Comparison of different genetic testing modalities applied in paediatric patients with steroid-resistant nephrotic syndrome.

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) are monogenic in some cases, however, there are still no clear guidelines on genetic testing in the clinical practice of SRNS in children. METHODS: Three hundred thirty-two children were diagnosed with SRNS, and all children underwent genetic testing, including gene panels and/or whole-exome/genome sequencing (WES/WGS), during treatment. We analysed the relationship between clinical manifestation and genotype, and compared different genetic testing methods' detection rates and prices. RESULTS: In this study, 30.12% (100/332) of children diagnosed with SRNS had monogenic causes of the disease. With 33.7% (122/332) of children achieving complete remission, 88.5% (108/122) received steroids combined with tacrolimus (TAC). In detectability, WES increased by 8.69% (4/46) on gene panel testing, while WGS increased by 4.27% (5/117) on WES, and WES was approximately 1/7 of the price of WGS for every further 1% increase in pathogenicity. CONCLUSIONS: We verified that steroids combined with TAC were the most effective option in paediatric SRNS. In detection efficiency, we found that WGS was the highest, followed by WES. The panel was the lowest, but the most cost-effective method when considering the economic-benefit ratio, and thus it should be recommended first in SRNS.

Manufacture of titanium alloy materials with bioactive sandblasted surfaces and evaluation of osseointegration properties.

Titanium alloys are some of the most important orthopedic implant materials currently available. However, their lack of bioactivity and osteoinductivity limits their osseointegration properties, resulting in suboptimal osseointegration between titanium alloy materials and bone interfaces. In this study, we used a novel sandblasting surface modification process to manufacture titanium alloy materials with bioactive sandblasted surfaces and systematically characterized their surface morphology and physicochemical properties. We also analyzed and evaluated the osseointegration between titanium alloy materials with bioactive sandblasted surfaces and bone interfaces by in vitro experiments with co-culture of osteoblasts and in vivo experiments with a rabbit model. In our in vitro experiments, the proliferation, differentiation, and mineralization of the osteoblasts on the surfaces of the materials with bioactive sandblasted surfaces were better than those in the control group. In addition, our in vivo experiments showed that the titanium alloy materials with bioactive sandblasted surfaces were able to promote the growth of trabecular bone on their surfaces compared to controls. These results indicate that the novel titanium alloy material with bioactive sandblasted surface has satisfactory bioactivity and osteoinductivity and exhibit good osseointegration properties, resulting in improved osseointegration between the material and bone interface. This work lays a foundation for subsequent clinical application research into titanium alloy materials with bioactive sandblasted surfaces.

Roles of irregularity of pore morphology in osteogenesis of Voronoi scaffolds: From the perspectives of MSC adhesion and mechano-regulated osteoblast differentiation.

Bone scaffolds designed based on the Voronoi-tessellation algorithm have been increasingly studied owing to their structural similarity with natural cancellous bone. The irregularity of pore morphology (IPM) influences the osteogenesis efficiency of Voronoi scaffolds since it may alter the static and hydromechanical microenvironments for the initial adhesion and mechano-regulated osteoblast differentiation (MrOD) of mesenchymal stem cells (MSCs). In this work, animal experiments were conducted to explore the relationship between IPM and osteogenesis efficiency in Voronoi scaffolds. A computational fluid dynamics (CFD) analysis based on discrete phase models was performed to predict the efficiency of MSC adhesion in different IPMs. Another combined finite element and CFD analysis based on the mechano-regulation algorithm was performed to predict the influence of IPM on the MrOD of the adhesive MSCs. The results showed that the osteogenesis efficiency of the Voronoi scaffolds increased as the IPM rose from low to moderate and then dropped as the IPM further rose. Same trends were also found in the MSC adhesion and MrOD, which caused by the changes of strain tensors on the strut surface and the tortuosity and fluid velocity of the fluid pathway. Moderate IPM induced the highest osteogenesis efficiency owing to its highest efficiencies of MSC adhesion and MrOD. This work identified the optimal IPM for the osteogenesis of Voronoi scaffolds and clarified its biomechanical mechanisms from the adhesion and mechano-regulated differentiation of MSCs, which is of great importance for guiding Voronoi scaffold design when it is used for bone defect repair.

Analysis of surgical strategies and efficacy in the treatment of Os odontoideum with atlantoaxial dislocation.

