Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo

Extracellular lysophosphatidate(LPA) is a potent bioactive lipid that signals through six G-protein-coupled receptors.This signaling is required for embryogenesis,tissue repair and remodeling processes.LPA is produced from circulating lysophosphatidylcholine by autotaxin(ATX),and is degraded outside cells by a family of three enzymes called the lipid phosphate phosphatases(LPPs).In many pathological conditions,particularly in cancers,LPA concentrations are increased due to high ATX expression and low LPP activity.In cancers,LPA signaling drives tumor growth,angiogenesis,metastasis,resistance to chemotherapy and decreased efficacy of radiotherapy.Hence,targeting the ATX-LPA-LPP axis is an attractive strategy for introducing novel adjuvant therapeutic options.In this review,we will summarize current progress in targeting the ATX-LPA-LPP axis with inhibitors of autotaxin activity,LPA receptor antagonists,LPA monoclonal antibodies,and increasing low LPP expression.Some of these agents are already in clinical trials and have applications beyond cancer,including chronic inflammatory diseases.     

Inhibition of Enterococcus faecium adherence to collagen by antibodies against high-affinity binding subdomains of Acm

Strains of Enterococcus faecium express a cell wall-anchored protein, Acm, which mediates adherence to collagen. Here, we (i) identify the minimal and high-affinity binding subsegments of Acm and (ii) show that anti-Acm immunoglobulin Gs (IgGs) purified against these subsegments reduced E. faecium TX2535 strain collagen adherence up to 73 and 50%, respectively, significantly more than the total IgGs against the full-length Acm A domain (28%) (P < 0.0001). Blocking Acm adherence with functional subsegment-specific antibodies raises the possibility of their use as therapeutic or prophylactic agents.     

Significance of p53 expression in ovarian tumors and its correlation to the morphological differentiation

Cancer of breast and cervix reign supreme among the fatal diseases in women globally. Interestingly the ovarian cancer has the highest mortality rate. This is attributed to its late clinical presentation and delayed diagnosis. The expression of p53 throws light on the prognosis of ovarian tumors. The surface epithelial tumors, especially the serous cystadenocarcinoma and non Hodgkin lymphoma of ovary where in the expression p53 was high compared to the benign and borderline tumors. Further the expression of p53 in tumors arising from germinal cells, sex-cord stromal cells are observed to be very low. The expression of p53 and its correlation to the morphology enhances the prognostic significance.     

Management of cap striae following challenging small incision lenticule extraction surgery – A case report

A 24-year-old female underwent small incision lenticule extraction (SMILE) for myopic astigmatism OU. In the left eye, cap-lenticular adhesion along with tearing of the cap occurred, resulting in a gaped incision and transverse striae involving the visual axis on the first post op day. Uncorrected distance visual acuity (UDVA) was 20/32. The case was managed with interface wash and stretching of the cap, in order to iron out the striae. Post intervention, the UDVA improved to 20/20, striae resolved, and interface remained clear through a follow-up of nine months, suggesting that cap striae in SMILE may be similarly managed as the flap striae in laser-assisted in situ keratomileusis (LASIK), resulting in satisfactory visual outcomes.     

Synthesis,biological evaluation,and molecular modeling of (<Emphasis Type="Italic">E</Emphasis>)-2-aryl-5-styryl-1,3,4-oxadiazole derivatives as acetylcholine esterase inhibitors

A library of 2,5-disubstituted 1,3,4-oxadiazole derivatives of (E)-2-aryl-5-(3,4,5-trimethoxystyryl)-1,3,4-oxadiazoles 4(a–o) and (E)-2-aryl-5-(2-benzo[d][1,3]dioxol-5-yl)vinyl)-1,3,4-oxadiazoles 5(a–q) were synthesized and evaluated for their in vitro acetylcholinesterase (AChE) inhibitory activity. All the synthesized compounds exhibited moderate to good inhibitory activity toward the AChE enzyme. Among the oxadiazole derivatives examined, compounds 4a, 4g, 5c, and 5m (IC₅₀ values of 24.89, 13.72, 37.65, and 19.63 μM, respectively) were found to be promising inhibitors of AChE. Molecular protein–ligand docking studies were examined for these compounds using GOLD docking software and their binding conformations were determined and the simultaneous interactions mode was also established for the potent derivatives.     

Experimental and finite element analysis of dynamic loading of the mouse forearm

Bone formation is reported to initiate in osteocytes by mechanotransduction due to dynamic loading of bone. The first step towards this is to characterize the dynamic strain fields in the overall bone. Here, the previously developed mouse forearm ulna‐radius model, subjected to static loading, has been further enhanced by incorporating a loading cap and applying a cyclic dynamic load to more closely approximate experimental biological conditions. This study also incorporates data obtained from strain gauging both the ulna and radius simultaneously. Based on separate experiments, the elastic modulus of the ulna and radius were determined to be 13.8 and 9.9 GPa, respectively. Another novel aspect of the numerical model is the inclusion of the interosseous membrane in the FE model with membrane stiffness ranging from 5–15 N/mm that have been found to give strain values closer to that from the experiments. Interestingly, the inclusion of the interosseous membrane helped to equalize the peak strain magnitudes in the ulna and radius (～1800 at 2 N load and ～3200 at 3.5 N), which was also observed experimentally. This model represents a significant advance towards being able to simulate through FE analysis the strain fields generated in vivo upon mechanical loading of the mouse forearm. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1580–1588, 2014.