Jingi Bae

The biomechanical performance of locking plate fixation with intramedullary fibular strut graft augmentation in the treatment of unstable fractures of the proximal humerus

We evaluated the biomechanical properties of two different methods of fixation for unstable fractures of the proximal humerus. Biomechanical testing of the two groups, locking plate alone (LP), and locking plate with a fibular strut graft (LPSG), was performed using seven pairs of human cadaveric humeri. Cyclical loads between 10 N and 80 N at 5 Hz were applied for 1,000,000 cycles. Immediately after cycling, an increasing axial load was applied at a rate of displacement of 5 mm/min. The displacement of the construct, maximum failure load, stiffness and mode of failure were compared. The displacement was significantly less in the LPSG group than in the LP group (p = 0.031). All maximum failure loads and measures of stiffness in the LPSG group were significantly higher than those in the LP group (p = 0.024 and p = 0.035, respectively). In the LP group, varus collapse and plate bending were seen. In the LPSG group, the humeral head cut out and the fibular strut grafts fractured. No broken plates or screws were seen in either group. We conclude that strut graft augmentation significantly increases both the maximum failure load and the initial stiffness of this construct compared with a locking plate alone.

The radiological parameters correlated with the alignment of the femoral component after Oxford Phase 3 unicompartmental knee replacement

The purpose of this study was to measure the radiological parameters of femoral component alignment of the Oxford Phase 3 unicompartmental knee replacement (UKR), and evaluate their effect on clinical outcome. Multiple regression analysis was used to examine the relative contributions of the radiological assessment of femoral component alignment in 189 consecutive UKRs performed by a single surgeon. The American Knee Society scores were compared between groups, defined as being within or outside recommended tolerances of the position of the femoral component. For the flexion/extension position 21 UKRs (11.1%) lay outside the recommended limits, and for posterior overhang of the femoral component nine (4.8%) lay outside the range. The pre-operative hip/knee/ankle (HKA) angle, narrowest canal distance from the distal femoral entry point of the alignment jig and coronal entry-point position had significant effects on the flexion/extension position. Pre-operative HKA angle had a significant influence on posterior overhang of the femoral component. However, there was no significant difference in American Knee Society scores relative to the position of the femoral component.

Arthrodesis of the knee using cannulated screws

We retrospectively evaluated eight patients who underwent arthrodesis of the knee using cannulated screws. There were six women and two men, with a mean age of 53 years. The indications for arthrodesis were failed total knee arthroplasty, septic arthritis, tuberculosis, and recurrent persistent infection. Solid union was achieved in all patients at a mean of 6.1 months. One patient required autogenous bone graft for delayed union. One suffered skin necrosis which was treated with skin grafting. The mean limb-length discrepancy was 3.1 cm. On a visual analogue scale, the mean pain score improved from 7.9 to 3.3. According to the Knee Injury and Osteoarthritis Outcome score quality of life items, the mean score improved from 38.3 pre-operatively to 76.6 at follow-up. Cannulated screws provide a high rate of union in arthrodesis of the knee with minimal complications, patient convenience, and a simple surgical technique.

Origin of lumbar spinal roots and their relationship to intervertebral discs: a cadaver and radiological study.

Previous studies on the anatomy of the lumbar spine have not clarified the precise relationship of the origin of the lumbar roots to their corresponding discs or their angulation to the dural sac. We studied 33 cadavers (25 formalin-preserved and eight fresh-frozen) and their radiographs to determine these details. All cadavers showed a gradual decrease in the angle of the nerve root from L1 to S1. The origin of the root was found to be below the corresponding disc for the L1 to L4 roots. In the formalin-preserved cadavers 8% of the L5 roots originated above, 64% below and 28% at the L4/L5 disc. In the fresh cadavers the values were 12.5%, 62.5% and 25%, respectively. For the S1 root 76% originated above and 24% at the L5-S1 disc in the formalin-preserved cadavers and 75% and 25%, respectively, in the fresh cadavers.A herniated disc usually compresses the root before division of the root sleeve. Thus, compression of the thecal sac before the origin of the root sleeve is common for L1 to L5 whereas compression at the root sleeve is common for S1. Our findings are of value in understanding the pathophysiology of prolapse of the disc and in preventing complications during surgery.

