Single-cell histone chaperones patterns guide intercellular communication of tumor microenvironment that contribute to breast cancer metastases.

BACKGROUND: Histone chaperones (HCs) are crucial for governing genome stability and gene expression in multiple cancers. However, the functioning of HCs in the tumor microenvironment (TME) is still not clearly understood. METHODS: Self-tested single-cell RNA-seq data derived from 6 breast cancer (BC) patients with brain and liver metastases were reanalyzed by nonnegative matrix factorization (NMF) algorithm for 36 HCs. TME subclusters were observed with BC and immunotherapy public cohorts to assess their prognosis and immune response. The biological effect of HSPA8, one of the HCs, was verified by transwell assay and wound-healing assays. RESULTS: Cells including fibroblasts, macrophages, B cells, and T cells, were classified into various subclusters based on marker genes. Additionally, it showed that HCs might be strongly associated with biological and clinical features of BC metastases, along with the pseudotime trajectory of each TME cell type. Besides, the results of bulk-seq analysis revealed that TME cell subclusters mediated by HCs distinguished significant prognostic value for BC patients and were relevant to patients' immunotherapy responses, especially for B cells and macrophages. In particular, CellChat analysis exhibited that HCs-related TME cell subclusters revealed extensive and diverse interactions with malignant cells. Finally, transwell and wound-healing assays exhibited that HSPA8 deficiency inhibited BC cell migration and invasion. CONCLUSIONS: Collectively, our study first dissected HCs-guided intercellular communication of TME that contribute to BC metastases.

Therapeutic Landscape of Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

Human epidermal growth factor receptor 2-positive breast cancer (HER2+BC) is a common malignancy that is prone to recurrence and metastasis in the early stages, resulting in a poor prognosis for patients. Many studies have suggested that targeted therapy promotes clinical outcomes in HER2+BC. With the introduction of trastuzumab in 1998, the prognosis of patients with early HER2+BC has improved significantly. However, owing to obstinate drug resistance and adverse events, the addition of new agents in standardized treatment has become a research hotspot. These promising agents include antibodies, antibody-drug conjugates, tyrosine kinase inhibitors, and anti-HER2 combined therapies. This article provides a brief description of the biology of BC and the expression of HER2, with the aim to provide an overview of the therapeutic landscape of HER2+BC by reviewing research results and introducing the latest evidence to provide a reference for clinical treatment.

Distribution of risk factors of ischemic stroke in Chinese young adults and its correlation with prognosis.

BACKGROUND: The risk factors for ischemic stroke in young people are complex, varied and closely related to prognosis. This study aims to analyze the risk factors for ischemic stroke in Chinese young people and to explore the main factors influencing the prognosis. METHOD: A total of 444 patients aged 16 to 45 years with ischemic stroke admitted to Suzhou tertiary hospital from 2011 to 2019 were retrospectively analyzed. Risk factors were identified according to the IPSS definition of pediatric stroke and the TOAST classification. All patients were followed up, and the modified Rankin score was used to evaluate the prognosis. Logistic regression analysis was used to explore the influencing factors of poor prognosis. RESULTS: Among the patients, 12 risk factors were found according to the IPSS definition of pediatric stroke, and 5 types of stroke were found according to the TOAST classification. A total of 299 patients had a good prognosis. Anemia, venous sinus thrombosis, isolated large-vessel occlusion, and high baseline NIHSS score were significant risk factors. CONCLUSION: The IPSS definition enables patients to be classified on the basis of more risk factors than other classification methods. The prognosis of ischemic stroke in young people is generally good in the 5 years following the event. Anemia, venous sinus thrombosis, isolated large-vessel occlusion and high baseline NIHSS score were associated with poor prognosis.

The Pan-Cancer Multi-Omics Landscape of FOXO Family Relevant to Clinical Outcome and Drug Resistance.

