The mechanisms, hallmarks, and therapies for brain aging and age-related dementia.

Age-related cognitive decline and dementia are significant manifestations of brain aging. As the elderly population grows rapidly, the health and socio-economic impacts of cognitive dysfunction have become increasingly significant. Although clinical treatment of dementia has faced considerable challenges over the past few decades, with limited breakthroughs in slowing its progression, there has been substantial progress in understanding the molecular mechanisms and hallmarks of age-related dementia (ARD). This progress brings new hope for the intervention and treatment of this disease. In this review, we categorize the latest findings in ARD biomarkers into four stages based on disease progression: healthy brain, pre-clinical, mild cognitive impairment, and dementia. We then systematically summarize the most promising therapeutic approaches to prevent or slow ARD at four levels: genome and epigenome, organelle, cell, and organ and organism. We emphasize the importance of early prevention and detection, along with the implementation of combined treatments as multimodal intervention strategies, to address brain aging and ARD in the future.

Reversal of tamoxifen resistance by artemisinin in ER+ breast cancer: bioinformatics analysis and experimental validation.

Breast cancer is the leading cause of cancer-related deaths in women worldwide, with Hormone Receptor (HR)+ being the predominant subtype. Tamoxifen (TAM) serves as the primary treatment for HR+ breast cancer. However, drug resistance often leads to recurrence, underscoring the need to develop new therapies to enhance patient quality of life and reduce recurrence rates. Artemisinin (ART) has demonstrated efficacy in inhibiting the growth of drug-resistant cells, positioning art as a viable option for counteracting endocrine resistance. This study explored the interaction between artemisinin and tamoxifen through a combined approach of bioinformatics analysis and experimental validation. Five characterized genes (ar, cdkn1a, erbb2, esr1, hsp90aa1) and seven drug-disease crossover genes (cyp2e1, rorc, mapk10, glp1r, egfr, pgr, mgll) were identified using WGCNA crossover analysis. Subsequent functional enrichment analyses were conducted. Our findings confirm a significant correlation between key cluster gene expression and immune cell infiltration in tamoxifen-resistant and -sensitized patients. scRNA-seq analysis revealed high expression of key cluster genes in epithelial cells, suggesting artemisinin's specific impact on tumor cells in estrogen receptor (ER)-positive BC tissues. Molecular target docking and in vitro experiments with artemisinin on LCC9 cells demonstrated a reversal effect in reducing migratory and drug resistance of drug-resistant cells by modulating relevant drug resistance genes. These results indicate that artemisinin could potentially reverse tamoxifen resistance in ER-positive breast cancer.

An exosome-derived lncRNA signature identified by machine learning associated with prognosis and biomarkers for immunotherapy in ovarian cancer.

Background: Ovarian cancer (OC) has the highest mortality rate among gynecological malignancies. Current treatment options are limited and ineffective, prompting the discovery of reliable biomarkers. Exosome lncRNAs, carrying genetic information, are promising new markers. Previous studies only focused on exosome-related genes and employed the Lasso algorithm to construct prediction models, which are not robust. Methods: 420 OC patients from the TCGA datasets were divided into training and validation datasets. The GSE102037 dataset was used for external validation. LncRNAs associated with exosome-related genes were selected using Pearson analysis. Univariate COX regression analysis was used to filter prognosis-related lncRNAs. The overlapping lncRNAs were identified as candidate lncRNAs for machine learning. Based on 10 machine learning algorithms and 117 algorithm combinations, the optimal predictor combinations were selected according to the C index. The exosome-related LncRNA Signature (ERLS) model was constructed using multivariate COX regression. Based on the median risk score of the training datasets, the patients were divided into high- and low-risk groups. Kaplan-Meier survival analysis, the time-dependent ROC, immune cell infiltration, immunotherapy response, and immune checkpoints were analyzed. Results: 64 lncRNAs were subjected to a machine-learning process. Based on the stepCox (forward) combined Ridge algorithm, 20 lncRNA were selected to construct the ERLS model. Kaplan-Meier survival analysis showed that the high-risk group had a lower survival rate. The area under the curve (AUC) in predicting OS at 1, 3, and 5 years were 0.758, 0.816, and 0.827 in the entire TCGA cohort. xCell and ssGSEA analysis showed that the low-risk group had higher immune cell infiltration, which may contribute to the activation of cytolytic activity, inflammation promotion, and T-cell co-stimulation pathways. The low-risk group had higher expression levels of PDL1, CTLA4, and higher TMB. The ERLS model can predict response to anti-PD1 and anti-CTLA4 therapy. Patients with low expression of PDL1 or high expression of CTLA4 and low ERLS exhibited significantly better survival prospects, whereas patients with high ERLS and low levels of PDL1 or CTLA4 exhibited the poorest outcomes. Conclusion: Our study constructed an ERLS model that can predict prognostic risk and immunotherapy response, optimizing clinical management for OC patients.

