Synergistic lethality between auranofin-induced oxidative DNA damage and ATR inhibition in cancer cells.

AIMS: Studies in the past have shown that inhibition of the ataxia telangiectasia and Rad3-related (ATR) kinase sensitizes cancer cells to genotoxic anticancer treatments, however, clinical use of ATR inhibitors in combination with DNA damaging chemotherapy is limited due to toxicity in healthy tissues. In this study, we investigated the synergistic anticancer effect between ATR inhibition and oxidative DNA damage induced by the thioredoxin reductase inhibitor auranofin. MAIN METHODS: Cytotoxicity was evaluated by cell viability assays. Western blot, comet assay, immunostaining and flow cytometry were performed to dissect the underlying mechanisms. In vivo efficacy was examined against tumor xenografts. KEY FINDINGS: Nontoxic doses of auranofin alone increased the levels of reactive oxygen species (ROS) in cancer but not noncancerous cells, resulting in oxidative DNA damage and activation of the ATR DNA damage response pathway selectively in cancer cells. Inhibition of ATR in auranofin-treated cancer cells resulted in unscheduled firing of dormant DNA replication origins, abrogation of the S phase cell cycle checkpoint and extensive DNA breakage, leading to replication catastrophe and potent synergistic lethality. Both the antioxidant NAC and the DNA polymerase inhibitor aphidicolin reduced replication stress and synergistic cytotoxicity, implicating replication stress-driven catastrophic cell death resulted from collision between oxidative DNA damage and dysregulated DNA replication. In vivo, auranofin and VE822 coadministration enabled marked regressions of tumor xenografts, while each drug alone had no effect. SIGNIFICANCE: As increased generation of ROS is a universal feature of tumors, our findings may open new routes to broaden the therapeutic potential of ATR inhibitors.

Convolutional neural network-based automatic cervical vertebral maturation classification method.

OBJECTIVES: This study aimed to develop a fully automated artificial intelligence-aided cervical vertebral maturation (CVM) classification method based on convolutional neural networks (CNNs) to provide an auxiliary diagnosis for orthodontists. METHODS: This study consisted of cephalometric images from patients aged between 5 and 18 years. After grouping them into six cervical stages (CSs) by orthodontists, a data set was constructed for analyzing CVM using CNNs. The data set was divided into training, validation, and test sets in the ratio of 70, 15, and 15%. Four CNN models namely, VGG16, GoogLeNet, DenseNet161, and ResNet152 were selected as the candidate models. After training and validation, the models were evaluated to determine which of them is most suitable for CVM analysis. Heat maps were analyzed for a deeper understanding of what the CNNs had learned. RESULTS: The final classification accuracy ranking was ResNet152>DenseNet161>GoogLeNet>VGG16, as evaluated on the test set. ResNet152 proved to be the best model among the four models for CVM classification with a weighted κ of 0.826, an average AUC of 0.933 and total accuracy of 67.06%. The F1 score rank for each subgroup was: CS6>CS1>CS4>CS5>CS3>CS2. The area of the third (C3) and fourth (C4) cervical vertebrae were activated when CNNs were assessing the images. CONCLUSION: CNN models proved to be a convenient, fast and reliable method for CVM analysis. CNN models have the potential to provide automatic auxiliary diagnostic tools in the future.

Biomimetic Biphasic Electrospun Scaffold for Anterior Cruciate Ligament Tissue Engineering.

BACKGROUND: Replacing damaged anterior cruciate ligaments (ACLs) with tissue-engineered artificial ligaments is challenging because ligament scaffolds must have a multiregional structure that can guide stem cell differentiation. Here, we designed a biphasic scaffold and evaluated its effect on human marrow mesenchymal stem cells (MSCs) under dynamic culture conditions as well as rat ACL reconstruction model in vivo. METHODS: We designed a novel dual-phase electrospinning strategy wherein the scaffolds comprised randomly arranged phases at the two ends and an aligned phase in the middle. The morphological, mechanical properties and scaffold degradation were investigated. MSCs proliferation, adhesion, morphology and fibroblast markers were evaluated under dynamic culturing. This scaffold were tested if they could induce ligament formation using a rodent model in vivo. RESULTS: Compared with other materials, poly(D,L-lactide-co-glycolide)/poly(ε-caprolactone) (PLGA/PCL) with mass ratio of 1:5 showed appropriate mechanical properties and biodegradability that matched ACLs. After 28 days of dynamic culturing, MSCs were fusiform oriented in the aligned phase and randomly arranged in a paving-stone-like morphology in the random phase. The increased expression of fibroblastic markers demonstrated that only the alignment of nanofibers worked with mechanical stimulation to promote effective fibroblast differentiation. This scaffold was a dense collagenous structure, and there was minimal difference in collagen direction in the orientation phase. CONCLUSION: Dual-phase electrospun scaffolds had mechanical properties and degradability similar to those of ACLs. They promoted differences in the morphology of MSCs and induced fibroblast differentiation under dynamic culture conditions. Animal experiments showed that ligamentous tissue regenerated well and supported joint stability.