The forkhead box O (FOXO) transcription factors (TFs) family are frequently mutated, deleted, or amplified in various human cancers, making them attractive candidates for therapy. However, their roles in pan-cancer remain unclear. Here, we evaluated the expression, prognostic value, mutation, methylation, and clinical features of four FOXO family genes (FOXO1, FOXO3, FOXO4, and FOXO6) in 33 types of cancers based on the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases. We used a single sample gene set enrichment analysis (ssGSEA) algorithm to establish a novel index called "FOXOs score". Moreover, we investigated the association between the FOXOs score and tumor microenvironment (TME), the responses to multiple treatments, along with drug resistance. We found that the FOXO family genes participated in tumor progression and were related to the prognosis in various types of cancer. We calculated the FOXOs score and found that it was significantly correlated with multiple malignant pathways in pan-cancer, including Wnt/beta-catenin signaling, TGF-beta signaling, and hedgehog signaling. In addition, the FOXOs score was also associated with multiple immune-related characteristics. Furthermore, the FOXOs score was sensitive for predicting the efficacy of diverse treatments in multiple cancers, especially immunotherapy. In conclusion, FOXO family genes were vital in pan-cancer and were strongly correlated with the TME. A high FOXOs score indicated an excellent immune-activated TME and sensitivity to multiple treatments. Hence, the FOXOs score might potentially be used as a biomarker in patients with a tumor.

Predictive Nomogram of Subsequent Liver Metastasis After Mastectomy or Breast-Conserving Surgery in Patients With Nonmetastatic Breast Cancer.

BACKGROUND: Metastasis accounts for the majority of deaths in patients with breast cancer. Liver metastasis is reported common for breast cancer patients. The purpose of this study was to construct a nomogram to predict the likelihood of subsequent liver metastasis in patients with nonmetastatic breast cancer, thus high-risk patient populations can be prevented and monitored. METHODS: A total of 1840 patients with stage I-III breast cancer were retrospectively included and analyzed. A nomogram was constructed to predict liver metastasis based on multivariate logistic regression analysis. SEER database was used for external validation. C-index, calibration curve and decision curve analysis were used to evaluate the predictive performance of the model. RESULTS: The nomogram included 3 variables related to liver metastasis: HER2 status (odds ratio (OR) 1.86, 95%CI 1.02 to 3.41; P = 0.045), tumor size (OR 3.62, 1.91 to 6.87; P < 0.001) and lymph node metastasis (OR 2.26, 1.18 to 4.34; P = 0.014). The C index of the training cohort, internal validation cohort and external validation cohort were 0.699, 0.814 and 0.791, respectively. The nomogram was well-calibrated, with no statistical difference between the predicted and the observed probabilities. CONCLUSION: We have developed and validated a robust tool enabled to predict subsequent liver metastasis in patients with nonmetastatic breast cancer. Distinguishing a population of patients at high risk of liver metastasis will facilitate preventive treatment or monitoring of liver metastasis.

Diagnostic and prognostic value of circular RNA CDR1as/ciRS-7 for solid tumours: A systematic review and meta-analysis.

The circular RNA, CDR1as/ciRS-7, functions as a vital regulator in various cancers; however, the predictive value of CDR1as remains controversial. Therefore, a comprehensive analysis for clarifying the precise diagnostic and prognostic value of CDR1as in solid tumours is needed. A literature review of several databases was conducted for identifying potential studies. Pooled odds ratios (ORs) and hazard ratios (HRs) were used for evaluating the diagnostic accuracy variables and survival. Overall, 15 studies (1787 patients) and 11 studies (1578 patients) were included for diagnostic and prognostic outcome syntheses, respectively. Up-regulated CDR1as expression was found to be correlated with worse clinicopathological characteristics, including the T status, N status, histological grade, TNM stage and distant metastasis. The synthesized sensitivity was 0.72 (95% confidence interval [CI], 0.65-0.79), and the specificity was 0.80 (95% CI, 0.74-0.86). The positive likelihood ratio (LR), negative LR and diagnostic odds ratio (DOR) were 3.70, 0.34 and 10.80, respectively. The area under the receiver operator characteristic curve was 0.84 (95% CI, 0.80-0.87). In the pooled prognostic analysis, patients with high CDR1as expression had worse overall survival (HR = 2.40, P < 0.001) and disease-free survival (HR = 1.74, P < 0.001). These results suggest that CDR1as is a reliable diagnostic and prognostic biomarker with high accuracy and efficiency, which may potentially facilitate clinical decisions on solid tumours in the future.

Development and validation of a stromal immune phenotype classifier for predicting immune activity and prognosis in triple-negative breast cancer.

Our study aims to construct a prognosis-related immune phenotype classifier for predicting clinical prognosis and immune activity in triple-negative breast cancer (TNBC). A total of 237 patients with TNBC from Sun Yat-sen University Cancer Center (SYSUCC) and 533 patients with TNBC from public datasets were included in our study. A stromal immune quantified index was generated with a LASSO Cox regression model based on five prognosis-related immune cells evaluated by CIBERSORT or IHC and was used to determine immune phenotypes. Immune features were evaluated in the samples before chemotherapy. A total of 119 patients in the SYSUCC training cohort were classified into immune Phenotypes A and B according to the density of stromal CD4+ T cells, γδ T cells, monocytes, M1 macrophages and M2 macrophages. Phenotype A predicted better survival than Phenotype B, and the classification was further validated in the testing cohort of 118 patients and the validation cohort of 533 patients. In the combined cohort, significant differences were found in Phenotype A compared to Phenotype B for the 5-year overall survival (83.5% vs 65.8%, respectively, P < .01) and the 5-year disease-free survival (87.3% vs 76.0%, respectively, P < .01). In Phenotype A, immune-related pathways were significantly enriched, and a higher level of immune checkpoint molecules, including PD-L1, PD-1 and CTLA-4, could be observed. The immune phenotype classification was an independent prognostic indicator for TNBC and might serve as a potential predictor for immune activity within the tumor microenvironment.

Breast-Conserving Therapy Versus Mastectomy in Young Breast Cancer Patients Concerning Molecular Subtypes: A SEER Population-Based Study.

Breast-conserving therapy was once a contraindication in young breast cancer patients (aged ≤40 years). Emerging studies suggest that breast-conserving therapy and mastectomy could achieve similar prognosis in this population. However, the effect of molecular subtype disparity on surgical strategy in these patients remains unclear. Data from 8656 young patients (aged ≤40 years) diagnosed with invasive breast cancer between in 2010 and 2014 were retrospectively reviewed from the Surveillance, Epidemiology, and End Results database. The Cox proportional hazards model was used to evaluate subtype-dependent relationships between the surgical method and survival. Of the 8656 patients, 4132 (47.7%) underwent breast-conserving therapy and 4524 (52.3%) underwent mastectomy. The median follow-up period was 30.0 months. Patients in the breast-conserving therapy group demonstrated better overall survival and breast cancer-specific survival than those in the mastectomy group (both p < 0.05). Patients with different molecular subtypes exhibited significant differences in overall survival and breast cancer-specific survival (p < 0.001). Patients with luminal subtypes experienced better overall survival and breast cancer-specific survival than those with the triple-negative subtype. Multivariate analysis revealed that overall mortality risk of the breast-conserving therapy group was lower than that of the mastectomy group among HR(+)HER-2(-) and HR(-)HER-2(-) patients (overall mortality risk of 36.3% [adjusted hazard ratio = 0.637 {95% confidence interval = 0.448-0.905}, p = 0.012] and 36.0% [adjusted hazard ratio = 0.640 {95% confidence interval = 0.455-0.901}, p = 0.010] respectively.) The breast cancer-specific mortality risk was also lower by a percentage similar to that of the overall mortality risk. In the HR(+)HER-2(+) group, the surgical method was an independent prognostic factor for breast cancer-specific survival (adjusted hazard ratio = 0.275 [95% confidence interval = 0.089-0.849], p = 0.025), while there was a trend that patients with breast-conserving therapy had better overall survival than those with mastectomy (p = 0.056). In the HR(-)HER-2(+) group, no significant difference was observed in overall survival and breast cancer-specific survival (p = 0.791 and p = 0.262, respectively). Breast-conserving therapy resulted in significantly better prognosis in patients with luminal and triple-negative subtypes, while no significant difference was observed in patients with the HER-2 enriched subtype. These results may be helpful in informing clinically precise decision-making for surgery in this population.

[Gly14]-humanin restores cathepsin D function via FPRL1 and promotes autophagic degradation of Ox-LDL in HUVECs.

BACKGROUND AND AIM: Abnormal aggregation of oxidized low-density lipoprotein (Ox-LDL) in vascular endothelial cells (VECs) is one of the major pathological changes in atherosclerotic lesions. Our research aimed to assess the mechanism of humanin (HN) in promoting autophagic degradation of Ox-LDL in HUVECs. METHODS AND RESULTS: Flow cytometry and lipid quantitation results showed that Ox-LDL caused lipid and cholesterol accumulation in HUVECs. Western blot results showed that Ox-LDL increased the expression of autophagy-related proteins P62 and LC3-II in a concentration-dependent manner. The cathepsin D activity assay showed that Ox-LDL inhibited the function of cathepsin D. HNG pretreatment reduced lipid and cholesterol aggregation in HUVECs induced by Ox-LDL, increased LC3-II protein level, decreased P62 protein content, and reversed Ox-LDL-induced cathepsin D functional impairment. Inhibition of the FPRL1 pathway by FPRL1 siRNA or the FPRL1-specific inhibitor Boc-MLF blocked all HNG's protective effects. These results indicate that HNG could restore cathepsin D activity and protein level in HUVECs to repair lysosomal functional damage induced by Ox-LDL, further repairing Ox-LDL-induced autophagic damage in HUVECs. CONCLUSION: HNG restores the activity of Ox-LDL-induced damaged lysosomal enzyme cathepsin D through its membrane protein receptor FPRL1 to promote autophagic degradation of Ox-LDL in HUVECs.

circRAD18 sponges miR-208a/3164 to promote triple-negative breast cancer progression through regulating IGF1 and FGF2 expression.

As a new rising star of non-coding RNA, circular RNAs (circRNAs) emerged as vital regulators with biological functions in diverse of cancers. However, the function and precise mechanism of the vast majority of circRNAs in triple-negative breast cancer (TNBC) occurrence and progression have not been clearly elucidated. In the current study, we identified and further investigated hsa_circ_0002453 (circRAD18) by analyzing our previous microarray profiling. Expression of circRAD18 was found significantly upregulated in TNBC compared with normal mammary tissues and cell lines. circRAD18 was positively correlated with T stage, clinical stage and pathological grade and was an independent risk factor for TNBC patients. We performed proliferation, colony formation, cell migration, apoptosis and mouse xenograft assays to verify the functions of circRAD18. Knockdown of circRAD18 significantly suppressed cell proliferation and migration, promoted cell apoptosis and inhibited tumor growth in functional and xenograft experiments. Through luciferase reporter assays, we confirmed that circRAD18 acts as a sponge of miR-208a and miR-3164 and promotes TNBC progression through upregulating IGF1 and FGF2 expression. Altogether, our research revealed the pivotal role of circRAD18-miR-208a/3164-IGF1/FGF2 axis in TNBC tumorigenesis and metastasis though the mechanism of competing endogenous RNAs. Thus, circRAD18 may serve as a novel prognostic biomarker and potential target for TNBC treatment in the future.

Identification of a 4-mRNA metastasis-related prognostic signature for patients with breast cancer.

Metastasis-related mRNAs have showed great promise as prognostic biomarkers in various types of cancers. Therefore, we attempted to develop a metastasis-associated gene signature to enhance prognostic prediction of breast cancer (BC) based on gene expression profiling. We firstly screened and identified 56 differentially expressed mRNAs by analysing BC tumour tissues with and without metastasis in the discovery cohort (GSE102484, n = 683). We then found 26 of these differentially expressed genes were associated with metastasis-free survival (MFS) in the training set (GSE20685, n = 319). A metastasis-associated gene signature built using a LASSO Cox regression model, which consisted of four mRNAs, can classify patients into high- and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter MFS (hazard ratio [HR] 3.89, 95% CI 2.53-5.98; P < 0.001), disease-free survival (DFS) (HR 4.69, 2.93-7.50; P < 0.001) and overall survival (HR 4.06, 2.56-6.45; P < 0.001) than patients with low-risk scores. The prognostic accuracy of mRNAs signature was validated in the two independent validation cohorts (GSE21653, n = 248; GSE31448, n = 246). We then developed a nomogram based on the mRNAs signature and clinical-related risk factors (T stage and N stage) that predicted an individual's risk of disease, which can be assessed by calibration curves. Our study demonstrated that this 4-mRNA signature might be a reliable and useful prognostic tool for DFS evaluation and will facilitate tailored therapy for BC patients at different risk of disease.

The PROTAC technology in drug development.

Currently, a new technology termed PROTAC, proteolysis targeting chimera, has been developed for inducing the protein degradation by a targeting molecule. This technology takes advantage of a moiety of targeted protein and a moiety of recognizing E3 ubiquitin ligase and produces a hybrid molecule to specifically knock down a targeted protein. During the first decade, three pedigreed groups worked on the development of this technology. To date, this technology has been extended by different groups, aiming to develop new drugs against different diseases including cancers. This review summarizes the contributions of the groups for the development of PROTAC. SIGNIFICANCE OF THE STUDY: This review summarized the development of the PROTAC technology for readers and also presented the author's opinions on the application of the technology in tumor therapy.

Gut microbiota reshapes cancer immunotherapy efficacy: Mechanisms and therapeutic strategies.

Gut microbiota is essential for maintaining local and systemic immune homeostasis in the presence of bacterial challenges. It has been demonstrated that microbiota play contrasting roles in cancer development as well as anticancer immunity. Cancer immunotherapy, a novel anticancer therapy that relies on the stimulation of host immunity, has suffered from a low responding rate and incidence of severe immune-related adverse events (irAEs). Previous studies have demonstrated that the diversity and composition of gut microbiota were associated with the heterogeneity of therapeutic effects. Therefore, alteration in microbiota taxa can lead to improved clinical outcomes in immunotherapy. In this review, we determine whether microbiota composition or microbiota-derived metabolites are linked to responses to immunotherapy and irAEs. Moreover, we discuss various approaches to improve immunotherapy efficacy or reduce toxicities by modulating microbiota composition.

Multi-omics analysis of disulfidptosis regulators and therapeutic potential reveals glycogen synthase 1 as a disulfidptosis triggering target for triple-negative breast cancer.

Disruption of disulfide homeostasis during biological processes can have fatal consequences. Excess disulfides induce cell death in a novel manner, termed as "disulfidptosis." However, the specific mechanism of disulfidptosis has not yet been elucidated. To determine the cancer types sensitive to disulfidptosis and outline the corresponding treatment strategies, we firstly investigated the crucial functions of disulfidptosis regulators pan-cancer at multi-omics levels. We found that different tumor types expressed dysregulated levels of disulfidptosis regulators, most of which had an impact on tumor prognosis. Moreover, we calculated the disulfidptosis activity score in tumors and validated it using multiple independent datasets. Additionally, we found that disulfidptosis activity was correlated with classic biological processes and pathways in various cancers. Disulfidptosis activity was also associated with tumor immune characteristics and could predict immunotherapy outcomes. Notably, the disulfidptosis regulator, glycogen synthase 1 (GYS1), was identified as a promising target for triple-negative breast cancer and validated via in vitro and in vivo experiments. In conclusion, our study elucidated the complex molecular phenotypes and clinicopathological correlations of disulfidptosis regulators in tumors, laying a solid foundation for the development of disulfidptosis-targeting strategies for cancer treatment.

Single-cell RNA sequencing elucidated the landscape of breast cancer brain metastases and identified ILF2 as a potential therapeutic target.

