Role of Platelet/Lymphocyte, Neutrophil/Lymphocyte, and Interleukin-37/Interleukin-17 Ratios in the Occurrence and Treatment of Rheumatoid Arthritis.

This study was designed to investigate the correlation of neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and interleukin (IL)-37/IL-17 ratio with the incidence/treatment of rheumatoid arthritis (RA). Firstly, fifty-eight patients with RA treated at the first affiliated hospital of Xinjiang Medical University from January 2018 to January 2019 were selected as the RA group; forty-nine healthy volunteers were enrolled in the control group. RA patients were treated with disease-modifying anti-rheumatic drugs (DMARDs). Next, the NLR, PLR, IL-37, IL-17 and 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) were deleted in two groups. Subsequently, Spearman correlation analysis was adopted for the correlations of various indicators before and after treatment in two groups. According to the analysis results, the levels of NLR, PLR, IL-37, and IL-17 before treatment in the RA group were higher than those in the control group (P < .05), but the difference in the IL-37/IL-17 level between the two groups was not significant (P > .05). After treatment, NLR, PLR, and IL-37/IL-17 levels were significantly reduced in RA patients (P < .05). NLR and PLR were significantly positively correlated with DAS28-ESR, ESR and C-reactive protein (CRP), of which represented the disease activity of RA. NLP was strongly correlated with IL-37/IL-17. Collectively, NLR, PLR, IL-37, and IL-17 are closely related to the occurrence of RA. In addition, NLR and IL-37/IL-17 are more suitable than PLR in reflecting the therapeutic effect. Therefore, IL-37/IL-17 can be considered as a new indicator for reflecting the treatment effectiveness of RA.

Targeting myocardial inflammation: investigating the therapeutic potential of atrial natriuretic peptide in atrial fibrosis.

BACKGROUND: Atrial Fibrillation (AF), a prevalent arrhythmic condition, is intricately associated with atrial fibrosis, a major pathological contributor. Central to the development of atrial fibrosis is myocardial inflammation. This study focuses on Atrial Natriuretic Peptide (ANP) and its role in mitigating atrial fibrosis, aiming to elucidate the specific mechanisms by which ANP exerts its effects, with an emphasis on fibroblast dynamics. METHODS AND RESULTS: The study involved forty Sprague-Dawley rats, divided into four groups: control, Angiotensin II (Ang II), Ang II + ANP, and ANP only. The administration of 1 µg/kg/min Ang II was given to Ang II and Ang II + ANP groups, while both Ang II + ANP and ANP groups received 0.1 µg/kg/min ANP intravenously for a duration of 14 days. Cardiac fibroblasts were used for in vitro validation of the proposed mechanisms. The study observed that rats in the Ang II and Ang II + ANP groups showed an increase in blood pressure and a decrease in body weight, more pronounced in the Ang II group. Diastolic dysfunction, a characteristic of the Ang II group, was alleviated by ANP. Additionally, ANP significantly reduced Ang II-induced atrial fibrosis, myofibroblast proliferation, collagen overexpression, macrophage infiltration, and the elevated expression of Interleukin 6 (IL-6) and Tenascin-C (TN-C). Transcriptomic sequencing indicated enhanced PI3K/Akt signaling in the Ang II group. Furthermore, in vitro studies showed that ANP, along with the PI3K inhibitor LY294002, effectively reduced PI3K/Akt pathway activation and the expression of TN-C, collagen-I, and collagen-III, which were induced by Ang II. CONCLUSIONS: The study demonstrates ANP's potential in inhibiting myocardial inflammation and reducing atrial fibrosis. Notably, ANP's effect in countering atrial fibrosis seems to be mediated through the suppression of the Ang II-induced PI3K/Akt-Tenascin-C signaling pathway. These insights enhance our understanding of AF pathogenesis and position ANP as a potential therapeutic agent for treating atrial fibrosis.

