Wide-scope targeted analysis of bioactive lipids in human plasma by LC/MS/MS.

Quantitative information on blood metabolites can be used in developing advanced medical strategies such as early detection and prevention of disease. Monitoring bioactive lipids such as steroids, bile acids, and PUFA metabolites could be a valuable indicator of health status. However, a method for simultaneously measuring these bioactive lipids has not yet been developed. Here, we report a LC/MS/MS method that can simultaneously measure 144 bioactive lipids, including steroids, bile acids, and PUFA metabolites, from human plasma, and a sample preparation method for these targets. Protein removal by methanol precipitation and purification of bioactive lipids by solid-phase extraction improved the recovery of the targeted compounds in human plasma samples, demonstrating the importance of sample preparation methods for a wide range of bioactive lipid analyses. Using the developed method, we studied the plasma from healthy human volunteers and confirmed the presence of bioactive lipid molecules associated with sex differences and circadian rhythms. The developed method of bioactive lipid analysis can be applied to health monitoring and disease biomarker discovery in precision medicine.

Comprehensive bioinformation analysis of homeodomain-leucine zipper gene family and expression pattern of HD-Zip I under abiotic stress in Salix suchowensis.

BACKGROUND: Homeodomain-leucine zipper (HD-Zip) transcription factors are plant-specific and play important roles in plant defense against environmental stresses. Identification and functional studies have been carried out in model plants such as rice, Arabidopsis thaliana, and poplar, but comprehensive analysis on the HD-Zip family of Salix suchowensis have not been reported. RESULTS: A total of 55 HD-Zip genes were identified in the willow genome, unevenly distributed on 18 chromosomes except for chromosome 19. And segmental duplication events containing SsHD-Zip were detected on all chromosomes except chromosomes 13 and 19. The SsHD-Zip were classified into 4 subfamilies subfamilies (I-IV) according to the evolutionary analysis, and members of each subfamily shared similar domain structure and gene structure. The combination of GO annotation and promoter analysis showed that SsHD-Zip genes responded to multiple abiotic stresses. Furthermore, the results of qPCR analysis showed that the SsHD-Zip I gene exhibited different degrees of expression under salt stress, PEG treatment and heat treatment. Moreover, there was a synergistic effect between SsHD-Zip I genes under stress conditions based on coregulatory networks analysis. CONCLUSIONS: In this study, HD-Zip transcription factors were systematically identified and analyzed at the whole genome level. These results preliminarily clarified the structural characteristics and related functions of willow HD-Zip family members, and it was found that SsHox34, SsHox36 and SsHox51 genes were significantly involved in the response to various stresses. Together, these findings laid the foundation for further research on the resistance functions of willow HD-Zip genes.

Systematic characterization of extracellular glycoproteins using mass spectrometry.

Surface and secreted glycoproteins are essential to cells and regulate many extracellular events. Because of the diversity of glycans, the low abundance of many glycoproteins, and the complexity of biological samples, a system-wide investigation of extracellular glycoproteins is a daunting task. With the development of modern mass spectrometry (MS)-based proteomics, comprehensive analysis of different protein modifications including glycosylation has advanced dramatically. This review focuses on the investigation of extracellular glycoproteins using MS-based proteomics. We first discuss the methods for selectively enriching surface glycoproteins and investigating protein interactions on the cell surface, followed by the application of MS-based proteomics for surface glycoprotein dynamics analysis and biomarker discovery. We then summarize the methods to comprehensively study secreted glycoproteins by integrating various enrichment approaches with MS-based proteomics and their applications for global analysis of secreted glycoproteins in different biological samples. Collectively, MS significantly expands our knowledge of extracellular glycoproteins and enables us to identify extracellular glycoproteins as potential biomarkers for disease detection and drug targets for disease treatment.

Soy-fortelin: A ghrelin sensitivity-enhancing peptide that stimulates food intake in aged mice.

