The emerging predictive and prognostic role of HER2 in HER2-negative early breast cancer: a retrospective study.

PURPOSE: Many patients with early breast cancer (eBC) undergoing neoadjuvant chemotherapy do not achieve pathological complete response (pCR), which is a prognostic factor. We examined the role of HER2-low expression in predicting pCR and prognosis in HER2-negative eBC. METHODS: We evaluated patients with stage I-III HER2-negative BC, treated between 2013 and 2023 at The Royal Marsden NHS Foundation Trust, London. Tumors were classified based on estrogen receptor (ER) status and into HER2-low and HER2-zero subgroups. We analyzed pCR rates, relapse-free survival (RFS) and overall survival (OS). RESULTS: 754 patients were included in the analysis. pCR rate was 8.9% in the ER+ /HER2-low, 16.5% in the ER+ /HER2-zero, 38.9% in the ER- ER-/HER2-low and 35.9% in the ER-/HER2-zero eBC (p < 0.001). Multivariable analysis showed a significantly lower pCR rate in HER2-low compared to HER2-zero BC in the ER+ subgroup. At a median follow-up of 63.8 months (59.9-67.4), we observed longer OS in HER2-low compared to HER2-zero patients in the overall and in the ER+ population. There was no predictive or prognostic impact of HER2-low status in the ER- population. CONCLUSION: This study supports the interpretation of HER2 status as a possible prognostic and predictive biomarker for HER2-negative eBC, especially among patients with ER+ disease.

Self-supporting noncovalent Choline Alginate/Tannic acid/Ag antibacterial films for strawberry preservation.

Packaging materials with peculiar antibacterial properties can shield off and inhibit microorganism proliferation, thus achieving packaging goals such as fresh-keeping, good hygiene, and biosafety. Especially, antibacterial films made of biocompatible substances have received wide attentions, which could effectively extend the shelf life, enhance food security, and guarantee economic benefits. Herein, a self-supporting hybrid antibacterial film was prepared based on non-covalently linked choline hydroxide (ChOH) and alginic acid (HAlg). Then tannic acid (TA) and silver ions were added to improve the mechanical and antimicrobial properties of this hybrid film. The rich hydroxyl groups from TA not only form multiple hydrogen bonds with ChAlg, but can also in situ reduce silver ions to silver nanoparticles, which were confirmed with various characterizations. In addition, the quantitative antibacterial test proved that the antibacterial rate was significantly improved after adding silver ions, reaching >60 %. In an actual storage test, we found that choline cation (Ch+) captured in antibacterial film by electrostatic interaction could achieve sustained release, i.e. sustainable bacteriostasis, and keep strawberries fresh for 48 h at room temperature. This work offers a new strategy for preparing antibacterial films via non-covalent weak interactions, explored an alternative antibacterial film for food packaging applications.

Etomidate enhances cerebellar CF-PC synaptic plasticity through CB1 receptor/PKA cascade in vitro in mice.

Etomidate (ET) is a widely used intravenous imidazole general anesthetic, which depresses the cerebellar neuronal activity by modulating various receptors activity and synaptic transmission. In this study, we investigated the effects of ET on the cerebellar climbing fiber-Purkinje cells (CF-PC) plasticity in vitro in mice using whole-cell recording technique and pharmacological methods. Our results demonstrated that CF tetanic stimulation produced a mGluR1-dependent long-term depression (LTD) of CF-PC excitatory postsynaptic currents (EPSCs), which was enhanced by bath application of ET (10 µM). Blockade of mGluR1 receptor with JNJ16259685, ET triggered the tetanic stimulation to induce a CF-PC LTD accompanied with an increase in paired-pulse ratio (PPR). The ET-triggered CF-PC LTD was abolished by extracellular administration of an N-methyl-(D)-aspartate (NMDA) receptor antagonist, D-APV, as well as by intracellular blockade of NMDA receptors activity with MK801. Furthermore, blocking cannabinoids 1 (CB1) receptor with AM251 or chelating intracellular Ca2+ with BAPTA, ET failed to trigger the CF-PC LTD. Moreover, the ET-triggered CF-PC LTD was abolished by inhibition of protein kinase A (PKA), but not by inhibition of protein kinase C inhibiter. The present results suggest that ET acts on postsynaptic NMDA receptor resulting in an enhancement of the cerebellar CF-PC LTD through CB1 receptor/PKA cascade in vitro in mice. These results provide new evidence and possible mechanism for ET anesthesia to affect motor learning and motor coordination by regulating cerebellar CF-PC LTD.