Inhibition of USP7 enhances CD8+ T cell activity in liver cancer by suppressing PRDM1-mediated FGL1 upregulation.

Lymphocyte activation gene 3 (LAG3), an immune checkpoint molecule expressed on activated T cells, functions as a negative regulator of immune responses. Persistent antigen exposure in the tumor microenvironment results in sustained LAG3 expression on T cells, contributing to T cell dysfunction. Fibrinogen-like protein 1 (FGL1) has been identified as a major ligand of LAG3, and FGL1/LAG3 interaction forms a novel immune checkpoint pathway that results in tumor immune evasion. In addition, ubiquitin-specific peptidase 7 (USP7) plays a crucial role in cancer development. In this study we investigated the role of USP7 in modulation of FGL1-mediated liver cancer immune evasion. We showed that knockdown of USP7 or treatment with USP7 inhibitor P5091 suppressed liver cancer growth by promoting CD8+ T cell activity in Hepa1-6 xenograft mice and in HepG2 or Huh7 cells co-cultured with T cells, whereas USP7 overexpression produced the opposite effect. We found that USP7 upregulated FGL1 in HepG2 and Huh7 cells by deubiquitination of transcriptional factor PR domain zinc finger protein 1 (PRDM1), which transcriptionally activated FGL1, and attenuated the CD8+ T cell activity, leading to the liver cancer growth. Interestingly, USP7 could be transcriptionally stimulated by PRDM1 as well in a positive feedback loop. P5091, an inhibitor of USP7, was able to downregulate FGL1 expression, thus enhancing CD8+ T cell activity. In an immunocompetent liver cancer mouse model, the dual blockade of USP7 and LAG3 resulted in a superior antitumor activity compared with anti-LAG3 therapy alone. We conclude that USP7 diminishes CD8+ T cell activity by a USP7/PRDM1 positive feedback loop on FGL1 production in liver cancer; USP7 might be a promising target for liver cancer immunotherapy.

Clinical practice guidelines for the nutrition of colorectal cancer patients: a systematic review.

PURPOSE: The aim of this study is to rigorously assess the methodological quality of published clinical practice guidelines (CPGs) related to nutrition among colorectal cancer patients, to compile consensus recommendations, and to evaluate the quality of the included CPGs. METHODS: The systematic search covered eight electronic databases, two relevant professional association websites, and six guideline websites from their inception up to January 22, 2023. The methodological quality of the eligible guidelines was evaluated using the Appraisal of Guidelines Research and Evaluation II (AGREE II) instrument, and then, consensus recommendations were synthesized. The scores for each domain were expressed as the mean ± standard deviation (SD). Using the mean score as the benchmark for comparison, they were subsequently ranked from highest to lowest. The included guidelines were then categorized as having "high," "moderate," or "low" quality based on their scores. RESULTS: The literature search yielded ten guidelines. The findings indicated that the "Clarity of presentation" domain had the highest mean score (65.2 ± 7.7). This demonstrates how the guidelines effectively articulate recommendations. Additionally, the "Scope and purpose" domain achieved a mean score of 60.7 ± 10.9, followed by "Rigor of development" (51.7 ± 15.7), "Editorial independence" (51.1 ± 21), "Stakeholder involvement" (48 ± 16.8), and "Applicability" domains (47.5 ± 17.3). Two CPGs received an overall rating of "high quality" and were recommended; four CPGs received an overall rating of "moderate" and were recommended with modifications; and four CPGs received an overall rating of "low quality" and were not recommended. Furthermore, this study compiled twenty consensus recommendations related to nine distinct clinical issues. CONCLUSION: This study identified disparities in the methodological quality of the included CPGs, particularly in the "Applicability" domain, thus emphasizing the need for advancement in clinical feasibility and implementation. Notably, there is few guidelines specifically targeting colorectal cancer nutrition. These synthesized findings provided an intuitive, convenient, and comprehensive reference for evaluating nutrition among colorectal cancer patients. When applying these results, users should make careful decisions based on their specific situations.

