The Potential Role of Non-coding RNAs in Regulating Ferroptosis in Cancer: Mechanisms and Application Prospects.

Cancer is the second leading cause of death globally. Despite some successes, conventional cancer treatments are insufficient to address the growing problem of drug resistance in tumors and to achieve efficient treatment outcomes. Therefore, there is an urgent need to explore new therapeutic options. Ferroptosis, a type of iron- and reactive oxygen species-dependent regulated cell death, has been closely associated with cancer development and progression. Non-coding RNAs (ncRNAs) are a class of RNAs that do not code for proteins, and studies have demonstrated their involvement in the regulation of ferroptosis in cancer. This review aims to explore the molecular regulatory mechanisms of ncRNAs involved in ferroptosis in cancer and to emphasize the feasibility of ferroptosis and ncRNAs as novel therapeutic strategies for cancer. We conducted a systematic and extensive literature review using PubMed, Google Scholar, Web of Science, and various other sources to identify relevant studies on ferroptosis, ncRNAs, and cancer. A deeper understanding of ferroptosis and ncRNAs could facilitate the development of new cancer treatment strategies.

A multi-classifier system integrated by clinico-histology-genomic analysis for predicting recurrence of papillary renal cell carcinoma.

Integrating genomics and histology for cancer prognosis demonstrates promise. Here, we develop a multi-classifier system integrating a lncRNA-based classifier, a deep learning whole-slide-image-based classifier, and a clinicopathological classifier to accurately predict post-surgery localized (stage I-III) papillary renal cell carcinoma (pRCC) recurrence. The multi-classifier system demonstrates significantly higher predictive accuracy for recurrence-free survival (RFS) compared to the three single classifiers alone in the training set and in both validation sets (C-index 0.831-0.858 vs. 0.642-0.777, p < 0.05). The RFS in our multi-classifier-defined high-risk stage I/II and grade 1/2 groups is significantly worse than in the low-risk stage III and grade 3/4 groups (p < 0.05). Our multi-classifier system is a practical and reliable predictor for recurrence of localized pRCC after surgery that can be used with the current staging system to more accurately predict disease course and inform strategies for individualized adjuvant therapy.

Improved Patient Adherence to Family-Based Helicobacter pylori Infection Control and Management Strategy in Central China and Its Influencing Factors.

BACKGROUND: Patient adherence status to the newly introduced family-based Helicobacter pylori (H. pylori) infection control and management strategy remains unclear, so are its influencing factors. We aim to investigate family members' adherence and its influencing factors during the family-based H. pylori infection management practice for related disease prevention. MATERIALS AND METHODS: Based on our previously family-based H. pylori survey in 2021, 282 families including 772 individuals were followed up 2 years after the initial survey to compare if the investigation and education might improve family member's adherence. The participant's adherence to H. pylori infection awareness, retest, treatment, publicity, gastroscopy, and hygiene habits were followed up, and their influencing factors were also analyzed. RESULTS: The overall participant's adherence to recommendations on H. pylori awareness, retest, treatment, publicity, gastroscopy, and hygiene habits were 77% (187/243), 67.3% (138/205), 60.1% (211/351), 46.5% (107/230), 45.6% (159/349), and 39.1% (213/545), respectively; and all showed improvements compared with their prior survey stages. The top reasons for rejection to treatment, retest, and gastroscopy were forgetting or unaware of H. pylori infection (30.3%), busy (32.8%), and asymptomatic (67.9%), respectively. Independent risk factor for low adherence to treatment was occupation (e.g., staff: OR 4.49, 95% CI 1.34-15.10). Independent favorable factors for treatment adherence were individuals at the ages of 18-44 years (OR 0.19, 95% CI 0.04-0.89) and had a large family size (e.g., four family members: OR 0.15, 95% CI 0.06-0.41); for retest adherence, it was individuals at the ages of 60-69 years (OR 0.23, 95% CI 0.06-0.97); for gastroscopy adherence, it was individuals at the age of 60-69 years (OR 0.46, 95% CI 0.28-0.75), and with gastrointestinal symptoms (OR 0.57, 95% CI 0.36-0.90). CONCLUSIONS: Family-based H. pylori management increases individual adherence to treatment, retest, and awareness, and there are also improved adherence to gastroscopy, publicity, and personal hygiene recommendations; further efforts are required to enhance the individual adherence rate for related disease prevention.

The effect of miR-381 on proliferation and prognosis of breast cancer by altering CCNA2 expression.

