Blockade of Platelet CysLT1R Receptor with Zafirlukast Counteracts Platelet Protumoral Action and Prevents Breast Cancer Metastasis to Bone and Lung.

Metastases are the main cause of death in cancer patients, and platelets are largely known for their contribution in cancer progression. However, targeting platelets is highly challenging given their paramount function in hemostasis. Using a high-throughput screening and platelet-induced breast tumor cell survival (PITCS) assay as endpoint, we identified the widely used anti-asthmatic drugs and cysteinyl leukotriene receptor 1 (CysLT1R) antagonists, zafirlukast and montelukast, as new specific blockers of platelet protumoral action. Here, we show that human MDA-B02 breast cancer cells produce CysLT through mechanisms involving microsomal glutathione-S-transferase 1/2/3 (MGST1/2/3) and that can modulate cancer cell-platelet interactions via platelet-CysLT1R. CysLT1R blockade with zafirlukast decreased platelet aggregation and adhesion on cancer cells and inhibited PITCS, migration, and invasion in vitro. Zafirlukast significantly reduced, by 90%, MDA-B02 cell dissemination to bone in nude mice and reduced by 88% 4T1 spontaneous lung metastasis formation without affecting primary tumor growth. Combined treatment of zafirlukast plus paclitaxel totally inhibited metastasis of 4T1 cells to the lungs. Altogether, our results reveal a novel pathway mediating the crosstalk between cancer cells and platelets and indicate that platelet CysLT1R represents a novel therapeutic target to prevent metastasis without affecting hemostasis.

Optimized Sandwich and Topological Structures for Enhanced Haptic Transparency.

Humans rely on multimodal perception to form representations of the world. This implies that environmental stimuli must remain consistent and predictable throughout their journey to our sensory organs. When it comes to vision, electromagnetic waves are minimally affected when passing through air or glass treated for chromatic aberrations. Similar conclusions can be drawn for hearing and acoustic waves. However, tools that propagate elastic waves to our cutaneous afferents tend to color tactual perception due to parasitic mechanical attributes such as resonances and inertia. These issues are often overlooked, despite their critical importance for haptic devices that aim to faithfully render or record tactile interactions. Here, we investigate how to optimize this mechanical transmission with sandwich structures made from rigid, lightweight carbon fiber sheets arranged around a 3D-printed lattice core. Through a comprehensive parametric evaluation, we demonstrate how this design paradigm provides superior haptic transparency, regardless of the lattice types. Drawing an analogy with topology optimization, our solution approaches a foreseeable technological limit. It offers a practical way to create high-fidelity haptic interfaces, opening new avenues for research on tool-mediated interactions.

Phononic Crystals Applied to Localised Surface Haptics.

Metamaterials are solid lattices with periodicities commensurate with desired wavelengths. Their geometric features can endow the bulk material with unusual properties, such as inter alia, negative indices of refraction or unique absorbing qualities. Mesoscale metamaterials and phononic crystals can be designed to cause the occurence of band gaps in the ultrasonic domain. These localised phenomena induce fixed boundary conditions that correspond to acoustic mirrors which, in turn, can be used to establish waveguides in thin plates. Ultrasonic lubrication has been successfully applied to create haptic interfaces that operate by modulating the apparent friction of a surface. In this article, we demonstrate that phononic crystals can be designed to localise the modulation of friction in specific portions of the surface of a thin plate, opening novel possibilities for the design of surface haptic interfaces.

Cisplatin unleashes Toll-like receptor 3-mediated apoptosis through the downregulation of c-FLIP in malignant mesothelioma.

Toll-like receptor 3 (TLR3) is an immune receptor that behaves like a death receptor in tumor cells, thereby providing an original target for cancer therapy. The therapeutic potential of TLR3 targeting in malignant mesothelioma, an aggressive and incurable neoplasia of the pleura and peritoneum, has so far not been addressed. We investigated TLR3 expression and sensitivity of human mesothelioma cell lines to the synthetic dsRNA Poly(I:C), alone or in combination with cisplatin, the gold standard chemotherapy in mesothelioma. Activation of TLR3 by Poly(I:C) induced apoptosis of 4/8 TLR3-positive cell lines but not of TLR3-negative cell lines. The combined cisplatin/Poly(I:C) treatment enhanced apoptosis of 3/4 Poly(I:C)-sensitive cell lines and overcame resistance to Poly(I:C) or cisplatin alone in 2/4 cell lines. Efficacy of the combined treatment relied on cisplatin-induced downregulation of c-FLIP, the main regulator of the extrinsic apoptotic pathway, leading to an enhanced caspase-8-mediated pathway. Of note, 6/6 primary cell samples isolated from patients with peritoneal mesothelioma expressed TLR3. Patient-derived cells were sensitive to Poly(I:C) alone while the combined cisplatin/Poly(I:C) treatment induced dramatic cell death. Our findings demonstrate that TLR3 targeting in combination with cisplatin presents an innovative therapeutic strategy in mesothelioma.