The Trp53 Hemizygous Mouse in Pharmaceutical Development: Points to Consider for Pathologists

ABSTRACT ILSI-HESI sponsored an international consortium for the evaluation of alternative models, including the Trp53 / mouse, for use in short-term carcinogenicit y testing of pharmaceuticals . Products of the ILSI evaluation included guidance for protocol design and assay interpretation, spontaneous tumor incidences, diagnostic criteria for common proliferative lesions, and results of assays for pharmaceutica l agents that are known human and/or rodent carcinogens and non-carcinogens . Based on the ILSI evaluation, recommende d protocol elements for this model include: 26-week study duration, groups 15/sex/dose, a positive control group (benzene or p-cresidine), a negative control group and 3 dose groups, the high dose set at MTD or MFD, routine in-life evaluations, and complete necropsies with microscopic evaluation of tissues. Favored statistical analyses are trend tests or pair-wise comparisons , with no adjustments for survival. For an assay to be valid, positive control groups must demonstrat e an effect, and the MTD or MFD must be reached in both sexes. Criteria for a negative response include a valid assay, no statistical increase in common tumors, no biologically signi cant numerical increase in rare tumors, and no tumor incidence above that of historical controls. Positive responses can consist of statistically signi cant increases in the incidence of a common tumor or numerical increases in a rare tumor, which may not be statistically signi cant. In either case, the incidence should be clearly above historical control values. Evidence of a dose response or occurrence of hyperplasia in a tissue with a neoplastic response can suppor t interpreting an assay as positive. The two most common spontaneou s tumors ( > 1%) in Trp53 / mice are malignant thymic lymphomas and subcutaneou s sarcomas. Use of implanted electronic transponder s can increase the incidence of sarcomas. Important rare spontaneou s tumors (incidence 1%) are osteosarcoma s and pulmonary adenomas. Many other tumor types have been reported to occur sporadically in Trp53 / mice. Diagnostic challenges for this model include differentiating lymphoma from atypical thymic hyperplasia and recognizing the variable histopatholog y of subcutaneous sarcomas. In reported bioassays, Trp53 / mice responded positively to genotoxic carcinogens , negatively to non-genotoxi c rodent carcinogens , and negatively to noncarcinogens , indicating that unlike the 2-year mouse assay, this short-term assay is not overly sensitive. Positive responses often elicited an increase in tumors that occur spontaneousl y. To successfully use this model, pathologists must understand the biology of the Trp53 tumor suppressor gene and the principles of protocol design and data interpretation for short-term bioassays. They must also know the historical response pattern of Trp53 / mice to test agents and be able to accurately diagnose tumors in this model. Use of the Trp53 / mouse presents the pharmaceutica l industry with several challenges, one of which is managing the uncertainty created by a lack of precedents for regulatory decisions about some possible outcomes for short-term carcinogenicity assays

Hierarchical domain structure and extremely large wall current in epitaxial BiFeO3 thin films

Funding: J.F.S. acknowledges the financial support of the Strategic Priority Research Program of the Chinese Academy of Sciences (grant number XDB07030200).Erasable electrical conductive domain walls in an insulating ferroelectric matrix provide novel functionalities for applications in logic and memory devices. The crux of such success requires sufficiently high wall currents to drive high‐speed and high‐power nanodevices. This work provides an appealing strategy to increase the current by two orders of magnitude through the careful selection of current flowing paths along the charged walls. The dense walls come into form through the hierarchical evolution of the 71°, 109°, and 180° domains of epitaxial BiFeO3 films in a planar‐geometry ferroelectric resistance‐switching memory cell. The engineered films grown on SrTiO3 and GdScO3 substrates allow the observation of detailed local configurations and the evolution of the different domain types using vector piezo‐force microscopy. The higher local electrical conductivity near the charged domain walls is identified by conductive atomic‐force microscopy. It is shown that 180° domain reversal proceeds by three‐step 71° rotations of the pristine domains. Surprisingly, a maximum current of ≈300 nA is observed for current paths along charge‐uncompensated head‐to‐head hierarchical domain walls connecting the two electrodes on the film surface. Furthermore, the achievable current level can be conveniently controlled by varying the relative directions of the initial polarization and the applied field.PostprintPeer reviewe

Place of Birth and Concepts of Wellbeing: An Analysis from Two Ethnographic Studies of Midwifery Units in England

