DNA damage response activated by anti-cancer agent, irofulven

The DNA damage response is a complex network of signals that coordinate to protect cells from accumulating mutations that lead to the development of cancer. Upon the introduction of DNA damage from either environmental or endogenous sources, the DNA damage response coordinates the control of cell cycle with DNA repair mechanisms to ensure genomic integrity within the cell. Mutations in proteins in this pathway lead to genomic instability and early onset of cancer. BRCA1 is a protein that plays a critical role in response to DNA damage caused by ionizing radiation and is responsible for approximately 50% of inherited breast and ovarian cancers. A key element in the response to DNA damage is the exact type of lesion produced. Irofulven represents a novel DNA damaging agent that may provide insight into specific signals involved. It also remains to be determined if tumors that have mutations in BRCA1 may be more or less sensitive to treatment with irofulven. The exact method by which irofulven kills cells also remains to be determined. Many chemotherapeutics are potent inducers of apoptosis and irofulven has been shown to activate elements of the apoptotic pathway. Previous work in our lab has shown the ability of irofulven to activate ATM and CHK2. Based on the fact that BRCA1 lies directly downstream in this pathway, we hypothesized that it plays a key role in the irofulven induced DNA damage response.;In our current study, we determined that BRCA1 plays a role in regulation of S and G2/M cell cycle checkpoints after irofulven exposure. We also demonstrated that DNA repair via homologous recombination plays a role in response to DNA damage induced by irofulven and that cells deficient in such repair are more sensitive to irofulven. Lastly, we demonstrated that the activation of apoptosis by irofulven is regulated by caspases 2 and 9, while caspase 8 seems to render cells resistant. Taken together, this study expanded our knowledge of signaling pathways activated by irofulven and provides a basis for targeted treatment in BRCA1 deficient breast and ovarian cancers

Experiential Education in the English Classroom

In this paper, the idea of experiential education is explored. Language learning has often been the way by which other subjects or ideas can be learned. In the English classroom, and essentially with any classroom, it is possible to allow students to discover things which would normally be experienced only outside the classroom. This is possible through video, role-playing and other techniques which help students to empathize with other people as a form of practice before they actually come in contact with anyone. This is especially important in the medical profession where practicum is an integral part of the learning process before actual contact with patients is allowed. An explanation and some examples of teaching in the English classroom are given in the Discussion

Observational Cosmology in Macroscopic Gravity

We discuss the construction of cosmological models within the framework of Macroscopic Gravity (MG), which is a theory that models the effects of averaging the geometry of space-time on large scales. We find new exact spatially homogeneous and isotropic FLRW solutions to the MG field equations, and investigate large-scale perturbations around them. We find that any inhomogeneous perturbations to the averaged geometry are severely restricted, but that possible anisotropies in the correlation tensor can have dramatic consequences for the measurement of distances. These calculations are a first step within the MG approach toward developing averaged cosmological models to a point where they can be used to interpret real cosmological data, and hence to provide a working alternative to the "concordance" LCDM model.Comment: 22 page

GENDER DIFFERENCES IN TECHNIQUE SELECTION: ELBOW AND WRIST JOINT LOADING DURING ROUND OFF IN GYMNASTICS

The aim of the study was to determine sex differences in the key elbow and wrist joint injury risk factors during different round-off (RO) techniques performed by young male and female gymnasts. Eight male and female young gymnasts performed 30 successful trials of RO with different hand positions (parallel [10], T-shape [10] and reverse [10]). Synchronized kinematic and kinetic data were collected for each trial. Two-way repeated measures ANOVA (3×2, technique×sex) and effect-size (ES) were used for statistical analysis. Risk factors including peak vertical ground reaction forces (VGRF), elbow and wrist compression forces, elbow internal adduction moments and elbow extension suggest that a RO in reverse and parallel techniques can be hazardous especially for young female gymnasts compared to male

Guided Discussion and Activities in English for Future Health Professionals: Relationships between Nursing and Community Design