Ghrelin sensitivity is known to decrease with aging in mice and humans, and the decrease contributes to anorexia with aging. In this study, we discovered novel ghrelin sensitivity-enhancing peptides. Ghrelin sensitivity was evaluated by examining whether dipeptide samples enhanced the calcium response to ghrelin in the growth hormone secretagogue receptor-transfected cell line. First, dipeptides were screened using a 336-dipeptide library and we revealed that Ser-Tyr (SY) potentiated ghrelin sensitivity in particular. Based on the structure-activity relationship determined using the dipeptide library and comprehensive analysis of peptides in the chymotrypsin digest of soy ß-conglycinin (ß-CG), which enhanced ghrelin sensitivity, candidate peptides were narrowed down. Among the chemosynthesized peptides, we discovered that an undecapeptide, SLVNNDDRDSY, corresponding to ß-CGα(267-277), stimulated ghrelin sensitivity in vitro. This peptide enhanced the orexigenic activity of ghrelin in C57BL/6 mice and stimulated food intake. Thus, we demonstrated that SLVNNDDRDSY stimulated ghrelin sensitivity in vitro and in vivo and named it "soy-fortelin". Moreover, orally administered soy-fortelin had a similar but smaller effect in the young C57BL/6 mice, whereas it strongly stimulated food intake in 2-year-old aged mice that exhibited high blood ghrelin levels and low ghrelin sensitivity. In conclusion, we discovered soy-fortelin as a novel peptide that enhances ghrelin sensitivity in vivo and in vitro and increases food intake in young and aged ghrelin-resistant mice. Soy-fortelin is the first food-derived peptide reported to enhance ghrelin sensitivity.

Analysis of anti-tumor effect and mechanism of GLS1 inhibitor CB-839 in colorectal cancer using a stroma-abundant tumor model.

BACKGROUND: Glutaminase 1 (GLS1), a key enzyme in glutamine metabolism in cancer cells, acts as a tumor promoter and could be a potential therapeutic target. CB-839, a GLS1-specific inhibitor, was developed recently. Herein, we aimed to elucidate the anti-tumor effects and mechanism of action of CB-839 in colorectal cancer (CRC). METHODS: Using the UCSC Xena public database, we evaluated GLS1 expression in various cancers. Immunostaining for GLS1 was performed on 154 surgically resected human CRC specimens. Subsequently, we examined the GLS1 mRNA expression levels in eight CRC cell lines and evaluated the association between GLS1 expression and CB-839 efficacy. To create a reproducible CRC model with abundant stroma and an allogeneic immune response, we co-transplanted CT26 and stem cells into BALB/c mice and treated them with CB-839. Finally, RNA sequencing of mouse tumors was performed. RESULTS: Database analysis showed higher GLS1 expression in CRC tissues than in normal colon tissues. Clinical samples from 114 of the 154 patients with CRC showed positive GLS1 expression. GLS1 expression in clinical CRC tissues correlated with vascular invasion. CB-839 treatment inhibited cancer cell proliferation depending on GLS1 expression in vitro and inhibited tumor growth and metastasis in the CRC mouse model. RNA sequencing revealed that CB-839 treatment inhibited stromal activation, tumor growth, migration, and angiogenesis. These findings were validated through in vitro and in vivo experiments and clinical specimen analysis. CONCLUSIONS: GLS1 expression in CRC plays important roles in tumor progression. CB-839 has inhibitory effects on cancer proliferation and the tumor microenvironment.

Experiential training course on spirituality for multidisciplinary palliative care teams in a hospital setting: a feasibility study.

BACKGROUND: There is widespread agreement about the importance of spiritual training programs (STPs) for healthcare professionals caring for cancer patients, and that reflecting on one's spirituality is the first step. Health professionals (HPs) working in hospitals must develop this dimension to guarantee the quality of life as well as spiritual and emotional support. In this paper, we propose a possible training format for hospital professionals and assess its implementation. METHODS: This is a phase 0-I study that follows the Medical Research Council (MRC) framework. The program was implemented for hospital palliative care specialists. The program included one theory lesson, three spiritual interactions, four pieces of reflective writing, and two individual follow-up sessions for each participant. The evaluation was performed quantitatively according to the MRC framework and qualitatively according to Moore's framework with data triangulation from interviews, reflective writings, and indicators. RESULTS: The program was implemented for palliative care physicians, nurses, psychologists, and bioethicists according to the plan, and the program components were highly appreciated by the participants. The results suggest the feasibility of a training course with some corrections, regarding both the components of the training and organizational issues. The qualitative analysis confirmed a shift in the meaning of the themes we identified. The trainees went from intrapersonal spirituality to interpersonal spirituality (engagement with the other person's spirituality, acknowledging their unique spiritual and cultural worldviews, beliefs, and practices), with colleagues, patients, and people close to them. The training had an impact on Moore's Level 3b. CONCLUSIONS: Spiritual training for hospital professionals working in palliative care is feasible. Having time dedicated to spirituality and the ongoing mentorship of spiritual care professionals were suggested as key elements. The next step is increasing awareness of spirituality from our hospital reality and creating a stable competent group (with nurses, chaplains, nuns, counselors, etc.) with the support of the management.

