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Development of effective strategies to manage the inevitable acquired resistance to osimertinib, a third-generation EGFR inhibitor for the treatment of EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), is urgently needed. This study reports that DNA topoisomerase II (Topo II) inhibitors, doxorubicin and etoposide, synergistically decreased cell survival, with enhanced induction of DNA damage and apoptosis in osimertinib-resistant cells; suppressed the growth of osimertinib-resistant tumors; and delayed the emergence of osimertinib-acquired resistance. Mechanistically, osimertinib decreased Topo II[alpha] levels in EGFRm NSCLC cells by facilitating FBXW7-mediated proteasomal degradation, resulting in induction of DNA damage; these effects were lost in osimertinib-resistant cell lines that possess elevated levels of Topo II[alpha]. Increased Topo II[alpha] levels were also detected in the majority of tissue samples from patients with NSCLC after relapse from EGFR tyrosine kinase inhibitor treatment. Enforced expression of an ectopic TOP2A gene in sensitive EGFRm NSCLC cells conferred resistance to osimertinib, whereas knockdown of TOP2A in osimertinib-resistant cell lines restored their susceptibility to osimertinib-induced DNA damage and apoptosis. Together, these results reveal an essential role of Topo II[alpha] inhibition in mediating the therapeutic efficacy of osimertinib against EGFRm NSCLC, providing scientific rationale for targeting Topo II to manage acquired resistance to osimertinib., Introduction Lung cancer has remained the leading cause of cancer death among both men and women, and it accounts for around one-fourth of all cancer deaths worldwide despite great efforts [...]

There is an urgent need to fully understand the biology of third generation EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs), particularly osimertinib, and to develop mechanism‐driven strategies to manage their acquired resistance. Transient receptor potential melastatin‐2 (TRPM2) functions as an important regulator of Ca2+ influx, but its role in mediating therapeutic efficacies of EGFR‐TKIs and acquired resistance to EGFR‐TKIs has been rarely studied. This study has demonstrated a previously undiscovered role of suppression of TRPM2 and subsequent inhibition of Ca2+ influx and induction of ROS and DNA damage in mediating apoptosis induction and the therapeutic efficacy of osimertinib against EGFR mutant NSCLC. The rebound elevation represents a key mechanism accounting for the emergence of acquired resistance to osimertinib and other third generation EGFR‐TKIs. Accordingly, targeting TRPM2 is a potentially promising strategy for overcoming and preventing acquired resistance to osimertinib, warranting further study in this direction including the development of cancer therapy‐optimized TRPM2 inhibitors. [ABSTRACT FROM AUTHOR]

Carbonized nano-Co3O4 particles and diatomite were used for preparation of the composite of carbonized nano-Co3O4/diatomite by pyrolysis method, the magnetic and absorption properties were studied. The composite was characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, vibrating sample magnetometer. The results show that the superparamagnetic nano-Co3O4 particles with average size of 50nm and amorphous activated carbon are uniformly dispersed in the surface and pores of diatomite to form a stable composite. Carbonized nano-Co3O4/diatomite composite indicates high magnetic and microwave absorption performance with maximum reflection loss of -14.7dB,

The gene that encodes the epidermal growth factor receptor (EGFR) is frequently overexpressed or mutated in human cancers, including glioblastoma. However, the efficacy of EGFR-targeted small-molecule inhibitors or monoclonal antibodies in glioblastomas that also have mutation or deletion of the gene encoding phosphatase and tensin homolog (PTEN) has been modest. We found that EGFR signaling was blocked by a small molecule (G5-7) that selectively inhibited Janus kinase 2 (JAK2)-mediated phosphorylation and activation of EGFR and STAT3 (signal transducer and activator of transcription 3) by binding to JAK2, thereby decreasing the activity of downstream signaling by mTOR (mammalian target of rapamycin) and inducing cell cycle arrest. G5-7 inhibited the proliferation of PTEN-deficient glioblastoma cell lines harboring a constitutively active variant of EGFR (U87MG/EGFRvIII) and human glioblastoma explant neurosphere cultures, but the drug only weakly inhibited the proliferation of either glioblastoma cell lines that were wild type for EGFR and stably transfected with PTEN (U87MG/PTEN) or normal neural progenitor cells and astrocytes. Additionally, G5-7 reduced vascular endothelial growth factor (VEGF) secretion and endothelial cell migration and induced apoptosis in glioblastoma xenografts, thereby suppressing glioblastoma growth in vivo. Furthermore, G5-7 was more potent than EGFR or JAK2 inhibitors that interfere with either ligand or adenosine 5'-triphosphate (ATP) binding at impeding glioblastoma cell proliferation, demonstrating that this allosteric JAK2 inhibitor may be an effective clinical strategy.

The phase change microcapsules of modified montmorillonite/paraffin were prepared by Pickering emulsion method. Analytic techniques of optical microscopy, scanning electron microscopy(SEM), infrared spectroscopy(FTIR), differential scanning calorimetry(DSC) and thermogravimetry(TG) were utilized for characterizing chemical structure, morphology and thermal properties. Results show that modified montmorillonite as a new type wall material has excellent performance for protecting core material of paraffin. FTIR spectra of phase change of modified montmorillonite/paraffin microcapsules shows that their characteristic peaks match with corresponding peaks of pure paraffin and modified montmorillonite. DSC results indicate that modified montmorillonite/paraffin microcapsules have similar solid-liquid phase change temperature with pure paraffin. The phase transition enthalpy values of microcapsules with paraffin contents varying from 55% to 80% are 110.5-147.2J/g, indicating that microcapsules have excellent thermal storage performance and the phase change properties can be adjusted by changing contents of paraffin. TG results confirm that modified montmorillonite/paraffin microcapsules have outstanding thermal stability. The presented study indicates that modified montmorillonite is a suitable wall material for preparing paraffin microcapsule. Modified montmorillonite/paraffin microcapsules have advantages of low cost and high performance with a great application potential in the field of thermal storage.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer and frequently metastasizes to LNs. Identifying metastasis-promoting factors is of immense clinical interest, as the prognosis for patients with even a single unilateral LN metastasis is extremely poor. Here, we report that p90 ribosomal S6 kinase 2 (RSK2) promotes human HNSCC cell invasion and metastasis. We determined that RSK2 was overexpressed and activated in highly invasive HNSCC cell lines compared with poorly invasive cell lines. Expression of RSK2 also correlated with metastatic progression in patients with HNSCC. Ectopic expression of RSK2 substantially enhanced the invasive capacity of HNSCC cells, while inhibition of RSK2 activity led to marked attenuation of invasion in vitro. Additionally, shRNA knockdown of RSK2 substantially reduced the invasive and metastatic potential of HNSCC cells in vitro and in vivo in a xenograft mouse model, respectively. Mechanistically, we determined that cAMP-responsive element-binding protein (CREB) and Hsp27 are phosphorylated and activated by RSK2 and are important for the RSK2-mediated invasive ability of HNSCC cells. Our findings suggest that RSK2 is involved in the prometastatic programming of HNSCC cells, through phosphorylation of proteins in a putative signaling network. Moreover, targeting RSK2 markedly attenuates in vitro invasion and in vivo metastasis of HNSCC cells, suggesting that RSK2 may represent a therapeutic target in the treatment of metastatic HNSCC., Introduction Metastasis continues to be the cause of more than 90% of human cancer deaths. However, how tumors spread and kill their host organism remains an enigma. Current underlying concepts [...]