Construction of a ferroptosis-related five-lncRNA signature for predicting prognosis and immune response in thyroid carcinoma.

BACKGROUND: Thyroid carcinoma (THCA) is the most common endocrine-related malignant tumor. Despite the good prognosis, some THCA patients may deteriorate into more aggressive diseases, leading to poor survival. This may be alleviated by developing a novel model to predict the risk of THCA, including recurrence and survival. Ferroptosis is an iron-dependent, oxidative, non-apoptotic form of cell death initially described in mammalian cells, and plays an important role in various cancers. To explore the potential prognostic value of ferroptosis in THCA, ferroptosis-related long non-coding RNAs (FRLs) were used to construct model for risk prediction of THCA. METHODS: RNA-sequencing data of THCA patients and ferroptosis-related genes were downloaded from The Cancer Genome Atlas (TCGA) and FerrDb, respectively. A total of 502 patients with complete data were randomly separated into a training cohort and a validation cohort at the ratio of 2:1. The Pearson correlation coefficients were calculated to determine the correlation between ferroptosis-related genes (FRGs) and the corresponding lncRNAs, and those meeting the screening conditions were defined as FRLs. Gene Expression Omnibus (GEO) database and qRT-PCR were used to verify the expression level of FRLs in THCA tissues. Univariate and multivariate cox regression analysis were performed to construct a FRLs signature based on lowest Akaike information criterion (AIC) value in the training cohort, then further tested in the validation cohort and the entire cohort. Gene set enrichment analysis (GSEA) and functional enrichment analysis were used to analyze the biological functions and signal pathways related to differentially expressed genes between the high-risk and low-risk groups. Finally, the relative abundance of different tumor-infiltrating immune cells were calculated by CIBERSORT algorithm. RESULTS: The patients were divided into high-risk group and low-risk group based on a 5-FRLs signature (AC055720.2, DPP4-DT, AC012038.2, LINC02454 and LINC00900) in training cohort, validation cohort and entire cohort. Through Kaplan-Meier analysis and area under ROC curve (AUC) value, patients in the high-risk group exhibited worse prognosis than patients in the low-risk group. GEO database and qRT-PCR confirmed that LINC02454 and LINC00900 were up-regulated in THCA. Univariate and multivariate cox regression analyses showed that the risk score was an independent prognostic indicator. GSEA and functional enrichment analysis confirmed that immune-related pathways against cancer were significantly activated in the low-risk THCA patients. Further analysis showed that the immune cells such as plasma cells, T cells CD8 and macrophages M1, and the expression of immune checkpoint molecules, including PD-1, PD-L1, CTLA4, and LAG3, were remarkably higher in the low-risk group. CONCLUSION: Our study used the TCGA THCA dataset to construct a novel FRLs prognostic model which could precisely predict the prognosis of THCA patients. These FRLs potentially mediate anti-tumor immunity and serve as therapeutic targets for THCA, which provided the novel insight into treatment of THCA.

Small molecule HDAC inhibitors: Promising agents for breast cancer treatment.

Breast cancer, a heterogeneous disease, is the most frequently diagnosed cancer and the second leading cause of cancer-related death among women worldwide. Recently, epigenetic abnormalities have emerged as an important hallmark of cancer development and progression. Given that histone deacetylases (HDACs) are crucial to chromatin remodeling and epigenetics, their inhibitors have become promising potential anticancer drugs for research. Here we reviewed the mechanism and classification of histone deacetylases (HDACs), association between HDACs and breast cancer, classification and structure-activity relationship (SAR) of HDACIs, pharmacokinetic and toxicological properties of the HDACIs, and registered clinical studies for breast cancer treatment. In conclusion, HDACIs have shown desirable effects on breast cancer, especially when they are used in combination with other anticancer agents. In the coming future, more multicenter and randomized Phase III studies are expected to be conducted pushing promising new therapies closer to the market. In addition, the design and synthesis of novel HDACIs are also needed.

A randomized Phase III trial of neoadjuvant recombinant human endostatin, docetaxel and epirubicin as first-line therapy for patients with breast cancer (CBCRT01).

