PRRSV non-structural protein 5 inhibits antiviral innate immunity by degrading multiple proteins of RLR signaling pathway through FAM134B-mediated ER-phagy.

Viruses employ various evasion strategies to establish prolonged infection, with evasion of innate immunity being particularly crucial. Porcine reproductive and respiratory syndrome virus (PRRSV) is a significant pathogen in swine industry, characterized by reproductive failures in sows and respiratory distress in pigs of all ages, leading to substantial economic losses globally. In this study, we found that the non-structural protein 5 (Nsp5) of PRRSV antagonizes innate immune responses via inhibiting the expression of type I interferon (IFN-I) and IFN-stimulated genes (ISGs), which is achieved by degrading multiple proteins of RIG-I-like receptor (RLR) signaling pathway (RIG-I, MDA5, MAVS, TBK1, IRF3, and IRF7). Furthermore, we showed that PRRSV Nsp5 is located in endoplasmic reticulum (ER), where it promotes accumulation of RLR signaling pathway proteins. Further data demonstrated that Nsp5 activates reticulophagy (ER-phagy), which is responsible for the degradation of RLR signaling pathway proteins and IFN-I production. Mechanistically, Nsp5 interacts with one of the ER-phagy receptor family with sequence similarity 134 member B (FAM134B), promoting the oligomerization of FAM134B. These findings elucidate a novel mechanism by which PRRSV utilizes FAM134B-mediated ER-phagy to elude host antiviral immunity.IMPORTANCEInnate immunity is the first line of host defense against viral infections. Therefore, viruses developed numerous mechanisms to evade the host innate immune responses for their own benefit. PRRSV, one of the most important endemic swine viruses, poses a significant threat to the swine industry worldwide. Here, we demonstrate for the first time that PRRSV utilizes its non-structural protein Nsp5 to degrade multiple proteins of RLR signaling pathways, which play important roles in IFN-I production. Moreover, FAM134B-mediated ER-phagy was further proved to be responsible for the protein's degradation. Our study highlights the critical role of ER-phagy in immune evasion of PRRSV to favor replication and provides new insights into the prevention and control of PRRSV.

The immune function of TLR4-1 gene in Octopus sinensis revealed by RNAi and RNA-seq.

Toll-like receptors (TLRs) are a class of conserved pattern recognition receptors (PRRs) that are crucial for initiating the innate immune response and aiding in the clearance of pathogenic organisms. Many studies have identified TLR4 as a distinctive member of the TLR family, capable of activating both the Myeloid differentiation factor 88-dependent signaling pathway (MyD88-dependent) and the TIR-domain-containing adaptor inducing IFN-ß dependent signaling pathway (TRIF-dependent). Nevertheless, the role of TLR4 in Cephalopoda is still largely unexplored. To elucidate the immune function of the OsTLR4-1 gene in Octopus sinensis, the OsTLR4-1 gene was first validated and analyzed in this study. The cDNA comprises a 2475 bp ORF region, encoding 824 amino acids. Evolutionary tree analysis indicated a high homology and a close phylogenetic relationship between the Octopus sinensis and other mollusks. RNA interference (RNAi) experiments demonstrated that the expression level of OsTLR4-1 gene and its protein in the lymphocytes of the RNAi group treated with OsTLR4-1 dsRNA was extremely significantly lower than that of the blank control group and negative control group (P < 0.01), and the expression of downstream genes of OsTLR4-1, including ligand MyD88, IRAK4, TRAF6, MKK6, Hsp90, COX2, TRAF3, and RIP1, were significantly down-regulated compared to the blank and negative control group (P < 0.01). Additionally, OsTLR4-1 expression in lymphocytes was highly significantly up-regulated in the LPS-treated group compared to the blank control group (P < 0.01), while its expression was extremely significantly lower in the LPS-treated group after OsTLR4-1 interference than in the blank control group (P < 0.01). The expression of its downstream effector genes Big Defensin (Big-Def) and histone H2A.V (H2A.V) was highly significantly up-regulated in lymphocytes in the LPS-treated group compared to the blank control group (P < 0.01), while their expression in the LPS-treated group after OsTLR4-1 interference was extremely significantly lower than that in the blank control group (P < 0.01). Through comparative transcriptome analysis of the RNAi group and the blank control group, it was found that differentially expressed genes were enriched in the Toll-like receptor signaling pathway, PI3K-AKT signaling pathway, P53 signaling pathway, MAPK signaling pathway, and NF-κB signaling pathway. qRT-PCR results of key genes in these pathways revealed a decrease in all genes except IκB and Jun2 genes. This study enhances our understanding of the immune function of the TLR gene family in O. sinensis and provides a foundation for further research into innate immune signaling pathways in cephalopods.

