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JAK2 V617F is a gain of function mutation that promotes cytokine-independent growth of myeloid cells and accounts for a majority of myeloproliferative neoplasms (MPN). Mutations in p53 are rarely found in these diseases before acute leukemia transformation, but this does not rule out a role for p53 deregulation in disease progression. Using Ba/F3-EPOR cells and ex vivo cultured CD34 + cells from MPN patients, we demonstrate that expression of JAK2 V617F affected the p53 response to DNA damage. We show that E3 ubiquitin ligase MDM2 accumulated in these cells, due to an increased translation of MDM2 mRNA. Accumulation of the La autoantigen, which interacts with MDM2 mRNA and promotes its translation, was responsible for the increase in MDM2 protein level and the subsequent degradation of p53 after DNA damage. Downregulation of La protein or cell treatment with nutlin-3, a MDM2 antagonist, restored the p53 response to DNA damage and the cytokine-dependence of Ba/F3-EPOR-JAK2 V617F cells. Altogether, these data indicate that the JAK2 V617F mutation affects p53 response to DNA damage through the upregulation of La antigen and accumulation of MDM2. They also suggest that p53 functional inactivation accounts for the cytokine hypersensitivity of JAK2 V617F MPN and might have a role in disease progression.

In scheduling problems with two competing agents, each one of the agents has his own set of jobs and his own objective function, but both share the same processor. The goal is to minimize the value of the objective function of one agent, subject to an upper bound on the value of the objective function of the second agent. In this paper we study two-agent scheduling problems on a proportionate flowshop. Three objective functions of the first agent are considered: minimum maximum cost of all the jobs, minimum total completion time, and minimum number of tardy jobs. For the second agent, an upper bound on the maximum allowable cost is assumed. We introduce efficient polynomial time solution algorithms for all cases.

JAK2(V617F) is a gain of function mutation that promotes cytokine-independent growth of myeloid cells and accounts for a majority of myeloproliferative neoplasms (MPN). Mutations in p53 are rarely found in these diseases before acute leukemia transformation, but this does not rule out a role for p53 deregulation in disease progression. Using Ba/F3-EPOR cells and ex vivo cultured CD34(+) cells from MPN patients, we demonstrate that expression of JAK2(V617F) affected the p53 response to DNA damage. We show that E3 ubiquitin ligase MDM2 accumulated in these cells, due to an increased translation of MDM2 mRNA. Accumulation of the La autoantigen, which interacts with MDM2 mRNA and promotes its translation, was responsible for the increase in MDM2 protein level and the subsequent degradation of p53 after DNA damage. Downregulation of La protein or cell treatment with nutlin-3, a MDM2 antagonist, restored the p53 response to DNA damage and the cytokine-dependence of Ba/F3-EPOR-JAK2(V617F) cells. Altogether, these data indicate that the JAK2(V617F) mutation affects p53 response to DNA damage through the upregulation of La antigen and accumulation of MDM2. They also suggest that p53 functional inactivation accounts for the cytokine hypersensitivity of JAK2(V617F) MPN and might have a role in disease progression.

In due-date assignment problems with a common flow-allowance, the due-date of a given job is defined as the sum of its processing time and a job-independent constant. We study flow-allowance on a single machine, with an objective function of a minmax type. The total cost of a given job consists of its earliness/tardiness and its flow-allowance cost components. Thus, we seek the job schedule and flow-allowance value that minimize the largest cost among all the jobs. Three extensions are considered: the case of general position-dependent processing times, the model containing an explicit cost for the due-dates, and the setting of due-windows. Properties of optimal schedules are fully analysed in all cases, and all the problems are shown to have polynomial time solutions.

We study the optimality of the very practical policy of equal allocation of jobs to batches in batch scheduling problems on an m-machine open shop. The objective is minimum makespan. We assume unit processing time jobs, machine-dependent setup times and batch availability. We show that equal allocation is optimal for a two-machine and a three-machine open shop. Although, this policy is not necessarily optimal for larger size open shops, it is shown numerically to produce very close-to-optimal schedules.

[JAK2.sup.V617F] is a gain of function mutation that promotes cytokine-independent growth of myeloid cells and accounts for a majority of myeloproliferative neoplasms (MPN). Mutations in p53 are rarely found in these diseases before acute leukemia transformation, but this does not rule out a role for p53 deregulation in disease progression. Using Ba/F3-EPOR cells and ex vivo cultured [CD34.sup.+] cells from MPN patients, we demonstrate that expression of [JAK2.sup.V617F] affected the p53 response to DNA damage. We show that E3 ubiquitin ligase MDM2 accumulated in these cells, due to an increased translation of MDM2 mRNA. Accumulation of the La autoantigen, which interacts with MDM2 mRNA and promotes its translation, was responsible for the increase in MDM2 protein level and the subsequent degradation of p53 after DNA damage. Downregulation of La protein or cell treatment with nutlin-3, a MDM2 antagonist, restored the p53 response to DNA damage and the cytokine-dependence of Ba/F3-EPOR [JAK2.sup.V617F] cells. Altogether, these data indicate that the [JAK2.sup.V617F] mutation affects p53 response to DNA damage through the upregulation of La antigen and accumulation of MDM2. They also suggest that p53 functional inactivation accounts for the cytokine hypersensitivity of [JAK2.sup.V617F] MPN and might have a role in disease progression.

Reduced range of motion, prosthetic impingement, and joint dislocation can all result from misalignment of the acetabular component (i.e. cup alignment) in patients undergoing total hip arthroplasty. Most methods for acetabular component alignment are designed to provide 45–50° abduction and 15–25° of operative anteversion (also known as flexion) with respect to the anterior pelvic plane coordinate system. Yet in most cases, this coordinate system is not assigned properly, due to differences in patient anatomy and improper positioning in the operating room. This misalignment can result in an error in the cup alignment, which can cause the above-mentioned consequences. This work presents a complete mathematical formulation for the analysis of the inaccuracies related to the anterior pelvic plane axes (APPA) definition and their effect on final cup orientation. We do this by introducing a method taken from Kinematics of Mechanisms, and by representing the errors in the APPA as three concurrent axes of rotation, followed by the version and abduction rotations which are defined relative to the previous rotations. We also present a sensitivity analysis of the results by introducing differential changes between sequential coordinate frames, which simulates the errors in the APPA and their effect on cup orientation. Finally, we demonstrate a computational method which provides corrected version and abduction angles to achieve the desired cup orientation, given that the actual measurement errors are known.

The JAK2 V617F mutation, present in the majority of polycythemia vera (PV) patients, causes constitutive activation of JAK2 and seems to be responsible for the PV phenotype. However, the transcriptional changes triggered by the mutation have not yet been totally characterized. In this study, we performed a large-scale gene expression study using serial analysis of gene expression in bone marrow cells of a newly diagnosed PV patient harboring the JAK2 V617F mutation and in normal bone marrow cells of healthy donors. JUNB was one of the genes upregulated in PV, and we confirmed, by quantitative real-time PCR, an overexpression of JUNB in hematopoietic cells of other JAK2 V617F PV patients. Using Ba/F3-EPOR cell lines and primary human erythroblast cultures, we found that JUNB was transcriptionally induced after erythropoietin addition and that JAK2 V617F constitutively induced JunB protein expression. Furthermore, JUNB knockdown reduced not only the growth of Ba/F3 cells by inducing apoptosis, but also the clonogenic and proliferative potential of human erythroid progenitors. These results establish a role for JunB in normal erythropoiesis and indicate that JunB may play a major role in the development of JAK2 V617F myeloproliferative disorders.