Synthesis and Anti-Breast Cancer Evaluation of Novel N-(Guanidinyl)benzenesulfonamides

Scientific and Technologial Innovation Programs of the Nanjing military region, China [10MA077]A series of 4-(substituted)-N-(guanidinyl)benzenesulfonamides bearing biologically active pyrazole, pyrimidine and pyridine moieties were prepared and evaluated for their anticancer activity against human tumor breast cell line (MCF7). These sulfonamides showed promising activity with IC50 values ranging from 49.5 to 70.2 mu M. The structure-activity relationship of the synthesized compounds was studied. Interestingly, it was found that the most potent compounds in this study were the corresponding 2-cyanoacrylate 3, 3-oxobutanoate 4, pyrazole 6, pyridine 9 and pyrazole 13. Compounds 7 and 8 are nearly as active as Doxorubicin as reference drug with (IC50 values = 70.2, 68.1 mu M), while compounds 5, 10 and 11 exhibited a moderate activity

Voltage-Gated Potassium Channel Kv13 Is Highly Expressed in Human Osteosarcoma and Promotes Osteosarcoma Growth

Scientific and Technologial Innovation Programs of of Nanjing Military Region, China [10MA077]Deregulation of voltage-gated potassium channel subunit Kv1.3 has been reported in many tumors. Kv1.3 promotes tumorigenesis by enhancing cell proliferation while suppressing apoptosis. However, the expression and function of Kv1.3 in osteosarcoma are unknown. In the present study, we detected the expression of Kv1.3 in human osteosarcoma cells and tissues by RT-PCR, Western blot and immunohistochemistry. We further examined cell proliferation and apoptosis in osteosarcoma MG-63 cells and xenografts following knockdown of Kv1.3 by short hairpin RNA (shRNA). We found that Kv1.3 was upregulated in human osteosarcoma. Knockdown of Kv1.3 significantly suppressed cell proliferation and increased apoptosis as demonstrated by enhanced cleavage of poly (ADP-ribose) polymerase (PARP) and the activation of Caspase-3/7. Furthermore, adenovirus delivered shRNA targeting Kv1.3 significantly inhibited the growth of MG-63 xenografts. Taken together, our results suggest that Kv1.3 is a novel molecular target for osterosarcoma therapy

Potassium Channel Ether à go-go1 Is Aberrantly Expressed in Human Liposarcoma and Promotes Tumorigenesis

The ether à go-go1 (Eag1) channel is overexpressed in a variety of cancers. However, the expression and function of Eag1 in liposarcoma are poorly understood. In the present study, the mRNA expression of Eag1 in different adipose tissue samples was examined by real-time PCR. Then, the protein expression of Eag1 in 131 different adipose tissues from 109 patients was detected by immunohistochemistry. Next, the associations between Eag1 expression and clinicopathological features of liposarcoma were analyzed. In addition, the effects of Eag1 on liposarcoma cell proliferation and cycle were evaluated by CCK-8, colony formation, xenograft mouse model, and flow cytometry, respectively. Finally, the activation of p38 mitogen-activated protein kinase (MAPK) was detected by Western blot analysis to explain the detailed mechanisms of oncogenic potential of Eag1 in liposarcoma. It was found that Eag1 was aberrantly expressed in over 67% liposarcomas, with a higher frequency than in lipoma, hyperplasia, inflammation, and normal adipose tissues. However, Eag1 expression was not correlated with clinicopathological features of liposarcoma. Eag1 inhibitor imipramine or Eag1-shRNA significantly suppressed the proliferation of liposarcoma cells in vitro and in vivo, accompanying with accumulation of cells in the G1 phase. These results suggest that Eag1 plays an important role in regulating the proliferation and cell cycle of liposarcoma cells and might be a potential therapeutic target for liposarcoma

Voltage-Gated Potassium Channel Kv1.3 Is Highly Expressed in Human Osteosarcoma and Promotes Osteosarcoma Growth

