Interaction between Nef and phosphatidylinositol-3-kinase leads to activation of p21-activated kinase and increased production of HIV

The negative factor (Nef) is one of six accessory proteins from primate lentiviruses (HIV-1, HIV-2, and SIV). It leads to high levels of viremia and the progression to AIDS in monkeys and humans. In this study, we demonstrated that Nef from HIV-1 binds to the regulatory subunit (p85) of phosphatidylinositol-3-kinase (PI3K). This interaction depended on the C-terminus of p85 and Nef. Moreover, PI3K was required to activate the Nef-associated p21-activated kinase (PAK). Finally, inhibition of PI3K blocked the activation of PAK and decreased the production of viral particles to levels observed with the Nef-deleted provirus. We conclude that Nef assembles a multiprotein signaling complex which is required for the optimal replication of HIV-1.     

Gene and miRNA expression in giant cell arteritis—a concise systematic review of significantly modified studies

Clinical Rheumatology - Giant cell arteritis (GCA) is a systemic vasculitis in individuals older than 50 years, characterized by headaches, visual disturbances, painful scalp, jaw...     

Increase in tumor-associated macrophages after antiangiogenic therapy is associated with poor survival among patients with recurrent glioblastoma

Antiangiogenic therapy is associated with increased radiographic responses in glioblastomas, but tumors invariably recur. Because tumor-associated macrophages have been shown to mediate escape from antiangiogenic therapy in preclinical models, we examined the role of macrophages in patients with recurrent glioblastoma. We compared autopsy brain specimens from 20 patients with recurrent glioblastoma who received antiangiogenic treatment and chemoradiation with 8 patients who received chemotherapy and/or radiotherapy without antiangiogenic therapy or no treatment. Tumor-associated macrophages were morphologically and phenotypically analyzed using flow cytometry and immunohistochemistry for CD68, CD14, CD163, and CD11b expression. Flow cytometry showed an increase in macrophages in the antiangiogenic-treated patients. Immunohistochemical analysis demonstrated an increase in CD68+ macrophages in the tumor bulk (P < .01) and infiltrative areas (P = .02) in antiangiogenic-treated patients. We also observed an increase in CD11b+ cells in the tumor bulk (P < .01) and an increase in CD163+ macrophages in infiltrative tumor (P = .02). Of note, an increased number of CD11b+ cells in bulk and infiltrative tumors (P = .05 and P = .05, respectively) correlated with poor overall survival among patients who first received antiangiogenic therapy at recurrence. In summary, recurrent glioblastomas showed an increased infiltration in myeloid populations in the tumor bulk and in the infiltrative regions after antiangiogenic therapy. Higher numbers of CD11b+ cells correlated with poor survival among these patients. These data suggest that tumor-associated macrophages may participate in escape from antiangiogenic therapy and may represent a potential biomarker of resistance and a potential therapeutic target in recurrent glioblastoma.     

Utility of serological biomarkers for giant cell arteritis in a large cohort of treatment-naïve patients

Clinical Rheumatology - Early diagnosis and treatment of giant cell arteritis (GCA) is crucial for preventing ischemic complications. Multiple serological markers have been identified; however,...     

Subperiosteal elevation of the ulnar nerve-Anatomical considerations and preliminary results

Mobilisation of the ulnar nerve often leads to perineural scarring. About 30 years ago, B.F. Korosec, M.D., developed a novel surgical approach to the distal humerus combined with osteotomy of the olecranon, which avoids visualisation or direct manipulation of the ulnar nerve. The main advantage of his technique lies in subperiosteal elevation of the ulnar nerve together with all structures of the cubital tunnel. In the present study, anatomical dissections of distal humerus structures were performed in a cadaver to define individual steps of the technique introduced by Dr. Korosec. Ten phases of the procedure were identified. Ten patients (4 males and 6 females) with type 13-C and 13-B fractures of the distal humerus (AO/ASIF) were operated on. The patients showed no clinical signs of ulnar nerve injury before surgery. During the operation, the ulnar nerve was electrically stimulated at the axilla and compound muscle action potentials were continuously recorded from hypothenar muscles. Latency and amplitude of the potentials were monitored. Analysis of these data using the unpaired t-test for median values revealed no statistically significant differences between individual stages of the operation (p<0.00625). An amplitude decrease accompanied by a latency increase by more than 10% over the baseline value was found to indicate impending nerve damage. The novel approach to the distal humerus presented in this article is a safe procedure.