovery in the computer-aided design process? An in vitro study.

OBJECTIVES: This study aimed to assess the effectiveness of patient-specific motion in restoring anterior guidance and to investigate the influence of occlusal plane position within a virtual articulator on the design of the anterior guide slope for incisors. METHODS: Twenty participants' intraoral scan, occlusal plane position, and jaw motion data were recorded. The maxillary anterior teeth were virtually prepared, and the crowns were designed based on average virtual articulator (AVR), personalized virtual articulator (ART), and patient-specific motion (PSM). The anterior guide slope of maxillary central incisors (S1, S2, Sc, Sp) and the mesio-distal angle (MDA) of the canine of prostheses were compared to that of natural teeth (NAT). One-Way ANOVA was utilized to evaluate the effectiveness of the three methods in restoring the anterior guidance of maxillary anterior teeth. RESULTS: The comparison of Sp and MDA showed no significant difference between the PSM and NAT groups (p > 0.05). However, Sp of the ART group was significantly smaller, while MDA was higher than that of the NAT group (p < 0.05). Sp did not differ significantly (p > 0.05) when the angle of the occlusal plane (AOP) was small. As the AOP increased, Sp of the ART and AVR groups were significantly smaller than that of the NAT group (p < 0.05). With a large AOP, Sp of the ART group was notably smaller than that of the NAT group (p < 0.05), while there was no significant difference between the AVR and NAT groups (p > 0.05). CONCLUSIONS: Occlusal design based on patient-specific motion proved more effective in restoring natural anterior guidance. The anterior guidance of prostheses designed using a virtual articulator was influenced by occlusal plane position. CLINICAL SIGNIFICANCE: The utilization of a jaw motion tracer facilitated the transfer of personalized occlusal plane positions and recorded jaw motion, which can be integrated into the digital prosthetic workflow for virtual occlusion adjustment. Occlusal design based on patient-specific motion more effectively restored lingual guidance of maxillary anterior crowns.

Fully digital workflow for the fabrication of occlusal stabilization splints based on individual mandibular movement.

OBJECTIVE: This study was conducted to present a completely digital workflow for the fabrication of occlusal stabilization splints using CAD/CAM systems and a digital face bow based on optical sensor technology. METHODS: Digital scans of the maxillary and mandibular arches of 20 volunteers were obtained using an intraoral scanner. Jaw relation and mandibular movements were recorded with a digital face bow via optical sensors. The virtual increase of the vertical dimension of occlusion (VDO) was then performed, after which computer-aided design (CAD) of the occlusal stabilization splints was carried out. The corresponding splints were then manufactured using digitally controlled technology. RESULTS: A completely digital workflow for the manufacturing of occlusal stabilization splints was found to be clinically feasible. The corresponding data analysis revealed high congruence between virtual and physical occlusal contacts on the occlusal splint. Moreover, the appropriate guidance of the anterior teeth area was easily obtainable, and the time for adjusting the occlusion was less. CONCLUSIONS: This study demonstrated that the fabrication of occlusal stabilization splints using a fully digital workflow is feasible. Compared to traditional impression-based manufacturing, several advantages of digital manufacturing include easy accessibility, time-efficient manufacturing, high-level accuracy in splint quality, and potential to manufacture duplicate splints. CLINICAL SIGNIFICANCE: The proposed fully digital approach may help young dentists fabricating stable occlusal splints with beneficial curative effects. Meanwhile, it could also improve the production efficiency of stable occlusal splints, saving time for both doctors and patients while reducing labor costs.

Correlation Between Clinical Characteristics and Radionuclide Salivagram Findings in Infants With Congenital Laryngeal Developmental Anomalies.

OBJECTIVE: To evaluate the correlation between clinical characteristics and radionuclide salivagram findings in infants with congenital laryngeal developmental anomalies, and determine the clinical characteristics that could predict the positive results of radionuclide salivagram. METHODS: 151 hospitalized infants with congenital laryngeal developmental anomalies were retrospectively included to assess the correlation between positive radionuclide salivagram results and clinical features, and a multivariate logistic regression model was constructed to identify significant correlates that jointly predict positive radionuclide salivagram results. RESULTS: Positive radionuclide salivagram results were significantly associated with fever, neurological diseases, congenital syndromes, and positive pathogenetic test results in univariate analysis. Positive radionuclide salivagram were significantly associated with fever (odds ratio [OR] = 3.494; 95% confidence interval [CI] 1.414-8.630; P = 0.007), neurological diseases (OR = 3.296; 95% CI 1.335-8.138; P = 0.010), and congenital syndromes (OR = 5.069, 95% CI 1.696-15.154; P = 0.004) in a multivariable logistic regression analysis. CONCLUSION: Fever, concurrent neurological diseases, and concurrent congenital syndromes were discovered as clinical factors that could predict positive radionuclide salivagram results and salivary aspiration should be highly suspected in infants with these clinical factors of congenital laryngeal developmental anomalies.