BACKGROUND: There are many classification systems for atlantoaxial dislocation (AAD). Among these systems, the definitions of irreducible AAD remain vague, and its treatments are not unified. OBJECTIVE: To explore the surgical strategies and efficacy for the treatment of os odontoideum (OO) with AAD. METHODS: The clinical data of 56 OO patients with AAD who underwent surgery from January 2017 to June 2021 were retrospectively analyzed. AAD was classified into four types, Type I and type II were treated with posterior fixation and fusion. Type III received posterior fixation and fusion after irreducible dislocations were converted to reducible dislocations by translateral mass release or transoral release. Type IV required transoral release for conversion into reducible dislocations before posterior fixation and fusion. The operation time, blood loss, and complications were recorded. The preoperative and postoperative neurological function changes were assessed using the Japanese Orthopedic Association (JOA) score. Postoperative fusion status was assessed by X-ray. RESULTS: There were 40 cases of type I-II, 14 cases of type III, and two cases of type IV AAD. The operation times of single posterior fixation and fusion, combined translateral mass release and combined transoral release were 130.52 ± 37.12 min, 151.11 ± 16.91 min and 188.57 ± 44.13 min, the blood loss were 162.63 ± 58.27 mL, 235.56 ± 59.94 mL, 414.29 ± 33.91 mL, respectively. One patient with type III died, one with type III underwent revision surgery due to infection, and three patients with type I had further neurological deterioration after operation. fifty-five patients were followed up for 12-24 months. The follow-up results showed that enough decompression was achieved and that fixation and fusion were effective. The JOA score increased from 9.58 ± 1.84 points preoperative to 13.09 ± 2.68 points at 3 months after operation, 14.07 ± 2.83 points at 6 months and 14.25 ± 2.34 at 12 months after operation, all significant differences compared with preoperative results (P < 0.05). CONCLUSION: OO patients with irreducible AAD can be treated by translateral mass release or transoral release combined with posterior fixation and fusion, while some of those with bony fusion can be treated by transoral release combined with posterior fixation and fusion.

Spinal dural arteriovenous fistula: A rare but treatable disease that should not be missed by orthopedic surgeons.

Objective: Spinal dural arteriovenous fistula (SDAVF) is a rare disease that is often misdiagnosed by orthopedic surgeons. We analyzed the reasons for the misdiagnosis and proposed countermeasures. Methods: Twenty-two SDAVF patients who were initially treated in orthopedics were included. The patients were divided into a correct diagnosis group (A) and a misdiagnosis group (B). The clinical data and prognosis were evaluated. Results: There were 10 patients in group A and 12 patients in group B. The clinical manifestations included limb numbness, weakness, and bladder and bowel dysfunction. Among these patients without spinal degenerative diseases which had typical magnetic resonance imaging (MRI) features in Group A were more than Group B (P < 0.05). More patients had spinal degenerative diseases in group B. In group A, seven patients were primarily diagnosed with a SDAVF after multidisciplinary teamwork (MDT). In group B, five patients were misdiagnosed with lumbar spinal stenosis, four with lumbar disc herniation, two with thoracic spinal stenosis, and one with cervical spinal stenosis and lumbar spinal stenosis and underwent cervical spinal canal and lumbar spinal canal decompression. The length of time for confirming the diagnosis was 7 months longer in group B than in group A. All patients underwent microsurgery treatment. The average follow-up duration was 11 months. The modified Aminoff-Logue Disability Scale scores showed a statistically significant difference in improvement between the two groups (P < 0.05). Conclusion: when patients with dysuria especially, have intermittent spinal nerve dysfunction, the possibility of SDAVF should be considered. Awareness of the specific clinical and spinal cord edema and flow voids on MRI of a SDAVF needs to be promoted for orthopedic surgeons. Timely MDT is an important measure for reducing misdiagnosis, and steroids or inappropriate surgery should be avoided until a SDAVF is completely excluded.

Whole-exome sequencing of a multicenter cohort identifies genetic changes associated with clinical phenotypes in pediatric nephrotic syndrome.

