Co-Delivery of siNRF2 and Sorafenib by a "Click" Dual Functioned Hyperbranched Nanocarrier for Synergistically Inducing Ferroptosis in Hepatocellular Carcinoma.

In the course of antitumor therapy, the complex tumor microenvironment and drug-mediated changes in cell signaling and biological processes lead to drug resistance. The effect of sorafenib is greatly limited by the specific tumor microenvironment induced by antiangiogenic therapy and ferroptosis resistance induced by the upregulation of nuclear factor erythroid-2 related factor 2 (NRF2). In this study, a pH responsive and amphiphilic hyperbranched polyglycerol, HDP, is synthesized based on a co-graft click chemistry pathway. This nano-scale carrier provides excellent drug-loading capacity, storing stability and pH responsibility, and effectively co-delivery of sorafenib and siRNA. Sorafenib and siNRF2 plays a greatly synergistic effect in inducing reactive oxygen species (ROS), iron overloading, depleting glutathione (GSH), and promoting lipid peroxidation. Importantly, verified in two different animal experiments, HDP-ss (HDP loaded with both siNRF2 and sorafenib) presents a superior anti-tumor effect, by achieving a tumor inhibition rate of ≈94%. Thus, HDP can serve as an excellent targeted delivery nanocarrier with good biocompatibility in antitumor therapy, and combined application of siNRF2 effectively improves the antitumor effect of sorafenib by overcoming NRF2-mediated ferroptosis resistance. Taken together, this study provides a novel therapeutic strategy to combat the drug resistance in antiangiogenic therapy and ferroptosis.

CKAP2L, transcriptionally inhibited by FOXP3, promotes breast carcinogenesis through the AKT/mTOR pathway.

Cytoskeleton-associated protein 2-like (CKAP2L) is a mitotic spindle protein and its high expression is reported to be associated with the poor prognosis of cancer patients. Interestingly, TNMplot website analysis indicated that CKAP2L expression was significantly higher in breast cancer (BC) tissues than in normal breast tissues (P < 0.001). Thus, this study was conducted to investigate the role of CKAP2L in breast carcinogenesis and its underlying molecular mechanisms. The mRNA and protein expression levels of CKAP2L in 40 paired fresh BC and para-carcinoma specimens were first analyzed, and the results confirmed the high expression of CKAP2L in BC tissues. Functional studies revealed that CKAP2L silencing dramatically suppressed the proliferation, migration, and invasion, induced cell cycle arrest and apoptosis of BC cells in vitro, and inhibited the growth of xenografted tumors in vivo. However, CKAP2L overexpression produced the opposite results. Mechanically, CKAP2L could activate the AKT/mTOR signaling pathway in BC cells accompanied by increased phosphorylation levels of AKT, mTOR, and p70S6K in CKAP2L-overexpressed cells. Forkhead box protein P3 (FOXP3), a transcription factor with tumor-suppressive properties, was proved to negatively regulate CKAP2L expression in BC cells through binding to the promoter of CKAP2L and inhibiting its transcription. In summary, the present study demonstrates that CKAP2L, transcriptionally regulated by FOXP3, activates the AKT/mTOR signaling pathway and promotes breast carcinogenesis. CKAP2L may serve as a promising target of therapeutic intervention for BC.

TRG16, targeted by miR-765, inhibits breast cancer stem cell-like properties via regulating the NF-κB pathway.