BACKGROUND: MiR-381 can regulate the expression of cyclin A2 (CCNA2) to inhibit the proliferation and migration of bladder cancer cells, but whether miR-381 has the same function in breast cancer is not well know. METHODS: The over express or silence miR-381 expressing cell lines were constructed by lentivirus infection to reveal the biological functions of miR-381 in vitro. The expression of miR-381 and CCNA2 in 162 breast cancer patients were detected to further reveal their impact and predictive value on progression-free survival (PFS) and overall survival (OS). RESULTS: After transfection of MDA-MB-231 and MCF-7 cells with miR-381 mimics, the expression of miR-381 was effectively up-regulated and CCNA2 was effectively down-regulated, while the opposite results were observed in tumour cell which transfected with miR-381 inhibitors. After transfection of cell lines with miR-381 mimics, tumour cell activity was significantly reduced, while the opposite results were observed in tumour cell which transfected with miR-381 inhibitors. The area under curves (AUCs) of miRNA-381 and CCNA2 for predicting PFS and OS were 0.711, 0.695, 0.694 and 0.675 respectively. Cox regression analysis showed that miRNA-381 ≥ 1.65 2-ΔΔCt and CCNA ≥ 2.95 2-ΔΔCt were the influence factors of PFS and OS, the hazard ratio (HR) values were 0.553, 2.075, 0.462 and 2.089, respectively. CONCLUSION: miR-381 inhibitors breast cancer cells proliferation and migration by down-regulating the expression of CCNA2, both of them can predict the prognosis of breast cancer.

miR-381 can regulate the expression of cyclin A2 and inhibit the proliferation and migration of bladder cancer cells, but whether miR-381 has the same function in breast cancer is not well know. We analysed the levels of miR-381 and cyclin A2 in breast cancer patients and breast cancer cells to reveal the mechanism of miR-381 affecting the expression of cyclin A2. We found miRNA-381 affects the proliferation and migration of breast cancer cells by down-regulating the expression of cyclin A2. The expression of serum miR-381 and cyclin A2 have important values in predicting the prognosis of breast cancer. Our findings provide mechanistic insights into how miR-381 regulates the proliferation and migration of breast cancer, as well as a new target for clinical treatment. Future research may focus on how to improve patient prognosis by up-regulating expression of miR-381 and down-regulating the expression of cyclin A2.

Jeotgalibacillus haloalkalitolerans sp. nov., a novel alkalitolerant and halotolerant bacterium, isolated from the confluence of the Fenhe River and the Yellow River.

A Gram-stain positive, aerobic, alkalitolerant and halotolerant bacterium, designated HH7-29 T, was isolated from the confluence of the Fenhe River and the Yellow River in Shanxi Province, PR China. Growth occurred at pH 6.0-12.0 (optimum, pH 8.0-8.5) and 15-40℃ (optimum, 32℃) with 0.5-24% NaCl (optimum, 2-9%). The predominant fatty acids (> 10.0%) were iso-C15:0 and anteiso-C15:0. The major menaquinones were MK-7 and MK-8. The polar lipids were phosphatidylglycerol, diphosphatidylglycerol and two unidentified phospholipids. Phylogenetic analyses based on the 16S rRNA gene sequence revealed that strain HH7-29 T was a member of the genus Jeotgalibacillus, exhibiting high sequence similarity to the 16S rRNA gene sequences of Jeotgalibacillus alkaliphilus JC303T (98.4%), Jeotgalibacillus salarius ASL-1 T (98.1%) and Jeotgalibacillus alimentarius YKJ-13 T (98.1%). The genomic DNA G + C content was 43.0%. Gene annotation showed that strain HH7-29 T had lower protein isoelectric points (pIs) and possessed genes related to ion transport and organic osmoprotectant uptake, implying its potential tolerance to salt and alkali. The average nucleotide identity, digital DNA-DNA hybridization values, amino acid identity values, and percentage of conserved proteins values between strain HH7-29 T and its related species were 71.1-83.8%, 19.5-27.4%, 66.5-88.4% and 59.8-76.6%, respectively. Based on the analyses of phenotypic, chemotaxonomic, phylogenetic and genomic features, strain HH7-29 T represents a novel species of the genus Jeotgalibacillus, for which the name Jeotgalibacillus haloalkalitolerans sp. nov. is proposed. The type strain is HH7-29 T (= KCTC 43417 T = MCCC 1K07541T).

