Pyrotinib versus placebo in combination with trastuzumab and docetaxel as first line treatment in patients with HER2 positive metastatic breast cancer (PHILA): randomised, double blind, multicentre, phase 3 trial.

OBJECTIVE: To assess the efficacy and safety of pyrotinib (an irreversible pan-HER (human epidermal growth factor receptor) inhibitor), trastuzumab, and docetaxel compared with placebo, trastuzumab, and docetaxel for untreated HER2 positive metastatic breast cancer. DESIGN: Randomised, double blind, placebo controlled, multicentre, phase 3 trial. SETTING: 40 centres in China between 6 May 2019 and 17 January 2022. PARTICIPANTS: 590 female patients (median age 52 (interquartile range 46-58) years) with untreated HER2 positive metastatic breast cancer. INTERVENTIONS: Eligible patients were randomised 1:1 to receive either oral pyrotinib (400 mg once daily) or placebo, both combined with intravenous trastuzumab (8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles) and docetaxel (75 mg/m2) on day 1 of each 21 day cycle. Randomisation was stratified by treatment history of trastuzumab in the (neo)adjuvant setting and hormone receptor status. Patients, investigators, and the sponsor's study team were masked to treatment assignment. MAIN OUTCOME MEASURES: The primary endpoint was progression-free survival as assessed by the investigator. RESULTS: Of the 590 randomised patients, 297 received pyrotinib, trastuzumab, and docetaxel treatment (pyrotinib group), and 293 received placebo, trastuzumab, and docetaxel treatment (placebo group). At data cut-off on 25 May 2022, the median follow-up was 15.5 months. The median progression-free survival according to the investigator was significantly longer in the pyrotinib group than in the placebo group (24.3 (95% confidence interval 19.1 to 33.0) months versus 10.4 (9.3 to 12.3) months; hazard ratio 0.41 (95% confidence interval 0.32 to 0.53); one sided P<0.001). Treatment related adverse events of grade 3 or higher were reported in 267 (90%) of the 297 patients in the pyrotinib group and 224 (76%) of the 293 patients in the placebo group. No treatment related deaths occurred in the pyrotinib group, and one (<1%; diabetic hyperosmolar coma) treatment related death occurred in the placebo group. Survival and toxicities are still under assessment with longer follow-up. CONCLUSIONS: Pyrotinib, trastuzumab, and docetaxel showed superiority by significantly improving progression-free survival compared with placebo, trastuzumab, and docetaxel in patients with untreated HER2 positive metastatic breast cancer. The toxicity was manageable. The findings support this dual anti-HER2 regimen as an alternative first line treatment option in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov NCT03863223.

Determination of vitamin K in infant formulas by liquid chromatography-online electrochemical reduction based on porous Pt/Ti electrode-fluorescence detection.

A highly sensitive and selective HPLC method for the determination of vitamin K vitamers including phylloquinone (PK) and menaquinones (MK-4) in infant formulas is described. The K vitamers were quantified with a fluorescence detector after online post-column electrochemical reduction occurring in a laboratory-made electrochemical reactor (ECR) equipped with platinum plated porous titanium (Pt/Ti) electrodes. The morphology of the electrode showed that the grain size of Pt was homogeneous and well plated on the porous Ti substrate, resulting in largely improved electrochemical reduction efficiency due to the large specific surface area. In addition, the operation parameters such as mobile phase/supporting electrolyte and working potential were optimized. The detection limits of PK and MK-4 were 0.81 and 0.78 ng g-1. Infant formula varying in stages were detected, showing PK ranged from 26.4 to 71.2 µg/100 g, while MK-4 was not detected.

Bias Stability Investigation of a Triaxial Navigation-Compatible Accelerometer with an Electrostatic Spring.

The bias stability performance of accelerometers is essential for an inertial navigation system. The traditional pendulous accelerometer usually has a flexible connection structure, which could limit the long-term bias stability. Here, based on the main technologies employed in previous space missions of our group, we developed a terrestrial triaxial navigation-compatible accelerometer. Because there is no mechanical connection between the inertial test mass and the frame, the bias performance relies on the stability of the equivalent electrostatic spring, where further sources are analyzed to get the optimal electrostatic force scheme. To investigate the bias stability under different ranges, the vertical and horizontal measurement ranges are designed at 5 g and ±10 mg, respectively. A low-noise high-voltage levitation scheme is adopted to extend the vertical measurement range from sub-mg to more than earth's 1-g gravity. Finally, the experimental validation results show that the 24-h bias stability of vertical and two horizontal directions come to 13.8 µg, 0.84 µg, and 0.77 µg, respectively.