CRP, IL-1α, IL-1ß, and IL-6 levels and the risk of breast cancer: a two-sample Mendelian randomization study.

Epidemiological studies have reported a positive association between chronic inflammation and cancer risk. However, the causal association between chronic inflammation and breast cancer (BC) risk remains unclear. Here, we performed a Mendelian randomization study to investigate the etiological role of chronic inflammation in BC risk. We acquired data regarding C-reactive protein (CRP), interleukin (IL)-1a, IL-1b, and IL-6 expression and BC related to single nucleotide polymorphisms (SNPs) from two larger consortia (the genome-wide association studies and the Breast Cancer Association Consortium). Next, we conducted the two-sample Mendelian randomization study to investigate the relationship of the abovementioned inflammatory factors with the incidence of BC. We found that genetically predicted CRP, IL-6, and IL-1a levels did not increase BC incidence (odds ratio (OR)CRP 1.06, 95% confidence interval (CI) 0.98-1.12, P = 0.2059, ORIL-6 1.05, 95% CI 0.95-1.16, P = 0.3297 and ORIL-1a 1.01, 95% CI 0.99-1.03, P = 0.2167). However, in subgroup analysis, genetically predicted IL-1b levels increased ER + BC incidence (OR 1.15, 95% CI 1.03-1.27, P = 0.0088). Our study suggested that genetically predicted IL-1b levels were found to increase ER + BC susceptibility. However, due to the support of only one SNP, heterogeneity and pleiotropy tests cannot be performed, which deserves further research.

Bile ductal mucosal dysplasia is a possible risk factor for adenocarcinoma in patients with adenomyomatous hyperplasia of the Vaterian system: a single-centre study from China.

BACKGROUND: The relationship between adenomyomatous hyperplasia of the Vaterian system(AV) and cancer is unclear, some reports suggest that AV is often combined with mucosal glandular dysplasia, but it is not clear whether mucosal glandular dysplasia is a risk factor for carcinogenesis of AV. The aim of this study was to retrospective analysis of role of ductal glandular dysplasia as a risk factor in the development of carcinoma in AV. METHODS: A total of 328 cases who underwent surgery with a final pathological diagnosis of adenomyomatous hyperplasia (AH) in the Chinese PLA General Hospital in BeiJing, China, between January 2005 and December 2021 were retrospectively collected. There were Seventeen cases(5%) in which the lesions were located in the common bile duct as well as the ampulla of Vater, and their clinical (age, sex, etc.), imaging (cholelithiasis, etc.) and pathological data (mucosal glandular dysplasia, etc.) were collected. Clinical data and pathological features of AV with or without mucosal glandular dysplasia were analyzed. RESULTS: There were 17 out of 328 cases of AH occurring in the Vaterian system (5%). Three of seventeen AV cases were associated with carcinoma (18%). Of three cases, two (12%) with the tumor lesions in the mucosal glands adjacent to the AH (biliary tract cancer and ampullary cancer), and one (6%) with carcinoma developed from AH itself in the ampulla of Vater. All carcinomas had adenomyomatous hyperplasia with nearby mucosal glandular dysplasia (MGD). The percentage of BTC or AC was higher in patients with concurrent AH and MGD compared to AH patients without MGD. The results show tendency toward statistical significance (P = 0.082). This difference was more obvious among AH with severe dysplasia compared to adenomyomatous hyperplasia with mild-moderate dysplasia (P = 0.018). CONCLUSION: This study is the first to find that AV is associated with biliary tract cancer and ampullary cancer. In AV, the mucosal glandular dysplasia may be a risk factor for the development of malignancy. The underlying mechanism for carcinogenesis of AV could be AH itself or its secretions stimulating mucosal glands hyperplasia, then mucosal glands dysplasia. AV may be a precancerous lesion.

CMTM6 promotes hepatocellular carcinoma progression through stabilizing ß-catenin.

CMTM6, a regulator of PD-L1 stability, has been implicated in the development of various cancers. However, the expression and role of CMTM6 in hepatocellular carcinoma (HCC) remains controversial. Our study revealed a negative correlation between CMTM6 expression and HCC prognosis through bioinformatics analysis and immunofluorescence staining. CMTM6 expression was also positively associated with alpha-fetoprotein (AFP) levels, supporting its potential as a prognostic marker for HCC. Using Cmtm6 knockout mice, we found that Cmtm6 deficiency inhibited HCC formation and cell proliferation in primary liver cancer models induced by DEN and DEN/CCl4. In HCC cell lines, CMTM6 promoted cell proliferation and interacted with ß-catenin, stabilizing it by preventing ubiquitination. In conclusion, our study suggested that CMTM6 upregulation promotes HCC cell proliferation through the ß-catenin pathway, making it a potential therapeutic target for HCC treatment.

