Sharon Xiaodai Lim

Targeting of the MNK–eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function

Significance Cancer stem cells (CSCs) frequently acquire the ability to self-renew and persist in their hosts by coopting normal stem cell programs. Blast crisis (BC) chronic myeloid leukemia is a prototypic example, as the acquired activation of β-catenin signaling that enables BC CSC function is also important in normal hematopoietic stem cell maintenance. In identifying eIF4E phosphorylation by the MNK kinases as a necessary step in β-catenin activation in BC CSCs, but not normal hematopoietic stem cells, we define a therapeutic target in BC. Our studies suggest that clinical trials with MNK kinase inhibitors are warranted in BC chronic myeloid leukemia. Chronic myeloid leukemia responds well to therapy targeting the oncogenic fusion protein BCR-ABL1 in chronic phase, but is resistant to treatment after it progresses to blast crisis (BC). BC is characterized by elevated β-catenin signaling in granulocyte macrophage progenitors (GMPs), which enables this population to function as leukemia stem cells (LSCs) and act as a reservoir for resistance. Because normal hematopoietic stem cells (HSCs) and LSCs depend on β-catenin signaling for self-renewal, strategies to specifically target BC will require identification of drugable factors capable of distinguishing between self-renewal in BC LSCs and normal HSCs. Here, we show that the MAP kinase interacting serine/threonine kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis is overexpressed in BC GMPs but not normal HSCs, and that MNK kinase-dependent eIF4E phosphorylation at serine 209 activates β-catenin signaling in BC GMPs. Mechanistically, eIF4E overexpression and phosphorylation leads to increased β-catenin protein synthesis, whereas MNK-dependent eIF4E phosphorylation is required for nuclear translocation and activation of β-catenin. Accordingly, we found that a panel of small molecule MNK kinase inhibitors prevented eIF4E phosphorylation, β-catenin activation, and BC LSC function in vitro and in vivo. Our findings identify the MNK–eIF4E axis as a specific and critical regulator of BC self-renewal, and suggest that pharmacologic inhibition of the MNK kinases may be therapeutically useful in BC chronic myeloid leukemia.

Hybrid Bilayer WSe2–CH3NH3PbI3 Organolead Halide Perovskite as a High‐Performance Photodetector

A high-performance 2D photodetector based on a bilayer structure comprising a WSe2 monolayer and CH3 NH3 PbI3 organolead halide perovskite is reported. High performance is realized by modification of the WSe2 monolayer with laser healing and perovskite functionalization. After modification, the output of the device was three orders of magnitude better than the pristine device; the performance is superior to that of most of the 2D photodetectors based on transition-metal-dichalcogenides (TMDs). This result indicates that combinatory TMDs-halide perovskite hybrids can be promising building blocks in optoelectronics.

Assembly of suspended graphene on carbon nanotube scaffolds with improved functionalities

With self-assembly being an efficient and often preferred process to build micro- and nano-materials into ordered macroscopic structures, we report a simple method to assemble monolayer graphene onto densified vertically aligned carbon nanotube (CNT) micropillars en route to unique functional three-dimensional microarchitecture. This hybrid structure provides new means of studying strain induced in suspended graphene. The strain induced could be controlled by the size and number of supporting microstructures, as well as laser-initiated localised relaxation of the graphene sheet. The assembled structure is also able to withstand high-energy electron irradiation with negligible effect on the electrical properties of the hybrid system. The hybrid system was further functionalised with quantum dots on the CNTs with the assembled top graphene layer as a transparent electrode. Significant improvements in photocurrent were achieved in this system.Graphical abstract

Rapid reversible electromigration of intercalated K ions within individual MoO3 nanobundle

Rapid and reversible electromigration of intercalated K ions within an individual layered single crystalline KxMoO3 nanobundle is observed. When an electric current was applied to a KxMoO3 nanobundle, the K ions migrated readily and rapidly in the flowing direction of electrons within the nanobundle and accumulated near an electrode. Upon reversal of the applied current, the accumulated K ions near one electrode were driven back and gathered near the opposite electrode. This observation is attributed to the unique structure of KxMoO3 where K ions occupy O vacancies in the nanobundle and the location of K ions is exactly the channel of high current density within the nanobundle. The duration required to induce significant accumulation of K ions and relaxation time of accumulated ions were significantly shorter than the value reported in other interstitial systems. The reversible ion movement was repeated for hundred times and remarkably there were no obvious sign of structural damage in the nanobundle.

Laser Modified ZnO/CdSSe Core-Shell Nanowire Arrays for Micro-Steganography and Improved Photoconduction

Arrays of ZnO/CdSSe core/shell nanowires with shells of tunable band gaps represent a class of interesting hybrid nanomaterials with unique optical and photoelectrical properties due to their type II heterojunctions and chemical compositions. In this work, we demonstrate that direct focused laser beam irradiation is able to achieve localized modification of the hybrid structure and chemical composition of the nanowire arrays. As a result, the photoresponsivity of the laser modified hybrid is improved by a factor of ~3. A 3D photodetector with improved performance is demonstrated using laser modified nanowire arrays overlaid with monolayer graphene as the top electrode. Finally, by controlling the power of the scanning focused laser beam, micropatterns with different fluorescence emissions are created on a substrate covered with nanowire arrays. Such a pattern is not apparent when imaged under normal optical microscopy but the pattern becomes readily revealed under fluorescence microscopy i.e. a form of Micro-Steganography is achieved.