Intraoperative radiotherapy: An alternative to whole-breast external beam radiotherapy in the management of highly selective breast cancer: A SEER database analysis.

OBJECTIVE: This study aimed to verify if intraoperative radiotherapy (IORT) can achieve the same survival outcome as whole-breast external beam radiotherapy (EBRT) in early breast cancer after breast-conserving surgery (BCS), and to explore the suitable candidates that can safely receive IORT after BCS. METHODS: Eligible post-BCS patients who received IORT or EBRT were included in the Surveillance, Epidemiology and End Results (SEER) database from 2010 to 2018. Risk factors that affected 5-year overall survival (OS) or breast cancer specific survival (BCSS) were identified by Cox proportional hazards regression analysis. Clinical characteristics, OS, and BCSS were comparatively analyzed between the two treatment modalities. RESULTS: The survival analysis after propensity score matching confirmed that patients who received IORT (n = 2200) had a better 5-year OS than those who received EBRT (n = 2200) (p = 0.015). However, the two groups did not differ significantly in 5-year BCSS (p = 0.381). This feature persisted even after multivariate analyses that took into account numerous clinical characteristics. Although there was no significant difference in BCSS between different subgroups of patients treated with IORT or EBRT, patients over 55 years of age, with T1, N0, non-triple negative breast cancers, hormone receptor-positive, and histologic grade II showed a better OS after receiving IORT. CONCLUSION: In low-risk, early-stage breast cancer, IORT was not inferior to EBRT considering 5-year BCSS and OS. Considering the equivalent clinical outcome but less radiotoxicity, IORT might be a reasonable alternative to EBRT in highly selective patients undergoing BCS.

Research trends and hotspots for frontotemporal dementia from 2000 to 2022: a bibliometric analysis.

Background: Frontotemporal dementia (FTD) is a neurodegenerative disease with clinical, pathological, and genetic heterogeneity. FTD is receiving increasing attention because it is the second leading cause of early-onset dementia after Alzheimer's disease. This study aimed to analyse the research trends and hotspots of FTD from 2000 to 2022 using bibliometrics. Methods: Papers related to FTD from 2000 to 2020 were systematically searched through the Web of Science Core Collection (WOSCC). Citespace and Vosviewer software were used to visually analyse the retrieved data of countries/regions, institutions, journals, authors, references, and keywords. Microsoft Excel was used to generate the annual publications and growth trends. Results: There were 10,227 papers included in the bibliometric analysis. The annual publication output on FTD has increased significantly from 2000 to 2022, with papers published in 934 academic journals and 87 countries/regions. The Journal of Alzheimer's Disease was the most popular, with 488 papers about FTD. The most productive countries/regions, institutions, and authors are the United States (n = 4,037), the University of California San Francisco (n = 687), and Miller, Bruce L. (n = 427), respectively. The article by Katya Rascovsky and her colleagues published on Brain in 2011 was the most cocited paper, with 625 citations. The research hotspots in this field were the clinical diagnostic criteria, subdivision, and pathological mechanism of FTD, such as tau protein, chromosome 17, progranulin, TDP-43, and C9orf72. Conclusion: The future research direction is based on biomarkers and pathological mechanisms to diagnose and differential diagnose FTD from the aspects of behavior, neuropathology, neuroimaging, and serum markers.

Serum Cystatin C levels increase with increasing visceral fat area in patients with type 2 diabetes mellitus.