Deregulation of voltage-gated potassium channel subunit Kv1.3 has been reported in many tumors. Kv1.3 promotes tumorigenesis by enhancing cell proliferation while suppressing apoptosis. However, the expression and function of Kv1.3 in osteosarcoma are unknown. In the present study, we detected the expression of Kv1.3 in human osteosarcoma cells and tissues by RT-PCR, Western blot and immunohistochemistry. We further examined cell proliferation and apoptosis in osteosarcoma MG-63 cells and xenografts following knockdown of Kv1.3 by short hairpin RNA (shRNA). We found that Kv1.3 was upregulated in human osteosarcoma. Knockdown of Kv1.3 significantly suppressed cell proliferation and increased apoptosis as demonstrated by enhanced cleavage of poly (ADP-ribose) polymerase (PARP) and the activation of Caspase-3/7. Furthermore, adenovirus delivered shRNA targeting Kv1.3 significantly inhibited the growth of MG-63 xenografts. Taken together, our results suggest that Kv1.3 is a novel molecular target for osterosarcoma therapy

Silencing of Ether à Go-Go 1 by shRNA Inhibits Osteosarcoma Growth and Cell Cycle Progression

Recently, a member of the voltage-dependent potassium channel (Kv) family, the Ether à go-go 1 (Eag1) channel was found to be necessary for cell proliferation, cycle progression and tumorigenesis. However, the therapeutic potential of the Eag1 channel in osteosarcoma remains elusive. In the present study, a recombinant adenovirus harboring shRNA against Eag1 was constructed to silence Eag1 expression in human osteosarcoma MG-63 cells. We observed that Eag1-shRNA inhibited the proliferation and colony formation of MG-63 cells due to the induction of G1 phase arrest. Moreover, in vivo experiments showed that Eag1-shRNA inhibited osteosarcoma growth in a xenograft nude mice model. In addition, selective inhibition of Eag1 significantly decreased the expression levels of cyclin D1 and E. Taken together, our data suggest that the Eag1 channel plays a crucial role in regulating the proliferation and cell cycle of osteosarcoma cells, and represents a new and effective therapeutic target for osteosarcoma

Effects of microendoscopy-assisted reduction and screw fixation through a single mini-incision on posterior cruciate ligament tibial avulsion fracture

Introduction There are various surgical approaches for the treatment of posterior cruciate ligament (PCL) injury-associated tibial fracture avulsion, including arthroscopy-assisted surgery and open posterior surgery. However, none of these treatments are perfect. We have established a simple procedure with microendoscopy-assisted reduction and cannulated screw fixation for the treatment of this disease through a single mini-incision. In this study, we delineated the effects of this surgical approach for patients with PCL tibial avulsion fracture. Patients and methods We retrospectively reviewed 24 patients with acute PCL tibial avulsion fracture treated via this method from 2004 to 2008. All the patients were implanted with cannulated screws (AO/ASIF, 3.5, 4.0 or 4.5 mm in diameter, 3-4 mm in length) for fixation by microendoscopy. The posterior drawer test (PDT) and KT-2000 arthrometer examination were performed to evaluate knee stability. The Lysholm knee scoring scale and the International Knee Documentation Committee (IKDC) scoring scale were used to assess knee function. Types and rates of complications and radiographic follow-up were reviewed for all cases. Results 23 of 24 cases achieved knee stability by PDT and KT-2000 examination. The Lysholm's score was improved from 43.8 +/- 4.6 to 95.3 +/- 3.8. The IKDC evaluation demonstrated an improved function in 17 cases with grade A, 6 with grade B, and 1 with grade C. No relevant complications were experienced by any patient. Conclusions Increased stability, functional improvement, and few complications were observed in patients of PCL injury-associated tibial fracture avulsion treated with the microendoscopy-assisted reduction and cannulated screw fixation through a single mini-incision.Nanjing Military Medical Technology Innovation Project during the 11th Five-Year Plan Period of China [08MA077

Artificial Disk Replacement Combined With Midlevel ACDF Versus Multilevel Fusion for Cervical Disk Disease Involving 3 Levels