A preliminary study on polycaprolactone and gelatin-based bilayered tubular scaffolds with hierarchical pore size constructed from nano and microfibers for vascular tissue engineering.

Due to the insufficient endothelialization and the poor colonization of smooth muscle cells (SMCs), small-diameter vascular tissue engineering is still challenging. An ideal vascular graft is expected to effectively support the formation of endothelial monolayer and the colonization of SMCs. In this study, we proposed a bilayered scaffold with hierarchical pore size constructed from nano and microfibers by electrospinning PCL-PEG-PCL (PCE) and a blend of PCE and gelatin (PCEG) sequentially. The structural features of nano and microfibers were tuned by the concentration of PCE and the proportion of PCE/gelatin in electrospun solution respectively. The results demonstrated the best nanofiber morphology and relatively high mechanical properties were achieved in 18% PCE (w/v) (PCE18) and PCE and gelatin with a weight ratio of 7:3 (P7G3) at a concentration of 18% (w/v) electrospun membranes. The in vitro co-culturing studies of cells and membranes indicated all the PCE membranes supported the proliferation and spreading of endothelial cells and the further endothelialization of the membranous surface, while PCEG membranes facilitated the migration inward of SMCs. Taking the porosity and mechanical properties into consideration, PCE18 and P7G3 were chosen to construct the inner and outer layers of the bilayered scaffold with hierarchical pore size respectively. The circumferential ring test demonstrated that the bilayered scaffold has good mechanical property both in dry and wet state. After cells were co-cultured with this bilayered scaffold for 7 days, the results manifested a continuous endothelial monolayer has formed on the luminal surface and the SMCs have started to colonized from outer layers, indicating the vast potential of this bilayered scaffold in vascular remodeling and regeneration.

Therapeutic Effect of Resection, Prosthetic Replacement and Open Reduction and Internal Fixation for the Treatment of Mason Type III Radial Head Fracture.

Aim of the Study: Mason type III radial head fractures are a source of concern due to the severe injury and poor recovery. At present, radial head resection, open reduction and internal fixation (ORIF), and prosthetic replacement are three common treatment methods for these fractures. The clinical efficacy and postoperative complications are controversial, which makes it difficult for physicians to determine the most appropriate regimen. Herein, this present prospective, non-randomized, parallel-controlled study was conducted to compare the therapeutic effects and identify the most effective treatment method for Mason type III radial head fracture. Materials and Methods: We assessed patients with Mason type III radial head fracture treated with resection, prosthetic replacement, and ORIF to compare preoperative and postoperative pain condition, elbow joint function, curative effect, and complication rate. A visual analog scale was used to score pain. The elbow joint function was observed using the Broberg-Morrey elbow joint score. Results: No significant differences were found in patient demographics among the resection, prosthetic replacement, and ORIF groups. The prosthetic replacement and ORIF procedures were more complex and had higher technical requirements. Prosthetic replacement and ORIF enabled higher elbow joint scores and lower pain scores than resection. Excellent and good ratings were highest and complication rates were lowest in the prosthetic replacement group, followed by the ORIF group. Conclusion: Our results showed that prosthetic replacement is more effective than ORIF and radial head resection in relieving pain, functional recovery and reducing complications in the treatment of Mason type III radial head fractures.

Biomimetic dual-oriented/bilayered electrospun scaffold for vascular tissue engineering.

Natural blood vessels have a multi-layered, cell-specific oriented spatial structure, mimicking of this structure is a promising way for blood vessel regeneration. In this study, a newly developed dual-oriented/bilayered small-diameter tubular scaffold was electrospun using a mixture of poly (ε-caprolactone) (PCL), poly (D, L-lactide-co-glycolide) (PLGA) and gelatin. The nanofiber orientations of the bilayers were spatially perpendicular to each other, aiming at guiding cell-specific orientation of smooth muscle cells (SMCs) and endothelial cells (ECs) in vitro respectively. The results showed that the hydrophilicity of scaffold was greatly improved by gelatin, and the mechanical property of this scaffold was the best among all. The in vitro degradation demonstrated that by mixing of three biodegradable polymers, a relatively fast degradation rate was achieved. After SMCs and ECs were seeded on scaffolds, cell viability, cellular morphology, and cytoskeleton behavior were investigated. The results revealed that as-electrospun scaffolds could promote both SMCs and ECs proliferation. Moreover, topographic cues offered by oriented nanofibers could guide the growth and orientation of SMCs and ECs. Therefore, the dual-oriented/bilayered electrospun scaffold is a superior structural and functional analogue to natural blood vessel and a potential candidate for vascular tissue engineering.