Noise investigation of an electrostatic accelerometer by a high-voltage levitation method combined with a translation-tilt compensation pendulum bench.

A high precision electrostatic accelerometer has widely been employed to measure gravity gradients and detect gravitational waves in space. The high-voltage levitation method is one of the solutions for testing electrostatic accelerometers on the ground, which aims at simultaneously detecting all six-degree-of-freedom movements of the electrostatic accelerometers engineering and flight prototypes. However, the noise performance in the high-voltage levitation test is mainly limited by seismic noise. The combined test of the accelerometer and vibration isolation platform is adopted to improve the detection precision of the high-voltage levitation method. In this paper, a high precision electrostatic accelerometer prototype is developed after designed appropriate mechanical parameters with a test mass weighing 300 g and with an estimated resolution of 2 × 10-12 m/s2/Hz1/2 from 0.01 to 0.4 Hz. Such a prototype is tested by the high-voltage levitation method, its measurement noise on the ground is mainly limited by the seismic noise, which is about 5 × 10-7 m/s2/Hz1/2 around 0.2 Hz and about 4 × 10-8 m/s2/Hz1/2 around 0.1 Hz. A vibration isolation pendulum bench based on the translation-tilt compensation principle is adopted for accelerometer prototype combined tests to suppress the seismic noise, which has a large bench area and the ability to adjust the tilt angle precisely. The measured accelerometer noise of the combined test with the translation-tilt compensation pendulum has reached 3 × 10-9 m/s2/Hz1/2 around 0.2 Hz, and it is about two orders of magnitude lower than the measurement noise on the ground. The combined test method provides technical guidance for further improving the noise level of ground test in the future.

An electrodialytic device for automated inorganic anion preconcentration with determination by ion chromatography-conductivity detection.

A 4-layer sandwiched device (4LSD) well suited for coupling to online ion chromatography (IC) systems was described and simultaneously performed target anion enrichment, matrix removal and sample injection within seconds. The basic assembly consisted of an extraction solution channel, a sample solution channel and two electrolyte channels. Cation-exchange resin (CER) was utilized to support the solution chamber, increase electrical conductivity and improve pressure resistance to achieve compatibility with a peristaltic pump. Filter placement ensured loop circulation of the 4LSD and prevented resin leakage. The 4LSD showed comparable performance to that of conventional solid-phase extraction (SPE) pretreatment in terms of matrix interference removal while enabling automation. The applied current, sample/extraction solution flow rate ratio, and initial concentration were discussed and optimized. Controllable 1-40-fold enrichment can be ensured. The migration phenomenon of different anions was discussed. F-, Cl-, NO2-, Br-, NO3-, SO42- and ClO4- exhibited satisfactory linear detection ranges within 2.5-1000 µg·L-1, and the calculated limits of detection (LODs) in milk formula were within the 0.097-0.79 mg·kg-1 range. The 4LSD was successfully applied to the determination of anions in milk formula with good spiked recoveries ranging between 92.54% and 107.2%, except for the NO2- recovery. The relative standard deviations (RSDs) ranged from 0.69% to 8.29%.

Investigation on Stray-Capacitance Influences of Coaxial Cables in Capacitive Transducers for a Space Inertial Sensor.

Ultra-sensitive inertial sensors are one of the key components in satellite Earth's gravity field recovery missions and space gravitational wave detection missions. Low-noise capacitive position transducers are crucial to these missions to achieve the scientific goal. However, in actual engineering applications, the sensor head and electronics unit usually place separately in the satellite platform where a connecting cable is needed. In this paper, we focus on the stray-capacitance influences of coaxial cables which are used to connect the mechanical core and the electronics. Specially, for the capacitive transducer with a differential transformer bridge structure usually used in high-precision space inertial sensors, a connecting method of a coaxial cable between the transformer's secondary winding and front-end circuit's preamplifier is proposed to transmit the AC modulated analog voltage signal. The measurement and noise models including the stray-capacitance of the coaxial cable under this configuration is analyzed. A prototype system is set up to investigate the influences of the cables experimentally. Three different types and lengths of coaxial cables are chosen in our experiments to compare their performances. The analysis shows that the stray-capacitance will alter the circuit's resonant frequency which could be adjusted by additional tuning capacitance, then under the optimal resonant condition, the output voltage noises of the preamplifier are measured and the sensitivity coefficients are also calibrated. Meanwhile, the stray-capacitance of the cables is estimated. Finally, the experimental results show that the noise level of this circuit with the selected cables could all achieve 1-2 × 10-7 pF/Hz1/2 at 0.1 Hz.

