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In the single-arm, phase 2 DESTINY-Breast01 trial, trastuzumab deruxtecan showed robust activity in patients with HER2-positive metastatic breast cancer who were refractory or resistant to trastuzumab emtansine; a population with scarce effective treatments. In DESTINY-Breast02, we aimed to compare the efficacy and safety of trastuzumab deruxtecan with treatment of physician's choice in this patient population. This randomised, open-label, multicentre, phase 3 trial was conducted at 227 sites (hospitals, university hospitals, clinics, community centres, and private oncology centres) in North America, Europe, Asia, Australia, Brazil, Israel, and Türkiye. Eligible patients were aged 18 years or older, had unresectable or HER2-positive metastatic breast cancer, previously received trastuzumab emtansine, disease progression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate renal and hepatic function. Patients were randomly assigned (2:1) to receive trastuzumab deruxtecan (intravenously at 5·4 mg/kg once every 3 weeks) or treatment of physician's choice using block randomisation. Treatment of physician's choice was either capecitabine (1250 mg/m2; orally twice per day on days 1–14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m2) plus lapatinib (1250 mg orally once per day on days 1–21), with a 21-day schedule. The primary endpoint was progression-free survival based on blinded independent central review in the full analysis set. This study is registered with ClinicalTrials.gov, NCT03523585. Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). 608 (100%) patients were included in the full analysis set. The median age was 54·2 years (IQR 45·5–63·4) in the trastuzumab deruxtecan group and 54·7 years (48·0–63·0) in the treatment of physician's choice group. 384 (63%) patients were White, 603 (99%) were female, and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2–28·4) in the trastuzumab deruxtecan group and 18·6 months (8·8–26·0) in the treatment of physician's choice group. Median progression-free survival by blinded independent central review was 17·8 months (95% CI 14·3–20·8) in the trastuzumab deruxtecan group versus 6·9 months (5·5–8·4) in the treatment of physician's choice group (HR 0·36 [0·28–0·45]; p<0·0001). The most common treatment-emergent adverse events were nausea (293 [73%] of 404 with trastuzumab deruxtecan vs 73 [37%] of 195 with treatment of physician's choice), vomiting (152 [38%] vs 25 [13%]), alopecia (150 [37%] vs eight [4%]), fatigue (147 [36%] vs 52 [27%]), diarrhoea (109 [27%] vs 105 [54%]), and palmar–plantar erythrodysaesthesia (seven [2%] vs 100 [51%]). Grade 3 or higher treatment-emergent adverse events occurred in 213 (53%) patients receiving trastuzumab deruxtecan versus 86 (44%) receiving treatment of physician's choice; whereas drug-related interstitial lung disease occurred in 42 (10%; including two grade 5 death events) versus one (<1%). DESTINY-Breast02 shows the favourable benefit–risk profile of trastuzumab deruxtecan in patients with HER2 positive metastatic breast cancer, as previously reported in DESTINY-Breast01, and is the first randomised study to show that one antibody-drug conjugate can overcome resistance to a previous one. Daiichi Sankyo and AstraZeneca.

