Manipulating Radiation-Sensitive Z-DNA Conformation for Enhanced Radiotherapy.

DNA double-strand breaks (DSBs) yield highly determines radiotherapy efficacy. However, improving the inherent radiosensitivity of tumor DNA to promote radiation-induced DSBs remains a challenge. Using theoretical and experimental models, the underexplored impact of Z-DNA conformations on radiosensitivity, yielding higher DSBs than other DNA conformations, is discovered. Thereout, a radiosensitization strategy focused on inducing Z-DNA conformation, utilizing CBL@HfO2 nanocapsules loaded with a Z-DNA inducer CBL0137, is proposed. A hollow mesoporous HfO2 (HM-HfO2) acts as a delivery and an energy depositor to promote Z-DNA breakage. The nanocapsule permits the smart DSBs accelerator that triggers its radiosensitization with irradiation stimulation. Impressively, the CBL@HfO2 facilitates the B-Z DNA conformational transition, augmenting DSBs about threefold stronger than irradiation alone, generating significant tumor suppression with a 30% cure rate. The approach enables DSBs augmentation by improving the inherent radiosensitivity of DNA. As such, it opens up an era of Z-DNA conformation manipulation in radiotherapy.

Case report: Microwave ablation is a safe and effective method for primary hyperparathyroidism in pregnancy.

Primary hyperparathyroidism (PHPT) is a rare disease in pregnancy and endangers the health of both pregnant women and fetuses. However, the treatments are very limited for PHPT and most of them are unsatisfactory because of the peculiar state in pregnancy. The only curable method is parathyroidectomy which can be safely performed in the second trimester of pregnancy. In this case, we reported a pregnant woman with primary parathyroid adenoma presenting hypercalcemia and severe vomit at the end of first trimester. Finally, she got cured by microwave ablation at the end of first trimester and gave birth to a healthy baby boy.

ER+/PR- phenotype exhibits more aggressive biological features and worse outcome compared with ER+/PR+ phenotype in HER2-negative inflammatory breast cancer.

The loss of progesterone receptor (PR) often predicts worse biological behavior and prognosis in estrogen receptor-positive (ER +) breast cancer. However, the impact of PR status on inflammatory breast cancer (IBC) has not been studied. Therefore, the purpose of our study was to investigate the influence of PR on IBC. Patients with ER+ and HER2-negative IBC were selected from the Surveillance, Epidemiology and End Results database. Pearson's χ2 test was used to compare the clinicopathological characteristics between patients with estrogen receptor-positive/progesterone receptor-positive (ER+/PR +) and patients with estrogen receptor-positive/progesterone receptor-negative (ER+/PR-). Univariate and multivariate analyses were performed to investigate the effects of PR status on the breast cancer-specific survival (BCSS) and overall survival (OS) in IBC. Overall, 1553 patients including 1157 (74.5%) patients with ER+/PR+ and 396 (25.5%) patients with ER+/PR- were analyzed in our study. The patients with ER+/PR- were more likely to be high histological grade (p < 0.001) and liver metastasis (p = 0.045) compared to patients with ER+/PR+. Despite higher chance of receiving chemotherapy (83.6% vs 77.3%, P = 0.008), patients with ER+/PR- showed worse BCSS (5-year BCSS rate, 34.3% vs 51.3%, P < 0.001) and OS (5-year OS rate, 31.3% vs 46.1%, P < 0.001) compared with ER+/PR+ phenotype. Multivariate survival analysis showed that patients with ER+/PR- still had worse BCSS (hazard ratios [HR]: 1.764, 95% confidence intervals [CI] 1.476-2.109, P < 0.001) and OS (HR: 1.675, 95% CI 1.411-1.975, P < 0.001) than ER+/PR+ phenotype. Furthermore, patients with ER+/PR- showed worse outcomes than ER+/PR+ phenotype in most subgroups, especially in patients with younger age (≤ 60 years), lower histological grade, lymph node involved and distant metastasis. Patients with ER+/PR- had more aggressive biological behaviors and worse outcomes than patients with ER+/PR+ in IBC. Stronger treatments maybe needed for IBC patients with ER+/PR-.

DNAJB4 suppresses breast cancer progression and promotes tumor immunity by regulating the Hippo signaling pathway.