Previous studies reported that cancer stem cells (CSCs) might be responsible for drug resistance and cancer progression. Transformation-Related Gene 16 Protein (TRG16), a pseudokinase, was reported to be a suppressor in some types of cancer and its overexpression impaired hepatocellular carcinoma cell stemness. However, the function of TRG16 in BC remains unclear. We found that TRG16 expression was significantly downregulated in BC tissues compared with adjacent tissues (n = 40; P < 0.001) and BC patients with lower expression of TRG16 had a worse prognosis. Forced expression of TRG16 inhibited BC stem cell-like properties as evidenced by decreased CD44-positive cells (CSC marker), reduced mammosphere quantity, and downregulated Nanog, aldehyde dehydrogenase, octamer-binding transcription factor 4, and SRY-box transcription factor 2 expression (CSC markers). Moreover, TRG16 overexpression inhibited self-renewal and invasion capabilities of BC cells in vitro as well as tumor growth in vivo but increased cisplatin sensitivity. However, TRG16 silencing had the opposite effects. Further mechanistic studies revealed that TRG16 was targeted and negatively regulated by miR-765, a facilitator of BC progression. TRG16 could suppress the activation of the NF-κB pathway in BC cells, which is a positive pathway in BC progression and contributes to the maintenance of cancer cell stemness. In conclusion, the results above demonstrate that TRG16, negatively regulated by miR-765, may inhibit the BC progression by regulating BC stem cell-like properties and this inhibition may be mediated by the NF-κB pathway. Our findings indicate that TRG16 may be a potential therapeutic targetable node for BC. TRG16, negatively regulated by miR-765, may inhibit the BC progression through regulating BC stem cell-like properties and this inhibition may be mediated by the NF-κB pathway.

Identification of Key Genes and Key Pathways in Breast Cancer Based on Machine Learning.

BACKGROUND Breast cancer is one of the most common malignant tumors among women worldwide. This study aimed to screen key genes and pathways for breast cancer diagnosis and treatment. MATERIAL AND METHODS We obtained public data from the NCBI GEO database. The data were divided into a control group (normal breast tissue) and a treatment group (breast cancer tissue). We screened 32 differentially expressed genes (DEGs) between normal breast and cancerous tissues and used GO analysis and GSEA to identify the key pathways. We then combined LASSO and SVM-RFE analyses to screen key genes, and used CIBERSORT to obtain the proportion of 22 types of immune cells. The relationships between key genes and immune-infiltrating cells were further explored. RESULTS We screened 32 DEGs from the 2 groups, including 27 downregulated genes and 5 upregulated genes. GO analysis indicated that the DEGs were mainly correlated with collagen-containing extracellular matrix (ECM), Wnt signaling pathway, and glycosaminoglycan binding. GSEA indicated that the treatment group was correlated with chromosome segregation and cell cycle while the control group was correlated with cornification, intermediate filament, and nuclear transcription. Through machine learning, SYNM, TGFBR3, and COL10A1 were screened as key genes. Numbers of CD8 T cells, gamma delta T cells, and M1 macrophages were significantly higher, while monocytes and follicular helper-T cells were significantly lower in the treatment group. The downregulated genes, SYNM and TGFBR3, were positively correlated with CD8 T cells and monocytes, but were negatively correlated with gamma delta T cells and M1 macrophages. The upregulated gene, COL10A1, was positively correlated with gamma delta T cells and M1 macrophages, and was negatively correlated with CD8 T cells, monocytes, and follicular helper-T cells. CONCLUSIONS SYNM, TGFBR3, and COL10A1 are diagnostic genes of breast cancer. They affect breast cancer cells by modulating immune-infiltrating cells.

Comparing the Prognoses of Breast-Conserving Surgeries for Differently Aged Women with Early Stage Breast Cancer: Use of a Propensity Score Method.

Background: To explore the effect of age on the prognosis of patients with early stage breast cancer after breast-conserving surgery (BCS) and to provide references for young patients. Methods: All clinical data of patients with early breast cancer undergoing BCS who were treated at Shengjing Hospital of China Medical University from January 2011 to May 2016 were obtained. The primary endpoints were local recurrence (LR) and distant recurrence, and the secondary endpoint was breast cancer-specific survival (BCSS). Chi-squared tests and Fisher's exact tests were used for statistical analysis. Disease-free survival (DFS) and BCSS were calculated by Kaplan-Meier survival analysis and compared using log-rank tests. Logistic regression was used for multivariable analysis of the effect of age in different subgroups. Propensity score matching (PSM) was used to reduce the bias confounding factors on oncological outcomes. Results: Younger patients had higher Ki-67 expression (P=0.048) and larger tumors (P=0.042) compared to older patients. No other clinical features were significantly different between age groups. There was no significant difference between the two groups in BCSS (P=0.186); however, DFS was significantly different before PSM (P=0.012). Triple-negative breast cancer and Ki-67 positivity combined with younger age at diagnosis were associated with a higher risk of recurrence (P=0.018 and P=0.046, respectively). After PSM, there were no significant differences in BCSS nor DFS between the two age groups (P=0.559 and P=0.261, respectively). Conclusion: BCS for young patients is not associated with increased DFS nor BCSS. However, young patients with triple-negative breast cancer and/or Ki-67 positivity have a poor prognosis. In sum, BCS may be appropriate for a subgroup of young patients.