Abstract Background Trastuzumab deruxtecan (T-DXd), an approved human epidermal growth factor receptor 2 (HER2)-directed antibody–drug conjugate, may cause treatment-emergent adverse events (TEAEs), most commonly gastrointestinal and hematologic TEAEs. This pooled analysis evaluated TEAEs across 2 doses of T-DXd in patients with different cancers to support safe and effective real-world use. Patients and Methods Data were pooled from 9 phase I-III clinical trials (DS8201-A-J101; DESTINY-Breast01/02/03/04; DESTINY-Lung01/02; DESTINY-Gastric01/02) of T-DXd 5.4 or 6.4 mg/kg every 3 weeks in patients (N = 1678) with metastatic breast, gastric, or lung cancer with varying HER2 expression or HER2 mutation status. Nausea, vomiting, neutropenia, fatigue, and interstitial lung disease (ILD) were evaluated for time to onset and dose-related outcomes. Antiemetic analysis was limited before a 2020 protocol change recommending prophylaxis. Results Common TEAEs (in ≥20%) were fatigue, nausea, vomiting, neutropenia, anemia, and thrombocytopenia; mostly grade 1 or 2. TEAEs leading to dose reduction, drug interruption, and discontinuation with T-DXd were 22.6%, 42.8%, and 17.7% (5.4 mg/kg), and 29.7%, 47.6%, and 16.6% (6.4 mg/kg), respectively. Neutropenia, nausea, and fatigue occurred in 34.6%, 74.6%, and 56.5% of patients (5.4 mg/kg) and 49.3%, 65.5%, and 52.8% (6.4 mg/kg). Adjudicated drug-related ILD occurred in 12.0% and 10.9%, respectively. Conclusion Gastrointestinal and hematologic TEAEs were most common, with nausea, neutropenia, and fatigue most commonly reported. ILD/pneumonitis occurred in ∼11%-12% of patients, with severe cases infrequent. Most TEAEs were low grade, though dose modifications highlight the need for proactive TEAE management, particularly in older patients and those with renal impairment.

In order to meet the demand of remote monitoring, this paper introduces a method of realizing remote monitoring based on mobile network and embedded system. Related key technologies include building remote monitoring terminal, sending and receiving of SMS, making and sending of MMS. By using S3C6410 hardware platform and Linux OS, as well as GPRS module, and developing phone specific program and interface in control terminal. Users can control and monitor the equipments and working condition in remote terminal or dangerous areas, and query their video images and abnormity information by sending phone SMS or clicking on developed phone interface buttons easily and conveniently.

Non-alcoholic steatohepatitis (NASH) is the severe form of non-alcoholic fatty liver disease, and is characterized by liver inflammation and fat accumulation. Dietary interventions, such as fibre, have been shown to alleviate this metabolic disorder in mice via the gut microbiota. Here, we investigated the mechanistic role of the gut microbiota in ameliorating NASH via dietary fibre in mice. Soluble fibre inulin was found to be more effective than insoluble fibre cellulose to suppress NASH progression in mice, as shown by reduced hepatic steatosis, necro-inflammation, ballooning and fibrosis. We employed stable isotope probing to trace the incorporation of 13 C-inulin into gut bacterial genomes and metabolites during NASH progression. Shotgun metagenome sequencing revealed that the commensal Parabacteroides distasonis was enriched by 13 C-inulin. Integration of 13 C-inulin metagenomes and metabolomes suggested that P. distasonis used inulin to produce pentadecanoic acid, an odd-chain fatty acid, which was confirmed in vitro and in germ-free mice. P. distasonis or pentadecanoic acid was protective against NASH in mice. Mechanistically, inulin, P. distasonis or pentadecanoic acid restored gut barrier function in NASH models, which reduced serum lipopolysaccharide and liver pro-inflammatory cytokine expression. Overall this shows that gut microbiota members can use dietary fibre to generate beneficial metabolites to suppress metabolic disease. The gut commensal Parabacteroides distasonis uses inulin to produce the odd-chain fatty acid pentadecanoic acid, which alleviates non-alcoholic steatohepatitis via improved barrier function in mice.

Lithium sulfide (Li2S) is considered to be the best potential substitution for sulfur-based cathodes due to its high theoretical specific capacity (1166 mAh g−1) and good compatibility with lithium metal-free anodes. However, the electrical insulation nature of Li2S and severe shuttling of lithium polysulfides lead to poor rate capability and cycling stability. Confining Li2S into polar conductive porous carbon is regarded as a promising strategy to solve these problems. In this work, N-doped porous carbon microspheres (NPCMs) derived from yeasts are designed and synthesized as a host to confine Li2S. Nano Li2S is successfully entered into the NPCMs’ pores to form N-doped porous carbon microspheres–Li2S composite (NPCMs–Li2S) by a typical liquid infiltration–evaporation method. NPCMs–Li2S not only delivers a high initial discharge capacity of 1077 mAh g−1 at 0.2 A g−1, but also displays good rate capability of 198 mAh g−1 at 5.0 A g−1 and long-term lifespan over 500 cycles. The improved cycling and high-rate performance of NPCMs–Li2S can be attributed to the NPCMs’ host, realizing the strong fixation of LiPSs and enhancing the electron and charge conduction of Li2S in NPCMs–Li2S cathodes.