Metagenomic analysis reveals gene taxonomic and functional diversity response to microplastics and cadmium in an agricultural soil.

Both microplastics (MPs) and heavy metals are common soil pollutants and can interact to generate combined toxicity to soil ecosystems, but their impact on soil microbial communities (e.g., archaea and viruses) remains poorly studied. Here, metagenomic analysis was used to explore the response of soil microbiome in an agricultural soil exposed to MPs [i.e., polyethylene (PE), polystyrene (PS), and polylactic acid (PLA)] and/or Cd. Results showed that MPs had more profound effects on microbial community composition, diversity, and gene abundances when compared to Cd or their combination. Metagenomic analysis indicated that the gene taxonomic diversity and functional diversity of microbial communities varied with MPs type and dose. MPs affected the relative abundance of major microbial phyla and genera, while their coexistence with Cd influenced dominant fungi and viruses. Nitrogen-transforming and pathogenic genera, which were more sensitive to MPs variations, could serve as the indicative taxa for MPs contamination. High-dose PLA treatments (10%, w/w) not only elevated nitrogen metabolism and pathogenic genes, but also enriched copiotrophic microbes from the Proteobacteria phylum. Overall, MPs and Cd showed minimal interactions on soil microbial communities. This study highlights the microbial shifts due to co-occurring MPs and Cd, providing evidence for understanding their environmental risks.

The Importance of Knowledge on Dementia Risk Factors in the General Public: A Cross-Sectional Study.

ABSTRACT: The purpose of this study was to determine the influence of knowledge and beliefs on beneficial behaviors and dementia risk scores. A online survey was conducted among Chinese community residents over 18 years old. Multivariate logistic regression was used to identify the impact of knowledge and beliefs on dementia risk scores and beneficial behaviors. The respondents were 760 adults (mean age = 47.6 years, 60.8% female). Knowledge and beliefs were associated with cognitive activities (knowledge, odds ratio [OR] = 1.04; beliefs, OR = 1.17) and dementia risk scores (knowledge, OR = 0.95; beliefs, OR = 0.82). Additionally, lower perceived susceptibility (OR = 1.68; 95% CI, 1.04 to 2.72) and higher perceived benefits (OR = 0.68; 95% CI, 0.57 to 0.80) were associated with lower dementia risk scores. Knowledge and beliefs can promote beneficial behaviors and reduce dementia risk. In particular, perceptions of dementia susceptibility and benefits should be enhanced, which will greatly reduce dementia risk in the general public.

53BP1-ACLY-SLBP-coordinated activation of replication-dependent histone biogenesis maintains genomic integrity.

p53-binding protein 1 (53BP1) regulates the DNA double-strand break (DSB) repair pathway and maintains genomic integrity. Here we found that 53BP1 functions as a molecular scaffold for the nucleoside diphosphate kinase-mediated phosphorylation of ATP-citrate lyase (ACLY) which enhances the ACLY activity. This functional association is critical for promoting global histone acetylation and subsequent transcriptome-wide alterations in gene expression. Specifically, expression of a replication-dependent histone biogenesis factor, stem-loop binding protein (SLBP), is dependent upon 53BP1-ACLY-controlled acetylation at the SLBP promoter. This chain of regulation events carried out by 53BP1, ACLY, and SLBP is crucial for both quantitative and qualitative histone biogenesis as well as for the preservation of genomic integrity. Collectively, our findings reveal a previously unknown role for 53BP1 in coordinating replication-dependent histone biogenesis and highlight a DNA repair-independent function in the maintenance of genomic stability through a regulatory network that includes ACLY and SLBP.

Targeting ACYP1-mediated glycolysis reverses lenvatinib resistance and restricts hepatocellular carcinoma progression.