Feasibility of modified radical mastectomy with nipple-areola preservation combined with stage I prosthesis implantation using air cavity-free suspension hook in patients with breast cancer.

BACKGROUND: Mastoscopic surgery is proven to have lower incidence of postoperative complications and better postoperative recovery than traditional breast cancer surgery. This study aimed to examine the feasibility of mastoscopic modified radical mastectomy (MRM) with skin nipple-areola preservation under air cavity-free suspension hook and stage I silicone prosthesis implantation (SMALND) compared with routine MRM. METHODS: This was a retrospective study of patients who underwent MRM for breast cancer at the Shengjing Hospital Affiliated to China Medical University between January 1, 2019, and June 30, 2019. Surgical outcomes, complications, satisfaction, and quality of life (Functional Assessment of Cancer Therapy-Breast [FACT-B] [Chinese version]) were compared between the two groups. RESULTS: A total of 87 patients were enrolled, with 30 underwent SMALND and 57 underwent routine MRM. The intraoperative blood loss in the SMALND group was lower than in the control group (165.3±44.1 vs. 201.4±52.7 ml, P=0.001), the operation time was longer (220.5±23.9 vs. 155.6±9.2 min, P<0.001), daily axillary drainage volume was smaller (20.2±3.6 vs. 24.1±3.0 ml, P<0.001), daily subcutaneous drainage volume was smaller (15.5±2.3 vs. 19.3±3.5 ml, P<0.001), the discharge time was shorter (7.5±1.6 vs. 9.0±1.8 days, P<0.001), and FACT-B scores were higher (83.8±5.6 vs. 72.1±4.6, P<0.001). The overall satisfaction was higher in the SMALND group than in the controls (76.7% vs. 54.4%, P=0.041). Compared with the controls, the occurrence rates of nipple and flap necrosis, upper limb edema, and paraesthesia in the SMALND group were lower within 6 months (all P<0.05). CONCLUSIONS: Compared with traditional MRM, SMALND had better surgical outcomes, higher satisfaction, higher quality of life, and lower complication rates.

Clinical and imaging characteristics of breast ductal carcinoma in situ with microinvasion.

BACKGROUND: We analyzed the clinical and imaging characteristics of patients with breast ductal carcinoma in situ with microinvasion (DCISM) and breast ductal carcinoma in situ (DCIS). METHODS: We analyzed the records of 40 patients diagnosed with DCISM and 61 patients with DCIS who were hospitalized at Shengjing Hospital (Shenyang, China) from January 2009 to June 2016. The size, hardness, and degree of calcification of tumors were determined by mammography and ultrasonography. RESULTS: In all, 37 DCISM patients and 45 DCIS patients showed clinical palpable masses (92.5% vs 73.77%, P = 0.018). Mammography showed that the mean size of tumor was larger in DCISM patients than that of DCIS patients (3.13 ± 1.51 vs 2.68 ± 1.77, P = 0.030). Ultrasound examination revealed calcification shadows in the solid tumor mass in 17 DCISM cases and 11 DCIS patients (42.5 vs 18.03%, P = 0.007). Furthermore, estrogen receptor positivity and progesterone receptor positivity were more common in DCIS patients (32.5% vs 54.10%, P = 0.033; 22.5% vs 45.90%, P = 0.017), and the percentage of menopausal patients were higher in DCISM patients than that of DCIS patients (70.00% vs 47.54%, P = 0.026). CONCLUSION: Clinically palpable and calcified tumor masses on sonography are more commonly encountered in DCISM lesions.

The long noncoding RNA HOTTIP promotes breast cancer cell migration, invasiveness, and epithelial-mesenchymal transition via the Wnt-ß-catenin signaling pathway.