This article is based on analysis of a series of ethnographic case studies of midwifery Units in England. Midwifery units are spaces that were developed to provide more home-like and less medically oriented care for birth that would support physiological processes of labour, women’s comfort and a positive experience of birth for women and their families. They are run by midwives, either on a hospital site alongside an obstetric unit (Alongside Midwifery Unit – AMU) or a freestanding unit away from an obstetric unit (Freestanding Midwifery Unit – FMU). Midwifery units have been designed and intended specifically as locations of wellbeing and although the meaning of the term is used very loosely in public discourse, this claim is supported by a large epidemiological study, which found that they provide safe care for babies while reducing use of medical interventions and with better health outcomes for the women. Our research indicated that midwifery units function as a protected space, one which uses domestic features as metaphors of home in order to promote a sense of wellbeing and to re-normalise concepts of birth, which had become inhabited by medical models and a preoccupation with risk. However, we argue that this protected space has a function for midwives as well as for birthing women. Midwifery units are intended to support midwives’ wellbeing following decades of professional struggles to maintain autonomy, midwife-led care and a professional identity founded on supporting normal, healthy birth. This development, which is focused on place of birth rather than other aspects of maternity care such as continuity, shows potential for restoring wellbeing on individual, professional and community levels, through improving rates of normal physiological birth and improving experiences of providing and receiving care. Nevertheless, this very focus also poses challenges for health service providers attempting to provide a ‘social model of care’ within an institutional context

Temporary formation of highly conducting domain walls for non-destructive read-out of ferroelectric domain-wall resistance switching memories

Funding: Strategic Priority Research Program of the Chinese Academy of Sciences (grant number XDB07030200) (JFS).Erasable conductive domain walls in insulating ferroelectric thin films can be used for non-destructive electrical read-out of the polarization states in ferroelectric memories. Still, the domain-wall currents extracted by these devices have not yet reached the intensity and stability required to drive read-out circuits operating at high speeds. This study demonstrated non-destructive read-out of digital data stored using specific domain-wall configurations in epitaxial BiFeO3 thin films formed in mesa-geometry structures. Partially switched domains, which enable the formation of conductive walls during the read operation, spontaneously retract when the read voltage is removed, reducing the accumulation of mobile defects at the domain walls and potentially improving the device stability. Three-terminal memory devices produced 14 nA read currents at an operating voltage of 5 V, and operated up to T = 85 °C. The gap length can also be smaller than the film thickness, allowing the realization of ferroelectric memories with device dimensions far below 100 nm.PostprintPostprintPeer reviewe

Murfreesboro Addresses

https://digitalcommons.acu.edu/crs_books/1086/thumbnail.jp

Evidence for steric regulation of fibrinogen binding to staphylococcus aureus fibronectin-binding protein A (FnBPA)

Background: Staphylococcus aureus fibronectin-binding protein A (FnBPA) binds fibronectin and fibrinogen at adjacent sites. Results: The fibrinogen-binding mechanism is similar but not identical to homologous bacterial proteins. Ternary complex formation by intact fibronectin and fibrinogen on adjacent FnBPA sites could not be demonstrated. Conclusion: Fibrinogen-binding is sterically regulated by fibronectin binding. Significance: Steric regulation might result in targeting of S. aureus to fibrin clots. ABSTRACT The adjacent fibrinogen (Fg)- and fibronectin (Fn)- binding sites on Fn-binding protein A (FnBPA), a cell-surface protein from Staphylococcus aureus, are implicated in the initiation and persistence of infection. FnBPA contains a single Fg-binding site (that also binds elastin) and multiple Fn-binding sites. Here, we solved the structure of the N2N3 domains containing the Fg-binding site of FnBPA in the apo-form and in complex with a Fg-peptide. The Fg-binding mechanism is similar to that of homologous bacterial proteins but without the requirement for “latch” strand residues. We show that the Fg- and the most N-terminal Fn-binding sites are non-overlapping but in close proximity. While Fg and a sub-domain of Fn can form a ternary complex on an FnBPA protein construct containing a Fg- and single Fn-binding site, binding of intact Fn appears to inhibit Fg binding, suggesting steric regulation. Given the concentrations of Fn and Fg in the plasma, this mechanism might result in targeting of S. aureus to fibrin-rich thrombi or elastin-rich tissues

A People’s History of Leisure Studies : Old Knowledge, New Knowledge and The Philadelphia Negro as a Foundational Text

