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Abstract Currently approved HER2-targeting antibody-drug conjugates (ADCs) for HER2-positive breast cancer (BC) are associated with safety concerns. In this multicenter, single-arm, dose-escalation (phase 1a) and dose-expansion (phase 1b) phase 1 trial (NCT03944499), patients with HER2-expressing advanced solid tumors received FS-1502 (an anti-HER2 ADC) with a 3 + 3 design in phase 1a; patients with metastatic HER2-positive BC received FS-1502 at the recommended phase 2 dose (RP2D) in phase 1b. The primary end points were dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and RP2D for phase 1a and objective response rate (ORR) for phase 1b. A total of 150 patients with HER2-expressing solid tumors (n = 5) and BC (n = 145) were enrolled (female, n = 146, 97.3%). One DLT each was reported at 3.0 and 3.5 mg/kg; the MTD was not reached. The RP2D was 2.3 mg/kg once every 3 weeks. Five (3.3%) patients experienced pneumonitis; four (2.7%) had grade 3 reversible ocular events. Of 67 HER2-positive BC patients receiving the RP2D, the best ORR was 53.7% (95% CI, 41.1-66.0%), including PRs confirmed (confirmed ORR, 37.5%) and pending for confirmation. FS-1502 was well tolerated with limited ocular and pulmonary findings and demonstrated promising antitumor activity in HER2-positive BC patients.

BackgroundRecent studies have confirmed that metabolites and immunocyte phenotype may be associated with the risk of lymphoma. However, the bidirectional causality between metabolites, immunocyte phenotype, disease risk, and whether immunity is an intermediate mediator between metabolism and lymphoma causality is still unclear.ObjectiveTo elucidate the causal relationship between metabolites, immune cell phenotypes, and lymphomas, we used two-sample Mendelian randomization (MR) and two-step MR analysis.MethodsApplying large-scale genome-wide association studies (GWAS) pooled data, we selected 1400 metabolites and 731 immunocyte phenotypes with eight lymphoma subtypes for two-sample bi-directional MR analysis. In addition, we used two-step MR to quantify the proportion of metabolite effects on lymphomas mediated by immunocyte phenotype.ResultsThis study yielded a bidirectional causal relationship between 17 metabolites and lymphoma and a bidirectional causal relationship between 12 immunocyte phenotypes and lymphoma. In addition, we found causal associations between metabolites and lymphomas, three groups of which were mediated by immunocyte phenotypes. Among them, CD27 on plasmablast/plasma cell (PB/PC) was a mediator of the positive association of arginine to glutamate ratio with chronic lymphocytic leukemia, with a mediator ratio of 14.60% (95% CI=1.29-28.00%, P=3.17 × 10-2). Natural killer (NK) cells as a percentage of all lymphocytes(NK %lymphocyte) was a mediator of the negative association of X-18922(unknown metabolite) levels with diffuse large B-cell lymphoma, with a mediation proportion of -8.940% (95% CI=-0.063-(-17.800) %, P=4.84 × 10-2). CD25 on IgD- CD24- B cell was the mediator of the positive association between X-24531(unknown metabolite) levels and diffuse large B-cell lymphoma, with a mediation proportion of 13.200% (95% CI=-0.156-26.200%, P=4.73 × 10-2).ConclusionIn the present study, we identified a causal relationship between metabolites and lymphoma, in which immunocyte phenotypes as mediators are involved in only a minor part. The mediators by which most metabolites affect the risk of lymphoma development remain unclear and require further exploration in the future.

In the further development of nuclear fusion energy, managing the high heat flux on a divertor target remains a significant issue. To address this, the development of innovative cooling channels capable of efficiently managing high heat loads is essential. Among various cooling techniques, the hypervapotron (HV) method stands out for its exceptional heat transfer capabilities. This study undertakes an in-depth analysis of a novel HV cooling channel, evaluating its heat transfer performance via an electron beam high heat flux testing system. The focus was on subcooled flow boiling, observing that the novel HV channel displayed varied flow patterns with increasing heat flux. Additionally, a comparative investigation was conducted to assess the heat transfer efficiency of this novel HV channel against traditional ITER-like HV channel and smooth channel. The analysis incorporated various system parameters, such as mass flow rate and system pressure, to understand their effects on heat transfer. To effectively predict the heat transfer performance of the novel HV channel, efforts have been made to evaluate existing and develop new heat transfer correlations for the channel. Furthermore, Artificial Neural Networks (ANNs) have also been utilized as a crucial approach in this predictive endeavor. The outcomes of this study hold significant implications for understanding and optimizing the design of cooling channels for divertor target in nuclear fusion reactors.