Increased detection rates of advanced colorectal adenoma in women with metabolic dysfunction-associated fatty liver disease.

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new concept with its own diagnostic criteria. There are few studies on its relationship with colorectal adenoma. Objective: This study aimed to explore the relationship between MAFLD and colorectal adenoma and to compare the predictive value of MAFLD with other risk factors. Methods: A total of 4436 consecutive physical examination subjects were enrolled. They all underwent colonoscopy and abdominal ultrasound. MAFLD was diagnosed by both fatty liver disease and metabolic dysfunction. The correlation between colorectal adenoma and MAFLD was studied using a logistic regression model. Results: The prevalence of MAFLD was 31.72 % (1407/4436). The adenoma detection rate in MAFLD patients was higher than that in controls (13.50 %, 190/1407 vs. 10.70 %, 324/3029, p < 0.001). Univariate analysis indicated that MAFLD individuals were 1.303-fold as likely to have colonic adenoma as controls [odds ratio (OR) 1.303 and 95 % confidence interval (CI), 1.076-1.578, p = 0.007]. Multivariate analysis showed that age, male sex, BMI and smoking were positively associated with the risk of colorectal adenoma, with OR values of 1.044 (95 % CI, 1.031 to 1.058), 1.720 (95 % CI, 1.221 to 2.424), 1.046 (95 % CI, 1.009 to 1.085) and 1.342 (95 % CI, 1.072 to 1.680), respectively. MAFLD in women, but not in men, had an independent relationship with increased detection of advanced adenoma (OR 3.932, 95 % CI, 1.023-15.1117, p = 0.046). Conclusion: Individuals with MAFLD are more likely to develop colorectal adenoma than those without MAFLD. The influence of MAFLD on advanced colorectal adenoma was especially prominent in females.

Effects of object working memory load on visual search in basketball players: an eye movement study.

BACKGROUND: Working memory may affect the athletes' visual search ability. OBJECTIVE: This study aimed to examine the differences in the performance of visual search tasks among basketball players of varying sport levels, considering the influence of different object working memory loads. METHOD: This study recruited forty-two participants who were divided into three groups based on the classification of elite athletes: competitive elite, semi-elite, and novice. RESULTS: Objective working memory load significantly impacts the accuracy of visual search, reaction time, and gaze fixation in basketball players. In the visual search task of the basketball sports scene, the inclusion of object working memory load led to a significant decrease in the accuracy of visual search, a significant increase in reaction time, a significant increase in the number of fixation points, and a more complex gaze trajectory. In a visual search task with object working memory load, the difference in reaction time between basketball players of different sport levels was observed during the search initiation time and scanning time, with higher sport levels associated with shorter reaction times. The effect of object working memory load on the eye movement phase of visual search varied among basketball players of different sport levels. For the novice group, the effect was on the reaction time during the verification phase, while for the semi-elite and competitive elite groups, the effect was on the reaction time during the scanning phase. CONCLUSION: The effect of object working memory load on visual search varied among basketball players of different sport levels.

RNF115/BCA2 deficiency alleviated acute liver injury in mice by promoting autophagy and inhibiting inflammatory response.

The E3 ubiquitin ligase RING finger protein 115 (RNF115), also known as breast cancer-associated gene 2 (BCA2), has been linked with the growth of some cancers and immune regulation, which is negatively correlated with prognosis. Here, it is demonstrated that the RNF115 deletion can protect mice from acute liver injury (ALI) induced by the treatment of lipopolysaccharide (LPS)/D-galactosamine (D-GalN), as evidenced by decreased levels of alanine aminotransaminase, aspartate transaminase, inflammatory cytokines (e.g., tumor necrosis factor α and interleukin-6), chemokines (e.g., MCP1/CCL2) and inflammatory cell (e.g., monocytes and neutrophils) infiltration. Moreover, it was found that the autophagy activity in Rnf115-/- livers was increased, which resulted in the removal of damaged mitochondria and hepatocyte apoptosis. However, the administration of adeno-associated virus Rnf115 or autophagy inhibitor 3-MA impaired autophagy and aggravated liver injury in Rnf115-/- mice with ALI. Further experiments proved that RNF115 interacts with LC3B, downregulates LC3B protein levels and cell autophagy. Additionally, Rnf115 deletion inhibited M1 type macrophage activation via NF-κB and Jnk signaling pathways. Elimination of macrophages narrowed the difference in liver damage between Rnf115+/+ and Rnf115-/- mice, indicating that macrophages were linked in the ALI induced by LPS/D-GalN. Collectively, for the first time, we have proved that Rnf115 inactivation ameliorated LPS/D-GalN-induced ALI in mice by promoting autophagy and attenuating inflammatory responses. This study provides new evidence for the involvement of autophagy mechanisms in the protection against acute liver injury.

Integrated analysis of single-cell RNA-seq and bulk RNA-seq unravels the heterogeneity of cancer-associated fibroblasts in TNBC.

BACKGROUND: The treatment of triple-negative breast cancer (TNBC) is one of the main focuses and key difficulties because of its heterogeneity, and the source of this heterogeneity is unclear. METHODS: Single-cell RNA (scRNA) and transcriptomics data of TNBC and normal breast samples were retrieved from Gene Expression Omnibus (GEO) database and TCGA-BRCA database. These cells were clustered using the t-SNE and UMAP method, and the marker genes for each cluster were found. We annotated the clusters using the published literature, CellMarker database and "SingleR" R package. RESULTS: A total of 1535 cells and 21785 genes from 6 TNBC patients and 2068 cells and 15868 genes from 3 normal breast tissues were used for downstream analyses. The scRNA data were divided into 14 clusters labeled into 8 cell types, including epithelial cells, immunocytes, CAFs/fibroblasts and etc. In the TNBC samples, CAFs were divided into three clusters and labelled as prCAFs, myCAFs and emCAFs, and the marker genes were DCN, FAP and RGS5, respectively. The prCAF subgroup is functionally characterized by promoting proliferation and multi drug resistance; myCAF subgroup is involved in constituting the extracellular matrix and collagen production, matrix composition and collagen production, and the emCAF functionally characterized by energy metabolism. CONCLUSIONS: TNBC has inter- and intra-tumor heterogeneity, and CAF is one of the sources of this heterogeneity. CD74, SASH3, CD2, TAGAP and CCR7 served as significant marker genes with prognostic and therapeutic value.

Severe mental illness and the risk of breast cancer: A two-sample, two-step multivariable Mendelian randomization study.

BACKGROUND: Based on epidemiological reports, severe mental illness (SMI) and breast cancer (BC) risk are linked positively. However, it is susceptible to clinical confounding factors, such as smoking, alcohol consumption, etc. Here, we performed a two-sample, two-step multivariable Mendelian randomization (MR) research to explore how the SMI etiologically influences BC risk and to quantify mediating effects of known modifiable risk factors. METHODS: Data concerning the single nucleotide polymorphism (SNP)-associated with schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), and BC were obtained from two large consortia: the Breast Cancer Association Consortium (BCAC) and the Psychiatric Genomics Consortium (PGC). Then, the correlations of the previous SMI with the BC prevalence and the potential impact of mediators were explored through the two-sample and two-step MR analyses. RESULTS: In two-sample MR, schizophrenia increased BC incidence (odds ratio (OR) 1.06, 95% confidence interval (CI) 1.02-1.10, P = 0.001). In subgroup analysis, schizophrenia increased ER+ BC (OR 1.06, 95% CI 1.03-1.10, P = 0.0009) and ER-BC (OR 1.06, 95% CI 1.01-1.11, P = 0.0123) incidences. Neither MDD nor BD elevated the BC risk. In two-step MR, smoking explained 11.29% of the schizophrenia-all BC risk association. CONCLUSIONS: Our study indicates that schizophrenia increases susceptibility to breast cancer, with smoking playing a certain mediating role. Therefore, BC screening and smoking should be incorporated into the health management of individuals with schizophrenia.

Effect of ERCC1 polymorphisms on the response to platinum-based chemotherapy: A systematic review and meta-analysis based on Asian population.

BACKGROUND: Platinum-based chemotherapy is one of the most common treatments for many cancers; however, the effect of chemotherapy varies from individual to individual. Excision repair cross complementation group 1 (ERCC1) is widely recognized as a key gene regulating nucleotide excision repair (NER) and is closely associated with platinum response. Many studies have yielded conflicting results regarding whether ERCC1 polymorphisms can affect the response to platinum and overall survival (OS). Therefore, it is necessary to perform a meta-analysis of patients with specific races and cancer types. METHODS: Eight databases (EMBASE, PubMed, Cochrane Library, Chinese National Knowledge Infrastructure, Scopus, VIP, China Biology Medicine disc and Wanfang databases) were searched. Results were expressed in terms of odds ratios (ORs), hazard ratios (HRs) and 95% CIs. RESULTS: In this study, rs11615, rs2298881 and rs3212986 SNPs were studied. In the comparison between CT and TT on the response to platinum, esophageal cancer [I2 = 0%, OR = 6.18, 95% CI(1.89,20.23), P = 0.003] and ovarian cancer [I2 = 0%, OR = 4.94, 95% CI(2.21,11.04), P<0.001] showed that the rs11615 CT genotype predicted a better response. In the comparison between CC and TT, ovarian cancer [I2 = 48.0%, OR = 6.15, 95% CI (2.56,14.29), P<0.001] indicated that the CC genotype predicted a better response. In the meta-analysis of OS, the CC genotype was related to longer OS than TT in ovarian cancer [TT vs CC: I2 = 57.7%, HR = 1.71, 95% CI (1.18, 2.49), P<0.001]. CONCLUSION: The ERCC1 rs11615 polymorphism was related to the response to platinum and OS, but the correlation is based on specific cancer types in the Asian population.

Macrophages Phenotype Regulated by IL-6 Are Associated with the Prognosis of Platinum-Resistant Serous Ovarian Cancer: Integrated Analysis of Clinical Trial and Omics.

Background: The treatment of platinum-resistant recurrent ovarian cancer (PROC) is a clinical challenge and a hot topic. Tumor microenvironment (TME) as a key factor promoting ovarian cancer progression. Macrophage is a component of TME, and it has been reported that macrophage phenotype is related to the development of PROC. However, the mechanism underlying macrophage polarization and whether macrophage phenotype can be used as a prognostic indicator of PROC remains unclear. Methods: We used ESTIMATE to calculate the number of immune and stromal components in high-grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas database. The differential expression genes (DEGs) were analyzed via protein-protein interaction network, Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) analysis to reveal major pathways of DEGs. CD80 was selected for survival analysis. IL-6 was selected for gene set enrichment analysis (GSEA). A subsequent cohort study was performed to confirm the correlation of IL-6 expression with macrophage phenotype in peripheral blood and to explore the clinical utility of macrophage phenotype for the prognosis of PROC patients. Results: A total of 993 intersecting genes were identified as candidates for further survival analysis. Further analysis revealed that CD80 expression was positively correlated with the survival of HGSOC patients. The results of GO and KEGG analysis suggested that macrophage polarization could be regulated via chemokine pathway and cytokine-cytokine receptor interaction. GSEA showed that the genes were mainly enriched in IL-6-STAT-3. Correlation analysis for the proportion of tumor infiltration macrophages revealed that M2 was correlated with IL-6. The results of a cohort study demonstrated that the regulation of macrophage phenotype by IL-6 is bidirectional. The high M1% was a protective factor for progression-free survival. Conclusion: Thus, the macrophage phenotype is a prognostic indicator in PROC patients, possibly via a hyperactive IL-6-related pathway, providing an additional clue for the therapeutic intervention of PROC.

Comprehensive analysis of a cuproptosis-related ceRNA network implicates a potential endocrine therapy resistance mechanism in ER-positive breast cancer.

BACKGROUND: While adjuvant endocrine therapy (ET) may decrease the mortality rate of estrogen receptor-positive (ER+) breast cancer (BC), the likelihood of relapse and metastasis due to ET resistance remains high. Cuproptosis is a recently discovered regulated cell death (RCD), whose role in tumors has yet to be elucidated. Thus, there is a need to study its specific regulatory mechanism in resistance to ET in BC, to identify novel therapeutic targets. METHODS: The prognostic cuproptosis-related genes (CRGs) in ER+ BC were filtered by undergoing Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses in TCGA-BRCA, and a CRGs risk signature was constructed using the correlation coefficient. Immune infiltration analysis, immune function analysis, tumor microenvironment (TME) analysis, immune checkpoint analysis, immunotherapy response analysis, drug sensitivity analysis, and pathway activation analysis were carried out among the high- and low-risk groups in turn. The central CRG of cuproptosis in ER+ BC resistance to ET was acquired through the intersection of protein interaction network (PPI) analysis, genes differentially expressed (DEGs) between human BC cells LCC9 and MCF-7 (GSE159968), and CRGs with prognostic significance in TCGA-BRCA ER+ BC. The miRNAs upstream of the core CRGs were predicted based on the intersection of 4 databases, miRDB, RNA22, miRWalk, and RNAlnter. Candidate miRNAs consisted of the intersection of predicted miRNAs and miRNAs differentially expressed in the LCC9 and MCF-7 cell lines (GSE159979). Candidate lncRNAs were the intersection of the differential lncRNAs from the LCC9 and MCF-7 cell lines and the survival-related lncRNAs obtained from a univariate Cox regression analysis. Pearson's correlation analysis was performed between mRNA-miRNA, miRNA-lncRNA, and mRNA-lncRNA expression separately. RESULTS: We constructed A risk signature of 4-CRGs to predict the prognosis of ER+ BC in TCGA-BRCA, a risk score = DLD*0.378 + DBT*0.201 + DLAT*0.380 + ATP7A*0.447 was used as the definition of the formula. There were significant differences between the high- and low-risk groups based on the risk score of 4-CRGs in aspects of immune infiltration, immune function, expression levels of immune checkpoint genes, and signaling pathways. DLD was determined to be the central CRG of cuproptosis in ER+ BC resistance to ET through the intersection of the PPI network analysis, DEGs between LCC9 and MCF-7 and 4-CRGs. Two miRNAs hsa-miR-370-3p and hsa-miR-432-5p were found taking DLD mRNA as a target, and the lncRNA C6orf99 has been hypothesized to be a competitive endogenous RNA that regulates DLD mRNA expression by sponging off hsa-miR-370-3p and hsa-miR-432-5p. CONCLUSION: This study built a prognostic model based on genes related to cuproptosis in ER+ BC. We considered DLD to be the core gene associated with resistance to ET in ER+ BC via copper metabolism. The search for promising therapeutic targets led to the establishment of a cuproptosis-related ceRNA network C6orf99/hsa-miR-370-3p and hsa-miR-432-5p/DLD.

PTGIS May Be a Predictive Marker for Ovarian Cancer by Regulating Fatty Acid Metabolism.

Background: Ovarian cancer tends to metastasize to the omentum, which is an organ mainly composed of adipose tissue. Many studies have found that fatty acid metabolism is related to the occurrence and metastasis of cancers. Therefore, it is possible that fatty acid metabolism-related genes (FAMRG) affect the prognosis of ovarian cancer patients. Methods: First, profiles of ovarian cancer and normal ovarian tissue transcriptomes were acquired from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases. A LASSO regression predictive model was developed via the "glmnet" R package. The nomogram was created via the "regplot." Gene Set Variation Analysis (GSVA), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO) analyses were conducted to determine the FAMRGs' roles. The percentage of immunocyte infiltration was calculated via CIBERSORT. Using "pRRophetic," the sensitivity of eight regularly used medications and immunotherapy was anticipated. Results: 125 genes were determined as different expression genes (DEGs). Based on RXRA, ECI2, PTGIS, and ACACB, a prognostic model is created and the risk score is calculated. Analyses of univariate and multivariate regressions revealed that the risk score was a distinct prognostic factor (univariate: HR: 2.855, 95% CI: 1.756-4.739, P < 0.001; multivariate: HR: 2.943, 95% CI: 1.800-4.812, P < 0.001). The nomogram demonstrated that it properly predicted the 1-year survival rate. The expression of memory B molecular units, follicular helper T molecular units, regulatory T molecular units, and M1 macrophages differed remarkably between the groups at high and low risk (P < 0.05). Adipocytokine signaling pathways, cancer pathways, and degradation of valine, leucine, and isoleucine vary between high- and low-risk populations. The findings of the GO enrichment revealed that the extracellular matrix and cellular structure were the two most enriched pathways. PTGIS, which is an important gene in fatty acid metabolism, was identified as the hub gene. This result was verified in ovarian cancer and ovarian tissues. The connection between the gene and survival was statistically remarkable (P = 0.015). The pRRophetic algorithm revealed that the low-risk group was more adaptable to cisplatin, doxorubicin, 5-fluorouracil, and etoposide (P < 0.001). Conclusion: PTGIS may be an indicator of prognosis and a possible therapeutic target for the therapy of ovarian cancer patients. The fatty acid metabolism of immune cells may be controlled, which has an indirect effect on cancer cell growth.

[Analysis of Related Factors of Autologous Peripheral Hematopoietic Stem Cell Mobilization in Patients with Lymphoma and Myeloma].

OBJECTIVE: To explore the related factors affecting of autologous peripheral hematopoietic stem cell mobilization in patients with single center lymphoma and multiple myeloma. METHODS: The clinical total of 30 patients with lymphoma or multiple myeloma who underwent autologous peripheral hematopoietic stem cell mobilization and transplantation in the Affiliated Hospital of Jiangsu University from March 2012 to December 2021 were retrospectively analyzed, including the patients' age, gender, disease type, chemotherapy course, mobilization scheme, collection times, CD34+ cell count, adverse events, days of neutrophil and platelet implantation after transplantation. The related factors affecting to the mobilization efficiency of peripheral blood stem cells was analyzed. RESULTS: The mobilization scheme had a significant effect on the mobilization success rate of CD34+ cells. The mobilization success rate and optimal mobilization rate of intermediate-dose VP-16+G-CSF were higher than that of high-dose VP-16+G-CSF (P<0.05); the mobilization success rate of patients with previous chemotherapy courses ≤4 was higher than that of patients with chemotherapy courses >4 (100% vs 72.22%, P<0.05); the mobilization success rate of lymphoma patients was lower than that of myeloma patients (66.67% vs 94.44%, P<0.05); the mobilization success rate of lymphoma patients who received intermediate-dose VP-16+G-CSF was higher than that received high-dose VP-16+G-CSF patients (100% vs 42.86%, P<0.05). Patients' gender, age, time from diagnosis to mobilization and disease status had no significant effect on the efficiency of stem cell mobilization. Fifteen patients (50%) had febrile neutropenia during stem cell mobilization. There was no statistical difference in the incidence of febrile neutropenia between the two mobilization schemes (P>0.05); the incidence of severe thrombocytopenia in intermediate-dose VP-16+G-CSF group was higher than that in high-dose VP-16+G-CSF group (P<0.05). There was no statistical difference in the time of granulocyte implantation and platelet implantation after stem cell transplantation in patients with different mobilization schemes (P>0.05). CONCLUSION: Mobilization regime, the number of previous chemotherapy course and disease type affect the mobilization efficiency of stem cells. Intermediate dose VP-16+G-CSF can improve the mobilization efficiency of stem cell in lymphoma patients, but should pay attention to the risk of bleeding.