The present study aimed to explore the association between serum cystatin C (Cys-C) levels and visceral fat area (VFA) in patients with type 2 diabetes mellitus (T2DM). A total of 208 previously diagnosed T2DM patients who visited our hospital from September 2019 to December 2021 were included and divided into three groups based on tertiles of Cys-C levels, namely, Groups C1, C2, and C3. The clinical data of the subjects were collected, biochemical parameters such as Cys-C levels were determined, and bioelectrical impedance analysis was applied to determine the VFA and subcutaneous fat area (SFA). The VFA in Group C1 was lower than that in Groups C2 and C3 (all P < 0.05), with no significant difference in VFA between Groups C2 and C3 (P > 0.05). Spearman's correlation analysis revealed that the serum Cys-C level was positively correlated with age, VFA, SFA, insulin resistance index, waist circumference, body mass index, systolic blood pressure, serum creatinine level, and blood uric acid level (r = 0.543, 0.353, 0.168, 0.148, 0.365, 0.264, 0.25, 0.497, and 0.155, respectively; P < 0.05) and negatively correlated with glycated haemoglobin levels (r = -0.175, P < 0.05). Univariate linear regression analysis revealed that VFA was positively correlated with the Cys-C level (ß = 0.002, 95% CI = 0.001-0.003, P < 0.05), with an increase of 0.002 mg/L in the Cys-C level for each 1 cm2 increase in VFA. Further multivariate linear regression analysis was performed with the serum Cys-C level as the dependent variable and age, VFA, SFA, insulin resistance (HOMA-IR), WC, BMI, SBP, Cr, UA, and HbA1c as the independent variables. The results suggested that VFA was positively correlated with serum Cys-C level (ß = 0.001, 95% CI = 0.000-0.002, P < 0.05), with serum Cys-C levels increasing by 0.001 mg/L for every 1 cm2 increase in VFA. Using a VFA ≥ 100 cm2 as the criterion for visceral obesity, ROC analysis revealed that the Cys-C level was a better predictor of visceral obesity, with an area under the ROC curve (AUC) of 0.701 (95% CI = 0.631-0.771, P < 0.05), an optimal cut-off of 0.905 mg/L, and a sensitivity and specificity of 58.3% and 75.2%, respectively. The results suggested that the serum Cys-C level was correlated with the VFA in patients with T2DM and that Cys-C may play a vital role in T2DM patients with visceral obesity.

Coping with family function changes: A qualitative study of couples facing advanced lung cancer.

Objective: This study aimed to explore the experiences of couples with advanced lung cancer in coping with changes in their family functioning. Methods: This study included patients with advanced lung disease and their spouses who were hospitalized in a tertiary hospital in Shanghai, China. Data were collected through interviews that focused on three key areas: (1) patient coping, (2) spousal coping, and (3) dyadic coping. Semi-structured qualitative interviews were conducted in Chinese and analyzed using Braun-Clarke thematic analysis. Results: A total of 15 couples participated in the study (12 male and 3 female patients). The average age of the patients was 63.73 years, and that of their partners was 63.20 years. Marriage duration ranged from 25 to 53 years. Three distinct themes emerged from the data: individual patient coping was expressed in four areas: struggle, acceptance of reality, cherishing the present and regaining hope, and rebuilding family life; spousal coping was expressed in three areas: acceptance and understanding of the patient, providing active support, and adjusting roles and sharing of family responsibilities; and dyadic coping was expressed in three areas: cognitive consistency of changes in family functioning, stress communication, and family adjustment and adaptation based on shared cognition. A relationship diagram of patients with advanced lung cancer and their spouses in coping with post-cancer changes in family functioning was constructed. Conclusions: Post-cancer coping with changes in family functioning in couples with advanced lung cancer is a continuous developmental and gradual evolutionary process, and there is a close relationship between the two that influences each other. Early assistance for couples to form consistent cognition and communicate effectively with the stress caused by the disease can help improve the family functioning of both partners and, in turn, improve the quality of life of patients. Therefore, it is recommended that clinicians conduct family- or couple-centered intervention studies aimed at improving the post-cancer quality of life of patients with advanced lung cancer.

Efficacy and safety of Tianqi Pingchan Granule, a compound Chinese herbal medicine, for levodopa-induced dyskinesia in Parkinson's disease: A randomized double-blind placebo-controlled trial.

