Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer.

IntroductionThe purpose of this study was to retrospectively explore the relationship between human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) expression and efficacy in patients receiving trastuzumab plus docetaxel (HT) or trastuzumab emtansine (T-DM1).MethodsPatients with HER2-positive, locally advanced or metastatic breast cancer (MBC) were randomly assigned to HT (n=70) or T-DM1 (n=67). HER2 status was assessed locally using immunohistochemistry or fluorescence in situ hybridization and confirmed retrospectively by central testing. HER2 mRNA expression was assessed using quantitative reverse transcriptase polymerase chain reaction.ResultsHER2 mRNA levels were obtained for 116/137 patients (HT=61; T-DM1=55). Median pretreatment HER2 mRNA was 8.9. The risk of disease progression in the overall population was lower with T-DM1 than with HT (hazard ratio (HR)=0.59; 95% confidence interval (CI) 0.36 to 0.97). This effect was more pronounced in patients with HER2 mRNA≥median (HR=0.39; 95% CI 0.18 to 0.85) versus ConclusionsThis exploratory analysis suggests that while overall, patients with HER2-positive MBC show improved PFS with T-DM1 relative to HT, the effect is enhanced in patients with tumor HER2 mRNA ≥ median.Trial registrationClinicalTrials.gov NCT00679341

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The COP9/signalosome complex is conserved in fission yeast and has a role in S phase

The COP9/signalosome complex is conserved from plant to mammalian cells. In Arabidopsis, it regulates the nuclear abundance of COP1, a transcriptional repressor of photomorphogenic development [1] [2]. All COP (constitutive photomorphogenesis) mutants inappropriately express genes that are normally repressed in the dark. Eight subunits (Sgn1-Sgn8) of the homologous mammalian complex have been purified [3] [4]. Several of these have been previously identified through genetic or protein interaction screens. No coherent model for COP9/signalosome function has yet emerged, but a relationship with cell-cycle progression by transcriptional regulation, protein localisation or protein stability is possible. Interestingly, the COP9/signalosome subunits possess domain homology to subunits of the proteasome regulatory lid complex [5] [6]. Database searches indicate that only Sgn5/JAB1 is present in Saccharomyces cerevisiae, precluding genetic analysis of the complex in cell-cycle regulation. Here we identify a subunit of the signalosome in the fission yeast Schizosaccharomyces pombe through an analysis of the DNA-integrity checkpoint. We provide evidence for the conservation of the COP9/signalosome complex in fission yeast and demonstrate that it functions during S-phase progression

Cylindrofridins A–C, Linear Cylindrocyclophane-Related Alkylresorcinols from the Cyanobacterium <i>Cylindrospermum stagnale</i>

A rapid and exhaustive one-step biomass extraction as well as an enrichment and cleanup procedure has been developed for HPLC-UV detection and quantification of closely related [7.7]­paracyclophanes and structural derivatives based on a two-phase solvent system. The procedure has been validated using the biomass of the carbamidocyclophane- and cylindrocyclophane-producing cyanobacterium <i>Nostoc</i> sp. CAVN2 and was utilized to perform a screening comprising 102 cyanobacterial strains. As a result, three new cylindrocyclophane-related alkylresorcinols, cylindrofridins A–C (<b>1</b>–<b>3</b>), and known cylindrocyclophanes (<b>4</b>–<b>6</b>) were detected and isolated from <i>Cylindrospermum stagnale</i> PCC 7417. Structures of <b>1</b>–<b>3</b> were elucidated by a combination of 1D and 2D NMR experiments, HRMS, and ECD spectroscopy. Cylindrofridin A (<b>1</b>) is the first naturally occurring [7.7]­paracyclophane-related monomeric derivative. In contrast, cylindrofridins B (<b>2</b>) and C (<b>3</b>) represent dimers related to <b>1</b>. Due to chlorination at the alkyl carbon atom in <b>1</b>–<b>3</b>, the site of [7.7]­paracyclophane macrocycle formation, the cylindrofridins represent linearized congeners of the cylindrocyclophanes. Compounds <b>1</b>–<b>3</b> were not toxic against nontumorigenic HaCaT cells (IC₅₀ values >25 μM) compared to the respective cylindrocyclophanes, but <b>1</b> was the only cylindrofridin showing moderate activity against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) and <i>Streptococcus pneumoniae</i> with MIC values of 9 and 17 μM, respectively

Burden of disease and increasing prevalence of inflammatory bowel disease in a population-based cohort in the Netherlands

Reported epidemiology and phenotype distributions vary widely and disease burden of inflammatory bowel disease (IBD) is poorly described. Our aim was to establish these features in a population-based cohort covering 319 976 inhabitants. Furthermore, differences between tertiary referral and peripheral hospital patients were quantified. IBD patients in the adherence area of three peripheral hospitals (2004-2012) were included. Medical and surgical treatment data were obtained. Quality of life and disease activity were evaluated. An outpatient cohort from a tertiary referral centre was accrued. A total of 1461 patients were included: 761 (52.1%) with ulcerative colitis (UC), 579 (39.5%) with Crohn's disease (CD) and 121 (8.3%) with IBD-unspecified. Point prevalence of IBD was 432.1 per 100 000 inhabitants in 2010, which increased significantly over time, P-value of less than 0.0001. The mean annual incidence was 17.2 for UC, 10.5 for CD and 2.2 for IBD-unspecified. Tertiary referral Crohn's patients used thiopurines and biological therapy and underwent surgery significantly more often than patients in peripheral hospitals (P <0.0001). Disease activity correlated negatively with quality of life (P <0.0001) in UC and CD. The prevalence of IBD is still increasing. Burden of disease was significantly more severe, mainly in Crohn's patients, in the referral centre, highlighting the importance of population-based studies to accurately describe phenotype distribution and disease burde