Epigenetic dysregulation in chronic myeloid leukaemia: A myriad of mechanisms and therapeutic options

The onset of global epigenetic changes in chromatin that drive tumor proliferation and heterogeneity is a hallmark of many forms cancer. Identifying the epigenetic mechanisms that govern these changes and developing therapeutic approaches to modulate them, is a well-established avenue pursued in translational cancer medicine. Chronic myeloid leukemia (CML) arises clonally when a hematopoietic stem cell (HSC) acquires the capacity to produce the constitutively active tyrosine kinase BCR-ABL1 fusion protein which drives tumor development. Treatment with tyrosine kinase inhibitors (TKI) that target BCR-ABL1 has been transformative in CML management but it does not lead to cure in the vast majority of patients. Thus novel therapeutic approaches are required and these must target changes to biological pathways that are aberrant in CML − including those that occur when epigenetic mechanisms are altered. These changes may be due to alterations in DNA or histones, their biochemical modifications and requisite ‘writer’ proteins, or to dysregulation of various types of non-coding RNAs that collectively function as modulators of transcriptional control and DNA integrity. Here, we review the evidence for subverted epigenetic mechanisms in CML and how these impact on a diverse set of biological pathways, on disease progression, prognosis and drug resistance. We will also discuss recent progress towards developing epigenetic therapies that show promise to improve CML patient care and may lead to improved cure rates

Welfare Analysis of Regulating Mobile Termination Rates in the UK (with an Application to the Orange/T-Mobile Merger)

This paper presents results from a calibrated welfare model of the UK mobile telephony market which includes many mobile networks; calls to and from the fixed network; networkbased price discrimination; and call externalities. The analysis focuses on the short-run effects of adopting lower mobile termination rates (MTRs) on total welfare, consumer surplus and profits. Our simulations show that reducing MTRs broadly in line with the recent European Commission Recommendation to either “long-run incremental cost”; reciprocal termination charges with fixed networks; or “bill-and-keep” (i.e. zero termination rates), increases social welfare, consumer surplus and networks’ profits. Depending on the strength of call externalities, social welfare may increase by as much as £360 million to £2.5 billion per year. The analysis thus lends support to a move away from fully-allocated cost pricing and towards much lower MTRs, with bill-and-keep frequently leading to the highest increase in welfare when call externalities matter. We also apply the model to estimate the welfare effects of the recently-approved merger between Orange and T-Mobile under two different scenarios concerning MTRs.telecommunications; regulation; mobile termination rates; network effects; welfare; simulations welfare, simulations

Implicit Contracts, Unemployment, and Labor Market Segmentation

We analyze the impact of imperfect contract enforcement on the emergence of unemployment. In an experimental labor market where trading parties can form long-term employment relationships, we compare a work environment where effort is observable, but not verifiable to a situation where explicit contracts are feasible. Our main result shows that unemployment is much higher when third-party contract enforcement is absent. Unemployment is involuntary, being caused by firms' employment and contracting policy. Moreover, we show that implicit contracting can lead to a segmentation of the labor market. Firms in both segments earn similar profits, but workers in the secondary sector face much less favorable conditions than their counterparts in primary-sector jobs.incentives, implicit contracts, unemployment, fairness, dual labor markets