The metabolic reprogramming of γ-aminobutyrate in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the most common head and neck malignancy. The oncometabolites have been studied in OSCC, but the mechanism of metabolic reprogramming remains unclear. To identify the potential metabolic markers to distinguish malignant oral squamous cell carcinoma (OSCC) tissue from adjacent healthy tissue and study the mechanism of metabolic reprogramming in OSCC. We compared the metabolites between cancerous and paracancerous tissues of OSCC patients by 1HNMR analysis. We established OSCC derived cell lines and analyzed their difference of RNA expression by RNA sequencing. We investigated the metabolism of γ-aminobutyrate in OSCC derived cells by real time PCR and western blotting. Our data revealed that much more γ-aminobutyrate was produced in cancerous tissues of OSCC patients. The investigation based on OSCC derived cells showed that the increase of γ-aminobutyrate was promoted by the synthesis of glutamate beyond the mitochondria. In OSCC cancerous tissue derived cells, the glutamate was catalyzed to glutamine by glutamine synthetase (GLUL), and then the generated glutamine was metabolized to glutamate by glutaminase (GLS). Finally, the glutamate produced by glutamate-glutamine-glutamate cycle was converted to γ-aminobutyrate by glutamate decarboxylase 2 (GAD2). Our study is not only benefit for understanding the pathological mechanisms of OSCC, but also has application prospects for the diagnosis of OSCC.

Evaluating the Predictive Value of a Coagulation-Related Gene Model in Glioma.

AIM: To evaluate coagulation related gene model as a biomarker for predicting prognosis of gliomas. MATERIAL AND METHODS: The mRNA expression and clinical data of glioma were downloaded from the TCGA and CGGA databases. Coagulation-related genes were downloaded from the KEGG database. The expression model was constructed using LASSO regression. The GBM data were divided into high and low-risk expression groups based on the median risk score, and the differences in overall survival and progression-free survival between them were calculated. The prognostic model was further validated using the TCGA-LGG and CGGA glioma databases, respectively. The accuracy of the risk score was calculated by ROC analysis for 1 year and 3 years. RESULTS: Four model genes, namely the SERPINA5, PLAUR, BDKRB1, and PTGIR, were identified, and the risk score was calculated as follows: risk score= SERPINA5*0.126264111304559 + PLAUR*0.288587629696211 + BDKRB1*0.349215422945011 + PTGIR*0.17334527969703, respectively. Based on glioma data from three groups, patients were divided into high and low-risk groups according to the median risk score. The overall survival, progression-free survival, and risk scores of the high-risk score group were worse than the low-risk group. The ROC curve analysis showed that the AUC values of the coagulation-related gene model at 1 year, 3 years, and 5 years were more than 0.65, validating the reliability of the prognostic model. CONCLUSION: This study established the correlation between the coagulation-related gene model and glioma prognosis, providing deeper insight into the mechanism and treatment of glioma.

Histopathology language-image representation learning for fine-grained digital pathology cross-modal retrieval.

Large-scale digital whole slide image (WSI) datasets analysis have gained significant attention in computer-aided cancer diagnosis. Content-based histopathological image retrieval (CBHIR) is a technique that searches a large database for data samples matching input objects in both details and semantics, offering relevant diagnostic information to pathologists. However, the current methods are limited by the difficulty of gigapixels, the variable size of WSIs, and the dependence on manual annotations. In this work, we propose a novel histopathology language-image representation learning framework for fine-grained digital pathology cross-modal retrieval, which utilizes paired diagnosis reports to learn fine-grained semantics from the WSI. An anchor-based WSI encoder is built to extract hierarchical region features and a prompt-based text encoder is introduced to learn fine-grained semantics from the diagnosis reports. The proposed framework is trained with a multivariate cross-modal loss function to learn semantic information from the diagnosis report at both the instance level and region level. After training, it can perform four types of retrieval tasks based on the multi-modal database to support diagnostic requirements. We conducted experiments on an in-house dataset and a public dataset to evaluate the proposed method. Extensive experiments have demonstrated the effectiveness of the proposed method and its advantages to the present histopathology retrieval methods. The code is available at https://github.com/hudingyi/FGCR.

Therapeutic Benefits and Prognostic Value of a Model Based on 7 Immune-associated Genes in Bladder Cancer.

