Investigations of the Telomerase Template Antagonist GRN163L and Implications for Augmenting Breast Cancer Therapy

Indiana University-Purdue University Indianapolis (IUPUI)Breast cancer is the second most common cancer among women in the US after skin cancer. While early detection and improved therapy has led to an overall decline in breast cancer mortality, metastatic disease remains largely incurable, indicating a need for improved therapeutic options for patients. Telomeres are repetitive (TTAGGG)n DNA sequences found at the end of chromosomes that protect the ends from recombination, end to end fusions, and recognition as damaged DNA. The enzyme telomerase acts to stabilize short telomeres, preventing apoptosis or senescence due to genomic instability. Telomerase is active in 85-90% of cancers, and inactive in most normal cells, making telomerase an attractive target for cancer therapy. Use of the telomerase-specific, lipidated oligonucleotide GRN163L can antagonize telomerase activity and telomere maintenance in cancer cells by preventing telomerase from binding to telomeres. GRN163L has been shown by our laboratory to inhibit breast cancer cell growth and metastasis in animal models. However, the mechanisms of cancer cell growth and metastatic inhibition via GRN163L are not completely understood. The overall goal of this research project was to further elucidate the role of telomerase in breast cancer cell survival by: 1) determining the effects of combining telomere dysfunction induced by GRN163L with a DNA damage inducer (irradiation); 2) elucidating the mechanisms underlying the cellular response to GRN163L and the effect of combination therapy with the mitotic inhibitor paclitaxel; and 3) testing the hypothesis that a telomerase inhibitor can augment the effects of trastuzumab in breast cancer cells with HER2 amplification. Results support the central hypothesis that the telomere dysfunction, structural and proliferative changes in breast cancer cells induced by GRN163L can synergize with irradiation, paclitaxel, and trastuzumab to inhibit the tumorigenicity of breast cancer cells both in vitro and in vivo. Furthermore, GRN163L can restore sensitivity of therapeutically resistant breast cancer cells to trastuzumab. These results provide insight into the role of telomerase in cancer cell growth. Additionally, implications of this research support GRN163L as an important part of therapeutic regimens for primary tumors, recurrence, and metastatic disease

Observing coherence in an incoherent paramagnetic nitrogen spin bath

The unpolarized spin environment surrounding a central spin qubit is typically considered as an incoherent source of dephasing, however, precise characterization and control of the spin bath can yield a resource for storing and sensing with quantum states. In this work, we use nitrogen-vacancy (NV) centers in diamond to measure the coherence of optically-dark paramagnetic nitrogen defects (P1 centers) and detect coherent interactions between the P1 centers and a local bath of $^{13}$C nuclear spins. The dipolar coupling between the P1 centers and $^{13}$C nuclear spins is identified by signature periodic collapses and revivals in the P1 spin coherence signal. We then demonstrate, using a range of dynamical decoupling protocols, that the probing NV centers and the P1 spins are coupled to independent ensembles of $^{13}$C nuclear spins. Our work illustrates how the optically-dark P1 spins, despite being unpolarized, can be used to extract information from their local environment and offers new insight into the interactions within a many-body system.Comment: 9 pages, 5 figures, comments welcom

Global action on the social determinants of health

Action on the social determinants of health (SDH) is required to reduce inequities in health. This article summarises global progress, largely in terms of commitments and strategies. It is clear that there is widespread support for a SDH approach across the world, from global political commitment to within country action. Inequities in the conditions in which people are born, live, work and age, are however driven by inequities in power, money and resources. Political, economic and resource distribution decisions made outside the health sector need to consider health as an outcome across the social distribution as opposed to a focus solely on increasing productivity. A health in all policies approach can go some way to ensure this consideration, and we present evidence that some countries are taking this approach, however given entrenched inequalities, there is some way to go. Measuring progress on the SDH globally will be key to future development of successful policies and implementation plans, enabling the identification and sharing of best practice. WHO work to align measures with the sustainable development goals will help to forward progress measurement

Chromosome characterization and variability in some Iridaceae from Northeastern Brazil

The chromosomes of 15 species of Iridaceae of the genera Alophia, Cipura, Eleutherine, Neomarica and Trimezia (subfamily Iridoideae) were examined after conventional Giemsa staining. The karyotypes of Alophia drummondii (2n = 14+1B, 28, 42 and 56), Cipura paludosa (2n = 14), C. xanthomelas (2n = 28) and Eleutherine bulbosa (2n = 12) were asymmetric; Neomarica candida, N. caerulea, N. humilis, N. glauca, N. gracilis, N. northiana and Neomarica sp. (2n = 18); N. cf. paradoxa (2n = 28), Trimezia fosteriana (2n = 52), T. martinicensis (2n = 54) and T. connata (2n = 82) were all generally symmetric. New diploid numbers of 2n = 56 for Alophia drummondii, 2n = 18 for N. candida, N. humilis, N. glauca, and N. gracilis, 2n = 28 for N. cf. paradoxa, and 2n = 82 for T. connata are reported. The karyotypic evolution of the studied species is discussed

