The m6A Reader YTHDF1 Improves Sevoflurane-Induced Neuronal Pyroptosis and Cognitive Dysfunction Through Augmenting CREB-BDNF Signaling.

Sevoflurane is one of the most widely used anesthetics in surgery which is the main cause of postoperative cognitive dysfunction (POCD). Previous reports confirmed that YTHDF1 is differently expressed in sevoflurane-induced POCD, while the roles and mechanistic details remain unclear. The molecular expressions were assessed using qRT-PCR, western blot, immunofluorescence and immunohistochemistry. Pathological change in the hippocampus tissues was analyzed using HE staining. Cognitive ability in rats was measured using MWM test. Hippocampal neuronal viability and apoptosis were measured by MTT assay and flow cytometry, respectively. The levels of pro-inflammatory cytokines were assessed using ELISA. The interaction between YTHDF1 and CREB was analyzed by RNA immunoprecipitation assay. YTHDF1 was significantly decreased in hippocampus tissues by sevoflurane exposure, and its overexpression could improve sevoflurane-induced neuron damage and cognitive dysfunction. Meanwhile, YTHDF1 upregulation repressed sevoflurane-induced activation of NLRP3 inflammation and pyroptosis in hippocampus tissues. Subsequently, YTHDF1 directly interacted to CREB mRNA to augment its stability and translation via a m6A-dependent manner, thus activating CREB/BDNF pathway. In addition, the inactivation of CREB/BDNF pathway could reverse the protective effects of YTHDF1 overexpression on sevoflurane-mediated neuronal damage and pyroptosis. These findings revealed that YTHDF1 improved sevoflurane-induced neuronal pyroptosis and cognitive dysfunction through activating CREB-BDNF signaling.

Propofol Versus Remimazolam on Cognitive Function, Hemodynamics, and Oxygenation During One-Lung Ventilation in Older Patients Undergoing Pulmonary Lobectomy: A Randomized Controlled Trial.

OBJECTIVES: To investigate the effects of remimazolam on postoperative cognitive function, intraoperative hemodynamics, and oxygenation in older patients undergoing lobectomy. DESIGN: A prospective, double-blind, randomized, controlled study. SETTING: A university hospital. PARTICIPANTS: Eighty-four older patients with lung cancer who underwent lobectomy, aged ≥65 years. INTERVENTIONS: Patients were divided randomly into the remimazolam (group R) and propofol (group P) groups. Group R underwent remimazolam anesthesia induction and maintenance, whereas group P underwent propofol anesthesia induction and maintenance. Cognitive function was assessed with neuropsychological tests 1 day before surgery and 7 days after surgery. The Clock Drawing Test, Verbal Fluency Test (VFT), Digit Symbol Switching Test (DSST), and Auditory Verbal Learning Test-Huashan (AVLT-H) assessed visuospatial ability, language function, attention, and memory, respectively. The systolic blood pressure (SBP), heart rate, mean arterial pressure (MAP), and cardiac index were recorded 5 minutes before induction of anesthesia (T0), 2 minutes after sedation (T1), 5 minutes after intubation with two-lung ventilation (T2), 30 minutes after one-lung ventilation (OLV) (T3), 60 minutes after OLV (T4), and at the end of surgery (T5), and the incidences of hypotension and bradycardia were recorded. The PaO2, oxygenation index (OI), and intrapulmonary shunt (Qs/Qt) were assessed at T0, T2, T3, T4, and T5. The levels of S-100ß and interleukin 6 were measured by enzyme-linked immunosorbent assay at T0, T5, 24 hours after surgery (T6), and on day 7 after surgery (T7). MEASUREMENTS AND MAIN RESULTS: The VFT, DSST, immediate recall AVLT-H, and short-delayed recall AVLT-H scores were significantly higher in group R than in group P on day 7 after surgery (p < 0.05). The SBP and MAP at T2 to T5 were significantly higher in group R than in group P, the incidence of hypotension was significantly lower in group R (9.5%) than in group P (35.7%) (p = 0.004), and remimazolam significantly reduced the dose of phenylephrine used (p < 0.05). The PaO2 and OI at T4 were significantly higher in group R than in group P, and Qs/Qt was significantly lower in group R than in group P. The levels of S-100ß at T5 were significantly lower in group R than in group P (p < 0.05). CONCLUSION: The results showed that remimazolam (versus propofol) may lessen the degree of short-term postoperative cognitive dysfunction measured by standard neuropsychological tests, better optimize intraoperative hemodynamics, and lead to improved oxygenation during OLV.