PURPOSE: Breast cancer is the most common cancer worldwide. Low DNAJB4 expression levels are strongly correlated with poor prognosis in breast cancer patients. However, the molecular mechanism by which DNAJB4 regulates breast cancer progression is unclear. METHODS: The expression of DNAJB4 was validated in human breast cancer tissues, normal human breast tissues, and breast cancer cell lines. CCK-8, colony-forming, and wound healing assays were used to assess the biological effect of DNAJB4 overexpression on cell proliferation and migration in MCF-7 cell lines. Bioinformatic analysis was used to identify the DNAJB4 related pathways in breast cancer. Epithelial-mesenchymal transition (EMT)-related biomarkers and Hippo pathway components were quantified by Western blots. Luciferase and Western blot assays were used to validate which miRNA regulates DNAJB4. In addition, the effects of DNAJB4 on in vivo tumor growth were assessed in xenograft models. RESULTS: DNAJB4 was expressed at low levels in human breast cancer tissues and breast cancer cell lines and correlated with poor prognosis. DNAJB4 overexpression significantly inhibited cell proliferation and migration in vitro by activating the Hippo pathway. The dual-luciferase assay showed that hsa-miR-183-5p targeted DNAJB4. Moreover, the effects of DNAJB4 could be reversed by miR-183-5p. In addition, the expression of DNAJB4 was strongly correlated with immune infiltration levels. Notably, DNAJB4 overexpression markedly enhanced CD4 + and CD8 + T cells and reduced PD-L1 levels in 4T1 tumors via the Hippo pathway, which retarded tumor growth in a subcutaneous xenograft tumor mouse model of 4T1 cells. CONCLUSIONS: The present study demonstrated that DNAJB4 overexpression inhibited the malignant biological behavior of breast cancer by regulating the Hippo pathway and tumor immunosuppressive environment.

Development and validation of nomograms for predicting survival outcomes in patients with T1-2N1 breast cancer to identify those who could not benefit from postmastectomy radiotherapy.

Purpose: In this study, we aimed to develop and validate nomograms for predicting the survival outcomes in patients with T1-2N1 breast cancer to identify the patients who could not benefit from postmastectomy radiotherapy (PMRT). Methods: Data from 10191 patients with T1-2N1 breast cancer were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Of them, 6542 patients who had not received PMRT formed the training set. Concurrently, we retrospectively enrolled 419 patients from the Affiliated Hospital of North Sichuan Medical College (NSMC), and 286 patients who did not undergo PMRT formed the external validation set. The least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses were used for selecting prognostic factors in the training set. Using the selected factors, two prognostic nomograms were constructed. The nomograms' performance was assessed using the concordance index (C-index), calibration curves, decision curve analysis (DCA), and risk subgroup classification. The stabilized inverse probability of treatment weights (IPTWs) was used to balance the baseline characteristics of the different risk groups. Finally, the survival outcomes and effectiveness of PMRT after IPTW adjustment were evaluated using adjusted Kaplan-Meier curves and Cox regression models. Results: The 8-year overall survival (OS) and breast cancer-specific survival (BCSS) rates for the SEER cohort were 84.3% and 90.1%, with a median follow-up time of 76 months, while those for the NSMC cohort were 84.1% and 86.9%, with a median follow-up time of 73 months. Moreover, significant differences were observed in the survival curves for the different risk subgroups (P < 0.001) in both SEER and NSMC cohorts. The subgroup analysis after adjustment by IPTW revealed that PMRT was significantly associated with improved OS and BCSS in the intermediate- (hazard ratio [HR] = 0.72, 95% confidence interval [CI]: 0.59-0.88, P=0.001; HR = 0.77, 95% CI: 0.62-0.95, P = 0.015) and high- (HR=0.66, 95% CI: 0.52-0.83, P<0.001; HR=0.74, 95% CI: 0.56-0.99, P=0.039) risk groups. However, PMRT had no significant effects on patients in the low-risk groups. Conclusion: According to the prognostic nomogram, we performed risk subgroup classification and found that patients in the low-risk group did not benefit from PMRT.

Single progesterone receptor-positive phenotype has the similar clinicopathological features and outcome as triple-negative subtype in metastatic breast cancer.

