A clinical tool to predict overall survival of elderly patients with soft tissue sarcoma after surgical resection.

With the aging world population, the incidence of soft tissue sarcoma (STS) in the elderly gradually increases and the prognosis is poor. The primary goal of this research was to analyze the relevant risk factors affecting the postoperative overall survival in elderly STS patients and to provide some guidance and assistance in clinical treatment. The study included 2,353 elderly STS patients from the Surveillance, Epidemiology, and End Results database. To find independent predictive variables, we employed the Cox proportional risk regression model. R software was used to develop and validate the nomogram model to predict postoperative overall survival. The performance and practical value of the nomogram were evaluated using calibration curves, the area under the curve, and decision curve analysis. Age, tumor primary site, disease stage, tumor size, tumor grade, N stage, and marital status, are the risk variables of postoperative overall survival, and the prognostic model was constructed on this basis. In the two sets, both calibration curves and receiver operating characteristic curves showed that the nomogram had high predictive accuracy and discriminative power, while decision curve analysis demonstrated that the model had good clinical usefulness. A predictive nomogram was designed and tested to evaluate postoperative overall survival in elderly STS patients. The nomogram allows clinical practitioners to more accurately evaluate the prognosis of individual patients, facilitates the progress of individualized treatment, and provides clinical guidance.

Breaking the Barriers of Therapy Resistance: Harnessing Ferroptosis for Effective Hepatocellular Carcinoma Therapy.

Ferroptosis is a type of cell death that relies on iron and is distinguished by the occurrence of lipid peroxidation and the buildup of reactive oxygen species. Ferroptosis has been demonstrated to have a significant impact on the advancement and resistance to treatment of hepatocellular carcinoma (HCC), thereby highlighting its potential as a viable therapeutic target. Ferroptosis was observed in HCC tissues in contrast to normal liver tissue. The inhibition of ferroptosis has been found to increase the viability of HCC cells and decrease their susceptibility to various anticancer therapies, including chemotherapy, radiotherapy, and immune checkpoint blockade. The administration of drugs that directly modulate ferroptosis regulators or induce excessive production of lipid-reactive oxygen species has demonstrated the potential to enhance the responsiveness of drug-resistant HCC cells to treatment. However, the precise mechanism underlying this phenomenon remains ambiguous. This review presents a comprehensive overview of the crucial role played by ferroptosis in enhancing the efficacy of treatment for hepatocellular carcinoma (HCC). The main aim of this study is to examine the feasibility of utilizing ferroptosis as a therapeutic approach to improve the efficacy of HCC treatment and overcome drug resistance.

Identification of Subtypes in Triple-negative Breast Cancer Based on Shared Genes Between Immunity and Cancer Stemness.

The correlation between triple-negative breast cancer (TNBC) and genes related to immunity and cancer stemness, particularly shared genes, remains unclear. This study aimed to investigate the correlation of immunity and cancer stemness with the molecular subtyping and survival rates in TNBC using bioinformatics approaches. Differential gene analysis was conducted to identify TNBC-associated differentially expressed genes (DEGs). Cancer stem cell (CSC)-related genes were obtained using weighted gene coexpression network analysis. Immune-related gene sets were retrieved from the literature. Venn analysis was performed to identify the shared DEGs between immunity and cancer stemness in TNBC. Cluster analysis and survival analysis based on the expression of these genes were conducted to identify TNBC subtypes with significant survival differences. A total of 5259 TNBC-associated DEGs, 2214 CSC-related genes, 1793 immune-related genes, and 44 shared DEGs between immunity and cancer stemness were obtained. Among them, 3 shared DEGs were closely associated with TNBC survival rates ( P <0.05). Cluster and survival analyses revealed that among 3 subtypes, cluster2 exhibited the best survival rate, and cluster3 showed the worst survival rate ( P <0.05). Dendritic cells were highly infiltrated in cluster2, while plasma cells and resting mast cells were highly infiltrated in cluster3 ( P <0.05). Genes shared by immunity and cancer stemness were capable of classifying TNBC samples. TNBC patients of different subtypes exhibited significant differences in immune profiles, genetic mutations, and drug sensitivity. These findings could provide new insights into the pathogenesis of TNBC, the immune microenvironment, and the selection of therapeutic targets for drug treatment.