Unraveling the Role of RNA-Binding Proteins, with a Focus on RPS5, in the Malignant Progression of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) represents a major global health concern, demanding a thorough understanding of its molecular mechanisms for effective therapeutic strategies. RNA-binding proteins (RBPs) play critical roles in post-transcriptional gene regulation, with their dysregulation increasingly recognized as a hallmark of various cancers. However, the specific contributions of RBPs to HCC pathogenesis and prevention remain incompletely understood. In this study, we systematically conducted an examination of the expression profiles and clinical relevance of RBPs in 556 clinical samples from well-established cohorts. Through comprehensive analyses, a subset of RBPs exhibiting significant overexpression in HCC was identified, establishing a noteworthy correlation between their aberrant expression and HCC progression. Furthermore, 40S ribosomal protein S5 (RPS5), a ribosomal protein, emerged as a potential key contributor in HCC progression. Rigorous analyses established a correlation between elevated RPS5 expression and advanced clinicopathological features, suggesting its potential as a prognostic biomarker. Experiments further confirmed the impact of RPS5 on pivotal cellular processes implicated in cancer progression, including cell proliferation and metastasis. Further mechanistic studies unveiled the potential of RPS5 to activate the cell cycle by binding to key molecules involved in the pathway, thereby promoting the malignant progression of HCC. Additionally, our analysis of the etiology behind RPS5 overexpression in HCC posited it as an outcome of transcriptional regulation by the transcription factors Nuclear Respiratory Factor 1 (NRF1) and MYC-associated zinc finger protein (MAZ). In conclusion, our study contributes to the growing evidence elucidating the intricate involvement of RBPs, exemplified by RPS5, in the malignant progression of HCC. The integration of genomic, transcriptomic, and functional analyses provides a comprehensive understanding of the regulatory mechanisms associated with RPS5 in HCC. This comprehensive analysis not only advances our knowledge of the molecular drivers behind HCC but also highlights the potential therapeutic relevance of targeting RBPs and their regulatory network for the development of more effective treatment strategies.

Comprehensive mastocytosis data analysis from a single center.

Mastocytosis is a very rare disorder and is divided into three prognostically distinct variants by World Health Organization: Cutaneous mastocytosis (CM), systemic mastocytosis (SM), and mast cell sarcoma or localized mast cell (MC) tumors. The wide range of complaints may cause patients to consult various clinics, with resulting mis- or underdiagnosis. Therefore, cooperation between different subspecialties is of paramount importance. In this article, we have compiled 104 adult mastocytosis cases diagnosed and followed in our Hematology and other clinics. 86 (82.7%) of 104 patients had systemic mastocytosis. Osteoporosis, disease-related complications, and secondary malignancies are important topics in this group. We know that indolent form has great survival. But smoldering or aggressive mastocytosis has a poor prognosis. CM and indolent SM have a significantly better prognosis compared to aggressive SM (p < 0.001). We found that the presence of more than 25% of mast cells in the bone marrow, the presence of concomitant marrow dysplasia, and the presence of disease-related complications affect survival (p < 0.001). In addition to the WHO classification, the IPSM scoring system is indicative of the prognosis in this rare disease.

Circulating microRNAs as diagnostic biomarkers for ischemic stroke: evidence from comprehensive analysis and real-world validation.

