Iron-Based Catalysts Derived from Iron-Containing Sludge for Enhanced Catalytic Performance of H2S Selective Catalytic Oxidation.

In this work, iron-containing sludge is used to prepare iron-based catalysts for efficient H2S selective catalytic oxidation. First, the effect of calcination temperatures on the catalytic activities of H2S selective oxidation is carried out and it can be found that S-500 calcined at 500 °C performs excellent catalytic activity. Then, the catalytic performance of the S-500 catalyst is further optimized using alkaline treatment with different concentrations of NaOH solution. The results indicate that S-500(2.0) treated with 2 M NaOH solution has the highest catalytic activity of H2S selective oxidation. Next, various characterization methods are used to analyze the structure and physical-chemical of the sludge-based catalysts. N2-Brunauer-Emmett-Teller (N2-BET) and X-ray photoelectron spectroscopy analyses show that the S-500(2.0) catalyst has the smallest average particle (11.17 nm), the biggest ratio of S ext/S micro(17.98) with bigger external specific surface area (49.09 m2·g-1), a higher proportion of Fe3+ species (50.88%), and surface adsorbed oxygen species (48.07%). Meanwhile, O2-TPD and CO2-TPD analysis indicates that the S-500(2.0) catalyst has a bigger value of the Oads/OTotal ratio (50.56%) and (CO2)(weak+moderate) /(CO2)Total ratio of (31.41%), indicating that there are much more oxygen vacancies and weak alkaline sites. As a result, the excellent catalytic performance of H2S selective oxidation can be attributed to its outstanding physical-chemical properties.

Marangoni-driven deterministic formation of softer, hollow microstructures for sensitivity-enhanced tactile system.

Microengineering the dielectric layers with three-dimensional microstructures has proven effective in enhancing the sensitivity of flexible pressure sensors. However, the widely employed geometrical designs of solid microstructures exhibit limited sensitivity over a wide range of pressures due to their inherent but undesired structural compressibility. Here, a Marangoni-driven deterministic formation approach is proposed for fabricating hollow microstructures, allowing for greater deformation while retarding structural stiffening during compression. Fluid convective deposition enables solute particles to reassemble in template microstructures, controlling the interior cavity with a void ratio exceeding 90%. The hollow micro-pyramid sensor exhibits a 10-fold sensitivity improvement across wider pressure ranges over the pressure sensor utilizing solid micro-pyramids, and an ultra-low detect limit of 0.21 Pa. With the advantages of facilitation, scalability, and large-area compatibility, such an approach for hollow microstructures can be expanded to other sensor types for superior performance and has considerable potential in robotic tactile and epidermal devices.

Metasurface-based optical system for miniaturization of atomic magnetometers.

Recent research has focused on miniaturizing atomic devices like magnetometers and gyroscopes for quantum precision measurements, leading to energy savings and broader application. This paper presents the design and validation of metasurface-based optical elements for atomic magnetometers' optical paths. These include highly efficient half-wave plates, polarizers, circular polarization generators, polarization-preserving reflectors, and polarizing beam splitters. These components, compatible with semiconductor manufacturing, offer a promising solution for creating ultra-thin, compact atomic devices.

Nitrate reduction to nitrogen in wastewater using mesoporous carbon encapsulated Pd-Cu nanoparticles combined with in-situ electrochemical hydrogen evolution.

The conversion of NO3--N to N2 is of great significance for zero discharge of industrial wastewater. Pd-Cu hydrogenation catalysis has high application prospects for the reduction of NO3--N to N2, but the existing form of Pd-Cu, the Pd-Cu mass ratio and the H2 evolution rate can affect the coverage of active hydrogen (*H) on the surface of Pd, thereby affecting N2 selectivity. In this work, mesoporous carbon (MC) is used as support to disperse Pd-Cu catalyst and is applied in an in-situ electrocatalytic H2 evolution system for NO3--N removal. The Pd-Cu particles with the average size of 6 nm are uniformly encapsulated in the mesopores of MC. Electrochemical in-situ H2 evolution can not only reduce the amount of H2 used, but the H2 bubbles can also be efficiently dispersed when PPy coated nickel foam (PPy/NF) is used as cathode. Moreover, the mesoporous structure of MC can further split H2 bubbles, reducing the coverage of *H on Pd. The highest 77% N2 selectivity and a relatively faster NO3--N removal rate constant (0.10362 min-1) can be achieved under the optimal conditions, which is superior to most reported Pd-Cu catalytic systems. The prepared catalyst is further applied to the denitrification of actual deplating wastewater. NO3--N with the initial concentration of 650 mg L-1 can be completely removed after 180 min of treatment, and the TN removal can be maintained at 72%.