A fully digital workflow to register maxillomandibular relation using a jaw motion tracer for fixed prosthetic rehabilitation: A technical report.

OBJECTIVE: This technique aimed to describe a fully digital workflow to register maxillomandibular relation for fixed prosthetic rehabilitation. CLINICAL CONSIDERATIONS: Mandibular kinematics could be reproduced in a four-dimensional (4D) virtual patient based on the intraoral scan, facial scan, cone beam computed tomography, and jaw motion trajectory, which helped record centric relation and determine a proper occlusal vertical dimension in a virtual environment. The therapeutic position could be exported directly to the dental computer-aided design software for digital waxing design with a facial scan. The 4D virtual patient was also used to verify the functional and esthetic outcomes of provisional restorations. CONCLUSIONS: This novel approach digitized the process of determination, delivery, and double-check of maxillomandibular relation, thus contributing to the establishment of a completely digital workflow for fixed prosthetic rehabilitation. CLINICAL SIGNIFICANCE: Registration of maxillomandibular relation, including centric relation and occlusal vertical dimension is critical to the success of prosthetic rehabilitation. Traditional procedures are complex and time-consuming, and heavily rely on the clinical experience of dentists. A fully digital approach to creating a 4D virtual patient and registering the maxillomandibular relation is established, which guides to determine a proper occlusal vertical dimension in centric relation. Digital delivery and double-check can simplify the conventional procedure and ensure that the determined maxillomandibular relation is reliable.

Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.

Objective : Our study aims to summarize and analyze the clinical characteristics of transient infantile hypertriglyceridemia (HTGTI) and variants in the glycerol-3-phosphate dehydrogenase 1 (GPD1) gene and the effect of HTGTI on the protein structure of GPD1. Methods: Retrospective analysis, using the general data, symptoms, signs, and auxiliary examinations, was performed on patients with HTGTI, which were confirmed by genetic testing in our hospital and reported cases online. The clinical data were analyzed using statistical and bioinformatic approaches. Results: A total of 31 genetically confirmed HTGTI patients were collected from our hospital and cases reported in the literature. The clinical manifestations showed the median age of onset was 6.0 (1.9, 12.0) months. All the patients had normal psychiatric status, but 22.6% of them presented growth retardation and short stature, 93.5% had hepatomegaly, and 16.1% had splenomegaly. Just a few children were reported with jaundice, cholestasis, and obesity (3.2-6.5%). The laboratory investigations showed that 96.8% of them had hypertriglyceridemia (HTG) with a median level of 3.1 (2.1, 5.5) mmol/L, but only 30.0% had returned to normal during follow-up. In addition, 93.5% of patients had elevated alanine aminotransferase (ALT) with an average level of 92.1 ± 43.5 U/L, while 38.7% had hypercholesterolemia. Upon abdominal imaging, all patients presented fatty liver and liver steatosis, with 66.7% of patients showing hepatic fibrosis. Statistical differences in triglyceride (TG) level were observed in the ≤6 months group compared with the older groups and in the 13 months to 6 years group with >6 years group (H = 22.02, P < 0.05). The restricted cubic spline model showed that severe HTG decreased in the early stage of infants to the normal level; however, it rebounded again to a mild or moderate level after the following days. The genetic test revealed that the main variant types of the GPD1 gene were missense variants (51.6%), followed by splicing variants (35.5%) and nonsense variants (12.9%). Of patients, 87.1% had homozygous variants, with the most frequent loci being c.361-1G > C and c.895G > A. Conclusion: The common manifestations of HTGTI were HTG, hepatomegaly, elevated liver transaminases, and hepatic steatosis in early infancy. However, the recurrence of aberrant HTG may pose long-term detrimental effects on HTGTI patients.