Ischemic stroke (IS) is the majority of strokes which remain the second leading cause of deaths in the last two decades. Circulating microRNAs (miRNAs) have been suggested as potential diagnostic and therapeutic tools for IS by previous studies analyzing their differential expression. However, inconclusive and controversial conclusions of these results have to be addressed. In this study, comprehensive analysis and real-world validation were performed to assess the associations between circulating miRNAs and IS. 29 studies with 112 miRNAs were extracted after manual selection and filtering, 12 differentially expressed miRNAs were obtained from our results of meta-analysis. These miRNAs were evaluated in 20 IS patients, compared to 20 healthy subjects. 4 miRNAs (hsa-let-7e-5p, hsa-miR-124-3p, hsa-miR-17-5p, hsa-miR-185-5p) exhibited the significant expression level in IS patient plasma samples. Pathway and biological process enrichment analysis for the target genes of the 4 validated miRNAs identified cellular senescence and neuroinflammation as key post-IS response pathways. The results of our analyses closely correlated with the pathogenesis and implicated pathways observed in IS subjects suggested by the literature, which may provide aid in the development of circulating diagnostic or therapeutic targets for IS patients.

Research on Comprehensive Evaluation and Early Warning of Transmission Lines' Operation Status Based on Dynamic Cloud Computing.

The current methods for evaluating the operating condition of electricity transmission lines (ETLs) and providing early warning have several problems, such as the low correlation of data, ignoring the influence of seasonal factors, and strong subjectivity. This paper analyses the sensitive factors that influence dynamic key evaluation indices such as grounding resistance, sag, and wire corrosion, establishes the evaluation criteria of the ETL operation state, and proposes five ETL status levels and seven principles for selecting evaluation indices. Nine grade I evaluation indices and twenty-nine grade II evaluation indices, including passageway and meteorological environments, are determined. The cloud model theory is embedded and used to propose a warning technology for the operation state of ETLs based on inspection defect parameters and the cloud model. Combined with the inspection defect parameters of a line in the Baicheng district of Jilin Province and the critical evaluation index data such as grounding resistance, sag, and wire corrosion, which are used to calculate the timeliness of the data, the solid line is evaluated. The research shows that the dynamic evaluation model is correct and that the ETL status evaluation and early warning method have reasonable practicability.

Identification of FGF13 as a Potential Biomarker and Target for Diagnosis of Impaired Glucose Tolerance.

Early identification of pre-diabetes provides an opportunity for intervention and treatment to delay its progression to type 2 diabetes mellitus (T2DM). We aimed to identify the biomarkers of impaired glucose tolerance (IGT) through bioinformatics analysis. The GSE76896 dataset, including non-diabetic (ND), IGT, and T2DM clinical samples, was deeply analyzed to identify 309 Co-DEGs for IGT and T2DM. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that inflammatory responses and the PI3K-AKT signaling pathway are important patho-physiological features of IGT and T2DM. Protein-protein interaction (PPI) network analysis and cytoHubba technolgy identified seven hub genes: namely, CCL2, CXCL1, CXCL8, EDN1, FGF13, MMP1, and NGF. The expression and ROC curves of these hub genes were validated using the GSE38642 dataset. Through an immunofluorescence assay, we found that the expression of FGF13 in islets of mice in the HFD and T2DM groups was significantly lower than in the control group. Similarly, the level of FGF13 in the sera of IGT and T2DM patients was lower than that in the healthy group. Together, these results suggest that FGF13 can be treated as a novel biomarker of IGT, which may provide new targets for the diagnosis and treatment of pre-diabetes and T2DM.

Changes in Multiple microRNA Levels with Antidepressant Treatment Are Associated with Remission and Interact with Key Pathways: A Comprehensive microRNA Analysis.