Objective: The emergence of immunotherapy has heralded a profound transformation in the therapeutic landscape of bladder cancer (BLAC). Immunotherapy, with its unique potential for "combination therapy", has brought about greater possibilities for treating BLCA. However, there is significant heterogeneity among bladder cancer patients, and a portion of those in advanced stages may not experience substantial benefits from chemotherapy. Immunotherapy offers a potential ray of hope for specific patient subsets. Thus, predicting the effectiveness of tumor immunotherapy and providing them with more precise treatment strategies hold paramount importance and clinical value in delivering personalized therapeutic interventions for advanced bladder cancer patients. This study is designed to establish a risk score model derived from immune-related genes that can effectively assess prognosis and immunotherapy outcomes in patients with bladder cancer. Methods: The IMvigor210 dataset served as our training set for developing the prognostic model based on immune-related genes. Robust 7-gene expression patterns were investigated from the training set. A time-dependent receiver operating characteristic (ROC) curve and Kaplan-Meier (KM)analysis were employed to determine the prognostic relevance of these gene patterns. Independent datasets collected from the Cancer Genome Atlas Program (TCGA) and Gene Expression Omnibus (GEO) databases were additionally utilized for re-determination. The association between the 7-gene signature-based risk score and immunological subtypes, tumor mutational burden (TMB), immune checkpoint expressions, and the proportion of immune cell infiltration was assessed within training and test sets. Furthermore, the training set's predictive potential for immunotherapy response was assessed using the 7-gene signature, and its validity was externally verified on three datasets (GSE176307, GSE140901, and GSE91016). By validating the 7-gene signature externally, we eneralized the findings beyond the original training set, and assessed the model's performance in diverse contexts. Consistent performance across these datasets reinforces the robustness and clinical utility of our 7-gene signature. Results: Employing the transcriptional and clinical information from the IMvigor210 for training, 348 patients were classified into two clusters with notable distinctions in prognostic stratification and immunotherapy efficacy. Seven immune-related genes Indoleamine 2,3-dioxygenase 1 (IDO1), TNF receptor superfamily member 17 (TNFRSF17), Killer Cell Lectin Like Receptor K1 (KLRK1), TNF receptor superfamily member 14 (TNFSF14), Lymphocyte-activation gene 3 (LAG3), Killer Cell Lectin Like Receptor C1 (KLRC1), and Ecto-5'-nucleotidase (NT5E) were screened based on different expression genes (DEGs) between the two clusters. The expression levels of these seven genes and the accompanying univariate component Cox regression coefficients, were computed to create a 7-gene signature-based risk score. The median value of the risk score was utilized to categorize the BLCA individuals into high-risk and low-risk groups. Researchers identified that in the low-risk group, individuals exhibited a noticeably improved chance of surviving. The external validation cohorts verified the risk score model's prognostic capacity. Furthermore, it was demonstrated that while low-risk individuals possessed higher TMB scores, higher expression of immune checkpoint genes, and lower levels of immunological infiltration, they responded more favorably to immunotherapy. The clinical relevance of the risk score model was validated in three immunotherapy groups. Conclusion: The risk score model might be utilized to forecast the prognosis and efficacy of immunotherapy in BLCA patients, offering a novel course of treatment for these individuals. For patients undergoing immunotherapy, this gene signature can help predict treatment response. Low-risk patients may benefit from more tailored monitoring and personalized immunotherapy regimens. However, more investigations are required to validate its accuracy and effectiveness in a prospective cohort with larger sample sizes.

JPT2 Affects Trophoblast Functions and Macrophage Polarization and Metabolism, and Acts as a Potential Therapeutic Target for Recurrent Spontaneous Abortion.

Recurrent spontaneous abortion (RSA) is a pregnancy-related condition with complex etiology. Trophoblast dysfunction and abnormal macrophage polarization and metabolism are associated with RSA; however, the underlying mechanisms remain unknown. Jupiter microtubule-associated homolog 2 (JPT2) is essential for calcium mobilization; however, its role in RSA remains unclear. In this study, it is found that the expression levels of JPT2, a nicotinic acid adenine dinucleotide phosphate-binding protein, are decreased in the villous tissues of patients with RSA and placental tissues of miscarried mice. Mechanistically, it is unexpectedly found that abnormal JPT2 expression regulates trophoblast function and thus involvement in RSA via c-Jun N-terminal kinase (JNK) signaling, but not via calcium mobilization. Specifically, on the one hand, JPT2 deficiency inhibits trophoblast adhesion, migration, and invasion by inhibiting the JNK/atypical chemokine receptor 3 axis. On the other hand, trophoblast JPT2 deficiency contributes to M1 macrophage polarization by promoting the accumulation of citrate and reactive oxygen species via inhibition of the JNK/interleukin-6 axis. Self-complementary adeno-associated virus 9-JPT2 treatment alleviates embryonic resorption in abortion-prone mice. In summary, this study reveals that JPT2 mediates the remodeling of the immune microenvironment at the maternal-fetal interface, suggesting its potential as a therapeutic target for RSA.