Fluorimetric detection of reserpine in mouse serum through online post-column electrochemical derivatization.

A novel method combining high-performance liquid chromatography with online post-column electrochemical derivatization and fluorescence detection was established for the detection of reserpine in mouse serum. Reserpine separation was conducted using a C18 column with 5 mM H3PO4 and acetonitrile (55/45, v/v) as eluent. Reserpine was then electro-oxidized into a strongly fluorescent compound using an electrolytic cell device. Detection parameters, such as potential and fluorescence wavelength, were optimized. The linearity of the proposed method ranged from 0.01 to 5.0 mg l-1 with a correlation coefficient of 0.9997. The limit of qualification (S/N = 10) and limit of detection (S/N = 3) were 9.7 and 2.9 µg l-1, respectively. Resperine recoveries from spiked blank and drug-treated mouse serum samples ranged from 92.0 to 115%.

Measurements of the gravitational constant using two independent methods.

The Newtonian gravitational constant, G, is one of the most fundamental constants of nature, but we still do not have an accurate value for it. Despite two centuries of experimental effort, the value of G remains the least precisely known of the fundamental constants. A discrepancy of up to 0.05 per cent in recent determinations of G suggests that there may be undiscovered systematic errors in the various existing methods. One way to resolve this issue is to measure G using a number of methods that are unlikely to involve the same systematic effects. Here we report two independent determinations of G using torsion pendulum experiments with the time-of-swing method and the angular-acceleration-feedback method. We obtain G values of 6.674184 × 10-11 and 6.674484 × 10-11 cubic metres per kilogram per second squared, with relative standard uncertainties of 11.64 and 11.61 parts per million, respectively. These values have the smallest uncertainties reported until now, and both agree with the latest recommended value within two standard deviations.

Simple coupled ultrahigh performance liquid chromatography and ion chromatography technique for simultaneous determination of folic acid and inorganic anions in folic acid tablets.

Folic acid plays a significant role during periods of rapid cells division and growth. Pregnant women require folic acid daily, either from dietary supplements or folic acid tablets in order to prevent fetal neural tube defects. In this work, a simple coupled ultrahigh performance liquid chromatography and ion chromatography technique was developed for simultaneous determination of folic acid and inorganic anions in folic acid tablets. A reversed-phase C18 column was used as the pretreatment column for on-line separating inorganic anions from organics. Inorganic anions were concentrated in the concentration column. Under the optimal chromatographic conditions, good sensitivity and linear calibration-curves (r≥0.9992) were obtained. Low detection limits were obtained in the range of 0.0032-0.40mgL-1 for all analytes. Repeatability results were satisfactory with relative standard deviations less than 1.50% (n=5). The developed method was utilized to analyze spiked folic acid tablet samples with good measured recoveries (92.4-107.4%).

Research and Development of Electrostatic Accelerometers for Space Science Missions at HUST.

High-precision electrostatic accelerometers have achieved remarkable success in satellite Earth gravity field recovery missions. Ultralow-noise inertial sensors play important roles in space gravitational wave detection missions such as the Laser Interferometer Space Antenna (LISA) mission, and key technologies have been verified in the LISA Pathfinder mission. Meanwhile, at Huazhong University of Science and Technology (HUST, China), a space accelerometer and inertial sensor based on capacitive sensors and the electrostatic control technique have also been studied and developed independently for more than 16 years. In this paper, we review the operational principle, application, and requirements of the electrostatic accelerometer and inertial sensor in different space missions. The development and progress of a space electrostatic accelerometer at HUST, including ground investigation and space verification are presented.

Application of a simple column-switching ion chromatography technique for removal of matrix interferences and sensitive fluorescence determination of acidic compounds (pharmaceutical drugs) in complex samples.