The optimal surgical approach for cervical disk disease remains a matter of debate, especially for multilevel disease. The purpose of this study was to compare the results of 2 surgical strategies for cervical disk disease involving 3 levels: hybrid constructs, artificial disk replacement combined with midlevel anterior cervical diskectomy and fusion (ACDF), and 3-level ACDF. The authors prospectively compared patients who had cervical disk disease involving 3 levels that was treated with hybrid constructs or with 3-level ACDF. Patients were asked to use the Neck Disability Index (NDI) to grade their pain intensity preoperatively and at routine postoperative intervals of 1, 3, 6, 12, and 24 months. Dynamic flexion and extension lateral cervical radiographs were obtained while in the standing position preoperatively and at the postoperative intervals. The angular range of motion for C2-C7 and the adjacent segments was measured using the Cobb method. Twenty-four patients were treated, 12 with hybrid constructs and 12 with 3-level ACDF. Both groups had significant postoperative improvement in NDI scores and neck pain (P.05). The hybrid constructs group showed faster recovery of C2-C7 range of motion. Mean C2-C7 range of motion of the hybrid constructs group recovered to that of the preoperative value, but that of the 3-level ACDF group did not (P<.05). Range of motion of the superior and inferior adjacent segments showed significant differences between the 2 groups at 12 and 24 months postoperatively (P<.05). These findings suggest that the hybrid constructs is a safe and effective alternative for cervical disk disease involving 3 levels. The definite stabilization and maintained range of motion can be achieved right away, which can ensure a good preliminary clinical outcome

Anterior Versus Posterior Approach for Four-level Cervical Spondylotic Myelopathy

The purpose of this study was to compare the results of 2 surgical strategies for 4-level cervical spondylotic myelopathy: a hybrid procedure using anterior cervical diskectomy and fusion (ACDF) combined with segmental corpectomy versus posterior laminectomy and fixation. Between 2002 and 2010, fifty-one patients with consecutive 4-level cervical spondylotic myelopathy were treated surgically, with 27 patients undergoing the hybrid procedure and 24 undergoing posterior laminectomy and fixation. Radiologic data were compared between the 2 groups, including cervical curvature and cervical range of motion (ROM) in the sagittal plane. Pre- and postoperative neurological status was evaluated using the Japanese Orthopaedic Association (JOA) scoring system and the Nurick grading system. Mean ROM at last follow-up was not significantly different between the 2 groups (P>.05). In the hybrid group, mean JOA score and Nurick grade improved from 9.6+/-1.4 and 2.74+/-0.45 respectively, preoperatively, to 13.9+/-1.3 and 0.86+/-0.38 respectively, postoperatively. In the fixation group, mean JOA score and Nurick grade improved from 9.4+/-1.2 and 2.81+/-0.42 respectively, preoperatively, to 13.1+/-1.5 and 1.32+/-0.36 respectively, postoperatively. The JOA scores and Nurick grades at last follow-up were significantly different between the 2 groups (P.05); however, JOA scores and Nurick grades at last follow-up showed better improvement in the hybrid group than in the fixation group (P.05)

A distal femoral supra-condylar plate: biomechanical comparison with condylar plate and first clinical application for treatment of supracondylar fracture

[09z020]An anatomical supra-condylar plate is designed and analysed by biomechanical testing. The biomechanical properties of the supra-condylar and condylar plate were compared in six matched pairs of cadaveric femurs. A transverse osteotomy gap was created to simulate an OTA/AO type A3 supracondylar fracture. The left and right specimens were fitted with supra-condylar and condylar plate, respectively. Nondestructive axial compression, three-point bending and torsion tests were performed, and the peak load of the bone-implant construction was measured. The fracture site suitable for supra-condylar plate application and its correlation with femoral length were calculated. The gender influence on it was also discussed. The difference of stiffness between the supra-condylar and condyle groups were not significant (P > 0.05) at 363.4 and 362.5 N/mm for compression, 229.5 and 237.6 N/mm in the sagittal plane and 195.5 and 188.4 N/mm in the coronal plane for three-point bending, and 7.5 and 7.9 Nm/deg for axial torsion, respectively. The peak load was 4438 +/- 136.15 N and 5215 +/- 174.33 N, respectively, for the two groups. The average extent of the fracture site suitable for the application of the supra-condylar plate was 70.86 +/- 4.61 mm. The femoral length and gender showed no influence on it. Despite the limited bone contact area provided by the supra-condylar plate, its construct stiffness is comparable to the condylar plate. The supra-condylar plate can be used to treat carefully-selected extra-articular supracondylar fractures

Posteromedial Anatomical Plate for the Treatment of Distal Tibial Fractures With Anterior Soft Tissue Injury

Nanjing Military Region [07M068