Abstract Background Type 2 diabetes mellitus (T2DM) is a chronic and life-threatening disease. Health-related quality of life (HRQoL) is vital for individuals with T2DM. However, little is known about the impact of psychological stability factors on HRQoL among individuals with T2DM in mainland China. Methods This multicenter cross-sectional study was conducted in five tertiary grade-A hospitals in Chongqing, China, from January to December 2019. A total of 385 individuals with T2DM were included by the convenient sample method. Fear of Progression (FOP) Questionnaire-short Form, Hypoglycemia Fear Survey II, diabetes-management self-efficacy scale, and EuroQol-5 Dimensions were used for data collection. Results The mean age of the 385 individuals was 57.65 (SD = 15.15) years, three-quarters of whom had a high school or above education level. The participants in our study had moderate HRQoL and were more likely to have poor scores in the pain/discomfort dimension. The FOP level was moderate on average, and 23.1% of individuals suffered from psychological dysfunction. The participants had higher levels of fear of hypoglycemia (FOH) and self-efficacy (SE). Multiple steppage-regression analysis predicted that higher levels of FOP and FOH, reduced SE, older age, longer duration since diagnosis, lower educational attainment, higher levels of HbA1c, and living with comorbid conditions were related to lower HRQoL. Conclusion This study showed that the HRQoL among Chinese T2DM patients may be impaired by increased FOP and FOH, decreased SE, and poor glycemic control. In addition, as the patient’s age and duration since diagnosis increase, their HRQoL further declines. We recommend improving HRQoL by encouraging individuals to attain more health education and resilience skills to enhance SE and reduce negative emotions among individuals with T2DM.

Abstract Aim The aim of this study is to examine the incidence and risk factors for intimate partner violence (IPV) among patients with gynaecological cancer. Design A cross‐sectional study design was employed. Methods Patients with gynaecological cancer were recruited from a tertiary hospital in Shandong, China. Eligible patients completed a survey including questions regarding their demographic and cancer‐related characteristics, IPV experience and dyadic coping. Results A total of 429 patients were surveyed, 31% of them reported previous experiences with IPV, and negotiation was the most common type reported. The following variables were associated with IPV: a husband, wife and child/children family structure; a husband, wife, child/children and parent‐in‐law family structure; an annual household income ≥¥50,000 ($7207); and a similar or greater income earned by the patient than by her partner. Patient or Public Contribution IPV in patients with gynaecological cancer is investigated in this study.

Abstract Background Surgery is a common treatment strategy for patients with neurofibromatosis type 1 (NF1)-related plexiform neurofibroma (PN) and has limited efficacy. FCN-159 is a novel anti-tumorigenic drug via selective inhibition of MEK1/2. This study assesses the safety and efficacy of FCN-159 in patients with NF1-related PN. Methods This is a multicenter, open-label, single-arm, phase I dose-escalation study. Patients with NF1-related PN that was non-resectable or unsuitable for surgery were enrolled; they received FCN-159 monotherapy daily in 28-day cycles. Results Nineteen adults were enrolled in the study, 3 in 4 mg, 4 in 6 mg, 8 in 8 mg, and 4 in 12 mg. Among patients included in dose-limiting toxicity (DLT) analysis, DLTs (grade 3 folliculitis) were reported in 1 of 8 patients (16.7%) receiving 8 mg and 3 of 3 (100%) patients receiving 12 mg. The maximum tolerated dose was determined to be 8 mg. FCN-159-related treatment-emergent adverse events (TEAEs) were observed in 19 patients (100%); most of which were grade 1 or 2. Nine (47.4%) patients reported grade 3 study-drug–related TEAEs across all dose levels, including four experiencing paronychia and five experiencing folliculitis. Of the 16 patients analyzed, all (100%) had reduced tumor size and six (37.5%) achieved partial responses; the largest reduction in tumor size was 84.2%. The pharmacokinetic profile was approximately linear between 4 and 12 mg, and the half-life supported once daily dosing. Conclusions FCN-159 was well tolerated up to 8 mg daily with manageable adverse events and showed promising anti-tumorigenic activity in patients with NF1-related PN, warranting further investigation in this indication. Trial registration ClinicalTrials.gov, NCT04954001. Registered 08 July 2021.

