X-linked lymphoproliferative syndrome (XLP or Duncan disease) is characterized by extreme sensitivity to Epstein-Barr virus (EBV), resulting in a complex phenotype manifested by severe or fatal infectious mononucleosis, acquired hypogammaglobulinemia and malignant lymphoma. We have identified a gene, SH2D1A, that is mutated in XLP patients and encodes a novel protein composed of a single SH2 domain. SH2D1A is expressed in many tissues involved in the immune system. The identification of SH2D1A will allow the determination of its mechanism of action as a possible regulator of the EBV-induced immune response.

The BRCA2 gene is mutated in familial breast and ovarian cancer, and its product is implicated in DNA repair and transcriptional regulation. Here we identify a protein, EMSY, which binds BRCA2 within a region (exon 3) deleted in cancer. EMSY is capable of silencing the activation potential of BRCA2 exon 3, associates with chromatin regulators HP1beta and BS69, and localizes to sites of repair following DNA damage. EMSY maps to chromosome 11q13.5, a region known to be involved in breast and ovarian cancer. We show that the EMSY gene is amplified almost exclusively in sporadic breast cancer (13%) and higher-grade ovarian cancer (17%). In addition, EMSY amplification is associated with worse survival, particularly in node-negative breast cancer, suggesting that it may be of prognostic value. The remarkable clinical overlap between sporadic EMSY amplification and familial BRCA2 deletion implicates a BRCA2 pathway in sporadic breast and ovarian cancer.

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Background: The combination of salmeterol and fluticasone propionate (SFC) and tiotropium bromide (TIO) are commonly used treatments in chronic obstructive pulmonary disease (COPD) but there are few data on their effectiveness when used together. We compared the effects of SFC 50/500 mg twice daily in addition to TIO 18 mg once daily with the individual treatments alone. Methods: 41 patients with COPD participated in a randomised, double blind, double dummy, three way crossover study with 2 week washout periods between treatments. Lung function assessment included plethysmography and spirometry. The primary end point was post-dose specific airways conductance (sGaw) area under the curve (AUC 0-4 h ) on day 14. Results: AUC 0-4 h sGaw was significantly higher on day 14 after SFC+TIO compared with TIO (22%) or SFC alone (27%) (both p,0.001). SFC+TIO significantly improved trough forced expiratory volume in 1 s compared with TIO alone (212 ml, p,0.001) and SFC alone (110 ml, p = 0.017) on day 14. Inspiratory capacity measurements also showed significant benefits for triple therapy over individual components on day 14. Subjects receiving SFC+TIO had clinically relevant improvements in Transition Dyspnoea Index (TDI) total score of 2.2 compared with TIO alone (p,0.001) (but not SFC alone, 0.7; NS) and used significantly less rescue medication (1.0 occasion less daily than TIO (p,0.001) and 0.6 less than SFC (p = 0.01)). Conclusion: SFC+TIO triple therapy led to greater improvements in bronchodilation compared with TIO and SFC alone. The advantages of triple therapy are observed across a range of physiologically important parameters, including airway conductance and lung volumes. Triple therapy also led to patient related benefits by improving TDI and use of rescue medication. Trial registration number: NCT00325169.Chronic obstructive pulmonary disease (COPD) is a multi-component disease with inflammation playing a key role, even in the early stages. 1 It is characterised by airflow obstruction that is both progressive and poorly reversible. 2 Drug treatments for COPD aim to control symptoms, maximise pulmonary function and reduce exacerbation rates. 2 The inhaled anticholinergic tiotropium (TIO) provides effective bronchodilation over 24 h and reduces symptoms. 3 4 These effects are associated with a reduction in exacerbation rates. 5 The long acting beta agonist (LABA) salmeterol is an alternative inhaled bronchodilator therapy and is often prescribed in a combination inhaler with the anti-inflammatory corticosteroid fluticasone propionate (FP). [6][7][8][9] This combination of salmeterol and FP (SFC) has demonstrated a broad range of anti-inflammatory effects 10 that are greater than those seen with inhaled corticosteroid (ICS) monotherapy 11 and the likely explanation for this is a molecular interaction (synergy) between the LABA and ICS. 12 The anti-inflammatory and bronchodilator effects of SFC provides greater symptom control, pulmonary function improvement and exacerbation reduction compared with eith...