Enhancing H2O2 Electrosynthesis at Industrial-Relevant Current in Acidic Media on Diatomic Cobalt Sites.

Electrocatalytic synthesis of hydrogen peroxide (H2O2) in acidic media is an efficient and eco-friendly approach to produce inherently stable H2O2, but limited by the lack of selective and stable catalysts under industrial-relevant current densities. Herein, we report a diatomic cobalt catalyst for two-electron oxygen reduction to efficiently produce H2O2 at 50-400 mA cm-2 in acid. Electrode kinetics study shows a >95% selectivity for two-electron oxygen reduction on the diatomic cobalt sites. In a flow cell device, a record-high production rate of 11.72 mol gcat-1 h-1 and exceptional long-term stability (100 h) are realized under high current densities. In situ spectroscopic studies and theoretical calculations reveal that introducing a second metal into the coordination sphere of the cobalt site can optimize the binding strength of key H2O2 intermediates due to the downshifted d-band center of cobalt. We also demonstrate the feasibility of processing municipal plastic wastes through decentralized H2O2 production.

Cushing's Syndrome in Pregnancy Secondary to Adrenocortical Adenoma: A Case Series and Review.

PURPOSE: To present a case series of Cushing's syndrome (CS) during pregnancy caused by adrenocortical adenomas, highlighting clinical features, hormonal assessments and outcomes. METHODS: We describe five pregnant women with CS, detailing clinical presentations and laboratory findings. RESULTS: Common clinical features included a full moon face, buffalo back and severe hypertension. Elevated blood cortisol levels with circadian rhythm disruption and suppressed adrenocorticotrophic hormone (ACTH) levels were observed. Imaging revealed unilateral adrenal tumours. Two cases underwent laparoscopic adrenalectomies during the second trimester, while three had postpartum surgery. All required hormone replacement therapy, with postoperative pathological confirmation of adrenocortical adenomas. CONCLUSION: Diagnosis of CS during pregnancy is challenging due to overlapping features with normal pregnancy: elevated blood cortisol levels and abnormal diurnal rhythm of blood cortisol, suppressed aid diagnosis. Treatment should be individualised due to a lack of explicit optimum therapeutic approaches. Laparoscopic adrenalectomy may be an optimal choice, along with multidisciplinary management including hormone replacement therapy.

Transcription Factor Pdr3p Promotes Carotenoid Biosynthesis by Activating GAL Promoters in Saccharomyces cerevisiae.

Pleiotropic drug resistance (PDR) family proteins have been extensively studied for their roles in transporting hydrophobic substances, including carotenoids. Overexpression of the PDR family regulator Pdr3p was recently found to boost the biosynthesis of carotenoids, which could not be explained by enhanced product secretion due to the meager extracellular proportions. To provide insights into the possible mechanism, comparative transcriptomics, reverse metabolic engineering, and electrophoretic mobility shift assay (EMSA) were conducted. Transcriptomic data suggested an unexpected correlation between Pdr3p overexpression and the transcriptional levels of GAL promoter-driven genes. This assumption was verified using mCherry and the lycopene synthetic pathway as the reporters. qRT-PCR and EMSA provided further evidence for the activation of GAL promoters by Pdr3p binding to their upstream activation sequences (UASs). This work gives insight into the mechanism of Pdr3p-promoted carotenoid production and highlights the complicated metabolic networking between transcriptional factors and promoters in yeast.

A Novel, Controllable, and Efficient Method for Building Highly Hydrophobic Aerogels.

