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The enzyme Na+/K+-ATPase (NKA) is important in the heart. Reductions in NKA activity and expression have often been observed in chronic kidney disease (CKD)-related heart injury. Previously, our group found that an antibody targeting the NKA1α1 subunit’s DR extracellular region (897DVEDSYGQQWTYEQR911) stimulated NKA activities and produced cardioprotective effects against ischemic injury and isoproterenol-induced cardiac remodeling. In here, we assessed whether DRm217, a specific DR antibody, exhibits cardioprotective effects in chronic renal failure models. In 5/6 nephrectomy (5/6 Nx) surgery to mimic CKD in Sprague Dawley rat, we observed that NKA activity and expression were depressed in the hearts of 5/6 Nx rats. DRm217, an NKA DR region antibody, alleviated heart hypertrophy and cardiac fibrosis under 5/6 Nx conditions. Further studies revealed that DRm217 inhibited Src activation and reduced reactive oxygen species (ROS) levels in hearts under 5/6 Nx conditions. Our findings imply that NKA could be a treatment target in CKD-related cardiac diseases. Prevention of CKD-induced myocardial injury by DRm217 provides an appealing therapeutic alternative.

Supplementary Figure S1 shows Exatecan cytotoxicity and sensitivity to multidrug resistant genes. Supplementary Figure S2 shows Exatecan and DXd/SN-38 sensitivity to multidrug resistant genes. Supplementary Figure S3 shows Exatecan toxicity in rat. Supplementary Figure S4 shows the design and optimization of T moiety. Supplementary Figure S5 shows physicochemical and functional equivalence of Tras-GGFG-DXd and DS-8201a. Supplementary Figure S6 show physicochemical profile of antibody-exatecan conjugates enabled by T moiety. Supplementary Figure S7 shows additional T moiety-exatecan and belotecan conjugates. Supplementary Figure S8 shows in vitro and in vivo stability of MTX-1000. Supplementary Figure S9 shows cellular dynamics and mechanism of MTX-1000. Supplementary Figure S10 shows colon cancer organoid response to ADCs. Supplementary Figure S11 shows bystander killing effect of MTX-1000, T-DM1 and Tras-GGFG-DXd in coculture conditions in vitro. Supplementary Figure S12 shows hematology and serum chemistry of MTX-1000 in monkey. Supplementary Figure S13 shows T moiety-exatecan ADCs show potent antitumor efficacy and improved therapeutic index. Supplementary Figure S14 shows T moiety-exatecan ADCs show higher antitumor potency in PDX models and better intratumor pharmacodynamic response. Supplementary Figure S15 shows T moiety-exatecan ADCs overcome treatment-resistance due to improved therapeutic index and intratumor pharmacodynamic response. Supplementary Figure S16 shows overcoming MDR resistance by T moiety exatecan ADCs or a combination of MDR inhibitor with DXd/SN-38 ADCs. Supplementary Figure S17 shows Exatecan/MTX-1000 and PARP/ATR inhibitor synergize in colon cancer cells. Supplementary Figure S18 shows a patient-derived xenograft (PDX) model with EGFR triple mutation. Supplementary Figure S19 shows MTX-1000 induces immunological cell death and enhances antitumor immunity of anti-PD-1.

Supplementary note shows the analytical characterization of the ADCs, and synthesis of drug-linkers

Supplementary Table S1 shows cytotoxicity of exatecan compared to DXd. Supplementary Table S2 shows selected hematologic parameters and biochemical parameters from the repeat-dose administration of exatecan mesylate studies in rats. Supplementary Table S3 shows in vitro ADC stability study of total antibody, ADC and free payload. Supplementary Table S4 shows pharmacokinetic parameters of total antibody, ADC and free payload. Supplementary Table S5 shows ADC (T: T-1000-e; D: DS-8201a) internalization rate on cell lines with different HER2 expression level. Supplementary Table S6 shows correlation of exatecan release and target expression. Supplementary Table S7 shows In vitro cytotoxicicity of HER-targeting MTX-1000, TROP2 targeting MTX-132 and HER3-targeting Patritumab-T1000-exatecan and their counterpart DXd-ADC.