To further assess the efficacy and safety of recombinant human endostatin (rh-endostatin), a Phase III, multicenter, prospective, randomized, controlled clinical trial was conducted. Patients to be treated with neoadjuvant docetaxel and epirubicin (DE) or DE plus rh-endostatin (DEE) were eligible for this trial. The primary endpoint was clinical/pathological response. Secondary endpoints included adverse events and quality of life (QOL). Finally, 803 patients were enrolled and randomly assigned to receive DE (n = 402) or DEE (n = 401) regimen. After three cycles of neoadjuvant therapy, "complete response" achieved in 14.2% of patients in DEE group versus 6.7% in DE group, "partial response" achieved in 76.8% versus 71.1%, while "stable disease" in 6.0% versus 18.9%, "progressive disease" in 3.0% versus 3.2% of patients. The rate of objective response in DEE and DE group was 91.0% and 77.9%, respectively (p < 0.001). In spite of a relatively higher pathological complete response achieved following the combination therapy, no significant difference was found between two arms. Adverse events were mostly of Grades 1-2. No significant difference in adverse event and QOL was found between the two arms. In conclusion, the combination of chemotherapy and rh-endostatin achieved better outcomes than chemotherapy alone, and thus can be considered as a promising therapeutic strategy for breast cancer.

PRMT5 determines the sensitivity to chemotherapeutics by governing stemness in breast cancer.

PURPOSE: Acquired resistance to chemotherapeutic agents in breast cancer is a major clinical challenge. Recent studies have shown that the emergence of cancer stem cells contributes to the development of drug resistance, and the protein arginine methyltransferase 5 (PRMT5) was crucial for the maintenance of stemness. However, the roles of PRMT5 in breast cancer cell stemness and the development of cancer drug resistance have not been clarified. In this study, we investigated the effect of PRMT5 on the sensitivity to doxorubicin and cell stemness in breast cancer. METHODS: PRMT5 expression was assessed in a panel of breast cancer cell lines (MDA-MB-231, MCF7, T-47D, BT-474, Au-565) and normal mammal epithelial cells (MCF10A). For knockdown of PRMT5 expression, two pairs of shRNAs as well as a control shRNA were utilized. Meanwhile, the wild-type PRMT5 and its catalytically dead counterpart (R368A) were stably overexpressed in MDA-MB-231 and MCF7 cells. The sensitivity to doxorubicin was determined by MTT assays, TUNEL assays, and Western blot analyses. To evaluate the degree of cell stemness, CD24/CD44-sorting and mammosphere formation experiments were performed. RESULTS: We demonstrated that PRMT5 regulates OCT4/A, KLF4, and C-MYC in breast cancer to govern stemness and affects the doxorubicin resistance of breast cancer. CONCLUSION: Our study suggests that PRMT5 may play an important role in the doxorubicin resistance of breast cancer.

The effects and mechanisms of SLC34A2 on maintaining stem cell-like phenotypes in CD147+ breast cancer stem cells.

The cancer stem cell (CSC) hypothesis has gained significant recognition in describing tumorigenesis. Identification of the factors critical to development of breast cancer stem cells (BCSCs) may provide insight into the improvement of effective therapies against breast cancer. In this study, we aim to investigate the biological function of SLC34A2 in affecting the stem cell-like phenotypes in BCSCs and its underlying mechanisms. We demonstrated that CD147+ cells from breast cancer tissue samples and cell lines possessed BCSC-like features, including the ability of self-renewal in vitro, differentiation, and tumorigenic potential in vivo. Flow cytometry analysis showed the presence of a variable fraction of CD147+ cells in 9 of 10 tumor samples. Significantly, SLC34A2 expression in CD147+ BCSCs was enhanced compared with that in differentiated adherent progeny of CD147+ BCSCs and adherently cultured cell line cells. In breast cancer patient cohorts, SLC34A2 expression was found increased in 9 of 10 tumor samples. By using lentiviral-based approach, si-SLC34A2-transduced CD147+ BCSCs showed decreased ability of sphere formation, cell viability in vitro, and tumorigenicity in vivo, which suggested the essential role of SLC34A2 in CD147+ BCSCs. Furthermore, PI3K/AKT pathway and SOX2 were found necessary to maintain the stemness of CD147+ BCSCs by using LY294002 or lentiviral-si-SOX2. Finally, we indicated that SLC34A2 could regulate SOX2 to maintain the stem cell-like features in CD147+ BCSCs through PI3K/AKT pathway. Therefore, our report identifies a novel role of SLC34A2 in BCSCs' state regulation and establishes a rationale for targeting the SLC34A2/PI3K/AKT/SOX2 signaling pathway for breast cancer therapy.