cGAS-ISG15-RAGE axis reprogram necroptotic microenvironment and promote lymphatic metastasis in head and neck cancer.

BACKGROUND: Cancer cells frequently evolve necroptotic resistance to overcome various survival stress during tumorigenesis. However, we have previously showed that necroptosis is widespread in head and neck squamous cell carcinoma (HNSCC) and contributes to tumor progression and poor survival via DAMPs-induced migration and invasiveness in peri-necroptotic tumor cells. This implicated an alternative strategy that cancers cope with necroptotic stress by reprogramming a pro-invasive necroptotic microenvironment (NME). Here, we aim to decipher how necroptotic cells shape the NME and affect HNSCC progression. METHODS: Both our pre-established cellular necroptotic model and newly established Dox-induce intratumoral necroptosis model were used to investigate how necroptosis affect HNSCC progression. Transcriptomic alterations in peri-necroptotic tumor cells were analyzed by RNA-seq and validated in the NME in mice and patients' samples. The differential DAMPs compositon among apopotosis. Necrosis, and necroptosis were analyzed by label-free proteomic technique, and the necroptosis-specific DAMPs were then identified and validated. The potential receptor for ISG15 were simulated using molecular docking and further validated by in vitro assays. Then the ISG15-RAGE axis was blocked by either knockdown of necroptotic-ISG15 release and RAGE inhibitor FPS-ZM1, and the impact on tumor progression were tested. Last, we further tested our findings in a HNSCC-patients cohort. RESULTS: Necroptosis played a crucial role in driving tumor-cell invasiveness and lymphatic metastasis via tumor-type dependent DAMPs-releasing. Mechanistically, necroptotic DAMPs induced peri-necroptotic EMT via NF-κB and STAT3 signaling. Furthermore, intrinsic orchestration between necroptotic and cGAS-STING signaling resulted in producing a group of interferon stimulated genes (ISGs) as HNSCC-dependent necroptotic DAMPs. Among them, ISG15 played an essential role in reprogramming the NME. We then identified RAGE as a novel receptor for extracellular ISG15. Either blockage of ISG15 release or ISG15-RAGE interaction dramatically impeded necroptosis-driven EMT and lymphatic metastasis in HNSCC. Lastly, clinicopathological analysis showed high ISG15 expression in NME. Extensive necroptosis and high tumor-cell RAGE expression correlated with tumor progression and poor survival of HNSCC patients. CONCLUSIONS: Our data revealed a previously unknown cGAS-ISG15-RAGE dependent reprogramming of the necroptotic microenvironment which converts the necroptotic stress into invasive force to foster HNSCC-cell dissemination. By demonstrating the programmatic production of ISG15 via necroptosis-cGAS orchestration and its downstream signaling through RAGE, we shed light on the unique role of ISG15 in HNSCC progression. Targeting such machineries may hold therapeutic potential for restoring intratumoral survival stress and preventing lymphatic metastasis in HNSCC.

Clinical efficacy of CDK4/6 inhibitor plus endocrine therapy in HR-positive/HER2-0 and HER2-low-positive metastatic breast cancer: a secondary analysis of PALOMA-2 and PALOMA-3 trials.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with traditional endocrine therapy (ET) are now the recommended first-line treatment for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (MBC). However, the benefits of adding CDK4/6 inhibitors to ET in HER2-low-positive and HER2-0 subgroups remain unclear. We aimed to assess the effectiveness of CDK4/6 inhibitors in combination with ET in patients with HR-positive, HER2-low-positive and HER2-0 MBC. METHODS: This secondary analysis assessed progression-free survival (PFS) among HER2-low-positive and HER2-0 patients enrolled in the double-blind, placebo-controlled randomised clinical trials PALOMA-2 and PALOMA-3. The study included 1186 HER2-negative, HR-positive female patients, with available immunohistochemistry (IHC) and/or in situ hybridization (ISH) results, across 17 countries enrolled between February 2013 and August 2014. HER2-low-positive status was defined by IHC 1+ or 2+ with negative ISH, and HER2-zero by IHC 0. Data analyses were conducted between March and May 2023. In the PALOMA-2 trial, patients were randomly assigned to receive either palbociclib or placebo, in combination with letrozole in the first-line treatment for HR-positive MBC. Patients in the PALOMA-3 study, who had progression or relapse during previous ET, were randomly allocated to receive either palbociclib plus fulvestrant or placebo plus fulvestrant. The primary endpoint was investigator-assessed PFS. Kaplan-Meier approach and Cox proportional hazards model were applied to estimate the association of treatment strategies with PFS among HER2-0 and HER2-low-positive populations. The two trials are registered with ClinicalTrials.gov, number NCT01740427 and NCT01942135. FINDINGS: Of the 666 patients with MBC from the PALOMA-2 study, there were 153 HER2-0 and 513 HER2-low-positive patients. In the HER2-0 population, no significant difference in PFS was observed between the palbociclib-letrozole and placebo-letrozole groups (hazard ratio = 0.79, 95% confidence interval [CI] 0.48-1.30, p = 0.34). In the HER2-low-positive population, palbociclib-letrozole demonstrated a significantly lower risk of PFS than placebo-letrozole group (hazard ratio = 0.52, 95% CI 0.41-0.66, p < 0.0001). The PALOMA-3 study analysed 520 patients with MBC. Within the 153 HER2-0 patients, the palbociclib-fulvestrant group showed a significantly longer PFS than the placebo-fulvestrant group (hazard ratio = 0.54, 95% CI 0.30-0.95, p = 0.034). Among the 367 HER2-low-positive patients, palbociclib-fulvestrant improved PFS (hazard ratio = 0.39, 95% CI 0.28-0.54, p < 0.0001). INTERPRETATION: The combination of a CDK4/6 inhibitor with ET significantly improved PFS in HER2-low-positive patients, while for HER2-0 patients, benefits were primarily observed in patients who had progressed on previous ET. Furthermore, HER2-0 patients may derive limited benefits from first-line CDK4/6 inhibitor treatment. Further work is needed to validate these findings and to delineate patient subsets that are most likely to benefit from the combination of CDK4/6 inhibitors and ET as first-line treatments. FUNDING: None.

Personalized prediction of postoperative complication and survival among Colorectal Liver Metastases Patients Receiving Simultaneous Resection using machine learning approaches: A multi-center study.

BACKGROUND: To predict clinical important outcomes for colorectal liver metastases (CRLM) patients receiving colorectal resection with simultaneous liver resection by integrating demographic, clinical, laboratory, and genetic data. METHODS: Random forest (RF) models were developed to predict postoperative complications and major complications (binary outcomes), as well as progression-free survival (PFS) and overall survival (OS) (time-to-event outcomes) of the CRLM patients based on data from two hospitals. The models were validated on an external dataset from an independent hospital. The clinical utility of the models was assessed via decision curve analyses (DCA). RESULTS: There were 1067 patients included in survival prediction analyses and 1070 patients included in postoperative complication prediction analyses. The RF models provided an assessment of the model contributions of features for outcomes and suggested KRAS, BRAF, and MMR status were salient for the PFS or OS predictions. RF model of PFS showed that the Brier scores at 1-, 3-, and 5-year PFS were 0.213, 0.202 and 0.188; and the AUCs of 1-, 3- and 5-year PFS were 0.702, 0.720 and 0.743. RF model of OS revealed that Brier scores of 1-,3-, and 5-year OS were 0.040, 0.183 and 0.211; and the AUCs of 1-, 3- and 5-year OS were 0.737, 0.706 and 0.719. RF model for postoperative complication resulted in an AUC of 0.716 and a Brier score of 0.196. DCA curves clearly demonstrated that the RF models for these outcomes exhibited a superior net benefit across a wide range of threshold probabilities, signifying their favorable clinical utility. The RF models consistently exhibited robust performance in both internal cross-validation and external validation. The individualized risk profile predicted by the models closely aligned with the actual survival outcomes observed for the patients. A web-based tool (https://kanli.shinyapps.io/CRLMRF/) was provided to demonstrate the practical use of the prediction models for new patients in the clinical setting. CONCLUSION: The predictive models and a web-based tool for personalized prediction demonstrated a moderate predictive performance and favorable clinical utilities on several key clinical outcomes of CRLM patients receiving simultaneous resection, which could facilitate the clinical decision-making and inform future interventions for CRLM patients.

Constructing High-performance Cobalt-based Environmental Catalysts from Spent Lithium-Ion Batteries: Unveiling Overlooked Roles of Copper and Aluminum from Current Collectors.

Converting spent lithium-ion batteries (LIBs) cathode materials into environmental catalysts has drawn more and more attention. Herein, we fabricated a Co3O4-based catalyst from spent LiCoO2 LIBs (Co3O4-LIBs) and found that the role of Al and Cu from current collectors on its performance is nonnegligible. The density functional theory calculations confirmed that the doping of Al and/or Cu upshifts the d-band center of Co. A Fenton-like reaction based on peroxymonosulfate (PMS) activation was adopted to evaluate its activity. Interestingly, Al doping strengthened chemisorption for PMS (from -2.615 eV to -2.623 eV) and shortened Co-O bond length (from 2.540 Å to 2.344 Å) between them, whereas Cu doping reduced interfacial charge-transfer resistance (from 28.347 kΩ to 6.689 kΩ) excepting for the enhancement of the above characteristics. As expected, the degradation activity toward bisphenol A of Co3O4-LIBs (0.523 min-1) was superior to that of Co3O4 prepared from commercial CoC2O4 (0.287 min-1). Simultaneously, the reasons for improved activity were further verified by comparing activity with catalysts doped Al and/or Cu into Co3O4. This work reveals the role of elements from current collectors on the performance of functional materials from spent LIBs, which is beneficial to the sustainable utilization of spent LIBs.

MeRIP sequencing reveals the regulation of N6-methyladenosine in muscle development between hypertrophic and leaner broilers.

Meat production performance is the most important economic trait in broilers, and skeletal muscle, as the largest organ in animals, is directly related to meat production during embryonic and postnatal growth and development. N6-Methyladenosine (m6A) is a chemical modification occurs on RNA adenosine that has been reported to participate in a variety of biological processes in all species. However, there are still few reports on the regulatory role of muscle growth and development in poultry after birth. This study aims to reveal the distribution of m6A modification sites in chicken pectoralis major muscle after birth and find out the regulatory relationship between m6A and muscle development. As representatives of leaner (Xinghua chicken [XH]) and hypertrophic (White Recessive Rock chicken [WRR]) broilers, there are significant differences in body weight, muscle fiber diameter, and muscle fiber cross-sectional area between XH and WRR chickens. RNA sequencing detected a total of 397 differentially expressed genes (DEG) in the pectoralis major muscle of XH and WRR chicken, and these DEGs were mainly enriched in catalytic activity and metabolic pathways. MeRIP sequencing results showed that among all 6,476 differentially modified m6A peaks, about 90% peaks (5,823) were differentially down regulated in XH chickens. The joint analysis of the mRNA and MeRIP sequencing data found 145 DEGs with differential m6A peak, ALKBH5 as a m6A demethylase, was also included. The highly expression of ALKBH5 in the muscle tissue of poultry and differential expression between XH and WRR chickens suggest that ALKBH5 may play a crucial role in regulating muscle development. Our results revealed that there were significant differences in growth rate, body weight, muscle fiber diameter, and fiber cross-section area between WRR and XH chicken, as well as significant differences in m6A methylation level and muscle metabolism level.

A hybrid particle swarm optimization algorithm for solving engineering problem.

To overcome the disadvantages of premature convergence and easy trapping into local optimum solutions, this paper proposes an improved particle swarm optimization algorithm (named NDWPSO algorithm) based on multiple hybrid strategies. Firstly, the elite opposition-based learning method is utilized to initialize the particle position matrix. Secondly, the dynamic inertial weight parameters are given to improve the global search speed in the early iterative phase. Thirdly, a new local optimal jump-out strategy is proposed to overcome the "premature" problem. Finally, the algorithm applies the spiral shrinkage search strategy from the whale optimization algorithm (WOA) and the Differential Evolution (DE) mutation strategy in the later iteration to accelerate the convergence speed. The NDWPSO is further compared with other 8 well-known nature-inspired algorithms (3 PSO variants and 5 other intelligent algorithms) on 23 benchmark test functions and three practical engineering problems. Simulation results prove that the NDWPSO algorithm obtains better results for all 49 sets of data than the other 3 PSO variants. Compared with 5 other intelligent algorithms, the NDWPSO obtains 69.2%, 84.6%, and 84.6% of the best results for the benchmark function ( f 1 - f 13 ) with 3 kinds of dimensional spaces (Dim = 30,50,100) and 80% of the best optimal solutions for 10 fixed-multimodal benchmark functions. Also, the best design solutions are obtained by NDWPSO for all 3 classical practical engineering problems.

Selective removal of thiosulfate from coke oven gas desulfurization wastewater by catalytic wet air oxidation with manganese-based oxide from spent ternary lithium-ion batteries.

Selective and efficient removal of thiosulfates (S2O32-) to recover high-purity and value-added thiocyanate products by fractional crystallization process is a promising route for the resource treatment of coke oven gas desulfurization wastewater. Herein, catalytic wet air oxidation (CWAO), with manganese-based oxide synthesized from spent ternary lithium-ion batteries (MnOx-LIBs), was proposed to selectively remove S2O32- from desulfurization wastewater. 98.0 % of S2O32- is selectively removed by the MnOx-LIBs CWAO system, which was 4.1 times that of the MnOx CWAO system. The synergistic effect among multiple metals from spent LIBs induces the enlarged specific surface area, increased reactive sites and formation of oxygen vacancy, promoting the adsorption and activation of O2, thereby realizing high-efficiency removal of S2O32-. The satisfactory selective removal efficiency can be maintained in the proposed system under complex environmental conditions. Notably, the proposed system is cost-effective and applicable to actual wastewater, in which 81.2 % of S2O32- is selectively removed from coke oven gas desulfurization wastewater. More importantly, compared with the typical processes, the proposed process is simpler and more environmentally-friendly. This work provides an alternative route to selectively remove S2O32- from coke oven gas desulfurization wastewater, expecting to drive the development of resource utilization of coke oven gas desulfurization wastewater.

Laser-Guided, Self-Confined Graphitization for High-Conductivity Embedded Electronics.

Facile fabrication of highly conductive and self-encapsulated graphene electronics is in urgent demand for carbon-based integrated circuits, field effect transistors, optoelectronic devices, and flexible sensors. The current fabrication of these electronic devices is mainly based on layer-by-layer techniques (separate circuit preparation and encapsulation procedures), which show multistep fabrication procedures, complicated renovation/repair procedures, and poor electrical property due to graphene oxidation and exfoliation. Here, we propose a laser-guided interfacial writing (LaserIW) technique based on self-confined, nickel-catalyzed graphitization to directly fabricate highly conductive, embedded graphene electronics inside multilayer structures. The doped nickel is used to induce chain carbonization, which firstly enhances the photothermal effect to increase the confined temperature for initial carbonization, and the generated carbon further increases the light-absorption capacity to fabricate high-quality graphene. Meanwhile, the nickel atoms contribute to the accelerated connection of carbon atoms. This interfacial carbonization inherently avoids the exfoliation and oxidation of the as-formed graphene, resulting in an 8-fold improvement in electrical conductivity (~20,000 S/m at 7,958 W/cm2 and 2 mm/s for 20% nickel content). The LaserIW technique shows excellent stability and reproducibility, with ±2.5% variations in the same batch and ±2% variations in different batches. Component-level wireless light sensors and flexible strain sensors exhibit excellent sensitivity (665 kHz/(W/cm2) for passive wireless light sensors) and self-encapsulation (<1% variations in terms of waterproof, antifriction, and antithermal shock). Additionally, the LaserIW technique allows for one-step renovation of in-service electronics and nondestructive repair of damaged circuits without the need to disassemble encapsulation layers. This technique reverses the layer-by-layer processing mode and provides a powerful manufacturing tool for the fabrication, modification, and repair of multilayer, multifunctional embedded electronics, especially demonstrating the immense potential for in-space manufacturing.

Vector magnetocardiography using compact optically-pumped magnetometers.

Optically pumped magnetometers can provide functionality for bio-magnetic field detection and mapping. This has attracted widespread attention from researchers in the biomedical science field. Magnetocardiography has been proven to be an effective method for examining heart disease. Notably, vector magnetocardiography obtains more spatial information than the conventional method by only taking a component that is perpendicular to the chest surface. In this work, a spin-exchange-relaxation-free (SERF) magnetometer with a compact size of 14 mm × 25 mm × 90 mm was developed. The device has a high sensitivity of 25 fT/ Hz. Meanwhile, in the multichannel working mode, synchronous sensor manipulation and data acquisition can be achieved through our control software without additional data acquisition boards. Since a typical SERF magnetometer only responds to dual-axis magnetic fields, two sensors are orthogonally arranged to form a vector detection channel. Our system consists of seven channels and allows 7 × 9 vector MCG mapping by scanning. High-quality heart vector signals are measured, and P peak, QRS peak, and T peak can be distinguished clearly. To better demonstrate the vectorial information, a vector scatter plot form is also provided. Through a basic bio-electric current model, it demonstrates that triaxial MCG measurements capture a richer spatial current information than traditional uniaxial MCG, offering substantial diagnostic potential for heart diseases and shedding more light on the inversion of cardiac issues.

Long-term use of etomidate disrupts the intestinal homeostasis and nervous system in mice.

Etomidate (ETO) is used as an anesthetic in surgery, but it is being abused in some populations. The damage caused by long-term intake of ETO to intestinal and brain functions is not yet clear, and it remains to be determined whether the drug affects the central nervous system through the gut-brain axis. This study aimed to investigate the neurotoxic and gastrointestinal effects of ETO at doses of 1 mg/kg and 3 mg/kg in mice over 14 consecutive days. The results showed that long-term injection of ETO led to drug resistance in mice, affecting their innate preference for darkness and possibly inducing dependence on ETO. The levels of 5-hydroxytryptamine in the brain, serum, and colon decreased by 37%, 51%, and 42% respectively, while the levels of γ-aminobutyric acid reduced by 38%, 52%, and 41% respectively. H&E staining revealed that ETO reduced goblet cells in the colon and damaged the intestinal barrier. The expression of tight junction-related genes Claudin4 and ZO-1 was downregulated. The intestinal flora changed, the abundance of Akkermansia and Lactobacillus decreased by 33% and 14%, respectively, while Klebsiella increased by 18%. TUNEL results showed that high-dose ETO increased apoptotic cells in the brain. The expression of Claudin1 in the brain was downregulated. Untargeted metabolomics analysis of the colon and brain indicated that ETO caused abnormalities in glycerophospholipid metabolism. Abnormal lipid metabolism might lead to the production or accumulation of lipotoxic metabolites, causing central nervous system diseases. ETO induced changes in the intestinal flora and metabolism, further affecting the central nervous system through the gut-brain axis. The study unveiled the detrimental effects on the brain and gastrointestinal system resulting from long-term intake of ETO, which holds significant implications for comprehending the adverse impact of ETO abuse on human health.

Non-Equivalent Donor-Acceptor Type Polymers as Dopant-Free Hole-Transporting Materials for Perovskite Solar Cells.