Long noncoding RNA HOTTIP (HOXA transcript at the distal tip) has recently been reported to have a role in the proliferation of various cancer cells, yet its role in cell migration, invasiveness, and the EMT (epithelial-mesenchymal transition) in breast cancer and the potential mechanisms remain unknown. Breast cancer cell lines MDA-MB-231 and MDA-MB-468 were transfected with shRNA (short hairpin RNA) that specifically targeting HOTTIP. We observed a remarkable decrease in migration and invasiveness in these two breast cancer cell lines after knock-down of HOTTIP by shHOTTIP. We also demonstrated that the EMT of these two breast cell lines was suppressed after HOTTIP knock-down, as evidenced by increased E-cadherin levels, and decreased levels of N-cadherin, Snail, and Twist. Moreover, HOTTIP silencing also suppressed tumor metastasis in nude mice in vivo. In addition, we found that the expression of ß-catenin was significantly decreased in breast cancer cells after knock-down of HOTTIP. In a further rescue experiment using overexpression of ß-catenin, the rates of cell migration, invasiveness, and EMT of HOTTIP-silenced breast cancer cells were promoted, disclosing a potential role of the Wnt-ß-catenin signaling pathway in this process. Overall, we discovered the positive regulatory function of HOTTIP in the migration, invasiveness, and EMT of breast cancer cells, via regulating the Wnt-ß-catenin pathway.

Preparation of polyphosphazene hydrogels for enzyme immobilization.

We report on the synthesis and application of a new hydrogel based on a methacrylate substituted polyphosphazene. Through ring-opening polymerization and nucleophilic substitution, poly[bis(methacrylate)phosphazene] (PBMAP) was successfully synthesized from hexachlorocyclotriphosphazene. By adding PBMAP to methacrylic acid solution and then treating with UV light, we could obtain a cross-linked polyphosphazene network, which showed an ultra-high absorbency for distilled water. Lipase from Candida rugosa was used as the model lipase for entrapment immobilization in the hydrogel. The influence of methacrylic acid concentration on immobilization efficiency was studied. Results showed that enzyme loading reached a maximum of 24.02 mg/g with an activity retention of 67.25% when the methacrylic acid concentration was 20% (w/w).

Lignin-Based Mesoporous Hollow Carbon@MnO2 Nanosphere Composite as an Anodic Material for Lithium-Ion Batteries.

The lignin-based mesoporous hollow carbon@MnO2 nanosphere composites (L-C-NSs@MnO2) were fabricated by using lignosulfonate as the carbon source. The nanostructured MnO2 particles with a diameter of 10~20 nm were uniformly coated onto the surfaces of the hollow carbon nanospheres. The obtained L-C-NSs@MnO2 nanosphere composite showed a prolonged cycling lifespan and excellent rate performance when utilized as an anode for LIBs. The L-C-NSs@MnO2 nanocomposite (24.6 wt% of MnO2) showed a specific discharge capacity of 478 mAh g-1 after 500 discharge/charge cycles, and the capacity contribution of MnO2 in the L-C-NSs@MnO2 nanocomposite was estimated ca. 1268.8 mAh g-1, corresponding to 103.2% of the theoretical capacity of MnO2 (1230 mAh g-1). Moreover, the capacity degradation rate was ca. 0.026% per cycle after long-term and high-rate Li+ insertion/extraction processes. The three-dimensional lignin-based carbon nanospheres played a crucial part in buffering the volumetric expansion and agglomeration of MnO2 nanoparticles during the discharge/charge processes. Furthermore, the large specific surface areas and mesoporous structure properties of the hollow carbon nanospheres significantly facilitate the fast transport of the lithium-ion and electrons, improving the electrochemical activities of the L-C-NSs@MnO2 electrodes. The presented work shows that the combination of specific structured lignin-based carbon nanoarchitecture with MnO2 provides a brand-new thought for the designation and synthesis of high-performance materials for energy-related applications.

A new surgical modality for breast reconstruction in patients with breast cancer: a case report and literature review.

