Despite magnetic hyperthermia being considered one of the most promising techniques for cancer treatment, until now spherical magnetite (Fe 3 O 4 ) or maghemite (γ-Fe 2 O 3 ) nanoparticles, which are the most commonly employed and only FDA approved materials, yield the limited heating capacity. Therefore, there is an increasing need for new strategies to improve the heating efficiency or the specific absorption rate (SAR) of these nanosystems. Recently, a large improvement in SAR has been reported for nanocubes of Fe 3 O 4 relative to their spherical counterpart, as a result of their enhanced surface anisotropy and chainlike particle formation. Considering the proven advantages of high aspect ratio onedimensional (1D) Fe 3 O 4 nanostructures over their spherical and cubic counterparts, such as larger surface area, multisegmented capabilities, enhanced blood circulation time, and prolonged retention in tumors, we propose a novel approach that utilizes this 1D nanostructure for enhanced hyperthermia. Here, we demonstrate that the SAR of iron oxide nanostructures can be enhanced and tuned by altering their aspect ratio. Calorimetric and ac magnetometry experiments performed for the first time on highly crystalline Fe 3 O 4 nanorods consistently show large SAR values (862 W/g for an ac field of 800 Oe), which are superior to spherical and cubic nanoparticles of similar volume (∼140 and ∼314 W/g, respectively). Increasing the aspect ratio of the nanorods from 6 to 11 improves the SAR by 1.5 times. The nanorods are rapidly aligned by the applied ac field, which appreciably increases the SAR values. A detailed analysis of the effect of the alignment of the nanorods in agar indicates an appreciable SAR increase up to 30% when the nanorods are parallel to the field. These findings pave a new pathway for the design of novel high-aspect ratio magnetic nanostructures for advanced hyperthermia.

Ferroelectret nanogenerators were recently introduced as a promising alternative technology for harvesting kinetic energy. Here we report the device's intrinsic properties that allow for the bidirectional conversion of energy between electrical and mechanical domains; thus extending its potential use in wearable electronics beyond the power generation realm. This electromechanical coupling, combined with their flexibility and thin film-like form, bestows dual-functional transducing capabilities to the device that are used in this work to demonstrate its use as a thin, wearable and self-powered loudspeaker or microphone patch. To determine the device's performance and applicability, sound pressure level is characterized in both space and frequency domains for three different configurations. The confirmed device's high performance is further validated through its integration in three different systems: a music-playing flag, a sound recording film and a flexible microphone for security applications.

Signal transducer and activator of transcription (STAT) 3 regulates many cardinal features of cancer including cancer cell growth, apoptosis resistance, DNA damage response, metastasis, immune escape, tumor angiogenesis, the Warburg effect, and oncogene addiction and has been validated as a drug target for cancer therapy. Several strategies have been employed to identify agents that target Stat3 in breast cancer but none has yet entered into clinical use. We used a high-throughput fluorescence microscopy search strategy to identify compounds in a drug-repositioning library (Prestwick library) that block ligand-induced nuclear translocation of Stat3 and identified piperlongumine (PL), a natural product isolated from the fruit of the pepper Piper longum. Piperlongumine inhibited Stat3 nuclear translocation, inhibited ligand-induced and constitutive Stat3 phosphorylation, and modulated expression of multiple Stat3-regulated genes. Surface plasmon resonance assay revealed that piperlongumine directly inhibited binding of Stat3 to its phosphotyrosyl (pY) peptide ligand. Phosphoprotein antibody array analysis revealed that PL does not modulate kinases known to activate Stat3 such as JAKs, Src kinase family members, or RTKs. PL inhibited anchorage-independent and anchorage-dependent growth of multiple breast cancer cell lines having increased pStat3 or total Stat3, and induced apoptosis. PL also inhibited mammosphere formation by tumor cells from patient derived xenografts (PDX). PL’s anti-tumorigenic function was causally linked to its Stat3-inhibitory effect. PL was non-toxic in mice up to a dose of 30 mg/Kg/day for 14 days and caused regression of breast cancer cell line xenografts in nude mice. Thus, PL represents a promising new agent for rapid entry into the clinic for use in treating breast cancer, as well as other cancers in which Stat3 plays a role.

Anti-tumor efficacy of T cells engineered to express chimeric antigen receptors (CARs) is dependent on their specificity, survival, and in vivo expansion following adoptive transfer. Toll-like receptor (TLR) and CD40 signaling in T cells can improve persistence and drive proliferation of antigen-specific CD4 and CD8 T cells following pathogen challenge or in graft-versus-host disease (GvHD) settings, suggesting that these costimulatory pathways may be co-opted to improve CAR-T cell persistence and function. Here, we present a novel strategy to activate TLR and CD40 signaling in human T cells using inducible MyD88/CD40 (iMC), which can be triggered in vivo via the synthetic dimerizing ligand, rimiducid, to provide potent costimulation to CAR-modified T cells. Importantly, the concurrent activation of iMC (with rimiducid) and CAR (by antigen recognition) is required for interleukin (IL)-2 production and robust CAR-T cell expansion and may provide a user-controlled mechanism to amplify CAR-T cell levels in vivo and augment anti-tumor efficacy.

Immunotherapy with T cells expressing chimeric antigen receptors (CARs) is an attractive approach to improve outcomes for patients with glioblastoma (GBM). IL13Rα2 is expressed at a high frequency in GBM but not in normal brain, making it a promising CAR T-cell therapy target. IL13Rα2-specific CARs generated up to date contain mutated forms of IL13 as an antigen-binding domain. While these CARs target IL13Rα2, they also recognize IL13Rα1, which is broadly expressed. To overcome this limitation, we constructed a panel of IL13Rα2-specific CARs that contain the IL13Rα2-specific single-chain variable fragment (scFv) 47 as an antigen binding domain, short or long spacer regions, a transmembrane domain, and endodomains derived from costimulatory molecules and CD3.ζ (IL13Rα2-CARs). IL13Rα2-CAR T cells recognized IL13Rα2-positive target cells in coculture and cytotoxicity assays with no cross-reactivity to IL13Rα1. However, only IL13Rα2-CAR T cells with a short spacer region produced IL2 in an antigen-dependent fashion. In vivo, T cells expressing IL13Rα2-CARs with short spacer regions and CD28.ζ, 41BB.ζ, and CD28.OX40.ζ endodomains had potent anti-glioma activity conferring a significant survival advantage in comparison to mice that received control T cells. Thus, IL13Rα2-CAR T cells hold the promise to improve current IL13Rα2-targeted immunotherapy approaches for GBM and other IL13Rα2-positive malignancies.