LncRNA SEMA3B-AS1 suppresses the tumor-initiating characteristics of triple negative breast cancer via engaging in MLL4-mediated H3K4 trimethylation.

Long noncoding RNAs (lncRNAs) are crucial regulators of tumor-initiating cells (TICs) and hold particular importance in triple negative breast cancer (TNBC). Yet, the precise mechanisms by which TIC-associated lncRNAs influence TNBC remain unclear. Our research utilized The Cancer Genome Atlas Breast Cancer (BC) data set to identify prognostic lncRNAs. We then conducted extensive assays to explore their impact on the tumor-initiating phenotype of TNBC cells and the underlying mechanisms. Notably, we found that low expression of lncRNA SEMA3B-AS1 correlated with unfavorable survival in BC patients. SEMA3B-AS1 was also downregulated in TNBC and linked to advanced tumor stage. Functional experiments confirmed its role as a TIC-suppressing lncRNA, curtailing mammosphere formation, ALDH + TIC cell proportion, and impairing clonogenicity, migration, and invasion. Mechanistic insights unveiled SEMA3B-AS1's nuclear localization and interaction with MLL4 (mixed-lineage leukemia 4), triggering H3K4 methylation-associated transcript activation and thus elevating the expression of SEMA3B, a recognized tumor suppressor gene. Our findings emphasize SEMA3B-AS1's significance as a TNBC-suppressing lncRNA that modulates TIC behavior. This study advances our comprehension of lncRNA's role in TNBC progression, advocating for their potential as therapeutic targets in this aggressive BC subtype.

A multifunctional hydrogel loaded with two nanoagents improves the pathological microenvironment associated with radiation combined with skin wounds.

Persistent oxidative stress and recurring waves of inflammation with excessive reactive oxygen species (ROS) and free radical accumulation could be generated by radiation. Exposure to radiation in combination with physical injuries such as wound trauma would produce a more harmful set of medical complications, which was known as radiation combined with skin wounds (RCSWs). However, little attention has been given to RCSW research despite the unsatisfactory therapeutic outcomes. In this study, a dual-nanoagent-loaded multifunctional hydrogel was fabricated to ameliorate the pathological microenvironment associated with RCSWs. The injectable, adhesive, and self-healing hydrogel was prepared by crosslinking carbohydrazide-modified gelatin (Gel-CDH) and oxidized hyaluronic acid (OHA) through the Schiff-base reaction under mild condition. Polydopamine nanoparticles (PDA-NPs) and mesenchymal stem cell-secreted small extracellular vesicles (MSC-sEV) were loaded to relieve radiation-produced tissue inflammation and oxidation impairment and enhance cell vitality and angiogenesis individually or jointly. The proposed PDA-NPs@MSC-sEV hydrogel enhanced cell vitality, as shown by cell proliferation, migration, colony formation, and cell cycle and apoptosis assays in vitro, and promoted reepithelization by attenuating microenvironment pathology in vivo. Notably, a gene set enrichment analysis of proteomic data revealed significant enrichment with adipogenic and hypoxic pathways, which play prominent roles in wound repair. Specifically, target genes were predicted based on differential transcription factor expression. The results suggested that MSC-sEV- and PDA-NP-loaded multifunctional hydrogels may be promising nanotherapies for RCSWs. STATEMENT OF SIGNIFICANCE: The small extracellular vesicle (sEV) has distinct advantages compared with MSCs, and polydopamine nanoparticles (PDA-NPs), known as the biological materials with good cell affinity and histocompatibility which have been reported to scavenge ROS free radicals. In this study, an adhesive, injectable, self-healing, antibacterial, ROS scavenging and amelioration of the radiation related microenvironment hydrogel encapsulating nanoscale particles of MSC-sEV and PDA-NPs (PDA-NPs@MSC-sEV hydrogel) was synthesized for promoting radiation combined with skin wounds (RCSWs). GSEA analysis profiled by proteomics data revealed significant enrichments in the regulations of adipogenic and hypoxic pathways with this multi-functional hydrogel. This is the first report of combining this two promising nanoscale agents for the special skin wounds associated with radiation.

Construction of Prognostic Risk Model of 5-Methylcytosine-Related Long Non-Coding RNAs and Evaluation of the Characteristics of Tumor-Infiltrating Immune Cells in Breast Cancer.

