Neurodegenerative phagocytes mediate synaptic stripping in Neuro-HIV.

Glial cell activation is a hallmark of several neurodegenerative and neuroinflammatory diseases. During HIV infection, neuroinflammation is associated with cognitive impairment, even during sustained long-term suppressive antiretroviral therapy. However, the cellular subsets contributing to neuronal damage in the CNS during HIV infection remain unclear. Using post-mortem brain samples from eight HIV patients and eight non-neurological disease controls, we identify a subset of CNS phagocytes highly enriched in LGALS3, CTSB, GPNMB and HLA-DR, a signature identified in the context of ageing and neurodegeneration. In HIV patients, the presence of this phagocyte phenotype was associated with synaptic stripping, suggesting an involvement in the pathogenesis of HIV-associated neurocognitive disorder. Taken together, our findings elucidate some of the molecular signatures adopted by CNS phagocytes in HIV-positive patients and contribute to the understanding of how HIV might pave the way to other forms of cognitive decline in ageing HIV patient populations

FISH and immunohistochemical status of the hepatocyte growth factor receptor (c-Met) in 184 invasive breast tumors

Grants PI05/0961 and PI06/1513 from Ministerio de Sanidad y Consumo ISCIII and RTICC 06/0020/1

Transformed dermatofibrosarcoma protuberans: real time polymerase chain reaction detection of COL1A1–PDGFB fusion transcripts in sarcomatous areas

BACKGROUND: Recent cytogenetic studies have shown that reciprocal translocation t (17;22)(q22;q13) and a supernumerary ring chromosome derived from the translocation r(17;22) are highly characteristic of dermatofibrosarcoma protuberans (DFSP). The chromosomal rearrangements fuse the collagen type Iα1 (COL1A1) and the platelet‐derived growth factor B‐chain (PDGFB) genes. The COL1A1–PDGFB fusion transcript has been shown not only in conventional DFSP but also in a small series of DFSP with fibrosarcomatons areas (DFSP‐FS) using reverse transcriptase‐based conventional polymerase chain reaction. Nothing is known about the status of the COL1A1–PDGFB chimaeric gene in the pleomorphic areas of DFSP‐PleoSarc (formerly known as DFSP‐malignant fibrous sarcoma). AIMS: To show the COL1A1–PDGFB fusion transcript in transformed malignant fibrous histiocytoma. METHOD: A real‐time polymerase chain reaction assay for the COL1A1–PDGFB fusion transcript in a series of DFSP containing sarcoma was conducted to determine whether the chimaeric gene could be identified in both components of DFSP‐FS and DFSP‐PleoSarc. Eight cases were analysed. RESULTS: In seven cases, transcriptable RNA was detected, and in these cases, translocations were found between COL1A1 and PDGFB genes involving exons 27, 32, 34, 40 and 47 of the COL1A1 gene and exon 2 of the PDGFB gene. CONCLUSIONS: From a diagnostic aspect, this assay can be particularly useful in confirming the diagnosis of sarcomatous DFSP. On the other hand, the COL1A1–PDGFB fusion gene was shown in three cases of DFSP containing pleomorphic sarcoma, which supports the theory of the common histogenesis

Alien Registration- Bedford, George (Bar Harbor, Hancock County)

https://digitalmaine.com/alien_docs/19928/thumbnail.jp

Analysis of EGFR Gene Amplification, Protein Over-expression and Tyrosine Kinase Domain Mutation in Recurrent Glioblastoma

Abstract Gefitinib and erlotinib are both selective EGFR tyrosine kinase inhibitors (EGFR-TKIs) that have produced responses in a small subgroup of lung cancer patients. The strongest evidence for a role of EGFR in the biology of glioblastoma stems from clinical trials in which 15–20% of recurrent glioblastoma patients experienced significant tumour regression in response to these small-molecule EGFR kinase inhibitors. We examined the protein-kinase domain of the EGFR gene, EGFR protein expression and EGFR gene amplification in 20 cases of recurrent GBMs. EGFR protein over-expression was found in 65% of cases. EGFR protein over-expression was associated with EGFR gene amplification in 35% of cases, and with high polysomy in 15% of cases. No mutations were found in the TK domain of the EGFR gene. Our results confirm that mutations in the kinase domain are absent in recurrent GBM, and this might be a preponderant factor in the lack of major clinical responses of TKIs in GBM, recent studies have suggested that responsiveness to EGFR kinase inhibitors was strongly associated with coexpression of EGFRvIII and PTEN. Further prospective validation of EGFRvIII and PTEN as predictors of the clinical response to EGFR kinase inhibitors in recurrent GBM is strongly anticipated

Secretion of VEGF-165 has unique characteristics, including shedding from the plasma membrane

Vascular endothelial growth factor (VEGF) is a critical regulator of endothelial cell differentiation and vasculogenesis during both development and tumor vascularization. VEGF-165 is a major form that is secreted from the cells via a poorly characterized pathway. Here we use green fluorescent protein- and epitope-tagged VEGF-165 and find that its early trafficking between the endoplasmic reticulum and the Golgi requires the small GTP-binding proteins Sar1 and Arf1 and that its glycosylation in the Golgi compartment is necessary for efficient post-Golgi transport and secretion from the cells. The relative temperature insensitivity of VEGF secretion and its Sar1 and Arf1 inhibitory profiles distinguish it from other cargoes using the "constitutive" secretory pathway. Prominent features of VEGF secretion are the retention of the protein on the outer surface of the plasma membrane and the stimulation of its secretion by Ca(2+) and protein kinase C. Of importance, shedding of VEGF-165 from the cell surface together with other membrane components appears to be a unique feature by which some VEGF is delivered to the surroundings to exert its known biological actions. Understanding VEGF trafficking can reveal additional means by which tumor vascularization can be inhibited by pharmacological interventions

Nonlesional epilepsy—a case report in adult epileptology

We report the case of a patient with nonlesional, pharmacoresistant epilepsy. Bilateral synchronous discharges as well as focal discharges were identified on electroencephalogram (EEG). After non-invasive and invasive presurgical evaluation, a probable epileptogenic zone was identified with concordant results of focal origin involvement of the left temporal pole. Resective epilepsy surgery provided seizure freedom (last follow-up at 12 months). The case nicely illustrates that bilateral synchronous discharges or/and a lack of lesions on neuroimaging are not contraindications to presurgical evaluation of epilepsy, which on the contrary should be offered to all patients with pharmacoresistant epilepsy. The case also illustrates the importance of combining electrophysiological, imaging, and neuropsychological information to guide intracranial EEG placement and improve postsurgical outcome