Upregulation of plasmacytoid dendritic cells in glioma.

The immune system fails to eradicate established tumors partly due to the induction of immune tolerance within tumor microenvironment. Plasmacytoid dendritic cells (pDCs) play critical roles in regulating immune system. In this study, we investigated pDC in the peripheral blood of glioma. CD4 + CD123 + BDCA2+ pDCs were tested from peripheral blood mononuclear cells in 40 glioma patients and 40 healthy controls by flow cytometry. The results revealed that proportion of pDCs was significantly increased in cases than in controls (0.52 ± 0.07 versus 0.21 ± 0.02 %, p < 0.001), whereas myeloid dendritic cells (mDCs) did not present any obvious difference between patients and healthy donors (0.25 ± 0.04 versus 0.18 ± 0.02 %, p = 0.217). We further studied pDCs in glioma patients with different clinical stages. Data showed that cases with smoking history had elevated level of pDCs than those non-smoker patients (0.91 ± 0.16 versus 0.48 ± 0.06 %, p = 0.004). Interestingly, we observed that patients with aphasia presented significantly elevated pDCs than those without aphasia (0.93 ± 0.12 versus 0.41 ± 0.07 %, p < 0.001). These data suggested that pDCs may be closely involved in the pathogenesis of glioma and may play roles in certain symptoms of the disease.

Lactylation-related gene signature for prognostic prediction and immune infiltration analysis in breast cancer.

Background: Lactylation is implicated in various aspects of tumor biology, but its relation to breast cancer remains poorly understood. This study aimed to explore the roles of the lactylation-related genes in breast cancer and its association with the tumor microenvironment. Methods: The expression and mutation patterns of lactylation-related genes were analyzed using the breast cancer data from The Cancer Genome Atlas (TCGA) database and GSE20685 datasets. Unsupervised clustering was used to identify two lactylation clusters. A lactylation-related gene signature was developed and validated using the training and validation cohorts. Immune cell infiltration and drug response were assessed. Results: We analyzed the mRNA expression, copy number variations, somatic mutations, and correlation networks of 22 lactylation-related genes in breast cancer tissues. We identified two distinct lactylation clusters with different survival outcomes and immune microenvironments. We further classified the patients into two gene subtypes based on lactylation clusters and identified a 7-gene signature for breast cancer survival prognosis. The prognostic score based on this signature demonstrated prognostic value and predicted the therapeutic response. Conclusion: Lactylation-related genes play a critical role in breast cancer by influencing tumor growth, immune microenvironment, and drug response. This lactylation-related gene signature may serve as a prognostic marker and a potential therapeutic target for breast cancer.

[Clinical application of endoscopic radical mastectomy for breast cancer combined with total pectoral muscle reconstruction with breast implants].