Understanding the association between the genetic and clinical phenotypes in children with nephrotic syndrome (NS) of different etiologies is critical for early clinical guidance. We employed whole-exome sequencing (WES) to detect monogenic causes of NS in a multicenter cohort of 637 patients. In this study, a genetic cause was identified in 30.0% of the idiopathic steroid-resistant nephrotic syndrome (SRNS) patients. Other than congenital nephrotic syndrome (CNS), there were no significant differences in the incidence of monogenic diseases based on the age at manifestation. Causative mutations were detected in 39.5% of patients with focal segmental glomerulosclerosis (FSGS) and 9.2% of those with minimal change disease (MCD). In terms of the patterns in patients with different types of steroid resistance, a single gene mutation was identified in 34.8% of patients with primary resistance, 2.9% with secondary resistance, and 71.4% of children with multidrug resistance. Among the various intensified immunosuppressive therapies, tacrolimus (TAC) showed the highest response rate, with 49.7% of idiopathic SRNS patients achieving complete remission. Idiopathic SRNS patients with monogenic disease showed a similar multidrug resistance pattern, and only 31.4% of patients with monogenic disease achieved a partial remission on TAC. During an average 4.1-year follow-up, 21.4% of idiopathic SRNS patients with monogenic disease progressed to end-stage renal disease (ESRD). Collectively, this study provides evidence that genetic testing is necessary for presumed steroid-resistant and idiopathic SRNS patients, especially those with primary and/or multidrug resistance.

The application of biomaterials in osteogenesis: A bibliometric and visualized analysis.

Osteogenesis serves an important role in bone tissue repairing. Novel biomaterials are widely prevalent as materials for orthopedic implants due to their biocompatibility and osteogenetic ability. The purpose of this study was to comprehensively analyze hotspots and future trend of biomaterials research in osteogenesis based on bibliometric and visualized analysis. A total of 1,523 papers about biomaterials research in osteogenesis between 2000 and 2021 were included in this study. During the above 20 years, China's leading position in the global biomaterials research in osteogenesis was obvious, and it was also the country that most frequently participates in international cooperation. Chinese Academy of Sciences was the most productive institution and the leader of research cooperation. Acta Biomaterialia and Biomaterials have published the largest number of articles in the field of biomaterials research in osteogenesis. Meanwhile, Acta Biomaterialia and Biomaterials were also the two journals with the highest total citation frequency. Wu CT, Chang J, Kaplan DL, and Xiao Y all made important contributions in the field of biomaterials research in osteogenesis. At present, there are five research hotspots in the field of biomaterials research in osteogenesis: 1) the immunomodulatory role of biomaterial-related inflammatory; 2) mechanisms of osteogenesis in biomaterials; 3) 3D printing and clinical application of biomaterials; 4) bone tissue engineering for biomaterial osteogenesis; and 5) regenerative medicine for biomaterial osteogenesis. The results of this study showed that mechanisms of osteogenesis in biomaterials, bone tissue engineering for biomaterial osteogenesis, and regenerative medicine for biomaterial osteogenesis will remain research hotspots in the future. International cooperation was also expected to expand and deepen the field of biomaterials research in osteogenesis.

Predictive Nomogram for Clinical Prognosis in Cervical Spondylotic Myelopathy With Intramedullary T2-Weighted Increased Signal Intensity: A Novel Digital Tool for Patient Prognosis Education.

Aims: To establish a predictive nomogram for clinical prognosis in cervical spondylotic myelopathy (CSM) with intramedullary T2-weighted increased signal intensity (ISI). Methods: The clinical data of 680 patients with CSM with intramedullary T2-weighted ISI were retrospectively analyzed. The patients were divided into the modeling group (476) and the validation group (204) by using a random number table at a ratio of 7:3. The independent prognostic factors were screened using multivariate logistic regression analysis. The factors were subsequently incorporated into the establishment of the predictive nomogram. The area under the receiver operating characteristic (ROC) curve (AUC) was undertaken to estimate the discrimination of the predictive nomogram. The calibration curve and the Hosmer-Lemeshow test were used to assess the calibration of the predictive nomogram. The clinical usefulness of the predictive nomogram was evaluated by decision curve analysis (DCA). Results: Based on the pre-operative Japanese Orthopedic Association (JOA) score, maximal canal compromise (MCC), and maximal spinal cord compression (MSCC), we established a predictive nomogram. The AUCs in the modeling group and validation group were 0.892 (95% CI: 0.861~0.924) and 0.885 (95% CI: 0.835~0.936), respectively, suggesting good discrimination of the nomogram. Calibration curves showed a favorable consistency between the predicted probability and the actual probability. In addition, the values of P of the Hosmer-Lemeshow were 0.253 and 0.184, respectively, suggesting good calibration of the nomogram. DCA demonstrated that the nomogram had good clinical usefulness. Conclusion: We established and validated a predictive nomogram for the clinical prognosis in CSM with intramedullary T2-weighted ISI. This predictive nomogram could help clinicians and patients identify high-risk patients and educate them about prognosis, thereby improving the prognosis of high-risk patients.

