Oligosaccharyltransferase Inhibition Induces Senescence in RTK-Driven Tumor Cells

Asparagine (N)-linked glycosylation is a protein modification critical for glycoprotein folding, stability, and cellular localization. To identify small molecules that inhibit new targets in this biosynthetic pathway, we initiated a cell-based high throughput screen and lead compound optimization campaign that delivered a cell permeable inhibitor (NGI-1). NGI-1 targets the oligosaccharyltransferase (OST), a hetero-oligomeric enzyme that exists in multiple isoforms and transfers oligosaccharides to recipient proteins. In non-small cell lung cancer cells NGI-1 blocks cell surface localization and signaling of the EGFR glycoprotein, but selectively arrests proliferation in only those cell lines that are dependent on EGFR (or FGFR) for survival. In these cell lines OST inhibition causes cell cycle arrest accompanied by induction of p21, autofluorescence, and changes in cell morphology; all hallmarks of senescence. These results identify OST inhibition as a potential therapeutic approach for treating receptor tyrosine kinase-dependent tumors and provides a chemical probe for reversibly regulating N-linked glycosylation in mammalian cells

Sciatica in the female patient: anatomical considerations, aetiology and review of the literature

The principal author was confronted few years ago with the case of a 38-year-old woman with a 5-month history of ill-defined L5 sciatic pain that was referred to an orthopaedic department for investigation and eventual surgical treatment for what was suspected to be herniated disc-related sciatica. Removal of her enlarged uterus found unexpectedly close to the sacroiliac joint upon lumbar MRI abolished her symptoms. Review of the literature showed that the lumbosacral trunk is vulnerable to pressure from any abdominal mass originating from the uterus and the ovaries. Physiological processes in the female patient and gynaecological diseases may be the source of sciatica, often not readily searched for, leading to fruitless investigations and surgical treatments. The aim of the paper is to highlight gynaecological and obstetrical causes of sciatica and sciatica-like symptoms. To prevent unproductive expenses and morbidity, a thorough gynaecological examination should be done even though neurological examination may be suggestive of a herniated intervertebral disc, and the cyclic pattern of pain related to menses should be routinely asked for