M6P/IGF2R loss of heterozygosity in head and neck cancer associated with poor patient prognosis

BACKGROUND: The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes for a multifunctional receptor involved in lysosomal enzyme trafficking, fetal organogenesis, cytotoxic T cell-induced apoptosis and tumor suppression. The purpose of this investigation was to determine if the M6P/IGF2R tumor suppressor gene is mutated in human head and neck cancer, and if allelic loss is associated with poor patient prognosis. METHODS: M6P/IGF2R loss of heterozygosity in locally advanced squamous cell carcinoma of the head and neck was assessed with six different gene-specific nucleotide polymorphisms. The patients studied were enrolled in a phase 3 trial of twice daily radiotherapy with or without concurrent chemotherapy; median follow-up for surviving patients is 76 months. RESULTS: M6P/IGF2R was polymorphic in 64% (56/87) of patients, and 54% (30/56) of the tumors in these informative patients had loss of heterozygosity. M6P/IGF2R loss of heterozygosity was associated with a significantly reduced 5 year relapse-free survival (23% vs. 69%, p = 0.02), locoregional control (34% vs. 75%, p = 0.03) and cause specific survival (29% vs. 75%, p = 0.02) in the patients treated with radiotherapy alone. Concomitant chemotherapy resulted in a better outcome when compared to radiotherapy alone only in those patients whose tumors had M6P/IGF2R loss of heterozygosity. CONCLUSIONS: This study provides the first evidence that M6P/IGF2R loss of heterozygosity predicts for poor therapeutic outcome in patients treated with radiotherapy alone. Our findings also indicate that head and neck cancer patients with M6P/IGF2R allelic loss benefit most from concurrent chemotherapy

A deletion encompassing Zic3 in Bent tail, a mouse model for X-linked neural tube defects.

Item does not contain fulltex

Molecular cytogenetic detection of 9q34 breakpoints associated with nail patella syndrome

The nail patella syndrome (NPS1) is an autosomal dominant disorder characterised by dysplasia of the finger nails and skeletal abnormalities. NPS1 has been mapped to 9q34, to a 1 cM interval between D9S315 and the adenylate kinase gene (AK1). We have mapped the breakpoints within the candidate NPS1 region in two unrelated patients with balanced translocations, One patient [46,XY,t(1;9) (q32,1;q34)] was detected during a systematic survey of old cytogenetic files in Denmark and southern Sweden. The other patient [46,XY,t(9;17) (q34,1;q25)] was reported previously D9S315 and AK1 were used to isolate YACs, from which endclones were used to isolate PACs, Two overlapping PAC clones span the 9q34 breakpoints in both patients, suggesting that NPS1 is caused by halopinsufficiency due to truncation or otherwise inactivation of a gene at or in the vicinity of the breakpoints

Crystal-structure Of Yersinia Protein-tyrosine-phosphatase At 2.5-angstrom And The Complex With Tungstate

PROTEIN tyrosine phosphatases (PTPases) and kinases coregulate the critical levels of phosphorylation necessary for intracellular signalling, cell growth and differentiation(1,2). Yersinia, the causative bacteria of the bubonic plague and other enteric diseases, secrete an active PTPase(3), Yop51, that enters and suppresses host immune cells(4,5). Though the catalytic domain is only similar to 20% identical to human PTP1B(6), the Yersinia PTPase contains all of the invariant residues present in eukaryotic PTPases(7), including the nucleophilic Cys 403 which forms a phosphocysteine intermediate during catalysis(3,8-10). We present here structures of the unliganded (2.5 Angstrom resolution) and tungstate-bound (2.6 Angstrom) crystal forms which reveal that Cys 403 is positioned at the centre of a distinctive phosphate-binding loop. This loop is at the hub of several hydrogen-bond arrays that not only stabilize a bound oxyanion, but may activate Cys 403 as a reactive thiolate. Binding of tungstate triggers a conformational change that traps the oxyanion and swings Asp 356, an important catalytic residue(7), by similar to 6 Angstrom into the active site. The same anion-binding loop in PTPases is also found in the enzyme rhodanese(11).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62819/1/370571a0.pd