Purpose: The role of 5-methylcytosine-related long non-coding RNAs (m5C-lncRNAs) in breast cancer (BC) remains unclear. Here, we aimed to investigate the prognostic value, gene expression characteristics, and correlation between m5C-lncRNA risk model and tumor immune cell infiltration in BC. Methods: The expression matrix of m5C-lncRNAs in BC was obtained from The Cancer Genome Atlas database, and the lncRNAs were analyzed using differential expression analysis as well as univariate and multivariate Cox regression analysis to eventually obtain BC-specific m5C-lncRNAs. A risk model was developed based on three lncRNAs using multivariate Cox regression and the prognostic value, accuracy, as well as reliability were verified. Gene set enrichment analysis (GSEA) was used to analyze the Kyoto Encyclopedia of Genes and Genomes signaling pathway enrichment of the risk model. CIBERSORT algorithm and correlation analysis were used to explore the characteristics of the BC tumor-infiltrating immune cells. Finally, reverse transcription-quantitative polymerase chain reaction was performed to detect the expression level of three lncRNA in clinical samples. Results: A total of 334 differential m5C-lncRNAs were identified, and three BC-specific m5C-lncRNAs were selected, namely AP005131.2, AL121832.2, and LINC01152. Based on these three lncRNAs, a highly reliable and specific risk model was constructed, which was proven to be closely related to the prognosis of patients with BC. Therefore, a nomogram based on the risk score was built to assist clinical decisions. GSEA revealed that the risk model was significantly enriched in metabolism-related pathways and was associated with tumor immune cell infiltration based on the analysis with the CIBERSORT algorithm. Conclusion: The efficient risk model based on m5C-lncRNAs associated with cancer metabolism and tumor immune cell infiltration could predict the survival prognosis of patients, and AP005131.2, AL121832.2, and LINC01152 could be novel biomarkers and therapeutic targets for BC.

Erratum: KCNN4 induces multiple chemoresistance in breast cancer by regulating BCL2A1.

[This corrects the article on p. 3302 in vol. 10, PMID: 33163271.].

KCNN4 induces multiple chemoresistance in breast cancer by regulating BCL2A1.

Multidrug chemoresistance is a major clinical obstacle in breast cancer treatment. We aimed to elucidate the sensitivity to therapeutics in gemcitabine-resistant breast cancer models. Pooled library screening combined with RNA-seq was conducted to explore the potential targets involved in gemcitabine resistance in breast cancer cells. Cytotoxicity and tumor xenograft assays were used to evaluate the effect of calcium-activated channel subfamily N member 4 (KCNN4) inhibitors on the cellular sensitivity of breast cancer cells to chemotherapeutic drugs both in vitro and in vivo. We found that KCNN4 is an important determinant for the cytotoxicity of gemcitabine. Elevated KCNN4 expression enhanced resistance to chemotherapeutic antimetabolites and promoted cell proliferation. Conversely, silencing KCNN4 or chemical inhibition of KCNN4 by the specific inhibitor TRAM-34 inhibited the chemoresistance and cell proliferation. Mechanistically, KCNN4 upregulated BCL2-related protein A1 (BCL2A1) to suppress apoptosis by activating RAS-MAPK and PI3K-AKT signaling. Moreover, high expression levels of KCNN4 and BCL2A1 were associated with shortened disease-free survival in the cohort studies. Collectively, our findings showed that KCNN4 is a key modulator of progression and drug resistance in breast cancer, indicating that targeting KCNN4 may serve as a promising therapeutic strategy to overcome multidrug chemoresistance in this disease.

Spinal Cord Syphilitic Gumma Presenting with Brown-Séquard Syndrome: A Case Report and Literature Review.

BACKGROUND: Spinal neurosyphilis manifesting as a solitary syphilitic gumma is exceedingly rare. There are non-specific imaging findings and challenges in the diagnosis of spinal syphilitic gumma, which could be easily misdiagnosed as tumor lesions and require surgical resection or biopsy. CLINICAL PRESENTATION: We report the case of a 45-year-old female patient who was diagnosed with Spinal syphilitic gumma. Our case is the first reported case of spinal cord syphilitic gumma with intradural-extramedullary and intramedullary involvement. CONCLUSION: Spinal syphilitic gumma exhibits diverse clinical manifestations, lacks specific imaging features, accompanied by the patient's history deliberately concealed. Since clinicians do not have sufficient knowledge about such rare cases, misdiagnosis and missed diagnosis will be likely. When there is clinical suspicion for spinal syphilitic gumma, clinicians should pay close attention to relevant medical history, carry out a comprehensive physical examination and specific serological tests and cerebrospinal fluid (CSF) analysis. In summary, in cases with stable neurologic conditions, a trial administration of intravenous penicillin with follow-up imaging may be the optimal treatment option, and in cases with rapid progression or acute exacerbation, a surgical resection together with systemic antibiotic treatment for syphilis after surgery may be the best treatment strategy.