Acylphosphatase 1 (ACYP1), a protein located in the mammalian cell cytoplasm, has been shown to be associated with tumor initiation and progression by functioning as a metabolism-related gene. Here we explored the potential mechanisms by which ACYP1 regulates the development of HCC and participates in the resistance to lenvatinib. ACYP1 can promote the proliferation, invasion, and migration capacities of HCC cells in vitro and in vivo. RNA sequencing reveals that ACYP1 markedly enhances the expression of genes related to aerobic glycolysis, and LDHA is identified as the downstream gene of ACYP1. Overexpression of ACYP1 upregulates LDHA levels, which then increases the malignancy potential of HCC cells. GSEA data analysis reveals the enrichment of differentially expressed genes in the MYC pathway, indicating a positive correlation between MYC and ACYP1 levels. Mechanistically, ACYP1 exerts its tumor-promoting roles by regulating the Warburg effect through activating the MYC/LDHA axis. Mass spectrometry analysis and Co-IP assays confirm that ACYP1 can bind to HSP90. The regulation of c-Myc protein expression and stability by ACYP1 is HSP90 dependent. Importantly, lenvatinib resistance is associated with ACYP1, and targeting ACYP1 remarkably decreases lenvatinib resistance and inhibits progression of HCC tumors with high ACYP1 expression when combined with lenvatinib in vitro and in vivo. These results illustrate that ACYP1 has a direct regulatory role in glycolysis and drives lenvatinib resistance and HCC progression via the ACYP1/HSP90/MYC/LDHA axis. Targeting ACYP1 could synergize with lenvatinib to treat HCC more effectively.

Virtual reality-based dementia educational programmes for formal and informal caregivers of people with dementia: A scoping review.

AIM: To map evidence of the existing virtual reality-based dementia educational programmes and the effects of these educational programmes on dementia formal and informal caregivers. DESIGN: A scoping review. METHODS: A comprehensive search of nine databases was conducted to find studies from the inception of the databases to October 2023. Two authors independently screened the titles and abstracts related to the eligibility criteria. Full texts of potentially relevant studies were read by one author and checked by a second. Data extraction and synthesis using NVivo 12 were undertaken by one author and checked by two other authors. RESULTS: Nineteen studies published between 2002 and 2022. The four randomised controlled studies and five qualitative studies were of moderate to good methodological quality. The 10 quasi-experimental studies were of weak to moderate quality. Fifteen virtual reality-based educational programmes had a positive influence on formal and informal caregivers, including improving caregivers' perceptions changing attitudes towards people with dementia, while the nursing competence of formal caregivers did not improve in short term. Educational programmes that covered dementia-related information and care strategies better improved the knowledge level of dementia formal and informal caregivers. CONCLUSIONS: The qualitative and quantitative studies of moderate to good quality included in this study support the idea that virtual reality-based dementia educational programmes may be a safe and effective way and have potential benefits for improving knowledge, perceptions, attitudes and nursing competence. IMPACT: This scoping review will provide an emerging teaching model for formal and informal caregivers of people with dementia and help them better understand the types and the influence of virtual reality-based dementia educational programmes. REPORTING METHOD: PRISMA-ScR. NO PATIENT OR PUBLIC CONTRIBUTION: Not required as this review in accordance with the aim to map existing literature from the dementia formal and informal caregivers' perspective.

Effect of thickened water swallow training in tube-feeding and dysphagia patients in the acute and early subacute phases of stroke: A quasi-experimental study.

BACKGROUND: Thickened water has been widely used in patients with dysphagia who receive oral feeding, but there is little evidence for tube-feeding patients. OBJECTIVE: To explore the effects of thickened water swallow training in tube-feeding and dysphagia patients in the acute and early subacute phases of stroke. METHODS: A quasi-experimental study. Hospitalised patients with acute and early subacute stroke who received tube feeding due to dysphagia were recruited from March to December 2021. Patients assigned to the intervention group (n = 23) received thickened water swallow training three times daily until the feeding tube was removed or they were discharged, and patients in the control group (n = 23) received usual care. The main outcomes were duration of tube feeding and rates of weaning at discharge. RESULTS: Patients in the intervention group had a shorter tube-feeding duration (p = .046) and a higher rate of weaning at discharge (p = .017) than those in the control group. Significant interaction effects between time and group were detected regarding quality of life except for the swallowing burden dimension. CONCLUSIONS: Thickened water swallow training is feasible and effective for stroke patients with tube feeding and can shorten the duration of tube feeding and improve the rates of weaning and quality of life. Healthcare providers in nonrehabilitation units should actively conduct swallowing function intervention training to maximise the potential for acute and early subacute phase rehabilitation.