Objective: The same clinicopathological features and prognosis have been reported between single progesterone receptor-positive (sPR-positive) and triple-negative phenotype in early-stage breast cancer, but such similarity has not been studied in metastatic breast cancer (MBC). Therefore, the purpose of this study was to estimate the difference between sPR-positive phenotype and other phenotypes in MBC. Methods: Patients with HER-2-negative MBC were selected from the Surveillance, Epidemiology and End Results database. Pearson's χ2 test was used to compare the difference of clinicopathologic factors between sPR-positive phenotype and other phenotypes. Univariate and multivariate analyses were performed to evaluate the effects of hormone receptor (HoR) phenotypes and other clinicopathologic factors on the cancer-specific survival (CSS) and overall survival (OS). Results: Overall, 10877 patients including 7060 patients (64.9%) with double HoR-positive (dHoR-positive), 1533 patients (14.1%) with single estrogen receptor-positive (sER-positive), 126 patients (1.2%) with sPR-positive and 2158 patients (19.8%) with double HoR-negative (dHoR-negative) were analyzed. The patients with sPR-positive or dHoR-negative were more likely to be younger, higher grade and tumor stage, visceral and brain metastasis than ER-positive phenotypes (P<0.001). MBC with sPR-positive had the similar CSS (HR: 1.135, 95%CI: 0.909-1.417, P=2.623) and OS (HR: 1.141, 95%CI: 0.921-1.413, P=0.229) as dHoR-negative, but worse outcome than ER-positive phenotypes. Chemotherapy significantly improved the survival for MBC, especially for sPR-positive MBC (CSS, HR: 0.39, 95%CI: 0.213-0.714, P=0.002; OS, HR: 0.366, 95%CI: 0.203-0.662, P=0.001). Conclusions: Patients with sPR-positive and triple-negative have similar biological behavior and prognosis in MBC. Chemotherapy may be a preferred recommendation for MBC with sPR-positive.

Tandem Repeat Generation and Novel Isothermal Amplification Based on Nonspecific Tailing and Replication Slippage.

BACKGROUND: Isothermal amplification is considered to be one of the most promising tools for point-of-care testing molecular diagnosis. However, its clinical application is severely hindered by nonspecific amplification. Thus, it is important to investigate the exact mechanism of nonspecific amplification and develop a high-specific isothermal amplification assay. METHODS: Four sets of primer pairs were incubated with Bst DNA polymerase to produce nonspecific amplification. Gel electrophoresis, DNA sequencing, and sequence function analysis were used to investigate the mechanism of nonspecific product generation, which was discovered to be nonspecific tailing and replication slippage mediated tandem repeats generation (NT&RS). Using this knowledge, a novel isothermal amplification technology, bridging primer assisted slippage isothermal amplification (BASIS), was developed. RESULTS: During NT&RS, the Bst DNA polymerase triggers nonspecific tailing on the 3'-ends of DNAs, thereby producing sticky-end DNAs over time. The hybridization and extension between these sticky DNAs generate repetitive DNAs, which can trigger self-extension via replication slippage, thereby leading to nonspecific tandem repeats (TRs) generation and nonspecific amplification. Based on the NT&RS, we developed the BASIS assay. The BASIS is carried out by using a well-designed bridging primer, which can form hybrids with primer-based amplicons, thereby generating specific repetitive DNA and triggering specific amplification. The BASIS can detect 10 copies of target DNA, resist interfering DNA disruption, and provide genotyping ability, thereby offering 100% accuracy for type 16 human papillomavirus detection. CONCLUSION: We discovered the mechanism for Bst-mediated nonspecific TRs generation and developed a novel isothermal amplification assay (BASIS), which can detect nucleic acids with high sensitivity and specificity.

Comparison of survival outcomes between axillary conservation and axillary lymph node dissections in N1 early breast cancer: a propensity-matched SEER analysis.