Serum miR-4530 sensitizes breast cancer to neoadjuvant chemotherapy by suppressing RUNX2.

PURPOSE: Neoadjuvant chemotherapy (NAC) plays a pivotal role in the treatment of locally advanced breast cancer (LABC); however, breast cancer is a heterogeneous disease, individual responses to chemotherapy are highly variable. Therefore, the purpose of the current research is to identify biomarkers that can predict the chemotherapeutic response. PATIENTS AND METHODS: We recruited 78 patients with primary breast cancer who underwent taxane- and anthracycline-based NAC; these patients were divided into sensitive and resistant groups according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The microRNA microarray was conducted to explore differentially expressed miRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) further validated the relationship between miR-4530 and chemosensitivity in breast cancer patients. RESULTS: No significant differences were observed between the two groups regarding the clinicopathological characteristics. miR-4530 showed the most potential involving breast cancer chemosensitivity. Mechanically, RUNX2 was identified one of the direct targets of miR-4530 and responsible for breast cancer chemosensitivity. CONCLUSION: Our results revealed that elevated serum miR-4530 levels may sensitize breast cancer to taxane- and anthracycline-based NAC by suppressing RUNX2; therefore, this miRNA has the potential to be a new biomarker for predicting breast cancer chemosensitivity.

MicroRNA-493 is a prognostic factor in triple-negative breast cancer.

Breast cancer is one of the most common malignant diseases in women. Triple-negative breast cancer (TNBC) shows higher aggressiveness and recurrence rates than other subtypes, and there are no effective targets or tailored treatments for TNBC patients. Thus, finding effective prognostic markers for TNBC could help clinicians in their ability to care for their patients. We used tissue microarrays (TMAs) to detect microRNA-493 (miR-493) expression in breast cancer samples. A miRCURY LNA detection probe specific for miR-493 was used in in situ hybridization assays. Staining results were reviewed by two independent pathologists and classified as high or low expression of miR-493. Kaplan-Meier survival plots and multivariate Cox analysis were carried out to clarify the relationship between miR-493 and survival. In the Kaplan-Meier analysis, patients with high miR-493 expression had better disease-free survival than patients with low miR-493 expression. After adjusting for common clinicopathological factors in breast cancer, the expression level of miR-493 was still a significant prognostic factor in breast cancer. Further subtype analysis revealed that miR-493 expression levels were only significantly prognostic in TNBC patients. These results were validated in the Molecular Taxonomy of Breast Cancer International Consortium database for overall survival. We proved the prognostic role of miR-493 in TNBC by using one of the largest breast cancer TMAs available and validated it in a large public RNA sequencing database.

A new electrochemical immunoassay for prion protein based on hybridization chain reaction with hemin/G-quadruplex DNAzyme.

In this work, a new electrochemical immunosensor was developed for prion protein assay based on hybridization chain reaction (HCR) with hemin/G-quadruplex DNAzyme for signal amplification. In this amplification system, the hemin/G-quadruplex DNAzyme simultaneously mimicked the biocatalytic functions for H2O2 reduction and L-cysteine oxidation. In the presence of L-cysteine, the hemin/G-quadruplex catalyzed the oxidation of L-cysteine to L-cystine. At the same time, H2O2 was produced under the oxygen condition. Then, the hemin/G-quadruplex could quickly catalyze the reduction of H2O2, mimicking the catalytic performance of horseradish peroxidase (HRP). Under the optimal conditions, the immunosensor showed a wide linear response range from 0.5 pg/mL to 100 ng/mL with the low detection limit of 0.38 pg/mL (3σ). By changing the specific antibody, this strategy could be easily extended to detect the infectious isoform of prion (PrPSc) and other proteins. Based on its good analytical performance, the developed method shows great potential applications in diagnosis of prion diseases at presymptomatic stage and bioanalysis.

Normal and cancerous mammary stem cells evade interferon-induced constraint through the miR-199a-LCOR axis.