Cardiovascular risk factors and breast cancer incidence in a large middle-aged cohort study.

BACKGROUND: Several studies have demonstrated that cardiovascular risk factors play a role in the etiology of breast cancer. However, the combined effect of cardiovascular risk factors on the risk of breast cancer is still uncertain. METHODS: Data from the Atherosclerosis Risk in Communities (ARIC) study, a prospective cohort of middle-aged women, were used to investigate the association of individual and combined cardiovascular risk factors with breast cancer. Cox proportional hazards models were applied to calculate the hazard ratio (HR) and 95% confidence intervals (CI). RESULTS: A total of 7501 women were included. During a mean follow-up of 19.7 years, 576 women were diagnosed with breast cancer. White women and premenopausal status were independently associated with increased risk of breast cancer. Of the individual cardiovascular risk factors, only obesity was independently associated with an increased risk of breast cancer (HR 1.29, 95% CI 1.04-1.61). Compared with women without cardiovascular risk factors, women having three or greater, but not those with fewer than three cardiovascular risk factors, had a significantly higher risk of developing breast cancer (HR 1.27, 95% CI 1.06-1.53). Subgroup analyses indicated that women with three or greater cardiovascular risk factors had higher risk of breast cancer among postmenopausal Black women, but not among premenopausal Black and White women. CONCLUSIONS: Combinations of cardiovascular risk factors are associated with increased risk of breast cancer in middle-aged women, especially in postmenopausal Black women. Joint interventions to modify cardiovascular risk factors could be used to prevent breast cancer in these higher-risk individuals.

Host-guest complexation of cyclophosphamide by carboxylatopillar[6]arene for increasing stability and enhancing its curative effect on breast carcinoma.

Advanced chemotherapy strategies are in urgent demand for improving antitumor efficacy on breast carcinoma. Herein, a drug delivery system comprised of host-guest complex between carboxylated pillar[6]arene (CP6A) and cyclophosphamide (CTX) has been designed with view to overcoming several drawbacks associated with this antitumor agent. NMR and fluorescence titration served to confirm the complexation of CTX/CP6A. Baring CP6A did not affect cell viability as inferred from comparison studies carried out in human normal mammary epithelial cells and breast adenocarcinoma cells. Stability experiment proved that complexation of CTX by CP6A could increase the inherent stability of CTX in phosphate buffer (pH = 7.4) at 37 °C in a statistically significant way. In vivo research confirmed that CTX/CP6A was not only able to promote antitumor efficacy but also reduce CTX-related systemic toxicity on breast adenocarcinoma cells derived subcutaneous tumor xenograft mouse models. This drug delivery system could also be extended to other clinical chemotherapeutic agents and it was expected to provide salutary profits for more patients.

Additional adjuvant capecitabine in early breast cancer patients: a meta-analysis of randomized controlled trials.

Aims: To assess the efficacy and safety of adjuvant capecitabine in early breast cancer patients. Methods: A literature search of databases was conducted to identify randomized controlled trials reporting the efficacy and toxicity of capecitabine as adjuvant therapy in early breast cancer patients. Results: Six studies were eligible and included a total of 6941 patients. Disease-free survival (hazard ratio = 0.79; 95% CI = 0.71-0.88; p < 0.0001) was significantly improved with additional capecitabine, whereas improvement in overall survival (OS) was not significant. The more pronounced benefits in both disease-free survival and OS were observed among triple-negative breast cancer patients. Conclusion: Additional capecitabine in the adjuvant setting conferred substantial disease-free survival benefit and a tendency toward improved OS. Triple-negative breast cancer patients can benefit from capecitabine irrespective of the administration sequence. Capecitabine may be considered a preferred additional treatment for early-stage triple-negative breast cancer patients, and sequential capecitabine can serve as an alternative choice for patients with poor tolerance.