BACKGROUND: Patients with Parkinson's disease (PD) undergoing long-term levodopa therapy are prone to develop levodopa-induced dyskinesia (LID). Amantadine is the main drug recommended for the treatment of LID by current guidelines, but it is far from meeting clinical needs. Tianqi Pingchan Granule (TPG), a compound Chinese herbal medicine, has been developed to relieve symptom of LID. OBJECTIVE: This randomized controlled trial evaluated the efficacy and safety of the combination of TPG and amantadine for LID. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This is a randomized double-blind placebo-controlled trial, conducted from January 2020 to August 2021 at 6 sites in Jiangsu, Zhejiang and Shanghai, China. One hundred PD patients with ≥ 0.5 h of LID were randomly assigned to either the TPG plus amantadine group (TPG group) or the placebo plus amantadine group (placebo group), and treated for a period of 12 weeks. To ensure unbiased results, all study participants, investigators and sponsors were unaware of group allocations. Additionally, the data analysts remained blinded until the analysis was finalized. MAIN OUTCOME MEASURES: The primary outcome was assessed using the Unified Dyskinesia Rating Scale (UDysRS) (Range 0-104). The key secondary end point was improvement of motor and non-motor symptoms. Safety analyses included all enrolled patients. RESULTS: One hundred patients were enrolled and randomized into the two treatment groups. The changes in UDysRS at week 12 were -11.02 for the TPG group and -4.19 for the placebo group (treatment difference -6.83 [-10.53 to -3.12]; P = 0.0004). Adverse events were reported for 2 of 50 patients (4.0%) in each of the groups. CONCLUSION: This study indicated that a 12-week treatment of amantadine plus TPG effectively reduced UDysRS scores and was well tolerated, demonstrating the efficacy and safety of TPG for the treatment of LID in PD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04173832. PLEASE CITE THIS ARTICLE AS: Zhang Y, Zhu XB, Zhao Y, Cui GY, Li WT, Yuan CX, Huang JP, Wan Y, Wu N, Song L, Zhao JH, Liang Y, Xu CY, Liu MJ, Gao C, Chen XX, Liu ZG. Efficacy and safety of Tianqi Pingchan Granule, a compound Chinese herbal medicine, for levodopa-induced dyskinesia in Parkinson's disease: A randomized double-blind placebo-controlled trial. J Integr Med. 2024; Epub ahead of print.

Early changes of microRNAs in blood one month after bariatric surgery.

BACKGROUND: Changes in microRNAs (miRNAs) are relevant to bariatric surgery and its comorbidities. The characteristics of changes in miRNAs of the early postoperative period following both bariatric procedures, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), as well as the factors that related to the effectiveness of early weight loss remain unclear. METHODS: We recruited 18 patients who performed SG and 15 patients who performed RYGB. Their preoperative and 1-month postoperative clinical data and fasting serum samples were collected, and the latter were analyzed by RNA-sequencing. Differential expression analysis of miRNAs was performed by the R-tool. Functional classification annotation and pathway enrichment analysis of targeted genes were analyzed by KOBAS software. The change profiles of miRNAs for both surgeries and their correlation with clinical characteristics and weight loss effectiveness were further analyzed. RESULTS: A total of 85 differentially expressed miRNAs were identified before and after SG, while a total of 76 were found before and after RYGB. The target genes of these miRNAs were similar in the Gene Ontology enrichment analysis in SG and RYGB, and the enrichment analysis in the Kyoto Encyclopedia of Genes and Genomes was mainly related to metabolic pathways. Hsa-miR-493-5p, hsa-miR-184, and hsa-miR-3199 exhibited similar changes in SG and RYGB, and the former two were correlated with clinical characteristics. Hsa-miR-6729-5p, hsa-miR-4659b-5p, and hsa-miR-2277-5p were correlated with the weight loss effectiveness of SG, while hsa-miR-4662a-5p was correlated with the weight loss effectiveness of RYGB. CONCLUSIONS: Short-term metabolic improvement and weight loss occurring after SG and RYGB surgery might be related to changes in miRNAs, which act on multiple biological pathways by regulating genes. In addition, some clinical characteristics and miRNAs were related to the effectiveness of early weight loss after SG and RYGB surgery. CLINICAL TRIAL REGISTRATION: ChiCTR2200058333.

Lipid Metabolism in Pregnancy Women with Hypothyroidism and Potential Influence on Pregnancy Outcome.