This work illustrates the introduction of a simple, rugged and flexible column-switching ion chromatography (IC) technique for an automated on-line QuEChERS extracted samples extracts washing followed by sensitive fluorescence (FLD) determination of five acidic pharmaceutical drugs namely; clofibric acid (CLO), ibuprofen (IBU), aspirin (ASP), naproxen (NAP) and flurobrofen (FLU) in three complex samples (spinach, apple and hospital sewage sludge). An old anion exchange column IonPac® AS11-HC was utilized as a pre-treatment column for on-line washing of inorganic and organic interferences followed by isocratic separation of five acidic drugs with another anion exchange IonPac® AS12A analytical column by exploiting the column-switching technique. This novel method exhibited good linearity with correlation coefficients (r2) for all drugs were in the range 0.976-0.996. The limit of detection and quantification of all five acidic drugs were in the range 0.024µg/kg to 8.70µg/kg and 0.082µg/kg to 0.029mg/kg, respectively, and better recoveries in the range 81.17-112.5% with percentage relative standard deviations (RSDs) less than 17.8% were obtained. This on-line sample pre-treatment method showed minimum matrix effect in the range of 0.87-1.25 except for aspirin. This simple rugged and flexible column-switching system required only 28min for maximum elimination of matrices and interferences in three complex samples extracts, isocratic separation of five acidic drugs and for the continuous regeneration of pre-treatment column prior to every subsequent analysis. Finally, this simple automated IC system was appeared so rugged and flexible, which can eliminate and wash out most of interference, impurities and matrices in complex samples, simply by adjusting the NaOH and acetonitrile concentration in washing mobile phase with maximum recoveries of acidic analytes of interest.

Detection of trace fluoride in serum and urine by online membrane-based distillation coupled with ion chromatography.

An online membrane-based distillation (MBD) coupled with ion chromatography (IC) method was proposed for automatic detection of trace fluoride (F-) in serum and urine samples. The system consisted of a sample vessel, a lab-made membrane module and an ion chromatograph. Hydrophobic polytetrafluoroethylene (PTFE) hollow fiber membrane was used in MBD which was directly performed in serum and urine samples to eliminate the matrix interferences and enrich fluoride, while enabling automation. The determination of fluoride in biological samples was carried out by IC with suppressed conductometric detection. The proposed method feasibly determined trace fluoride in serum and urine matrices with the optimized parameters, such as acid concentration, distillation temperature, and distillation time, etc. Fluoride exhibited satisfactory linearity in the range of 0.01-5.0mg/L with a correlation coefficient of 0.9992. The limit of detection (LOD, S/N=3) and limit of quantification (LOQ, S/N=10) were 0.78µg/L and 2.61µg/L, respectively. The relative standard deviations of peak area and peak height were all less than 5.15%. The developed method was validated for the determination of fluoride in serum and urine with good spiked recoveries ranging between 97.1-101.9%. This method also can be proposed as a suitable alternative for the analysis of fluoride in other complex biological samples.

Graphene-coated polymeric anion exchangers for ion chromatography.

Carbonaceous stationary phases have gained much attention for their peculiar selectivity and robustness. Herein we report the fabrication and application of a graphene-coated polymeric stationary phase for anion exchange chromatography. The graphene-coated particles were fabricated by a facile evaporation-reduction method. These hydrophilic particles were proven appropriate substrates for grafting of hyperbranched condensation polymers (HBCPs) to make pellicular anion exchangers. The new phase was characterized by zeta potentials, Fourier transform infrared spectroscopy, thermogravimetry and scanning electron microscope. Frontal displacement chromatography showed that the capacities of the anion exchangers were tuned by both graphene amount and HBCPs layer count. The chromatographic performance of graphene-coated anion exchangers was demonstrated with separation of inorganic anions, organic acids, carbohydrates and amino acids. Good reproducibility was obtained by consecutive injections, indicating high chemical stability of the coating.

Poly (styrene-divinyl benzene-glycidylmethacrylate) stationary phase grafted with poly amidoamine (PAMAM) dendrimers for rapid determination of phenylene diamine isomers in HPLC.

A novel high performance liquid stationary phase was prepared by grafting poly amidoamine (PAMAM) dendrimers to poly (styrene-divinyl benzene-glycidylmethacrylate) matrix in this work. Different generations of PAMAM dendrimers grafted to polymer matrices containing different glycidylmethacrylate amounts by reacting with epoxy groups in glycidylmethacrylate molecules. The synthesized PAMAM dendrimers and stationary phase were characterized by fourier transform infrared spectroscopy, scanning electron microscope, N2 adsorption/desorption, elemental analysis and thermo gravimetric analyzer. The proposed stationary phase was suitable for rapid separation of phenylene diamine isomers and aminobenzene. The separation mechanism of benzene rings attraction and amino repulsion was verified by retention behaviors of methylamine, phenylamine, phenylene diamine, naphthylamine and toluene. The reliability of the stationary phase was demonstrated by separation and determination of phenylene diamine isomers including m-phenylene diamine, o-phenylene diamine and p-phenylene diamine in hair dye precursors within 10min. Satisfactory resolution and short analysis time make the columns promising for determination of aniline compounds in various fields.

Hydrothermal carbonaceous sphere based stationary phase for anion exchange chromatography.