Establishment of an ovarian cancer omentum metastasis-related prognostic model by integrated analysis of scRNA-seq and bulk RNA-seq.

OBJECTIVE: Ovarian cancer has the highest mortality rate among gynecological malignant tumors, and it preferentially metastasizes to omental tissue, leading to intestinal obstruction and death. scRNA-seq is a powerful technique to reveal tumor heterogeneity. Analyzing omentum metastasis of ovarian cancer at the single-cell level may be more conducive to exploring and understanding omentum metastasis and prognosis of ovarian cancer at the cellular function and genetic levels. METHODS: The omentum metastasis site scRNA-seq data of GSE147082 were acquired from the GEO (Gene Expression Omnibus) database, and single cells were clustered by the Seruat package and annotated by the SingleR package. Cell differentiation trajectories were reconstructed through the monocle package. The ovarian cancer microarray data of GSE132342 were downloaded from GEO and were clustered by using the ConsensusClusterPlus package into omentum metastasis-associated clusters according to the marker genes gained from single-cell differentiation trajectory analysis. The tumor microenvironment (TME) and immune infiltration differences between clusters were analyzed by the estimate and CIBERSORT packages. The expression matrix of genes used to cluster GSE132342 patients was extracted from bulk RNA-seq data of TCGA-OV (The Cancer Genome Atlas ovarian cancer), and least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression were performed to establish an omentum metastasis-associated gene (OMAG) signature. The signature was then tested by GSE132342 data. Finally, the clinicopathological characteristics of TCGA-OV were screened by univariate and multivariate Cox regression analysis to draw the nomogram. RESULTS: A total of 9885 cells from 6 patients were clustered into 18 cell clusters and annotated into 14 cell types. Reconstruction of differentiation trajectories divided the cells into 5 branches, and a total of 781 cell trajectory-related characteristic genes were obtained. A total of 3769 patients in GSE132342 were subtyped into 3 clusters by 74 cell trajectory-related characteristic genes. Kaplan-Meier (K-M) survival analysis showed that the prognosis of cluster 2 was the worst, P < 0.001. The TME analysis showed that the ESTIMATE score and stromal score in cluster 2 were significantly higher than those in the other two clusters, P < 0.001. The immune infiltration analysis showed differences in the fraction of 8 immune cells among the 3 clusters, P < 0.05. The expression data of 74 genes used for GEO clustering were extracted from 379 patients in TCGA-OV, and combined with survival information, 10 candidates for OMAGs were filtered by LASSO. By using multivariate Cox regression, the 6-OMAGs signature was established as RiskScore = 0.307*TIMP3 + 3.516*FBN1-0.109*IGKC + 0.209*RPL21 + 0.870*UCHL1 + 0.365*RARRES1. Taking TCGA-OV as the training set and GSE132342 as the test set, receiver operating characteristic (ROC) curves were drawn to verify the prognostic value of 6-OMAGs. Screened by univariate and multivariate Cox regression analysis, 3 (age, cancer status, primary therapy outcome) of 5 clinicopathological characteristics were used to construct the nomogram combined with risk score. CONCLUSION: We constructed an ovarian cancer prognostic model related to omentum metastasis composed of 6-OMAGs and 3 clinicopathological features and analyzed the potential mechanism of these 6-OMAGs in ovarian cancer omental metastasis.

Establishment of prognostic model for postoperative patients with metaplastic breast cancer: Based on a retrospective large data analysis and Chinese multicenter study.

Purpose: Models for predicting postoperative overall survival of patients with metaplastic breast cancer have not yet been discovered. The purpose of this study is to establish a model for predicting postoperative overall survival of metaplastic breast cancer patients. Methods: Patients in the Surveillance, Epidemiology, and End Results database diagnosed with MBC from 2010 to 2015 were selected and randomized into a SEER training cohort and an internal validation cohort. We identified independent prognostic factors after MBC surgery based on multivariate Cox regression analysis to construct nomograms. The discriminative and predictive power of the nomogram was assessed using Harrell's consistency index (C-index) and calibration plots. The decision curve analysis (DCA) was used to evaluate the clinical usefulness of the model. We verify the performance of the prediction model with a Chinese multi-center data set. Results: Multifactorial analysis showed that age at diagnosis, T stage, N stage, M stage, tumor size, radiotherapy, and chemotherapy were important prognostic factors affecting OS. The C-index of nomogram was higher than the eighth edition of the AJCC TNM grading system in the SEER training set and validation set. The calibration chart showed that the survival rate predicted by the nomogram is close to the actual survival rate. It has also been verified in the SEER internal verification set and the Chinese multi-center data set. Conclusion: The prognostic model can accurately predict the post-surgical OS rate of patients with MBC and can provide a reference for doctors and patients to establish treatment plans.