Objective: To investigate the effectiveness of endoscopic radical mastectomy for breast cancer combined with total pectoral muscle reconstruction with breast implants. Methods: The clinical data of 138 female patients with breast cancer who met the selection criteria between April 2019 and December 2023 were retrospectively analyzed. The mean age of the patients was 43.8 years (range, 27-61 years). The maximum diameter of the tumors ranged from 1.00 to 7.10 cm, with an average of 2.70 cm. Pathological examination showed that 108 cases were positive for both estrogen receptor and progesterone receptor, and 40 cases were positive for human epidermal growth factor receptor 2. All patients underwent endoscopic radical mastectomy for breast cancer combined with total pectoral muscle reconstruction with breast implants. The operation time, intraoperative blood loss, prosthesis size, and occurences of nipple-areola complex (NAC) ischemia, flap ischemia, infection, and capsular contracture were recorded. The Breast-Q2.0 score was used to evaluate breast aesthetics, patient satisfaction, and quality of life (including the social mental health score, breast satisfaction score, and chest pain score). Patients were divided into two groups based on the time of operation after the technique was implemented: group A (within 1 year, 25 cases) and group B (after 1 year, 113 cases). The above outcome indicators were compared between the two groups. Furthermore, based on the postoperative follow-up duration, patients were classified into a short-term group (follow-up time was less than 1 year) and a long-term group (follow-up time was more than 1 year). The baseline data and postoperative Breast-Q2.0 scores were compared between the two groups. Results: The average operation time was 120.76 minutes, the average intraoperative blood loss was 23.77 mL, and the average prosthesis size was 218.37 mL. Postoperative NAC ischemia occurred in 21 cases (15.22%), flap ischemia in 30 cases (21.74%), infection in 23 cases (16.67%), capsular contracture in 33 cases (23.91%), and prosthesis removal in 2 cases (1.45%). The operation time of group A was significantly longer than that of group B ( P<0.05), and there was no significant difference in intraoperative blood loss, prosthesis size, and related complications between the two groups ( P>0.05). All patients were followed up 3-48 months (mean, 20 months). There were 33 cases in the short-term group and 105 cases in the long-term group. There was no significant difference in baseline data such as age, body mass index, number of menopause cases, number of neoadjuvant chemotherapy cases, number of axillary lymph node dissection cases, breast cup size, degree of breast ptosis, and postoperative radiotherapy constituent ratio between the two groups ( P>0.05). At last follow-up, the breast satisfaction score in the patients' Breast-Q2.0 score ranged from 33 to 100, with an average of 60.9; the social mental health score ranged from 38 to 100, with an average of 71.3; the chest pain score ranged from 20 to 80, with an average of 47.3. The social mental health score of the long-term group was significantly higher than that of the short-term group ( P<0.05); there was no significant difference in breast satisfaction scores and chest pain scores between the two groups ( P>0.05). No patient died during the follow-up, and 2 patients relapsed at 649 days and 689 days postoperatively, respectively. The recurrence-free survival rate was 98.62%. Conclusion: Endoscopic radical mastectomy for breast cancer combined with total pectoral muscle reconstruction with breast implants has fewer complications and less damage, and the aesthetic effect of reconstructed breast is better.

MGP+ and IDO1+ tumor-associated macrophages facilitate immunoresistance in breast cancer revealed by single-cell RNA sequencing.

Immunotherapy is widely applied for the treatment of breast cancer, but to which some patients respond poorly or develop resistance. Therefore, the mechanism needs to be further studied. Transcriptomic data of 31 breast cancer patients treated with anti-programmed death receptor 1 (PD-1) was downloaded from the VIB-KULeuven Center for Cancer Biology to analyze the changes in myeloid cells in tumor tissues before and after immunotherapy. And 24 cell populations that may be immune-related were further identified. Representative cell populations were also screened and validated through cellular and animal experiments to evaluate the relevant molecular expression and pathways of tumor-associated macrophages (TAMs) in the tumor microenvironment. The results demonstrated that MGP+ TAMs and IDO1+ TAMs influenced the efficacy of immunotherapy in breast cancer patients. After anti-PD-1 treatment, Increased numbers of MGP+ TAMs and IDO1+ TAMs in breast cancer patients upregulated pro-tumorigenic factors associated with resistance to immunosuppressive therapy. This study provides new biomarkers for immunotherapy to predict therapeutic responses and overcome potential resistance to immunotherapy. It is an important complement to the immunosuppression caused by TAMs after immunotherapy for breast cancer.

Prognostic significance of USP22 as an oncogene in papillary thyroid carcinoma.

Ubiquitin-specific protease 22 (USP22), a novel deubiquitinating enzyme, has been associated with metastasis, therapy resistance, and cell cycle progression. The purpose of this study was to investigate the expression level of USP22 in papillary thyroid carcinoma (PTC) samples and to evaluate its clinical significance in PTC patients. USP22 expression was examined in 30 fresh PTC tissues and paired adjacent noncancerous tissues by real-time quantitative RT-PCR. Immunohistochemistry for USP22 was performed on additional 156 PTC tissues. The clinical significance of USP22 expression was analyzed. We found that the expression levels of USP22 mRNA and protein in PTC tissues were both significantly higher than those in noncancerous tissues. Clinicopathological analysis showed that USP22 expression was significantly correlated with tumor size (p=0.036), extracapsular invasion (p=0.012), multifocality (p=0.014), lymph node metastasis (p=0.022), distant metastasis (p=0.005), and TNM stage (p=0.002). The Kaplan-Meier survival curves revealed that USP22 expression was associated with poor prognosis in PTC patients. USP22 expression was an independent prognostic marker of overall patient survival in a multivariate analysis. Our findings suggest that USP22 is an independent predictor of poor prognosis of PTC patients.