A fully automated dual-online multifunctional ultrahigh pressure liquid chromatography system for high-throughput proteomics analysis.

A fully automated dual-online multifunctional ultrahigh pressure liquid chromatography (DO-MULTI-UPLC) system has been developed for high throughput proteome analyses of complex peptide mixtures. The system employs two online solid phase extraction (SPE) columns (150μm inner diameter×3cm), two capillary reverse phase (RP) columns (75μm×100cm) and a strong cation exchange (SCX) column (150μm×15cm) on a single system utilizing one binary pump and one isocratic pump. With the automated operation of six switching valves, the selection of LC experiments between single-dimensional RPLC and online two-dimensional SCX/RPLC were achieved automatically, without manual intervention, while two RPLC columns were used independently and alternatively. By essentially removing the dead time for column equilibration between experiments, in either 1D mode or 2D experimental mode, the current system was demonstrated to increase the experimental throughput by about two folds, while keeping the inter-column reproducibility of peptide elution time in less than 1% of gradient time. The advantageous features of the proposed system were demonstrated by its application to proteome samples of varying complexities.

Integrated analysis of global proteome, phosphoproteome, and glycoproteome enables complementary interpretation of disease-related protein networks

Multi-dimensional proteomic analyses provide different layers of protein information, including protein abundance and post-translational modifications. Here, we report an integrated analysis of protein expression, phosphorylation, and N-glycosylation by serial enrichments of phosphorylation and N-glycosylation (SEPG) from the same tissue samples. On average, the SEPG identified 142,106 unmodified peptides of 8,625 protein groups, 18,846 phosphopeptides (15,647 phosphosites), and 4,019 N-glycopeptides (2,634 N-glycosites) in tumor and adjacent normal tissues from three gastric cancer patients. The combined analysis of these data showed that the integrated analysis additively improved the coverages of gastric cancer-related protein networks; phosphoproteome and N-glycoproteome captured predominantly low abundant signal proteins, and membranous or secreted proteins, respectively, while global proteome provided abundances for general population of the proteome. Therefore, our results demonstrate that the SEPG can serve as an effective approach for multi-dimensional proteome analyses, and the holistic profiles of protein expression and PTMs enabled improved interpretation of disease-related networks by providing complementary information.

The influence of surgical factors on dislocation of the meniscal bearing after Oxford medial unicompartmental knee replacement: a case–control study

The aim of this study was to evaluate the risk factors for dislocation of the bearing after a mobile-bearing Oxford medial unicompartmental knee replacement (UKR) and to test the hypothesis that surgical factors, as measured from post-operative radiographs, are associated with its dislocation From a total of 480 UKRs performed between 2001 and 2012, in 391 patients with a mean age of 66.5 years (45 to 82) (316 female, 75 male), we identified 17 UKRs where bearing dislocation occurred. The post-operative radiological measurements of the 17 UKRs and 51 matched controls were analysed using conditional logistic regression analysis. The post-operative radiological measurements included post-operative change in limb alignment, the position of the femoral and tibial components, the resection depth of the proximal tibia, and the femoral component-posterior condyle classification. We concluded that a post-operative decrease in the posterior tibial slope relative to the pre-operative value was the only significant determinant of dislocation of the bearing after medial Oxford UKR (odds ratio 1.881; 95% confidence interval 1.272 to 2.779). A post-operative posterior tibial slope < 8.45° and a difference between the pre-operative and post-operative posterior tibial slope of > 2.19° may increase the risk of dislocation.

Comprehensive proteome profiling of platelet identified a protein profile predictive of responses to an antiplatelet agent sarpogrelate.