A Meta-Analysis on Vitamin D Supplementation and Asthma Treatment.

Background: Vitamin D, as an immunomodulator, may be related to the therapeutic effect of asthma patients, but the research in this area is still controversial. The aim of this meta-analysis was to analyze the role of vitamin D supplementation in the treatment of asthma patients. Materials and Methods: Randomized Controlled Trials (RCTs) of vitamin D supplementation in asthma were searched in PubMed, EMBASE, and the Cochrane library. Primary outcomes were forced expiratory volume in one second (FEV1), asthma exacerbations, Asthma Control Test scores (ACT scores), and fractional exhaled nitric oxide (FENO). Results: A total of 10 RCTs were included, including 1,349 patients. Vitamin D supplementation didn't affect the ACT scores (SMD = 0.04, 95% CI = -0.13 to 0.21, P = 0.87), FEV1 (SMD = 0.04, 95% CI = -0.35 to 0.43, P < 0.01) and FENO (SMD = -0.01, 95% CI = -0.22 to 0.20, P = 0.27), but reduced the rate of asthma exacerbations (RR = 0.69, 95% CI = 0.41 to 0.88, P < 0.01), especially in subgroups of children (RR = 0.46, 95% CI = 0.30 to 0.70, P = 0.83) and follow up time less than 6 months (RR = 0.45, 95% CI = 0.32 to 0.63, P = 0.95). Additionally, though there was only one study included in the subgroup, it significantly enhanced FEV1 at the last visit for patients whose FEV1 baseline value was less than 70% (SMD = 0.94, 95% CI = 0.47 to 1.41). Conclusion: Vitamin D supplementation can reduce asthma exacerbations, especially in children, and within 6 months of follow up time. In addition, vitamin D has a positive effect on improving FEV1 of patients whose FEV1 baseline value is less than 70%, but more RCTs are still needed to support this conclusion. Systematic Review Registration: [https://inplasy.com], identifier [10.37766/inplasy20 22.6.0049].

Mycoplasma pneumoniae among Chinese Outpatient Children with Mild Respiratory Tract Infections during the Coronavirus Disease 2019 Pandemic.

Mycoplasma pneumoniae is a common pathogen causing respiratory disease in children. We sought to investigate the epidemiology of M. pneumoniae among outpatient children with mild respiratory tract infections (RTIs) during the coronavirus disease 2019 (COVID-19) pandemic. Eligible patients were prospectively enrolled from January 2020 to June 2021. Throat swabs were tested for M. pneumoniae RNA. M. pneumoniae IgM was tested by a colloidal gold assay. Macrolide resistance and the effect of the COVID-19 countermeasures on M. pneumoniae prevalence were assessed. Symptom scores, treatments, and outcomes were evaluated. Eight hundred sixty-two eligible children at 15 centers in China were enrolled. M. pneumoniae was detected in 78 (9.0%) patients. Seasonally, M. pneumoniae peaked in the first spring and dropped dramatically to extremely low levels over time until the next summer. Decreases in COVID-19 prevalence were significantly associated with decreases in M. pneumoniae prevalence (r = 0.76, P = 0.001). The macrolide resistance rate was 7.7%. The overall sensitivity and specificity of the colloidal gold assay used in determining M. pneumoniae infection were 32.1% and 77.9%, respectively. No more benefits for improving the severity of symptoms and outcomes were observed in M. pneumoniae-infected patients treated with a macrolide than in those not treated with a macrolide during follow-up. The prevalences of M. pneumoniae and macrolide resistance in outpatient children with mild RTIs were at low levels in the early stage of the COVID-19 pandemic but may have rebounded recently. The colloidal gold assay for M. pneumoniae IgM may be not appropriate for diagnosis of M. pneumoniae infection. Macrolides should be used with caution among outpatients with mild RTIs. IMPORTANCE This is the first and largest prospective, multicenter, active, population-based surveillance study of the epidemiology of Mycoplasma pneumoniae among outpatient children with mild respiratory tract infections (RTIs) during the COVID-19 pandemic. Nationwide measures like strict face mask wearing and restrictions on population movement implemented to prevent the spread of COVID-19 might also effectively prevent the spread of M. pneumoniae. The prevalence of M. pneumoniae and the proportion of drug-resistant M. pneumoniae isolates in outpatient children with mild RTIs were at low levels in the early stage of the COVID-19 pandemic but may have rebounded recently. The colloidal gold assay for M. pneumoniae IgM may be not appropriate for screening and diagnosis of M. pneumoniae infection. Macrolides should be used with caution among outpatients with mild RTIs.

