Pivotal Role of Inosine Triphosphate Pyrophosphatase in Maintaining Genome Stability and the Prevention of Apoptosis in Human Cells

Pure nucleotide precursor pools are a prerequisite for high-fidelity DNA replication and the suppression of mutagenesis and carcinogenesis. ITPases are nucleoside triphosphate pyrophosphatases that clean the precursor pools of the non-canonical triphosphates of inosine and xanthine. The precise role of the human ITPase, encoded by the ITPA gene, is not clearly defined. ITPA is clinically important because a widespread polymorphism, 94C>A, leads to null ITPase activity in erythrocytes and is associated with an adverse reaction to thiopurine drugs. We studied the cellular function of ITPA in HeLa cells using the purine analog 6-N hydroxylaminopurine (HAP), whose triphosphate is also a substrate for ITPA. In this study, we demonstrate that ITPA knockdown sensitizes HeLa cells to HAP-induced DNA breaks and apoptosis. The HAP-induced DNA damage and cytotoxicity observed in ITPA knockdown cells are rescued by an overexpression of the yeast ITPase encoded by the HAM1 gene. We further show that ITPA knockdown results in elevated mutagenesis in response to HAP treatment. Our studies reveal the significance of ITPA in preventing base analog-induced apoptosis, DNA damage and mutagenesis in human cells. This implies that individuals with defective ITPase are predisposed to genome damage by impurities in nucleotide pools, which is drastically augmented by therapy with purine analogs. They are also at an elevated risk for degenerative diseases and cancer

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

Biological control of postharvest diseases by microbial antagonists: how many mechanisms of action?

The postharvest phase has been considered an environment for successful application of biological control agents (BCAs). However, the interactions between fungal pathogen, host (fruit), and antagonist are influenced by several parameters such as temperature, oxidative stresses, oxygen composition and water activity that could determine the success of biocontrol. Knowledge of the modes of action of BCAs is essential in order to enhance their viability and increase their potential in disease control. The antagonists display a wide range of modes of action: antibiosis, competition for nutrients and space, parasitism and induction of resistance are considered the main ones. Their efficacy, however, is related to the host and the pathogen; sometimes, these mechanisms could act simultaneously, and it is therefore difficult to establish which is related to a specific antifungal action. The current review presents a brief summary of the research that has led to a better understanding of the mode of action of BCAs with particular emphasis on the most recent literature

Biological Control of Postharvest Diseases by Microbial Antagonists

The postharvest phase has been considered a very suitable environment for successful application of biological control agents (BCAs), since the first work on the biological control of brown rot disease of stone fruit was reported by Pusey and Wilson [1]. Sure enough, the conditions of constant temperature and high humidity seem to offer more chances to BCAs, increasing their antifungal activity [2]. BCAs are living organisms and act following different antagonistic strategies depending on pathogens, host and environment. Knowledge of their modes of action is therefore essential to enhance their viability and increase their potentiality in disease control. In general, antagonists used for biocontrol of postharvest diseases are yeasts and bacteria, and to a lesser extent fungi, and they have been widely reviewed [3\u20137]. Antagonists can display a wide range of modes of action, at different stages of their activity, relating to different hosts, pathogens; sometimes-different modes act simultaneously, and it is therefore difficult to establish which individual mechanism has contributed to a specific antifungal action. Considerable information is available with respect to their efficacy, their application under storage conditions, and their mixture with safe substances or according to the formulation. However, the mechanisms by which BCAs exert their activity against pathogens have not yet been fully elucidated [5] and sometimes, in order to achieve maximum effectiveness in postharvest phase, were combined with physical and chemical methods including heat treatments, gamma or UV-C irradiation, and controlled atmosphere (CA). The bottleneck of the biocontrol matter remains the BCAs formulation often done in association with private companies, due to the high costs of production and the regulatory barriers to BCAs registration in different countries that often do not encourage their dissemination. Also, a formulation often could reduce the activity of antagonists with respect to the fresh cells [2]