Aerogels prepared using freeze-drying methods have the potential to be insulation materials or absorbents in the fields of industry, architecture, agriculture, etc., for their low heat conductivity, high specific area, low density, degradability, and low cost. However, their native, poor water resistance caused by the hydrophilicity of their polymer matrix limits their practical application. In this work, a novel, controllable, and efficient templating method was utilized to construct a highly hydrophobic surface for freeze-drying aerogels. The influence of templates on the macroscopic morphology and hydrophobic properties of materials was investigated in detail. This method provided the economical and rapid preparation of a water-resistant aerogel made from polyvinyl alcohol (PVA) and montmorillonite (MMT), putting forward a new direction for the research and development of new, environmentally friendly materials.

Alpine grassland greening on the Northern Tibetan Plateau driven by climate change and human activities considering extreme temperature and soil moisture.

Alpine grassland is among the world's most vulnerable ecosystems, characterized by a high sensitivity to climate change (CC) and human activities (HA). Quantifying the relative contributions of CC and HA to grassland change plays a crucial role in safeguarding grassland ecological security and devising sustainable grassland management strategies. Although there were adequate studies focusing on the separate impacts of CC and HA on alpine ecosystem, insufficient attention has been given to investigating the effects of extreme temperatures and soil moisture. In this study, the spatiotemporal variations of alpine grassland were analyzed based on MODIS NDVI during the growing season from 2000 to 2020 in Naqu, using partial least squares regression and residual analysis methods to analyze the importance of climate factors and the impacts of CC and HA on grassland change. The results show that the NDVI during the growing season in Naqu exhibited an increasing trend of 0.0046/10a. At the biome scale, the most significant and rapid increase was observed in alpine desert and alpine desert grassland. Extreme temperature and soil moisture (SM) exerted a more significant importance on alpine grassland at whole scale. SM always showed a significant importance at biome and grid scale. The contributions of CC and HA to the change during the growing season were calculated as 0.0032/10a and 0.0015/10a, respectively, accounting for 68.05 % and 31.05 %. CC dominated the increase in NDVI during the growing season; HA contributed positively to NDVI in most areas of Naqu. The results are expected to enhance our understanding of grassland variations under CC and HA and provide a scientific basis for future ecological conservation in alpine regions.

Degradation of organic pollutants accompanied by the ultrasonic separation of the spent lithium-ion battery cathode materials.

Since the majority of valuable components in spent lithium-ion batteries, such as lithium, exists in the electrode materials, common studies focused on the treatment of the cathode materials, which ignored the harm of residual electrolyte. The cavitation and thermal effects produced by ultrasonic can not only be used for the separation of electrode materials, but also have a wide range of applications in the field of sewage pollutant degradation. This work used ultrasonic to treat simulated electrolyte (propylene carbonate (PC)) solution of spent lithium-ion batteries, explored the effect of ultrasonic power, the addition amount of H2O2 solution (30 wt%) and reaction temperature on the degradation of electrolyte, and analysed the ultrasonic degradation reaction from the perspective of reaction kinetics. And the synchronous experiment of cathode material separation and electrolyte degradation was conducted under the optimal conditions. The results showed that the highest degradation efficiency of PC in the electrolyte was 83.08% under the condition of ultrasonic power of 900 W, the addition of H2O2 solution (30 wt%) of 10.2 mL, reaction temperature of 120°C and reaction time of 120 minutes, and the separation efficiency was 100%. This work reduced the environmental and health risks in the cathode material separation process and was conducive to the green development of spent lithium-ion battery recycling technology.

Drought thresholds that impact vegetation reveal the divergent responses of vegetation growth to drought across China.

Identifying droughts and accurately evaluating drought impacts on vegetation growth are crucial to understanding the terrestrial carbon balance across China. However, few studies have identified the critical drought thresholds that impact China's vegetation growth, leading to large uncertainty in assessing the ecological consequences of droughts. In this study, we utilize gridded surface soil moisture data and satellite-observed normalized difference vegetation index (NDVI) to assess vegetation response to droughts in China during 2001-2018. Based on the nonlinear relationship between changing drought stress and the coincident anomalies of NDVI during the growing season, we derive the spatial patterns of satellite-based drought thresholds (T SM ) that impact vegetation growth in China via a framework for detecting drought thresholds combining the methods of feature extraction, coincidence analysis, and piecewise linear regression. The T SM values represent percentile-based drought threshold levels, with smaller T SM values corresponding to more negative anomalies of soil moisture. On average, T SM is at the 8.7th percentile and detectable in 64.4% of China's vegetated lands, with lower values in North China and Jianghan Plain and higher values in the Inner Mongolia Plateau. Furthermore, T SM for forests is commonly lower than that for grasslands. We also find that agricultural irrigation modifies the drought thresholds for croplands in the Sichuan Basin. For future projections, Earth System Models predict that more regions in China will face an increasing risk for ecological drought, and the Hexi Corridor-Hetao Plain and Shandong Peninsula will become hotspots of ecological drought. This study has important implications for accurately evaluating the impacts of drought on vegetation growth in China and provides a scientific reference for the effective ecomanagement of China's terrestrial ecosystems.