Monodisperse carbonaceous spheres produced by the hydrothermal carbonization of sucrose were first applied as green stationary phase for ion chromatography after quaternization. Depending on the polycondensation of methylamine and 1,4-butanediol diglycidyl ether, polymer containing quaternary ammonium groups were facilely grafted onto the surfaces of hydrothermal carbonaceous spheres (HCSs). The quaternized HCSs with different number of polyelectrolyte layers were characterized by scanning electron microscopy, brunauer-emmett-teller, fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, thermogravimetric analysis and elemental analysis. The measurements of breakthrough curves demonstrated that more layers of grafted polyelectrolyte resulted in higher anion exchange capacity of stationary phase. With good stability, common inorganic anions, monocarboxylic acids, polarizable anions and carbohydrates were effectively separated on the stationary phases, respectively. The high hydrophilicity of HCS surface afforded excellent peak symmetry for all analytes. Furthermore, high-capacity HCSs stationary phase was successfully applied to detect fluoride in tea samples.

Self-calibration method of the bias of a space electrostatic accelerometer.

The high precision space electrostatic accelerometer is an instrument to measure the non-gravitational forces acting on a spacecraft. It is one of the key payloads for satellite gravity measurements and space fundamental physics experiments. The measurement error of the accelerometer directly affects the precision of gravity field recovery for the earth. This paper analyzes the sources of the bias according to the operating principle and structural constitution of the space electrostatic accelerometer. Models of bias due to the asymmetry of the displacement sensing system, including the mechanical sensor head and the capacitance sensing circuit, and the asymmetry of the feedback control actuator circuit are described separately. According to the two models, a method of bias self-calibration by using only the accelerometer data is proposed, based on the feedback voltage data of the accelerometer before and after modulating the DC biasing voltage (Vb) applied on its test mass. Two types of accelerometer biases are evaluated separately using in-orbit measurement data of a space electrostatic accelerometer. Based on the preliminary analysis, the bias of the accelerometer onboard of an experiment satellite is evaluated to be around 10-4 m/s2, about 4 orders of magnitude greater than the noise limit. Finally, considering the two asymmetries, a comprehensive bias model is analyzed. A modified method to directly calibrate the accelerometer comprehensive bias is proposed.

Octadecylamine-modified poly (glycidylmethacrylate-divinylbenzene) stationary phase for HPLC determination of N-nitrosamines.

Poly (glycidylmethacrylate-divinylbenzene) (Poly (GMA-DVB)) microspheres were prepared by the two-staged swelling and polymerization method, and modified with octadecylamine (ODA) to obtain ODA-poly (GMA-DVB) stationary phase for HPLC. The new material was characterized by scanning electron microscope, nitrogen adsorption-desorption measurement, Fourier transform infrared spectrum, elemental analysis and thermogravimetric analysis. The results showed that poly (GMA-DVB) microspheres had good monodispersity, porosity and ball shapes. The diameters and specific surface area of the microspheres were about 6µm and 396m(2)g(-1), respectively. ODA-poly (GMA-DVB) stationary phase had good thermal stability. Furthermore, the chromatographic performance of the stationary phase was illustrated by separating n-alkylbenzenes, mono-substituted benzenes and N-nitrosamines. Auxiliary quantum chemistry calculation was also carried out to evaluate the interaction mechanism. According to the evaluation, ODA-poly (GMA-DVB) stationary phase exhibited good hydrophobicity and hydrophobic selectivity, strong stereo-selectivity, polar interaction and π-π interaction. The multi-interaction mechanisms could very likely guarantee its excellent chromatographic performance for the analysis of complex samples. Finally, the column was successfully applied in the determination of N-nitrosamines in pickles sample.

Hydrothermal carbon nanosphere-based agglomerated anion exchanger for ion chromatography.

This work reports the application of hydrothermal carbon nanospheres (HCNSs) as stationary phases in ion chromatography. HCNSs were facilely quaternized through polycondensation of methylamine and 1,4-butanediol diglycidyl ether. The quaternization was confirmed by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. Owing to the electrostatic interaction, quaternized HCNSs were equably attached onto the surface of sulfonated polystyrene-divinylbenzene (PS-DVB) beads to construct the anion exchangers. The aggregation was verified by scanning electron microscopy and elemental analysis. Common anions, aliphatic monocarboxylic acids, polarizable anions, and aromatic acids were well separated on the stationary phases with good stability and symmetry. The prepared column was further applied to detect phosphate content in Cola drink samples. The limit of detection (S/N=3) was 0.09mg/L, and the relative standard deviation (n=10) of retention time was 0.31%. The average recovery was 99.58%.