To study the manufacturing method of the tungsten armored first wall of tokamak devices, the W-316 L steel (W-SS) composite coatings were fabricated on 316 L steel substrates by detonation spraying (DS) as the interlayer of pure tungsten coatings manufactured by atmospheric plasma spraying (APS). The main characteristics and performance under transient heat shocks of the APS W/DS W-SS /substrate-based three-layer coating system were studied and compared with the APS W/substrate-based coating system. The results showed the porosity of the DS W-SS was about 1.9% with most of the pores smaller than 70 nm. In contrast, the porosity of the APS W reached about 8.6% and most of the pores were up to hundreds of nanometers. The bonding strength tests proved that both the adhesions of APS W to DS W-SS and DS W-SS to the substrate were much higher (almost 1.5 times) than the adhesion of APS W to the substrates. The three-layer specimens performed much better than the APS W/substrate specimens during the transient heat shock tests as expected. Besides, a special microstructure variation occurred on the three-layer specimens before its damage under the tests which was considered helpful to prolong its life-span under high heat flux. In a conclusion, the DS W-SS interlayer improved the service performance of the APS W/substrate-based coating significantly and demonstrates its potential for application in current tokamak experimental devices.

Copper oxides (CuO) can selectively catalyze the electrochemical reduction of CO2 to hydrocarbons and oxygenates. Here, the authors study the activity and morphological evolution of 2D CuO nanosheets under applied electrode potentials to conclude the primacy of dendritic shapes and involvement of a new coupling pathway.

Ternary logic has been proven to carry an information ratio 1.58 times that of binary logic and is capable to reduce circuit interconnections and complexity of operations. However, the excessive transistor count of ternary logic gates has impeded their industry applications for decades. With the modulation of the ferroelectric negative capacitance (NC) properties on the channel potential, MOSFETs show many novel features including steep subthreshold swing and non-saturation output characteristics, based on which an ultra-compact ternary inverter can be achieved. Compared with traditional bulk materials, layered 2D materials and 2D ferroelectrics provide a clean interface and better electrostatic control and reliability. Even though ultra-low SS (∼10 mV/dec) has been experimentally demonstrated in ferroelectric-negative capacitance-incorporated 2D semiconductor (NC2D) FETs, the available models are still rare for large-scale circuit simulations. In this study, the superb electrical properties of pure 2D material stack-based NC2D FETs (layered CuInP2S6 adopted as the 2D ferroelectric layer) are investigated through device modeling based on the Landau–Khalatnikov (LK) equations in HSPICE. We managed to realize an ultra-compact ternary inverter with one NC2D-PMOS (WSe2) and one NC2D-NMOS (MoS2) in HSPICE simulations, whose transistor count is significantly reduced compared with other counterparts. We also proposed a novel input waveform scheme to solve the hysteresis problem caused by ferroelectric modulation to avoid logic confusion. Additionally, the power consumption and propagation delay of the NC2D-based ternary inverter are also investigated. This work may provide some insights into the design and applications of ferroelectric-incorporated 2D semiconductor devices.