High-Quality Chest Compression for Cardiopulmonary Resuscitation Using Newly-Designed Automatic Device.

High-quality chest compression during cardiopulmonary resuscitation (CPR) can remarkably improve survival rate and reduce the risk of secondary injury. In this study, a newly-designed automatic chest compression device was applied on an animal model and the effects of chest compression were examined in comparison of manual compression and machine compression by a commercialized device. Three pigs (weight:30±2 kg) were used for the experiment. A LUCAS2 CPR machine and the newly-designed CPR device were used for automatic compression treatment. Compression pressure and chest displacement were collected in the process of CPR. Regarding the statistical distribution of compression depths, the new CPR device showed a mean of the depths at 1.64 inches, which was greater than that of manual (mean = 1.21 inches) and of LUCAS2 (mean = 1.18 inches). In addition, the new CPR device showed a standard deviation (SD) of compression depths at 0.07 inches, which was lower than that of manual (SD = 0.15 inches) and of LUCAS2 (SD = 0.25 inches). These results suggested that the new CPR device performed higher compression depths with lower compression variability, indicating enforced compression and better stability. This study provided a preliminarily outcomes validating the new CPR device, which may play a role in high-quality chest compression for the first aid in emergency.Clinical Relevance- This study established an animal model to validate a newly-designed automatic device for CPR. Comparing with manual chest compression and automatic compression using LUCAS2, the new device showed greater compression depths and better stability, which may provide more effective CPR treatment for clinical usage.

Optical authentication method based on correspondence ghost imaging.

Ghost imaging technology has a great application potential in optical security because of its non-local characteristics. In this paper, on the basis of computational ghost imaging, an optical authentication scheme is proposed that utilizes the correspondence imaging technique for the preliminary reconstruction of the object image, and then authenticates the image by a nonlinear correlation algorithm. Different from the previous optical authentication schemes that usually adopted random selection of measurements, this authentication method consciously selects the bucket detector measurement values with large fluctuation and can achieve authentication using ultra-low data volumes less than 1% of the Nyquist limit. In brief, this scheme is easy to implement and has a simpler algorithm and higher stability, which is a tremendous advantage in practical optical authentication systems. The simulation and physical experimental results demonstrate the feasibility of the scheme.

Terrace-Rich Ultrathin PtCu Surface on Earth-Abundant Metal for Oxygen Reduction Reaction.

The activity and stability of the platinum electrode toward the oxygen reduction reaction are size-dependent. Although small nanoparticles have high Pt utilization, the undercoordinated Pt sites on their surface are assumed to have too strong oxygen binding strength, thus often leading to compromised activity and surface instability. Herein, we report an extended nanostructured PtCu ultrathin surface to reduce the number of low-coordination sites without sacrificing the electrochemical active surface area (ECSA). The surface shows (111)-oriented characteristics, as proven by electrochemical probe reactions and spectroscopies. The PtCu surface brings over an order of magnitude increase in specific activity relative to commercial Pt/C and nearly 4-fold enhancement in ECSA compared to traditional thin films. Moreover, due to the weak absorption of air impurities (e.g., SO2, NO, CO) on highly coordinated sites, the catalyst displays enhanced contaminant tolerance compared with nanoparticulate Pt/C. This work promises a broad screening of extended nanostructured surface catalysts for electrochemical conversions.

A multiple Kirkendall strategy for converting nanosized zero-valent iron to highly active Fenton-like catalyst for organics degradation.

