Biomechanical comparison of lumbar spine instability between laminectomy and bilateral laminotomy for spinal stenosis syndrome – an experimental study in porcine model

<p>Abstract</p> <p>Background</p> <p>The association of lumbar spine instability between laminectomy and laminotomy has been clinically studied, but the corresponding <it>in vitro </it>biomechanical studies have not been reported. We investigated the hypothesis that the integrity of the posterior complex (spinous process-interspinous ligament-spinous process) plays an important role on the postoperative spinal stability in decompressive surgery.</p> <p>Methods</p> <p>Eight porcine lumbar spine specimens were studied. Each specimen was tested intact and after two decompression procedures. All posterior components were preserved in Group A (Intact). In Group B (Bilateral laminotomy), the inferior margin of L4 lamina and superior margin of L5 lamina were removed, but the L4–L5 supraspinous ligament was preserved. Fenestrations were made on both sides. In Group C (Laminectomy) the lamina and spinous processes of lower L4 and upper L5 were removed. Ligamentum flavum and supraspinous ligament of L4–L5 were removed. A hydraulic testing machine was used to generate an increasing moment up to 8400 N-mm in flexion and extension. Intervertebral displacement at decompressive level L4–L5 was measured by extensometer</p> <p>Results</p> <p>The results indicated that, under extension motion, intervertebral displacement between the specimen in intact form and at two different decompression levels did not significantly differ (<it>P </it>> 0.05). However, under flexion motion, intervertebral displacement of the laminectomy specimens at decompression level L4–L5 was statistically greater than in intact or bilateral laminotomy specimens (<it>P </it>= 0.0000963 and <it>P </it>= 0.000418, respectively). No difference was found between intact and bilateral laminotomy groups. (<it>P </it>> 0.05).</p> <p>Conclusion</p> <p>We concluded that a lumbar spine with posterior complex integrity is less likely to develop segment instability than a lumbar spine with a destroyed anchoring point for supraspinous ligament.</p

Survivin counteracts the therapeutic effect of microtubule de-stabilizers by stabilizing tubulin polymers

<p>Abstract</p> <p>Background</p> <p>Survivin is a dual function protein. It inhibits the apoptosis of cells by inhibiting caspases, and also promotes cell growth by stabilizing microtubules during mitosis. Over-expression of survivin has been demonstrated to induce drug-resistance to various chemo-therapeutic agents such as cisplatin (DNA damaging agent) and paclitaxel (microtubule stabilizer) in cancers. However, survivin-induced resistance to microtubule de-stabilizers such as <it>Vinca </it>alkaloids and Combretastatin A-4 (CA-4)-related compounds were seldom demonstrated in the past. Furthermore, the question remains as to whether survivin plays a dominant role in processing cytokinesis or inhibiting caspases activity in cells treated with anti-mitotic compounds. The purpose of this study is to evaluate the effect of survivin on the resistance and susceptibility of human cancer cells to microtubule de-stabilizer-induced cell death.</p> <p>Results</p> <p>BPR0L075 is a CA-4 analog that induces microtubule de-polymerization and subsequent caspase-dependent apoptosis. To study the relationship between the expression of survivin and the resistance to microtubule de-stabilizers, a KB-derived BPR0L075-resistant cancer cell line, KB-<it>L30</it>, was generated for this study. Here, we found that survivin was over-expressed in the KB-<it>L30 </it>cells. Down-regulation of survivin by siRNA induced hyper-sensitivity to BPR0L075 in KB cells and partially re-stored sensitivity to BPR0L075 in KB-<it>L30 </it>cells. Western blot analysis revealed that down-regulation of survivin induced microtubule de-stabilization in both KB and KB-<it>L30 </it>cells. However, the same treatment did not enhance the down-stream caspase-3/-7 activities in BPR0L075-treated KB cells. Translocation of a caspase-independent apoptosis-related molecule, apoptosis-inducing factor (AIF), from cytoplasm to the nucleus was observed in survivin-targeted KB cells under BPR0L075 treatment.</p> <p>Conclusion</p> <p>In this study, survivin plays an important role in the stability of microtubules, but not with caspases inhibition. Over-expression of survivin counteracts the therapeutic effect of microtubule de-stabilizer BPR0L075 probably by stabilizing tubulin polymers, instead of the inhibition of caspase activity in cancer cells. Besides microtubule-related caspase-dependent cell death, caspase-independent mitotic cell death could be initiated in survivin/BPR0L075 combination treatments. We suggest that combining microtubule de-stabilizers with a survivin inhibitor may attribute to a better clinical outcome than the use of anti-mitotic monotherapy in clinical situations.</p

Dual Kit/Aur Inhibitors as Chemosensitizing Agents for the Treatment of Melanoma: Design, Synthesis, Docking Studies and Functional Investigation