Individual treatment outcomes to antidepressants varies widely, yet the determinants to this difference remain elusive. MicroRNA (miRNA) gene expression regulation in major depressive disorder (MDD) has attracted interest as a biomarker. This 4-week randomized controlled trial examined changes in the plasma miRNAs that correlated with the treatment outcomes of mirtazapine (MIR) and selective serotonin reuptake inhibitor (SSRI) monotherapy. Pre- and post- treatment, we comprehensively analyzed the miRNA levels in MDD patients, and identified the gene pathways linked to these miRNAs in 46 patients. Overall, 141 miRNA levels significantly demonstrated correlations with treatment remission after 4 weeks of MIR, with miR-1237-5p showing the most robust and significant correlation after Bonferroni correction. These 141 miRNAs displayed a negative correlation with remission, indicating a decreasing trend. These miRNAs were associated with 15 pathways, including TGF-ß and MAPK. Through database searches, the genes targeted by these miRNAs with the identified pathways were compared, and it was found that MAPK1, IGF1, IGF1R, and BRAF matched. Alterations in specific miRNAs levels before and after MIR treatment correlated with remission. The miRNAs mentioned in this study have not been previously reported. No other studies have investigated treatment with MIR. The identified miRNAs also correlated with depression-related genes and pathways.

Health risk cause of water around landfill in hilly area and prevention and control countermeasures.

Evaluating the health risks of the groundwater and surface water in landfill areas is of great significance to the health and safety of local residents. The current practice of health risk assessment is based only on the analysis results of groundwater and surface water samples, which reflect the current situation of water security in landfill areas. However, due to the neglect of risk causes analysis, thus a health risk assessment is insufficient to provide rigorous scientific countermeasures for risk prevention and control. The health risks caused by groundwater and surface water is mainly controlled by the water quality, which is comprehensively controlled by the conditions of its formation and evolution. When a landfill site is located in a hilly area, the environmental characteristics, causes, main controlling factors, and evolution processes of the surface water and groundwater in different parts of the catchment are significantly different. This study used a municipal solid waste landfill area in a hilly area as an example and defined the causes and main controlling factors of regional health risks caused by water based on an analysis of the characteristics of natural and anthropogenic factors affecting the groundwater and surface water. Then, prevention and control countermeasures were proposed for health risks caused by water in different parts of the landfill area. This study provides a method for the causes analysis and prevention and control countermeasures of health risks caused by water in municipal solid waste landfills in hilly areas.

Identification of shared neoantigens in esophageal carcinoma by the combination of comprehensive analysis of genomic data and in silico neoantigen prediction.

Neoantigens are attractive targets for cancer immunotherapy. The identification of neoantigens shared by different patients could promote the broad application of neoantigen-based immunotherapy. This study aimed to investigate shared neoantigens in esophageal carcinoma. By combining a comprehensive analysis of mutation data of 722 patients with esophageal carcinoma (EC) and in silico neoantigen prediction, we obtained 216 recurrent neoantigen candidates predicted to bind to high-frequency class I human leukocyte antigen (HLA) alleles. We further performed immunogenicity validation tests on five high-frequency HLA-A*0201 binding neoantigens derived from TP53 mutations. The results demonstrated that the peptides p53 H193R193_203, R248Q245_254, and R273H264_274 could efficiently prime peptide-specific CD8+ T cells to secrete IFN-γ and lyse mutant peptide-pulsed T2 cells. In conclusion, we obtained a group of shared neoantigen candidates in esophageal carcinoma and validated the immunogenicity of three novel TP53 neoantigens. These peptides might be potential targets for immunotherapy.

Comprehensive Analysis of Congenital Adrenal Hyperplasia Using Long-Read Sequencing.

BACKGROUND: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder that has been included in newborn screening programs. Current approaches to gene testing for CAH are facing challenges because of the complexity of the CYP21A2 locus and genetic heterogeneity of the disease. METHODS: A comprehensive analysis of CAH (CACAH) combining long-range locus-specific PCR and long-read sequencing (LRS) was developed to perform full sequence analysis of 5 common CAH candidate genes, including CYP21A2, CYP11B1, CYP17A1, HSD3B2, and StAR. In a blind retrospective study, the clinical utility of CACAH was evaluated in 37 samples by comparing to standard CAH testing using multiplex ligation-dependent probe amplification (MLPA) plus Sanger sequencing. RESULTS: Of the 37 clinical samples, a total of 69 pathogenic variants were identified, comprising 65 CYP21A2 variants, 2 HSD3B2 variants, and 2 CYP17A1 variants. For CYP21A2, the most frequent variant was c.518T > A (29.2%), followed by c.293-13C/A > G (21.5%). Compared with the current CAH testing using MLPA plus Sanger sequencing, the CACAH assay showed 100% specificity and 100% sensitivity, and precisely determined the junction sites of deletions/insertions and cis-trans configuration of multiple variants without analyzing family samples. Moreover, CACAH identified a case carrying 2 copies of CYP21A1 with the c.1451_1452delinsC variant on the same chromosome, which was not confirmed by MLPA plus Sanger sequencing. CONCLUSION: LRS-based CACAH can determine all genotypes of CAH accurately and reliably in one assay, presenting a comprehensive approach for CAH genetic diagnosis and carrier screening.