The global, regional, and national disease burden of breast cancer attributable to tobacco from 1990 to 2019: a global burden of disease study.

OBJECTIVE: Tobacco has been identified as a significant contributory element to the development of breast cancer. Our objective was to evaluate the spatiotemporal trends of tobacco-related breast cancer at the global, regional, and national scales during 1990-2019. METHODS: We extracted data on mortality, disability adjusted of life years (DALYs), age-standardized mortality rate (ASMR), and age-standardized DALYs rate (ASDR) from the Global Burden of Disease (GBD) study 2019. Estimated annual percentage change (EAPC) was computed to assess the temporal change in ASDR and ASMR. RESULTS: In 2019, the deaths and DALYs attributed to tobacco-related breast cancer were estimated to be 35,439 (95% UI: 22,179-48,119) and 1,060,590 (95% UI: 622,550-1,462,580), respectively. These figures accounted for 5.1% and 5.2% of the total burden of breast cancer. ASMR and ASDR increased in low SDI regions, remained stable in low-middle and middle SDI regions and declined in high and high-middle SDI regions. The burden of breast cancer attributable to tobacco varied notably among regions and nations. Oceania, Southern Latin America, and Central Europe were the GBD regions with the highest number of ASMR and DALYs. There was a positive relationship between age-standardized rate and SDI value in 2019 across 204 nations or territories. A negative association was observed between the EAPC in ASMR or ASDR and the human development index (HDI) in 2019 (R = -0.55, p < 0.01 for ASMR; R = -0.56, p < 0.01 for ASDR). CONCLUSION: Tobacco is one important and modifiable risk factor for breast cancer. The heterogeneity in both the spatial and temporal distribution can be attributed to factors such as aging, population growth, and SDI. These findings substantiate the necessity of expediting the enforcement of tobacco-free legislation in order to safeguard populations from the detrimental effects of tobacco.

The miR-146b-3p/TNFAIP2 axis regulates cell differentiation in acute myeloid leukaemia.

Our purpose is to verify that miR-146b-3p targets the downstream transcript TNFAIP2 in order to reveal the machinery underlying the miR-146b-3p/TNFAIP2 axis regulating acute myeloid leukaemia (AML) differentiation. Bioinformatics analyses were performed using multiple databases and R packages. The CD11b+ and CD14+ cell frequencies were detected using flow cytometry and immunofluorescence staining. The TNFAIP2 protein expression was evaluated using western blotting, immunocytochemistry and immunofluorescence staining. The qRT-PCR was conducted to detect the expression of TNFAIP2 and miR-146b-3p. TNFAIP2 and its correlated genes were enriched in multiple cell differentiation pathways. TNFAIP2 was upregulated upon leukaemic cell differentiation. miR-146b-3p directly targeted TNFAIP2, resulting in a decrease in TNFAIP2 expression. Forced expression of TNFAIP2 or knockdown of miR-146b-3p significantly induced the differentiation of MOLM-13 cells. In this study, we demonstrated that TNFAIP2 is a critical driver in inducing differentiation and that the miR-146b-3p/TNFAIP2 axis involves in regulating cell differentiation in AML.

Hepatocellular Carcinoma Subtyping and Prognostic Model Construction Based on Chemokine-Related Genes.

BACKGROUND: Chemokines not only regulate immune cells but also play significant roles in development and treatment of tumors and patient prognoses. However, these effects have not been fully explained in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: We conducted a clustering analysis of chemokine-related genes. We then examined the differences in survival rates and analyzed immune levels using single-sample Gene Set Enrichment Analysis (ssGSEA) for each subtype. Based on chemokine-related genes of different subtypes, we built a prognostic model in The Cancer Genome Atlas (TCGA) dataset using the survival package and glmnet package and validated it in the Gene Expression Omnibus (GEO) dataset. We used univariate and multivariate regression analyses to select independent prognostic factors and used R package rms to draw a nomogram reflecting patient survival rates at 1, 3, and 5 years. RESULTS: We identified two chemokine subtypes and, after screening, found that Cluster1 had higher survival rates than Cluster2. In addition, in terms of immune evaluation, stromal evaluation, ESTIMATE evaluation, immune abundance, immune function, and expressions of various immune checkpoints, immune levels of Cluster1 were significantly better than those of Cluster2. The immunophenoscore (IPS) of HCC patients in Cluster1 was significantly higher than that in Cluster2. Furthermore, we established a prognostic model consisting of 9 genes, which correlated with chemokines. Through testing, Riskscore was revealed as an independent prognostic factor, and the model could effectively predict HCC patients' prognoses in both TCGA and GEO datasets. CONCLUSION: This study resulted in the development of a novel prognostic model related to chemokine genes, providing new targets and theoretical support for HCC patients.

Matrine exerts an anti-tumor effect via regulating HN1 in triple breast cancer both in vitro and in vivo.

The treatment of triple-negative breast cancer (TNBC) cannot meet medical needs, and it is urgent to find new drugs for intervention. This study aimed to investigate the anti-tumor effect of matrine on the proliferation and apoptosis of TNBC cells based on HN1 regulation in vitro and in vivo. TNBC cell lines (MDA-MB-453 and HCC-1806) were treated with varying concentrations of matrine (0, 1.0, 2.0, 3.0, 4.0, and 5.0 mM). CCK-8, colony formation assay, transwell assay, and flow cytometry assay were employed to detect proliferation, clone formation, invasion, and apoptosis of TNBC cells. Western blot analysis was applied to detect the protein expression of apoptosis HN1. The effects of matrine on tumor growth, protein expression of HN1, and apoptosis in vivo were validated by xenograft tumor models and histology. It was found that matrine inhibited proliferation, colony formation, and invasion and promoted apoptosis of TNBC cells in vitro. HN1 expression was suppressed by matrine. HN1 overexpression perceptibly reversed the above-mentioned additive effect in vitro. In vivo experiments found that matrine inhibited tumor growth and the expression of HN1 protein but promoted the protein expression of Cleared-Caspase-3. Above all, this study demonstrated that matrine inhibited proliferation and promoted apoptosis of TNBC cells via suppressing HN1 expression. Targeting HN1 by matrine may provide new insights into the therapeutic management of patients with TNBC.

Effectiveness of adjuvant chemotherapy for elderly patients with triple-negative breast cancer.

There is little evidence determining whether elderly patients (from 70 to 90 years old) with triple-negative breast cancer could benefit from adjuvant chemotherapy (AC).  This study explores the effect of AC in these population following surgery. A total of 4610 patients were identified in the Surveillance, Epidemiology, and End Results database (2010-2018). Multiple imputation by chained equations was performed to impute missing data. Inverse probability of treatment weighting (IPTW) was applied to reduce the selection bias. IPTW-adjusted Kaplan-Meiers survival analysis and Cox proportional hazards models were performed to compare breast cancer specific survival (BCSS) and overall survival (OS) in the two treatment groups. The patients were classified into the chemotherapy (n=1989) and the observation (n=2621) groups. The percentage of patients receiving AC versus observation increased significantly from 2010 to 2018 (estimated annual percentage change, 1.49%; 95%CI, 0.75-2.16%, p=0.002). The 5-year IPTW-adjusted rates of BCSS and OS in AC group were better than that in observation group (BCSS: 82.32% vs. 78.42%, p=0.010; OS: 75.54% vs. 64.65%, p<0.001). The patients could benefit from AC based on the results of IPTW-adjusted Cox proportional hazards regression analysis (BCSS: HR, 0.77, 95%CI, 0.62-0.94, p=0.012; OS: HR, 0.66, 95%CI, 0.57-0.78, p<0.001). AC was associated with a significant outcome benefit across the year at diagnosis, marital status, stage, lymph node, surgery, and radiation subgroups (all p<0.050). Patients with T1ab could not benefit from AC (p>0.050). In conclusion, we presented a BCSS and OS benefit from AC in elderly patients with triple-negative breast cancer (TNBC). AC remained a reasonable treatment approach in these specific patients. For the patients with T1ab, de-escalated treatment would be administrated with caution.

Construction of a four-mRNA prognostic signature with its ceRNA network in CESC.

Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) tumorigenesis involves a combination of multiple genetic alteration processes. Constructing a survival-associated competing endogenous RNA (ceRNA) network and a multi-mRNA-based prognostic signature model can help us better understand the complexity and genetic characteristics of CESC. In this study, the RNA-seq data and clinical information of CESC patients were downloaded from The Cancer Genome Atlas. Differentially expressed mRNAs, lncRNAs and miRNAs were identified with the edgeR R package. A four-mRNA prognostic signature was developed by multivariate Cox regression analysis. Kaplan-Meier survival with the log-rank tests was performed to assess survival rates. The relationships between overall survival (OS) and clinical parameters were evaluated by Cox regression analysis. A survival-associated ceRNA network was constructed with the multiMiR package and miRcode database. Kyoto encyclopedia of genes and genomes (KEGG) analysis and gene ontology analyses were used to identify the functional role of the ceRNA network in the prognosis of CESC. A total of 298 differentially expressed mRNAs, 8 miRNAs, and 29 lncRNAs were significantly associated with the prognosis of CESC. A prognostic signature model based on 4 mRNAs (OPN3, DAAM2, HENMT1, and CAVIN3) was developed, and the prognostic ability of this signature was indicated by the AUC of 0.726. Patients in the high-risk group exhibited significantly worse OS. The KEGG pathways, TGF-ß and Cell adhesion molecules, were significantly enriched. In this study, a CESC-associated ceRNA network was constructed, and a multi-mRNA-based prognostic model for CESC was developed based on the ceRNA network, providing a new perspective for cancer pathogenesis research.

[Research Progress of Fibroblast Growth Factor Receptor Signaling Pathway in Breast Cancer].

Breast cancer,one of the common malignant tumors in women,has shown rising incidence in recent years,posing a serious threat to women's health.The advancement of molecular biology facilitates the revealing of the relationships between signaling pathways and breast cancer.Fibroblast growth factor receptor (FGFR) signaling pathway plays an important role in the proliferation,survival,differentiation,migration,and apoptosis of breast cancer cells.Strategies targeting the FGFR signaling pathway thus exhibit a promising prospect in breast cancer treatment.

TP53 Mutation Infers a Poor Prognosis and Is Correlated to Immunocytes Infiltration in Breast Cancer.

Background: This study aimed to investigate the TP53 mutation, its potential immune features, its prognostic value, and its impact on immune infiltration in patients with breast cancer (BC). Methods: We downloaded the somatic mutation data and clinicopathologic features of BC patients from the TCGA GDC database, UCSC Xena platform, and International Cancer Genome Consortium (ICGC) database. The association between the TP53 mutation, clinicopathology features, and overall survival (OS) in BC patients was analyzed. We evaluated the potential role of the TP53 mutation in the immune therapy response, including the tumor mutation burden (TMB), microsatellite instability (MSI), and tumor immune dysfunction and exclusion (TIDE). Moreover, ESTIMATE was employed to assess the ImmuneScore and StromalScore in BC patients. We also explored immunocyte infiltration related to the TP53 mutation and its potential mechanism. Immunohistochemistry (IHC) was performed to validate the association between the expression of CXCL1, CXCL10, and CCL20 and TP53 status. Results: We found that the TP53 mutation was significantly associated with the shorter OS (p = 0.038) and was also an independent predictive factor of OS for BC patients (p < 0.001). Compared to that in the wild type group, the TP53-mutant group showed a higher TMB value (P< 0.001), MSI value (p = 0.077), and TIDE value (p < 0.001) with respect to BC patient immunotherapy. In addition, the ImmuneScore and StromalScore were both significantly increased in the TP53-mutant group (ImmuneScore: p < 0.001; StromalScore: p = 0.003). The results of CIBERSORT suggested that the TP53 mutation significantly promoted the infiltration of Tregs, T helper cells, and M0-type macrophages. KEGG and GSEA enrichment results suggested that the IL-17 signaling pathway and antigen processing and presentation pathways were significantly enriched in the TP53-mutant group. Importantly, based on IHC results of immune-related hub-genes, the chemokines CXCL1, CXCL10, and CCL20 were significantly upregulated in the TP53-mutant group in BC patients. Conclusion: These results indicate that a TP53 mutation might serve as a biomarker for BC prognosis and is related to immunocyte infiltration in the tumor microenvironment.

The characteristics and novel clinical implications of CD4+CXCR5+Foxp3+ follicular regulatory T cells in breast cancer.

BACKGROUND: Follicular regulatory T cells (Tfr) are a subset of regulatory T cells (Tregs) that suppress the humoral immune response in the germinal center. They are associated with increased rates of disease stabilization and decreased autoantibody levels in a variety of tumor and autoimmune diseases. The binding of T-cell immunoglobulin mucin 3 (TIM-3) and its ligand on the surface of Tfr cells could result in the depletion of T lymphocytes and the termination of the immune response mediated by helper T cell 1. However, the role of Tfr cells in breast cancer (BC) remains unclear. METHODS: In this study, we detected the expression of CD4+CXCR5+Foxp3+Tfr cells in the peripheral blood of 35 BC patients and 30 healthy control patients by flow cytometry, and analyzed the relationship between Tfr cells and the clinical characteristics of patients. In addition, the expression of TIM-3 on the surface of Tfr cells in 6 triple-negative BC (TNBC) patients was further investigated using mass spectrometry. RESULTS: We found a significant increase in Tfr cells in BC patients compared to healthy control patients (23.47%±9.70% vs. 10.99%±4.68%; P=0.001). Notably, the increase was more significant in early stage than advanced stage TNBC patients (28.52%±10.75% vs. 18.69%±5.19%; P=0.006), and there was a negative correlation between Tfr cells and serum lactate dehydrogenase (LDH) in early stage TNBC patients (r=-0.585; P=0.008). Additionally, we found that the expression of Tfr cells was higher in TNBC patients than luminal BC patients (28.25%±10.11% vs. 18.5%±8.15%; P=0.028); however, there was no significant difference in expression in hormone receptor positive (HR+) BC and hormone receptor negative (HR-) BC (P=0.141) patients. Notably, the surface of Tfr cells of TNBC patients had higher levels of TIM-3 expression than those of healthy control patients (3.93±0.92 vs. 2.65±0.15, respectively; t=-3.02; P<0.05), which the mass spectrometry showed were positively correlated with the intracellular Foxp3 expression of Tfr cells (r=0.82; P=0.036). CONCLUSIONS: Our results suggest that circulating Tfr cells and the expression of TIM-3 were significantly increased in BC patients, which were related to stage and histological type, and may be involved in the pathogenesis of BC.

Molecular and Phylogenetic Characterization of Non-O157 Shiga Toxin-Producing Escherichia coli Strains in China.