Abstract Atom-thin transition metal dichalcogenides (TMDs) have emerged as fascinating materials and key structures for electrocatalysis. So far, their edges, dopant heteroatoms and defects have been intensively explored as active sites for the hydrogen evolution reaction (HER) to split water. However, grain boundaries (GBs), a key type of defects in TMDs, have been overlooked due to their low density and large structural variations. Here, we demonstrate the synthesis of wafer-size atom-thin TMD films with an ultra-high-density of GBs, up to ~1012 cm−2. We propose a climb and drive 0D/2D interaction to explain the underlying growth mechanism. The electrocatalytic activity of the nanograin film is comprehensively examined by micro-electrochemical measurements, showing an excellent hydrogen-evolution performance (onset potential: −25 mV and Tafel slope: 54 mV dec−1), thus indicating an intrinsically high activation of the TMD GBs.

Summary: Replacement of today’s established chemical production processes by “green” sustainable alternatives has become a scientific priority. The oxidative conversion of 5-hydroxymethylfurfural (5-HMF) to the biopolymer component 2.5-furandicarboxylic acid paired with green electrolytic hydrogen production is a promising emerging green process. Here, we present a family of active selective and stable interlayer anion-tuned NiX (X = Fe, Mn, Co, V) bimetallic-layered, double-hydroxide catalysts for the selective oxidation of 5-HMF to 2.5-furandicarboxylic acid in a zero-gap MEA-type electrolyzer. We report that tuning the structural interlayer distance of the catalyst by anion exchange gives rise to previously unachieved catalytic performance for the anodic production of the biopolymer building block. Operando differential electrochemical mass spectrometry analysis reveals the electrode window for the perfectly selective HMF conversion. The role of the catalyst dopants, their real surface areas, the stability of the catalytic interface, and aspects of its favorable techno-economics are discussed.

Memristors offer great advantages as a new hardware solution for neuromorphic computing due to their fast and energy‐efficient matrix vector multiplication. However, the nonlinear weight updating property of memristors makes it difficult to be trained in a neural network learning process. Several compensation schemes have been proposed to mitigate the updating error caused by nonlinearity; nevertheless, they usually involve complex peripheral circuits design. Herein, stochastic and adaptive learning methods for weight updating are developed, in which the inaccuracy caused by the memristor nonlinearity can be effectively suppressed. In addition, compared with the traditional nonlinear stochastic gradient descent (SGD) updating algorithm or the piecewise linear (PL) method, which are most often used in memristor neural network, the design is more hardware friendly and energy efficient without the consideration of pulse numbers, duration, and directions. Effectiveness of the proposed method is investigated on the training of LeNet‐5 convolutional neural network. High accuracy, about 93.88%, on the Modified National Institute of Standards and Technology handwriting digits datasets is achieved (with typical memristor nonlinearity as ±1), which is close to the network with complex PL method (94.7%) and is higher than the original nonlinear SGD method (90.14%).

Abstract Investigations on external electrostatic field (EEF)‐enhanced liquid water evaporation have been reported decades ago, which suggest that molecular alignment and polarization tuned by EEF accelerating the phase change process could be responsible for EEF‐enhanced water evaporation. However, a detailed study revealing the role of EEF in altering the intermolecular and intramolecular water structure is lacking. Herein, an EEF is proved to tune water state by accelerating the thermal movement of water molecules, lowering the molecular escaping energy, and loosening the hydrogen bond structure. The detailed mechanisms and field interactions (heat and electrostatic) are investigated by in situ Raman characterizations and molecular dynamic simulations, which reveal that an EEF can effectively reduce the free energy barrier of water evaporation and then increase the evaporated water molecule flux. As a proof of concept, an EEF is integrated into an interfacial two‐dimentional solar steam generator, enhancing the efficiency by up to 15.6%. Similar to a catalyst lowing activation energy and enhancing kinetics of a chemical reaction, the EEF enhances water state tuning, lowers evaporation enthalpy, and then boosts steam generation rate with negligible additional energy consumption, which can serve as a generic method for water evaporation enhancement in water harvesting, purification, and beyond.