Background: Breast preservation can considerably improve the postoperative living quality of breast cancer patients. Through this study, we proposed a novel, safe, and effective surgical modality for breast preservation in patients with early breast cancer. Case Description: Herein, we present a case report of a patient with early-stage breast cancer (T1cN0M0), who underwent skin-sparing nipple areola hypodermic gland resection combined with primary breast reconstruction using silicone implants. The patient was administered with general anesthesia, and the implants were inserted using a insufflation-free suspension and hook suspension under the pectoralis major muscle. The patient was followed up on postoperative days 1, 2, 7, 14, 30, 60, and 100 to check for any complications, such as upper limb edema, paresthesia, or flap necrosis. The patient experienced no complications. No obvious surgical scars or axillary surface infections were observed. The patient was satisfied with the surgical outcome, and this treatment approach reduced her treatment costs by approximately USD 2,600. Conclusions: The new surgical procedure for breast reconstruction considerably improved the quality of life of the patient; no postoperative complications such as skin flap necrosis, paresthesia, or upper limb edema were experienced by the patient; and the treatment costs were reduced. In addition, this method effectively overcomes the concerns related to axillary space instability and limited operative space, rendering it worthy of promotion in clinical practice.

Feasibility analysis of treating breast cancer patients with breast-conserving surgery via a periareolar incision combined with non-lipolytic suspension-type mastoscopy.

The purpose is to analyze and compare postoperative recovery and complication incidence between a periareolar incision combined with Suspension-type Mastoscopic Axillary Lymph Node Dissection (SMALND) and traditional inflated Mastoscopic Axillary Lymph Node Dissection (MALND). This was a randomized trial conducted from June 1, 2020, to April 30, 2022, in the Department of Second Breast Surgery, Shengjing Hospital of China Medical University, and the Department of Thyroid and Breast Surgery, Zibo Central Hospital, in accordance with the criteria of inclusion and exclusion. Overall, 126 patients diagnosed and treated for early-stage breast cancer were selected to undergo periareolar-incision breast-conserving surgery. Those patients who underwent periareolar-incision surgery combined with SMALND formed the observation group (SMALND Group), while those who underwent periareolar-incision surgery combined with traditional inflation became MALND Group. In the two groups, paired data "t" was used to examine, analyze, and compare the postoperative daily drainage volume and drain removal time, while paired data "χ2" was used to examine, analyze, and compare the incidences of postoperative upper limb edema and paresthesia. There were 64 cases in the SMALND Group and 62 cases in the MALND Group. Between the two clusters, no differences were found in age, clinical staging, BMI, and breast cancer classification (P > 0.05). The intraoperative surgery time of the SMALND Group was 43.37 ± 6.27 min while that of the MALND Group was longer: 45.72 ± 4.25 min (P < 0.05). The intraoperative hemorrhage volume of the SMALND Group was 88.33 ± 16.79 ml, less than that of the MALND Group: 96.76 ± 26.85 ml (P < 0.05). The postoperative axillary mean daily drainage volume of the SMALND Group was 38.17 ± 5.55 ml, less than that of the MALND Group: 40.72 ± 7.25 ml (P < 0.05). The drain removal time of the SMALND Group was 7.50 ± 1.60, less than that of the MALND Group: 9.00 ± 1.80 (P < 0.05). The upper limb edema incidence rate of the SMALND Group was 3.12% (2/64) and had no obvious difference from the MALND Group, which was 4.83% (3/62) (P = 0.62). The paresthesia incidence rate of the SMALND Group was 18.75% (12/64), while that of the MALND Group was 17.7% (11/62), without an obvious difference (P = 0.88). For axillary lymph node dissection, the use of non-lipolytic suspension-type mastoscopy has reduced the intraoperative hemorrhage volume of patients, shortened surgery time and postoperative recovery time, saved treatment expenses for patients, and avoided complications such as hypercapnia and subcutaneous emphysema caused by traditional inflated mastoscopic surgery. Moreover, it has not increased the incidence of postoperative upper limb edema and paresthesia, supporting its safety and effectiveness.

Effects of neoadjuvant stereotactic body radiotherapy plus adebrelimab and chemotherapy for triple-negative breast cancer: A pilot study.

