Dasatinib inhibits CXCR4 signaling in chronic lymphocytic leukaemia cells and impairs migration towards CXCL12

Chemokines and their ligands play a critical role in enabling chronic lymphocytic leukaemia (CLL) cells access to protective microenvironmental niches within tissues, ultimately resulting in chemoresistance and relapse: disruption of these signaling pathways has become a novel therapeutic approach in CLL. The tyrosine kinase inhibitor dasatinib inhibits migration of several cell lines from solid-organ tumours, but effects on CLL cells have not been reported. We studied the effect of clinically achievable concentrations of dasatinib on signaling induced by the chemokine CXCL12 through its' receptor CXCR4, which is highly expressed on CLL cells. Dasatinib pre-treatment inhibited Akt and ERK phosphorylation in CLL cells upon stimulation with CXCL12. Dasatinib also significantly diminished the rapid increase in actin polymerisation observed in CLL cells following CXCL12 stimulation. Moreover, the drug significantly inhibited chemotaxis in a transwell assay, and reduced the percentage of cells able to migrate beneath a CXCL12-expressing murine stromal cell line. Dasatinib also abrogated the anti-apoptotic effect of prolonged CXCL12 stimulation on cultured CLL cells. These data suggest that dasatinib, akin to other small molecule kinase inhibitors targeting the B-cell receptor signaling pathway, may redistribute CLL cells from protective tissue niches to the peripheral blood, and support the investigation of dasatinib in combination strategies

Low recurrence rate of a two-layered closure repair for primary and recurrent midline incisional hernia without mesh

Background: Incisional hernia is a serious complication after abdominal surgery and occurs in 11-23% of laparotomies. Repair can be done, for instance, with a direct suture technique, but recurrence rates are high. Recent literature advises the use of mesh repair. In contrast to this development, we studied the use of a direct suture repair in a separate layer technique. The objective of this retrospective observational study is to assess the outcomes (recurrences and complications) of a two-layered open closure repair for primary and recurrent midline incisional hernia without the use of mesh. Methods: In an observational retrospective cohort study, we analysed the hospital and outpatient records of 77 consecutive patients who underwent surgery for a primary or recurrent incisional hernia between 1st May 2002 and 8th November 2006. The repair consisted of separate continuous suturing of the anterior and posterior fascia, including the rectus muscle, after extensive intra-abdominal adhesiolysis. Results: Forty-one men (53.2%) and 36 women (46.8%) underwent surgery. Sixty-three operations (81.8%) were primary repairs and 14 (18.2%) were repairs for a recurrent incisional hernia. Of the 66 patients, on physical examination, three had a recurrence (4.5%) after an average follow-up of 2.6 years. The 30-day postoperative mortality was 1.1%. Wound infection was seen in five patients (6.5%). Conclusions: A two-layered suture repair for primary and recurrent incisional hernia repair without mesh with extensive adhesiolysis was associated with a recurrence rate comparable to mesh repair and had an acceptable complication rate

Incisional hernia after upper abdominal surgery: A randomised controlled trial of midline versus transverse incision

Objectives: To determine whether a transverse incision is an alternative to a midline incision in terms of incisional hern

Enterocutaneous fistula due to mesh fixation in the repair of lateral incisional hernia: a case report

Enterocutaneous fistula following mesh repair of incisional hernia is usually due to mesh erosion of the underlying viscus and presents late. We describe an early enterocutaneous fistula due to an unusual but a potential mode of bowel injury during mesh fixation. This case is reported to emphasize the need for greater attention to the technique of mesh fixation. We suggest laparoscopic guidance to prevent this serious complication in lateral Incisional hernias with ill defined edges of the defect

The local economic development processes in low-income countries: the case of the metropolis of Chegutu in Zimbabwe

Local authorities are widely regarded as catalysts accelerating localised processes of economic development in industrialised countries but in low-income countries they are perceived as dysfunctional, inefficient and ineffective in meeting and addressing societal demands. This abstract view is however, not grounded in empirical research. As such, utilising the case of the metropolis of Chegutu a survey was designed to empirically explicate the economic processes militating its economic development. The findings are useful to policy-makers, local government authorities and management scholars. The study's unique contribution lies in its examination of the processes of local economic development in a low-income country

The PI3-kinase delta inhibitor idelalisib (GS-1101) targets integrin-mediated adhesion of chronic lymphocytic leukemia (CLL) cell to endothelial and marrow stromal cells

