Blockade of Discoidin Domain Receptor Signaling with Sitravatinib Reveals DDR2 as a Mediator of Neuroblastoma Pathogenesis and Metastasis.

Oncogene-driven expression and activation of receptor tyrosine kinases (RTK) promotes tumorigenesis and contributes to drug resistance. Increased expression of the kinases DDR2 (Discoid Domain Receptor 2), RET, PDGFRA, KIT, MET, and ALK (Anaplastic Lymphoma Kinase) independently correlate with decreased overall survival (OS) and event free survival (EFS) of pediatric neuroblastoma. The multikinase inhibitor sitravatinib targets DDR2, RET, PDGFRA, KIT and MET with low nanomolar activity and we therefore tested its efficacy against orthotopic and syngeneic tumor models. Sitravatinib markedly reduced cell proliferation and migration in vitro independently of MYCN (N-Myc proto-oncogene), ALK, or MYC (c-Myc proto-oncogene) status, and inhibited proliferation and metastasis of human orthotopic xenografts. Oral administration of sitravatinib to homozygous Th-MYCN transgenic mice (Th-MYCN+/+) after tumor initiation completely arrested further tumor development with no mice dying of disease while maintained on sitravatinib treatment (control cohort 57 days median time to sacrifice). Among these top kinases, DDR2 expression has the strongest correlation with poor survival and high stage at diagnosis, and the highest sensitivity to the drug. We confirmed on-target inhibition of collagen-mediated activation of DDR2. Genetic knockdown of DDR2 partially phenocopies Sitravatinib treatment, limiting tumor development and metastasis across tumor models. Analysis of single cell sequencing data demonstrated that DDR2 is restricted to mesenchymal-type tumor subpopulations and is enriched in Schwann Cell Precursor (SCP) subpopulations found in high-risk disease. These data define an unsuspected role for sitravatinib as a therapeutic agent in neuroblastoma and reveal a novel function for DDR2 as a driver of tumor growth and metastasis.

In-situ synthesized V2CTx MXene-based immune tag for the electrochemical detection of Interleukin 6 (IL-6) from breast cancer cells.

Interleukin-6 (IL-6) is a proinflammatory cytokine with a critical role in immune regulation and treatment of many diseases, including breast cancer. Herein, we developed a novel V2CTx MXene-based immunosensor for rapid and accurate IL-6 detection. The chosen substrate was V2CTx, a 2-dimensional (2D) MXene nanomaterial with excellent electronic properties. Prussian blue (Fe4[Fe(CN)6]3), used for its electrochemical properties, and spindle-shaped gold nanoparticles (Au SSNPs), used to combine with antibodies, were in-situ synthesized on the surface of the MXene. The in-situ synthesis ensures a firm chemical connection compared to other tags formed by a less stable physical absorption. Inspired by a sandwich ELISA test, the modified V2CTx tag was captured by the electrode surface with cysteamine to detect the analyte, IL-6, after being attached with a capture antibody (cAb). Benefiting from an increased surface area, an enhanced charge transfer rate, and a firm connection of the tag, this biosensor exhibited excellent analytical performance. The high sensitivity, high selectivity, and wide detection range covering the IL-6 level of both healthy individuals and breast cancer patients were obtained to meet clinical demands. Herein, this V2CTx MXene-based immunosensor is a potential therapeutic and diagnostic point-of-care alternative to routine ELISA IL-6 detection methods.

CuO/Cu composite nanospheres on a TiO2 nanotube array for amperometric sensing of glucose.

A non-enzymatic glucose sensor based on the use of CuO-Cu nanospheres placed on a TiO2 nanotube (TNT) array with excellent performance is described. The electrode was fabricated by coating the CuO-Cu nanospheres onto the TNT array through electrochemical deposition. The CuO-Cu nanospheres with a diameter of ~200 nm are well dispersed on the TNT surface, which warrants smooth interaction and a 3D nanostructure with high uniformity. The modified electrode was then used for amperometric determination of glucose in 0.1 M NaOH solution. Figures of merit include (a) a typical working voltage of 0.65 V (vs. Ag/AgCl). (b) a linear range as wide as from 0.2-90 mM, (c) good sensitivity (234 µA mM-1 cm-2), and a 19 nM lower detection limit. The sensor is selective over ascorbic acid (AA), dopamine (DA), uric acid (UA), lactose, sucrose, and fructose. Graphical abstract.

Experimental investigation of magnetically actuated separation using tangential microfluidic channels and magnetic nanoparticles.

A novel continuous switching/separation scheme of magnetic nanoparticles (MNPs) in a sub-microlitre fluid volume surrounded by neodymium permanent magnet is studied in this work using tangential microfluidic channels. Polydimethylsiloxane tangential microchannels are fabricated using a novel micromoulding technique that can be done without a clean room and at much lower cost and time. Negligible switching of MNPs is seen in the absence of magnetic field, whereas 90% of switching is observed in the presence of magnetic field. The flow rate of MNPs solution had dramatic impact on separation performance. An optimum value of the flow rate is found that resulted in providing effective MNP separation at much faster rate. Separation performance is also investigated for a mixture containing non-magnetic polystyrene particles and MNPs. It is found that MNPs preferentially moved from lower microchannel to upper microchannel resulting in efficient separation. The proof-of-concept experiments performed in this work demonstrates that microfluidic bioseparation can be efficiently achieved using functionalised MNPs, together with tangential microchannels, appropriate magnetic field strength and optimum flow rates. This work verifies that a simple low-cost magnetic switching scheme can be potentially of great utility for the separation and detection of biomolecules in microfluidic lab-on-a-chip systems.