Mechanochemical destruction and mineralization of solid-phase hexabromocyclododecane assisted by microscale zero-valent aluminum.

Hexabromocyclododecane (HBCD) has been listed in Annex A of the Stockholm Convention as a persistent and bio-accumulative chemical. While HBCD is often present in the solid form for its low solubility, cost-effective technologies have been lacking for the degradation of solid-phase HBCD. In this work, mechanochemical (MC) destruction of high-energy ball milling was employed for direct destruction of solid-phase HBCD, where a strong reducer, microscale zero-valent aluminum (mZVAl), was used as the co-milling agent. The new mZVAl-assisted MC process achieved complete debromination and mineralization of HBCD within 3 h milling. The optimal operating parameters were determined, including the milling atmosphere, the milling speed, the mZVAl-to-HBCD molar ratio, and the ball-to-mZVAl mass ratio. Fourier transform infrared spectrometry and Raman analyses revealed that the organic structures of HBCD were destroyed and organic bromine was completely converted into inorganic bromide, accompanied by the generation of amorphous and graphite carbon. Analysis of the milled samples by GC-MS demonstrated the absence of obvious organic matter after MC treatment, also indicating the complete degradation and conversion of HBCD to inorganic compounds. Further X-ray photoelectron spectroscopic analysis indicates that the fresh surface of mZVAl was generated upon the MC treatment, and Al(0) served as a strong reducing agent (e-donor) for reductive debromination and destruction of the carbon skeleton. The mZVAl-assisted MC milling appears promising as a non-combustion approach for effective destruction and carbonization/mineralization of solid-phase HBCD or potentially other persistent organic pollutants.

CCCTC-binding factor transcriptionally regulates Galectin-7 and activates the JNK/STAT3 axis to aggravate bronchial epithelial cell injury.

OBJECTIVE: Studies have shown that the expression of CCCTC-binding factor (CTCF) is significantly upregulated in the airway epithelial cells of asthmatic patients, suggesting that CTCF may play an important role in the progression of asthma. MATERIAL/METHODS: Human bronchial epithelial cells BEAS-2B were stimulated with transforming growth factor-ß1 (TGF-ß1) at a concentration of 10 ng/ml, and CTCF overexpression plasmid and CTCF small interfering RNA were transfected into the cells. The proliferation, apoptosis, inflammatory factor secretion, and airway remodeling marker protein expression of injured cells were detected. We bidirectionally regulated Galectin-7 expression in TGF-ß1-induced BEAS-2B cells and overexpress CTCF, while interfering with Galectin-7 to further explore the regulatory effect of CTCF on Galectin-7. We introduced SP600125, a c-Jun N-terminal kinase c-Jun (JNK) pathway inhibitor, to investigate whether CTCF affects asthma progression through the JNK pathway. RESULTS: The expression of CTCF in BEAS-2B cells induced by TGF-ß1 was significantly upregulated, interfering with CTCF expression promoted cell proliferation, inhibited apoptosis, reduced inflammatory factors secretion, and decreased the expression of airway remodeling marker protein. Luciferase reporter gene analysis and chromatin immunoprecipitation verified that CTCF directly bound to Galectin-7 promoter. The effect of Galectin-7 on cells is consistent with the effect of CTCF on cells. The regulatory effect of CTCF on injured cells was indeed mediated by activation of the JNK/STAT3 axis. CONCLUSIONS: CTCF transcriptionally regulated Galectin-7 and activated JNK/STAT3 axis to aggravate bronchial epithelial cell injury.

Application of visualization technology of multimode data fusion in occlusal rehabilitation.

