Mutations and Deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascades Which Alter Therapy Response

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cascades can contribute to: resistance to other pathway inhibitors, chemotherapeutic drug resistance, premature aging as well as other diseases. This review will first describe these pathways and discuss how genetic mutations and epigenetic alterations can result in resistance to various inhibitors

Principle-agent Incentives, Excess Caution, and Market Inefficiency: Evidence from Utility Regulation

Regulators and firms often use incentive schemes to attract skillful agents and to induce them to put forth effort in pursuit of the principals’ goals. Incentive schemes that reward skill and effort, however, may also punish agents for adverse outcomes beyond their control. As a result, such schemes may induce inefficient behavior, as agents try to avoid actions that might make it easier to directly associate a bad outcome with their decisions. In this paper, we study how such caution on the part of individual agents may lead to inefficient market outcomes, focusing on the context of natural gas procurement by regulated public utilities. We posit that a regulated natural gas distribution company may, due to regulatory incentives, engage in excessively cautious behavior by foregoing surplus increasing gas trades that could be seen ex post as having caused supply curtailments to its customers. We derive testable implications of such behavior and show that the theory is supported empirically in ways that cannot be explained by conventional price risk aversion or other explanations. Furthermore, we demonstrate that the reduction in efficient trade caused by the regulatory mechanism is most severe during periods of relatively high demand and low supply, when the benefits of trade would be greatest

How do genetically disabled adults view selective reproduction? : impairment, identity and genetic screening

Background: Genomic medicine is rapidly evolving, particularly in the domain of reproduction. Population carrier screening for a range of disorders is becoming possible using whole genome/exome sequencing. However, very little is known about the views of genetically disabled attitudes towards selective reproduction. Methods: Forty-three in-depth qualitative interviews were carried out with adults living with different types of genetic condition, recruited through support groups and clinics. Interviews covered participants’ experiences of their condition and their views towards genetic intervention in reproduction. Thematic analysis of the data using Nvivo 11 was undertaken and participants were assigned categorises as either supporting, not-supporting, or having ambivalent views. Results: The majority of participants (65%) expressed either disapproval of, or held ambivalent views towards, selective reproduction. Key reasons for non-support included regarding genetic impairment as part of personal identity and the prioritisation of social and environmental barrier removal. Key reasons for support of selective reproduction included negative and externalising attitudes towards genetic impairment and a belief in the importance of informed reproductive decision-making. Conclusion: The degree to which participants identified with their impairment, more so than how they valued it, was significant in determining attitudes towards selective reproduction. Those who supported genetic screening viewed their impairment as separate to themselves, whilst participants who considered their impairment as integral to their identity were most likely to report ambivalence or negative attitudes. Policy makers and stakeholders considering the role of genetic carrier screening panels might usefully engage with adults affected by heritable disease as well as disability identity politics when considering the acceptability and social impact of genetic screening programmes