BACKGROUND: Sentinel lymph node dissection (SLND) is an alternative to axillary lymph node dissection (ALND) for breast cancer surgery. But the criteria of SLND only for patients with limited disease in the sentinel node is disputed. METHODS: From the Surveillance, Epidemiology, and End Results (SEER) database, 2000-2015, we identified 97,296 early breast cancer females with 1-3 axillary lymph nodes macro-metastasis. Of them, 1-5 (axillary conservation group), 6-9, and ≥ 10 (ALND group) axillary lymph nodes were dissected in 28,639, 16,838, and 51,819 patients, respectively. According to the criteria of the ACOSOG Z0011 trial, two historical cohort studies of patients who underwent lumpectomy or mastectomy were conducted and the survival outcomes between ALND and axillary conservation were compared. RESULTS: Overall, dissection of 6-9 regional lymph nodes resulted in the worst prognosis. After propensity-matched analysis, it was found that patients in the axillary conservation group had worse survival than the ALND group in overall survival. No significant difference in prognosis between the group undergoing lumpectomy was found both in OS and BCSS. Subgroup analysis revealed that Grade 3, T2, two lymph nodes positive, or Her2 positive were the main causes of worse survival in the axillary conservation group. CONCLUSION: Not all patients with N1 early breast cancer suit axillary conservation. Axillary conservation was sufficient in patients who were treated with lumpectomy. ALND cannot be omitted in patients who were ineligible for the Z0011 and undergoing mastectomy with the following characteristics: T2, Grade 3, two positive lymph nodes, and Her2 positive, which may be better complemented to the Z0011 trial. Hence, under different surgical methods, the clinical precision treatment of ALND or axillary preservation is essential.

Adjuvant radiation therapy for older women with early-stage breast cancer: a propensity-matched SEER analysis.

INTRODUCTION: The purpose was to evaluate the effect of adjuvant radiation therapy on the survival prognosis of older women with early-stage breast cancer under different surgical treatments. METHODS: We collected patients from the Surveillance, Epidemiology and End Results (SEER) database. Elderly female patients (≥ 70 years) with stage I-IIB diagnosed with invasive carcinoma in 1988-2017 were included. After propensity score matching (PSM), the prognosis of patients who underwent breast-conserving surgery or mastectomy was calculated separately. The effects of radiotherapy on the survival of three special population groups (breast-conserving surgery + T1N0M0 + ER positive, mastectomy + T3N0M0 and mastectomy + T1-2N1M0) were analyzed selectively. RESULTS: Of 106,553 older women with early-stage breast cancer were identified. 48,630 patients had received radiotherapy, while 57,923 patients had not. After PSM, older women undergoing breast-conserving surgery benefited significantly from radiotherapy (both OS and BCSS p < 0.001), for patients with T1N0M0 and ER-positive breast cancer (both OS and BCSS p < 0.001). In the subgroup of T1-2N1M0 breast cancer treated by mastectomy, patients undergoing radiotherapy had a worse survival as well (OS p < 0.001; BCSS p = 0.0907). While in the subgroup of T3N0M0 breast cancer treated by mastectomy, survival analyses showed no statistical differences between patients receiving radiation or not (OS p = 0.1778, BCSS p = 0.6957). CONCLUSIONS: This study indicated the clinical effects of radiation on older women who received different surgical treatments. Our study suggested that radiotherapy should be omitted in older women undergoing mastectomy + T3N0M0 or T1-2N1M0 and radiotherapy could be considered in women with T1N0M0 + ER-positive undergoing breast-conserving surgery.

Effect of cell density on the malignant biological behavior of breast cancer by altering the subcellular localization of ANXA2 and its clinical implications

To investigate the subcellular localization of ANXA2 in breast cancer of different cell densities in humans and its relationship with the clinicopathological features of patients. To investigate the differences in ANXA2 subcellular localization in MDA-MB-231 cells of different cell densities. To compare the proliferation, invasion, and migration ability of MDA-MB-231 cells under different ANXA2 subcellular localization.MethodsImmunohistochemistry was applied to detect the subcellular localization of ANXA2 in tissue sections of 60 breast cancer patients, and the association with ANXA2 subcellular localization was verified in conjunction with cell density. To investigate the relationship between cell density and clinicopathological data of breast cancer patients. To establish high- and low-density models of MDA-MB-231 breast cancer cell lines and verify the subcellular localization of ANXA2 using immunofluorescence and observation under confocal microscopy. The proliferation, migration, and invasion ability of MDA-MB-231 cells under different subcellular localization of ANXA2 were detected and compared using CCK-8 assay and Transwell assay. After changing the subcellular localization of ANXA2 in high-density MDA-MB-231 cells with PY-60, changes in biological behaviors of the compared MDA-MB-231 cells were observed. Two different 4T1 cell lines with high and low densities were implanted subcutaneously in nude mice to observe the effects of different cell densities on tumor growth in nude mice.ResultsThe clinical data showed that breast cancer with high cell density had higher T stage and higher TNM stage, and the cell density was positively correlated with breast cancer mass size. ANXA2 was mainly localized to the cell membrane when the cell density of breast cancer cells was high and to the cytoplasm when the cell density was low. (AU)

A comparative analysis of diagnostic values of high-frequency ultrasound and fiberoptic ductoscopy for pathologic nipple discharge.

