The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells

A therapeutic strategy for treating cancer is to target and eradicate cancer stem cells (CSCs) without harming their normal stem cell counterparts. The success of this approach relies on the identification of molecular pathways that selectively regulate CSC function. Using BCR-ABL-induced chronic myeloid leukemia (CML) as a disease model for CSCs, we show that BCR-ABL downregulates the Blk gene (encoding B-lymphoid kinase) through c-Myc in leukemic stem cells (LSCs) in CML mice and that Blk functions as a tumor suppressor in LSCs but does not affect normal hematopoietic stem cells (HSCs) or hematopoiesis. Blk suppresses LSC function through a pathway involving an upstream regulator, Pax5, and a downstream effector, p27. Inhibition of this Blk pathway accelerates CML development, whereas increased activity of the Blk pathway delays CML development. Blk also suppresses the proliferation of human CML stem cells. Our results show the feasibility of selectively targeting LSCs, an approach that should be applicable to other cancers.     

Stem cells from human apical papilla decrease neuro-inflammation and stimulate oligodendrocyte progenitor differentiation via activin-A secretion

Secondary damage following spinal cord injury leads to non-reversible lesions and hampering of the reparative process. The local production of pro-inflammatory cytokines such as TNF-α can exacerbate these events. Oligodendrocyte death also occurs, followed by progressive demyelination leading to significant tissue degeneration. Dental stem cells from human apical papilla (SCAP) can be easily obtained at the removal of an adult immature tooth. This offers a minimally invasive approach to re-use this tissue as a source of stem cells, as compared to biopsying neural tissue from a patient with a spinal cord injury. We assessed the potential of SCAP to exert neuroprotective effects by investigating two possible modes of action: modulation of neuro-inflammation and oligodendrocyte progenitor cell (OPC) differentiation. SCAP were co-cultured with LPS-activated microglia, LPS-activated rat spinal cord organotypic sections (SCOS), and LPS-activated co-cultures of SCOS and spinal cord adult OPC. We showed for the first time that SCAP can induce a reduction of TNF-α expression and secretion in inflamed spinal cord tissues and can stimulate OPC differentiation via activin-A secretion. This work underlines the potential therapeutic benefits of SCAP for spinal cord injury repair.     

A recurrent mutation in PALB2 in Finnish cancer families

BRCA1, BRCA2 and other known susceptibility genes account for less than half of the detectable hereditary predisposition to breast cancer. Other relevant genes therefore remain to be discovered. Recently a new BRCA2-binding protein, PALB2, was identified. The BRCA2-PALB2 interaction is crucial for certain key BRCA2 DNA damage response functions as well as its tumour suppression activity. Here we show, by screening for PALB2 mutations in Finland that a frameshift mutation, c.1592delT, is present at significantly elevated frequency in familial breast cancer cases compared with ancestry-matched population controls. The truncated PALB2 protein caused by this mutation retained little BRCA2-binding capacity and was deficient in homologous recombination and crosslink repair. Further screening of c.1592delT in unselected breast cancer individuals revealed a roughly fourfold enrichment of this mutation in patients compared with controls. Most of the mutation-positive unselected cases had a familial pattern of disease development. In addition, one multigenerational prostate cancer family that segregated the c.1592delT truncation allele was observed. These results indicate that PALB2 is a breast cancer susceptibility gene that, in a suitably mutant form, may also contribute to familial prostate cancer development.     

Perpendicular switching of a single ferromagnetic layer induced by in-plane current injection

Modern computing technology is based on writing, storing and retrieving information encoded as magnetic bits. Although the giant magnetoresistance effect has improved the electrical read out of memory elements, magnetic writing remains the object of major research efforts. Despite several reports of methods to reverse the polarity of nanosized magnets by means of local electric fields and currents, the simple reversal of a high-coercivity, single-layer ferromagnet remains a challenge. Materials with large coercivity and perpendicular magnetic anisotropy represent the mainstay of data storage media, owing to their ability to retain a stable magnetization state over long periods of time and their amenability to miniaturization. However, the same anisotropy properties that make a material attractive for storage also make it hard to write to. Here we demonstrate switching of a perpendicularly magnetized cobalt dot driven by in-plane current injection at room temperature. Our device is composed of a thin cobalt layer with strong perpendicular anisotropy and Rashba interaction induced by asymmetric platinum and AlOx interface layers. The effective switching field is orthogonal to the direction of the magnetization and to the Rashba field. The symmetry of the switching field is consistent with the spin accumulation induced by the Rashba interaction and the spin-dependent mobility observed in non-magnetic semiconductors, as well as with the torque induced by the spin Hall effect in the platinum layer. Our measurements indicate that the switching efficiency increases with the magnetic anisotropy of the cobalt layer and the oxidation of the aluminium layer, which is uppermost, suggesting that the Rashba interaction has a key role in the reversal mechanism. To prove the potential of in-plane current switching for spintronic applications, we construct a reprogrammable magnetic switch that can be integrated into non-volatile memory and logic architectures. This device is simple, scalable and compatible with present-day magnetic recording technology.