The effects of oral nutritional supplements interventions on nutritional status in patients undergoing colorectal cancer surgery: A systematic review.

BACKGROUND: The high incidence of malnutrition in patients undergoing colorectal cancer surgery can lead to unplanned weight loss, sarcopenia and reduced grip strength to the extent that it can seriously affect the prognosis of colorectal cancer patients. OBJECTIVE: This study investigated the effect of oral nutritional supplements (ONS) on the prevalence of grip strength, unplanned weight loss and sarcopenia in patients undergoing colorectal cancer surgery. METHODS: We systematically searched randomized controlled studies from CINAHL, PubMed, Embase, Cochrane and Web of Science and three Chinese databases (CNKI, Wan-Fang database, VIP database) from database creation to September 2023. The risk of bias in individual studies was assessed using the Cochrane Collaboration tool, and the certainty of evidence was assessed using the five GRADE criteria. Statistical analysis was performed using the RevMan 5.3 software, and information that could not be meta-analysed was reviewed in the form of a literature summary. RESULTS: Eleven papers met the inclusion criteria with a combined sample size of 1070 cases, including 532 cases in the trial group and 538 cases in the control group. Four papers reported the effect of ONS on grip strength and included very low-quality evidence supporting no effect of ONS on grip strength. Ten studies reported the effect of ONS on body weight and body mass index (BMI) and included very low-quality evidence supporting a positive ONS on weight and BMI changes. Meta-analysis showed a significant reduction in weight loss (12-15 weeks) and BMI loss (12-15 weeks) in patients with colorectal cancer in the ONS group. The effect of ONS on the prevalence of sarcopenia after hospital discharge was reported in two studies, and meta-analysis showed a significant reduction in the prevalence of postoperative sarcopenia in colorectal cancer patients in the ONS group, but the quality of evidence was low. CONCLUSIONS: This study showed that the use of ONS in patients undergoing surgery for colorectal cancer improved patient weight loss and BMI reduction and reduced the prevalence of postoperative sarcopenia but did not improve patient grip strength. The quality of evidence for inclusion in the article was low or very low, and further studies are needed to provide better evidence.

A fully digital workflow to design anterior guidance for an implant-supported single crown using a modified patient-specific motion technique.

Current methods for designing anterior guidance of anterior fixed prostheses are either complicated or lack accuracy. The article describes a fully digital workflow to design individualized anterior guidance of an implant-supported single crown by using a modified patient-specific motion technique. The technique aims to optimize the digital occlusal design workflow, thereby improving the occlusal fit and long-term stability of anterior fixed prostheses.

The impact of education/training on nurses caring for patients with stroke: a scoping review.

BACKGROUND: Stroke survivors have complex needs that necessitate the expertise and skill of well-trained healthcare professionals to provide effective rehabilitation and long-term support. Limited knowledge exists regarding the availability of specialized education and training programs specifically designed for nurses caring for stroke patients. AIM: This review aims to assess the content and methods of training for nurses caring for stroke patients, examine its impact on both nurses and patients, and identify key facilitators and barriers to its implementation. METHODS: We conducted a comprehensive scoping review by reviewing multiple databases, including PubMed, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Embase, Web of Science, Scopus, ProQuest Dissertations and Theses, Google Scholar, and Cochrane databases. Data extraction and narrative synthesis were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. RESULTS: Seventeen articles were included in this review. We found that education/training not only enhanced patients' self-care abilities, nursing outcomes, and satisfaction, but also had a positive impact on the knowledge, skills, and practices of nurses. The obstacles to education/training included feasibility and cost-effectiveness, while the driving factors were management support and participation, professional education/training, and controlled environment creation. CONCLUSIONS: This review highlights the crucial role of education/training in enhancing stroke care provided by nurses. Effective education/training integrates various educational methods and management support to overcome implementation barriers and optimize clinical practice benefits. These findings indicate the necessity of universal and consistent stroke education/training for nurses to further improve patient outcomes in stroke care.