The effect of anticoagulants on venous thrombosis prevention after knee arthroscopy: a systematic review.

PURPOSE: Knee arthroscopy, with its unique advantages, has become a routine surgery and is widely carried out around the world. Venous thromboembolism (VTE) after knee arthroscopy is a potentially serious complication. This article analyzes the effects of anticoagulant therapy after knee arthroscopy. METHODS: We used key words or entry terms without any limitations to search the PubMed, Embase, and Cochrane Library databases. Randomized controlled trials (RCTs) of drug prophylaxis for VTE after knee arthroscopy until November 2017 were included in our review. RESULTS: This systematic review identified nine RCTs, consisting of 4290 patients, investigating drug prophylaxis in knee arthroscopy. There are three main drugs for preventing thrombosis after arthroscopic knee surgery: low-molecular-weight heparin (LMWH), rivaroxaban, and aspirin. Our study concluded that there is no difference in symptomatic VTE (excluding symptomatic distal DVT) risk during anticoagulant prophylaxis (RR, 0.98; 95% CI, 0.44-2.19; I2 value = 0%; P = 0.97). Moreover, there was a lower incidence of symptomatic distal DVT (RR, 0.16; 95% CI, 0.06-0.45; I2 value = 0%; P = 0.0005) in the anticoagulant group than in the control group. CONCLUSIONS: In our study, anticoagulant therapy after knee arthroscopy was ineffective. We recommend that anticoagulants not be provided routinely after knee arthroscopy.

Efficacy and safety of low-molecular-weight heparin after knee arthroscopy: A meta-analysis.

BACKGROUND: Venous thromboembolism (VTE) is considered a potentially serious complication of knee arthroscopy and leads to conditions such as deep venous thrombosis (DVT) and pulmonary embolism (PE). Low-molecular-weight heparin (LMWH) is widely employed in knee arthroscopy to reduce perioperative thromboembolic complications. However, the efficacy and safety of LMWH in knee arthroscopy remains unclear. METHODS: Seven randomized controlled clinical trials on LMWH in knee arthroscopy were identified and included in this meta-analysis. The main outcomes of the effectiveness (prevention of DVT and PE) and complications (death, major bleeding, and minor bleeding) of LMWH in knee arthroscopic surgery were assessed using Review Manager 5.3 software. RESULTS: The meta-analysis indicated that LMWH prophylaxis comprised 79% of asymptomatic DVT. No association was found in symptomatic VTE (RR: 0.90; 95% confidence interval [CI]: 0.39-2.08; P = 0.80), symptomatic DVT (RR: 0.79; 95% CI: 0.28-2.23; P = 0.66), symptomatic PE (RR: 1.36; 95% CI: 0.37-4.97; P = 0.64) and major bleeding (RR: 0.70; 95% CI: 0.12-3.95; P = 0.68) risk during LMWH prophylaxis were identified. Death was not reported in these studies. Moreover, there was a lower incidence of minor bleeding (RR: 0.64; 95% CI: 0.49 to 0.83; P = 0.001) in the control group than in the LMWH group. CONCLUSION: Compared with the control group, the group treated with LMWH after knee arthroscopy was no association in reducing the symptomatic VTE rate, symptomatic DVT rate or symptomatic PE rate. The symptomatic VTE rate was 0.5% (11/2,166) in the LMWH group versus 0.6% (10/1,713) in the control group. Although the limitations of this meta-analysis cannot be ignored, the results of our study show that LMWH after knee arthroscopy is ineffective. We recommend that LMWH should not be routinely provided for knee arthroscopy. TRIAL REGISTRATION: ClinicalTrials.gov NCT03164746.

Long-term Results of Primary Hip Arthroplasty with Cup Inclination Angle Bigger than Fifty Degrees.