The tungsten divertor of the Experimental Advanced Superconducting Tokamak (EAST) device operates at varying temperatures and strong electromagnetic fields during plasma operation. In order to monitor the thermomechanical and electromagnetic responses of the structural components, a strain sensor system has been proposed to be applied in the EAST device. To develop this technology, two initial experiments on the thermal strain measurement of a tungsten divertor module of the EAST have been carried out using electrical strain gages and optical strain sensors. However, some engineering issues were exposed during the experiments. Under this condition, all these issues are summarized and discussed this time. Moreover, a comparison between the two techniques has been made when applied in the tungsten divertor. To make them more suitable for the application in the tungsten divertor of the EAST, several activities including a thermomechanical simulation, the welding technologies for the sensors’ installation and a thermal stability test on the optical strain sensors were conducted. Based on these progresses, it is expected that the strain monitoring system will be established in the EAST device in the near future. Keywords: Tungsten divertor, Strain monitoring, Electrical strain gage, Fiber Bragg Grating, EAST

Antimonene (Sb) is a novel kind of two-dimensional (2D) material that is predicted to be promising for various applications, such as water splitting and semiconductor devices. Several methods have been reported to prepare Sb nanoflakes/nanofilms; however, it is still relatively difficult to prepare Sb nanofilms. In this work, a method of low-power magnetron sputtering deposition was used for the preparation of Sb nanofilms with lateral dimensions on the centimeter scale and controllable film thickness. It was found that the control of the deposition temperature is important for the final crystalline structure of the nanofilms. Furthermore, the application of the nanofilms as a catalyst for water splitting (hydrogen evolution reaction (HER) and oxygen evolution reaction (OER)) was demonstrated.

A chemical vapor deposition method has been proven to produce large scale monolayer graphene. However, it is often reported that such graphene contains a varying amount of defects. In this work, methane precursors of different purities [99.99% (4-9G), 99.90% (3-9G), and 98.90% (2-9G)] were used. It is shown that the introduction of defects occurs during graphene growth. It has been attributed to the presence of trace oxygen molecules in the gas precursors. By controlling the amount of oxygen present, one is able to tune the defect density in graphene at will. It is purported that the oxygen reacts with methane to yield methanol and formaldehyde. The latter is oxidized to formic acid. As the graphene network expands, the alcohol and formic acid are incorporated as C—O and O—C=O functional groups. In turn, the graphene experiences an overall global tensile strain due to local bond distortion induced by the electronegative oxygen containing groups. Furthermore, the presence of N2 molecules impedes the proper coalescing of carbon-containing molecules for the formation of the sp2-rich carbon network. Electrical measurement conducted suggests that a high purity precursor (4-9G) induces the least amount of defects, which confers a high Seebeck coefficient (105.1 µV/K) and a low sheet resistance (58.3 Ω). In the case of a larger volume of oxygen in the precursor, electrical performance decreases generally.

The molecular mechanism of heterosis or hybrid vigor, where F1 hybrids of genetically diverse parents show superior traits compared to their parents, is not well understood. Here, we studied the molecular regulation of heterosis in four F1 cabbage hybrids that showed heterosis for several horticultural traits, including head size and weight. To examine the molecular mechanisms, we performed a global transcriptome profiling in the hybrids and their parents by RNA sequencing. The proportion of genetic variations detected as single nucleotide polymorphisms and small insertion–deletions as well as the numbers of differentially expressed genes indicated a larger role of the female parent than the male parent in the genetic divergence of the hybrids. More than 86% of hybrid gene expressions were non-additive. More than 81% of the genes showing divergent expressions showed dominant inheritance, and more than 56% of these exhibited maternal expression dominance. Gene expression regulation by cis-regulatory mechanisms appears to mediate most of the gene expression divergence in the hybrids; however, trans-regulatory factors appear to have a higher effect compared to cis-regulatory factors on parental expression divergence. These observations bring new insights into the molecular mechanisms of heterosis during the cabbage head development.

With the approaching end of Moore’s Law (that the number of transistors in a dense integrated circuit doubles every two years), the logic data density in modern binary digital integrated circuits can hardly be further improved due to the physical limitation. In this aspect, ternary logic (0, 1, 2) is a promising substitute to binary (0, 1) because of its higher number of logic states. In this work, we carry out a systematical study on the emerging two-dimensional (2D) materials (MoS2 and Black Phosphorus)-based ternary logic from individual ternary logic devices to large scale ternary integrated circuits. Various ternary logic devices, including the standard ternary inverter (STI), negative ternary inverter (NTI), positive ternary inverter (PTI) and especially the ternary decrement cycling inverter (DCI), have been successfully implemented using the 2D materials. Then, by taking advantage of the optimized ternary adder algorithm and the novel ternary cycling inverter, we design a novel ternary ripple-carry adder with great circuitry simplicity. Our design shows about a 50% reduction in the required number of transistors compared to the existing ternary technology. This work paves a new way for the ternary integrated circuits design, and shows potential to fulfill higher logic data density and a smaller chip area in the future.