Association between HLA alleles and sub-phenotype of childhood steroid-sensitive nephrotic syndrome.

BACKGROUND: Few studies have addressed the effects of human leukocyte antigen (HLA) alleles on different clinical sub-phenotypes in childhood steroid-sensitive nephrotic syndrome (SSNS), including SSNS without recurrence (SSNSWR) and steroid-dependent nephrotic syndrome/frequently relapse nephrotic syndrome (SDNS/FRNS). In this study, we investigated the relationship between HLA system and children with SSNSWR and SDNS/FRNS and clarified the value of HLA allele detection for precise typing of childhood SSNS. METHODS: A total of 241 Chinese Han individuals with SSNS were genotyped using GenCap-WES Capture Kit, and four-digit resolution HLA alleles were imputed from available Genome Wide Association data. The distribution and carrying frequency of HLA alleles in SSNSWR and SDNS/FRNS were investigated. Additionally, logistic regression and mediating effects were used to examine the relationship between risk factors for disease process and HLA system. RESULTS: Compared with SSNSWR, significantly decreased serum levels of complement 3 (C3) and complement 4 (C4) at onset were detected in SDNS/FRNS (C3, P < 0.001; C4, P = 0.018). The average time to remission after sufficient initial steroid treatment in SDNS/FRNS was significantly longer than that in SSNSWR (P = 0.0001). Low level of C4 was further identified as an independent risk factor for SDNS/FRNS (P = 0.008, odds ratio = 0.174, 95% confidence interval 0.048-0.630). The HLA-A*11:01 allele was independently associated with SSNSWR and SDNS/FRNS (P = 0.0012 and P = 0.0006, respectively). No significant HLA alleles were detected between SSNSWR and SDNS/FRNS. In addition, a mediating effect among HLA-I alleles (HLA-B*15:11, HLA-B*44:03 and HLA-C*07:06), C4 level and SDNS/FRNS was identified. CONCLUSIONS: HLA-I alleles provide novel genetic markers for SSNSWR and SDNS/FRNS. HLA-I antigens may be involved in steroid dependent or frequent relapse in children with SSNS as mediators of immunoregulation.

Relationship between the elastic modulus of the cage material and the biomechanical properties of transforaminal lumbar interbody fusion: A logarithmic regression analysis based on parametric finite element simulations.

BACKGROUND AND OBJECTIVE: Conventional method for evaluating the biomechanical effects of a specific elastic modulus of cage (cage-E) on spinal fusions requires establishing a "one-on-one" biomechanical model, which seems laborious and inefficient when dealing with the emergence of numerous cage materials with various cage-Es. We aim to offer a much convenient method to instantly predicting the biomechanical effects of any targeted cage-E on transforaminal lumbar interbody fusion (TLIF) by using a parametric finite element (FE) analysis to determining the regression relationship between cage-E and biomechanical properties of TLIF. MATERIALS AND METHODS: A L4/5 FE TLIF construct was modeled. Cage-E was linearly increased from 0.1 GPa (cancellous bone) to 110 GPa (titanium alloy). The function equations for assessing the influence of cage-E on the biomechanical indexes of TLIF were established using a logarithmic regression analysis. EXPERIMENTAL RESULTS: As cage-E increased from 0.1 GPa to 110 GPa, all the biomechanical indexes initially increased or decayed rapidly, and then slowed over time. Logarithmic regression models and functional equations were successfully established between cage-E and these indexes (P<0.0001). Their determination coefficients ranged from 0.72 to 0.99. The range of motions decreased from 0.37-1.10° to 0.20-1.07°. The mean stresses of the central and peripheral grafts reduced from 0.10-0.41 and 0.25-0.42 MPa to 0.03-0.04 and 0.19-0.27 MPa, respectively. In addition, the maximum stresses of the screw-bone interface and posterior instrumentation reduced from 11.76-25.04 and 8.91-84.68 MPa to 9.71-18.92 and 6.99-70.59 MPa, respectively. Finally, the maximum stresses of the cage and endplate increased from 0.28-1.35 MPa and 3.90-8.63 MPa to 14.86-36.16 MPa and 11.01-36.55 MPa, respectively. CONCLUSIONS: The decrease of cage-E reduces the risks of cage subsidence, cage breakage, and pseudarthrosis, while increasing the risk of instrumentation failure. The logarithmic regression models optimally demonstrate the relationship between cage-E and biomechanical properties of TLIF. The functional equations based on these models can be adopted to predict the biomechanical effects of any targeted cage-Es on TLIF, which effectively simplifies the procedures for the biomechanical assessments of cage materials.