Sarpogrelate is an antiplatelet agent widely used to treat arterial occlusive diseases. Evaluation of platelet aggregation is essential to monitor therapeutic effects of sarpogrelate. Currently, no molecular signatures are available to evaluate platelet aggregation. Here, we performed comprehensive proteome profiling of platelets collected from 18 subjects before and after sarpogrelate administration using LC-MS/MS analysis coupled with extensive fractionation. Of 5423 proteins detected, we identified 499 proteins affected by sarpogrelate and found that they strongly represented cellular processes related to platelet activation and aggregation, including cell activation, coagulation, and vesicle-mediated transports. Based on the network model of the proteins involved in these processes, we selected three proteins (cut-like homeobox 1; coagulation factor XIII, B polypeptide; and peptidylprolyl isomerase D) that reflect the platelet aggregation-related processes after confirming their alterations by sarpogrelate in independent samples using Western blotting. Our proteomic approach provided a protein profile predictive of therapeutic effects of sarpogrelate.

Quantitative Proteomics Reveals β2 Integrin-mediated Cytoskeletal Rearrangement in Vascular Endothelial Growth Factor (VEGF)-induced Retinal Vascular Hyperpermeability

Retinal vascular hyperpermeability causes macular edema, leading to visual deterioration in retinal diseases such as diabetic retinopathy and retinal vascular occlusion. Dysregulation of junction integrity between endothelial cells by vascular endothelial growth factor (VEGF) was shown to cause retinal vascular hyperpermeability. Accordingly, anti-VEGF agents have been used to treat retinal vascular hyperpermeability. However, they can confer potential toxicity through their deleterious effects on maintenance and survival of neuronal and endothelial cells in the retina. Thus, it is important to identify novel therapeutic targets for retinal vascular hyperpermeability other than VEGF. Here, we prepared murine retinas showing VEGF-induced vascular leakage from superficial retinal vascular plexus and prevention of VEGF-induced leakage by anti-VEGF antibody treatment. We then performed comprehensive proteome profiling of these samples and identified retinal proteins for which abundances were differentially expressed by VEGF, but such alterations were inhibited by anti-VEGF antibody. Functional enrichment and network analyses of these proteins revealed the β2 integrin pathway, which can prevent dysregulation of junction integrity between endothelial cells through cytoskeletal rearrangement, as a potential therapeutic target for retinal vascular hyperpermeability. Finally, we experimentally demonstrated that inhibition of the β2 integrin pathway salvaged VEGF-induced retinal vascular hyperpermeability, supporting its validity as an alternative therapeutic target to anti-VEGF agents.

Multi-omics analysis identifies pathways and genes involved in diffuse-type gastric carcinogenesis induced by E-cadherin, p53, and Smad4 loss in mice

The molecular mechanisms underlying the pathogenesis of diffuse‐type gastric cancer (DGC) have not been adequately explored due to a scarcity of appropriate animal models. A recently developed tool well suited for this line of investigation is the Pdx‐1‐Cre;Cdh1F/+;Trp53F/F;Smad4F/F (pChePS) mouse model that spontaneously develops metastatic DGC showing nearly complete E‐cadherin loss. Here, we performed a proteogenomic analysis to uncover the molecular changes induced by the concurrent targeting of E‐cadherin, p53, and Smad4 loss. The gene expression profiles of mouse DGCs and in vivo gastric phenotypes from various combinations of gene knockout demonstrated that these mutations collaborate to activate cancer‐associated pathways to generate aggressive DGC. Of note, WNT‐mediated epithelial‐to‐mesenchymal transition (EMT) and extracellular matrix (ECM)‐cytokine receptor interactions were prominently featured. In particular, the WNT target gene osteopontin (OPN) that functions as an ECM cytokine is highly upregulated. In validation experiments, OPN contributed to DGC stemness by promoting cancer stem cell (CSC) survival and chemoresistance. It was further found that Bcl‐xL acts as a targetable downstream effector of OPN in DGC CSC survival. In addition, Zeb2 and thymosin‐β4 (Tβ4) were identified as prime candidates as suppressors of E‐cadherin expression from the remaining Cdh1 allele during DGC development. Specifically, Tβ4 suppressed E‐cadherin expression and anoikis while promoting cancer cell growth and migration. Collectively, these proteogenomic analyses broaden and deepen our understanding of the contribution of key driver mutations in the stepwise carcinogenesis of DGC through novel effectors, namely OPN and Tβ4.