The role of PKC/PKR in aging, Alzheimer's disease, and perioperative neurocognitive disorders.

Background: The incidence of perioperative neurocognitive disorders (PNDs) is reportedly higher in older patients. Mitochondrial and synaptic dysfunctions have consistently been demonstrated in models of aging and neurodegenerative diseases; nonetheless, their role in PND is not well understood. Methods: The Morris water maze and elevated plus maze tests were used to assess the learning and memory abilities of both C57BL/6 and 3×Tg-AD mice of different ages (8 and 18 months). PND was induced by laparotomy in C57BL/6 mice and 3×Tg-AD mice (8 months old). Markers associated with neuroinflammation, mitochondrial function, synaptic function, and autophagy were assessed postoperatively. The roles of protein kinase C (PKC) and double-stranded RNA-dependent protein kinase (PKR) were further demonstrated by using PKC-sensitive inhibitor bisindolylmaleimide X (BIMX) or PKR-/- mice. Results: Significant cognitive impairment was accompanied by mitochondrial dysfunction and autophagy inactivation in both aged C57BL/6 and 3×Tg-AD mice. Laparotomy induced a significant neuroinflammatory response and synaptic protein loss in the hippocampus. Cognitive and neuropathological changes induced by aging or laparotomy were further exacerbated in 3×Tg-AD mice. Deficits in postoperative cognition, hippocampal mitochondria, autophagy, and synapse were significantly attenuated after pharmacological inhibition of PKC or genetic deletion of PKR. Conclusions: Our findings suggest similar pathogenic features in aging, Alzheimer's disease, and PND, including altered mitochondrial homeostasis and autophagy dysregulation. In addition, laparotomy may exacerbate cognitive deficits associated with distinct neuronal inflammation, mitochondrial dysfunction, and neuronal loss independent of genetic background. The dysregulation of PKC/PKR activity may participate in the pathogenesis of these neurodegenerative diseases.

Construction of a breast cancer prognosis model based on alternative splicing and immune infiltration.

BACKGROUND: Breast cancer (BC) is the most common malignancy among women in the world. Alternative splicing (AS) is an important mechanism for regulating gene expression and producing proteome diversity, which is closely related to tumorigenesis. Understanding the role of AS in BC may be helpful to reveal new therapeutic targets for clinical interventions. METHODS: RNA-seq, clinical and AS data of TCGA-BRCA were downloaded from TCGA and TCGA SpliceSeq databases. AS events associated with prognosis were filtered by univariate Cox regression. The AS risk model of BC was built by Lasso regression, random forest and multivariate Cox regression. The accuracy of the AS risk model and clinicopathological factors were evaluated by time-dependent receiver operating characteristic (ROC) curves. The significant factors were used to construct the nomogram model. Tumor microenvironment analysis, immune infiltration and immune checkpoint analysis were performed to show the differences between the high and low AS risk groups. The expression differences of genes of AS events constituting the risk model in tumor tissues and normal tissues were analyzed, the genes with significant differences were screened, and their relationship with prognosis, tumor microenvironment, immune infiltration and immune checkpoint were analyzed. Finally, Pearson correlation analysis was used to calculate the correlation coefficient between splicing factors (SF) and prognostic AS events in TCGA-BRCA. The results were imported into Cytoscape, and the associated network was constructed. RESULTS: A total of 21,232 genes had 45,421 AS events occurring in TCGA-BRCA, while 1604 AS events were found to be significantly correlated with survival. The BRCA risk model consisted of 5 AS events, (TTC39C|44853|AT*- 2.67) + (HSPBP1|52052|AP*- 4.28) + (MAZ|35942|ES*2.34) + (ANK3|11845|AP*1.18) + (ZC3HAV1|81940|AT*1.59), which were confirmed to be valuable for predicting BRCA prognosis to a certain degree, including ROC curve, survival analysis, tumor microenvironment analysis, immune infiltration and immune checkpoint analysis. Based on this, we constructed a nomogram prediction model composed of clinicopathological features and the AS risk signature. Furthermore, we found that MAZ was a core gene indicating the connection of tumor prognosis and AS events. Ultimately, a network of SF-AS regulation was established to reveal the relationship between them. CONCLUSIONS: We constructed a nomogram model combined with clinicopathological features and AS risk score to predict the prognosis of BC. The detailed analysis of tumor microenvironment and immune infiltration in the AS risk model may further reveal the potential mechanisms of BC recurrence and development.