Unraveling the efficacy network: A network meta-analysis of adjuvant external beam radiation therapy methods after hepatectomy.

BACKGROUND: Primary liver cancer is a malignant tumor with a high recurrence rate that significantly affects patient prognosis. Postoperative adjuvant external radiation therapy (RT) has been shown to effectively prevent recurrence after liver cancer resection. However, there are multiple RT techniques available, and the differential effects of these techniques in preventing postoperative liver cancer recurrence require further investigation. AIM: To assess the advantages and disadvantages of various adjuvant external RT methods after liver resection based on overall survival (OS) and disease-free survival (DFS) and to determine the optimal strategy. METHODS: This study involved network meta-analyses and followed the PRISMA guidelines. The data of qualified studies published before July 10, 2023, were collected from PubMed, Embase, the Web of Science, and the Cochrane Library. We included relevant studies on postoperative external beam RT after liver resection that had OS and DFS as the primary endpoints. The magnitudes of the effects were determined using risk ratios with 95% confidential intervals. The results were analyzed using R software and STATA software. RESULTS: A total of 12 studies, including 1265 patients with hepatocellular carcinoma (HCC) after liver resection, were included in this study. There was no significant heterogeneity in the direct paired comparisons, and there were no significant differences in the inclusion or exclusion criteria, intervention measures, or outcome indicators, meeting the assumptions of heterogeneity and transitivity. OS analysis revealed that patients who underwent stereotactic body radiotherapy (SBRT) after resection had longer OS than those who underwent intensity modulated radiotherapy (IMRT) or 3-dimensional conformal RT (3D-CRT). DFS analysis revealed that patients who underwent 3D-CRT after resection had the longest DFS. Patients who underwent IMRT after resection had longer OS than those who underwent 3D-CRT and longer DFS than those who underwent SBRT. CONCLUSION: HCC patients who undergo liver cancer resection must consider distinct advantages and disadvantages when choosing between SBRT and 3D-CRT. IMRT, a RT technique that is associated with longer OS than 3D-CRT and longer DFS than SBRT, may be a preferred option.

Association between loneliness and mental health among nurses: a cross-sectional research in China

This study explored the association between loneliness and mental health among nurses in China during the COVID-19 pandemic. This cross-sectional study was conducted from March to April 2022. We enrolled 2,811 nurses from a tertiary hospital in China. Demographic characteristics, lifestyle factors, work-related factors, and psychological characteristics were collected from participants via a self-reported questionnaire. Loneliness was measured with the three-item short form of the Revised UCLA Loneliness Scale, and the Patient Health Questionnaire (PHQ-9) and the General Anxiety Disorder (GAD-7) scale were used to measure mental health. Adjusted odds ratios (ORs) and 95% confidence intervals (CI) were determined using binary logistic regression. Among participants in this study, 12.0% (337) experienced loneliness, and 7.8% (219) and 6.7% (189) reported depression and anxiety, respectively. The loneliness scores were categorized into three levels (3, 4-6, and 7-9). For depression, compared with the lowest reference, the ORs and 95% CI across the tertile were 1.31 (0.69-1.84) and 2.53 (1.11-5.76) after adjustment, respectively, and the P-value for trend was 0.045. For anxiety, compared with the lowest reference, the ORs and 95%CI across the tertile were 1.84 (1.28-2.63) and 2.52 (1.57-4.10) after adjustment, respectively; the P-value for trend was 0.004. This study showed that loneliness was significantly associated with poor mental health among nurses during the COVID-19 pandemic. These findings suggested that medical establishments should offer interventions for nurses to prevent mental health problems by targeting this modifiable risk factor.

Plasmon-Stimulated Colorimetry Biosensor Array for the Identification of Multiple Metabolites.