Background: Emerging data have supported the immunostimulatory role of radiotherapy, which could exert a synergistic effect with immune checkpoint inhibitors (ICIs). With proven effective but suboptimal effect of ICI and chemotherapy in triple-negative breast cancer (TNBC), we designed a pilot study to explore the efficacy and safety of neoadjuvant stereotactic body radiotherapy (SBRT) plus adebrelimab and chemotherapy in TNBC patients. Methods: Treatment-naïve TNBC patients received two cycles of intravenous adebrelimab (20 mg/kg, every 3 weeks), and SBRT (24 Gy/3 f, every other day) started at the second cycle, then followed by six cycles of adebrelimab plus nab-paclitaxel (125 mg/m² on days 1 and 8) and carboplatin (area under the curve 6 mg/mL per min on day 1) every 3 weeks. The surgery was performed within 3-5 weeks after the end of neoadjuvant therapy. Primary endpoint was pathological complete response (pCR, ypT0/is ypN0). Secondary endpoints included objective response rate (ORR), residual cancer burden (RCB) 0-I, and safety. Results: 13 patients were enrolled and received at least one dose of therapy. 10 (76.9%) patients completed SBRT and were included in efficacy analysis. 90% (9/10) of patients achieved pCR, both RCB 0-I and ORR reached 100% with three patients achieved complete remission. Adverse events (AEs) of all-grade and grade 3-4 occurred in 92.3% and 53.8%, respectively. One (7.7%) patient had treatment-related serious AEs. No radiation-related dermatitis or death occurred. Conclusions: Adding SBRT to adebrelimab and neoadjuvant chemotherapy led to a substantial proportion of pCR with acceptable toxicities, supporting further exploration of this combination in TNBC patients. Funding: None. Clinical trial number: NCT05132790.

LINC00982 Inhibits the Proliferation, Migration, and Invasion of Breast Cancer Cells Through the miR-765/DPF3 Axis.

Breast cancer (BC) is one of the most frequently occurring malignant tumors in female adults. The long intergenic nonprotein coding RNA 00982 (LINC00982) has been regarded as a cancer suppressor in several human cancers. However, the function and the underlying mechanisms of LINC00982 have not been studied in BC. The present study found that LINC00982 was significantly downregulated in BC tumor tissues, and the low LINC00982 level predicts a poor prognosis of BC. Through the overexpression and suppression of LINC00982 in two BC cell lines, we found that LINC00982 could inhibit cell proliferation, migration, and invasion by suppressing the activity of the signal transducer and activator of transcription 3 (STAT3)/nuclear factor kappa B (NF-κB) signal pathway. Furthermore, luciferase reporter assay has been used to verify that LINC00982 functions as a molecular sponge for miR-765, which could target DPF3. The relative expression of miR-765 decreased with LINC00982 overexpressing, and DPF3 increased at the same time. In addition, the suppression of cell malignant phenotype caused by overexpression of LINC00982 can be reversed by inhibition of DPF3. To verify the function of LINC00982 in vivo, the BC cells were implanted in nude mice and the results suggested the tumor growth and malignant phenotype were suppressed by LINC00982. In this study, we prove that LINC00982 regulates the growth and development of BC through STAT3/NF-κB signal pathway, mediated by the miR-765/DPF3 axis. LINC00982 may function as a target molecule to take part in the prognosis and therapy of BC.

A multicentre single arm phase 2 trial of neoadjuvant pyrotinib and letrozole plus dalpiciclib for triple-positive breast cancer.

Current therapies for HER2-positive breast cancer have limited efficacy in patients with triple-positive breast cancer (TPBC). We conduct a multi-center single-arm phase 2 trial to test the efficacy and safety of an oral neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib (a CDK4/6 inhibitor) in patients with treatment-naïve, stage II-III TPBC with a Karnofsky score of ≥70 (NCT04486911). The primary endpoint is the proportion of patients with pathological complete response (pCR) in the breast and axilla. The secondary endpoints include residual cancer burden (RCB)-0 or RCB-I, objective response rate (ORR), breast pCR (bpCR), safety and changes in molecular targets (Ki67) from baseline to surgery. Following 5 cycles of 4-week treatment, the results meet the primary endpoint with a pCR rate of 30.4% (24 of 79; 95% confidence interval (CI), 21.3-41.3). RCB-0/I is 55.7% (95% CI, 44.7-66.1). ORR is 87.4%, (95% CI, 78.1-93.2) and bpCR is 35.4% (95% CI, 25.8-46.5). The mean Ki67 expression reduces from 40.4% at baseline to 17.9% (P < 0.001) at time of surgery. The most frequent grade 3 or 4 adverse events are neutropenia, leukopenia, and diarrhoea. There is no serious adverse event- or treatment-related death. This fully oral, chemotherapy-free, triplet combined therapy has the potential to be an alternative neoadjuvant regimen for patients with TPBC.

m6A-Mediated Tumor Invasion and Methylation Modification in Breast Cancer Microenvironment.