Thyroid hormone (TH) is essential for maintaining normal physiological processes during pregnancy, including the metabolism of energy materials in both the mother and fetus and the growth and development of fetal bone and nervous system. TH can act on the liver, fat, and other tissues and organs to participate in lipid synthesis and breakdown through multiple pathways. Consequently, abnormal thyroid function is often accompanied by lipid metabolism disorders. Both clinical and subclinical hypothyroidism, as well as dyslipidemia during pregnancy, have been shown to be associated with an increased risk of multiple adverse pregnancy outcomes. Recently, there has been an increased interest in studying the alteration of lipidomic and hypothyroidism (both clinical and subclinical hypothyroidism) during pregnancy. Studies have suggested that altered lipid molecules might be used as potential biomarker and associated with adverse maternal and neonatal outcome. Thus, we summarized the associations between lipid metabolism and clinical or subclinical hypothyroidism during pregnancy in this review. Then, we discussed the underlying mechanisms of thyroid dysfunction and lipid metabolism. In addition, we reviewed the possible effect of dyslipidemia on pregnancy and neonatal outcome. However, the relationship between hypothyroidism during pregnancy and changes in the lipid profile and how to intervene in the occurrence and development of adverse pregnancy outcomes require further study.

Postoperative EEG abnormalities in relation to neurodevelopmental outcomes after pediatric cardiac surgery.

BACKGROUND: We had reported that postoperative EEG background including sleep-wake cycle (SWC) and discharge (seizures, spikes/sharp waves) abnormalities were significantly correlated with adverse early outcomes in children after cardiac surgery. We aimed to analyze the relations between these EEG abnormalities and neurodevelopmental outcomes at about 2 years after cardiac surgery. METHODS: We enrolled 121 patients undergoing cardiac surgery at 3.3 months (0.03 ~ 28 months). EEG abnormalities described above during the first postoperative 48 h were evaluated. Griffiths Mental Development Scales-Chinese was used to evaluate the quotients of overall development and 5 subscales of the child's locomotor, language, personal-social, eye-hand coordination and performance skills at 16 ~ 31 months of age. RESULTS: EEG background abnormalities occurred in 59/121 (48.8%) patients and 33 (55.9%) unrecovered to normal by 48 h. Abnormal SWC occurred in 15 (12.4%) patients and 7 (5.8%) unrecovered to normal by 48 h. EEG seizures occurred in 11 (9.1%) patients with frontal lobe seizures in 4. Spikes/sharp waves occurred in 100 (82.6%). EEG background abnormalities, number of spikes/sharp waves and frontal lobe seizures were significantly associated with neurodevelopmental impairment at about 1 ~ 2 year after surgery (Ps ≤ 0.05). CONCLUSIONS: Most parameters of EEG abnormalities were significantly associated with neurodevelopmental impairment after cardiac surgery. IMPACT: Neurodevelopmental impairment in children with congenital heart disease remain poorly understood. Previous studies had reported that either EEG seizures or background abnormalities were associated with worse neurodevelopmental outcomes. Our present study showed that all the EEG background and discharge abnormalities including EEG background, seizures and spikes/sharp waves in the early postoperative period were significantly associated with neurodevelopmental impairment at about 1 ~ 2 years after cardiac surgery. Comprehensive evaluation of early postoperative EEG may provide further insights about postoperative brain injury, its relation with neurodevelopmental impairment, and guide to improve clinical management.

Effects of low-dose methotrexate with MMI in patients with Graves' disease: results of a randomized clinical trial.

CONTEXT: Supplemental methotrexate (MTX) may affect the clinical course of Graves' disease (GD). OBJECTIVE: Evaluate efficacy of add-on MTX on medical treatment in GD. DESIGN: Prospective, open-label, randomized supplementation controlled trial. SETTING: Academic endocrine outpatient clinic. PATIENTS: One hundred and fifty-three untreated hyperthyroid patients with GD. INTERVENTION: Patients received MTX 10 mg/d with methimazole (MMI) or MMI only. MTX and MMI were discontinued at months 12-18 in euthyroid patients. MAIN OUTCOME MEASURES: Discontinuation rate at months 18 in each group. RESULTS: In the MTX with MMI group, the discontinuation rate was higher than the MMI group at months 15-18 (50.0 vs. 33.3%, P=0.043, 95% CI 1.020 to 3.922; and 55.6 vs 38.9%, P=0.045, 95%CI 1.011 to 3.815, respectively). The decrease in TRAb levels in the MTX with MMI group was significant from baseline to months 6 compared to the MMI alone group [MTX+MMI 67.22% (43.12-80.32), MMI 54.85% (33.18-73.76), P= 0.039) and became more significant from months 9 [MTX+MMI 77.79% (62.27-88.18), MMI 69.55% (50.50-83.22), P= 0.035] to months 18 (P < 0.01 in 15-18 months). A statistically significant difference between the levels of TRAb in the MTX with MMI group and the MMI group at 9-18 months. There were no significant differences in the levels of FT3, FT4 and TSH between two groups. No serious drug-related adverse events were observed in both groups(P=0.771). CONCLUSIONS: Supplemental MTX with MMI resulted in higher discontinuation rate and improvement in decreased TRAb levels to homeostatic levels faster than methimazole treatment alone at months 12-18.