Contextual logic for quantum systems

In this work we build a quantum logic that allows us to refer to physical magnitudes pertaining to different contexts from a fixed one without the contradictions with quantum mechanics expressed in no-go theorems. This logic arises from considering a sheaf over a topological space associated to the Boolean sublattices of the ortholattice of closed subspaces of the Hilbert space of the physical system. Differently to standard quantum logics, the contextual logic maintains a distributive lattice structure and a good definition of implication as a residue of the conjunction.Comment: 16 pages, no figure

Building of the global movement for health equity: from Santiago to Rio and beyond.

Health inequalities are present throughout the world, both within and between countries. The Commission on Social Determinants of Health drew attention to dramatic social gradients in health within most countries and made proposals for action. These inequalities are not inevitable. The purpose of this article is to report on activity that has taken place worldwide after the report by the Commission on Social Determinants of Health. First, we summarise the global situation. Second, we summarise an interim report of the emerging findings from an independent review of social determinants and the health divide, which was commissioned by the WHO European region. The world conference on social determinants of health will be held in Rio de Janeiro, Brazil, in October, 2011. This summit provides an opportunity to galvanise support, prioritise action, and respond to the call by the Commission on Social Determinants of Health for social justice as a route to a fair distribution of health

Opsonophagocytic Killing Assay to Measure Anti–Group A Streptococcus Antibody Functionality in Human Serum

The opsonophagocytic killing assay (OPKA) is designed to measure the functionality of strain-specific antibodies and, therefore, assess protective immunity or the immunogenicity of Group A Streptococcus (GAS) (type A Streptococcus pyogenes) vaccines. Opsonization of GAS for phagocytosis is an important mechanism by which antibodies protect against disease in vivo. The Opsonophagocytic Index or Opsonic Index (OI) is the estimated dilution of antisera that kills 50% of the target bacteria. Here, we describe the protocol of the standardized GAS OPKA developed by Jones et al., 2018

Introduction to Categories and Categorical Logic

The aim of these notes is to provide a succinct, accessible introduction to some of the basic ideas of category theory and categorical logic. The notes are based on a lecture course given at Oxford over the past few years. They contain numerous exercises, and hopefully will prove useful for self-study by those seeking a first introduction to the subject, with fairly minimal prerequisites. The coverage is by no means comprehensive, but should provide a good basis for further study; a guide to further reading is included. The main prerequisite is a basic familiarity with the elements of discrete mathematics: sets, relations and functions. An Appendix contains a summary of what we will need, and it may be useful to review this first. In addition, some prior exposure to abstract algebra - vector spaces and linear maps, or groups and group homomorphisms - would be helpful.Comment: 96 page

Antibody responses to nasopharyngeal carriage of Streptococcus pneumoniae in adults: A longitudinal household study

Background. Natural immunity to Streptococcus pneumoniae is thought to be induced by exposure to S. pneumoniae or cross-reactive antigens. No longitudinal studies of carriage of and immune responses to S. pneumoniae have been conducted using sophisticated immunological laboratory techniques.Methods. We enrolled 121 families with young children into this study. Nasopharyngeal (NP) swabs were collected monthly for 10 months from all family members and were cultured in a standard fashion. Cultured S. pneumoniae isolates were serotyped. At the beginning (month 0) and end (month 10) of the study, venous blood was collected from family members 118 years old. Serotype-specific antipolysaccharide immunoglobulin G (IgG) and functional antibody and antibodies to pneumolysin, pneumococcal surface protein A (PspA), and pneumococcal surface antigen A (PsaA) were measured in paired serum samples.Results. Levels of anticapsular IgG increased significantly after carriage of serotypes 9V, 14, 18C, 19F, and 23F by an individual or family member. For serotype 14, a higher level of anticapsular IgG at the beginning of the study was associated with reduced odds of carriage (P = .0006). There was a small (similar to 20%) but significant increase in titers of antibodies to PsaA and pneumolysin but no change in titers of antibody to PspA.Conclusions. Adults respond to NP carriage by mounting anticapsular and weak antiprotein antibody responses, and naturally induced anticapsular IgG can prevent carriage