Rationally designing highly catalytic and stable nanozymes for metabolite monitoring is of great importance because of their huge potential in early disease diagnosis. Herein, a novel nanozyme based on hierarchically structured CuS/ZnS with a highly efficient peroxidase (POD)-mimic capability was developed and synthesized for multiple metabolite determination and recognition via the plasmon-stimulated biosensor array strategy. The designed nanozyme can simultaneously harvest plasmon triggered hot electron-hole pairs and generate photothermal properties, leading to a sharply boosted POD-mimic capability under 808 nm laser irradiation. Interestingly, because of the interaction diversity of the metabolite with POD-like nanomaterials, the unique inhibitory effect of metabolites on the POD-mimic activity could be the signal response as the differentiation. Thus, utilizing TMB as a typical chromogenic substrate in the addition of H2O2, the designed colorimetric biosensor array can produce diverse fingerprints for the three vital metabolisms (cysteine (Cys), ascorbic acid (AA), and glutathione (GSH)), which can be precisely identified by principal component analysis (PCA). Notably, a distinct fingerprint of a single metabolite with different levels and metabolite mixtures is also achieved with a detection limit of 1 µM. Most importantly, cell lysis could be effectively discriminated by the biosensor assay, implying its great potential in clinical diagnosis.

Mutational signature and prognosis in adenocarcinoma of the bladder.

Adenocarcinoma of the bladder is a rare urinary bladder carcinoma with limited therapy options due to lack of molecular characterization. Here, we aimed to reveal the mutational and transcriptomic landscapes of adenocarcinoma of the bladder and assess any relationship with prognosis. Between February 2015 and June 2021, a total of 23 patients with adenocarcinoma of the bladder were enrolled. These included 16 patients with primary bladder adenocarcinomas and seven patients with urachal adenocarcinoma. Whole exome sequencing (16 patients), whole genome sequencing (16 patients), bulk RNA sequencing (RNA-seq) (19 patients), and single-cell RNA-seq (5 patients) were conducted for the specimens. Correlation analysis, survival analysis, and t-tests were also performed. Prevalent T>A substitutions were observed among somatic mutations, and major trinucleotide contexts included 5'-CTC-3' and 5'-CTG-3'. This pattern was mainly contributed by COSMIC signature 22 related to chemical carcinogen exposure (probably aristolochic acid), which has not been reported in bladder adenocarcinoma. Moreover, genes with copy number changes were also enriched in the KEGG term 'chemical carcinogenesis'. Transcriptomic analysis suggested high immune cell infiltration and luminal-like features in the majority of samples. Interestingly, a small fraction of samples with an APOBEC-derived mutational signature exhibited a higher risk of disease progression compared with samples with only a chemical carcinogen-related signature, confirming the molecular and prognostic heterogeneity of bladder adenocarcinoma. This study presents mutational and transcriptomic landscapes of bladder adenocarcinoma, and indicates that a chemical carcinogen-related mutational signature may be related to a better prognosis compared with an APOBEC signature in adenocarcinoma of the bladder. © 2024 The Pathological Society of Great Britain and Ireland.

NCAM mimetic peptide P2 synergizes with bone marrow mesenchymal stem cells in promoting functional recovery after stroke.

The neural cell adhesion molecule (NCAM) promotes neural development and regeneration. Whether NCAM mimetic peptides could synergize with bone marrow mesenchymal stem cells (BMSCs) in stroke treatment deserves investigation. We found that the NCAM mimetic peptide P2 promoted BMSC proliferation, migration, and neurotrophic factor expression, protected neurons from oxygen-glucose deprivation through ERK and PI3K/AKT activation and anti-apoptotic mechanisms in vitro. Following middle cerebral artery occlusion (MCAO) in rats, P2 alone or in combination with BMSCs inhibited neuronal apoptosis and induced the phosphorylation of ERK and AKT. P2 combined with BMSCs enhanced neurotrophic factor expression and BMSC proliferation in the ischemic boundary zone. Moreover, combined P2 and BMSC therapy induced translocation of nuclear factor erythroid 2-related factor, upregulated heme oxygenase-1 expression, reduced infarct volume, and increased functional recovery as compared to monotreatments. Treatment with LY294002 (PI3K inhibitor) and PD98059 (ERK inhibitor) decreased the neuroprotective effects of combined P2 and BMSC therapy in MCAO rats. Collectively, P2 is neuroprotective while P2 and BMSCs work synergistically to improve functional outcomes after ischemic stroke, which may be attributed to mechanisms involving enhanced BMSC proliferation and neurotrophic factor release, anti-apoptosis, and PI3K/AKT and ERK pathways activation.

The effects of health education and exercise style changes on the maturation of autologous arteriovenous fistula in hemodialysis patients: A randomized controlled trial.