BACKGROUND: This study aimed to compare the diagnostic accuracy of high-frequency ultrasound (HFUS) and fiberoptic ductoscopy (FDS) for pathologic nipple discharge (PND). METHODS: HFUS and FDS were conducted in 210 patients with PND (248 lesions) treated at our hospital. The diagnostic accuracy of these two methods was compared using pathological diagnosis as the standard. RESULTS: Among 248 lesions, 16 and 15 of 16 malignant lesions were accurately diagnosed by HFUS and FDS, respectively. Of 232 benign lesions, 183 and 196 cases were accurately diagnosed by HFUS and FDS, respectively. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of HFUS in diagnosis of intraductal lesions were 84.36% (95% CI 79.26-88.39%), 60% (95% CI 23.07-92.89%), 96.03% (95% CI 96.55-99.83%), and 7.31% (95% CI 2.52-19.4%) respectively. The sensitivity, specificity, PPV, and NPV of FDS in diagnosis of intraductal lesions were 86.83% (95% CI 82.00-90.52%), 100% (95% CI 56.55-100%), 100% (95% CI 98.21-100%), and 13.51% (95% CI 5.91-27.98%) respectively. Diagnostic accuracy rates of HFUS and FDS were 83.87% (208/248) and 85.08% (211/248), respectively, exhibiting no statistically differences (χ2 = 0.80, P > 0.05). The accuracy of HFUS combined with FDS was 93.14% (231/248), showing statistically differences (χ2 = 10.91, P < 0.05). CONCLUSIONS: Both HFUS and FDS demonstrated high diagnostic values for PND. HFUS has the advantage of non-invasive for nipple discharge with duct ectasia, exhibited good qualitative and localization diagnostic values. It is the preferred evaluation method for patients with nipple discharge. When HFUS cannot identify the cause of PND, FDS can be considered.

A pH/H2 O2 /MMP9 Time-Response Gel System with Sparchigh Tregs Derived Extracellular Vesicles Promote Recovery After Acute Myocardial Infarction.

Regulatory T cells overexpressing SPARC (secreted protein acidic and cysteine rich) (Sparchigh Tregs) can help repair infarct tissues after acute myocardial infarction (AMI). This research demonstrates that Sparchigh Treg-derived extracellular vesicles (EVs) effectively improved cardiac function through proinflammatory factors IL-1ß, IL-6, and TNF-α inhibition and collagen synthesis related gene Col3a1 promotion in AMI; moreover, a composite hydrogel-EVs system (DHPM(4APPC)_EVs) is designed based on Sparchigh Treg-derived EVs with CXCR2 overexpressing and pH/H2 O2 /MMP9 temporally responsive gel microspheres. In AMI, due to the levels of chemokine, pH, H2 O2 , and MMP9 enzymes in the infarct area, DHPM(4APPC)_EVs can effectively target the infarct area, release the loaded EVs, form the gel to capture the released EVs, and slowly release the captured EVs, contribute to promote EVs to stay in the infarct area for a long time to play the repair function, so as to reduce myocardial injury and promote the improvement of cardiac function. The proposed system in this research provides a potential approach for the treatment of AMI in the future.

Effect of cell density on the malignant biological behavior of breast cancer by altering the subcellular localization of ANXA2 and its clinical implications.