CLL cell trafficking between blood and tissue compartments is an integral part of the disease process. Idelalisib, a phosphoinositide 3-kinase delta (PI3K\u3b4) inhibitor causes rapid lymph node shrinkage, along with an increase in lymphocytosis, prior to inducing objective responses in CLL patients. This characteristic activity presumably is due to CLL cell redistribution from tissues into the blood, but the underlying mechanisms are not fully understood. We therefore analyzed idelalisib effects on CLL cell adhesion to endothelial and bone marrow stromal cells (EC, BMSC). We found that idelalisib inhibited CLL cell adhesion to EC and BMSC under static and shear flow conditions. TNF\u3b1-induced VCAM-1 (CD106) expression in supporting layers increased CLL cell adhesion and accentuated the inhibitory effect of idelalisib. Co-culture with EC and BMSC also protected CLL from undergoing apoptosis, and this EC- and BMSC-mediated protection was antagonized by idelalisib. Furthermore, we demonstrate that CLL cell adhesion to EC and VLA-4 (CD49d) resulted in the phosphorylation of Akt, which was sensitive to inhibition by idelalisib. These findings demonstrate that idelalisib interferes with integrin-mediated CLL cell adhesion to EC and BMSC, providing a novel mechanism to explain idelalisib-induced redistribution of CLL cells from tissues into the blood

Stability and error analysis for a diffuse interface approach to an advection-diffusion equation on a moving surface

In this paper we analyze a fully discrete numerical scheme for solving a parabolic PDE on a moving surface. The method is based on a diffuse interface approach that involves a level set description of the moving surface. Under suitable conditions on the spatial grid size, the time step and the interface width we obtain stability and error bounds with respect to natural norms. Furthermore, we present test calculations that confirm our analysis

Components Separation Technique Combined with a Double-Mesh Repair for Large Midline Incisional Hernia Repair

Background The surgical treatment of large midline incisional hernias remains a challenge. The aim of this report is to present the results of a new technique for large midline incisional hernia repair which combines the components- separation technique with a double-prostheticmesh repair. Methods The records of all consecutive patients who received a double-mesh combined with the componentsseparation technique for ventral hernia repair were reviewed. The clinical, surgical, and follow-up data were analyzed. Results Nine patients [3 women, 6 men; median age = 62 years (range = 26-77)] were included in the study. Median transverse defect size was 20 cm (range = 15-25). The median duration of hospital stay was 8 days (range = 5-17). Postoperative complications occurred in 66% (6/9). Follow-up [median = 13 months (range = 3-49)] showed no recurrent hernias, but one patient had a small hernia after a relaparotomy for colon carcinoma recurrence. The overall occurrence of wound infections was 44% (4/9). There was no mortality. Conclusion The components-separation technique in combination with a double-mesh has shown a low recurrence rate in the short-term follow-up. However, there is a considerable occurrence of postoperative wound infections. Long-term results of the hernia recurrence rate have to be awaited

PRED_PPI: a server for predicting protein-protein interactions based on sequence data with probability assignment

<p>Abstract</p> <p>Background</p> <p>Protein-protein interactions (PPIs) are crucial for almost all cellular processes, including metabolic cycles, DNA transcription and replication, and signaling cascades. Given the importance of PPIs, several methods have been developed to detect them. Since the experimental methods are time-consuming and expensive, developing computational methods for effectively identifying PPIs is of great practical significance.</p> <p>Findings</p> <p>Most previous methods were developed for predicting PPIs in only one species, and do not account for probability estimations. In this work, a relatively comprehensive prediction system was developed, based on a support vector machine (SVM), for predicting PPIs in five organisms, specifically humans, yeast, <it>Drosophila</it>, <it>Escherichia coli</it>, and <it>Caenorhabditis elegans</it>. This PPI predictor includes the probability of its prediction in the output, so it can be used to assess the confidence of each SVM prediction by the probability assignment. Using a probability of 0.5 as the threshold for assigning class labels, the method had an average accuracy for detecting protein interactions of 90.67% for humans, 88.99% for yeast, 90.09% for <it>Drosophila</it>, 92.73% for <it>E. coli</it>, and 97.51% for <it>C. elegans</it>. Moreover, among the correctly predicted pairs, more than 80% were predicted with a high probability of ≥0.8, indicating that this tool could predict novel PPIs with high confidence.</p> <p>Conclusions</p> <p>Based on this work, a web-based system, Pred_PPI, was constructed for predicting PPIs from the five organisms. Users can predict novel PPIs and obtain a probability value about the prediction using this tool. Pred_PPI is freely available at <url>http://cic.scu.edu.cn/bioinformatics/predict_ppi/default.html</url>.</p