Antibody–drug conjugates (ADC) using DNA topoisomerase I inhibitor DXd/SN-38 have transformed cancer treatment, yet more effective ADCs are needed for overcoming resistance. We have designed an ADC class using a novel self-immolative T moiety for traceless conjugation and release of exatecan, a more potent topoisomerase I inhibitor with less sensitivity to multidrug resistance (MDR). Characterized by enhanced therapeutic indices, higher stability, and improved intratumoral pharmacodynamic response, antibody–T moiety–exatecan conjugates targeting HER2, HER3, and TROP2 overcome the intrinsic or treatment resistance of equivalent DXd/SN-38 ADCs in low-target-expression, large, and MDR+ tumors. T moiety–exatecan ADCs display durable antitumor activity in patient-derived xenograft and organoid models representative of unmet clinical needs, including EGFR ex19del/T790M/C797S triple-mutation lung cancer and BRAF/KRAS–TP53 double-mutant colon cancer, and show synergy with PARP/ATR inhibitor and anti–PD-1 treatment. High tolerability of the T moiety–exatecan ADC class in nonhuman primates supports its potential to expand the responding patient population and tumor types beyond current ADCs.Significance:ADCs combining a novel self-immolative moiety and topoisomerase I inhibitor exatecan as payload show deep and durable response in low-target-expressing and MDR+ tumors resistant to DXd/SN-38 ADCs without increasing toxicity. This new class of ADCs has the potential to benefit an additional patient population beyond current options.See related commentary by Gupta et al., p. 817.This article is highlighted in the In This Issue feature, p. 799

The sufficient interface contact in the composite absorbing material is beneficial to increase the dielectric loss and promote the microwave absorption performance. In this paper, the composite nanoparticles (NPs), Fe3O4 covered with ultra-thin carbon layer (Fe3O4/C), were synthesized by simple high temperature solution-phase and subsequent high-temperature steam carbonization methods. Small size Fe3O4/C composite NPs have large heterogeneous interfaces, which can control the polarization loss of composite NPs through the method of interface regulation and achieve high microwave absorption performance. The strongest reflection loss of the composite NPs with an average particle size of 52 nm can reach −58.5 dB at 14.88 GHz with a thickness of 2 mm, and the corresponding effective absorption (RL ≤ -10 dB) bandwidth (EAB) is 5.63 GHz (12.37–18 GHz). In particular, the high-efficiency absorption (RL ≤ -20 dB) bandwidth of Fe3O4/C can reach 15.44 GHz (2–17.44 GHz) with a thickness of 1.7–10 mm. The current method for controlling polarization loss provide a meaningful reference for future microwave absorption research.

Twin Marine Lifter (TML) is a specially designed heavy-lifting system consisting of two vessels for offshore installation & decommissioning. The system is developed multi-functionally in the heavy lifting sector to be cost-effective. Conceptually, they can be used in tandem for the platform installation and decommissioning of both topsides and jackets or carrying out by single lift configuration for other offshore construction tasks such as wind farm equipment installation. These flexible and versatile solutions to a wider range of potential clients also constrain the shape and the main particulars of the vessels, which results in extra challenges coming from the stability properties of the specific multi-body system compared to traditional single vessel operations, and there are few literatures could be referred to. In view of the highly complicated motions in the multi-body system at lifting phases, the topological model reflecting the flexible connections among bodies in system during the operation is constructed to obtain theoretical estimation of the roll stability of the targeted decommission topside. The virtual prototype technology based on ADAMS (Automatic Dynamic Analysis of Mechanical Systems) considering the coupling boundary of control factors including capability of the DP power and the compensation system are introduced by experimental data to correctly estimate the influence of multi-body motions on the roll stability of the topside in a synchronized way. A fast analysis and prediction methodology on the roll stability limiting criteria of the multi-body system is proposed. It would provide a safety guarantee and technical support for the design of the specific apparatus and the successful decision making on schemes of a new type of offshore operation mode.

TLS (Topsides Lifting System) utilization is a modern fast lifting technology developed for offshore platform installation. The positive prospects have seen from its sound and efficient performance at the offshore operation. To improve the feasibility of dual barge float-over operations, two new individual barges are designed in application with TLS. The targeting TLS system is equipped with motion compensation system that consists of several sets of lifting beams. Because the flexible mechanical couplings and the hydrodynamic interactions between bodies, the dynamic characteristics of system will be more complex. Some of the eigen modes might be excited by wave loads and could potentially lead to large responses. To demonstrate the dynamic properties of the new operation mode, a mechanical and hydrodynamic coupled multi-body model is established. Each lifting beam is modeled as a rigid body with X and Y degree of freedom relative to the barge. The motion compensation system is considered with a passive mode, and a spring-damper model is used to simulate its property. The coupled hydrodynamic forces of two barges are analyzed first. The eigen value analysis is conducted to identify the natural periods and eigen modes of the coupled multi-body system. A strong coupling of roll and sway motions of barge, and the heave motion of topside is observed. The sensitivity study about the parameters of lifting beams for system natural periods are carried out. The motions of barges and topside and the global dynamic loads acting on topside in regular waves are also presented. The results indicate that the heave motions decrease but the roll and pitch motions increase at their natural frequency compared with motions of the rigid connected system. The global dynamic loads acting on topside are decreased. The analyzed dynamic properties provide an initial cognition reference of the new operation system and help with the system design especially for TLS.