Low expression of N-myc downstream-regulated gene 2 in oesophageal squamous cell carcinoma correlates with a poor prognosis.

BACKGROUND: It is currently unclear whether a correlation exists between N-myc downstream-regulated gene 2 (NDRG2) expression and oesophageal squamous cell carcinoma (ESCC). The aim of this study was to examine the underlying clinical significance of NDRG2 expression in ESCC patients and to investigate the effects of NDRG2 up-regulation on ESCC cell growth in vitro and in vivo. METHODS: Immunohistochemistry was used to determine the level of NDRG2 expressions in ESCC tissue, which was then compared to specific clinicopathological features in the patient and tissue specimens. Factors associated with patient survival were analysed. Moreover, the effects of up-regulating NDRG2 expression on the growth of an ESCC cell line were examined by MTT, colony formation, DNA replication activity and nude mouse model assays. RESULTS: Notably low expression of NDRG2 in ESCC patients was inversely associated with clinical stage, NM classification, histological differentiation and patients' vital status (all P < 0.05). ESCC patients expressing high levels of NDRG2 exhibited a substantially higher 5-year overall survival rate than NDRG2-negative patients. Furthermore, NDRG2 over-expression reduced the proliferation, colony formation and DNA replication activity in ESCC cells, as well as inhibiting the growth of ESCC cells in vivo. CONCLUSION: The present experiments demonstrated that NDRG2 may be a diagnostic and prognostic marker in patients with ESCC, and up-regulation of NDRG2 might act as a promising therapeutic strategy for aggressive ESCC.

Neoadjuvant rh-endostatin, docetaxel and epirubicin for breast cancer: efficacy and safety in a prospective, randomized, phase II study.

BACKGROUND: Recombinant human endostatin (rh-endostatin) is a novel antiangiogenesis drug developed in China. Previous experiments have shown that rh-endostatin can inhibit the proliferation and migration of endothelial cells and some types of tumor cells. In this study, we evaluated the efficacy and safety profiles of combination therapy of rh-endostatin and neoadjuvant chemotherapy for breast cancer patients in a prospective, randomized, controlled, phase II trial. METHODS: Sixty-eight patients with core-biopsy confirmed breast cancer were allocated randomly to two groups to receive 3 cycles of intravenous administration of either neoadjuvant DE (docetaxel: 75 mg/m2, d1, epirubicin: 75 mg/m2, d1, every 3 weeks), or neoadjuvant DE combined with rh-endostatin (7.5 mg/m2, d1-d14, every 3 weeks). The primary end point was clinical response based upon Response Evaluation Criteria in Solid Tumors, and the secondary end point was safety and quality of life. RESULTS: All patients were assessable for toxicity and 64 (94.2%) were assessable for efficacy evaluation. The objective response rate was 67.7% for chemotherapy (n = 31) and 90.9% for rh-endostatin plus chemotherapy (n = 33) (P = 0.021). A retrospective subset analysis revealed that rh-endostatin was more effective in premenopausal patients and patients with ECOG score of zero (P = 0.002 and P = 0.049, respectively). Five patients in the rh-endostatin plus chemotherapy arm achieved pathologic complete response compared with 2 in the chemotherapy arm (P = 0.428). No significant difference was identified in quality of life score and side effects (P > 0.05). CONCLUSION: The combination of rh-endostatin with chemotherapy produced a higher tumor response rate without increasing toxicity in breast cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT00604435.

Identification of periductal mastitis and granulomatous lobular mastitis: a literature review.