OBJECTIVES: This study aimed to present a method for multi-modal medical data fusion that could be used for increased vertical dimension of occlusion (VDO) and occlusal rehabilitation in a digital manner, thus facilitating the process of clinical diagnosis and restoration. METHODS: With the aid of a computer software, a visual and operable four-dimensional virtual dental patient was created by data fusion of intraoral scan, extra-oral face scan, cone-beam computed tomography, and dynamic occlusal movement trace to conduct a systematical review of the occlusion and temporomandibular joint of the virtual patient. This approach could be used for increased VDO on the basis of the aesthetics of anterior teeth and the restoration space of posterior teeth. It allowed jaw reconstruction and occlusal rehabilitation with fixed prosthesis by using computer-aided design and manufacturing (CAD/CAM) devices. RESULTS: A visual and operable four-dimensional virtual dental patient was created by integrating the method for multimodal medical data fusion with CAD/CAM devices, thus making the process of occlusal rehabilitation with fixed prosthesis safer and more convenient than before. CONCLUSIONS: With the method for multimodal medical data fusion, the presented application enables the fusion of different data sources of the patient at the same time and space by creating a virtual patient. It is useful for showing the function and anatomical structure of the patient's oral and maxillofacial system in a visual and convenient manner, thus providing a powerful tool in the process of clinical diagnosis and restoration.

Clinical characteristics and effectiveness of antiviral agents in hospitalized children with infectious mononucleosis in China: A multicenter retrospective study.

IMPORTANCE: The clinical characteristics of infectious mononucleosis (IM) in Chinese children have not been evaluated in multicenter studies, and the effectiveness of antiviral treatment are controversial. OBJECTIVE: To investigate the clinical characteristics of Chinese children with IM and current status of antiviral therapy for affected patients. METHODS: Hospitalized patients with IM were enrolled between 2018 and 2020 in five children's hospitals in China. The clinical characteristics were compared among four age groups: <3 years, 3-<6 years, 6-<10 years, and ≥10 years. The clinical characteristics of IM and effectiveness of antiviral therapy were compared among patients receiving acyclovir (ACV), ganciclovir (GCV), and no antiviral therapy (i.e., non-antiviral group). RESULTS: In total, 499 patients were analyzed; most patients were 3-<6 years of age. The most common symptoms and signs included fever (100%), lymphadenopathy (98.6%), pharyngitis (86.4%), eyelid edema (76.8%), and snoring (72.9%). There were significant differences in rash, hepatomegaly, and liver dysfunction among the four age groups. Patients aged < 3 years had a lower incidence of liver dysfunction and a higher incidence of rash. Among the 499 patients, 50.1% were treated with GCV, 26.3% were treated with ACV, and 23.6% received no antiviral therapy. Compared with the non-antiviral group, patients in the ACV and GCV groups had longer durations of fever (P < 0.001). There were no significant differences in the incidences of complications among the three treatment groups. INTERPRETATION: The incidence of IM in Chinese children peaked at 3-<6 years of age. Clinical features of IM varied according to age. Patients receiving antiviral therapy exhibited more serious clinical manifestations than did patients without antiviral therapy. The effectiveness of antiviral therapy for IM requires further analysis.

Transient infantile hypertriglyceridemia with jaundice: A case report.

RATIONALE: Transient infantile hypertriglyceridemia (HTGTI) is a rare autosomal recessive inherited disease caused by inactivating mutations in the glycerol-3-phosphate dehydrogenase 1 gene. To date, only a few patients have been reported worldwide. The symptoms of the affected individuals present a certain degree of transient hypertriglyceridemia, hepatomegaly, elevated liver enzymes, persistent fatty liver and hepatic fibrosis in early infancy. However, the clinical characteristics and pathogenesis of this disease are remain unclear. PATIENT CONCERNS: A one month and twenty-five days old girl was admitted to hospital because of persisted jaundice and hepatomegaly for fifty days. DIAGNOSE: The girl was diagnosed with HTGTI coincident with a noval mutation in glycerol-3-phosphate dehydrogenase 1. INTERVENTION: She was advised to take low-fat diet and supplement of medium-chain fatty acids. OUTCOMES: Her jaundice was gradually normal at the age of 4 months without any treatment, and hypertriglyceridemia were normal at the age of 13 months, but still had elevated transaminases and hepatic steatosis. LESSONS: Jaundice may be a novel phenotype in HTGTI. The report contributes to the expansion of HTGTI's gene mutation spectrum and its clinical manifestations.

Degradation of hexabromocyclododecane (HBCD) by nanoscale zero-valent aluminum (nZVAl).