Cross-cultural adaptation and validation of the Australian National University Alzheimer Disease Risk Index (ANU-ADRI) for Chinese community-dwelling residents: A cross-sectional Study.

OBJECTIVE: To cross-culturally adapt the Australian National University Alzheimer Disease Risk Index (ANU-ADRI) and verify the reliability and validity of its cognitive activity domain. METHODS: According to Beaton's guidelines, the ANU-ADRI was were translated into Chinese. The psychometric properties of ANU-ADRI its cognitive activity was conducted among community-dwelling residents (n = 442) in Changchun, Harbin and Hegang from December 2021 to July 2023. RESULTS: The Chinese version of the ANU-ADRI had good content validity and face validity. Exploratory factor analysis of cognitive activity revealed a 3-factor structure, with a cumulative variance contribution rate of 64.124 %. Confirmatory factor analysis revealed a good model fit (x2/df = 1.664, RMSEA = 0.055, RMR = 0.090, GFI = 0.942, CFI = 0.919, IFI = 0.921, TLI = 0.902, and NFI = 0.824). The internal consistency (Cronbach's α = 0.807) and test-retest reliability (ICC = 0.787) were considered satisfactory. CONCLUSION: The ANU-ADRI showed acceptable reliability and validity for assessing risk factors for Alzheimer's disease among middle-aged and elderly community-dwelling residents.

'Implicit rationing of nursing care processes'-Decision-making in ICU nurses' experiences: A qualitative study.

BACKGROUND: Implicit rationing of nursing care is defined as the withholding of necessary nursing measures for patients because of a lack of nursing resources. However, no studies have explored the experience of decision-making about implicit rationing of nursing care in an intensive care unit (ICU). AIM: To explore the process of ICU nurses' decisions and judgement based on the conceptual framework of implicit rationing of nursing care. STUDY DESIGN: A qualitative study was undertaken between June 2020 and September 2020. The data collection methods were participative observation and interview. Eighteen ICU nurses participated in interviews. A thematic analysis was performed for the data analysis. RESULTS: The following five themes emerged: assessment of the condition and nature of nursing and time taken; strategies for setting personal priorities; plan implementation under mitigation strategy; existing nursing in reality; evaluation of the implementation of implicit rationing care. Nurses choose different strategies during plan implementation. CONCLUSIONS: In the absence of explicit guidelines on rationing nursing care, nurses often rely on intuitive and situational decision-making processes for setting priorities. Given the vulnerability of ICU patients and the absence of family caregivers, nurses bear a heightened ethical responsibility to provide care. Establishing a positive nursing culture is essential. It is both reasonable and effective to organize work by accurately quantifying workload, improving staffing levels and optimizing scheduling methods. These themes align with the decision-making process outlined in the conceptual framework and offer fresh perspectives. RELEVANCE TO CLINICAL PRACTICE: Nurses have a greater responsibility to provide care in an ethical manner and to increase awareness of the importance of holistic nursing care for the patient, that is to raise awareness of the importance of care that is often missed. Nurses actively adopt strategies to reduce implicit rationing of nursing care, including teamwork, organized nursing, working overtime and ignoring quality. The findings highlight the importance of creating a positive nursing culture that encourages nurses to adopt positive strategies.

Breaking Iron Homeostasis: Iron Capturing Nanocomposites for Combating Bacterial Biofilm.