OBJECTIVE: To investigate the subcellular localization of ANXA2 in breast cancer of different cell densities in humans and its relationship with the clinicopathological features of patients. To investigate the differences in ANXA2 subcellular localization in MDA-MB-231 cells of different cell densities. To compare the proliferation, invasion, and migration ability of MDA-MB-231 cells under different ANXA2 subcellular localization. METHODS: Immunohistochemistry was applied to detect the subcellular localization of ANXA2 in tissue sections of 60 breast cancer patients, and the association with ANXA2 subcellular localization was verified in conjunction with cell density. To investigate the relationship between cell density and clinicopathological data of breast cancer patients. To establish high- and low-density models of MDA-MB-231 breast cancer cell lines and verify the subcellular localization of ANXA2 using immunofluorescence and observation under confocal microscopy. The proliferation, migration, and invasion ability of MDA-MB-231 cells under different subcellular localization of ANXA2 were detected and compared using CCK-8 assay and Transwell assay. After changing the subcellular localization of ANXA2 in high-density MDA-MB-231 cells with PY-60, changes in biological behaviors of the compared MDA-MB-231 cells were observed. Two different 4T1 cell lines with high and low densities were implanted subcutaneously in nude mice to observe the effects of different cell densities on tumor growth in nude mice. RESULTS: The clinical data showed that breast cancer with high cell density had higher T stage and higher TNM stage, and the cell density was positively correlated with breast cancer mass size. ANXA2 was mainly localized to the cell membrane when the cell density of breast cancer cells was high and to the cytoplasm when the cell density was low. The CCK-8 assay showed that the proliferation rate of MDA-MB-231 cells increased (P < 0.05) after shifting the subcellular localization of ANXA2 from the cell membrane to the cytoplasm. Transwell invasion assay and Transwell migration assay showed that the invasion and migration ability of MDA-MB-231 cells increased significantly after the subcellular localization of ANXA2 was transferred from the cell membrane to the cytoplasm (P < 0.05). The animal experiments showed that high-density breast cancer cells could promote the growth of subcutaneous tumors in nude mice relative to low-density breast cancer cells. CONCLUSION: Cell density can regulate the subcellular localization of ANXA2, and changes in the subcellular localization of ANXA2 are accompanied by the changes in the biological behavior of breast cancer.

What Is the Optimal Strategy for Drain Removal After Mastectomy and Axillary Surgery in Breast Cancer Patients? A Multicenter, Three-Arm Randomized Clinical Trial.

INTRODUCTION: The best strategy for drain removal after mastectomy and axillary surgery in breast cancer patients has remained controversial. We conducted a multicenter, three-arm randomized clinical trial to determine the optimal strategy. METHODS: A total of 187 eligible breast cancer patients who underwent mastectomy and axillary surgery were randomized into 10 mL (n = 62), 20 mL (n = 63), and 30 mL (n = 63) groups for drain removal on the first day when the output decreased to a corresponding volume in 24 h. The drain duration, total drain duration, incidence of seroma, quality of life, outpatient visit times, healthcare costs, and postoperative complications were evaluated. RESULTS: The median axillary drain durations and total drain durations were all significantly different between three groups (both P < 0.001). The incidences of seroma were 31.1%, 38.3%, and 52.1%, and the difference between the 30 mL and 10 mL groups was significant (RR = 2.41). The 20 mL group reported significantly better quality of life (QoL) in terms of physical functioning (PF) at the 2-week (30 mL versus 20 mL, HR:-14.18) and 3-week (20 mL versus 10 mL, HR: 11.65) follow-up and role functioning (RF) at the 2-week follow-up (20 mL versus 10 mL, HR: 18.15). No between-group differences were found in G-QoL, outpatient visits, costs, or complications. CONCLUSIONS: The 20 mL group had a moderate drain duration, total drain duration, and incidence of seroma but a significant advantage over the other two groups in terms of PF and RF, with relatively low outpatient costs and comparable postoperative complication rates. These findings could aid in clinical decision-making regarding drain removal timing (http://www.chictr.org.cn/: ChiCTR2000028729).

Targeted Intervention of NF2-YAP Signaling Axis in CD24-Overexpressing Cells Contributes to Encouraging Therapeutic Effects in TNBC.

Triple-negative breast cancer (TNBC) cells have not been usefully classified, and no targeted therapeutic plans are currently available, resulting in a high recurrence rate and metastasis potential. In this research, CD24high cells accounted for the vast majority of TNBC cells, and they were insensitive to Taxol but sensitive to ferroptosis agonists and effectively escaped phagocytosis by tumor-associated macrophages. Furthermore, the NF2-YAP signaling axis modulated the expression of ferroptosis suppressor protein 1 (FSP1) and CD24 in CD24high cells, with subsequent ferroptotic regulation and macrophage phagocytosis. In addition, a precision targeted therapy system was designed based on the pH level and glutathione response, and it can be effectively used to target CD24high cells to induce lysosomal escape and drug burst release through CO2 production, resulting in enhanced ferroptosis and macrophage phagocytosis through FSP1 and CD24 inhibition mediated by the NF2-YAP signaling axis. This system achieved dual antitumor effects, ultimately promoting cell death and thus inhibiting TNBC tumor growth, with some tumors even disappearing. The composite nanoprecision treatment system reported in this paper is a potential strategic tool for future use in the treatment of TNBC.