Background and Objective: Non-puerperal mastitis (NPM) is a breast disease with poor clinical manifestations, which seriously affects women's health and quality of life. Due to the low incidence rate of the disease and the paucity of related research, there is much misdiagnosis and mis-management of periductal mastitis (PDM) and granulomatous lobular mastitis (GLM). Therefore, understanding the differences between PDM and GLM, in terms of etiology and clinical manifestations, is crucial for patient treatment and prognosis. At the same time, choosing different treatment methods may not achieve the best treatment effect, so the appropriate treatment method can often reduce the patient's pain and reduce the recurrence of the patient's disease. Methods: The PubMed database was searched for articles published from 1 January 1990 to 16 June 2022 using the following search terms: "non-puerperal mastitis", "periductal mastitis", "granulomatous lobular mastitis", "mammary duct ectasia", "idiopathic granulomatous mastitis", "plasma cell mastitis", and "identification". The key findings of the related literatures were analyzed and summarized. Key Content and Findings: We systematically described the key points in the differential diagnosis, treatment, and prognosis of PDM and GLM. The use of different animal models for research and novel drugs to treat the disease were also described in this paper. Conclusions: The key points in the differentiation of the two diseases are clearly explained, and the respective treatment options and prognosis are summarized.

Authentication of a survival nomogram for non-invasive micropapillary breast cancer.

Purpose: We aimed at establishing a nomogram to accurately predict the overall survival (OS) of non-metastatic invasive micropapillary breast carcinoma (IMPC). Methods: In the training cohort, data from 429 patients with non-metastatic IMPC were obtained through the Surveillance, Epidemiology, and End Results (SEER) database. Other 102 patients were enrolled at the Xijing Hospital as validation cohort. Independent risk factors affecting OS were ascertained using univariate and multivariate Cox regression. A nomogram was established to predict OS at 3, 5 and 8 years. The concordance index (C-index), the area under a receiver operating characteristic (ROC) curve and calibration curves were utilized to assess calibration, discrimination and predictive accuracy. Finally, the nomogram was utilized to stratify the risk. The OS between groups was compared through Kaplan-Meier survival curves. Results: The multivariate analyses revealed that race (p = 0.047), surgery (p = 0.003), positive lymph nodes (p = 0.027), T stage (p = 0.045) and estrogen receptors (p = 0.019) were independent prognostic risk factors. The C-index was 0.766 (95% CI, 0.682-0.850) in the training cohort and 0.694 (95% CI, 0.527-0.861) in the validation cohort. Furthermore, the predicted OS was consistent with actual observation. The AUCs for OS at 3, 5 and 8 years were 0.786 (95% CI: 0.656-0.916), 0.791 (95% CI: 0.669-0.912), and 0.774 (95% CI: 0.688-0.860) in the training cohort, respectively. The area under the curves (AUCs) for OS at 3, 5 and 8 years were 0.653 (95% CI: 0.498-0.808), 0.683 (95% CI: 0.546-0.820), and 0.716 (95% CI: 0.595-0.836) in the validation cohort, respectively. The Kaplan-Meier survival curves revealed a significant different OS between groups in both cohorts (p<0.001). Conclusion: Our novel prognostic nomogram for non-metastatic IMPC patients achieved a good level of accuracy in both cohorts and could be used to optimize the treatment based on the individual risk factors.

Design, strategies, and therapeutics in nanoparticle-based siRNA delivery systems for breast cancer.

Utilizing small interfering RNA (siRNA) as a treatment for cancer, a disease largely driven by genetic aberrations, shows great promise. However, implementing siRNA therapy in clinical practice is challenging due to its limited bioavailability following systemic administration. An attractive approach to address this issue is the use of a nanoparticle (NP) delivery platform, which protects siRNA and delivers it to the cytoplasm of target cells. We provide an overview of design considerations for using lipid-based NPs, polymer-based NPs, and inorganic NPs to improve the efficacy and safety of siRNA delivery. We focus on the chemical structure modification of carriers and NP formulation optimization, NP surface modifications to target breast cancer cells, and the linking strategy and intracellular release of siRNA. As a practical example, recent advances in the development of siRNA therapeutics for treating breast cancer are discussed, with a focus on inhibiting cancer growth, overcoming drug resistance, inhibiting metastasis, and enhancing immunotherapy.

Willingness to receive COVID-19 vaccination and adverse effects after vaccination in breast cancer survivors during the COVID-19 pandemic: a cross-sectional retrospective study of a Chinese population.