An Oxidative Stress-Related Gene Pair (CCNB1/PKD1), Competitive Endogenous RNAs, and Immune-Infiltration Patterns Potentially Regulate Intervertebral Disc Degeneration Development.

Oxidative stress (OS) irreversibly affects the pathogenesis of intervertebral disc degeneration (IDD). Certain non-coding RNAs act as competitive endogenous RNAs (ceRNAs) that regulate IDD progression. Analyzing the signatures of oxidative stress-related gene (OSRG) pairs and regulatory ceRNA mechanisms and immune-infiltration patterns associated with IDD may enable researchers to distinguish IDD and reveal the underlying mechanisms. In this study, OSRGs were downloaded and identified using the Gene Expression Omnibus database. Functional-enrichment analysis revealed the involvement of oxidative stress-related pathways and processes, and a ceRNA network was generated. Differentially expressed oxidative stress-related genes (De-OSRGs) were used to construct De-OSRG pairs, which were screened, and candidate De-OSRG pairs were identified. Immune cell-related gene pairs were selected via immune-infiltration analysis. A potential long non-coding RNA-microRNA-mRNA axis was determined, and clinical values were assessed. Eighteen De-OSRGs were identified that were primarily related to intricate signal-transduction pathways, apoptosis-related biological processes, and multiple kinase-related molecular functions. A ceRNA network consisting of 653 long non-coding RNA-microRNA links and 42 mRNA-miRNA links was constructed. Three candidate De-OSRG pairs were screened out from 13 De-OSRG pairs. The abundances of resting memory CD4+ T cells, resting dendritic cells, and CD8+ T cells differed between the control and IDD groups. CD8+ T cell infiltration correlated negatively with cyclin B1 (CCNB1) expression and positively with protein kinase D1 (PKD1) expression. CCNB1-PKD1 was the only pair that was differentially expressed in IDD, was correlated with CD8+ T cells, and displayed better predictive accuracy compared to individual genes. The PKD1-miR-20b-5p-AP000797 and CCNB1-miR-212-3p-AC079834 axes may regulate IDD. Our findings indicate that the OSRG pair CCNB1-PKD1, which regulates oxidative stress during IDD development, is a robust signature for identifying IDD. This OSRG pair and increased infiltration of CD8+ T cells, which play important roles in IDD, were functionally associated. Thus, the OSRG pair CCNB1-PKD1 is promising target for treating IDD.

Evaluation of Energy Absorption Capabilities of Polyethylene Foam under Impact Deformation.

Foams are widely used in protective applications requiring high energy absorption under impact, and evaluating impact properties of foams is vital. Therefore, a novel test method based on a shock tube was developed to investigate the impact properties of closed-cell polyethylene (PE) foams at strain rates over 6000 s-1, and the test theory is presented. Based on the test method, the failure progress and final failure modes of PE foams are discussed. Moreover, energy absorption capabilities of PE foams were assessed under both quasi-static and high strain rate loading conditions. The results showed that the foam exhibited a nonuniform deformation along the specimen length under high strain rates. The energy absorption rate of PE foam increased with the increasing of strain rates. The specimen energy absorption varied linearly in the early stage and then increased rapidly, corresponding to a uniform compression process. However, in the shock wave deformation process, the energy absorption capacity of the foam maintained a good stability and exhibited the best energy absorption state when the speed was higher than 26 m/s. This stable energy absorption state disappeared until the speed was lower than 1.3 m/s. The loading speed exhibited an obvious influence on energy density.

[Expression of Semaphorin 3A after spinal cord injury].