PROS1 shapes the immune-suppressive tumor microenvironment and predicts poor prognosis in glioma.

Background: Glioma is the most malignant cancer in the brain. As a major vitamin-K-dependent protein in the central nervous system, PROS1 not only plays a vital role in blood coagulation, and some studies have found that it was associated with tumor immune infiltration. However, the prognostic significance of PROS1 in glioma and the underlying mechanism of PROS1 in shaping the tumor immune microenvironment (TIME) remains unclear. Methods: The raw data (including RNA-seq, sgRNA-seq, clinicopathological variables and prognosis, and survival data) were acquired from public databases, including TCGA, GEPIA, CGGA, TIMER, GEO, UALCAN, and CancerSEA. GO enrichment and KEGG pathway analyses were performed using "cluster profiler" package and visualized by the "ggplot2" package. GSEA was conducted using R package "cluster profiler". Tumor immune estimation resource (TIMER) and spearman correlation analysis were applied to evaluate the associations between infiltration levels of immune cells and the expression of PROS1. qRT-PCR and WB were used to assay the expression of PROS1. Wound-healing assay, transwell chambers assays, and CCK-8 assays, were performed to assess migration and proliferation. ROC and KM curves were constructed to determine prognostic significance of PROS1 in glioma. Results: The level of PROS1 expression was significantly increased in glioma in comparison to normal tissue, which was further certificated by qRT-PCR and WB in LN-229 and U-87MG glioma cells. High expression of PROS1 positively correlated with inflammation, EMT, and invasion identified by CancerSEA, which was also proved by downregulation of PROS1 could suppress cells migration, and proliferation in LN-229 and U-87MG glioma cells. GO and KEGG analysis suggested that PROS1 was involved in disease of immune system and T cell antigen receptor pathway. Immune cell infiltration analysis showed that expression of PROS1 was negatively associated with pDC and NK CD56 bright cells while positively correlated with Macrophages, Neutrophils in glioma. Immune and stromal scores analysis indicated that PROS1 was positively associated with immune score. The high level of PROS1 resulted in an immune suppressive TIME via the recruitment of immunosuppressive molecules. In addition, Increased expression of PROS1 was correlated with T-cell exhaustion, M2 polarization, poor Overall-Survival (OS) in glioma. And it was significantly related to tumor histological level, age, primary therapy outcome. The results of our experiment and various bioinformatics approaches validated that PROS1 was a valuable poor prognostic marker. Conclusion: Increased expression of PROS1 was correlated with malignant phenotype and associated with poor prognosis in glioma. Besides, PROS1 could be a possible biomarker and potential immunotherapeutic target through promoting the glioma immunosuppressive microenvironment and inducing tumor-associated macrophages M2 polarization.

Correlation Analysis of Breast and Thyroid Nodules: A Cross-Sectional Study.

OBJECTIVE: Based on physical examination, to explore the relationship between breast mass (BM) and thyroid nodule (TN) prevalence, and to further explore other related factors that affect the occurrence of BM and TN. METHODS: From January 1, 2018, to January 1, 2021, 12,538 female subjects received breast and thyroid ultrasound examinations at the same time in the health examination center of the Affiliated Hospital of North Sichuan Medical College. Univariate analysis and multivariate logistic analysis were used to screen the relevant factors affecting TN and BM, and propensity score matching was used to further verify the results of the relationship between breast and thyroid. RESULTS: A total of 4975 (39.7%) of the included subjects have BM and a total of 6315 (50.4%) have TN,2557 (20.4%) had both BM and TN. The logistic regression results show that patients with TN are more likely to suffer from BM [OR = 1.185, 95% CI (1.099-1.278), p<0.0001]. In addition, age, free T4, HDL, height, BMI, systolic blood pressure, diastolic blood pressure, and albumin are independent factors affecting the occurrence of BM; patients with BM are more likely to have TN [OR = 1.180, 95% CI (1.094-1.272), p<0.0001], and age, free T3, free T4, AST, ALT, albumin, height, and BMI are independent influencing factors on the occurrence of TN. The result of propensity score matching confirmed the relationship between BM and TN. CONCLUSION: There is a bidirectional pathogenic relationship between BM and TN, women with BM are at increased risk of TN, and women with TN are more likely to have BM. Thyroid hormone is not only related to the occurrence of TN but also affects the occurrence of BM.

