The paradox of cancer genes in non-malignant conditions: implications for precision medicine.

Next-generation sequencing has enabled patient selection for targeted drugs, some of which have shown remarkable efficacy in cancers that have the cognate molecular signatures. Intriguingly, rapidly emerging data indicate that altered genes representing oncogenic drivers can also be found in sporadic non-malignant conditions, some of which have negligible and/or low potential for transformation to cancer. For instance, activating KRAS mutations are discerned in endometriosis and in brain arteriovenous malformations, inactivating TP53 tumor suppressor mutations in rheumatoid arthritis synovium, and AKT, MAPK, and AMPK pathway gene alterations in the brains of Alzheimer's disease patients. Furthermore, these types of alterations may also characterize hereditary conditions that result in diverse disabilities and that are associated with a range of lifetime susceptibility to the development of cancer, varying from near universal to no elevated risk. Very recently, the repurposing of targeted cancer drugs for non-malignant conditions that are associated with these genomic alterations has yielded therapeutic successes. For instance, the phenotypic manifestations of CLOVES syndrome, which is characterized by tissue overgrowth and complex vascular anomalies that result from the activation of PIK3CA mutations, can be ameliorated by the PIK3CA inhibitor alpelisib, which was developed and approved for breast cancer. In this review, we discuss the profound implications of finding molecular alterations in non-malignant conditions that are indistinguishable from those driving cancers, with respect to our understanding of the genomic basis of medicine, the potential confounding effects in early cancer detection that relies on sensitive blood tests for oncogenic mutations, and the possibility of reverse repurposing drugs that are used in oncology in order to ameliorate non-malignant illnesses and/or to prevent the emergence of cancer

Accountants\u27 responsibility for the information they report: An historical case study of financial information

This paper describes an instructional case that uses historical documentation to enable the reader to consider his/her own responsibility for the preparation and reporting of information. In this case, the reader is provided a summarized income statement. Then, as detailed information about the financial statement is introduced, the reader is asked to consider the ethics of preparing and using the statement. The financial statement represents a projected income statement for a Holocaust camp prisoner during World War II. The statement includes anticipated revenue from the selling of body parts upon the prisoner\u27s death, estimated as nine months from the time of arrival at the camp. Usage of the case should develop a reader\u27s understanding that accountants\u27 responsibility for the preparation of information should not be separate from what the information reports or the intended use of the information

Transparency and Accountability for Bequests: The Case of Long Island College Hospital

Restricted bequests to not-for-profit organizations can be challenging. Often there is significant lag time between commitment of bequest and death of donor, when operational changes in the beneficiary organization may occur that make adherence to bequest restrictions difficult. Governance systems, external to and within the organization, should exist to monitor the organization’s acceptance and use of bequests. Using the $138 million bequest by Donald and Mildred Othmer to Long Island College Hospital as an example, we consider the stewardship of charitable bequests and the failure of the governance mechanisms in accepting and maintaining bequest restrictions

An operational measure of liquidity

Economists' view of liquidity is askin to Supreme Court Justice Stewart's View of hard-core pornography: I shall not ... attempt further to define (it) .... But I know it when I see it. Embedding the process of selling an asset in a search environment enables us to provide an exact definition of liquidity: an asset's liquidity is the expected time until it is sold while pursuing an optimal (in the sense of maximization of expected discounted net proceeds) policy. Our analysis reveals that this definition is compatible with most other notions of liquidity and, in particular, with those of Keynes1 , impatience, the discount associated with a quick sale, and predictability

Construction of Non-Perturbative, Unitary Particle-Antiparticle Amplitudes for Finite Particle Number Scattering Formalisms

Starting from a unitary, Lorentz invariant two-particle scattering amplitude , we show how to use an identification and replacement process to construct a unique, unitary particle-antiparticle amplitude. This process differs from conventional on-shell Mandelstam s,t,u crossing in that the input and constructed amplitudes can be off-diagonal and off-energy shell. Further, amplitudes are constructed using the invariant parameters which are appropriate to use as driving terms in the multi-particle, multichannel non-perturbative, cluster decomposable, relativistic scattering equations of the Faddeev-type integral equations recently presented by Alfred, Kwizera, Lindesay and Noyes. It is therefore anticipated that when so employed, the resulting multi-channel solutions will also be unitary. The process preserves the usual particle-antiparticle symmetries. To illustrate this process, we construct a J=0 scattering length model chosen for simplicity. We also exhibit a class of physical models which contain a finite quantum mass parameter and are Lorentz invariant. These are constructed to reduce in the appropriate limits, and with the proper choice of value and sign of the interaction parameter, to the asymptotic solution of the non-relativistic Coulomb problem, including the forward scattering singularity, the essential singularity in the phase, and the Bohr bound-state spectrum

Donor conception and (dis)closure in the UK::siblingship, friendship and kinship

As many aspects of assisted conception become familiar, others emerge not only as unfamiliar, but also unpredicted. This article focuses on a newly emergent kin figure – the donor sibling. It suggests that the anthropology of friendship might have as much to tell us about the significance of the donor sibling in Euro-American kinship thinking as the anthropology of kinship. The article locates the donor-sibling in changes in UK legislation and policy that have increasingly promoted more transparency and ‘openness’ in donor conception

Control of inflorescence architecture in tomato by BTB/POZ transcriptional regulators

Plant productivity depends on inflorescences, flower-bearing shoots that originate from the stem cell populations of shoot meristems. Inflorescence architecture determines flower production, which can vary dramatically both between and within species. In tomato plants, formation of multiflowered inflorescences depends on a precisely timed process of meristem maturation mediated by the transcription factor gene TERMINATING FLOWER (TMF), but the underlying mechanism is unknown. We show that TMF protein acts together with homologs of the Arabidopsis BLADE-ON-PETIOLE (BOP) transcriptional cofactors, defined by the conserved BTB (Broad complex, Tramtrack, and Bric-a-brac)/POZ (POX virus and zinc finger) domain. TMF and three tomato BOPs (SlBOPs) interact with themselves and each other, and TMF recruits SlBOPs to the nucleus, suggesting formation of a transcriptional complex. Like TMF, SlBOP gene expression is highest during vegetative and transitional stages of meristem maturation, and CRISPR/Cas9 elimination of SlBOP function causes pleiotropic defects, most notably simplification of inflorescences into single flowers, resembling tmf mutants. Flowering defects are enhanced in higher-order slbop tmf mutants, suggesting that SlBOPs function with additional factors. In support of this, SlBOPs interact with TMF homologs, mutations in which cause phenotypes like slbop mutants. Our findings reveal a new flowering module defined by SlBOP-TMF family interactions that ensures a progressive meristem maturation to promote inflorescence complexity

Anisotropic Aerogels for Studying Superfluid 3^3He

It may be possible to stabilize new superfluid phases of $^{3}$He with anisotropic silica aerogels. We discuss two methods that introduce anisotropy in the aerogel on length scales relevant to superfluid $^{3}$He. First, anisotropy can be induced with uniaxial strain. A second method generates anisotropy during the growth and drying stages. We have grown cylindrical $\sim$98% aerogels with anisotropy indicated by preferential radial shrinkage after supercritical drying and find that this shrinkage correlates with small angle x-ray scattering (SAXS). The growth-induced anisotropy was found to be $\sim90^\circ$ out of phase relative to that induced by strain. This has implications for the possible stabilization of superfluid phases with specific symmetry.Comment: 6 pages, 4 figures, submitted to Quantum Fluids and Solids (QFS) conference 200