Comprehensive Analysis of Ixazomib-Induced Adverse Events Using the Japanese Pharmacovigilance Database.

BACKGROUND: Ixazomib is an orally available proteasome inhibitor for multiple myeloma with adverse effects such as gastrointestinal symptoms, skin rashes, and thrombocytopenia reported in clinical trials and post-marketing surveillance, resulting in treatment discontinuation. However, comprehensive adverse event (AE) assessments for ixazomib are lacking. OBJECTIVES: Herein, we aimed to determine the frequency and risk of AEs associated with ixazomib in Japanese patients using the Japanese Adverse Event Reporting Database (JADER). Additionally, the time to onset and post hoc outcomes of unique AEs were clarified. METHODS: To investigate the association between ixazomib and AEs, we analyzed the JADER database, comprising voluntary AE reports submitted to the Pharmaceuticals and Medical Devices Agency, between April 2004 and June 2021. AEs with ≥10 reports were included in the analysis, and criteria for the presence of AE signals were defined as meeting the requirements of proportional report ratio ≥2 and χ2 ≥ 4. Characteristic AEs were analyzed considering time to onset and onset outcomes. RESULTS: Of 34 extracted AEs, 18 presented AE signals. The 12 post hoc outcomes with fatality rates ≥10% included septic shock (50.0%), infection (41.2%), heart failure (16.7%), pneumonia (14.2%), and tumor necrosis syndrome (13.3%). A median of the time to onset showed that 11 of the 18 AEs occurred from ixazomib initiation to approximately 1 month later. CONCLUSION: Our results suggest that ixazomib may increase the incidence of 18 AEs, 11 of which occurred within the first month of treatment. Furthermore, 8 AEs were found to have potentially fatal outcomes at a rate of ≥10%. Therefore, monitoring AEs during the first month of treatment appears necessary.

Identifying, exploring and integrating the spiritual dimension in proactive care planning: A mixed methods evaluation of a communication training intervention for multidisciplinary palliative care teams.

BACKGROUND: Patients receiving palliative care value attention given to their spiritual needs. However, these needs often remain unexplored as healthcare professionals lack the skills to identify and explore them and to integrate this information into care plans. AIM: To evaluate the effects of an interactive communication training intervention for palliative care teams in order to identify and explore the spiritual dimension and integrate it in patients' care plans. DESIGN: A mixed methods pre-post study, including self-assessment questionnaires, evaluation of videos with simulated consultations (applied competence) and medical record review (implementation). SETTING/PARTICIPANTS: Three palliative care teams including nurses (N = 21), physicians (N = 14) and spiritual caregivers (N = 3). RESULTS: The questionnaires showed an improvement on 'Patient and family-centred communication' of the End-of-life professional caregiver survey (+0.37, p < 0.01; the 8-item S-EOLC (+0.54, p < 0.01) and regarding the Spiritual Care Competence Scale, on the three subscales used (+0.27, p < 0.01, +0.29, p < 0.01 and +0.32, p < 0.01). Video evaluations showed increased attention being paid to patient's aims and needs. The medical record review showed an increase in anticipation on the non-somatic dimension (OR: 2.2, 95% CI: 1.2-4.3, p < 0.05) and, using the Mount Vernon Cancer Network assessment tool, addressing spiritual issues (OR: 10.9, 95% CI: 3.7-39.5, p < 0.001). CONCLUSIONS: Our training intervention resulted in increased palliative care professionals' competence in identifying and exploring patients' spiritual issues, and their integration in multidimensional proactive palliative care plans. The intervention directly addresses patients' spiritual concerns and adds value to their palliative care plans.