OBJECTIVE: To investigate expression of Semaphorin 3A in rats after spinal cord injury and explore possible mechanism of inhibiting of axonal regeneration after SCI. METHODS: Forty healthy female SD rats, 8 weeks old, weighing (210.00±9.88) g, were randomly divided into control group(20 rats in group A) and model group(20 rats in group B). In control group, removal of T10 lamina and partial removal of T9 and T11 lamina were performed, and no further operation was performed on spinal cord (pseudo operation). In model group, the total T10 and partial T9, T11 partial lamina were incised and the spinal cord transection was performed to create animal models of spinal cord injury. The rats were perfused and spinal cord tissue obtained at 3, 7, 14, 28 and 42 days after surgery (4 rats in each group at each time point), respectively, and then HE staining was performed. Meanwhile, the expression of Semaphoring 3A was detected in accordance with the protocol of SP kit. RESULTS: After a simple spinal cord transection injury, hemorrhagic necrosis, localized edema, neurodegeneration, necrosis, and cyst formation occurred in the injured area, and glial scar formation occurred in glial cells. Semaphorin 3A expression levels in control group was low in the gray matter area. There was no expression of Semaphorin 3A in the injured area of spinal cord injury in model group 3 days after operation. On the 14th day, the expression of Semaphorin 3A in the injured area of spinal cord injury increased significantly and was at a high level. On the 28th day, the expression of Semaphorin 3A was moderate. On the 42th day, the positive expression of Semaphorin 3A returned to normal level. CONCLUSION: The increased expression of Semaphorin 3A after spinal cord injury may be one of the mechanisms that inhibit axonal regeneration.

Prognosis of C4 dislocation with spinal cord injury following psychological intervention.

OBJECTIVE: To investigate the effect of psychological intervention on the prognosis of patients with C4 dislocation and spinal cord injury. METHODS: We investigated target patients admitted between 2010 and 2018. Patients' mental state, quality of life and neurological function at different time points were evaluated to examine the relationship between psychological intervention and recovery and prognosis of acute and critical spinal cord injury. RESULTS: All patients showed improvements in clinical symptoms, neurological function and quality of life. Psychological intervention significantly improved Zung Self-Rating Anxiety Scale score, Zung Self-Rating Depression Scale score and SF-36 Mental Component Summary score within 3 months. Japanese Orthopaedic Association neurological function score and SF-36 Physical Component Summary score were significantly improved after 1-year follow-up. Psychological intervention did not improve 2-year survival. CONCLUSION: Timely and professional psychological intervention can eliminate the psychological disorders of C4 dislocation patients with spinal cord injury. This has a positive effect on their quality of life and prognosis.

Association between potential primary care emergency service and general practitioner care utilisation in New South Wales.

OBJECTIVE: To examine patterns of potential primary care (PPC) ED presentations and any association between PPC ED presentations and frequency of general practitioner (GP) care utilisation in New South Wales, Australia. METHODS: Retrospective cross-sectional study of 6 221 762 New South Wales patients who had at least one service in public hospitals, EDs or Medical Benefit Schedule claimable for GP service between 2013/2014 and 2014/2015 is conducted to examine association between PPC ED presentations and GP care utilisation using logistic regression adjusting for comorbidity index and a number of other covariates. Data over 2010/2011 to 2014/2015 are included for analyses of trends and patterns in PPC ED and GP care utilisation. RESULTS: Forty-one percent of the ED presentations were PPC ED presentations over the 5 years 2010/2011 to 2014/2015. Population rates of PPC ED presentations and GP care both increased over the period, with higher PPC ED presentation rates in regional areas, and higher GP care rates in major cities. GP care utilisation was associated with reduced odds for PPC ED presentations, with the adjusted odds ratios ranging from 0.28 for patients with one GP care service to 0.48 for patients with five or more GP care services compared with patients with none. Increased comorbidity index was also associated with increased risk of PPC ED presentations. CONCLUSION: GP care utilisation was associated with reduced risk for any PPC ED presentations after adjusting for comorbidity index and the other factors.

Circ-ABCB10 Contributes to Paclitaxel Resistance in Breast Cancer Through Let-7a-5p/DUSP7 Axis.