Hexabromocyclododecane (HBCD) has been listed in Annex A of the Stockholm Convention on Persistent Organic Pollutants (POPs) in 2013, but till now there is a lack of efficient methods for its degradation. In this study, nanoscale zero-valent aluminum (nZVAl), an excellent reductant with a very low redox potential of E0(Al3+/Al0) = -1.662 V and strong electron transfer ability, was used to reductively degrade HBCD. Nearly 100% HBCD was degraded within 8 h reaction at 25 °C in ethanol/water (v/v, 50/50) solution without pH adjustment. And about 67% cyclododecatriene (CDT) was obtained, which is the complete debromination product. What's more, the yield of Br- could achieve nearly 100% after optimizing conditions. The reaction was strongly promoted by increasing the dosages of nZVAl or decreasing the initial concentration of HBCD. The temperature had the most significant influence and the degradation was completed in 40 min with elevating the reaction temperature to 45 °C. The reaction mechanism was further revealed through the characterization of nZVAl particles before and after the reaction by SEM-EDS, TEM, HRTEM, XRD, and XPS. It was found that, after corrosion of the oxide film on the surface of nZVAl, metallic aluminum inside was exposed. The reactive sites were provided and electrons released were transferred from nZVAl to HBCD, causing HBCD degraded to dibromocyclododecadiene (DBCD) and then CDT by reductive debromination. These findings imply that nZVAl can degrade HBCD efficiently with no extra energy input and this offers a new idea for better treatment of HBCD.

Silencing of Gal-7 inhibits TGF-ß1-induced apoptosis of human airway epithelial cells through JNK signaling pathway.

Apoptosis of epithelial cells is regarded as the initial pathological process of many lung diseases, including asthma. Previous studies have identified that galectin-7 (Gal-7), a regulator of apoptosis, was overexpressed in bronchial epithelial cells in asthma. However, the effect and mechanism of Gal-7 in the progression of asthma is still unclear. In this study, we investigated the expression and role of Gal-7 in the apoptosis of bronchial epithelial cells BEAS-2B upon TGF-ß1 stimulation. TGF-ß1 significantly induced apoptosis of BEAS-2B cells, as determined by flow cytometry. Western blot results revealed that the mRNA and protein expression of Gal-7 were obviously increased after TGF-ß1 stimulation. Small interfering RNA (siRNA)-mediated knockdown of Gal-7 abrogated TGF-ß1-evoked cell apoptosis. Simultaneously, increased Bcl-2 expression, decreased Bax expression and the cleavage of poly ADP-ribose polymerase (PARP) and caspase-3 activity were also monitored in TGF-ß1-treated cells after Gal-7 siRNA transfection. Gal-7 silence also inhibited TGF-ß1-induced c-Jun N-terminal kinase (JNK) phosphorylation in BEAS-2B cells. Furthermore, anisomycin, a specific activator for JNK, reversed the effect of Gal-7 siRNA on cell apoptosis induced by TGF-ß1. These results demonstrate that Gal-7 silence attenuates TGF-ß1-induced apoptosis in bronchial epithelial cells through the inactivation of JNK pathway. Therefore, Gal-7 may act as a potential target for asthma treatment.

PPARγ Agonist PGZ Attenuates OVA-Induced Airway Inflammation and Airway Remodeling via RGS4 Signaling in Mouse Model.

Peroxisome proliferator-activated receptor-γ (PPARγ) agonist pioglitazone (PGZ) exhibits potential protective effects in asthma. Recently, regulator of G protein 4 (RGS4) has been reported to be associated with immunological and inflammatory responses. However, no evidence has shown the influence of PPARγ on RGS4 expression in airway disorders. In this study, BALB/c mice received ovalbumin (OVA) sensitization followed by OVA intranasal challenge for 90 days to establish a chronic asthma mouse model. Accompanied with OVA challenge, the mice received administration of PPARγ agonist PGZ (10 mg/kg) intragastrically or RGS4 inhibitor CCG 63802 (0.5 mg/kg) intratracheally. Invasive pulmonary function tests were performed 24 h after last challenge. Serum, bronchoalveolar lavage fluid (BALF), and lung tissues were collected for further analyses after the mice were sacrificed. We found that PPARγ agonist PGZ administration significantly attenuated the pathophysiological features of OVA-induced asthma and increased the expression of RGS4. In addition, the attenuating effect of PGZ on airway inflammation, hyperresponsiveness (AHR), and remodeling was partially abrogated by administration of RGS4 inhibitor CCG 63802. We also found that the downregulation of RGS4 by CCG 63802 also significantly increased inflammatory cell accumulation and AHR, and increased levels of IL-4, IL-13, eotaxin, IFN-γ, and IL-17A in BALF, and total and OV-specific IgE in serum. Furthermore, the inhibitory effects of PGZ on the activations of ERK and Akt/mTOR signaling, and MMPs were apparently reversed by CCG 63802 administration. In conclusion, the protective effect of PGZ on OVA-induced airway inflammation and remodeling might be partly regulated by RGS4 expression through ERK and Akt/mTOR signaling.