BACKGROUND: Upper limb exercise has long been considered to be the main means to promote autogenous arteriovenous fistula (AVF) maturation, but in practice exercise intensity and compliance are both typically lacking. Several randomized controlled trials (RCTs) have demonstrated the good effects of functional resistance or pressure exercise in patients with AVF. However, many patients' have difficulty complying with upper limb exercise programs without systematic health education. Therefore, we argue that resistance and pressure exercise supported by health education is actually the most beneficial for AVF patients. METHODS: We randomly divided 114 patients into a control group and an experimental group of 57 patients each. In the control group, conventional care was used, and in the experimental group, online health education based on the IMB (Information-Motivation-Behavior skills) model and functional resistance and pressure upper limb exercises was implemented with the AVF side arm. The failure rate of AVF maturation, clinical maturation time, cephalic venous blood flow, vessel diameter, and vessel skin thickness were compared between the two groups. RESULTS: Fifty-five cases were included for each in the final study. The primary outcome of this study was the failure rate of AVF maturation. Secondary outcomes included clinical maturation time, cephalic vein flow, vessel diameter, and vessel thickness. The failure rate of AVF maturation in the experimental group was significantly lower than that in the control group, and the clinical maturation time in the experimental group was significantly shorter than that in the control group. For the remaining three indicators, there were between-group effects, time effects, and interaction effects in both groups. Comparison between groups showed that there was no statistical difference in the observed indicators of cephalic vein flow, vessel diameter, or vessel thickness between the two groups before the intervention but that there was a statistical difference at the end of the 4th, 8th, and 12th weeks of the intervention. A 2 × 2 comparison also showed that there was a statistical difference between the three indicators at each time point within the two groups. CONCLUSION: IMB model-based online health education combined with functional resistance and pressure exercises can improve AVF maturation status and accelerate AVF maturation within 12 weeks of surgery.

FKBP5 regulates trophoblast-macrophage crosstalk in recurrent spontaneous abortion through PI3K/AKT and NF-κB signaling pathways.

FK506-binding protein 5 (FKBP5) contributes to many diseases; However, it remains unclear whether FKBP5 is relevant to recurrent spontaneous abortion (RSA) and the mechanisms by which it is involved in maternal-fetal immunological tolerance. Placental tissue was collected in women with normal pregnancy and RSA and examined for FKBP5 expression. Human trophoblast cell lines and THP-1-derived M0 macrophages were used to explore the role of FKBP5 in RSA and its mechanism. The role of FKBP5 on pregnancy outcomes was assessed using a mouse model of miscarriage. This study found that upregulation of FKBP5 at the placental interface is involved in the pathogenesis of RSA by depressing trophoblast function and promoting M1-type macrophage polarization. First, FKBP5 expression was upregulated in the villi of RSA, and FKBP5 regulated trophoblast function by inhibiting HAPLN1 expression through suppression of PI3K/AKT signaling. In addition, FKBP5 inhibited trophoblast IL-6 secretion by suppressing PI3K/AKT signaling, thereby promoting macrophage polarization toward the M1 phenotype. Meanwhile, FKBP5 was significantly elevated in decidual macrophages from patients with RSA and promoted M1 macrophage polarization via ROS/NF-κB signaling and further inhibited trophoblast function. Finally, FKBP5 inhibitors improved embryo resorption rate in miscarried mice. In conclusion, FKBP5 is essential in maintaining pregnancy and trophoblast-macrophage crosstalk in the maternal-fetal interface, which may be a potential target for diagnosing and treating RSA.

Novel potential urinary biomarkers for effective diagnosis and prognostic evaluation of high-grade bladder cancer.

Background: High-grade bladder cancer (HGBC) has a higher malignant potential, recurrence and progression rate compared to low-grade phenotype. Its early symptoms are often vague, making non-invasive diagnosis using urinary biomarkers a promising approach. Methods: The gene expression data from urine samples of patients with HGBC was extracted from the GSE68020 dataset. The clinical information and gene expression data in tumor tissues of HGBC patients were obtained from The Cancer Genome Atlas (TCGA) database. Multivariate Cox analysis was used to predict the optimal risk model. The protein-protein interaction (PPI) analysis was performed via the Search Tool for the Retrieval of Interacting Genes (STRING) database and visualized using Cytoscape. Overall survival (OS) was evaluated in the Gene Expression Profiling Interactive Analysis (GEPIA) online platform. Competing endogenous RNA (ceRNA) network was also visualized using Cytoscape. The expression levels of specific genes were assessed through quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Moreover, co-expressed genes and potential biological functions related to specific genes were explored based on the Cancer Cell Line Encyclopedia (CCLE) database. Results: A total of 560 differentially expressed genes (DEGs) were identified when comparing the urine sediment samples from HGBC patients with the benign ones. Using these urinary DEGs and the clinical information of HGBC patients, we developed an optimal risk model consisting of eight genes to predict the patient outcome. By integrating the node degree values in the PPI network with the expression changes in both urine and tissue samples, eighteen hub genes were selected out. Among them, DKC1 and SNRPG had the most prominent comprehensive values, and EFTUD2, LOR and EBNA1BP2 were relevant to a worse OS in bladder cancer patients. The ceRNA network of hub genes indicated that DKC1 may be directly regulated by miR-150 in HGBC. The upregulation of both SNRPG and DKC1 were detected in HGBC cells, which were also observed in various tumor tissues and malignant cell lines, displaying high correlations with other hub genes. Conclusions: Our study may provide theoretical basis for the development of effective non-invasive detection and treatment strategies, and further research is necessary to explore the clinical applications of these findings.