BACKGROUND: We analyzed the n6-methyladenosine (m6A) modification patterns of immune cells infiltrating the tumor microenvironment of breast cancer (BC) to provide a new perspective for the early diagnosis and treatment of BC. METHODS: Based on 23 m6A regulatory factors, we identified m6A-related gene characteristics and m6A modification patterns in BC through unsupervised cluster analysis. To examine the differences in biological processes among various m6A modification modes, we performed genomic variation analysis. We then quantified the relative infiltration levels of different immune cell subpopulations in the tumor microenvironment of BC using the CIBERSORT algorithm and single-sample gene set enrichment analysis. Univariate Cox analysis was used to screen for m6A characteristic genes related to prognosis. Finally, we evaluated the m6A modification pattern of patients with a single BC by constructing the m6Ascore based on principal component analysis. RESULTS: We identified three different m6A modification patterns in 2128 BC samples. A higher abundance of the immune infiltration of the m6Acluster C was indicated by the results of CIBERSORT and the single-sample gene set enrichment analysis. Based on the m6A characteristic genes obtained through screening, the m6Ascore was determined. The BC patients were segregated into m6Ascore groups of low and high categories, which revealed significant survival benefits among patients with low m6Ascores. Additionally, the high-m6Ascore group had a higher mutation frequency and was associated with low PD-L1 expression, and the m6Ascore and tumor mutation burden showed a positive correlation. In addition, treatment effects were better in patients in the high-m6Ascore group. CONCLUSIONS: In case of a single patient with BC, the immune cell infiltration characteristics of the tumor microenvironment and the m6A methylation modification pattern could be evaluated using the m6Ascore. Our results provide a foundation for improving personalized immunotherapy of BC.

A Cellulose-Derived Nanofibrous MnO2-TiO2-Carbon Composite as Anodic Material for Lithium-Ion Batteries.

A bio-inspired nanofibrous MnO2-TiO2-carbon composite was prepared by utilizing natural cellulosic substances (e.g., ordinary quantitative ashless filter paper) as both the carbon source and structural matrix. Mesoporous MnO2 nanosheets were densely immobilized on an ultrathin titania film precoated with cellulose-derived carbon nanofibers, which gave a hierarchical MnO2-TiO2-carbon nanoarchitecture and exhibited excellent electrochemical performances when used as an anodic material for lithium-ion batteries. The MnO2-TiO2-carbon composite with a MnO2 content of 47.28 wt % exhibited a specific discharge capacity of 677 mAh g-1 after 130 repeated charge/discharge cycles at a current rate of 100 mA g-1. The contribution percentage of MnO2 in the composite material is equivalent to 95.1% of the theoretical capacity of MnO2 (1230 mAh g-1). The ultrathin TiO2 precoating layer with a thickness ca. 2 nm acts as a crucial interlayer that facilitates the growth of well-organized MnO2 nanosheets onto the surface of the titania-carbon nanofibers. Due to the interweaved network structures of the carbon nanofibers and the increased content of the immobilized MnO2, the exfoliation and aggregation, as well as the large volume change of the MnO2 nanosheets, are significantly inhibited; thus, the MnO2-TiO2-carbon electrodes displayed outstanding cycling performance and a reversible rate capability during the Li+ insertion/extraction processes.

Metformin reverses PARP inhibitors-induced epithelial-mesenchymal transition and PD-L1 upregulation in triple-negative breast cancer.

Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising targeted therapies for BRCA-mutated cancers by blocking repair of DNA double-strand breaks. However, resistance to PARP inhibitors (PARPi) has been described in some patients lowering the overall response rates. To investigate the underlying mechanisms of PARPi resistance, we developed the adaptive resistant clones in triple-negative breast cancer cell lines. We identified epithelial-mesenchymal transition (EMT) and upregulation of programmed death-ligand 1 (PD-L1) in resistant cells and further demonstrated the important role of Akt S473 phosphorylation in PARPi resistance. In addition, PARPi mediated EMT is independent of PD-L1 upregulation. Blocking the p-Akt S473 axis by metformin reversed EMT and PD-L1 expression which sensitized PARPi-resistant cells to cytotoxic T cells. Thus, a combination of metformin and PARP inhibitors may be a promising therapeutic strategy to increase the efficacy of PARP inhibitors and tumor sensitivity to immunotherapy.

Synergism of PARP inhibitor fluzoparib (HS10160) and MET inhibitor HS10241 in breast and ovarian cancer cells.

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are promising targeted therapeutics for breast and ovarian cancers bearing a germline BRCA1/2 mutation (BRCA m), and several have already received regulatory approval in the United States. In patients with a BRCA m cancer, PARPi can increase the burden of unrepaired DNA double-strand breaks by blocking PARP activity and trapping PARP1 onto damaged DNA. Resistance to PARP inhibitors can block the formation of DNA double-strand breaks through BRCA-related DNA repair pathway. MET is a hyper-activated receptor tyrosine kinase expressed in multiple cancer types and the activation contributes to resistance to DNA damage-inducing therapeutic drugs. Our previous study showed that MET inhibition by pan-kinase inhibitors has synergism with PARPi in suppressing growth of breast cancer in vitro and in xenograft tumor models. In this study, we validated the inhibitory effect of novel inhibitors, HS10241 (selective MET inhibitor) and HS10160 (PARPi), to their target respectively in triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC) cells. We further demonstrated that these two inhibitors function synergistically in eliminating TNBC and HGSOC cells; combining with HS10241 increased DNA double-strand breaks induced by HS10160 in cancer cells; and PARP1 tyrosine (Y)-907 phosphorylation (PARP1 p-Y907) can be an effective biomarker as an indicator of MET-mediated PARPi in HGSOC. Our results suggest that the combination of HS10241 and HS10160 may benefit patients bearing tumors overexpressing MET as well as those resistant to single-agent PARPi treatment.

Induction of biliary cholangiocarcinoma cell apoptosis by 103Pd cholangial radioactive stent gamma-rays.

BACKGROUND: In recent years, interventional tumor therapy, involving implantation of intra-cholangial metal stents through percutaneous trans-hepatic punctures, has provided a new method for treating cholangiocarcinoma. (103)Pd cholangial radioactive stents can concentrate high radioactive dosages into the malignant tumors and kill tumor cells effectively, in order to prevent re-stenosis of the lumen caused by a relapsed tumor. The aim of the present study was to investigate the efficacy of gamma-rays released by the (103)Pd biliary duct radioactive stent in treating cholangiocarcinoma via induction of biliary cholangiocarcinoma cell apoptosis. METHODS: A group of biliary duct cancer cells was collectively treated with a dose of gamma-rays. Cells were then examined by the 3-(4, 5-dimethyl thiazol-2-yl)-2, 5-diphenyl terazolium-bromide (MTT) technique for determining the inhibition rate of the biliary duct cancer cells, as well as with other methods including electron microscopy, DNA agarose gel electrophoresis, and flow cytometry were applied for the evaluation of their morphological and biochemical characteristics. The growth curve and the growth inhibition rate of the cells were determined, and the changes in the ultrastructure of the cholangiocarcinoma cells and the DNA electrophoresis bands were examined under a UV-lamp. RESULTS: The gamma-ray released by (103)Pd inhibited cholangiocarcinoma cell growth, as demonstrated when the growth rate of the cells was stunned by a gamma-ray with a dosage larger than 197.321 MBq. Typical features of cholangiocarcinoma cell apoptosis were observed in the 197.321 MBq dosage group, while cell necrosis was observed when irradiated by a dosage above 245.865 MBq. DNA agarose gel electrophoresis results were different between the 197.321 MBq irradiation dosage group, the 245.865 MBq irradiation dosage group, and the control group. CONCLUSIONS: (103)Pd radioactive stents which provide a radioactive dosage of 197.321 MBq are effective in the treatment of cholangiocarcinoma; (103)Pd radioactive stents should be useful for the clinical treatment of cholangiocarcinoma.