Effect of midkine on gemcitabine resistance in biliary tract cancer.

Gemcitabine­based chemotherapy is one of the most effective and commonly used chemotherapeutic regimens for biliary tract cancer (BTC). However, development of resistance to this drug limits its efficacy. The present study aimed to explore the effects of midkine (MDK) on the resistance of BTC cells to gemcitabine. Cell viability and proliferation were measured by a Cell Counting Kit­8 assay and 5­ethynyl­2'­deoxyuridine staining, respectively. Western blot analysis was used to detect the expression of E­cadherin and vimentin. The results indicated that BTC cell lines were more resistant to gemcitabine plus MDK compared with gemcitabine alone. In terms of the underlying mechanism, MDK promoted the epithelial to mesenchymal transition (EMT) of BTC cells and the enhancing effect of MDK on gemcitabine resistance was abrogated when the EMT was blocked with small interfering (si)RNA targeting Twist. In addition, MDK promoted the expression of Notch­1, while knockdown of Notch­1 by siRNA blocked the EMT process in the BTC cell lines. Taken together, these results indicated that MDK promoted gemcitabine resistance of BTC through inducing EMT via upregulating Notch­1. It was suggested that inhibition of the EMT is a promising strategy to overcome MDK­induced drug resistance.

Preparation and comparison of tacrolimus-loaded solid dispersion and self-microemulsifying drug delivery system by in vitro/in vivo evaluation.

This study aimed to compare the dissolution and the intestinal absorption of tacrolimus in self-microemulsifying drug delivery system (SMEDDS) and solid dispersion (SD). Poloxamer 188 SD was prepared by the combination of the solvent evaporation method and the freeze drying method. Hydroxypropyl methylcellulose (HPMC) SD was prepared by the solvent evaporation method combined with the vacuum drying method. The formation of SD was confirmed by SEM images which showed new solid phases. The SMEDDS was composed of oil (Labrafil M1944 CS 28%), surfactant (Cremophor EL 48%) and co-surfactant (Transcutol P 24%). The self microemulsion formed by the SMEDDS upon aqueous media had spherical droplets with a hydrodynamic size of 46.0±3.2nm. The dissolution of tacrolimus from SD and SMEDDS was performed in sink and non-sink conditions with various pH. As revealed by the DSC and FT-IR, the tacrolimus was molecularly or amorphously dispersed in the SMEDDS and SD. The in vivo intestinal absorption study in rats showed that both SMEDDS and SD improved the absorption of tacrolimus over the raw tacrolimus while the SMEDDS exhibited lower absorption rate constant (Ka) and apparent permeability coefficients (Papp) than the SD. The self-prepared SD with poloxamer 188 or HPMC had comparable intestinal absorption as compared with Prograf®. The tacrolimus-loaded SMEDDS and SD would be further compared by in vivo pharmacokinetic study.

Gene signatures associated with drug resistance to irinotecan and oxaliplatin predict a poor prognosis in patients with colorectal cancer.

The identification of novel survival predictors may help to improve the appropriate management of colorectal cancer (CRC). In the present study, two gene sets associated with irinotecan or oxaliplatin resistance in CRC cell lines were first identified and subsequently applied to the clinical CRC microarray dataset GSE14333. Subsequently, a 60-gene irinotecan resistance-associated signature and a 13-gene oxaliplatin resistance-associated signature were established, which were able to classify CRC patients into high- and low-risk subgroups with varied clinical outcomes [irinotecan-resistance gene signature: hazard ratio (HR)=0.4607, 95% confidence interval (CI)=0.3369-0.6300, P<0.0001; oxaliplatin-resistance gene signature: HR=0.6119, 95% CI=0.4547-0.8233, P=0.0008]. The performance of these two gene expression signatures in predicting outcome risk were also validated in two other independent CRC gene expression microarray datasets, GSE17536 (irinotecan-resistance gene signature: HR=0.5318, 95% CI=0.3359-0.8419, P=0.0079; oxaliplatin-resistance gene signature: HR=0.5383, 95% CI=0.3400-0.8521, P=0.0114) and GSE17537 (irinotecan-resistance gene signature: HR=0.2827, 95% CI=0.1173-0.6813, P=0.0088; oxaliplatin-resistance gene signature: HR=0.2378, 95% CI=0.09773-0.5784, P=0.0023). Furthermore, the combination of these two gene classifiers demonstrated a superior performance in CRC prognosis prediction than either used individually. Therefore, this study proposed novel gene classifier models for CRC prognosis prediction, which may be potentially useful to inform treatment decisions for patients with CRC in clinical settings.