Proteomic analysis reveals the antiviral effects of baicalin on pseudorabies virus.

Pseudorabies virus (PRV) poses a significant threat to livestock and even humans. Baicalin, a bioactive flavonoid glycoside with medicinal potential, has been reported to have various biological activities. However, its inhibitory effect on PRV remains poorly understood. In this study, we proved that baicalin effectively inhibits PRV infection. Proteomic analysis revealed that baicalin reduces the expression of 14 viral proteins, which are associated with virus replication, release and immune evasion. Furthermore, the abundance of 116 host proteins was altered by PRV infection, but restored to normal levels after treatment with baicalin. Pathway analysis indicated that baicalin mitigates reactive oxygen species (ROS) and suppresses abnormal mitochondrion by reducing the expression of NFU1 iron­sulfur cluster scaffold homolog (NFU1) protein induced by PRV. Notably, baicalin also activates the complete coagulation cascade by increasing the expression of coagulation factor III (F3) protein and enhances nucleoplasm by upregulating the expression of solute carrier family 3 member 2 (SLC3A2) and CCAAT enhancer binding protein beta (CEBPB) proteins, contributing to its inhibitory effects on PRV. Our findings implied that baicalin has the potential to be developed as an anti-PRV drug and provide insights into the underlying molecular basis.

Application-based big data development framework for health sciences libraries.

The study is a part of a student research project on performance-based evaluation of big data application in health sciences libraries. It presents a theoretical framework of the performance-based evaluation system for health institutes' libraries in the digital environment. The health sciences libraries' systematic approach was judged based on the five main components (data culture, organisational infrastructure, responsibilities, skills and technology competence) of big data analytics (BDA). A comprehensive literature review of the published studies was undertaken related to BDA, including the diffusion of innovation theory, and the theoretical background of the technology acceptance model to produce an application-based big data development framework for the health sciences libraries. The application-based evaluation model integrates BDA in health sciences libraries for improving library services and performance. The study proposed a need for skilled professionals with the knowledge and experience both professionally and technically. Finally, the study proposed a model that will help to measure the organisation's ability to analyse vast amounts of data to empirically validate the association concerning big data analysis and analytical practices in health libraries.

Association between lower neutrophil-to-albumin ratio and early neurological improvement in patients with acute cerebral infarction after intravenous thrombolysis.

Elevated neutrophil counts and decreased albumin levels have been linked to an unfavorable prognosis in acute cerebral infarction (ACI). The objective of this study is to explore the correlation between the neutrophil-to-albumin ratio (NAR) and the early neurological improvement (ENI) of ACI patients following intravenous thrombolysis (IVT). ACI patients who underwent IVT between June 2019 and June 2023 were enrolled. The severity of ACI was assessed using the National Institutes of Health Stroke Scale (NIHSS). ENI was defined as a reduction in NIHSS score of ≥ 4 or complete resolution of neurological deficit within 24 h after IVT. Propensity score match (PSM) and logistic regression analysis were used to explore the correlation between these variables and the early neurological outcomes of patients. A total of 545 ACI patients were included, with 253 (46.4 %) experiencing ENI. Among the 193 pairs of patients after PSM, there was a significant association between NAR and ENI (OR, 0.89; 95 % CI, 0.85-0.94; p < 0.001). The restricted cubic splines analysis revealed a significant nonlinear correlation between NAR and ENI (p for nonlinear = 0.0004; p for overall = 0.0002). The optimal cutoff for predicting ENI was determined as a NAR level of 10.20, with sensitivity and specificity values of 73.6 % and 60.9 %. NAR levels are associated with ENI in ACI patients after IVT. The decreased levels of NAR indicate an increased likelihood of post-thrombolysis ENI in ACI patients.

Discharge preparation experiences and needs of intergenerational caregivers of neonatal intensive care unit preterm: A qualitative study.