ACACB is a novel metabolism-related biomarker in the prediction of response to cetuximab therapy inmetastatic colorectal cancer.

Cetuximab is one of the most valuable targeted therapy monoclonal antibodies in the treatment of metastatic colorectal cancer (CRC). However, the mechanisms affecting cetuximab resistance in CRC treatment remain unclear. Metabolism, especially fatty acid metabolism, has been reported to play an important role in tumor treatment. The correlation between cetuximab resistance and metabolism and whether it can be a new biomarker to evaluate the sensitivity of cetuximab in CRC treatment still need to be further explored. In this study, we perform a comprehensive analysis to confirm the relationship between fatty acid metabolism and cetuximab resistance, and the differentially expressed genes (DEGs) related to cetuximab drug resistance in CRC are screened by bioinformatics technology. We find that acetyl-CoA carboxylase beta (ACACB), ADH1C, CES1, MGLL, FMO5, and GPT are the hub DEGs, and ACACB is the most important biomarker among them. In addition, we systematically analyze the role of ACACB in the tumorigenesis of CRC, including tissue expression, CRC cell growth, cetuximab sensitivity, and potential downstream pathways, by using bioinformatics techniques, in vitro experiments and clinical cohort validation. Our results confirm that cetuximab resistance is correlated with metabolism. ACACB can lead to decreased sensitivity to cetuximab in CRC, and its mechanism may be related to EGFR phosphorylation, which could affect the activation of the mTOR/Akt signaling pathway and regulation of CDT1-, cyclin D1-, and p21-related cell cycle modulation.

On the origin and evolution of the asteroid Ryugu: A comprehensive geochemical perspective.

Presented here are the observations and interpretations from a comprehensive analysis of 16 representative particles returned from the C-type asteroid Ryugu by the Hayabusa2 mission. On average Ryugu particles consist of 50% phyllosilicate matrix, 41% porosity and 9% minor phases, including organic matter. The abundances of 70 elements from the particles are in close agreement with those of CI chondrites. Bulk Ryugu particles show higher δ18O, Δ17O, and ε54Cr values than CI chondrites. As such, Ryugu sampled the most primitive and least-thermally processed protosolar nebula reservoirs. Such a finding is consistent with multi-scale H-C-N isotopic compositions that are compatible with an origin for Ryugu organic matter within both the protosolar nebula and the interstellar medium. The analytical data obtained here, suggests that complex soluble organic matter formed during aqueous alteration on the Ryugu progenitor planetesimal (several 10's of km), <2.6 Myr after CAI formation. Subsequently, the Ryugu progenitor planetesimal was fragmented and evolved into the current asteroid Ryugu through sublimation.

Role of Nuclear-Receptor-Related 1 in the Synergistic Neuroprotective Effect of Umbilical Cord Blood and Erythropoietin Combination Therapy in Hypoxic Ischemic Encephalopathy.

Neonatal hypoxic-ischemic encephalopathy (HIE) results in neurological impairments; cell-based therapy has been suggested as a therapeutic avenue. Previous research has demonstrated the synergistically potentiated therapeutic efficacy of human umbilical cord blood (UCB) by combining recombinant human erythropoietin (EPO) treatment for recovery from HIE. However, its molecular mechanism is not entirely understood. In the present study, we analyzed the mechanisms underlying the effect of combination treatment with EPO and UCB by transcriptomic analysis, followed by gene enrichment analysis. Mouse HIE model of the neonate was prepared and randomly divided into five groups: sham, HIE, and UCB, EPO, and UCB+EPO treatments after HIE. A total of 376 genes were differentially expressed when |log2FC| ≥ 1-fold change expression values were considered to be differentially expressed between UCB+EPO and HIE. Further assessment through qRT-PCR and gene enrichment analysis confirmed the expression and correlation of its potential target, Nurr1, as an essential gene involved in the synergistic effect of the UCB+EPO combination. The results indicated the remarkable activation of Wnt/ß-catenin signaling by reducing the infarct size by UCB+EPO treatment, accompanied by Nurr1 activity. In conclusion, these findings suggest that the regulation of Nurr1 through the Wnt/ß-catenin pathway exerts a synergistic neuroprotective effect in UCB and EPO combination treatment.