TIPE2 Inhibits the Expression of Asthma-Related Inflammatory Factors in Hyperstretched Bronchial Epithelial Cells Through the Wnt/ß-Catenin Pathway.

Childhood asthma, an airway inflammatory disease, is a serious threat to the child's quality of life. Recently, TIPE2 expression was reported to be decreased in children with asthma. Therefore, additional studies focusing on TIPE2 might provide an approach for treating childhood asthma. In this study, we found that TIPE2 was poorly expressed in hyperstretched human bronchial epithelial cells (BEAS-2B). TIPE2 overexpression also significantly suppressed the stretch-induced secretion of asthma-related inflammatory factors (TNF-α, TSLP, MMP-9, and VEGF). In contrast, TIPE2 inhibition significantly promoted the secretion of TNF-α, TSLP, MMP-9, and VEGF. Furthermore, overexpression of TIPE2 remarkably inhibited the activation of Wnt/ß-catenin in hyperstretched BEAS-2B cells, while siTIPE2 activated Wnt/ß-catenin in hyperstretched BEAS-2B cells. Further analysis showed that the Wnt/ß-catenin signal inhibitor Dkk-1 could further enhance the TIPE2-induced suppression of Wnt/ß-catenin signaling, which also suppressed the siTIPE2-induced secretion of TNF-α, TSLP, MMP-9, and VEGF in hyperstretched BEAS-2B cells. Dkk-1 reversed the effects of siRNA-TIPE2 on Wnt/ß-catenin signaling and inflammatory cytokines. In summary, we have exhibited that TIPE2 inhibited the expression of asthma-related inflammatory factors in hyperstretched BEAS-2B cells by suppressing the Wnt/ß-catenin signaling pathway. TIPE2 may be involved in airway inflammation during asthma attack, and it may be used as a potential therapeutic target for bronchial epithelial inflammation in childhood asthma.

Blocking hepatic metastases of colon cancer cells using an shRNA against Rac1 delivered by activatable cell-penetrating peptide.

Hepatic metastasis is one of the critical progressions of colon cancer. Blocking this process is key to prolonging survival time in cancer patients. Studies on activatable cell-penetrating peptides (dtACPPs) have demonstrated their potential as gene carriers. It showed high tumor cell-targeting specificity and transfection efficiency and low cytotoxicity in the in vitro settings of drug delivery. However, using this system to silence target genes to inhibit metastasis in colorectal cancer cells has not been widely reported and requires further investigation. In this study, we observed that expression of Rac1, a key molecule for cytoskeletal reorganization, was higher in hepatic metastatic tumor tissue compared with prime colon cancer tissue and that patients with high Rac1-expressing colon cancer showed shorter survival time. Base on these findings, we created dtACPP-PEG-DGL (dtACPPD)/shRac1 nanoparticles and demonstrated that they downregulated Rac1 expression in colon cancer cells. Moreover, we observed inhibitory effects on migration, invasion and adhesion in HCT116 colorectal cancer cells in vitro, and our results showed that Rac1 regulated colon cancer cell matrix adhesion through the regulation of cytofilament dynamics. Moreover, mechanically, repression of Rac1 inhibiting cells migration and invasion by enhancing cell to cell adhesion and reducing cell to extracellular matrix adhesion. Furthermore, when atCDPPD/shRac1 nanoparticles were administered intravenously to a HCT116 xenograft model, significant tumor metastasis to the liver was inhibited. Our results suggest that atCDPP/shRac1 nanoparticles may enable the blockade of hepatic metastasis in colon cancer.