Background: Breast cancer (BC) patients have a higher mortality rate after COVID-19 infection, but data on vaccination of BC patients and attitude towards COVID-19 vaccination and safety after vaccination are lacking. We wanted to understand the willingness and factors of BC survivors to receive a COVID-19 vaccine, and their adverse reactions. The purpose is to judge the safety of vaccination, and find strategies to promote vaccination in BC patients. Methods: Offline and online questionnaire surveys were provided in outpatient clinics and on an online follow-up platform, respectively, to collect information. Factors influencing vaccination willingness were analyzed by univariate and multivariate logistic regression. All statistical tests were performed bilaterally, and a P value <0.05 was considered statistically significant. Patients who have been vaccinated need to fill in questions about the impact on quality of life after vaccination, the type and frequency of vaccination, and side effects. Results: A total of 497 valid questionnaires were collected; 289 (58.1%) BC survivors were vaccinated with a COVID-19 vaccine, and 379 (76.26%) BC survivors had a fully or basically accepting attitude toward vaccination. Survivors over 70 years of age, educated only to high school level, and those receiving chemotherapy had significantly lower levels of acceptance of COVID-19 vaccines. Multivariate logistic regression analyses suggested that treatment status and cognitive attitude were independent factors influencing COVID-19 vaccination among BC survivors. The main reason for being vaccinated was "doctor recommendation" (57.26%). Unwillingness to receive a COVID-19 vaccine was mainly due to "the unknown safety of the vaccine in cancer patients" (67.80%). A total of 97.56% of the survivors believed that vaccination had no or almost no effect on their quality of life. Among the BC survivors, 18 (6.23%) had adverse reactions after vaccination. All adverse reactions were grade 1 or 2, and no adverse reactions of grade 3 or above were reported. The adverse reactions reported by 15 survivors (83.33%) markedly improved within 1 week. Conclusions: In terms of cognitive attitudes toward COVID-19 vaccines, elderly individuals and those with a lower education level were less receptive to vaccination. Therefore, attention to elderly survivors can help improve the vaccination rate.

PRMT5 reduces immunotherapy efficacy in triple-negative breast cancer by methylating KEAP1 and inhibiting ferroptosis.

BACKGROUND: As an emerging treatment strategy for triple-negative breast cancer (TNBC), immunotherapy acts in part by inducing ferroptosis. Recent studies have shown that protein arginine methyltransferase 5 (PRMT5) has distinct roles in immunotherapy among multiple cancers by modulating the tumor microenvironment. However, the role of PRMT5 during ferroptosis, especially for TNBC immunotherapy, is unclear. METHODS: PRMT5 expression in TNBC was measured by IHC (immunohistochemistry) staining. To explore the function of PRMT5 in ferroptosis inducers and immunotherapy, functional experiments were conducted. A panel of biochemical assays was used to discover potential mechanisms. RESULTS: PRMT5 promoted ferroptosis resistance in TNBC but impaired ferroptosis resistance in non-TNBC. Mechanistically, PRMT5 selectively methylated KEAP1 and thereby downregulated NRF2 and its downstream targets which can be divided into two groups: pro-ferroptosis and anti-ferroptosis. We found that the cellular ferrous level might be a critical factor in determining cell fate as NRF2 changes. In the context of higher ferrous concentrations in TNBC cells, PRMT5 inhibited the NRF2/HMOX1 pathway and slowed the import of ferrous. In addition, a high PRMT5 protein level indicated strong resistance of TNBC to immunotherapy, and PRMT5 inhibitors potentiated the therapeutic efficacy of immunotherapy. CONCLUSIONS: Our results reveal that the activation of PRMT5 can modulate iron metabolism and drive resistance to ferroptosis inducers and immunotherapy. Accordingly, PRMT5 can be used as a target to change the immune resistance of TNBC.

[Combination of recombinant human endostatin and neoadjuvant chemotherapy for breast cancer].