There is a great realization that a professor teaching an introductory or philosophical foundations course in the field of leisure studies comes to, if that professor may not be from the dominant culture of most Western societies. This realization is as stark as their numerical presence in their respective departments. Why are the philosophical foundations of the field devoid of the experiences, voices, and perspectives populations of color, or even more broadly, the populations of the global majority? And, why is there an absence of historical discussions on the field’s role in perpetrating or condoning activities that hindered or constrained populations of color full access, enjoyment, and articulation of leisure? As we move forward in the field more globally, thinking and discussing the new and progressive ways that we can conceive the sociology of leisure, it is imperative that we rethink our philosophical foundations in reconciliation of the potential harm it may have caused (and may continue to harm) and the actual good it can invoke in assisting the myriad of scholars who are pushing more progressive efforts for a critical leisure paradigm (Spracklen, Lashua, Sharpe and Swain, 2017). The objectives of this manuscript are: 1) to briefly categorize the research in the field on Race and ethnicity; 2) to outline the key canonical texts of the field; 3) to consider and reconceptualize a racially and ethnically inclusive foundation for the field utilizing The Philadelphia Negro: A Social Study as an example; and, 4) to identify some of the specific areas that this change and inclusion would impact or realign the field’s history

Incidence and Risk of QTc Interval Prolongation among Cancer Patients Treated with Vandetanib: A Systematic Review and Meta-analysis

Vandetanib is a multikinase inhibitor that is under assessment for the treatment of various cancers. QTc interval prolongation is one of the major adverse effects of this drug, but the reported incidence varies substantially among clinical trials. We performed a systematic review and meta-analysis to obtain a better understanding in the risk of QTc interval prolongation among cancer patients administered vandetanib.Eligible studies were phase II and III prospective clinical trials that involved cancer patients who were prescribed vandetanib 300 mg/d and that included data on QTc interval prolongation. The overall incidence and risk of QTc interval prolongation were calculated using random-effects or fixed-effects models, depending on the heterogeneity of the included studies. Nine trials with 2,188 patients were included for the meta-analysis. The overall incidence of all-grade and high-grade QTc interval prolongation was 16.4% (95% CI, 8.1-30.4%) and 3.7% (8.1-30.4%), respectively, among non-thyroid cancer patients, and 18.0% (10.7-28.6%) and 12.0% (4.5-28.0%), respectively, among thyroid cancer patients. Patients with thyroid cancer who had longer treatment duration also had a higher incidence of high-grade events, with a relative risk of 3.24 (1.57-6.71), than patients who had non-thyroid cancer. Vandetanib was associated with a significantly increased risk of all-grade QTc interval prolongation with overall Peto odds ratios of 7.26 (4.36-12.09) and 5.70 (3.09-10.53) among patients with non-thyroid cancer and thyroid cancer, respectively, compared to the controls.Treatment with vandetanib is associated with a significant increase in the overall incidence and risk of QTc interval prolongation. Different cancer types and treatment durations may affect the risk of developing high-grade QTc interval prolongation

OAS1 Polymorphisms Are Associated with Susceptibility to West Nile Encephalitis in Horses

West Nile virus, first identified within the United States in 1999, has since spread across the continental states and infected birds, humans and domestic animals, resulting in numerous deaths. Previous studies in mice identified the Oas1b gene, a member of the OAS/RNASEL innate immune system, as a determining factor for resistance to West Nile virus (WNV) infection. A recent case-control association study described mutations of human OAS1 associated with clinical susceptibility to WNV infection. Similar studies in horses, a particularly susceptible species, have been lacking, in part, because of the difficulty in collecting populations sufficiently homogenous in their infection and disease states. The equine OAS gene cluster most closely resembles the human cluster, with single copies of OAS1, OAS3 and OAS2 in the same orientation. With naturally occurring susceptible and resistant sub-populations to lethal West Nile encephalitis, we undertook a case-control association study to investigate whether, similar to humans (OAS1) and mice (Oas1b), equine OAS1 plays a role in resistance to severe WNV infection. We identified naturally occurring single nucleotide mutations in equine (Equus caballus) OAS1 and RNASEL genes and, using Fisher's Exact test, we provide evidence that mutations in equine OAS1 contribute to host susceptibility. Virtually all of the associated OAS1 polymorphisms were located within the interferon-inducible promoter, suggesting that differences in OAS1 gene expression may determine the host's ability to resist clinical manifestations associated with WNV infection