Tumour-initiating cells, or cancer stem cells (CSCs), possess stem-cell-like properties observed in normal adult tissue stem cells. Normal and cancerous stem cells may therefore share regulatory mechanisms for maintaining self-renewing capacity and resisting differentiation elicited by cell-intrinsic or microenvironmental cues. Here, we show that miR-199a promotes stem cell properties in mammary stem cells and breast CSCs by directly repressing nuclear receptor corepressor LCOR, which primes interferon (IFN) responses. Elevated miR-199a expression in stem-cell-enriched populations protects normal and malignant stem-like cells from differentiation and senescence induced by IFNs that are produced by epithelial and immune cells in the mammary gland. Importantly, the miR-199a-LCOR-IFN axis is activated in poorly differentiated ER- breast tumours, functionally promotes tumour initiation and metastasis, and is associated with poor clinical outcome. Our study therefore reveals a common mechanism shared by normal and malignant stem cells to protect them from suppressive immune cytokine signalling.

The different outcomes between breast-conserving surgery and mastectomy in triple-negative breast cancer: a population-based study from the SEER 18 database.

Breast-conserving surgery (BCS) including radiotherapy (RT) has been demonstrated to provide at least equivalent prognosis to mastectomy in early-stage breast cancer. However, studies on triple-negative breast cancer (TNBC) patients are relatively scarce. The current population-based study aimed to investigate the distinct outcomes between BCS+RT and mastectomy in patients with TNBC. Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we enrolled 11,514 female TNBC cases diagnosed during the years 2010-2013. Those patients were subdivided into BCS+RT (5,469) and mastectomy groups (6,045), and we conducted a survival comparison between the two groups. The endpoints were breast cancer-specific survival (BCSS) and overall survival (OS). In the overall cohort, patients with BCS+RT exhibited distinctly better breast cancer-specific survival (BCSS) (log-rank, p < 0.001) and overall survival (OS) (log-rank, p < 0.001) than did mastectomy patients. When stratifying the TNBC patients according to age, histology grade, TNM stage, tumor size, and lymph node (LN) status, most patients in the BCS+RT group presented with better survival than did the patients in the mastectomy group, except for the grade I (log-rank, p = 0.830, both BCSS and OS) and stage I (log-rank, BCSS, p = 0.127; OS, p = 0.093) patients. In addition, after adjusting for confounding variables by multivariable Cox proportional hazard analysis, BCS+RT still tended to present with higher BCSS and OS. In conclusion, from our study on SEER data, BCS+RT displayed elevated BCSS and OS in TNBC patients compared to mastectomy, at least equally. Our study provided further evidence for surgeons that BCS with RT is available for TNBC patients.

The association of uric acid with leukoaraiosis.

Objective To explore the possible correlation between uric acid levels and leukoaraiosis (LA). Methods This cross-sectional study enrolled patients who presented with some neurological discomfort (e.g. dizziness, headache, mild cognitive impairment). Potential demographic and clinical risk factors associated with LA, including sex, age, hypertension, diabetes mellitus, smoking, alcohol consumption, dyslipidaemia, plasma fibrinogen, D-dimer, uric acid, and homocysteine, were investigated using univariate and multivariate logistic regression analyses. Results A total of 268 patients were enrolled in the study and divided into the LA group ( n = 164) and the non-LA group ( n = 104). Compared with the non-LA group, uric acid was significantly higher in the LA group (mean ± SD: 356.49 ± 121.85 µmol/l versus 289.96 ± 102.98 µmol/l). Multivariate logistic regression analyses showed that uric acid was an independent risk factor for LA (odds ratio 1.285; 95% confidence interval 1.062, 1.556). Conclusion Hyperuricaemia was an independent risk factor for leukoaraiosis in Chinese patients.

Similar outcomes between adenoid cystic carcinoma of the breast and invasive ductal carcinoma: a population-based study from the SEER 18 database.

Adenoid cystic carcinoma of the breast (breast-ACC) is a rare and indolent tumor with a good prognosis despite its triple-negative status. However, we observed different outcomes in the present study. Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we enrolled a total of 89,937 eligible patients with an estimated 86 breast-ACC cases and 89,851 invasive ductal carcinoma (IDC) patients. In our study, breast-ACC among women presented with a higher proportion of triple-negative breast cancer (TNBC), which was more likely to feature well-differentiated tumors, rare regional lymph node involvement and greater application of breast-conserving surgery (BCS). Kaplan-Meier analysis revealed that patients with breast-ACC and breast-IDC patients had similar breast cancer-specific survival (BCSS) and overall survival (OS). Moreover, using the propensity score matching method, no significant difference in survival was observed in matched pairs of breast-ACC and breast-IDC patients. Additionally, BCSS and OS did not differ significantly between TNBC-ACC and TNBC-IDC after matching patients for age, tumor size, and nodal status. Further subgroup analysis of molecular subtype indicated improved survival in breast-ACC patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/Her2-) tumors compared to IDC patients with HR+/Her2- tumors. However, the survival of ACC-TNBC and IDC-TNBC patients was similar. In conclusion, ACCs have an indolent clinical course and result in similar outcomes compared to IDC. Understanding these clinical characteristics and outcomes will endow doctors with evidence to provide the same intensive treatment for ACC-TNBC as for IDC-TNBC and lead to more individualized and tailored therapies for breast-ACC patients.