Irisin, a newly discovered myokine, is considered as a promising candidate for the treatment of metabolic disturbances and cardiovascular diseases. In the present study, we used two animal models, apolipoprotein E-deficient mice fed on a high-cholesterol diet and a mouse carotid partial ligation model to test the anti-atherosclerotic effect of irisin. Irisin treatment (0.5 μg/g body weight/day) significantly reduced the severity of aortic atherosclerosis in apolipoprotein E-deficient mice fed on a high-cholesterol diet and suppressed carotid neointima formation in a carotid partial ligation model. It was associated with decreased inflammation and cell apoptosis in aortic tissues. In addition, in a cell culture model, irisin restored ox-LDL-induced human umbilical vein endothelial cell dysfunction by reducing the levels of inflammatory genes via inhibiting the reactive oxygen species (ROS)/ p38 MAPK/ NF-κB signaling pathway activation and inhibiting cell apoptosis via up-regulating Bcl-2 and down-regulating Bax and caspase-3 expression. Our study demonstrated that irisin significantly reduced atherosclerosis in apolipoprotein E-deficient mice via suppressing ox-LDL-induced cell inflammation and apoptosis, which might have a direct therapeutic effect on atherosclerotic diseases.

A rapid LC-MS/MS method with good accuracy and sensitivity was developed and validated for the pharmacokinetics study of metoprolol (MP) in beagle dogs. The plasma samples were simply precipitated by methanol and then analyzed by LC-MS/MS. An Ultimate XB-C18 column (150 × 2.1 mm ID, 5 μm) was used for separation, with methanol-water containing 0.2% formic acid (65:35, v/v) as the mobile phase at a flow rate of 0.2 mL/min. Monitoring ions of MP and internal standard (hydroxypioglitazone) were m/z 268.1/115.6 and m/z 373.1/150.2, respectively. The linear range was 3.03–416.35 ng/mL with an average correlation coefficient of 0.9996, and the limit of quantification was 3.03 ng/mL. The intra- and inter-day precision was less than 15%. At low, middle and high concentrations, the recovery, the matrix effect and the accuracy was in the range of 76.06%–95.25%, 93.67%–104.19% and 95.20%–99.96% respectively. The method was applied for the pharmacokinetics study of MP tartrate tablets (50 mg). The AUC0-t, Tmax and Cmax were respectively 919.88 ± 195.67 μg/L·h, 0.96 ± 0.33 h, 349.12 ± 78.04 ng/mL.

Antimicrobial peptides (AMPs) are small peptides and play important roles in host innate immune response against microbial invasion. Aquatic animals secrete different kinds of antimicrobial peptides which have antimicrobial activity towards microorganisms. NK-lysins, mature peptides produced by cytotoxic T lymphocytes and natural killer cells, are comprised of 74–78 amino acid residues, demonstrating broad-spectrum antimicrobial activity against bacteria, fungi, protozoa, and parasites. In this study, three distinct NK-lysin mature peptide (mNKLs), transcripts (76 amino acid residues) cloned from the channel catfish (Ictalurus punctatus) head kidney were ligated into plasmid vector pET-32a(+) to express the mNKLs fusion protein. The fusion protein was successfully expressed in E. coli Rosetta (DE3) under optimized conditions. After purification by affinity column chromatography, the fusion protein was successfully cleaved by enterokinase and released the peptide mNKLs. Tricine-SDS-PAGE results showed that mNKLs (approximately 8.6 kDa) were successfully expressed. The purified peptide mNKLs exhibited antibacterial activity against Staphylococcus aureus and E. coli.