Small worlds and board interlocking in Brazil: a longitudinal study of corporate networks, 1997-2007

Social Network Analysis (SNA) is an emerging research field in finance, above all in Brazil. This work is pioneering in that it is supported by reference to different areas of knowledge: social network analysis and corporate governance, for dealing with a similarly emerging topic in finance; interlocking boards, the purpose being to check the validity of the small-world model in the Brazilian capital market, and the existence of associations between the positioning of the firm in the network of corporate relationships and its worth. To do so official data relating to more than 400 companies listed in Brazil between 1997 and 2007 were used. The main results obtained suggest that the configuration of the networks of relationships between board members and companies reflects the small-world model. Furthermore, there seems to be a significant relationship between the firm’s centrality and its worth, described according to an “inverted U” curve, which suggests the existence of optimum values of social prominence in the corporate network

Lapatinib monotherapy in patients with HER2-overexpressing relapsed or refractory inflammatory breast cancer: final results and survival of the expanded HER2+ cohort in EGF103009, a phase II study.

BACKGROUND: Inflammatory breast cancer is an aggressive and biologically distinct form with a higher frequency of HER2 overexpression than other breast cancers. For patients with resistance to conventional anthracycline or taxane and trastuzumab treatment, options are limited. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor tyrosine kinases, previously had a 50% response rate in a cohort of 30 patients with HER2-overexpressing (HER2+) recurrent or anthracycline-refractory inflammatory breast cancer. We aimed to assess efficacy of lapatinib in an expanded cohort of patients with relapsed or refractory HER2+ disease. METHODS: From March, 2005, to September, 2007, 126 patients with relapsed or refractory HER2+ inflammatory breast cancer were treated with lapatinib 1500 mg once daily in a non-randomised, open-label, phase II study. Pretreatment tumour biopsies were done to verify pathological features of inflammatory breast cancer. Skin disease was assessed every 4 weeks, and response in sites of measurable locally advanced or metastatic disease were assessed by response evaluation in solid tumours (RECIST) criteria every 8 weeks. The primary aim was to assess combined objective response rate, by clinically evaluable skin disease criteria and RECIST, if applicable. Analyses were done by intention to treat; patients with missing data were treated as non-responders. This study is registered with ClinicalTrials.gov, number NCT00105950. FINDINGS: Clinical presentation and biomarker analysis showed a tumour molecular profile consistent with inflammatory breast cancer. No patients had complete response. 49 patients (39%; 95% CI 30-48) had partial response. Median progression-free survival was 14.6 weeks (95% CI 12.1-16.0), with median duration of response of 20.9 weeks (12.7-32.1). Likelihood of response to lapatinib was not affected by previous treatment with trastuzumab. 130 (92%) of 141 patients had at least one adverse event; 45 (32%) had serious adverse events, the most common were dyspnoea (eight patients) and pleural effusion (six). Five patients had fatal adverse events that were possibly treatment related. INTERPRETATION: Lapatinib monotherapy is a potentially effective treatment for relapsed or refractory HER2+ inflammatory breast cancer. FUNDING: GlaxoSmithKline.Clinical Trial, Phase IIJournal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Discovery of 3‑(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl‑3<i>H</i>‑imidazo[4,5‑<i>b</i>]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor

The work in this paper describes the optimization of the 3-(3-phenyl-3<i>H</i>-imidazo­[4,5-<i>b</i>]­pyridin-2-yl)­pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (<b>21a</b>). The cocrystal structure of compound <b>21a</b> bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound <b>21a</b> demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound <b>21a</b> also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma