Engineering Glucosamine-6-Phosphate Synthase to Achieve Efficient One-Step Biosynthesis of Glucosamine.

As an important functional monosaccharide, glucosamine (GlcN) is widely used in fields such as medicine, food nutrition, and health care. Here, we report a distinct GlcN biosynthesis method that utilizes engineered Bacillus subtilis glucosamine-6-phosphate synthase (BsGlmS) to convert D-fructose to directly generate GlcN. The best variant obtained by using a combinatorial active-site saturation test/iterative saturation mutagenesis (CAST/ISM) strategy was a quadruple mutant S596D/V597G/S347H/G299Q (BsGlmS-BK19), which has a catalytic activity 1736-fold that of the wild type toward D-fructose. Upon using mutant BK19 as a whole-cell catalyst, D-fructose was converted into GlcN with 65.32% conversion in 6 h, whereas the wild type only attained a conversion rate of 0.31% under the same conditions. Molecular docking and molecular dynamics simulations were implemented to provide insights into the mechanism underlying the enhanced activity of BK19. Importantly, the BsGlmS-BK19 variant specifically catalyzes D-fructose without the need for phosphorylated substrates, representing a significant advancement in GlcN biosynthesis.

Discovery of indole-2-one derivatives as BRD4 (BD1) selective inhibitors.

Bromodomain protein 4 (BRD4) is a member of the BET family, and its overexpression is closely associated with the development of many tumors. Inhibition of BRD4 shows great therapeutic potential in anti-tumor, and pan-BRD4 inhibitors show adverse effects of dose limiting toxicity and thrombocytopenia in clinical trials. To improve clinical effects and reduce side effects, more efforts have focused on seeking selective inhibitors of BD1 or BD2. Herein, a series of indole-2-one derivatives were designed and synthesized through docking-guided optimization to find BRD4-BD1 selective inhibitors, and their BRD4 inhibitory and antiproliferation activities were evaluated. Among them, compound 21r had potent BRD4 inhibitory activity (the IC50 values of 41 nM and 313 nM in BD1 and BD2 domain), excellent anti-proliferation (the IC50 values of 4.64 ± 0.30 µM, 0.78 ± 0.03 µM, 5.57 ± 1.03 µM against HL-60, MV-4-11 and HT-29 cells), and displayed low toxicity against normal cell GES-1 cells. Further studies revealed that 21r inhibited proliferation by decreasing the expression of proto-oncogene c-Myc, blocking cell cycle in G0/G1 phase, and inducing apoptosis in MV-4-11 cells in a dose-dependent manner. All the results showed that compound 21r was a potent BRD4 inhibitor with BD1 selectivity, which had potential in treatment of leukemia.

Deletion of TECRL promotes skeletal muscle repair by up-regulating EGR2.

Myogenic regeneration relies on the proliferation and differentiation of satellite cells. TECRL (trans-2,3-enoyl-CoA reductase like) is an endoplasmic reticulum protein only expressed in cardiac and skeletal muscle. However, its role in myogenesis remains unknown. We show that TECRL expression is increased in response to injury. Satellite cell-specific deletion of TECRL enhances muscle repair by increasing the expression of EGR2 through the activation of the ERK1/2 signaling pathway, which in turn promotes the expression of PAX7. We further show that TECRL deletion led to the upregulation of the histone acetyltransferase general control nonderepressible 5, which enhances the transcription of EGR2 through acetylation. Importantly, we showed that AAV9-mediated TECRL silencing improved muscle repair in mice. These findings shed light on myogenic regeneration and muscle repair.

The relationship between family resilience, post-traumatic growth, and caregiver burden among family caregivers of stroke survivors: a cross-sectional study.

The study aimed to explore the relationship between family resilience, post-traumatic growth(PTG), and caregiver burden among family caregivers of stroke survivors. Researchers conducted a cross-sectional study to recruit 253 family caregivers of stroke survivors from a public hospital in Shandong Province, China. Caregivers completed sociodemographic information, the Shortened Chinese Version of the Family Resilience Assessment Scale, the Post-traumatic Growth Inventory, and the Zarit Caregiver Burden Interview. We used Amos 24.0 to construct structural equation models and examine the mediating effects of stroke survivors' post-traumatic growth. Family resilience was positively associated with post-traumatic growth, and both family resilience and post-traumatic growth were negatively associated with caregiver burden. Post-traumatic growth partially mediated the relationship between family resilience and caregiver burden, and the mediating effect accounted for 21.27% of the total effect. Targeted interventions should address family resilience and post-traumatic growth as protective factors of caregiver burden.

Initiating PeriCBD to probe perinatal influences on neurodevelopment during 3-10 years in China.

Adverse perinatal factors can interfere with the normal development of the brain, potentially resulting in long-term effects on the comprehensive development of children. Presently, the understanding of cognitive and neurodevelopmental processes under conditions of adverse perinatal factors is substantially limited. There is a critical need for an open resource that integrates various perinatal factors with the development of the brain and mental health to facilitate a deeper understanding of these developmental trajectories. In this Data Descriptor, we introduce a multicenter database containing information on perinatal factors that can potentially influence children's brain-mind development, namely, periCBD, that combines neuroimaging and behavioural phenotypes with perinatal factors at county/region/central district hospitals. PeriCBD was designed to establish a platform for the investigation of individual differences in brain-mind development associated with perinatal factors among children aged 3-10 years. Ultimately, our goal is to help understand how different adverse perinatal factors specifically impact cognitive development and neurodevelopment. Herein, we provide a systematic overview of the data acquisition/cleaning/quality control/sharing, processes of periCBD.

The Impact of Spironolactone Co-administration on Cyclosporin Initial Dosage Optimization for Pediatric Refractory Nephrotic Syndrome.

OBJECTIVES: Cyclosporin has been used for the treatment of pediatric refractory nephrotic syndrome (PRNS). However, the narrow therapeutic window and large pharmacokinetic variability make it difficult to individualize cyclosporin administration. Meanwhile, spironolactone has been reported to affect cyclosporin metabolism in PRNS patients. This study aims to explore the initial dosage optimization of cyclosporin in PRNS based on the impact of spironolactone co-administration. METHODS: Monte Carlo simulation based on a previously established cyclosporin population pharmacokinetic model for PRNS was used to design cyclosporin dosing regimen. RESULTS: In this study, the probability of drug concentration reaching the target and the convenience of times of administration were considered comprehensively. The optimal administration regimen in PRNS without spironolactone was 6, 5, 4 and 3 mg/kg cyclosporin split into two doses for the body weight of 5-8, 8-18, 18-46 and 46-70 kg, respectively. The optimal administration regimen in PRNS with spironolactone was 4, 3, 2 mg/kg cyclosporin split into two doses for body weight of 5-14, 14-65, and 65-70 kg, respectively. CONCLUSION: The cyclosporin dosing regimen for PRNS based on Monte Carlo simulation was systematically developed and the initial dosage optimization of cyclosporin in PRNS was recommended for the first time.

Effects of tacrolimus on proteinuria in Chinese and Indian patients with idiopathic membranous nephropathy: the results of machine learning study.

PURPOSE: The present study aims to explore the effects of tacrolimus on proteinuria in patients with idiopathic membranous nephropathy (IMN) and recommend an appropriate dosage schedule via machine learning method. METHODS: The Emax model was constructed to analyze the effects of tacrolimus on proteinuria in patients with IMN. Data were mined from published literature and machine learning was built up with Emax model, among which the efficacy indicator was proteinuria change rates from baseline. 463 IMN patients were included for modeling, and tacrolimus therapeutic window concentrations were 4-10 ng/ml. RESULTS: In machine learning model, the Emax from tacrolimus effecting proteinuria in IMN patients was -72.7%, the ET50 was 0.43 months, and the time to achieving 25% Emax, 50% Emax, 75% Emax, and 80% (plateau) Emax of tacrolimus on proteinuria in patients with IMN were 0.15, 0.43, 1.29, and 1.72 months, respectively. CONCLUSION: For achieving better therapeutic effects from tacrolimus on proteinuria in patients with IMN, tacrolimus concentration range need to be maintained at 4-10 ng/ml for at least 1.72 months.

[Source Apportionment of Morphine in Wastewater].

It is a new approach to identify legal or illegal use of morphine through information on municipal wastewater. However, the sources of morphine in wastewater are complex, and distinguishing the contribution of different sources has become a key issue. A total of 262 influent samples from 61 representative wastewater treatment plants in a typical city were collected from October 2022 to March 2023. The concentrations of morphine, codeine, thebaine, papaverine, noscapine, and monoacetylmorphine were analyzed in wastewater and poppy straws. Combined with the proportion of alkaloids in poppy straws, the source analysis of alkaloids in wastewater was analyzed using the ratio method and positive matrix factorization model (PMF). Only five alkaloids were detected in wastewater, and monoacetylmorphine, a metabolite of heroin, was not detected. The concentrations of morphine and codeine were significantly higher than those of noscapine, papaverine, and thebaine. By constructing the ratios of codeine/(morphine + codeine) and noscapine/(noscapine + codeine), the source of poppy straw could be qualitatively distinguished. The PMF results showed that three sources of morphine for medical use, poppy straw, and codeine contributed 44.9%, 43.7%, and 9.4%, respectively. The different sources varied in these months due to the COVID-19 and influenza A outbreaks, in which the use of drugs containing poppy straws and codeine was the main source, whereas the use of morphine analgesics remained relatively stable. Inventory analysis further demonstrated the reliability of the source contributions from the PMF model, and morphine was not abused in this city.

Role of ArcA in the regulation of antibiotic sensitivity in avian pathogenic Escherichia coli.

Avian pathogenic Escherichia coli (APEC) is one of the common extraintestinal infectious disease pathogens in chickens, geese, and other birds, inducing serious impediments to the development of the poultry industry. Hence, investigating how bacteria regulate themselves amidst different challenging conditions is immense essential in prevention and treatment for bacterial pathogen infections. The ArcA regulatory factor has been reported to regulate oxygen availability in strains, but its role in regulation of antibiotics resistance in APEC is unclear. This study delved into understanding how ArcA regulates antibiotic resistance in APEC. An E. coli APEC40 arcA knockout strain was constructed, and the regulatory mechanism of arcA on APEC antibiotic susceptibility was identified by drug sensitivity test, colony counting assay, real-time quantitative PCR, ß-galactosidase assays and electrophoretic mobility shift assay (EMSA). The results showed that ArcA directly binds to the promoter region of the outer membrane protein OmpC/OmpW and regulates bacterial susceptibility to kanamycin and penicillin G. At the same time, the double knockout of ompW and ompW/arcA resulted in an increase in resistance to kanamycin compared to the deletion of the arcA gene. This outcome provided experimental proof suggesting that the outer membrane protein OmpW could serve as a crucial pathway for the ingress of kanamycin into cells. These results confirmed the important regulatory role of ArcA transcription factors under APEC antibiotic stress.

Large language model for horizontal transfer of resistance gene: From resistance gene prevalence detection to plasmid conjugation rate evaluation.

The burgeoning issue of plasmid-mediated resistance genes (ARGs) dissemination poses a significant threat to environmental integrity. However, the prediction of ARGs prevalence is overlooked, especially for emerging ARGs that are potentially evolving gene exchange hotspot. Here, we explored to classify plasmid or chromosome sequences and detect resistance gene prevalence by using DNABERT. Initially, the DNABERT fine-tuned in plasmid and chromosome sequences followed by multilayer perceptron (MLP) classifier could achieve 0.764 AUC (Area under curve) on external datasets across 23 genera, outperforming 0.02 AUC than traditional statistic-based model. Furthermore, Escherichia, Pseudomonas single genera based model were also be trained to explore its predict performance to ARGs prevalence detection. By integrating K-mer frequency attributes, our model could boost the performance to predict the prevalence of ARGs in an external dataset in Escherichia with 0.0281-0.0615 AUC and Pseudomonas with 0.0196-0.0928 AUC. Finally, we established a random forest model aimed at forecasting the relative conjugation transfer rate of plasmids with 0.7956 AUC, drawing on data from existing literature. It identifies the plasmid's repression status, cellular density, and temperature as the most important factors influencing transfer frequency. With these two models combined, they provide useful reference for quick and low-cost integrated evaluation of resistance gene transfer, accelerating the process of computer-assisted quantitative risk assessment of ARGs transfer in environmental field.

Elimination of subtelomeric repeat sequences exerts little effect on telomere essential functions in Saccharomyces cerevisiae.

Telomeres, which are chromosomal end structures, play a crucial role in maintaining genome stability and integrity in eukaryotes. In the baker's yeast Saccharomyces cerevisiae, the X- and Y'-elements are subtelomeric repetitive sequences found in all 32 and 17 telomeres, respectively. While the Y'-elements serve as a backup for telomere functions in cells lacking telomerase, the function of the X-elements remains unclear. This study utilized the S. cerevisiae strain SY12, which has three chromosomes and six telomeres, to investigate the role of X-elements (as well as Y'-elements) in telomere maintenance. Deletion of Y'-elements (SY12YΔ), X-elements (SY12XYΔ+Y), or both X- and Y'-elements (SY12XYΔ) did not impact the length of the terminal TG1-3 tracks or telomere silencing. However, inactivation of telomerase in SY12YΔ, SY12XYΔ+Y, and SY12XYΔ cells resulted in cellular senescence and the generation of survivors. These survivors either maintained their telomeres through homologous recombination-dependent TG1-3 track elongation or underwent microhomology-mediated intra-chromosomal end-to-end joining. Our findings indicate the non-essential role of subtelomeric X- and Y'-elements in telomere regulation in both telomerase-proficient and telomerase-null cells and suggest that these elements may represent remnants of S. cerevisiae genome evolution. Furthermore, strains with fewer or no subtelomeric elements exhibit more concise telomere structures and offer potential models for future studies in telomere biology.

Potential value of CT-based comprehensive nomogram in predicting occult lymph node metastasis of esophageal squamous cell paralaryngeal nerves: a two-center study.

PURPOSE: The aim of this study is to construct a combined model that integrates radiomics, clinical risk factors and machine learning algorithms to predict para-laryngeal lymph node metastasis in esophageal squamous cell carcinoma. METHODS: A retrospective study included 361 patients with esophageal squamous cell carcinoma from 2 centers. Radiomics features were extracted from the computed tomography scans. Logistic regression, k nearest neighbor, multilayer perceptron, light Gradient Boosting Machine, support vector machine, random forest algorithms were used to construct radiomics models. The receiver operating characteristic curve and The Hosmer-Lemeshow test were employed to select the better-performing model. Clinical risk factors were identified through univariate logistic regression analysis and multivariate logistic regression analysis and utilized to develop a clinical model. A combined model was then created by merging radiomics and clinical risk factors. The performance of the models was evaluated using ROC curve analysis, and the clinical value of the models was assessed using decision curve analysis. RESULTS: A total of 1024 radiomics features were extracted. Among the radiomics models, the KNN model demonstrated the optimal diagnostic capabilities and accuracy, with an area under the curve (AUC) of 0.84 in the training cohort and 0.62 in the internal test cohort. Furthermore, the combined model exhibited an AUC of 0.97 in the training cohort and 0.86 in the internal test cohort. CONCLUSION: A clinical-radiomics integrated nomogram can predict occult para-laryngeal lymph node metastasis in esophageal squamous cell carcinoma and provide guidance for personalized treatment.

A system dynamics-based model for the evolution of environmental group events.

Based on the system dynamics theory, this paper establishes an environmental mass event evolution model and explores the evolution law of mass events caused by environmental problems. From a methodological point of view, the mixed-strategy evolutionary game principle and dynamic punishment measures are combined, and simulation analysis is carried out by Anylogic software, and the results show that there is no stable evolutionary equilibrium solution for the two sides of the game in the traditional asymmetric mixed-strategy game model, and after adjusting the game payoff matrix and incorporating the dynamic punishment strategy, stable evolutionary equilibrium solutions appear in the evolutionary game model, and the system begins to tend to be stabilized. The process and conclusions of the simulation experiment provide methodological reference and theoretical support for the analysis of the evolution of environmental mass events.

A distributed data processing scheme based on Hadoop for synchrotron radiation experiments.

With the development of synchrotron radiation sources and high-frame-rate detectors, the amount of experimental data collected at synchrotron radiation beamlines has increased exponentially. As a result, data processing for synchrotron radiation experiments has entered the era of big data. It is becoming increasingly important for beamlines to have the capability to process large-scale data in parallel to keep up with the rapid growth of data. Currently, there is no set of data processing solutions based on the big data technology framework for beamlines. Apache Hadoop is a widely used distributed system architecture for solving the problem of massive data storage and computation. This paper presents a set of distributed data processing schemes for beamlines with experimental data using Hadoop. The Hadoop Distributed File System is utilized as the distributed file storage system, and Hadoop YARN serves as the resource scheduler for the distributed computing cluster. A distributed data processing pipeline that can carry out massively parallel computation is designed and developed using Hadoop Spark. The entire data processing platform adopts a distributed microservice architecture, which makes the system easy to expand, reduces module coupling and improves reliability.

Zonular instability-associated morphologic features in eyes with primary angle closure disease using the swept-source anterior segment - optical coherence tomography system.

BACKGROUND: This study aims to investigate the morphologic features of the crystalline lens in Primary Angle Closure Disease (PACD) patients with zonular instability during cataract surgery using the swept-source CASIA 2 Anterior Segment-Optical Coherence Tomography (AS-OCT) system. METHODS: A total of 398 eyes (125 PACD eyes with zonular instability, 133 PACD eyes with zonular stability, and 140 cataract patient controls) of 398 patients who underwent cataract surgery combined or not glaucoma surgery between January 2021 and January 2023 were enrolled. The crystalline lens parameters were measured by CASIA2 AS-OCT. Then, logistic regression was performed to evaluate the risk factors associated with zonular instability. RESULTS: The results revealed that PACD eyes had a more anterior lens equator position, a steeper anterior curvature of lens, shorter Axial Length (AL), shallower Anterior Chamber Distance (ACD), higher Lens Vault (LV) and thicker Lens Thickness (LT), when compared to eyes in the cataract control group. Furthermore, PACD eyes in the zonular instability group had steeper front R, front Rs and Front Rf, flatter back Rf, thicker lens anterior part thickness, higher lens anterior-to-posterior part thickness ratios, shallower ACD, and greater LV, when compared to PACD eyes with zonular stability. The logistic regression analysis, which was adjusted for age and gender, revealed that zonular instability was positively correlated with anterior part thickness, lens anterior-to-posterior part thickness ratio, and LV, but was negatively correlated with lens anterior radius and ACD. CONCLUSION: Steeper anterior curvature, increased lens anterior part thickness, higher anterior-to-posterior part thickness ratio, shallower ACD, and greater LV are the anatomic features of PACD eyes associated with zonular instability.

The electrochemistry of stable sulfur isotopes versus lithium.

Sulfur in nature consists of two abundant stable isotopes, with two more neutrons in the heavy one (34S) than in the light one (32S). The two isotopes show similar physicochemical properties and are usually considered an integral system for chemical research in various fields. In this work, a model study based on a Li-S battery was performed to reveal the variation between the electrochemical properties of the two S isotopes. Provided with the same octatomic ring structure, the cyclo-34S8 molecules form stronger S-S bonds than cyclo-32S8 and are more prone to react with Li. The soluble Li polysulfides generated by the Li-34S conversion reaction show a stronger cation-solvent interaction yet a weaker cation-anion interaction than the 32S-based counterparts, which facilitates quick solvation of polysulfides yet hinders their migration from the cathode to the anode. Consequently, the Li-34S cell shows improved cathode reaction kinetics at the solid-liquid interface and inhibited shuttle of polysulfides through the electrolyte so that it demonstrates better cycling performance than the Li-32S cell. Based on the varied shuttle kinetics of the isotopic-S-based polysulfides, an electrochemical separation method for 34S/32S isotope is proposed, which enables a notably higher separation factor than the conventional separation methods via chemical exchange or distillation and brings opportunities to low-cost manufacture, utilization, and research of heavy chalcogen isotopes.

Consequences of plateau pika disturbance on plant-soil carbon and nitrogen in alpine meadows.

The presence of burrowing mammals can have extensive effects on plants and soils, creating bare soil patches in alpine meadows and potentially altering plant-soil carbon (C) and nitrogen (N). This study focuses on the plateau pika (Ochotona curzoniae) to examine the responses of plant-soil C and N to a small burrowing mammal from quadrat scale to plot scale. The density of active burrow entrances in disturbed plots was used as an indicator of the disturbance intensity of plateau pikas. The study found that the below-ground biomass (BGB) and its C and N, as well as soil C and N concentrations were significantly lower in bare soil areas than in vegetated areas and undisturbed plots. This shows that the quadrat scale limited the estimation of the C and N sequestration potential. Therefore, further research on the plot scale found that the disturbance by plateau pika significantly reduced plant biomass and BGB carbon stock. However, plateau pika did not affect soil C and N stocks or ecosystem C and N stocks. These findings suggest the bare soil patches formed by plateau pika caused plant and soil heterogeneity but had a trade-off effect on plant-soil C and N stocks at the plot scale. Nevertheless, moderate disturbance intensity increased the C and N sequestration potential in grassland ecosystems. These results provide a possible way to estimate how disturbance by small burrowing mammals affects C and N cycling in grassland ecosystems while accurately assessing the effects of small burrowing mammal densities on C and N in grassland ecosystems.

The GRHL3-regulated long non-coding RNA lnc-DC modulates keratinocytes differentiation by interacting with IGF2BP2 and up-regulating ZNF750.