High expression of microRNA-454 is associated with poor prognosis in triple-negative breast cancer.

MicroRNA-454 (miR-454) has been reported to play an oncogenic or tumor suppressor role in most cancers. However, the clinical relevance of miR-454 in breast cancer remains unclear. We examined the expression of miR-454 in a tissue microarray containing 534 breast cancer specimens from female patients at Fudan University Shanghai Cancer Center using in situ hybridization (ISH). Of these, 250 patients formed the training set and the other 284 were the validation set. The relationship between miR-454 and clinical outcome was analyzed by the Kaplan-Meier method. High expression of miR-454 indicated worse disease-free survival (DFS) in both cohorts (P = 0.006 for training set; P = 0.010 for validation set). Furthermore, in the triple-negative breast cancer (TNBC) subtype, miR-454 was positively correlated with worse clinical outcome (P = 0.013 for training set, P = 0.014 for validation set). In addition, patients in the low miR-454 expression cohort had better response to anthracycline compared to non-anthracycline chemotherapy (P = 0.056), but this difference was not observed in the high miR-454 expression cohort. Our findings indicated that miR-454 is a potential predictor of prognosis and chemotherapy response in TNBC.

Effect of nodal status on clinical outcomes of triple-negative breast cancer: a population-based study using the SEER 18 database.

Triple-negative breast cancer (TNBC) is an aggressive malignancy with a poor prognosis. Data from the Surveillance, Epidemiology and End Results database (2010-2012) were used to identify 10,771 patients with TNBC, and we assessed the effects of lymph node (LN) status on breast cancer-specific survival (BCSS) and overall survival (OS). In our study, a Kaplan-Meier plot showed that LN-negative patients (N0) had better survival outcomes than LN-positive patients and that patients with ≥10 positive LNs (N3) exhibited the worst survival outcomes regardless of tumor size. A pairwise comparison showed no difference in survival outcomes among each group stratified by tumor size. Further, for LN-positive patients with a tumor size ≤2 cm (T1) or >5 cm (T3), there were similar outcomes between patients with one to three LNs (N1) and those with four to nine LNs (N2), whereas N1 patients experienced significantly better survival outcomes than N3 patients (P<0.001). Therefore, ten metastatic lymph nodes was the cut-off value for poor prognosis. Nevertheless, for patients with a tumor size of 2-5 cm (T2), the extent of LN involvement contributed prognostic value to OS but not BCSS. In summary, we found that nodal status and tumor size exhibited distinct interaction patterns for predicting the outcomes of TNBC. These results provide deeper insight into the prognostic value of nodal status in TNBC.

Difference in characteristics and outcomes between medullary breast carcinoma and invasive ductal carcinoma: a population based study from SEER 18 database.

Medullary breast carcinoma (MBC) is a unique histological subtype of breast cancer. Our study was designed to identify difference in characteristics and outcomes between MBC and invasive ductal carcinoma (IDC), and further confirm the prognostic factors of MBC. Utilizing Surveillance, Epidemiology, and End Results (SEER), we identified 84,764 eligible patients, including 309 MBC and 84,455 IDC. Compared with the IDC group, the MBC group was associated with younger age at diagnosis, higher grade, more advanced stage, larger tumor size, and higher proportion of triple-negative breast cancer (TNBC). Kaplan-Meier analysis and univariate Cox proportional hazard regression model showed that patients with IDC had significantly better breast cancer-specific survival (BCSS) compared to MBC, but they had similar overall survival (OS). However, MBC histology was no longer a surrogate for worse BCSS or OS after 1:1 matching by age, American Joint Committee on Cancer (AJCC) stage, grade and breast subtype. In addition, it was exposed that not married status, high grade, large tumor size, positive nodal status, the subtype of TNBC and no receipt of radiation therapy were significantly associated with poor BCSS and OS. In conclusion, MBC demonstrated more aggressive behavior but similar outcomes compared to IDC, which may be determined by prognostic factors such as breast subtype. These results not only confer deeper insight into MBC but contribute to individualized and tailored therapy, and thereby may improve clinical management and outcomes.