Melanoma is the most serious form of skin cancer but its medication is still far from being safe and thoroughly effective. The search of novel therapeutic approaches represents therefore a health emergency to push through eagerly. In this study, we describe a novel class of dual c-Kit/Aur inhibitors, characterized by a 1,2,4-triazole core and developed by a structure-based optimization of a previously developed hit, and report the evidence of their significance as drug candidates for the treatment of melanoma. Compound 6a, merging the best inhibitory profile against the target kinases, showed anti-proliferative efficacy against the human melanoma cell lines A2058, expressing the BRAF V600D mutation, and WM266-4, expressing BRAF V600E. Significantly, it displayed also a highly synergistic profile when tested in combination with vemurafenib, thus proving its efficacy not only per se but even in a combination therapy, which is nowadays acknowledged as the cornerstone approach of the forthcoming tumour management

Pyrazole compound BPR1P0034 with potent and selective anti-influenza virus activity

<p>Abstract</p> <p>Background</p> <p>Influenza viruses are a major cause of morbidity and mortality around the world. More recently, a swine-origin influenza A (H1N1) virus that is spreading via human-to-human transmission has become a serious public concern. Although vaccination is the primary strategy for preventing infections, influenza antiviral drugs play an important role in a comprehensive approach to controlling illness and transmission. In addition, a search for influenza-inhibiting drugs is particularly important in the face of high rate of emergence of influenza strains resistant to several existing influenza antivirals.</p> <p>Methods</p> <p>We searched for novel anti-influenza inhibitors using a cell-based neutralization (inhibition of virus-induced cytopathic effect) assay. After screening 20,800 randomly selected compounds from a library from ChemDiv, Inc., we found that BPR1P0034 has sub-micromolar antiviral activity. The compound was resynthesized in five steps by conventional chemical techniques. Lead optimization and a structure-activity analysis were used to improve potency. Time-of-addition assay was performed to target an event in the virus life cycle.</p> <p>Results</p> <p>The 50% effective inhibitory concentration (IC₅₀) of BPR1P0034 was 0.42 ± 0.11 μM, when measured with a plaque reduction assay. Viral protein and RNA synthesis of A/WSN/33 (H1N1) was inhibited by BPR1P0034 and the virus-induced cytopathic effects were thus significantly reduced. BPR1P0034 exhibited broad inhibition spectrum for influenza viruses but showed no antiviral effect for enteroviruses and echovirus 9. In a time-of-addition assay, in which the compound was added at different stages along the viral replication cycle (such as at adsorption or after adsorption), its antiviral activity was more efficient in cells treated with the test compound between 0 and 2 h, right after viral infection, implying that an early step of viral replication might be the target of the compound. These results suggest that BPR1P0034 targets the virus during viral uncoating or viral RNA importation into the nucleus.</p> <p>Conclusions</p> <p>To the best of our knowledge, BPR1P0034 is the first pyrazole-based anti-influenza compound ever identified and characterized from high throughput screening to show potent (sub-μM) antiviral activity. We conclude that BPR1P0034 has potential antiviral activity, which offers an opportunity for the development of a new anti-influenza virus agent.</p

BPR1K653, a Novel Aurora Kinase Inhibitor, Exhibits Potent Anti-Proliferative Activity in MDR1 (P-gp170)-Mediated Multidrug-Resistant Cancer Cells

Over-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells.BPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats.BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments

Preliminary biomechanical study of different acetabular reinforcement devices for acetabular reconstruction.

Acetabular reinforcement devices (ARDs) are frequently used as load-sharing devices to allow allograft incorporation in revision hip arthroplasty with massive acetabular bone loss. The key to a successful reconstruction is robust fixation of the device to the host acetabulum. Interlocking fixation is expected to improve the initial stability of the postoperative construct. However, all commercially available ARDs are designed with non-locking fixation. This study investigates the efficacy of standard ARDs modified with locking screw mechanisms for improving stability in acetabular reconstruction.Three types of ARDs were examined to evaluate the postoperative compression and angular stability: i) standard commercial ARDs, ii) standard ARDs modified with monoaxial and iii) standard ARDs modified with polyaxial locking screw mechanisms. All ARDs were implanted into osteomized synthetic pelvis with pelvic discontinuity. Axial compression and torsion tests were then performed using a servohydraulic material testing machine that measured load (angle) versus displacement (torque). Initial stability was compared among the groups.Equipping ARDs with interlocking mechanisms effectively improved the initial stability at the device/bone interface compared to standard non-locked ARDs. In both compression and torsion experiments, the monoaxial interlocking construct demonstrated the highest construct stiffness (672.6 ± 84.1 N/mm in compression and 13.3 ± 1.0 N · m/degree in torsion), whereas the non-locked construct had the lowest construct stiffness (381.4 ± 117.2 N/mm in compression and 6.9 ± 2.1 N · m/degree in torsion) (P < 0.05).Our study demonstrates the potential benefit of adding a locking mechanism to an ARD. Polyaxial ARDs provide the surgeon with more flexibility in placing the screws at the cost of reduced mechanical performance. This in vitro study provides a preliminary evaluation of biomechanical performance for ARDs with or without interlocking mechanisms, actual clinical trial deserves to be further investigated in future studies