BACKGROUND: Most of studies suggest the cup inclination angle is controversial. All of the studies previous have not control the prosthesis type and head diameter, it is difficult to determine relative or synergistic effects of cup angle. METHODS: We retrospectively reviewed 54 patients (61 hips) with primary total hip arthroplasties which cup inclination angle bigger than 500 after a mean 11.8 years follow-up. All the prosthesis are noncemented cup with a 28 mm metal head(Trilogy Acetabular Shell, Zimmer). The cup inclination was divided into three groups, 50-550 in 26 hips, 55-600 in 21 hips, and bigger than 600 in 14 hips. An immediate postoperative radiograph was compared with a follow-up radiograph. The polyethylene wear rates and abduction of the acetabular cups was measured in all of the patients. RESULTS: The preoperative mean Harris hip score improved from 47.36 to 94.3 points at 10 years. The survivorship of the cup was 100% at 10 years. The mean rate of liner wear was 0.144 ± 0.031 mm/y (0.105-0.178 mm/y) in cup inclination angle between 500-550, and 0.260 ± 0.043 mm/y (0.215-0.394 mm/y) in angle between 550-600, 0. 403 ± 0.016 mm/y (0.378-0.423 mm/y) in angle bigger than 600. The different cup inclination groups are different with liner and volumetric wear. CONCLUSION: For the metal-on-polyethylene prostheses, the liner wear obvious correlate with cup inclination after angle bigger than 500. It can be concluded that the ideal abduction angle for metal-on-polyethylene prostheses should be less than 55° in hip total replacement.

Correlation of Cup Inclination Angle with Liner Wear for Metal-on-polyethylene in Hip Primary Arthroplasty.

OBJECTIVES: The relationship between cup inclination angle and liner wear is controversial. Most authors in the published literature agree that the ideal cup inclination is associated with lower inner wear; however, some disagree. All previous studies did not control for femoral head diameter and inclination, so it is difficult to assess the relative or synergistic effects of cup angle on outcomes. METHODS: We retrospectively reviewed 154 patients (171 hips) with primary total hip arthroplasties performed from 2001 to 2004. All surgeries had been performed by the same physician team. A posterior approach was applied in all patients. All prostheses were non-cemented cups with a 28-mm metal head. Inclusion criteria included that the radiographic material was not completed or lost for primary or last follow up. Patients were divided into four groups according to different cup inclination angle. There were 108 hips with inclination angles below 50°; 35 hips with angles between 50° and 55°; 17 hips with angles between 55° and 60°; and 11 hips with angles greater than 60°. An immediate postoperative radiograph was compared with a follow-up radiograph. Clinical and radiographic data were collected on standardized hip evaluation forms preoperatively, 6 months after surgery and at yearly follow-up visits. Radiographs were digitized and enlarged 100%. After the radiographs were digitized, polyethylene wear rates and acetabular cup abduction were measured on all patients with Cavas 15.0 software. The results were analyzed using Student's two-tailed paired t-test with SPSS 11.5. RESULTS: The preoperative mean Harris hip score improved from 45.36 to 93.5 points 10 years after surgery. No acetabular component was revised for aseptic loosening. Three patients (three hips) had to undergo bone grafting and a lined arthroplasty for severe osteolysis around the acetabular component. The rate of implant survival at 10 years with respect to loosening was 100%. The mean liner wear rate was 0.135 mm/year in cups with inclination angles below 50°, 0.144 mm/year between 50° and 55°, 0.260 mm/year between 55° and 60°, and 0.403 mm/year when the angle was greater than 60°. Liner wear increased when the cup angle was larger than 55° (P < 0.05). CONCLUSIONS: For metal-on-polyethylene prostheses, liner wear correlates with cup inclination angle larger than 55°. The ideal abduction angle for metal-on-polyethylene prostheses is less than 55°.

Establishing a Customized Guide Plate for Osteotomy in Total Knee Arthroplasty Using Lower-extremity X-ray and Knee Computed Tomography Images.

BACKGROUND: The conventional method cannot guarantee the precise osteotomies required for a perfect realignment and a better prognosis after total knee arthroplasty (TKA). This study investigated a customized guide plate for osteotomy placement in TKAs with the aid of the statistical shape model technique using weight-bearing lower-extremity X-rays and computed tomography (CT) images of the knee. METHODS: From October 2014 to June 2015, 42 patients who underwent a TKA in Guizhou Provincial People's Hospital were divided into a guide plate group (GPG, 21 cases) and a traditional surgery group (TSG, 21 cases) using a random number table method. In the GPG group, a guide plate was designed and printed using preoperative three-dimensional measurements to plan and digitally simulate the operation. TSG cases were treated with the conventional method. Outcomes were obtained from the postoperative image examination and short-term follow-up. RESULTS: Operative time was 49.0 ± 10.5 min for GPG, and 62.0 ± 9.7 min in TSG. The coronal femoral angle, coronal tibial angle, posterior tibial slope, and the angle between the posterior condylar osteotomy surface and the surgical transepicondylar axis were 89.2 ± 1.7°, 89.0 ± 1.1°, 6.6 ± 1.4°, and 0.9 ± 0.3° in GPG, and 86.7 ± 2.9°, 87.6 ± 2.1°, 8.9 ± 2.8°, and 1.7 ± 0.8° in TSG, respectively. The Hospital for Special Surgery scores 3 months after surgery were 83.7 ± 18.4 in GPG and 71.5 ± 15.2 in TSG. Statistically significant differences were found between GPG and TSG in all measurements. CONCLUSIONS: A customized guide plate to create an accurate osteotomy in TKAs may be created using lower-extremity X-ray and knee CT images. This allows for shorter operative times and better postoperative alignment than the traditional surgery. Application of the digital guide plate may also result in better short-term outcomes.