Distant metastasis remains the primary cause of morbidity in patients with breast cancer. Hence, the development of more efficacious strategies and the exploration of potential targets for patients with metastatic breast cancer are urgently needed. The data of six patients with breast cancer brain metastases (BCBrM) from two centres were collected, and a comprehensive landscape of the entire tumour ecosystem was generated through the utilisation of single-cell RNA sequencing. We utilised the Monocle2 and CellChat algorithms to investigate the interrelationships among each subcluster. In addition, multiple signatures were collected to evaluate key components of the subclusters through multi-omics methodologies. Finally, we elucidated common expression programs of malignant cells, and experiments were conducted in vitro and in vivo to determine the functions of interleukin enhancer-binding factor 2 (ILF2), which is a key gene in the metastasis module, in BCBrM progression. We found that subclusters in each major cell type exhibited diverse characteristics. Besides, our study indicated that ILF2 was specifically associated with BCBrM, and experimental validations further demonstrated that ILF2 deficiency hindered BCBrM progression. Our study offers novel perspectives on the heterogeneity of BCBrM and suggests that ILF2 could serve as a promising biomarker or therapeutic target for BCBrM.

The burgeoning importance of PIWI-interacting RNAs in cancer progression.

PIWI-interacting RNAs (piRNAs) are a class of small noncoding RNA molecules that specifically bind to piwi protein family members to exert regulatory functions in germ cells. Recent studies have found that piRNAs, as tissue-specific molecules, both play oncogenic and tumor suppressive roles in cancer progression, including cancer cell proliferation, metastasis, chemoresistance and stemness. Additionally, the atypical manifestation of piRNAs and PIWI proteins in various malignancies presents a promising strategy for the identification of novel biomarkers and therapeutic targets in the diagnosis and management of tumors. Nonetheless, the precise functions of piRNAs in cancer progression and their underlying mechanisms have yet to be fully comprehended. This review aims to examine current research on the biogenesis and functions of piRNA and its burgeoning importance in cancer progression, thereby offering novel perspectives on the potential utilization of piRNAs and piwi proteins in the management and treatment of advanced cancer.

Pan-Cancer Single-Cell and Spatial-Resolved Profiling Reveals the Immunosuppressive Role of APOE+ Macrophages in Immune Checkpoint Inhibitor Therapy.

The heterogeneity of macrophages influences the response to immune checkpoint inhibitor (ICI) therapy. However, few studies explore the impact of APOE+ macrophages on ICI therapy using single-cell RNA sequencing (scRNA-seq) and machine learning methods. The scRNA-seq and bulk RNA-seq data are Integrated to construct an M.Sig model for predicting ICI response based on the distinct molecular signatures of macrophage and machine learning algorithms. Comprehensive single-cell analysis as well as in vivo and in vitro experiments are applied to explore the potential mechanisms of the APOE+ macrophage in affecting ICI response. The M.Sig model shows clear advantages in predicting the efficacy and prognosis of ICI therapy in pan-cancer patients. The proportion of APOE+ macrophages is higher in ICI non-responders of triple-negative breast cancer compared with responders, and the interaction and longer distance between APOE+ macrophages and CD8+ exhausted T (Tex) cells affecting ICI response is confirmed by multiplex immunohistochemistry. In a 4T1 tumor-bearing mice model, the APOE inhibitor combined with ICI treatment shows the best efficacy. The M.Sig model using real-world immunotherapy data accurately predicts the ICI response of pan-cancer, which may be associated with the interaction between APOE+ macrophages and CD8+ Tex cells.

Recent advances in exosome-based immunotherapy applied to cancer.

Cancer stands as a prominent contributor to global mortality rates, necessitating immediate attention toward the exploration of its treatment options. Extracellular vesicles have been investigated as a potential cancer therapy in recent years. Among them, exosomes, as cell-derived nanovesicles with functions such as immunogenicity and molecular transfer, offer new possibilities for immunotherapy of cancer. However, multiple studies have shown that exosomes of different cellular origins have different therapeutic effects. The immunomodulatory effects of exosomes include but are not limited to inhibiting or promoting the onset of immune responses, regulating the function of molecular signaling pathways, and serving as carriers of antitumor drugs. Therefore, this mini-review attempts to summarize and evaluate the development of strategies for using exosomes to package exogenous cargos to promote immunotherapy in cancer.