Nanosized zero-valent iron (nZVI) is a promising persulfate (PS) activator, however, its structurally dense oxide shell seriously inhibited electrons transfer for O-O bond cleavage of PS. Herein, we introduced sulfidation and phosphorus-doped biochar for breaking the pristine oxide shell with formation of FeS and FePO4-containing mixed shell. In this case, the faster diffusion rate of iron atoms compared to shell components triggered multiple Kirkendall effects, causing inward fluxion of vacancies with further coalescing into radial nanocracks. Exemplified by trichloroethylene (TCE) removal, such a unique "lemon-slice-like" nanocrack structure favored fast outward transfer of electrons and ferrous ions across the mixed shell to PS activation for high-efficient generation and utilization of reactive species, as evidenced by effective dechlorination (90.6%) and mineralization (85.4%) of TCE. [Formula: see text] contributed most to TCE decomposition, moreover, the SnZVI@PBC gradually became electron-deficient and thus extracted electrons from TCE with achieving nonradical-based degradation. Compared to nZVI/PS process, the SnZVI@PBC/PS system could significantly reduce catalyst dosage (87.5%) and PS amount (68.8%) to achieve nearly complete TCE degradation, and was anti-interference, stable, and pH-universal. This study advanced mechanistic understandings of multiple Kirkendall effects-triggered nanocrack formation on nZVI with corresponding rational design of Fenton-like catalysts for organics degradation.

An Ex Vivo Porcine Model for Hydrodynamic Testing of Experimental Aortic Valve Procedures and Novel Medical Devices.

The options for testing new cardiac procedures and investigative medical devices prior to use in an animal model are limited. In this study, we present a method for mounting a porcine aortic valve in a pulse duplicator to evaluate its hydrodynamic properties. These properties can then be evaluated before and after the procedure under investigation is performed and/or the investigative medical device is applied. Securing the inflow segment presents some difficulty owing to the lack of circumferential myocardium in the left ventricular outflow tract. This method addresses that issue by securing the inflow segment using the anterior leaflet of the mitral valve and then suturing the left ventricular free wall around the inflow fixture. The outflow segment is secured simply by inserting the fixture into an incision in the superior aspect of the aortic arch. We found that specimens had significantly different hydrodynamic properties before and after tissue fixation. This finding induced us to use fresh specimens in our testing and should be considered when using this method. In our work, we used this method to test novel intracardiac patch materials for use in the valvular position by performing an aortic valve neocuspidization procedure (Ozaki procedure) on the mounted porcine aortic valves. These valves were tested before and after the procedure to assess the change in hydrodynamic properties in comparison to the native valve. Herein, we report a platform for hydrodynamic testing of experimental aortic valve procedures that enables comparison with the native valve and between different devices and techniques used for the procedure under investigation.

Plasma metabolic fingerprints for large-scale screening and personalized risk stratification of metabolic syndrome.

Direct diagnosis and accurate assessment of metabolic syndrome (MetS) allow for prompt clinical interventions. However, traditional diagnostic strategies overlook the complex heterogeneity of MetS. Here, we perform metabolomic analysis in 13,554 participants from the natural cohort and identify 26 hub plasma metabolic fingerprints (PMFs) associated with MetS and its early identification (pre-MetS). By leveraging machine-learning algorithms, we develop robust diagnostic models for pre-MetS and MetS with convincing performance through independent validation. We utilize these PMFs to assess the relative contributions of the four major MetS risk factors in the general population, ranked as follows: hyperglycemia, hypertension, dyslipidemia, and obesity. Furthermore, we devise a personalized three-dimensional plasma metabolic risk (PMR) stratification, revealing three distinct risk patterns. In summary, our study offers effective screening tools for identifying pre-MetS and MetS patients in the general community, while defining the heterogeneous risk stratification of metabolic phenotypes in real-world settings.

Synthesis of Oxazolidines and Dihydroxazines via Cyclization of α-Aminated Ketones.

A new approach to oxazolidines and dihydroxazines was developed by regioselective cyclization of α-aminated ketones under transition metal-free conditions. Oxazolidine derivatives were generated in the presence of chloro benziodoxole and TFA, while dihydroxazines were formed without a hypervalent iodine reagent. The reaction was performed under room temperature and gave the products in good to excellent yields.