Lay abstract The authors' meta-analysis focused on the adjuvant role of capecitabine in early-stage breast cancer patients. The authors combined data from different studies to show that disease-free survival was significantly improved with additional capecitabine as adjuvant chemotherapy. The more pronounced survival benefits were observed among triple-negative breast cancer patients irrespective of the administration sequence (concurrent/sequential). Capecitabine may be considered a preferred additional treatment for early-stage triple-negative breast cancer patients, and sequential capecitabine can serve as an alternative choice for patients with poor tolerance.

Metabolic classification of circulating tumor cells as a biomarker for metastasis and prognosis in breast cancer.

BACKGROUND: Circulating tumor cells (CTCs) has been demonstrated as a promising liquid biopsy marker for breast cancer (BC). However, the intra-patient heterogeneity of CTCs remains a challenge to clinical application. We aim at profiling aggressive CTCs subpopulation in BC utilizing the distinctive metabolic reprogramming which is a hallmark of metastatic tumor cells. METHODS: Oncomine, TCGA and Kaplan-Meier plotter databases were utilized to analyze expression and survival relevance of the previously screened metastasis-promoting metabolic markers (PGK1/G6PD) in BC patients. CTCs detection and metabolic classification were performed through micro-filtration and multiple RNA in situ hybridization using CD45 and PGK1/G6PD probes. Blood samples were collected from 64 BC patients before treatment for CTCs analysis. Patient characteristics were recorded to evaluate clinical applications of CTCs metabolic subtypes, as well as morphological EMT subtypes classified by epithelial (EpCAM/CKs) and mesenchymal (Vimentin/Twist) markers. RESULTS: PGK1 and G6PD expressions were up-regulated in invasive BC tissues compared with normal mammary tissues. Increased tissue expressions of PGK1 or G6PD indicated shortened overall and relapse-free survival of BC patients (P < 0.001). Blood GM+CTCs (DAPI+CD45-PGK1/G6PD+) was detectable (range 0-54 cells/5 mL) in 61.8% of tCTCs > 0 patients. Increased GM+CTCs number and positive rate were correlated with tumor metastasis and progression (P < 0.05). The GM+CTCs ≥ 2/5 mL level presented superior AUC of ROC at 0.854 (95% CI 0.741-0.968) in the diagnosis of BC metastasis (sensitivity/specificity: 66.7%/91.3%), compared with that of tCTCs (0.779) and CTCs-EMT subtypes (E-CTCs 0.645, H-CTCs 0.727 and M-CTCs 0.697). Moreover, GM+CTCs+ group had inferior survival with decreased 2 years-PFS proportion (18.5%) than GM+CTCs- group (87.9%; P = 0.001). CONCLUSIONS: This work establishes a PGK1/G6PD-based method for CTCs metabolic classification to identify the aggressive CTCs subpopulation. Metabolically active GM+CTCs subtype is suggested a favorable biomarker of distant metastasis and prognosis in BC patients.

Gemcitabine and Capecitabine Combination Chemotherapy in Patients with Metastatic Breast Cancer Pretreated with Anthracyclines and/or Taxanes.

BACKGROUND: Owing to the need for effective and tolerable new regimens for the treatment of patients with metastatic breast cancer (MBC) previously treated with anthracyclines and/or taxanes, we aimed to assess the activity and safety of the gemcitabine plus capecitabine combination chemotherapy. METHODS: Sixty-four patients were enrolled. Treatment consisted of gemcitabine 1,000 mg/m2 intravenously on days 1 and 8, plus oral capecitabine at 1,250 mg/m2 twice daily on days 1-14. The primary end point was the overall response rate (ORR). Secondary objectives included the disease control rate (DCR), overall survival (OS), progression-free survival (PFS), toxicity, and predictive factors. RESULTS: In the 64 patients, the ORR and DCR was 28.1 and 67.2%. Median OS and PFS were 23.6 and 13.4 months, respectively. Toxicities were mild and curable. CONCLUSION: The combination of gemcitabine and capecitabine is an effective and tolerable treatment for MBC previously treated with anthracyclines and/or taxanes.

Experimental Study of Magnetic Multi-Walled Carbon Nanotube-Doxorubicin Conjugate in a Lymph Node Metastatic Model of Breast Cancer.