Electron donor (D)-electron acceptor (A) type conjugated polymers present bright prospects as dopant-free hole-transporting materials (HTMs) for perovskite solar cells (PVSCs). Most of the reported D-A polymeric HTMs contain equivalent amounts of D and A units, while the appropriate excess proportion of D units could optimize the aggregation state of polymer chains and improve the hole transport properties of the polymers. Herein, a non-equivalent D-A copolymerization strategy was utilized to develop three indacenodithiophene-benzotriazole-based polymeric HTMs for PVSCs, named as F-10, F-15, and F-20, and the equivalent D-A polymer F-00 was studied in parallel. Effects of D : A ratio on the hole transport properties of these D-A type polymeric HTMs, including energy level, molecular stacking, hole mobility, and surface morphology, were investigated by theoretical simulation and test analysis. F-15 performed best due to the appropriate D : A ratio, endowing the PVSCs a champion power conversion efficiency of 20.37 % with high stability, which confirms the fine-tuning D : A ratio via non-equivalent D-A copolymerization strategy is very helpful to construct D-A type polymeric HTMs for high-performance PVSCs.

Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial.

BACKGROUND: Pembrolizumab has shown efficacy in persistent, recurrent, or metastatic cervical cancer. The effect of chemoradiotherapy might be enhanced by immunotherapy. In this phase 3 trial, we assessed the efficacy and safety of adding pembrolizumab to chemoradiotherapy in locally advanced cervical cancer. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial, adults (age ≥18 years) at 176 medical centres in 30 countries with newly diagnosed, high-risk, locally advanced cervical cancer were randomly assigned (1:1) using an interactive voice-response system with integrated web response to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Randomisation was stratified by planned external beam radiotherapy type (intensity-modulated radiotherapy or volumetric-modulated arc therapy vs non-intensity-modulated radiotherapy or non-volumetric-modulated arc therapy), cervical cancer stage at screening (International Federation of Gynecology and Obstetrics 2014 stage IB2-IIB node positive vs stage III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy equivalent dose in 2 Gy fractions). Primary endpoints were progression-free survival per Response Evaluation Criteria in Solid Tumours version 1.1-by investigator or by histopathologic confirmation of suspected disease progression-and overall survival. Primary analysis was conducted in the intention-to-treat population, which included all randomly allocated participants. Safety was assessed in the as-treated population, which included all randomly allocated patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04221945, and is closed to new participants. FINDINGS: Between June 9, 2020, and Dec 15, 2022, 1060 participants were randomly assigned to treatment, with 529 assigned to the pembrolizumab-chemoradiotherapy group and 531 to the placebo-chemoradiotherapy group. At data cutoff (Jan 9, 2023), median follow-up was 17·9 months (IQR 11·3-22·3) in both treatment groups. Median progression-free survival was not reached in either group; rates at 24 months were 68% in the pembrolizumab-chemoradiotherapy group versus 57% in the placebo-chemoradiotherapy group. The hazard ratio (HR) for disease progression or death was 0·70 (95% CI 0·55-0·89, p=0·0020), meeting the protocol-specified primary objective. Overall survival at 24 months was 87% in the pembrolizumab-chemoradiotherapy group and 81% in the placebo-chemoradiotherapy group (information fraction 42·9%). The HR for death was 0·73 (0·49-1·07); these data have not crossed the boundary of statistical significance. Grade 3 or higher adverse event rates were 75% in the pembrolizumab-chemoradiotherapy group and 69% in the placebo-chemoradiotherapy group. INTERPRETATION: Pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co (MSD).

Optimizing prediction accuracy for early recurrent lumbar disc herniation with a directional mutation-guided SVM model.

Percutaneous endoscopic lumbar discectomy (PELD) is one of the main means of minimally invasive spinal surgery, and is an effective means of treating lumbar disc herniation, but its early recurrence is still difficult to predict. With the development of machine learning technology, the auxiliary model based on the prediction of early recurrent lumbar disc herniation (rLDH) and the identification of causative risk factors have become urgent problems in current research. However, the screening ability of current models for key factors affecting the prediction of rLDH, as well as their predictive ability, needs to be improved. Therefore, this paper presents a classification model that utilizes wrapper feature selection, developed through the integration of an enhanced bat algorithm (BDGBA) and support vector machine (SVM). Among them, BDGBA increases the population diversity and improves the population quality by introducing directional mutation strategy and guidance-based strategy, which in turn allows the model to secure better subsets of features. Furthermore, SVM serves as the classifier for the wrapper feature selection method, with its classification prediction results acting as a fitness function for the feature subset. In the proposed prediction method, BDGBA is used as an optimizer for feature subset filtering and as an objective function for feature subset evaluation based on the classification results of the support vector machine, which improves the interpretability and prediction accuracy of the model. In order to verify the performance of the proposed method, this paper proves the performance of the model through global optimization experiments and prediction experiments on real data sets. The accuracy of the proposed rLDH prediction model is 93.49% and sensitivity is 88.33%. The experimental results show that Level of herniated disk, Modic change, Disk height, Disk length, and Disk width are the key factors for predicting rLDH, and the proposed method is an effective auxiliary diagnosis method.

Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model.

The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PLpro) is a promising but challenging drug target. We designed and synthesized 85 noncovalent PLpro inhibitors that bind to a recently discovered ubiquitin binding site and the known BL2 groove pocket near the S4 subsite. Leads inhibited PLpro with the inhibitory constant Ki values from 13.2 to 88.2 nanomolar. The co-crystal structures of PLpro with eight leads revealed their interaction modes. The in vivo lead Jun12682 inhibited SARS-CoV-2 and its variants, including nirmatrelvir-resistant strains with EC50 from 0.44 to 2.02 micromolar. Oral treatment with Jun12682 improved survival and reduced lung viral loads and lesions in a SARS-CoV-2 infection mouse model, suggesting that PLpro inhibitors are promising oral SARS-CoV-2 antiviral candidates.

The competitive mechanism of EZH1 and EZH2 in promoting oral squamous cell carcinoma.

Enhancer of Zeste Homolog 1 (EZH1) and Enhancer of Zeste Homolog 2 (EZH2) are the key components of polycomb repressive complex 2 (PRC2); however, the roles of these proteins in oral squamous cell carcinoma (OSCC) have yet to be elucidated. In this study, we aimed to determine the respective roles of these proteins in OSCC by investigating the expression levels of EZH1 and EZH2 in OSCC tissues (N = 63) by immunohistochemistry. In addition, we used lentiviruses to construct stable OSCC cell lines that overexpressed EZH1 and EZH2. Then, we investigated these cell lines for cell viability, colony formation capacity, stemness, and epithelial-mesenchymal transition (EMT). Binding competition between EZH1 and EZH2 with PRC2 was further evaluated using Co-immunoprecipitation (Co-IP). Compared with normal tissues, the expression levels of EZH2 in OSCC tissues was up-regulated, while the expression of EZH1 was down-regulated. EZH2 enhanced cell viability, colony formation capacity, stemness, and EMT, while EZH1 did not. Furthermore, analysis indicated that EZH1 and EZH2 bound competitively to PRC2 and influenced the methylation status of H3K27. In conclusion, our findings verified that EZH1 and EZH2 play opposing roles in OSCC and that EZH1 and EZH2 compete as the key component of PRC2, thus affecting the characteristics of OSCC via the methylation of H3K27.

A candidate antibody drug for prevention of malaria.

Over 75% of malaria-attributable deaths occur in children under the age of 5 years. However, the first malaria vaccine recommended by the World Health Organization (WHO) for pediatric use, RTS,S/AS01 (Mosquirix), has modest efficacy. Complementary strategies, including monoclonal antibodies, will be important in efforts to eradicate malaria. Here we characterize the circulating B cell repertoires of 45 RTS,S/AS01 vaccinees and discover monoclonal antibodies for development as potential therapeutics. We generated >28,000 antibody sequences and tested 481 antibodies for binding activity and 125 antibodies for antimalaria activity in vivo. Through these analyses we identified correlations suggesting that sequences in Plasmodium falciparum circumsporozoite protein, the target antigen in RTS,S/AS01, may induce immunodominant antibody responses that limit more protective, but subdominant, responses. Using binding studies, mouse malaria models, biomanufacturing assessments and protein stability assays, we selected AB-000224 and AB-007088 for advancement as a clinical lead and backup. We engineered the variable domains (Fv) of both antibodies to enable low-cost manufacturing at scale for distribution to pediatric populations, in alignment with WHO's preferred product guidelines. The engineered clone with the optimal manufacturing and drug property profile, MAM01, was advanced into clinical development.