The association between molecular type and prognosis of patients with stage IV breast cancer: an observational study based on SEER database.

BACKGROUND: Molecular subtype, the basis for personalized treatment of breast cancer, is of great value in evaluating prognosis and guiding treatment of early-stage breast cancer. However, its value in stage IV patients remains unclear. In this study, we investigated the association between molecular subtype and prognosis of de novo stage IV breast cancer using Surveillance, Epidemiology, and End Results (SEER) database with the purpose to provide evidence for optimal therapeutic options for breast cancer patients. METHODS: We retrospectively analyzed de novo stage IV breast cancer patients with the SEER Program data from 2010 to 2015. Characteristics of patients with different molecular subtypes were compared by chi-square test and survival curves for breast cancer specific survival (BCSS) according to subtypes were plotted by Kaplan-Meier method. The Cox proportional hazards model was performed to search for independent prognostic factors in stage IV breast cancer patients. RESULTS: A total of 11,974 patients were included in this study, among which 7,100 (59.30%) patients were of HR+/HER2-, 2,093 (17.48%) of HR+/HER2+, 1,139 (9.51%) of HR-/HER2+ and 1,642 (13.71%) of HR-/HER2-. Multivariate Cox analysis revealed that molecular subtype, age, race, marital status, grade, surgery and chemotherapy were independent prognostic factors for BCSS in de novo stage IV patients. Taking HR+/HER2- patients as reference, HR+/HER2+ patients had better BCSS (HR =0.81, 95% CI: 0.75-0.88, P<0.001), HR-/ HER2- patients had worse BCSS (HR =1.42, 95% CI: 1.29-1.46, P<0.001) and HR-/HER2+ patients had no significant difference (HR =1.03, 95% CI: 0.98-1.08, P=0.188). In patients with different single organ metastases, the prognosis of HR+/HER2+ subtype was the best (except brain metastasis), while that of HR-/HER2- subtype was the worst. CONCLUSIONS: Molecular subtypes were closely associated with the prognosis of de novo stage IV breast cancer. Among the four subtypes, HR+/HER2+ patients had the best prognosis while HR-/HER2- patients had the worst. The prognosis of patients with different single organ metastases was the same, but in patients with brain metastases, HR+/HER2+ ones did not have a significantly better prognosis than other subtypes except triple-negative type.

Supraclavicular lymph node dissection with radiotherapy versus radiotherapy alone for operable breast cancer with synchronous ipsilateral supraclavicular lymph node metastases: a real-world cohort study.

BACKGROUND: The role of supraclavicular lymph node dissection (SCLD) in the treatment of breast cancer with ipsilateral supraclavicular lymph node metastasis (ISLM) remains controversial. We evaluated the role of SCLD in the treatment of breast cancer with ISLM and identified patients who may benefit from SCLD. METHODS: Data on patients presenting with breast cancer to the Breast Disease Center, Southwest Hospital, The Army Medical University from January 2004 and December 2017 were retrospectively screened. The median duration of follow-up was 36 months (2-175 months). 305 patients who were recently diagnosed with ISLM were eligible for the analysis. RESULTS: Overall, 9,236 women presented with breast cancer during the study period. Among the patients included, 146 and 159 received SCLD with radiotherapy (RT) and RT alone, respectively. Synchronous ISLM without distant metastases were present in 3.6% cases. The 3- and 5-year overall survival (OS) and disease-free survival (DFS) rates were 79.5% and 73.9%, respectively, and 67.5% and 54.8%, respectively. However, SCLD with RT was not associated with superior survival on both univariate and multivariate analyses. On stratified analyses, patients with non-luminal A tumors with 4-9 positive axillary lymph nodes who underwent SCLD with RT had both superior OS (HR =5.296; 95% CI: 1.857-15.107; P=0.001) and DFS (HR =5.331; 95% CI: 2.348-12.108; P<0.001) compared with those who received RT alone. CONCLUSIONS: SCLD may not beneficial in improving survival for unselected breast cancer patients with ISLNM. There is less of a tendency to perform SCLD in the luminal A group.