BACKGROUND The lymphatic system plays a significant role in the defense of a subject against breast cancer and is one of the major pathways for the metastasis of breast cancer. To improve the prognosis, many means, including surgery, radiotherapy, and chemotherapy, have been used. However, the combination of all these modalities has limited efficacy. Lymph nodes, therefore, have become an exceptionally potential target organ in cancer chemotherapy. MATERIAL AND METHODS A lymph node metastatic model of breast cancer was established in BALB/c mice. Magnetic multi-walled carbon nanotube carrier with good adsorption and lymph node-targeting capacity was prepared and conjugated with doxorubicin to make the magnetic multi-walled carbon nanotube-doxorubicin suspension. Dispersions of doxorubicin, magnetic multi-walled carbon nanotube-doxorubicin, and magnetic multi-walled carbon nanotube were injected into lymph node metastatic mice to compare their inhibitory effects on tumor cells in vivo. Inhibition of these dispersions on EMT-6 breast cancer cells was detected via MTT assay in vitro. RESULTS Although no significant difference was found between the effects of doxorubicin and magnetic multi-walled carbon nanotube-doxorubicin with the same concentration of doxorubicin on EMT-6 breast cancer cells in vitro, in terms of sizes of metastatic lymph nodes and xenograft tumors, apoptosis in metastatic lymph nodes, and adverse reactions, the magnetic multi-walled carbon nanotube-doxorubicin group differed significantly from the other groups. CONCLUSIONS The magnetic multi-walled carbon nanotube-doxorubicin clearly played an inhibitory role in lymph node metastases to EMT-6 breast cancer cells.

Invasive micropapillary carcinoma of the breast had poor clinical characteristics but showed no difference in prognosis compared with invasive ductal carcinoma.

BACKGROUND: It is controversial for prognosis of invasive micropapillary carcinoma (IMPC) compared with invasive ductal carcinoma (IDC) of the breast. To better understand the difference between IMPC and IDC prognoses, we conducted this retrospective study. METHODS: Data from 33 patients with IMPC were retrospectively reviewed, and the clinicopathologic characteristics and survival status were compared with those of 347 patients with IDC who were treated during the same period. RESULTS: The IMPC cases were of larger tumor size, greater proportion of nodal involvement, and an increased incidence of lymphovascular invasion compared with IDC cases. The overall survival (OS), local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and failure-free survival (FFS) rates were not significantly different between IMPC and IDC. The 3-year OS rate was 97 vs 94.2 % for the IMPC and IDC patients, respectively. The 3-year FFS rate was 87.9 vs 86.2 % for the IMPC and IDC patients, respectively. For IMPC patients, the 3-year LRFS rate was 93.9 % and in IDC patients was 89.0 %. The 3-year DMFS rates of IMPC patients was 90.9 % and IDC patients was 89 %. CONCLUSIONS: IMPC had poor clinical characteristics, but it showed no difference in OS, FFS, LRFS, and DMFS compare with IDC.

Use of Acellular Dermal Matrices in One-stage Implant-based Breast Reconstruction.

Implant-based breast reconstruction is the most common choice in breast cancer patients. Recently,the acellular dermal matrix (ADM) technique has been widely used in implant-based breast reconstruction in the western countries. This article briefly reviews the biological characteristics,history,types,surgical techniques,and postoperative complications of ADM.

The expression of CXCL13 and its relation to unfavorable clinical characteristics in young breast cancer.

BACKGROUND: Young breast cancer occupies a higher and higher proportion of breast cancer, especially in Asia, and is associated with a more unfavorable prognosis compared with the disease arising in older women. However, the poor prognosis of young breast cancer cannot be fully explained by the clinical and molecular factors. METHODS: This study investigated 1125 Chinese breast cancer patients diagnosed from 2009 to 2013. A data mining of gene expression profiles was performed for the young and older breast cancer patients, identifying significantly differentially expressed genes. Quantitative RT-PCR, Western blotting and immunohistochemistry assay were carried out for the clinical sample validations. RESULTS: The investigation firstly displayed that young patients (≤45 years) accounted for 47.6 % (535/1125) of breast cancer, and clinically associated with some unfavorable factors related to poor prognosis, such as invasive pathological type, high tumor grade, lymph node positive, ER negative and triple-negative subtype. Subsequently, 553 significantly differentially expressed genes were identified by the data mining. Of them, a set of genes related to immune function were observed to be up-regulated in young patients with breast cancer. Impressively, the CXCL13 (C-X-C motif chemokine 13) expression level showed the most significant difference (FC = 2.64, P = 8.2 × 10(-4)). Furthermore, the validations with clinical samples and correlation analysis demonstrated that CXCL13 was indeed highly expressed in young breast cancer and closely associated with some prognostic factors including lymph node positive and ER negative. CONCLUSION: This is the first to indicate the clinical relevance of CXCL13 to young breast cancer and represents a potential therapeutic target for young breast cancer.

[Advances in studies on metabolic syndrome and breast cancer].

Breast cancer is one of the most common malignancies in women. Over these years, the morbidity of metabolic syndrome (MS) has also been increasing in China, probably due to changes in economies and lifestyles. As a result, the association to between these two diseases has at tracted much attention. Results demonstrated the presence of MS was associated with breast cancer risk, and the risk became higher when more MS components were present compared to no components. Moreover, a specific association was indicated between MS and breast cancer recurrence and metastasis to some extent as well. Further, for breast cancer patients, being diagnosed with MS can increase the mortality and lead to poor prognosis. The mechanisms underlying the association is not clear yet, but several factors are speculated to be the possible causes, including the elevated level of insulin, insulin like growth factor-1, leptin and pro-inflammatory cytokines, the decreased level of adiponectin as well as the interaction between DBC1 and SIRT1. The prognosis of patients with breast cancer combined MS can be improved by means of changing diet habits, increasing physical activities and drug-intervention. Although the specific mechanisms underlying the association are still need to be elucidated, better understanding of the association must help us with new strategies for the prevention and treatment of breast cancer.

Slowing the expansion of impervious surfaces: the key to promoting high-quality and sustainable regional development.

Sponge cities are disaster-resilient and sustainable infrastructure, and the emergence of impervious surfaces hinders the construction of sponge cities. In response to the United Nations' 2030 Sustainable Development Goals, the study of the spatio-temporal evolution and influencing factors of impervious surfaces provides an effective basis for the construction of sponge cities. In this paper, multi-source remote sensing images (Landsat 4-5 TM was used in 2000 and 2010, Landsat 8 OLI/TIRS was used in 2020) were used as data sources to construct a multi-feature impervious surface estimation model. By combining and refining the advantages of MISI, NDBI, and BUAI feature indices, we obtained the impervious surface cover of Nanchang City in 2000, 2010, and 2020. And its spatio-temporal evolution characteristics were analyzed by using the ESDA. The main factors of the impervious surface were analyzed by using the ordinary panel data model and the spatial durbin model. Results: (1) From 2000 to 2020, the impervious surface area of Nanchang City increased from 516.13 to 1075.12 km2. The overall impervious surface distribution in Nanchang City expressed a significant neighborhood distribution; (2) socio-economic factors had a positive role in promoting the impervious surface of Nanchang City. Among them, the correlation coefficient of the economic development index (0.2332), real estate investment (0.1518), and gross industrial output value (0.0453) were the most significant in the local areas; (3) the economic development index (0.2307), real estate investment (0.0251), and passenger volume (0.1679) stimulated the growth of impervious surfaces in adjacent areas, and the total population (-0.8074) had a buffering effect on adjacent areas. In order to promote the sustainable development of the region, it is necessary to propose corresponding measures and suggestions based on the impervious surface of Nanchang City.

Safety, Efficacy, and Pharmacokinetics of SHR-A1811, a Human Epidermal Growth Factor Receptor 2-Directed Antibody-Drug Conjugate, in Human Epidermal Growth Factor Receptor 2-Expressing or Mutated Advanced Solid Tumors: A Global Phase I Trial.