Dynamic changes in three biomarkers predict early-stage hepatocellular carcinoma in patients with chronic hepatitis B receiving antiviral therapy.

PURPOSE: Patients with chronic hepatitis B (CHB) remain at risk for hepatocellular carcinoma during antiviral therapy. We aimed to clarify the values of alpha-fetoprotein (AFP), lectin-reactive fraction of AFP (AFP-L3), and des-γ-carboxyprothrombin (DCP) for early warning of HCC. METHODS: A total of 1348 CHB patients received antiviral therapy and follow-up every 26 weeks. Eighty-four patients with HCC were age-, sex-, and cirrhosis-matched with 168 controls. AFP, AFP-L3, and DCP were compared between the groups from 104 weeks before HCC diagnosis (- 104 w) to the time of diagnosis (0 w). RESULTS: Of the 84 HCC patients, 60 (71.4%) had early-stage HCC, AFP increased from - 26 w, and AFP-L3 and DCP increased from - 78 w. However, levels were unchanged in controls. ΔAFP, ΔAFP-L3, and ΔDCP showed similar abilities for predicting HCC (P > 0.05). Receiver operating characteristic curve analysis showed that AFP had better diagnostic performance for HCC than AFP-L3, DCP, or their combination. The cut-off values of AFP, AFP-L3, and DCP were 5.3 ng/mL, 1.05%, and 31.5 mAU/mL, respectively. Notably, lower AFP values were required to diagnose HCC in patients with detectable HBV DNA (4.1 ng/mL) or elevated alanine aminotransferase (5.2 ng/mL). CONCLUSIONS: Changes in AFP, AFP-L3, and DCP can help to predict HCC in CHB patients receiving antiviral therapy. A lower AFP value is needed to diagnose HCC, especially in patients with detectable HBV DNA or elevated alanine aminotransferase.

Nomogram incorporating potent inflammatory indicators for overall survival estimation of patients with primary oral squamous cell carcinoma.

Background: Inflammation has been recognized to be a factor that substantially influences tumorigenesis and tumor prognosis. Hence, this study was aimed to investigate an inflammatory marker with the most potent prognostic ability and to evaluate the survival estimation capability of dynamic change in this marker for patients suffered from oral squamous cell carcinoma (OSCC). Methods: 469 patients' inflammatory indicators including lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic inflammatory response index (SIRI), were calculated. Their predictive abilities for overall survival (OS) were evaluated by Kaplan-Meier curves to screen for the one with the most potent prognostic value. The predictive ability of dynamic changes in this marker was verified and a predictive nomogram incorporating inflammatory indicators was developed. Results: A high LMR was identified to be an indicator of a satisfactory survival rate. Compared with that of other inflammatory markers, area under the receiver operating characteristics (ROC) curve (AUC) of LMR for 1-year and 3-year OS was significantly larger (P<0.001). Dynamic LMR change remained an significant parameter for predicting OS (OR: 2.492, 95% CI: 1.246-4.981, p = 0.010). The nomogram incorporating LMR exhibited a superior prognostic significance than the TNM system, as suggested by the C-index (0.776 vs 0.651 in primary cohort; 0.800 vs 0.707 in validation cohort, P<0.001) and AUC. Conclusions: LMR was demonstrated to possess a more potent survival estimation capability than the other three inflammatory parameters. Dynamic changes in LMR serves as a significant parameter for overall survival estimation of primary OSCC patients. The established nomogram incorporating inflammatory markers showed more accuracy and sensitivity for survival estimation of primary OSCC patients.