Given the scarcity of novel antibiotics, the eradication of bacterial biofilm infections poses formidable challenges. Upon bacterial infection, the host restricts Fe ions, which are crucial for bacterial growth and maintenance. Having coevolved with the host, bacteria developed adaptive pathways like the hemin-uptake system to avoid iron deficiency. Inspired by this, we propose a novel strategy, termed iron nutritional immunity therapy (INIT), utilizing Ga-CT@P nanocomposites constructed with gallium, copper-doped tetrakis (4-carboxyphenyl) porphyrin (TCPP) metal-organic framework, and polyamine-amine polymer dots, to target bacterial iron intakes and starve them. Owing to the similarity between iron/hemin and gallium/TCPP, gallium-incorporated porphyrin potentially deceives bacteria into uptaking gallium ions and concurrently extracts iron ions from the surrounding bacteria milieu through the porphyrin ring. This strategy orchestrates a "give and take" approach for Ga3+/Fe3+ exchange. Simultaneously, polymer dots can impede bacterial iron metabolism and serve as real-time fluorescent iron-sensing probes to continuously monitor dynamic iron restriction status. INIT based on Ga-CT@P nanocomposites induced long-term iron starvation, which affected iron-sulfur cluster biogenesis and carbohydrate metabolism, ultimately facilitating biofilm eradication and tissue regeneration. Therefore, this study presents an innovative antibacterial strategy from a nutritional perspective that sheds light on refractory bacterial infection treatment and its future clinical application.

An intrinsic purine metabolite AICAR blocks lung tumour growth by targeting oncoprotein mucin 1.

BACKGROUND: Lung cancer cells overexpress mucin 1 (MUC1) and active subunit MUC1-CT. Although a peptide blocks MUC1 signalling, metabolites targeting MUC1 are not well studied. AICAR is a purine biosynthesis intermediate. METHODS: Cell viability and apoptosis were measured in AICAR-treated EGFR-mutant and wild-type lung cells. AICAR-binding proteins were evaluated by in silico and thermal stability assays. Protein-protein interactions were visualised by dual-immunofluorescence staining and proximity ligation assay. AICAR-induced whole transcriptomic profile was determined by RNA sequencing. EGFR-TL transgenic mice-derived lung tissues were analysed for MUC1 expression. Organoids and tumours from patients and transgenic mice were treated with AICAR alone or in combination with JAK and EGFR inhibitors to evaluate treatment effects. RESULTS: AICAR reduced EGFR-mutant tumour cell growth by inducing DNA damage and apoptosis. MUC1 was one of the leading AICAR-binding and degrading proteins. AICAR negatively regulated JAK signalling and JAK1-MUC1-CT interaction. Activated EGFR upregulated MUC1-CT expression in EGFR-TL-induced lung tumour tissues. AICAR reduced EGFR-mutant cell line-derived tumour formation in vivo. Co-treating patient and transgenic mouse lung-tissue-derived tumour organoids with AICAR and JAK1 and EGFR inhibitors reduced their growth. CONCLUSIONS: AICAR represses the MUC1 activity in EGFR-mutant lung cancer, disrupting protein-protein interactions between MUC1-CT and JAK1 and EGFR.

Pathogen-Activated Macrophage Membrane Encapsulated CeO2 -TCPP Nanozyme with Targeted and Photo-Enhanced Antibacterial Therapy.

Nanozymes with peroxidase-mimic activity have recently emerged as effective strategies for eliminating infections. However, challenges in enhancing catalytic activities and the ability to target bacteria have hindered the broader application of nanozymes in bacterial infections. Herein, a novel nanozyme based on mesoporous CeO2 nanosphere and meso-tetra(4-carboxyphenyl)porphine (TCPP) encapsulated within pathogen-activated macrophage membranes, demonstrates photodynamic capability coupled with photo-enhanced chemodynamic therapy for selective and efficient antibacterial application against infected wounds. Interestingly, the expression of Toll-like receptors accordingly upregulates when macrophages are co-cultured with specific bacteria, thereby facilitating to recognition of the pathogen-associated molecular patterns originating from bacteria. The CeO2 not only serve as carriers for TCPP, but also exhibit intrinsic peroxidase-like catalytic activity. Consequently, Staphylococcus aureus (S. aureus)-activated macrophage membrane-coated CeO2 -TCPP (S-MM@CeO2 -TCPP) generated singlet oxygen, and simultaneously promoted photo-enhanced chemodynamic therapy, significantly boosting reactive oxygen species (ROS) to effectively eliminate bacteria. S-MM@CeO2 -TCPP specifically targeted S. aureus via Toll-like receptor, thereby directly disrupting bacterial structural integrity to eradicate S. aureus in vitro and relieve bacteria-induced inflammation to accelerate infected wound healing in vivo. By selectively targeting specific bacteria and effectively killing pathogens, such strategy provides a more efficient and reliable alternative for precise elimination of pathogens and inflammation alleviation in microorganism-infected wounds.

A Novel Z-Scheme Heterostructured Bi2 S3 /Cu-TCPP Nanocomposite with Synergistically Enhanced Therapeutics against Bacterial Biofilm Infections in Periodontitis.

Porphyrin-based antibacterial photodynamic therapy (aPDT) has found widespread applications in treating periodontitis. However, its clinical use is limited by poor energy absorption, resulting in limited reactive oxygen species (ROS) generation. To overcome this challenge, a novel Z-scheme heterostructured nanocomposite of Bi2 S3 /Cu-TCPP is developed. This nanocomposite exhibits highly efficient light absorption and effective electron-hole separation, thanks to the presence of heterostructures. The enhanced photocatalytic properties of the nanocomposite facilitate effective biofilm removal. Theoretical calculations confirm that the interface of the Bi2 S3 /Cu-TCPP nanocomposite readily adsorbs oxygen molecules and hydroxyl radicals, thereby improving ROS production rates. Additionally, the photothermal treatment (PTT) using Bi2 S3 nanoparticles promotes the release of Cu2+ ions, enhancing the chemodynamic therapy (CDT) effect and facilitating the eradication of dense biofilms. Furthermore, the released Cu2+ ions deplete glutathione in bacterial cells, weakening their antioxidant defense mechanisms. The synergistic effect of aPDT/PTT/CDT demonstrates potent antibacterial activity against periodontal pathogens, particularly in animal models of periodontitis, resulting in significant therapeutic effects, including inflammation alleviation and bone preservation. Therefore, this design of semiconductor-sensitized energy transfer represents an important advancement in improving aPDT efficacy and the treatment of periodontal inflammation.

In silico model for miRNA-mediated regulatory network in cancer.

Deregulation of gene expression is associated with the pathogenesis of numerous human diseases including cancer. Current data analyses on gene expression are mostly focused on differential gene/transcript expression in big data-driven studies. However, a poor connection to the proteome changes is a widespread problem in current data analyses. This is partly due to the complexity of gene regulatory pathways at the post-transcriptional level. In this study, we overcome these limitations and introduce a graph-based learning model, PTNet, which simulates the microRNAs (miRNAs) that regulate gene expression post-transcriptionally in silico. Our model does not require large-scale proteomics studies to measure the protein expression and can successfully predict the protein levels by considering the miRNA-mRNA interaction network, the mRNA expression, and the miRNA expression. Large-scale experiments on simulations and real cancer high-throughput datasets using PTNet validated that (i) the miRNA-mediated interaction network affects the abundance of corresponding proteins and (ii) the predicted protein expression has a higher correlation with the proteomics data (ground-truth) than the mRNA expression data. The classification performance also shows that the predicted protein expression has an improved prediction power on cancer outcomes compared to the prediction done by the mRNA expression data only or considering both mRNA and miRNA. Availability: PTNet toolbox is available at http://github.com/CompbioLabUCF/PTNet.