High-Strength Magnetic Hydrogels with Photoweldability Made by Stepwise Assembly of Magnetic-Nanoparticle-Integrated Aramid Nanofiber Composites.

Hydrogels capable of transforming in response to a magnetic field hold great promise for applications in soft actuators and biomedical robots. However, achieving high mechanical strength and good manufacturability in magnetic hydrogels remains challenging. Here, inspired by natural load-bearing soft tissues, a class of composite magnetic hydrogels is developed with tissue-mimetic mechanical properties and photothermal welding/healing capability. In these hydrogels, a hybrid network involving aramid nanofibers, Fe3O4 nanoparticles, and poly(vinyl alcohol) is accomplished by a stepwise assembly of the functional components. The engineered interactions between nanoscale constituents enable facile materials processing and confer a combination of excellent mechanical properties, magnetism, water content, and porosity. Furthermore, the photothermal property of Fe3O4 nanoparticles organized around the nanofiber network allows near-infrared welding of the hydrogels, providing a versatile means to fabricate heterogeneous structures with custom designs. Complex modes of magnetic actuation are made possible with the manufactured heterogeneous hydrogel structures, suggesting opportunities for further applications in implantable soft robots, drug delivery systems, human-machine interactions, and other technologies.

Integrated analysis of multi-omics data reveals T cell exhaustion in sepsis.

Background: Sepsis is a heterogeneous disease, therefore the single-gene-based biomarker is not sufficient to fully understand the disease. Higher-level biomarkers need to be explored to identify important pathways related to sepsis and evaluate their clinical significance. Methods: Gene Set Enrichment Analysis (GSEA) was used to analyze the sepsis transcriptome to obtain the pathway-level expression. Limma was used to identify differentially expressed pathways. Tumor IMmune Estimation Resource (TIMER) was applied to estimate immune cell abundance. The Spearman correlation coefficient was used to find the relationships between pathways and immune cell abundance. Methylation and single-cell transcriptome data were also employed to identify important pathway genes. Log-rank test was performed to test the prognostic significance of pathways for patient survival probability. DSigDB was used to mine candidate drugs based on pathways. PyMol was used for 3-D structure visualization. LigPlot was used to plot the 2-D pose view for receptor-ligand interaction. Results: Eighty-four KEGG pathways were differentially expressed in sepsis patients compared to healthy controls. Of those, 10 pathways were associated with 28-day survival. Some pathways were significantly correlated with immune cell abundance and five pathways could be used to distinguish between systemic inflammatory response syndrome (SIRS), bacterial sepsis, and viral sepsis with Area Under the Curve (AUC) above 0.80. Seven related drugs were screened using survival-related pathways. Conclusion: Sepsis-related pathways can be utilized for disease subtyping, diagnosis, prognosis, and drug screening.

In Vitro Proof of Concept of a First-Generation Growth-Accommodating Heart Valved Conduit for Pediatric Use.

Currently available heart valve prostheses have no growth potential, requiring children with heart valve diseases to endure multiple valve replacement surgeries with compounding risks. This study demonstrates the in vitro proof of concept of a biostable polymeric trileaflet valved conduit designed for surgical implantation and subsequent expansion via transcatheter balloon dilation to accommodate the growth of pediatric patients and delay or avoid repeated open-heart surgeries. The valved conduit is formed via dip molding using a polydimethylsiloxane-based polyurethane, a biocompatible material shown here to be capable of permanent stretching under mechanical loading. The valve leaflets are designed with an increased coaptation area to preserve valve competence at expanded diameters. Four 22 mm diameter valved conduits are tested in vitro for hydrodynamics, balloon dilated to new permanent diameters of 23.26 ± 0.38 mm, and then tested again. Upon further dilation, two valved conduits sustain leaflet tears, while the two surviving devices reach final diameters of 24.38 ± 0.19 mm. After each successful dilation, the valved conduits show increased effective orifice areas and decreased transvalvular pressure differentials while maintaining low regurgitation. These results demonstrate concept feasibility and motivate further development of a polymeric balloon-expandable device to replace valves in children and avoid reoperations.