OBJECTIVE: Recombinant human endostatin (rh-Endostatin), a protein modified by an additional nine-amino acid sequence to the N-terminal of endostatin, is a novel antiangiogenesis drug developed in China. The preclinical data suggested that it can inhibit proliferation and migration not only in endothelial cells, but also in some types of tumor cells. Theoretically, antiangiogenesis drugs should also be effective in the therapy of other solid tumors, including breast cancer. Here a prospective, randomized, controlled, phase II trial of combining rh-Endostatin and neoadjuvant chemotherapy was performed to evaluate its efficacy and safety profiles in patients with breast cancer. METHODS: A total of 68 patients with pathologically confirmed breast cancer were randomly assigned to receive the neoadjuvant DE regimen (docetaxel: 75 mg/m(2), d1, epirubicin: 75 mg/m(2), d1) every 3 weeks with or without rh-Endostatin (7.5 mg/m(2), d1-d14). Surgical resection was performed after 3 cycles of neoadjuvant treatment. The primary end-points were objective response rate (ORR) and pathological complete response rate (PCRR) while the secondary end-points quality of life (QOL) and toxicity. RESULTS: Among all of them, 64 were assessable for efficacy and 68 for toxicity. The ORRs were 90.9% (30/33) and 67.7% (21/31) in the combination and control groups respectively (P = 0.021). The stratification analysis showed that rh-Endostatin was more effective in the treatment of pre-menopausal and Eastern Cooperative Oncology Group (ECOG) = 0 patients (P < 0.05). The PCRRs were 15.2% (5/33) and 6.5% (2/31) in the combination and control groups respectively (P = 0.428). No significant difference was identified in QOL score and side effects (P > 0.05). CONCLUSIONS: Compared with DE regimen alone, the combination of rh-Endostatin with DE chemotherapy may achieve a higher ORR with no increased toxicity in breast cancer patients. Thus it can be utilized safely and effectively in the neoadjuvant treatment of breast cancer.

[Serum level of MMP-2 in early breast cancer and its correlation with circulating tumor cells].

OBJECTIVE: To explore the serum levels of MMP-2 in early breast cancer and its clinical significance and correlation with the circulating tumor cells in the patients. METHODS: The serum levels of MMP-2 in breast fibroadenoma (n = 10) and breast cancer (n = 72) were detected by enzyme-linked immunosorbent assay (ELISA). And CK19 mRNA was measured by quantitative reverse transcription-polymerase chain reaction in blood as an index of circulating tumor cells in the patients. RESULTS: The serum level of MMP-2 in breast cancer was significantly higher than that in breast fibroadenoma (12.24 vs 2.21 µg/L, P = 0.003). Subgroup analysis showed that the serum levels of MMP-2 were higher in HER-2 positive patients than those in HER-2 negative ones (16.77 vs 10.02 µg/L, P = 0.022). CK19 mRNA was found in blood samples from 30 cases of breast cancer and the positive rate was 41.7%. However, it was not detected in the patients with breast fibroadenoma. The mean levels of serum MMP-2 were (15.48 ± 2.02) and (7.16 ± 1.55) µg/L in CK19 positive and negative patients respectively. Significant difference existed between two groups (P = 0.013). CONCLUSION: The serum level of MMP-2 in early breast cancer is closely correlated with blood micrometastasis. And its high level may be an important contributing factor for the metastasis of breast cancer.

Role of STING protein in breast cancer: mechanisms and therapeutic implications.

Breast cancer is one of the most frequent causes of cancer related death worldwide, and despite the significant advances in therapeutic approaches, a significant proportion of patients succumb to metastasis and tumor recurrence. Breast cancer is an immunogenic cancer, and therefore, immunotherapy is considered a major therapeutic strategy. The survival rate has been increased significantly in HER2+ breast cancers after immunotherapy by monoclonal antibodies alone, or combined with chemical anti-cancer agents. Moreover, in triple negative breast cancer (TNBC), a number of novel agents called immune checkpoint inhibitors have shown optimal efficacy. The major hindrance in cancer immunotherapy is frequent development of resistance and cancer remission. cGAS-STING pathway has a key role in anti-cancer immunity as its downstream signals especially type I interferon (IFN) acts as a link between innate and adaptive immunity. Considering the roles of type I IFN in enhancing dendritic cells activity, promoting the functions of CD8+ T cells, and protecting the effector cells against apoptosis, the induction of cGAS-STING pathway demonstrated promising therapeutic effects against breast cancer, especially in triple negative breast cancers. In this review, we discuss the latest findings and the recent advances regarding the role of cGAS-STING pathway and its activation in breast cancer.