MYBL2 amplification in breast cancer: Molecular mechanisms and therapeutic potential.

The MYBL2 gene, also known as B-MYB, is essential to regulate vital cellular processes including cell proliferation, differentiation and DNA repair. Changes in these pathways can facilitate cancer development and as such targeting these processes represent an effective method to treat multiple cancer types. Alterations in gene expression have been identified in cancer cells including changes in MYBL2, which appears to be of particular significance in breast cancer (BC) patients.

On your marks, get SET(D1A): the race to protect stalled replication forks.

We recently identified that methylation of lysine 4 of histone H3 (H3K4) by SETD1A (SET domain containing 1A) maintains genome stability by protecting newly-replicated DNA from degradation. Mechanistically, SETD1A-dependent histone methylation regulates nucleosome mobilisation by FANCD2 (FA complementation group D2), a crucial step in maintaining genome integrity with important implications in chemo-sensitivity.

MYBL2 Supports DNA Double Strand Break Repair in Hematopoietic Stem Cells.

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases characterized by blood cytopenias that occur as a result of somatic mutations in hematopoietic stem cells (HSC). MDS leads to ineffective hematopoiesis, and as many as 30% of patients progress to acute myeloid leukemia (AML). The mechanisms by which mutations accumulate in HSC during aging remain poorly understood.

The productivity limit of manufacturing blood cell therapy in scalable stirred bioreactors.

Manufacture of red blood cells (RBCs) from progenitors has been proposed as a method to reduce reliance on donors. Such a process would need to be extremely efficient for economic viability given a relatively low value product and high (2 × 10 ) cell dose. Therefore, the aim of these studies was to define the productivity of an industry standard stirred-tank bioreactor and determine engineering limitations of commercial red blood cells production.

The autoimmune-associated genetic variant PTPN22 R620W enhances neutrophil activation and function in patients with rheumatoid arthritis and healthy individuals.

Objectives: A genetic variant of the leukocyte phosphatase PTPN22 (R620W) is strongly associated with autoimmune diseases including rheumatoid arthritis (RA). Functional studies on the variant have focussed on lymphocytes, but it is most highly expressed in neutrophils. We have investigated the effects of the variant on neutrophil function in health and in patients with RA.

Differential expression of CD148 on leukocyte subsets in inflammatory arthritis.

Introduction: Monocytic cells play a central role in the aetiology of rheumatoid arthritis, and manipulation of the activation of these cells is an approach currently under investigation to discover new therapies for this and associated diseases. CD148 is a transmembrane tyrosine phosphatase that is highly expressed in monocytes and macrophages and, since this family of molecules plays an important role in the regulation of cell activity, CD148 is a potential target for the manipulation of macrophage activation. For any molecule to be considered a therapeutic target, it is important for it to be increased in activity or expression during disease.

Does oxidative inactivation of CD45 phosphatase in rheumatoid arthritis underlie immune hyporesponsiveness?

The protein tyrosine phosphatase (PTP) CD45 is critical in regulating the earliest steps in T-cell-receptor signaling but, similar to all PTPs, it is susceptible to oxidative inactivation. Given the widely reported effects of oxidant damage associated with rheumatoid arthritis (RA), we examined whether CD45 phosphatase activity was altered in CD4(+) T cells from RA patients and related this to CD4(+) T-cell function and redox status. CD45 phosphatase specific activity in T cells from RA peripheral blood (PB) and synovial fluid was 56% and 59% lower than in healthy control (HC) PB, respectively.

Measuring the specific activity of the protein tyrosine phosphatase Lyp.

Altered function of the protein tyrosine phosphatase (PTP) Lyp (PTPN22) has been implicated in the pathogenesis of a number of human diseases, and so accurate assessment of its functional activity is needed to further our understanding of its biology. We have developed an in vitro method to measure the specific catalytic activity of the Lyp phosphatase. Lyp is captured from cell lysates using an anti-Lyp monoclonal antibody coated 96-well plate, and activity measured by dephosphorylation of a fluorescent substrate, 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP).