A multicenter single-arm trial of neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2-positive breast cancer.

The objective of this multicenter, single-arm trial (ChiCTR1900022293) was to explore the efficacy and safety of neoadjuvant therapy with epirubicin, cyclophosphamide, and pyrotinib followed by docetaxel, trastuzumab, and pyrotinib (ECPy-THPy) in the treatment of patients with stage II-III HER2-positive breast cancer. The present study enrolled patients with stage II-III HER2-positive breast cancer. Epirubicin and cyclophosphamide were administrated for four 21-day cycles, followed by four cycles of docetaxel and trastuzumab. Pyrotinib was taken orally once per day throughout the treatment period. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0) rate in the modified intention-to-treat (mITT) population. In total, 175 patients were included. The tpCR rate was 68.6% (95% CI, 60.7-75.8%), while the objective response rate was 89.1%. In the post-hoc subgroup analysis, no association between clinical characteristics and the tpCR rate was observed. The most common grade ≥3 adverse events were diarrhea (54.3%), followed by white blood cell count decreased (5.1%), and neutrophil count decreased (4.6%). In conclusion, the neoadjuvant regimen with ECPy-THPy showed promising pathological response and clinical benefits with an acceptable safety profile in patients with stage II-III HER2-positive breast cancer.

Combination of ultrafast dynamic contrast-enhanced MRI-based radiomics and artificial neural network in assessing BI-RADS 4 breast lesions: Potential to avoid unnecessary biopsies.

Objectives: To investigate whether combining radiomics extracted from ultrafast dynamic contrast-enhanced MRI (DCE-MRI) with an artificial neural network enables differentiation of MR BI-RADS 4 breast lesions and thereby avoids false-positive biopsies. Methods: This retrospective study consecutively included patients with MR BI-RADS 4 lesions. The ultrafast imaging was performed using Differential sub-sampling with cartesian ordering (DISCO) technique and the tenth and fifteenth postcontrast DISCO images (DISCO-10 and DISCO-15) were selected for further analysis. An experienced radiologist used freely available software (FAE) to perform radiomics extraction. After principal component analysis (PCA), a multilayer perceptron artificial neural network (ANN) to distinguish between malignant and benign lesions was developed and tested using a random allocation approach. ROC analysis was performed to evaluate the diagnostic performance. Results: 173 patients (mean age 43.1 years, range 18-69 years) with 182 lesions (95 benign, 87 malignant) were included. Three types of independent principal components were obtained from the radiomics based on DISCO-10, DISCO-15, and their combination, respectively. In the testing dataset, ANN models showed excellent diagnostic performance with AUC values of 0.915-0.956. Applying the high-sensitivity cutoffs identified in the training dataset demonstrated the potential to reduce the number of unnecessary biopsies by 63.33%-83.33% at the price of one false-negative diagnosis within the testing dataset. Conclusions: The ultrafast DCE-MRI radiomics-based machine learning model could classify MR BI-RADS category 4 lesions into benign or malignant, highlighting its potential for future application as a new tool for clinical diagnosis.

Silencing long non-coding RNA HNF1A-AS1 inhibits growth and resistance to TAM of breast cancer cells via the microRNA-363/SERTAD3 axis.

Long non-coding RNAs (lncRNAs) can exert effects on drug resistance of cancer cells. This study investigated the role of lncRNA HNF1A-antisense 1 (HNF1A-AS1) in growth and Tamoxifen (TAM) sensitivity of breast cancer (BC) cells. HNF1A-AS1 expression was promoted in BC cells and tissues. BC cells with HNF1A-AS1 silencing were constructed to detect cell proliferation. TAM resistant cell line with HNF1A-AS1 silencing and parent cell line with overexpressed HNF1A-AS1 were constructed to measure drug resistance. Silencing HNF1A-AS1 reduced proliferation and TAM resistance of BC cells. The downstream microRNAs (miRs) of HNF1A-AS1 and its targets were figured out and their functions in TAM resistance of BC cells were identified. HNF1A-AS1 sponged miR-363 to promote SERTAD3 expression. Downregulation of miR-363 or upregulation of SERTAD3 stimulated TAM resistance of BC cells. The findings in vitro were reproduced in in vivo experiments. It could be concluded that silencing HNF1A-AS1 inhibited growth and drug resistance to TAM of BC cells through the miR-363/SERTAD3 axis and the inactivation of the TGF-ß/Smad pathway.

Carvacrol affects breast cancer cells through TRPM7 mediated cell cycle regulation.

As the most prevalent cancer for females, breast cancer is also the second most popular cancer type overall. More efforts are needed to research new drugs and combination therapies for this disease. A naturally derived transient receptor potential melastatin-like 7 channel (TRPM7) inhibitor, carvacrol, was found to have anti-cancer potentials. We hypothesized that carvacrol affects breast cancer cells through TRPM7 mediated cell cycle regulation. Cell viability and apoptosis of breast cancer cell lines BT-483, BT-474, MCF-7, MDA-MB-231, and MDA-MB-453 were determined using the CCK-8 assay and ELISA respectively. TRPM7 in MDA-MB-231, MCF-7 was knocked down. Functional TRPM7 in MDA-MB-231, MCF-7, and HEK293 cells were tested with western blotting, patch-clamp, and fura-2 quench assay. The cell cycle and the regulatory proteins were determined by flow cytometry and western blotting. Results showed that carvacrol inhibited the viability of breast cancer cells with different potency. At 200 µM, MDA-MB-231 was the most sensitive, and MCF-7 was the least sensitive. At >200 µM, the apoptosis was dramatically induced. Carvacrol inhibited TRPM7 functions in MDA-MB-231, MCF-7, and HEK293. Carvacrol at 200 µM increased cells in the G1/G0 phase and decreased cells in the S and G2/M phase by regulating some cyclin proteins in MDA-MB-231. These effects were blocked by the knockdown of TRPM7. This study demonstrated that carvacrol suppresses breast cancer cells by cell cycle regulation and the TRPM7 pathway is one of the pharmacological mechanisms.

Knockdown of circDENND4C inhibits glycolysis, migration and invasion by up-regulating miR-200b/c in breast cancer under hypoxia.

BACKGROUND: Hypoxia is a key feature of breast cancer, which affects cancer development, metastasis and metabolism. Previous studies suggested that circular RNAs (circRNAs) could participate in cancer progression and hypoxia regulation. This study aimed to investigate the role of circRNA differentially expressed in normal cells and neoplasia domain containing 4C (circDENND4C) in breast cancer progression under hypoxia. METHODS: Forty-three patients with breast cancer were involved in this study. Breast cancer cell lines MDA-MB-453 and SK-BR-3 were cultured under hypoxia (1% O2) for experiments in vitro. The expression levels of circDENND4C, microRNA-200b (miR-200b) and miR-200c were measured by quantitative real-time polymerase chain reaction. Glycolysis was investigated by glucose consumption, lactate production and hexokinase II (HK2) protein level. Migration and invasion were evaluated via trans-well assay and protein levels of matrix metallopeptidase 9 (MMP9) and MMP2. The interaction between circDENND4C and miR-200b or miR-200c was explored by bioinformatics analysis, luciferase assay and RNA immunoprecipitation. Murine xenograft model was established to investigate the anti-cancer role of circDENND4C in vivo. RESULTS: circDENND4C highly expressed in breast cancer was up-regulated in response to hypoxia. Knockdown of circDENND4C decreased glycolysis, migration and invasion in breast cancer cells under hypoxia. circDENND4C was validated as a sponge of miR-200b and miR-200c. Deficiency of miR-200b or miR-200c reversed the suppressive effect of circDENND4C knockdown on breast cancer progression. Moreover, silence of circDENND4C reduced xenograft tumor growth by increasing miR-200b and miR-200c. CONCLUSION: circDENND4C silence suppresses glycolysis, migration and invasion in breast cancer cells under hypoxia by increasing miR-200b and miR-200c.

Bifunctional Chelating Supramolecular Polymer and Its Application in Downregulation of Cellular Iron Uptake.

A bifunctional chelating supramolecular polymer (SP-Ch) is constructed from a brush-like macromolecule (P-Ch) through hydrogen bonds. Two kinds of norbornene derivatives are used to synthesize P-Ch in which phosphonic acid as a side-group of polynorbornene can act as a chelating group and ascorbic acid as a side-chain capper of polynorbornene can reduce Fe3+ to Fe2+. It can attach to cell membranes and form two kinds of "barriers" to hinder cells from iron uptake by virtue of phosphonic acid and ascorbic acid. Higher monomer conversion and polymerization degree of P-Ch are achieved when the ratio among M1, M2, and G2 is set as 50:10:1 and SP-Ch particles reach to submicrometer levels (mean size of 147.5 nm). The best chelating and reducing capacities of SP-Ch for Fe3+ are 0.034 and 0.047 mg/mg, respectively. After being treated with SP-Ch, the amount of iron in MCF-7 cells is reduced from 3.376 to 1.784 ng/105 cells after 48 h, which confirms that the cellular iron uptake is downregulated. As a result, iron deprivation induces growth inhibition of MCF-7 cells.

Role of Circulating Tumor Cell (CTC) Monitoring in Evaluating Prognosis of Triple-Negative Breast Cancer Patients in China.

BACKGROUND Breast cancer (BC) is the most common malignant tumor in females. This study investigated the role and utility of CTC monitoring in evaluating the prognosis of triple-negative breast cancer patients. MATERIAL AND METHODS We enrolled 286 female triple-negative breast cancer patients who were diagnosed at and received radical resection surgery in our hospital. Peripheral venous blood samples were collected preoperatively and at 3 and 7 days postoperative, and the Cell Search system was used to detect CTC in peripheral blood. We analyzed the relationship between preoperative CTC level and clinical pathological characteristics of patients. Kaplan-Meier method was used to establish progression-free survival curves and overall survival curves, we used the log-rank test to compare the survival rate, and we explored the effects of preoperative and postoperative CTC levels on patient survival. RESULTS Compared with preoperative levels, the average CTC content in peripheral blood of breast cancer patients was significantly increased at 3 days after surgery, and then decreased to the preoperative baseline level by 7 days after surgery. The 3-year overall survival rate and progression-free survival rate in patients with CTC >5/7.5 mL peripheral blood were significantly lower than in patients with CTC <5/7.5 mL peripheral blood detected preoperatively and at 3 and 7 days postoperatively. CONCLUSIONS Dynamic monitoring of preoperative and postoperative CTC levels can accurately predict recurrence and progression of disease, and is important in postoperative monitoring and prognosis evaluation.

Effects of hyperandrogenism on metabolic abnormalities in patients with polycystic ovary syndrome: a meta-analysis.

BACKGROUND: The study evaluated the effect of hyperandrogenism (HA) in polycystic ovary syndrome (PCOS) on metabolic parameters. METHODS: We searched PubMed, EMBASE, Cochrane, Web of Science, Chinese Biomedical Database (CBM), China National Knowledge Infrastructure (CNKI), WanFang data and VIP for clinical observational studies. The study evaluated PCOS patients with or without HA on metabolic parameters was included. Prevalence of metabolic syndrome, indexes of insulin resistance (IR) including homeostasis model assessment IR index (HOMA-IR), incidence of IR, biomarkers of serum lipid metabolism such as total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), and low density lipoprotein (LDL). RESULTS: Of 4457 identified trials, 32 observational studies were included for the final analysis comprising 9556 female with PCOS. 6482 cases were having HA, and the others were negative. There were significant differences in the incidence of metabolic syndrome, HOMA-IR, rate of IR, TC level and HDL level between PCOS patients with or without HA, except for LDL level. No significant publication bias was found as P value of Egger's test was 0.82. CONCLUSIONS: HA play an important role in metabolic disorders in PCOS patients. The incidence of metabolic syndrome, IR indexes, and most biomarkers of serum lipid metabolism were significantly different between patients with and without HA.

alpha-Adrenoceptor agonists for the treatment of vasovagal syncope: a meta-analysis of worldwide published data.

AIM: The present study was aimed at evaluating present randomized controlled trials (RCTs) regarding the effect of alpha-adrenoceptor agonists on vasovagal syncope (VVS). METHODS: According to inclusion and exclusion criteria, articles were selected from medical electronic databases. RCTs were then assessed based on the Juni assessment, and meta-analysis was completed using the Review Manager 4.2 software. Indication to further evaluate effects was the recurrence of syncope during follow-up treatment or a response in the head-up tilt test (HUT) after treatment. The results were stated as odd ratio (OR), with a 95% confidence interval (CI) and a p < 0.05 significant level. RESULTS: In total, six RCTs were selected. Funnel plot analysis showed possible publication bias. Meta-analysis of the six RCTs, including all 165 patients in the treatment group and 164 patients in the control group, indicated that alpha-adrenoceptor agonists were more effective than placebos in treating VVS (OR = 0.21, 95% CI: 0.06-0.77, p = 0.02). The further, weighted independent t-test disclosed that the weighted mean percentage of responders for midodrine (76.3%+/- 7.7%) was significantly higher than that for etilefrine (65.5%+/- 15.4%) (t = 5.863, p < 0.001). CONCLUSION: The currently published RCTs support that alpha-adrenoceptor agonists might be effective for VVS. Midodrine can be regarded as a better choice compared with etilefrine.

Homogeneous polyhedral oligomeric silsesquioxane (POSS)-supported Pd-diimine complex and synthesis of polyethylenes end-tethered with a POSS nanoparticle via ethylene "living" polymerization.

A POSS-supported Pd-diimine complex, an homogeneous analog of a supported catalyst, was synthesized and applied for the unique synthesis of narrow-distributed polyethylene chains containing an end-tethered POSS nanoparticle by ethylene "living" polymerization.