PURPOSE: This study aimed to explore the real experiences and needs of neonatal intensive care unit (NICU) preterm intergenerational caregivers for discharge preparation and provide a basis for nursing staff to formulate systemic and personalized health education plans and continuous nursing plans for preterm discharge. DESIGN AND METHODS: This was a descriptive qualitative study. An objective sampling method was used to select 16 intergenerational caregivers of preterm infants admitted to the NICU of tertiary obstetrics and gynecology hospitals in Zhejiang and Jilin provinces from December 2023 to February 2024. Semi-structured interviews were conducted on the day of discharge of the preterm infants and six weeks after discharge. Colaizzi's seven-step analysis method was used to analyze the interview data. RESULTS: Based on the existence, relatedness, and growth (ERG) theory, the discharge preparation experiences and needs of neonatal intergenerational caregivers in the NICU were summarized into three themes: psychological condition, care capacity condition, and multi-party support needs. CONCLUSIONS: In the process of hospital discharge preparation, intergenerational caregivers of premature infants in NICU have multiple needs, including enhancing nursing ability and obtaining psychological and multi-party support. It is helpful to take effective interventions to improve their readiness for discharge. PRACTICE IMPLICATIONS: The nursing staff should develop personalized discharge health education plans and continuous nursing plans to improve the level of discharge preparation. PATIENT OR PUBLIC CONTRIBUTIONS: There were no patient or public contributions.

SPDYC serves as a prognostic biomarker related to lipid metabolism and the immune microenvironment in breast cancer.

Breast cancer remains the most common malignant carcinoma among women globally and is resistant to several therapeutic agents. There is a need for novel targets to improve the prognosis of patients with breast cancer. Bioinformatics analyses were conducted to explore potentially relevant prognostic genes in breast cancer using The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) databases. Gene subtypes were categorized by machine learning algorithms. The machine learning-related breast cancer (MLBC) score was evaluated through principal component analysis (PCA) of clinical patients' pathological statuses and subtypes. Immune cell infiltration was analyzed using the xCell and CIBERSORT algorithms. Kyoto Encyclopedia of Genes and Genomes enrichment analysis elucidated regulatory pathways related to speedy/RINGO cell cycle regulator family member C (SPDYC) in breast cancer. The biological functions and lipid metabolic status of breast cancer cell lines were validated via quantitative real-time polymerase chain reaction (RT‒qPCR) assays, western blotting, CCK-8 assays, PI‒Annexin V fluorescence staining, transwell assays, wound healing assays, and Oil Red O staining. Key differentially expressed genes (DEGs) in breast cancer from the TCGA and GEO databases were screened and utilized to establish the MLBC score. Moreover, the MLBC score we established was negatively correlated with poor prognosis in breast cancer patients. Furthermore, the impacts of SPDYC on the tumor immune microenvironment and lipid metabolism in breast cancer were revealed and validated. SPDYC is closely related to activated dendritic cells and macrophages and is simultaneously correlated with the immune checkpoints CD47, cytotoxic T lymphocyte antigen-4 (CTLA-4), and poliovirus receptor (PVR). SPDYC strongly correlated with C-C motif chemokine ligand 7 (CCL7), a chemokine that influences breast cancer patient prognosis. A significant relationship was discovered between key genes involved in lipid metabolism and SPDYC, such as ELOVL fatty acid elongase 2 (ELOVL2), malic enzyme 1 (ME1), and squalene epoxidase (SQLE). Potent inhibitors targeting SPDYC in breast cancer were also discovered, including JNK inhibitor VIII, AICAR, and JW-7-52-1. Downregulation of SPDYC expression in vitro decreased proliferation, increased the apoptotic rate, decreased migration, and reduced lipid droplets. SPDYC possibly influences the tumor immune microenvironment and regulates lipid metabolism in breast cancer. Hence, this study identified SPDYC as a pivotal biomarker for developing therapeutic strategies for breast cancer.

PCK1-mediated glycogenolysis facilitates ROS clearance and chemotherapy resistance in cervical cancer stem cells.

Cervical cancer, one of the most common gynecological cancers, is primarily caused by human papillomavirus (HPV) infection. The development of resistance to chemotherapy is a significant hurdle in treatment. In this study, we investigated the mechanisms underlying chemoresistance in cervical cancer by focusing on the roles of glycogen metabolism and the pentose phosphate pathway (PPP). We employed the cervical cancer cell lines HCC94 and CaSki by manipulating the expression of key enzymes PCK1, PYGL, and GYS1, which are involved in glycogen metabolism, through siRNA transfection. Our analysis included measuring glycogen levels, intermediates of PPP, NADPH/NADP+ ratio, and the ability of cells to clear reactive oxygen species (ROS) using biochemical assays and liquid chromatography-mass spectrometry (LC-MS). Furthermore, we assessed chemoresistance by evaluating cell viability and tumor growth in NSG mice. Our findings revealed that in drug-resistant tumor stem cells, the enzyme PCK1 enhances the phosphorylation of PYGL, leading to increased glycogen breakdown. This process shifts glucose metabolism towards PPP, generating NADPH. This, in turn, facilitates ROS clearance, promotes cell survival, and contributes to the development of chemoresistance. These insights suggest that targeting aberrant glycogen metabolism or PPP could be a promising strategy for overcoming chemoresistance in cervical cancer. Understanding these molecular mechanisms opens new avenues for the development of more effective treatments for this challenging malignancy.

Acute kidney injury in cancer patients receiving anti-vascular endothelial growth factor monoclonal antibody vs. immune checkpoint inhibitors: a retrospective real-world study.

BACKGROUND: Anti-vascular endothelial growth factor monoclonal antibody (anti-VEGF) or immune checkpoint inhibitors (ICIs) combined with chemotherapy are commonly administered to cancer patients. Although cancer patients receiving anti-VEGF or ICIs have been reported to experience an increased risk of acute kidney injury (AKI), comparative studies on the AKI incidence have not been evaluated. METHODS: Cancer patients receiving anti-VEGF or ICIs were retrospectively selected from the hospital information system of the First Affiliated Hospital of Wenzhou Medical University between Jan, 2020 and Dec, 2022 and were divided into two groups according to the treatment regimen: anti-VEGF group and ICIs group. The baseline characteristics were propensity-score matched. The primary outcome was sustained AKI. A comparison of cumulative incidence of sustained AKI was performed by Kaplan-Meier curves and log-rank test. Risks for outcomes were assessed using Cox proportional regression. RESULTS: A total of 1581 cancer patients receiving anti-VEGF (n = 696) or ICIs (n = 885) were included in the primary analysis. The ICIs group had a higher cumulative incidence of sustained AKI within one year than the anti-VEGF group (26.8% vs. 17.8%, P < 0.001). Among 1392 propensity score matched patients, ICIs therapy (n = 696) was associated with an increased risk of sustained AKI events in the entire population (HR 2.0; 95%CI 1.3 to 2.5; P = 0.001) and especially in those with genitourinary cancer (HR 4.2; 95%CI 1.3 to 13.2; P = 0.015). Baseline serum albumin level (> 35 g/l) was an important risk factor for a lower incidence of sustained AKI in the anti-VEGF group (HR 0.5; 95%CI 0.3 to 0.9; P = 0.027) and the ICIs group (HR 0.3; 95%CI 0.2 to 0.5; P < 0.001). CONCLUSIONS: Among cancer patients in this real-world study, treatment with ICIs increased incidence of sustained AKI in one year. Baseline serum albumin level was an important risk factor for sustained AKI. The risk factors for sustained AKI differed between the anti-VEGF group and the ICIs group. TRIAL REGISTRATION: The study has been registered at ClinicalTrials.gov (NCT06119347) on 11/06/2023.

Strategies to Regulate the Degradation and Clearance of Mesoporous Silica Nanoparticles: A Review.

Mesoporous silica nanoparticles (MSNs) have attracted extensive attention as drug delivery systems because of their unique meso-structural features (high specific surface area, large pore volume, and tunable pore structure), easily modified surface, high drug-loading capacity, and sustained-release profiles. However, the enduring and non-specific enrichment of MSNs in healthy tissues may lead to toxicity due to their slow degradability and hinder their clinical application. The emergence of degradable MSNs provided a solution to this problem. The understanding of strategies to regulate degradation and clearance of these MSNs for promoting clinical trials and expanding their biological applications is essential. Here, a diverse variety of degradable MSNs regarding considerations of physiochemical properties and doping strategies of degradation, the biodistribution of MSNs in vivo, internal clearance mechanism, and adjusting physical parameters of clearance are highlighted. Finally, an overview of these degradable and clearable MSNs strategies for biosafety is provided along with an outlook of the encountered challenges.