BACKGROUND: Aberrant keratinocytes differentiation has been demonstrated to be associated with a number of skin diseases. The roles of lncRNAs in keratinocytes differentiation remain to be largely unknown. OBJECTIVE: Here we aim to investigate the role of lnc-DC in regulating epidermal keratinocytes differentiation. METHODS: Expression of lnc-DC in the skin was queried in AnnoLnc and verified by FISH. The lncRNA expression profiles during keratinocytes differentiation were reanalyzed and verified by qPCR and FISH. Gene knock-down and over-expression were used to explore the role of lnc-DC in keratinocytes differentiation. The downstream target of lnc-DC was screened by whole transcriptome sequencing. CUT&RUN assay and siRNAs transfection was used to reveal the regulatory effect of GRHL3 on lnc-DC. The mechanism of lnc-DC regulating ZNF750 was revealed by RIP assay and RNA stability assay. RESULTS: Lnc-DC was biasedly expressed in skin and up-regulated during epidermal keratinocytes differentiation. Knockdown lnc-DC repressed epidermal keratinocytes differentiation while over-express lnc-DC showed the opposite effect. GRHL3, a well-known transcription factor regulating keratinocytes differentiation, could bind to the promoter of lnc-DC and regulate its expression. By whole transcriptome sequencing, we identified that ZNF750 was a downstream target of lnc-DC during keratinocytes differentiation. Mechanistically, lnc-DC interacted with RNA binding protein IGF2BP2 to stabilize ZNF750 mRNA and up- regulated its downstream targets TINCR and KLF4. CONCLUSION: Our study revealed the novel role of GRHL3/lnc-DC/ZNF750 axis in regulating epidermal keratinocytes differentiation, which may provide new therapeutic targets of aberrant keratinocytes differentiation related skin diseases.

Eight-month intensive meditation-based intervention improves refractory hallucinations and delusions and quality of life in male inpatients with schizophrenia: a randomized controlled trial.

AIM: This study investigated the impact of an 8-month daily-guided intensive meditation-based intervention (iMI) on persistent hallucinations/delusions and health-related quality of life (QoL) in male inpatients with schizophrenia with treatment-refractory hallucinations and delusions (TRHDs). METHODS: A randomized controlled trial assigned 64 male inpatients with schizophrenia and TRHD equally to an 8-month iMI plus general rehabilitation program (GRP) or GRP alone. Assessments were conducted at baseline and the third and eighth months using the Positive and Negative Syndrome Scale (PANSS), 36-Item Short Form-36 (SF-36), and Five Facet Mindfulness Questionnaire (FFMQ). Primary outcomes measured PANSS reduction rates for total score, positive symptoms, and hallucinations/delusions items. Secondary outcomes assessed PANSS, SF-36, and FFMQ scores for psychotic symptoms, health-related QoL, and mindfulness skills, respectively. RESULTS: In the primary outcome, iMI significantly improved the reduction rates of PANSS total score, positive symptoms, and hallucination/delusion items compared with GRP at both the third and eighth months. Treatment response rates (≥25% reduction) for these measures significantly increased in the iMI group at the eighth month. Concerning secondary outcomes, iMI significantly reduced PANSS total score and hallucination/delusion items, while increasing scores in physical activity and mindfulness skills at both the third and eighth months compared with GRP. These effects were more pronounced with an 8-month intervention compared with a 3-month intervention. CONCLUSIONS: An iMI benefits patients with TRHDs by reducing persistent hallucinations/delusions and enhancing health-related QoL. Longer iMI duration yields superior treatment outcomes.

Proteomic and metabolomic features in patients with HCC responding to lenvatinib and anti-PD1 therapy.

Combination therapy (lenvatinib/programmed death-1 inhibitor) is effective for treating unresectable hepatocellular carcinoma (uHCC). We reveal that responders have better overall and progression-free survival, as well as high tumor mutation burden and special somatic variants. We analyze the proteome and metabolome of 82 plasma samples from patients with hepatocellular carcinoma (HCC; n = 51) and normal controls (n = 15), revealing that individual differences outweigh treatment differences. Responders exhibit enhanced activity in the alternative/lectin complement pathway and higher levels of lysophosphatidylcholines (LysoPCs), predicting a favorable prognosis. Non-responders are enriched for immunoglobulins, predicting worse outcomes. Compared to normal controls, HCC plasma proteins show acute inflammatory response and platelet activation, while LysoPCs decrease. Combination therapy increases LysoPCs/phosphocholines in responders. Logistic regression/random forest models using metabolomic features achieve good performance in the prediction of responders. Proteomic analysis of cancer tissues unveils molecular features that are associated with side effects in responders receiving combination therapy. In conclusion, our analysis identifies plasma features associated with uHCC responders to combination therapy.