Shiga toxin-producing Escherichia coli (STEC) causes diarrhea and hemorrhagic colitis with life-threatening complications, such as hemolytic uremic syndrome. The aim of this study was to assess the molecular epidemiologic features of non-O157 STEC strains from different resources in China and illustrate the role of animal reservoirs or animal-derived foodstuffs in human STEC infections. A collection of 301 non-O157 STEC isolates from domestic and wild animals (i.e., cattle, goat, pig, yak, pika, and antelope), raw meats (i.e., beef, pork, mutton, chicken, and duck), diarrheal patients, and healthy carriers in different regions of China were selected in this study. Of the 301 analyzed STEC isolates, 67 serogroups, and 118 serotypes were identified; this included some predominant serogroups associated with human disease, such as O26, O45, O103, O111, and O121. Eighteen different combinations of stx subtypes were found. Eleven isolates carried the intimin gene eae, 93 isolates contained ehxA, and 73 isolates carried astA. The prevalence of other putative adhesion genes saa, paa, efa1, and toxB was 28.90% (87), 6.98% (21), 2.31% (7), and 1% (3), respectively. The phylogenetic distribution of isolates was analyzed by multilocus sequence typing (MLST). Ninety-four sequence types were assigned across the 301 isolates. A subset of isolates recovered from yak and pika residing in the similar wild environments, Qinghai-Tibetan plateau, showed similar genetic profiles and more tendencies to cluster together. Isolates from goat and mutton exhibited close genetic relatedness with those from human-derived isolates, providing evidence that transmission may have occurred locally within intraspecies or interspecies, and importantly, from animal reservoirs, or raw meats to humans. Comparing isolates in this study with highly virulent strains by MLST, along with serotyping and virulence profiles, it is conceivable that some of isolates from goat, yak, or raw meats may have potential to cause human diseases.

Genetic Diversity of Intimin Gene of Atypical Enteropathogenic Escherichia coli Isolated from Human, Animals and Raw Meats in China.

Atypical enteropathogenic Escherichia coli (aEPEC) is considered to be an emerging enteropathogen that is more prevalent than typical EPEC in developing and developed countries. The major adherence factor, intimin, an outer membrane protein encoded by eae, plays a pivotal role in the pathogenesis of aEPEC. This study investigated the distribution and polymorphisms of intimin subtypes of 143 aEPEC strains from diarrheal patients, healthy carriers, animals, and raw meats in China. These aEPEC strains belonged to more than 71 different serotypes, which comprised 52 O serogroups and 24 H types. Sixty-eight different eae genotypes and 19 intimin subtypes were detected. Eighteen, eight, seven, and five intimin subtypes were identified from 86 diarrheal patients, 14 healthy carriers, 19 animals, and 24 raw meats strains, respectively. Intimin ß1 was the most prevalent subtype in strains from diarrheal patients (34.88%) and animals (47.37%). There was a statistically significant difference in the distribution of eae-ß1 between diarrheal patients and healthy carriers (P = 0.004). Intimin-θ was more predominant among raw meat strains (50%) than among diarrheal patients strains (12.79%, P = 0.0003), healthy carrier strains (7.14%, P = 0.007), or animal strains (15.79%, P = 0.020). The two predominant subtypes (eae-ß1 and eae-θ) had considerable polymorphisms with no significant differences among the four sources. PFGE analysis revealed 119 distinct patterns and the strains were clustered into 11 groups with similarity indices ranging from 63% to 100%. These results suggest that in China, aEPEC strains from different sources are highly heterogeneous. Animals and raw meats are important sources of genetically diverse intimin-harboring aEPEC, which might serve as important transmission vehicles of these bacteria.

[Investigation on distribution of Yersinia enterocolitica in Henan province between 2005 and 2011].

OBJECTIVE: To investigate the distribution of Yersinia enterocolitica in Henan province from 2005 to 2011. METHODS: A total of 6700 samples of stool specimen were collected from diarrhea patients and different domestic animals between 2005 and 2011 from Zhengzhou, Suixian and Dengfeng, as well as flies and the daub specimens of raw and cooked meat products. The bacteria were isolated by cold enrichment method, analyzed by the systematic biochemistry to determine the serotypes and bio-types, and tested the virulence genes by PCR method. RESULTS: A total of 216 strains of Yersinia enterocolitica were isolated from 11 kinds of animal hosts and foods, while 29.63% (64/216) of them were from swine. The dominant epidemic serotypes of the Yersinia enterocolitica were O: 5 and O: 8, accounted for 23.2% (50/216) and 20.4% (44/216), respectively; type 1A was the dominant bio-type, accounted for 84.7% (183/216). The dominant serotype and bio-type differed a lot among various hosts.16 pathogenic strains were isolated from swine, followed by diarrhea patients (6 strains) and dogs (6 strains). CONCLUSION: The distribution of the host of Yersinia enterocolitica was widespread, while swine was the dominant animal host.