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• Comparing with the existing 'combined' QZS designs with parallel arrangement of both negative- and positive-stiffness elements, a 'monolithic' beam-like QZS design was proposed with balanced ultra-low stiffness and nonlinear behaviors, which has the obvious benefits in terms of lightweightness and integration. • The 1–3D configurations of the metastructure with different combinations of the QZS unit cells in series or/and in parallel were investigated, which provides the design guidelines for the 3D metastructure with customizable level of load-carrying capacity and deformation space. • The developed optimization design method was a powerful tool to achieve targeted QZS feature with complex geometry of the flexural beam microstructure, and it was successfully utilized to quantitatively control the metastructure's load-carrying capacity and vibration isolation ability. • A practical engineering application was presented with the metastructure's vibration isolation performance being successfully demonstrated on a real spacecraft's control moment gyros (CMG) (up to 90% reduction in 100–600 Hz frequency range with only a 4.5% gain in mass). Quasi-zero stiffness (QZS) isolators have demonstrated appropriate low-frequency vibration isolation performance without sacrificing the load-bearing capacity. The current 'combined' design of QZS isolators, however, suffers from complex mechanisms and cumbersome assembly, requiring the parallel arrangement of both negative-stiffness and positive-stiffness elements. Inspired by the multi-functional integration ability of metastructure, this study explores a lightweight design of three-dimensional (3D) QZS metastructure with 'monolithic' beam-like unit cells. The study begins with the optimization design method to reach customizable QZS features in the vibration isolation metastructure for complex working environments. Then, it turns to rapid manufacturing to fabricate the metastructure prototypes, whose static and vibration test results demonstrate good agreements with the analytical and numerical results. In an experiment for the vibration isolation of a typical control moment gyro (CMG) of spacecraft, the QZS metastructure exhibited excellent vibration isolation performance (up to 90% reduction in 100–600 Hz frequency range) with only a 4.5% gain in mass. As such, the proposed 3D QZS metastructure paves a new way to the design of lightweight, compact and broadband vibration isolators. [Display omitted] [ABSTRACT FROM AUTHOR]

Thermoplastic polyurethane (TPU) has been widely implemented in many fields due to its good elasticity. Microcellular foaming not only can achieve weight reduction, but also can enhance the elasticity of TPU products. However, the enhancement of elasticity by foaming is limited, while the introduction of corrugated structures can significantly improve the elasticity of TPU foams. Considering the difficulties to produce TPU parts with corrugated structures for conventional processes, fused filament fabrication (FFF) combined with microcellular foaming was developed to fabricate TPU foams with high elasticity. An FFF 3D printer was used to prepare solid TPU samples with corrugated structures, and microcellular foaming was used to fabricate foamed TPU samples. As expected, the corrugated structures have been successfully and precisely preserved in the obtained TPU foams, and further, the TPU foams have expansion ratio of more than 7 and cell density of higher than 1012 cells/cm3. Thanks to the corrugated structures and refined cellular morphology, the 7.09 expanded TPU foams exhibited outstanding compressive properties with an energy loss coefficient of 28% and a maximum stress of higher than 0.25 MPa. It is further found that introducing the corrugated structures or enlarging cell sizes could improve the elasticity and buffering performance of TPU foams. [Display omitted] • Thermoplastic polyurethane (TPU) foam with corrugated structures was achieved. • Fused deposition modeling was used to prepare solid corrugated TPU samples. • 7-fold TPU foam with corrugated structures was fabricated by microcellular foaming. • Corrugated structures improved the elasticity and compressive strength of TPU foam. [ABSTRACT FROM AUTHOR]

[Display omitted] Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 enhanced VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, a purine biosynthesis inhibitor, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired AraC resistance showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. In vivo studies revealed significantly prolonged survival upon combination therapy of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia compared to the vehicle control. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis. [ABSTRACT FROM AUTHOR]

[Display omitted] The combination of venetoclax (VEN) and azacitidine (AZA) has become the standard of care for acute myeloid leukemia (AML) patients who are ≥ 75 years or unfit for intensive chemotherapy. Though initially promising, resistance to the combination therapy is an issue and VEN + AZA-relapsed/refractory patients have dismal outcomes. To better understand the mechanisms of resistance, we developed VEN + AZA-resistant AML cell lines, MV4-11/VEN + AZA-R and ML-2/VEN + AZA-R, which show > 300-fold persistent resistance compared to the parental lines. We demonstrate that these cells have unique metabolic profiles, including significantly increased levels of cytidine triphosphate (CTP) and deoxycytidine triphosphate (dCTP), changes in fatty acid and amino acid metabolism and increased utilization and reliance on glycolysis. Furthermore, fatty acid transporter CD36 is increased in the resistant cells compared to the parental cells. Inhibition of glycolysis with 2-Deoxy-D-glucose re-sensitized the resistant cells to VEN + AZA. In addition, the VEN + AZA-R cells have increased levels of the antiapoptotic protein Mcl-1 and decreased levels of the pro-apoptotic protein Bax. Overexpression of Mcl-1 or knockdown of Bax result in resistance to VEN + AZA. Our results provide insight into the molecular mechanisms contributing to VEN + AZA resistance and assist in the development of novel therapeutics to overcome this resistance in AML patients. [ABSTRACT FROM AUTHOR]