This paper presents an optimal design process for the steering system of a forklift vehicle. An efficient procedure for minimizing the engine-induced idle vibration is developed in this study. Reciprocating unbalance and gas pressure torque as two major sources of engine excitation are studied. Using the field vibration tests and FEM analysis, the cause and characteristics of steering system’s idle vibration are recognized. So as to distribute the characteristic modes based on the optimization strategy, global sensitivity analysis of the main parameters is also carried out to achieve the optimal combination of the optimization factors. Based on all analysis above, some structure modifications for optimization are presented to control the idle vibration. The effectiveness and rationality of the improvements are also verified through experimental prototyping testing. This study also makes it possible to provide a design guideline using CAE (computer aided engineering) analysis for some other objects.

In various fields of positioning engineering, it is important to clarify the sliding motion, especially the stick slip phenomenon, for a wide range of scales positioning stage which works at a relative low sliding speed. In this paper, the sliding system of stick-slip motion is modeled based on a mass-spring-dampness system which includes four parameters. Meanwhile, a numerical simulation based on the Pro/ENGINEER software was conducted in order to study the relationship between stick slip behavior and its impact factors, such as the mass, stiffness, friction coefficient and damping coefficient. Moreover, experiments results are also provided to show the rationality of the theoretical analysis and the computer simulation.

The topological Hall effect (THE) has been discovered in ultrathin SrRuO3 (SRO) films, where the interface between the SRO layer and another oxide layer breaks the inversion symmetry resulting in the appearance of THE. Thus, THE only occurs in ultra-thin SRO films of several unit cells. In addition to employing a heterostructure, the inversion symmetry can be broken intrinsically in bulk SRO by introducing defects. In this study THE is observed in 60 nm thick SRO films, in which defects and lattice distortions are introduced by helium ion irradiation. The irradiated SRO films exhibit a pronounced THE in a wide temperature range from 5 K to 80 K. These observations can be attributed to the emergence of Dzyaloshinskii-Moriya interaction as a result of artificial inversion symmetry breaking associated to the lattice defect engineering. The creation and control of the THE in oxide single layers can be realized by ex situ film processing. Therefore, this work provides new insights into the THE and illustrates a promising strategy to design novel spintronics devices.

A high quality diffraction grating not only depends on the location accuracy of the positioning stage fixing the grating blank, but also the groove straightness error of the scratch system. As a key of diffraction grating fabrication technology at the nanometer scale, more attention should be paid to the dynamic characteristic of the scratch system. In this paper, both theoretical analysis and model simulation are carried out in order to study the vibration performance of the vibration source (slider crank mechanism) and knife-bridge. Moreover, the multi-body dynamics analysis of the knife-bridge is also calculated.

The rare-earth nickelates are a rich playground for transport properties, known to host non-Fermi liquid character, resistance saturation and metal-insulator transitions. We report a study of transport in LaNiO3 in the presence of tunable disorder induced by irradiation. While pristine LaNiO3 samples are metallic, highly irradiated samples show insulating behaviour at all temperatures. Using irradiation fluence as a tuning handle, we uncover an intermediate region hosting a metal-insulator transition. This transition falls within the Mott-Ioffe-Regel regime wherein the mean free path is comparable to lattice spacing. In the high temperature metallic regime, we find a transition from non-Fermi liquid to a Fermi-liquid-like character. On the insulating side of the metal-insulator transition, we find behaviour that is consistent with weak localization. This is reflected in magnetoresistance that scales with the square of the field and in resistivity. In the highly irradiated insulating samples, we find good agreement with variable range hopping, consistent with Anderson localization. We find qualitatively similar behaviour in thick PrNiO3 films as well. Our results demonstrate that ion irradiation can be used to tailor transport, serving as an excellent tool to study the physics of localization.