Multi-omics analyses unravel DNA damage repair-related clusters in breast cancer with experimental validation.

Background: As one of the most common malignancies worldwide, breast cancer (BC) exhibits high heterogeneity of molecular phenotypes. The evolving view regarding DNA damage repair (DDR) is that it is context-specific and heterogeneous, but its role in BC remains unclear. Methods: Multi-dimensional data of transcriptomics, genomics, and single-cell transcriptome profiling were obtained to characterize the DDR-related features of BC. We collected 276 DDR-related genes based on the Molecular Signature Database (MSigDB) database and previous studies. We acquired public datasets included the SCAN-B dataset (GEO: GSE96058), METABRIC database, and TCGA-BRCA database. Corresponding repositories such as transcriptomics, genomics, and clinical information were also downloaded. We selected scRNA-seq data from GEO: GSE176078, GSE114727, GSE161529, and GSE158724. Bulk RNA-seq data from GEO: GSE176078, GSE18728, GSE5462, GSE20181, and GSE130788 were extracted for independent analyses. Results: The DDR classification was constructed in the SCAN-B dataset (GEO: GSE96058) and METABRIC database, Among BC patients, there were two clusters with distinct clinical and molecular characteristics: the DDR-suppressed cluster and the DDR-active cluster. A superior survival rate is found for tumors in the DDR-suppressed cluster, while those with the DDR-activated cluster tend to have inferior prognoses and clinically aggressive behavior. The DDR classification was validated in the TCGA-BRCA cohort and shown similar results. We also found that two clusters have different pathway activities at the genomic level. Based on the intersection of the different expressed genes among these cohorts, we found that PRAME might play a vital role in DDR. The DDR classification was then enabled by establishing a DDR score, which was verified through multilayer cohort analysis. Furthermore, our results revealed that malignant cells contributed more to the DDR score at the single-cell level than nonmalignant cells. Particularly, immune cells with immunosuppressive properties (such as FOXP3+ CD4+ T cells) displayed higher DDR scores among those with distinguishable characteristics. Conclusion: Collectively, this study performs general analyses of DDR heterogeneity in BC and provides insight into the understanding of individualized molecular and clinicopathological mechanisms underlying unique DDR profiles.

Peripheral blood CD19 positive B lymphocytes increase after ischemic stroke and correlate with carotid atherosclerosis.

Introduction: Atherosclerosis is the primary pathological basis of ischemic stroke, and dyslipidemia is one of its major etiological factors. Acute ischemic stroke patients exhibit imbalances in lymphocyte subpopulations, yet the correlation between these dynamic changes in lymphocyte subpopulations and lipid metabolism disorders, as well as carotid atherosclerosis in stroke patients remains poorly understood. Methods: We retrospectively analyzed the demographic data, risk factors of cerebrovascular disease, laboratory examination (lymphocyte subsets, lipid indexes, etc.), clinical features and c;/]-sity from December 2017 to September 2019 and non-stroke patients with dizziness/vertigo during the same period. Results: The results showed that peripheral B lymphocyte proportions are elevated in acute ischemic stroke patients compared with those of the control group (13.6 ± 5.3 vs. 11.7 ± 4.4%, p = 0.006). Higher B lymphocyte proportions are associated with concurrent dyslipidemia, increased levels of vascular risk factors including triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and very-low-density lipoprotein cholesterol (VLDL-C), as well as decreased levels of the protective factor high-density lipoprotein cholesterol (HDL-C). Elevated B lymphocyte proportions are independently correlated with carotid atherosclerosis in stroke patients. Discussion: We found CD19 positive B Lymphocytes increase after ischemic stroke and correlate with Carotid Atherosclerosis. Lymphocyte subpopulations should be highlighted in stroke patients.