Structure–Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells

Clinically used BCR-ABL1 inhibitors for the treatment of chronic myeloid leukemia do not eliminate leukemic stem cells (LSC). It has been shown that MNK1 and 2 inhibitors prevent phosphorylation of eIF4E and eliminate the self-renewal capacity of LSCs. Herein, we describe the identification of novel dual MNK1 and 2 and BCR-ABL1 inhibitors, starting from the known kinase inhibitor 2. Initial structure-activity relationship studies resulted in compound 27 with loss of BCR-ABL1 inhibition. Further modification led to orally bioavailable dual MNK1 and 2 and BCR-ABL1 inhibitors 53 and 54, which are efficacious in a mouse xenograft model and also reduce the level of phosphorylated eukaryotic translation initiation factor 4E in the tumor tissues. Kinase selectivity of these compounds is also presented.

Direct laser micropatterning of GeSe2 nanostructures film with controlled optoelectrical properties

We demonstrate that a direct focused laser beam irradiation is able to achieve localized modification on GeSe2 nanostructures (NSs) film. Using a scanning focused laser beam setup, micropatterns on GeSe2 NSs film are created directly on the substrate. Controlled structural and chemical changes of the NSs are achieved by varying laser power and the treatment environment. The laser modified GeSe2 NSs exhibit distinct optical, electrical and optoelectrical properties. Detailed characterization is carried out and the possible mechanisms for the laser induced changes are discussed. The laser modified NSs film shows superior photoconductivity properties as compared to the pristine nanostructure film. The construction of micropatterns with improved functionality could prove to be useful in miniature optoelectrical devices.

Laser assisted blending of Ag nanoparticles in an alumina veil: a highly fluorescent hybrid

We report a functional hybrid made of silver nanoparticles (AgNPs) embedded in an amorphous aluminium oxide (alumina) film. This laser-initiated process allows formation of AgNPs and amorphous alumina in localized regions defined by the scanning laser beam. Due to metal enhanced fluorescence, this hybrid exhibits strong blue fluorescence emission under ultraviolet excitation. Upon irradiating with electrons at dosages of 1 to 20 mC cm-2, AgNPs become more metallic while the Al film is further oxidised. As a result, the fluorescing property is intensified. Using a hybrid irradiated with 10 mC cm-2, the electronic conductivity of the sample is improved by 11.5 times compared to that of the as-synthesized hybrid film. Excitation by UV light on the sample results in an increase in the detected current of nearly 29 times. Given that the electron beam patterned message is selectively visible only under UV or blue light irradiation, this hybrid film is thus a possible platform for steganographic transmission.

Optimization of Selective Mitogen-Activated Protein Kinase Interacting Kinases 1 and 2 Inhibitors for the Treatment of Blast Crisis Leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by bcr-abl1, a constitutively active tyrosine kinase fusion gene responsible for an abnormal proliferation of leukemic stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term relief to CML patients. However, for a proportion of them, BCR-ABL1 inhibition will become ineffective at treating the disease, and CML will progress to blast crisis (BC) CML with poor prognosis. BC-CML is often associated with excessive phosphorylated eukaryotic translation initiation factor 4E (eIF4E), which renders LSCs capable of proliferating via self-renewal, oblivious to BCR-ABL1 inhibition. In vivo, eIF4E is exclusively phosphorylated on Ser209 by MNK1/2. Consequently, a selective inhibitor of MNK1/2 should reduce the level of phosphorylated eIF4E and re-sensitize LSCs to BCR-ABL1 inhibition, thus hindering the proliferation of BC LSCs. We report herein the structure-activity relationships and pharmacokinetic properties of a selective MNK1/2 inhibitor clinical candidate, ETC-206, which in combination with dasatinib prevents BC-CML LSC self-renewal in vitro and enhances dasatinib antitumor activity in vivo.

Templating nanotraffic light – dynamic tricoloured blinking silver nanoclusters on a graphene oxide film

We present a graphene oxide (GO) film as a superior substrate for the controlled anchoring and micropatterning of a blinking silver nanocluster–nanoparticle hybrid. Localised laser reduction of the GO film in the presence of AgNO3 solution results in the controlled deposition of Ag nanoparticles (NPs) onto the reduced GO (rGO) film. Upon irradiation by blue light, some of these NPs turn into nanoblinkers (AgO/Agn hybrid) exhibiting dynamic tricolored fluorescence intermittency. Via the scanning laser beam, a wide variety of micropatterns with a high density of nanoblinkers are achieved on the GO/rGO film. Most remarkably, the nanoblinkers formed on GO/rGO remain vibrant even after a period of 1 year, unlike other substrates (CNT, SiO2/Si wafer) studied. Furthermore, both the micro-patterns and tricoloured blinking behaviour are preserved upon their transfer from the GO film onto other surfaces such as glass and a PDMS film. The hybrid material can also be used to detect Rhodamine B dye where the fluorescing colour of the Ag nanoblinkers changes upon interaction with the dye. The shade of fluorescence and the blinking rate of the nanoblinkers are highly dependent on the duration of interaction between the nanoblinkers and the Rhodamine B molecules.