Optimizing poly (ADP-ribose) polymerase inhibition through combined epigenetic and immunotherapy

Triple‐negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor survival outcomes. Currently, there are no targeted therapies available for TNBCs despite remarkable progress in targeted and immune‐directed therapies for other solid organ malignancies. Poly (ADP‐ribose) polymerase inhibitors (PARPi) are effective anticancer drugs that produce good initial clinical responses, especially in homologous recombination DNA repair‐deficient cancers. However, resistance is the rule rather than the exception, and recurrent tumors tend to have an aggressive phenotype associated with poor survival. Many efforts have been made to overcome PARPi resistance, mostly by targeting genes and effector proteins participating in homologous recombination that are overexpressed during PARPi therapy. Due to many known and unknown compensatory pathways, genes, and effector proteins, overlap and shared resistance are common. Overexpression of programmed cell death‐ligand 1 (PD‐L1) and cancer stem cell (CSC) sparing are novel PARPi resistance hypotheses. Although adding programmed cell death‐1 (PD‐1)/PD‐L1 inhibitors to PARPi might improve immunogenic cell death and be crucial for durable responses, they are less likely to target the CSC population that drives recurrent tumor growth. Lysine‐specific histone demethylase‐1A and histone deacetylase inhibitors have shown promising activity against CSCs. Combining epigenetic drugs such as lysine‐specific histone demethylase‐1A inhibitors or histone deacetylase inhibitors with PARPi/anti‐PD‐1/PD‐L1 is a novel, potentially synergistic strategy for priming tumors and overcoming resistance. Furthermore, such an approach could pave the way for the identification of new upstream epigenetic and genetic signatures.This work was supported by the National Health and Medical Research Council (Grant ID APP1068065) and the UC Deepwater Scholarship (TP)

Interleukin-17 in Various Ocular Surface Inflammatory Diseases

Recently, the association of Th-17 cells or IL-17 with ocular inflammatory diseases such as uveitis, scleritis and dry eye syndrome was discovered. We assessed whether interleukin (IL)-17 was present in the tears of various ocular surface inflammatory diseases and the tear IL-17 concentrations were clinically correlated with various ocular surface inflammatory diseases. We measured concentrations of IL-17 in tears of normal subjects (n = 28) and patients (n = 141) with meibomian gland dysfunction (MGD), dry eye syndrome (DES), Sjögren syndrome (SS), Stevens-Johnson syndrome (SJS), graft-versus-host disease (GVHD), filamentary keratitis, and autoimmune keratitis associated with rheumatoid arthritis or systemic lupus erythematosus. Clinical epitheliopathy scores were based on the surface area of corneal and conjunctival fluorescein staining. The mean concentrations of IL-17 in tears of patients with filamentary keratitis, GVHD, autoimmune keratitis, SS, DES, MGD, SJS were significantly higher in order than that in normal subjects. Tear IL-17 concentration was significantly correlated with clinical epitheilopathy scores in the patients with systemic inflammatory disease, while tear IL-17 was not correlated with clinical severity of the cornea and conjunctiva in the dry eye patients without any systemic inflammatory disease. Tear IL-17 is likely to correlate clinically with corneal disease severity only in the patients with systemic inflammatory disease

2013 WSES guidelines for management of intra-abdominal infections

Peer reviewe

Semi-structured messages are surprisingly useful for computer-supported coordination

O objetivo deste artigo foi estabelecer um panorama do gasto público ambiental per capita nas dez maiores economias regionais do Paraná, ponderando três períodos: de 2002 a 2005, de 2006 a 2009 e de 2010 a 2013. O conceito de gasto público ambiental utilizado, considerou as variáveis da despesa agregada, nas categorias de gestão ambiental e saneamento, com a agregação de todas as subcategorias, e na categoria agricultura, com a seleção de subcategorias com finalidade ambiental. As fontes de dados foram a Secretaria do Tesouro Nacional, o Instituto Brasileiro de Geografia e Estatística, o Instituto Paranaense de Desenvolvimento Econômico e Social e os balanços gerais do Paraná e das prefeituras. A metodologia teve como base a estatística descritiva. Os resultados do gasto público ambiental per capital indicaram em média o valor de R$66,33 ao ano, correspondentes a um desembolso total de R$ 8,3 bilhões no período Os municípios com os maiores valores absolutos foram: Curitiba, São José dos Pinhais, Londrina e Cascavel; e em termos per capita: Araucária, São José dos Pinhais, Cascavel e Curitib

are Surprisingly Useful for Computer-Supported Coordination

Management in the 1990s is an industry and governmental agency supported research program. Its aim is to develop a better understanding of the managerial issues of the 1990s and how to deal most effectively with them, particularly as these issues revolve around anticipated advances in Information Technology. Assisting the work of the Sloan School scholars with financial support and as working partners in research are