BACKGROUND: Paclitaxel (PTX) is one of the widely used chemotherapy drugs in breast cancer (BC) treatment. Unfortunately, the survival rate of metastatic BC patients remains poor due to PTX resistance. Therefore, uncovering the underlying mechanism behind the PTX resistance of BC cells is crucial for BC therapy. METHODS: The enrichment of circular RNA ATP binding cassette subfamily B member 10 (circ-ABCB10), let-7a-5p and dual specificity phosphatase 7 (DUSP7) was measured by quantitative real time polymerase chain reaction (qRT-PCR) in PTX-resistant and PTX-sensitive BC tissues and cells. Chemoresistance, apoptosis, invasion and autophagy of BC cells were measured by 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, transwell invasion assay and Western blot assay, respectively. The binding sites between let-7a-5p and circ-ABCB10 or DUSP7 were predicted by Starbase bioinformatic software, and the combination was confirmed by dual-luciferase reporter assay. The protein expression of DUSP7 was examined by Western blot assay. Murine xenograft model was established to confirm the role of circ-ABCB10 in vivo. RESULTS: Circ-ABCB10 depletion promoted the PTX sensitivity and apoptosis while suppressed the invasion and autophagy of PTX-resistant BC cells. Circ-ABCB10 could bind to let-7a-5p in BC cells, and circ-ABCB10 contributed to PTX resistance of BC cells via let-7a-5p. DUSP7 is a direct target of let-7a-5p in BC cells, and the accumulation of DUSP7 reversed the promoting effects of let-7a-5p overexpression on the PTX sensitivity and apoptosis and the inhibitory impact on the invasion and autophagy of PTX-resistant BC cells. Circ-ABCB10 interference suppressed the growth of BC tumors in vivo. CONCLUSION: Circ-ABCB10 mediated PTX resistance, apoptosis, invasion and autophagy of BC cells via let-7a-5p/DUSP7 axis.

Oral delivery of imatinib through galactosylated polymeric nanoparticles to explore the contribution of a saccharide ligand to absorption.

Imatinib (IMT) is a selective tyrosine kinase inhibitor clinically used for treating chronic myeloid leukemia and malignant gastrointestinal stromal tumors. However, oral administration of IMT is challenged by its high oral dose, low intestinal solubility and adverse reactions. This work aimed to investigate the effect of galactose ligand on polymeric nanoparticles-facilitated oral absorption of IMT. N-oleoyl-D-galactosamine was synthesized for fabricating biomimetic galactose-modified nanoparticles (GNPs) in an attempt to improve the oral bioavailability of IMT. IMT-loaded GNPs (IMT-GNPs) were prepared using a solvent diffusion technique and characterized by particle size, morphology, and entrapment efficiency (EE). The in vitro release and in vivo oral bioavailability of IMT-GNPs were comparatively studied with bulk IMT and IMT-loaded nanoparticles (IMT-NPs), respectively. The resultant IMT-GNPs were 122.0 nm around in particle size with a polydispersity index (PDI) of 0.201. IMT-GNPs possessed a high EE (93.06%) and exhibited a sustained effect on drug release. After oral administration, IMT-GNPs significantly enhanced the oral bioavailability of IMT, up to 152.3% relative to IMT suspensions, whereas IMT-NPs merely resulted in an increase to 115.2%. Cellular uptake and ex vivo intestinal transport imaging demonstrated that GNPs were armed with higher cellular affinity and intestinal epithelial permeability compared with galactose-free IMT-NPs. These results provide solid evidence that galactose modification has great potential to ulteriorly promote the oral absorption of IMT on the base of nanoparticles, which may be conducive to achieve the synergy and attenuation of IMT.

Intratympanic injection of dexamethasone after failure of intravenous prednisolone in simultaneous bilateral sudden sensorineural hearing loss.

PURPOSE: This study aimed to analyze outcomes of intratympanic injection of dexamethasone after failure of intravenous prednisolone in simultaneous bilateral sudden sensorineural hearing loss (SSNHL). MATERIALS AND METHODS: The cases of simultaneous bilateral SSNHL treated in our hospital from March 2007 to March 2018 were retrospectively analyzed. During the earlier period (March 2007 to February 2012), the cases were treated by intravenous prednisolone only, and classified into group A. During the late period (February 2012 to March 2018), intratympanic injection of dexamethasone after failure of intravenous prednisolone therapy was employed to treat simultaneous bilateral SSNHL, and these patients were enrolled in group B. Effective rates of the two treatment modalities in groups A and B were compared. RESULTS: In group A, 3 of 40 ears obtained complete recovery, and 4 ears achieved partial recovery after intravenous prednisolone treatment, with the effective rate of only 17.5% (7/40 ears). In contrast, 6 of 44 ears in group B achieved complete recovery, and 10 ears got partial recovery, with the effective rate of 36.4% (16/44 ears). There was significant difference in the effective rate between the two groups. CONCLUSION: Intratympanic injection of dexamethasone after failure of intravenous prednisolone therapy was a better choice for simultaneous bilateral SSNHL compared to traditional intravenous prednisolone therapy.

