The hydrogen-poor superluminous supernova iPTF 13ajg and its host galaxy in absorption and emission

We present imaging and spectroscopy of a hydrogen-poor superluminous supernova (SLSN) discovered by the intermediate Palomar Transient Factory, iPTF 13ajg. At a redshift of z = 0.7403, derived from narrow absorption lines, iPTF 13ajg peaked at an absolute magnitude of M u, AB = -22.5, one of the most luminous supernovae to date. The observed bolometric peak luminosity of iPTF 13ajg is 3.2 × 1044 erg s-1, while the estimated total radiated energy is 1.3 × 1051 erg. We detect narrow absorption lines of Mg I, Mg II, and Fe II, associated with the cold interstellar medium in the host galaxy, at two different epochs with X-shooter at the Very Large Telescope. From Voigt profile fitting, we derive the column densities log N(Mg I) =11.94 ± 0.06, log N(Mg II) =14.7 ± 0.3, and log N(Fe II) =14.25 ± 0.10. These column densities, as well as the Mg I and Mg II equivalent widths of a sample of hydrogen-poor SLSNe taken from the literature, are at the low end of those derived for gamma-ray bursts (GRBs) whose progenitors are also thought to be massive stars. This suggests that the environments of hydrogen-poor SLSNe and GRBs are different. From the nondetection of Fe II fine-structure absorption lines, we derive a lower limit on the distance between the supernova and the narrow-line absorbing gas of 50 pc. The neutral gas responsible for the absorption in iPTF 13ajg exhibits a single narrow component with a low velocity width, ΔV = 76 km s-1, indicating a low-mass host galaxy. No host galaxy emission lines are detected, leading to an upper limit on the unobscured star formation rate (SFR) of SFR. Late-time imaging shows the iPTF 13ajg host galaxy to be faint, with g AB 27.0 and R AB ≥ 26.0 mag, corresponding to M B, Vega ≳ -17.7 mag. © 2014. The American Astronomical Society. All rights reserved.

Co-targeting of convergent nucleotide biosynthetic pathways for leukemia eradication

Pharmacological targeting of metabolic processes in cancer must overcome redundancy in biosynthetic pathways. Deoxycytidine (dC) triphosphate (dCTP) can be produced both by the de novo pathway (DNP) and by the nucleoside salvage pathway (NSP). However, the role of the NSP in dCTP production and DNA synthesis in cancer cells is currently not well understood. We show that acute lymphoblastic leukemia (ALL) cells avoid lethal replication stress after thymidine (dT)-induced inhibition of DNP dCTP synthesis by switching to NSP-mediated dCTP production. The metabolic switch in dCTP production triggered by DNP inhibition is accompanied by NSP up-regulation and can be prevented using DI-39, a new high-affinity small-molecule inhibitor of the NSP rate-limiting enzyme dC kinase (dCK). Positron emission tomography (PET) imaging was useful for following both the duration and degree of dCK inhibition by DI-39 treatment in vivo, thus providing a companion pharmacodynamic biomarker. Pharmacological co-targeting of the DNP with dT and the NSP with DI-39 was efficacious against ALL models in mice, without detectable host toxicity. These findings advance our understanding of nucleotide metabolism in leukemic cells, and identify dCTP biosynthesis as a potential new therapeutic target for metabolic interventions in ALL and possibly other hematological malignancies

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Development of New Deoxycytidine Kinase Inhibitors and Noninvasive in Vivo Evaluation Using Positron Emission Tomography

Combined inhibition of ribonucleotide reductase and deoxycytidine kinase (dCK) in multiple cancer cell lines depletes deoxycytidine triphosphate pools leading to DNA replication stress, cell cycle arrest and apoptosis. Evidence implicating dCK in cancer cell proliferation and survival stimulated our interest in developing small molecule dCK inhibitors. Following a high throughput screen of a diverse chemical library, a structure-activity relationship study was carried out. Positron Emission Tomography (PET) using (18)F-L-1-(2′-deoxy-2′-FluoroArabinofuranosyl) Cytosine ((18)F-L-FAC), a dCK-specific substrate, was used to rapidly rank lead compounds based on their ability to inhibit dCK activity in vivo. Evaluation of a subset of the most potent compounds in cell culture (IC(50) = ∼1 – 12 nM) using the (18)F-L-FAC PET pharmacodynamic assay identified compounds demonstrating superior in vivo efficacy

Calcaneocuboid Joint Arthritis of the Midfoot Precedes Tibiotalar Joint Arthritis.

Surgical models have best shown the relationship between ankle and mid-foot osteoarthritis, although findings regarding the calcaneocuboid joint have varied. To the authors\u27 knowledge, no studies have evaluated the relationship between degenerative changes across the tibiotalar and calcaneocuboid joints. The goal of this study was to determine whether such a relationship exists and which joint degenerates first. A single examiner evaluated 694 tibiotalar and calcaneocuboid joints to determine the presence of osteoarthritis. Multiple linear regression analysis was conducted with a standard P value cutoff (P\u3c.05) and 95% confidence interval. The average incidence of tibiotalar and calcaneocuboid osteoarthritis in specimens older than 40 years was compared with the incidence in those 40 years and younger. A positive correlation between tibiotalar and calcaneocuboid osteoarthritis was noted. African-American subjects were less likely than white subjects to have tibiotalar osteoarthritis. The finding of right and left tibiotalar and calcaneocuboid osteoarthritis in subjects 40 years and younger showed that midfoot arthritis was significantly more common than arthritis of the ankle. The prevalence of calcaneocuboid osteoarthritis remains stable after 40 years of age, and the prevalence of tibiotalar osteoarthritis approaches that of calcaneocuboid osteoarthritis. Calcaneocuboid osteoarthritis precedes tibiotalar osteoarthritis. Altered biomechanics involved in calcaneocuboid osteoarthritis are transferred to the tibiotalar joint, leading to tibiotalar osteoarthritis as the subject ages. Early education, surveillance, physical therapy, shoe adjustment, and orthotics may help to reduce the forces across the midfoot and prevent ankle arthritis in the long term