A robust prognostic signature for hormone-positive node-negative breast cancer

Background: Systemic chemotherapy in the adjuvant setting can cure breast cancer in some patients that would otherwise recur with incurable, metastatic disease. However, since only a fraction of patients would have recurrence after surgery alone, the chal

Rigid Phencyclidine Analogues. Binding to the Phencyclidine and σ₁ Receptors

Three phencyclidine (PCP) analogues possessing a highly rigid carbocyclic structure and an attached piperidine ring which is free to rotate were synthesized. Each analogue has a specific fixed orientation of the ammonium center of the piperidinium ring to the centrum of the phenyl ring. The binding affinities of the rigid analogues 1-piperidino-7,8-benzobicyclo[4.2.0]octene (14), 1-piperidinobenzobicyclo[2.2.1]heptene (16), and 1-piperidinobenzobicyclo[2.2.2]octene (13) for the PCP receptor ([3H]TCP) and σ-receptor (NANM) were determined. The three analogues show low to no affinity for the PCP receptor but good affinity for the σ-receptor and can be considered σ-receptor selective ligands with PCP/σ ratios of 13, 293, and 368, respectively. The binding affinities for the σ-receptor are rationalized in terms of a model for the σ-pharmacophore

Modeling precision treatment of breast cancer

© 2013 Daemen et al.; licensee BioMed Central Ltd.Background: First-generation molecular profiles for human breast cancers have enabled the identification of features that can predict therapeutic response; however, little is known about how the various da

The Intramolecular Asymmetric Pauson−Khand Cyclization as a Novel and General Stereoselective Route to Benzindene Prostacyclins: Synthesis of UT-15 (Treprostinil)

A general and novel solution to the synthesis of biologically important stable analogues of prostacyclin PGI2, namely benzindene prostacyclins, has been achieved via the stereoselective intramolecular Pauson−Khand cyclization (PKC). This work illustrates for the first time the synthetic utility and reliability of the asymmetric PKC route for synthesis and subsequent manufacture of a complex drug substance on a multikilogram scale. The synthetic route surmounts issues of individual step stereoselectivity and scalability. The key step in the synthesis involves efficient stereoselection effected in the PKC of a benzoenyne under the agency of the benzylic OTBDMS group, which serves as a temporary stereodirecting group that is conveniently removed via benzylic hydrogenolysis concomitantly with the catalytic hydrogenation of the enone PKC product. Thus the benzylic chiral center dictates the subsequent stereochemistry of the stereogenic centers at three carbon atoms (C3a, C9a, and C1)

Base editing of haematopoietic stem cells rescues sickle cell disease in mice

Sickle cell disease (SCD) is caused by a mutation in the β-globin gene HBB(1). We used a custom adenine base editor (ABE8e-NRCH)(2,3) to convert the SCD allele (HBB(S)) to Makassar β-globin (HBB(G)), a non-pathogenic variant(4,5). Ex vivo delivery of mRNA encoding base editor with a targeting guide RNA into hematopoietic stem and progenitor cells (HSPCs) from SCD patients resulted in 80% HBB(S)-to-HBB(G) conversion. Sixteen weeks after transplantation of edited human HSPCs into immunodeficient mice, HBB(G) frequency was 68% and bone marrow reticulocytes demonstrated a 5-fold decrease in hypoxia-induced sickling, indicating durable editing. To assess the physiological effects of HBB(S) base editing, we delivered ABE8e-NRCH and guide RNA into HSPCs from a humanized SCD mouse(6), followed by transplantation into irradiated mice. After sixteen weeks, Makassar β-globin represented 79% of β-globin protein in blood and hypoxia-induced sickling was reduced 3-fold. Mice receiving base-edited HSPCs showed rescue of hematologic parameters to near-normal levels and reduced splenic pathology compared to unedited controls. Secondary transplantation of edited bone marrow confirmed durable editing of long-term hematopoietic stem cells and revealed that ≥20% HBB(S)-to-HBB(G) editing is sufficient for phenotypic rescue. Base editing of human HSPCs avoided p53 activation and larger deletions observed following Cas9 nuclease treatment. These findings suggest a one-time autologous treatment for SCD that eliminates pathogenic HBB(S), generates benign HBB(G), and minimizes undesired consequences of double-strand DNA breaks