Cementless total hip arthroplasty with structural allograft for massive acetabular defect in hip revision.

OBJECTIVE: To study retrospectively 20 hip revison patients treated by cementless total hip arthroplasty with structural allograft. METHODS: Twenty patients suffering from aseptic loosening of an uncemented cup complicated by a large defect underwent cementless total hip arthroplasty with structural allograft and were followed up for at least 5 years. Clinical results were evaluated by Harris score and leg length measurements. Radiographic analysis included implants migration, graft absorbance, osteolysis and liner wear. RESULTS: No cup loosening or graft reabsorption was found at final follow-up. Clinical improvements in pain and functional status were demonstrated during the follow-up period. The mean Harris hip scores improved from 29 preoperatively (range 20-41) to 81 postoperatively (range 73-89). CONCLUSION: Our study shows that cementless total hip arthroplasty with allograft is a good way for massive defect in acetabular bone stock.

[Clinical observation of anterior bone graft fusion and internal fixation to treat adjacent multivertebral tuberculosis in one-stage].

OBJECTIVE: To evaluate the method and effectiveness of anterior focus clearance with autograft bone fusion and internal fixation in treating of adjacent multivertebral tuberculosis in one-stage. METHODS: Between March 2007 and September 2009, 8 cases of thoracic vertebra tuberculosis were treated. Of 8 cases, 6 were male and 2 were female, aged 32 years on average (range, 20-42 years). The disease duration ranged from 8 to 14 months (mean, 10.2 months). Affected vertebrae included thoracic vertebrae in 35 cases and lumbar vertebrae in 11 cases; 5 vertebrae were involved in 4 cases, 6 vertebrae in 3 cases, and 8 vertebrae in 1 case. According to Frankel classification, there were 2 cases of grade C, 4 cases of grade D, and 2 cases of grade E. All patients had different kyphosis with the Cobb angle of (25.1 +/- 6.6) degrees. All patients received antituberculous therapy 4-6 weeks preoperatively; after complete clearance lesions, autograft bone fusion and internal fixation were performed, and then antituberculous therapy was given for 18 months. RESULTS: All incisions healed by first intention. Eight patients were followed up 18-48 months (mean, 29 months). According to JIN Dadi et al. criterion, 7 cases recovered after first operation, 1 case of relapsed tuberculosis with sious was cured after re-focus clearance. The Cobb angle was (19.5 +/- 4.2) degrees at 7 days after operation and was (22.3 +/- 3.6) degrees at last follow-up, showing significant differences when compared with the preoperative value (P < 0.05). The nerve function of all cases were classified as Frankel grade E. CT scan showed bone graft fusion at 6-8 months after operation. No loosening or displacement of grafted bone and internal fixation occurred during follow-up. CONCLUSION: The treatment of adjacent multivertebral tuberculosis by anterior focus clearance, intervertebral autograft, and internal fixation in one-stage is effective. Anterior bone fusion and internal fixation in one-stage can correct kyphosis effectively and rebuild spinal stability, so it is a good choice for surgical treatment of adjacent multivertebral tuberculosis.

A systematic review of radiological outcomes of highly cross-linked polyethylene versus conventional polyethylene in total hip arthroplasty.

The purpose of this study was to summarise the best evidence to assess radiological outcomes of highly cross-linked polyethylene compared with conventional polyethylene in total hip arthroplasty. All randomised, controlled clinical trials comparing highly cross-linked polyethylene with conventional polyethylene were sought and then analysed by two independent reviewers using the Cochrane collaboration guidelines. Eight studies in seven articles were identified as eligible for inclusion. Due to the clinical and methodological heterogeneity, data from the studies included could not be pooled. No failures related to highly cross-linked polyethylene were reported. All highly cross-linked polyethylene groups had a significantly lower wear or penetration than conventional polyethylene groups. This preliminary result suggests that highly cross-linked polyethylene has significantly less wear than conventional polyethylene.