Effects of Titanium Mesh Cage End Structures on the Compressive Load at the Endplate Interface: A Cadaveric Biomechanical Study.

BACKGROUND This study aimed to evaluate whether obliquely angled and ring-shaped titanium mesh cage (TMC) end structures can improve the compressive load on the endplate interface in anterior cervical corpectomy and fusion (ACCF). MATERIAL AND METHODS A total of 23 volunteers underwent cervical lateral x-ray. The oblique angle of the superior endplate was measured, which was used to construct the gradient of the TMC end. Forty-two fresh cadaveric vertebral bodies were harvested and randomly distributed among four TMC groups with different ends. The baseline indicators of bone mineral density and anteroposterior and transverse dimensions were recorded. The superior endplate was placed at an angle of 12° when performing uniaxial compression testing. The maximum loads of the four TMCs were assessed. RESULTS There were no significant differences among the groups regarding the baseline indicators. The conventional TMC had the lowest maximum load (1362.3±221.78 N, p<0.05), whereas the TMC with an obliquely end ring had the highest maximum load (2095.82±285.64 N, p<0.05). The maximum loads of the TMCs with oblique footprints and flat end ring were much higher than that of the conventional TMC (p<0.05) but significantly lower than that of the TMC with the obliquely end ring (p<0.05), with average values of 1806.91±246.98 N and 1725.3±213.33 N, respectively. CONCLUSIONS Both the ring shape and oblique angle of the TMC end contributed to an increase in compressive force and are advocated for use in TMC structure optimization to decrease the incidence of TMC subsidence in ACCF.

Single-Level Anterior Cervical Corpectomy and Fusion Using a New 3D-Printed Anatomy-Adaptive Titanium Mesh Cage for Treatment of Cervical Spondylotic Myelopathy and Ossification of the Posterior Longitudinal Ligament: A Retrospective Case Series Study.

BACKGROUND The aim of this study was to evaluate the clinical and radiological outcomes of the use of a new 3D-printed anatomy-adaptive titanium mesh cage (AA-TMC) for single-level anterior cervical corpectomy and fusion (ACCF) in patients with cervical spondylotic myelopathy (CSM) and ossification of the posterior longitudinal ligament (OPLL). MATERIAL AND METHODS We retrospectively reviewed the records of 15 consecutive patients who underwent ACCF surgeries with AA-TMC implantation. The Japanese Orthopedic Association (JOA) scoring system, a visual analogue scale (VAS), the mean intervertebral height (MIBH) of the surgical segments, and the surgical segmental angle (SSA) were recorded preoperatively, immediately after surgery and at the final follow-up visit. The outcomes of these parameters at different time points were compared. RESULTS Six months after ACCF surgery, solid bony fusions of the surgical level were achieved in all patients. The mean MIBH was 21.05±1.99 mm preoperatively, 27.51±1.44 mm immediately after surgery (P<0.05), and 26.85±1.25 mm at the last follow-up visit (P<0.05). At the last follow-up visit, none of the AA-TMCs exhibited severe subsidence (>3 mm). The mean SSA was 6.66±7.08° preoperatively, 14.03±2.3° immediately after surgery (P<0.05), and 15.09±2.1° at the final follow-up visit (P>0.05). The mean VAS and JOA scores were 6.6±1.26 and 10.47±2.07, respectively, preoperatively and 2.47±1.3 and 13.6±1.96 immediately after surgery, respectively (P<0.05). At the last follow-up visit, the mean VAS and JOA were further restored to 1.67±1.18 and 14.9±1.39, respectively (P<0.05). CONCLUSIONS The application of the AA-TMC in single-level ACCF significantly relieved symptoms of CSM and OPLL. The rational design of the AA-TMC restores the surgical segmental curvature, maintains the intervertebral height, and prevents postoperative subsidence-related complications.