PURPOSE: SHR-A1811 is an antibody-drug conjugate composed of an anti-human epidermal growth factor receptor 2 (HER2) antibody trastuzumab, a cleavable linker, and a topoisomerase I inhibitor payload. We assessed the safety, tolerability, antitumor activity, and pharmacokinetics of SHR-A1811 in heavily pretreated HER2-expressing or mutated advanced solid tumors. METHODS: This global, multi-center, first-in-human, phase I trial was conducted at 33 centers. Patients who had HER2-expressing or mutated unresectable, advanced, or metastatic solid tumors and were refractory or intolerant to standard therapies were enrolled. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg once every 3 weeks. The primary end points were dose-limiting toxicity, safety, and the recommended phase II dose. RESULTS: From September 7, 2020, to February 27, 2023, 307 patients who had undergone a median of three (IQR, 2-5) previous treatment regimens in the metastatic setting received SHR-A1811 treatment. As of data cutoff (February 28, 2023), one patient from the 6.4 mg/kg group experienced dose-limiting toxicities (pancytopenia and colitis). The most common grade 3 or higher adverse events (AEs) included decreased neutrophil count (119 [38.8%]) and decreased WBC count (70 [22.8%]). Interstitial lung disease occurred in only eight (2.6%) patients. Serious AEs and deaths occurred in 70 (22.8%) and 13 (4.2%) patients, respectively. SHR-A1811 led to objective responses in 59.9% (184/307) of all patients, 76.3% (90/118) of HER2-positive breast cancer, 60.4% (55/91) of HER2 low-expressing breast cancer, and 45.9% (39/85 with evaluable tumor responses) of the 98 nonbreast tumors. CONCLUSION: SHR-A1811 exhibited acceptable tolerability, promising antitumor activity, and a favorable pharmacokinetic profile in heavily pretreated advanced solid tumors. The recommended phase II dose of 4.8 or 6.4 mg/kg was selected for various tumor types.

MT1-MMP in breast cancer: induction of VEGF-C correlates with metastasis and poor prognosis.

BACKGROUND: Recent evidence suggests that vascular endothelial growth factor-C (VEGF-C)- dependent tumour production promotes lymphangiogenesis, while membrane-type matrix 1 metalloproteinase (MT1-MMP) is involved in the critical steps leading to carcinogenesis. However, the role of MT1-MMP in lymphangiogenesis and lymphatic metastasis remains poorly understood. In the present study, we investigated the relationship between MT1-MMP and VEGF-C in human breast cancer and correlated MT1-MMP and VEGF-C expression with lymphangiogenesis and prognosis. METHODS: MT1-MMP and VEGF-C levels were compared in five breast carcinoma cell lines. We used a membrane invasion assay to assess the effect of MT1-MMP and VEGF-C expression, as well as anti-MT1-MMP and VEGF-C antibodies, on cancer cell invasion. We further assessed MT1-MMP and VEGF-C immunoreactivity and lymph vessels in a cohort of human breast cancer specimens (n = 106) and associated MT1-MMP and VEGF-C expression with clinicopathological parameters, such as lymphatic vessel density (LVD), and patient prognosis. RESULTS: MT1-MMP and VEGF-C expression differed among the five breast cancer cell lines and MT1-MMP and VEGF-C expression were correlated with tumour cell invasion. VEGF-C mRNA expression levels and invasive activity of MDA-MB-231 cells was inhibited by an anti-MT1-MMP antibody in a concentration-dependent manner. A significant correlation was found between the expression of MT1-MMP and VEGF-C in breast cancer patient samples and elevated MT1-MMP and VEGF-C expression was associated with higher LVD, lymph node metastasis, cancer stage, and a decline in overall survival rates. CONCLUSIONS: Our data demonstrate that MT1-MMP expression is closely correlated with VEGF-C expression, and that MT1-MMP promotes lymphangiogenesis by up-regulating VEGF-C expression in human breast cancer. Thus, elevated MT1-MMP may serve as a significant prognostic factor in breast cancer.

Sauchinone inhibits breast cancer cell proliferation through regulating microRNA-148a-3p/HER-2 axis.

BACKGROUND: Sauchinone is extracted from the root of Saururus chinensis and exhibits potent antitumor effects in various human cancers. However, how sauchinone is involved in breast cancer has not been well studied. METHODS: Cells apoptosis, cell proliferation, and cycle distribution were evaluated. Xenograft tumor mouse model was constructed to investigate the roles of sauchinone. The relevant protein expression was detected by western blot. RESULTS: We found that sauchinone significantly reduced proliferation and survival, also induced apoptosis of MCF-7 and Bcap-37 cells in vitro. Sauchinone significantly increased miR-148a-3p expression, and human epidermal growth factor receptor (HER)-2 targeted on miR-148a-3p. Sauchinone exposure downregulated HER-2 expression whose overexpression partly eliminated the inhibitory effect of sauchinone. Further, sauchinone efficiently inhibited breast cancer progression through downregulating HER-2 expression in vivo. CONCLUSION: Our results indicate that sauchinone efficiently inhibits breast cancer progression through regulating miR-148a-3p/HER-2 axis, suggesting that sauchinone could be an effective anticancer agent for breast cancer.

Pyrotinib versus placebo in combination with trastuzumab and docetaxel as first line treatment in patients with HER2 positive metastatic breast cancer (PHILA): randomised, double blind, multicentre, phase 3 trial.

OBJECTIVE: To assess the efficacy and safety of pyrotinib (an irreversible pan-HER (human epidermal growth factor receptor) inhibitor), trastuzumab, and docetaxel compared with placebo, trastuzumab, and docetaxel for untreated HER2 positive metastatic breast cancer. DESIGN: Randomised, double blind, placebo controlled, multicentre, phase 3 trial. SETTING: 40 centres in China between 6 May 2019 and 17 January 2022. PARTICIPANTS: 590 female patients (median age 52 (interquartile range 46-58) years) with untreated HER2 positive metastatic breast cancer. INTERVENTIONS: Eligible patients were randomised 1:1 to receive either oral pyrotinib (400 mg once daily) or placebo, both combined with intravenous trastuzumab (8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles) and docetaxel (75 mg/m2) on day 1 of each 21 day cycle. Randomisation was stratified by treatment history of trastuzumab in the (neo)adjuvant setting and hormone receptor status. Patients, investigators, and the sponsor's study team were masked to treatment assignment. MAIN OUTCOME MEASURES: The primary endpoint was progression-free survival as assessed by the investigator. RESULTS: Of the 590 randomised patients, 297 received pyrotinib, trastuzumab, and docetaxel treatment (pyrotinib group), and 293 received placebo, trastuzumab, and docetaxel treatment (placebo group). At data cut-off on 25 May 2022, the median follow-up was 15.5 months. The median progression-free survival according to the investigator was significantly longer in the pyrotinib group than in the placebo group (24.3 (95% confidence interval 19.1 to 33.0) months versus 10.4 (9.3 to 12.3) months; hazard ratio 0.41 (95% confidence interval 0.32 to 0.53); one sided P<0.001). Treatment related adverse events of grade 3 or higher were reported in 267 (90%) of the 297 patients in the pyrotinib group and 224 (76%) of the 293 patients in the placebo group. No treatment related deaths occurred in the pyrotinib group, and one (<1%; diabetic hyperosmolar coma) treatment related death occurred in the placebo group. Survival and toxicities are still under assessment with longer follow-up. CONCLUSIONS: Pyrotinib, trastuzumab, and docetaxel showed superiority by significantly improving progression-free survival compared with placebo, trastuzumab, and docetaxel in patients with untreated HER2 positive metastatic breast cancer. The toxicity was manageable. The findings support this dual anti-HER2 regimen as an alternative first line treatment option in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov NCT03863223.

Risk-association of CYP11A1 polymorphisms and breast cancer among Han Chinese women in Southern China.

Exposure to endogenous sex hormones has been reported as a risk factor for breast cancer. The CYP11A1 gene encodes the key enzyme that catalyzes the initial and rate-limiting step in steroid hormone synthesis. In this study, the associations between single nucleotide polymorphisms (SNPs) in CYP11A1 and breast cancer susceptibility were examined. Six SNPs in CYP11A1 were genotyped using the MassARRAY IPLEX platform in 530 breast cancer patients and 546 healthy controls. Association analyses based on a χ(2) test and binary logistic regression were performed to determine the odds ratio (OR) and 95% confidence interval (95% CI) for each SNP. Two loci (rs2959008 and rs2279357) showed evidence of associations with breast cancer risk. The variant genotype C/T-C/C of rs2959008 was significantly associated with a decreased risk (age-adjusted OR, 0.75; 95% CI, 0.58-0.96; P = 0.023) compared with the wild-type TT. However, the homozygous TT variant of rs2279357 exhibited increased susceptibility to breast cancer (age-adjusted OR, 1.44; 95% CI, 1.05-1.98; P = 0.022). The locus rs2959003 also showed an appreciable effect, but no associations were observed for three other SNPs. Our results suggest that polymorphisms of CYP11A1 are related to breast cancer susceptibility in Han Chinese women of South China.

Prevalence of breast fibroadenoma in healthy physical examination population in Guangdong province of China: a cross-sectional study.

OBJECTIVE: To provide an accurate assessment of the prevalence of breast fibroadenoma in a large population and to confirm the diagnostic accuracy of ultrasound for fibroadenoma. DESIGN: This was a cross-sectional survey. SETTING: This research was conducted at Nanfang Hospital, Guangzhou, Guangdong, China. PARTICIPANTS: A total of 11 898 women aged 18-40 years who underwent breast screening between 1 January 2019 and 31 December 2019 were included in the fibroadenoma prevalence study. From 1 June 2019 to 31 December 2019, 342 breast lesions with pathology reports and preoperative ultrasound images were collected for diagnostic fibroadenoma testing (vs histological diagnostic testing). PRIMARY OUTCOME MEASURES: Pearson's χ2 test was performed to compare the prevalence of different lesions between age groups, and descriptive statistics were used to report the clinical characteristics of fibroadenoma. For ultrasound diagnosis, fibroadenoma was defined as a well-circumscribed lesion with round or oval shape, consisting of a homogeneously hypoechoic or isoechoic solid mass, located parallel to the chest wall with a smooth margin and no posterior shadowing. Diagnostic test results for breast fibroadenoma were stratified by diagnostic type (histological vs ultrasound). RESULTS: Of the women aged 18-40 years, 27.6% (3285/11 898) had an ultrasound diagnosis offibroadenoma. Of these, the prevalence of fibroadenoma was stable across age groups (p=0.14) and did not differ between the left and right sides of the breast. Almost two-thirds of women presented with a single fibroadenoma, and most fibroadenomas did not exceed 1 cm in size. The sensitivity and specificity for fibroadenoma were 97.0% (95% CI for sensitivity: 93.7% to 98.8%) and 91.4% (95% CI for specificity: 85.4% to 95.5%) for ultrasonography, respectively. CONCLUSIONS: The prevalence of fibroadenoma in South China is as high as 27.6%, and ultrasound could be used as a tool to diagnose fibroadenoma.

lnc­MICAL2­1 sponges miR­25 to regulate DKK3 expression and inhibits activation of the Wnt/ß­catenin signaling pathway in breast cancer.

The Dickkopf 3 (DKK3) protein antagonizes the Wnt receptor complex in the Wnt signaling pathway; however, to date, there have been no relevant studies investigating its upstream regulatory mechanism in breast cancer (BC), to the best of our knowledge. The present study aimed to explore whether long non­coding RNA MICAL2­1 (lnc­MICAL2­1) sponged microRNA (miR)­25 to regulate DKK3 and inhibit activation of the Wnt/ß­catenin signaling pathway. The Atlas of non­coding RNA in Cancer database was used to measure the expression levels of lnc­MICAL2­1 and their correlation with DKK3 expression levels. In addition, cell proliferation, invasion and migration were determined following the silencing or overexpression of lnc­MICAL2­1. The binding between lnc­MICAL2­1 and miR­25, or miR­25 and DKK3 was verified using RNA pull­down and dual­luciferase reporter assays. The effects of overexpression or knockdown of lnc­MICAL2­1 on DKK3 expression and the Wnt signaling pathway were further evaluated in a nude mouse xenograft model. The results revealed that, compared with in adjacent normal tissue, the expression levels of lnc­MICAL2­1 were downregulated in BC tissues, and the expression levels of lnc­MICAL2­1 were found to be positively correlated with DKK3 expression. The overexpression of lnc­MICAL2­1 in BC cells upregulated the mRNA expression levels of DKK3 and inhibited their proliferation. Results from the RNA pull­down and dual luciferase reporter assays validated that lnc­MICAL2­1 could bind to miR­25, which targets DKK3. The in vivo experimental data demonstrated that lnc­MICAL2­1 inhibited tumor growth via regulating the Wnt signaling pathway. In conclusion, the findings of the present study highlighted a novel molecular mechanism through which lnc­MICAL2­1 may regulate the DKK3­mediated Wnt signaling pathway in BC, highlighting potential targets for the treatment of the disease.