Based on the integral theorems for mean curvature and Gauss curvature, geometric conservation laws for perfect Y-branched carbon nanotubes are presented. From the conservation laws, simple geometric regulations observed by spontaneous Y-branched carbon nanotubes are revealed, i.e. the angle between two neighbouring branches should be 120° and the radii of the three branches should be equal. These results coincide well with all experimental facts without exceptions. Possible applications of the geometric regulations to the design of super carbon nanostructures with self-similarities are predicted.

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Resistance to chemotherapy is still a challenge for the treatment of acute myeloid leukemia. Combination use of histone deacetylase inhibitors (HDACIs) and proteasome inhibitors may provide a potential way to overcome drug resistance. One of the HDACIs, valproic acid (VPA), and a proteasome inhibitor, bortezomib (BOR), were assessed. Co-exposure of cells to VPA and BOR inhibited proliferation, arrested the cell cycle in G0-G1 phase and induced apoptosis in both HL60 and HL60A cells. These events were accompanied by the inhibition of cyclin D1 and human telomerase reverse transcriptase (hTERT) as well as telomerase activity. Moreover, synergism of proliferation inhibition was found in HL60A, superior to the additivity in HL60. The effects of combination treatment on cell cycle arrest and telomerase activity inhibition in HL60A were also more striking than those in HL60. In summary, our findings provide an insight into future clinical applications of the VPA-BOR combination regimen for AML, especially in those cases which are resistant to conventional chemotherapy.

As tyrosine kinase inhibitors (e.g., Imatinib, IM) fail to induce long-term response in some chronic myeloid leukemia (CML), novel therapies targeting leukemia-dysregulated pathways are necessary. Nuclear-cytoplasmic trafficking of proteins play a key role in the development of leukemia and drug resistance. KPT-330 (Selinexor), an inhibitor of chromosome region maintenance 1 (CRM1, nuclear receptor exportin 1, XPO1), demonstrated activities against a few hematological malignancies. We examined the anti-leukemic efficacy of KPT-330 in IM-resistant CML. Cell viability was examined by MTS assay. Apoptosis and cell cycle were assessed by flow cytometry. CRM1 mRNA was detected by PCR. Expression of CRM1 protein and its cargo proteins were determined by western blot or immunofluorescent staining. Furthermore, we engrafted nude mice subcutaneously with IM-resistant CML K562G. Mice were treated with IM, KPT-330 alone or in combination. Expression of CRM1 in CML were markedly higher than control. KPT-330 inhibited proliferation, induced cell cycle arrest and apoptosis of K562 and K562G. IC50 of IM on K562G was reduced by KPT-330. Mechanistically, KPT-330 inhibited CRM1 and increased the nuclear/cytoplasm ratio of BCR-ABL and P27. p-AKT was downregulated while p-STAT1 and caspase-3 were upregulated. Furthermore, KPT-330 showed anti-leukemic effect in primary IM-resistant CML with T315I mutation in CRM1-dependent manner. In K562G xenograft mice model, KPT-330 inhibited tumor growth and sensitized K562G to IM in vivo. To conclude, KPT-330 showed anti-leukemic activity and sensitized CML to IM in CRM1-dependent manner in vitro and in vivo. KPT-330 represents an alternative therapy for IM-refractory CML, warranting further investigation of CRM1 as therapeutic target.