Recent interest in community design has become evident in medical circles. Relationships between a community’s design, its function, and citizens’ health are an increasing concern for people who care about the quality of human life. Among these people, an influential group is health professionals. They can play a great part in how a community can be constructed or (re)designed to afford better living conditions in society. To develop a sense of the importance of involvement in community planning and clarify the health needs of citizens, and to rethink ideas about responsibilities of health professionals, medical education should provide classes, seminars, lectures and activities to give students chances to explore possibilities of direct involvement for creating a healthy community. At the Tottori University Faculty of Medicine, a seminar was held for 3rd-year nursing students and faculty members on community development and design as related to health. The main lecturer explained how trends in various diseases and increases in obesity in the United States are directly related to how communities are designed. Although the lecture was in English, translation into Japanese was provided with a question-and-answer period at the end. In preparation for the lecture, students were given two questions on the relationship between nursing and community design. As this lecture occurred at the end of the year, further study could not be done. This paper presents ideas for giving future health professionals opportunities to explore a new direction. Class activities are outlined with an emphasis on English language teaching and learning techniques

Atm-Dependent Chk2 Activation Induced By Anticancer Agent, Irofulven

Irofulven (6-hydroxymethylacylfulvene, HMAF, MGI 114) is one of a new class of anticancer agents that are semisynthetic derivatives of the mushroom toxin illudin S. Preclinical studies and..

Willingness to comply with biosecurity in livestock facilities: Evidence from experimental simulations

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Disease in U.S. animal livestock industries annually costs over a billion dollars. Adoption and compliance with biosecurity practices is necessary to successfully reduce the risk of disease introduction or spread. Yet, a variety of human behaviors, such as the urge to minimize time costs, may induce non-compliance with biosecurity practices. Utilizing a “serious gaming” approach, we examine how information about infection risk impacts compliance with biosecurity practices. We sought to understand how simulated environments affected compliance behavior with treatments that varied using three factors: (1) the risk of acquiring an infection, (2) the delivery method of the infection risk message (numerical, linguistic and graphical), and (3) the certainty of the infection risk information. Here we show that compliance is influenced by message delivery methodology, with numeric, linguistic, and graphical messages showing increasing efficacy, respectively. Moreover, increased situational uncertainty and increased risk were correlated with increases in compliance behavior. These results provide insight toward developing messages that are more effective and provide tools that will allow managers of livestock facilities and policy makers to nudge behavior toward more disease resilient systems via greater compliance with biosecurity practices

Decision-making in livestock biosecurity practices amidst environmental and social uncertainty: Evidence from an experimental game

Livestock industries are vulnerable to disease threats, which can cost billions of dollars and have substantial negative social ramifications. Losses are mitigated through increased use of disease-related biosecurity practices, making increased biosecurity an industry goal. Currently, there is no industry-wide standard for sharing information about disease incidence or on-site biosecurity strategies, resulting in uncertainty regarding disease prevalence and biosecurity strategies employed by industry stakeholders. Using an experimental simulation game, with primarily student participants, we examined willingness to invest in biosecurity when confronted with disease outbreak scenarios. We varied the scenarios by changing the information provided about 1) disease incidence and 2) biosecurity strategy or response by production facilities to the threat of disease. Here we show that willingness to invest in biosecurity increases with increased information about disease incidence, but decreases with increased information about biosecurity practices used by nearby facilities. Thus, the type or context of the uncertainty confronting the decision maker may be a major factor influencing behavior. Our findings suggest that policies and practices that encourage greater sharing of disease incidence information should have the greatest benefit for protecting herd health

Impact of human CA8 on thermal antinociception in relation to morphine equivalence in mice

Recently, we showed that murine dorsal root ganglion (DRG) Car8 expression is a cis-regulated eQTL that determines analgesic responses. In this report, we show that transduction through sciatic nerve injection of DRG with human wild-type carbonic anhydrase-8 using adeno-associated virus viral particles (AAV8-V5-CA8WT) produces analgesia in naive male C57BL/6J mice and antihyperalgesia after carrageenan treatment. A peak mean increase of about 4 s in thermal hindpaw withdrawal latency equaled increases in thermal withdrawal latency produced by 10 mg/kg intraperitoneal morphine in these mice. Allometric conversion of this intraperitoneal morphine dose in mice equals an oral morphine dose of about 146 mg in a 60-kg adult. Our work quantifies for the first time analgesia and antihyperalgesia in an inflammatory pain model after DRG transduction by CA8 gene therapy