HMGB1 is a key factor for tamoxifen resistance and has the potential to predict the efficacy of CDK4/6 inhibitors in breast cancer.

Breast cancer is the leading cause of cancer death in women. Hormone-receptor-positive breast cancer (HR + BC) is the most common pathological type of breast cancer, of which the main treatment method is endocrine therapy. Unfortunately, primary or acquired drug resistance greatly limits its efficacy. In recent years, the newly launched CDK4/6 inhibitors could effectively reverse endocrine resistance in breast cancer. However, considering their expensive price and side effects, it is particularly important to find out effective biomarkers and screen sensitive patients. Here, we found through bioinformatics analysis that high mobility group box 1 (HMGB1) expression increased in endocrine-resistant HR + BC. In clinical specimens, the higher expression of HMGB1 was associated with shorter progression-free survival (PFS) for HR + BC patients with endocrine therapy after surgery. For endocrine-resistant breast cancer, compared with HMGB1-negative patients, HMGB1-positive patients who received CDK4/6 inhibitors treatment benefited more in PFS. Moreover, we demonstrated that HMGB1 promoted tamoxifen resistance by combining with the Toll-like receptor 4 (TLR4) and activating nuclear factor kappa B (NF-κB) pathway. CDK4/6 inhibitors could downregulate the expression of HMGB1 and suppress the TLR4-NF-κB pathway, and in turn reverse tamoxifen resistance. These results illuminated the critical role of HMGB1 in the process of tamoxifen resistance, explained the mechanism of CDK4/6 inhibitors reversing tamoxifen resistance, and suggested the feasibility of HMGB1 as a potential biomarker for screening sensitive patients receiving CDK4/6 inhibitors.

Tumor-associated macrophages secrete CC-chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer.

Breast cancer is the most prevalent malignancy among women. Although endocrine therapy is effective, the development of endocrine resistance is a major clinical challenge. The tumor microenvironment (TME) promotes tumor malignancy, and tumor-associated macrophages (TAM) within the TME play a crucial role in endocrine resistance. Herein, we aimed to elucidate the relationship between TAM and the endocrine-resistant phenotype of breast cancer. Macrophages were cultured with conditioned medium (CM) from tamoxifen-sensitive (MCF7-S) or -resistant (MCF7-R) MCF7 breast cancer cells. M2 polarization was detected by CD163 immunofluorescence. To determine the effect on endocrine resistance, MCF7 cells were cultured in the supernatant of different TAM, and then treated with tamoxifen. CC-chemokine ligand 2 (CCL2) immunohistochemistry was carried out on pathological sections from 100 patients with invasive estrogen receptor-positive breast cancer. We found that macrophages cultured in the CM of MCF7-S and MCF7-R cells were induced into TAM, with a more obvious M2 polarization in the latter. Tamoxifen resistance was increased by culture in TAM medium. TAM secreted CCL2, which increased endocrine resistance in breast cancer cells through activation of the PI3K/Akt/mTOR signaling pathway. High expression of CCL2 was correlated with infiltration of CD163+macrophages (r = 0.548, P < .001), and patients with high CCL2 expression presented shorter progression-free survival than those with low CCL2 expression (P < .05). We conclude that CCL2 secreted by TAM activates PI3K/Akt/mTOR signaling and promotes an endocrine resistance feedback loop in the TME, suggesting that CCL2 and TAM may be novel therapeutic targets for patients with endocrine-resistant breast cancer.

[Application and prospect of "couplet medicine" techniques in preservation of Chinese medicinal materials].

Chinese medicinal materials (CMMs) are easily to be contaminated by all kinds of molds to produce various mycotoxins due to their internal factors and the external environmental conditions during the growth, harvesting, processing, and especially storage processes. This will not only affect the quality of CMMs, resulting in enormous financial loss, but also influence the safety and effectiveness of CMMs, posing potential threats to human health. With the increase in awareness of "traditional Chinese medicine health" idea, more and more attention has been paid on how to prevent and control these CMMs from being mouldy to guarantee their safety. Some physical and chemical techniques have been restricted for protecting CMMs due to their own disadvantages. As a green, safe and economic strategy for the preservation of CMMs, "couplet medicine" technique based on the principle of "protecting CMM with another CMM" has been developed: two kinds of CMMs are stored together and fight against each other to prevent mildew metamorphism, exhibiting no obvious changes in color, smell and quality. Nowadays, certain application results have been obtained for the "antagonistic storage" method based on the above mode and principle. In this paper, we would review and discuss the mechanism, practical application and the problems of "couplet medicine" technique, and provide scientific evidences for developing safe and effective tools to protect CMMs from being mouldy.

High dielectric transparent polymer composite with well-organized carboxymethyl cellulose microfibers in silicon elastomer fabricated under direct current electric field.

The combination of transparency, high dielectric permittivity, biocompatibility and flexibility is highly desired in the embedded capacitors. Herein, we show that assembling biodegradable sodium carboxymethyl cellulose (CMC) microfibers in biocompatible silicon elastomer (PDMS) under direct current (DC) electric field enables the production of high dielectric constant composite film with above desired properties. This process leads to the formation of columns of CMC microfibers spanning across the thickness direction, thus generating microfiber depleted regions in between fibers and polymer matrix. The as-prepared composite film with CMC (15 wt%) aligned exhibits a remarkable and an almost sevenfold higher dielectric permittivity as compared to that of the film with CMC randomly dispersed (72 vs 11.4, at 100 Hz). This high CMC loading does not compromise the flexibility and optical transmittance. Interestingly, the compression modulus along the thickness direction increases by >20 times from 16.4 MPa (CMC unaligned) to 339.9 MPa (CMC aligned). We demonstrate a facile strategy of fabricating high dielectric materials combining transparency, biocompatibility, flexibility and compression resistant, making the dielectric materials more versatile. This work shows that biomass derived CMC is a promising filler for high dielectric constant polymer composites benefiting from electric field driven construction of ordered micromorphology.

Electrochemical ammonia synthesis by reduction of nitrate on Au doped Cu nanowires.

Electrochemical nitrate reduction reaction (NO3 -RR) to synthesize valuable ammonia (NH3) is considered as a green and appealing alternative to enable an artificial nitrogen cycle. However, as there are other NO3 -RR pathways present, selectively guiding the reaction pathway towards NH3 is currently challenged by the lack of efficient catalyst. Here, we demonstrate a novel electrocatalyst for NO3 -RR consisting of Au doped Cu nanowires on a copper foam (CF) electrode (Au-Cu NWs/CF), which delivers a remarkable NH3 yield rate of 5336.0 ± 159.2 µg h-1 cm-2 and an exceptional faradaic efficiency (FE) of 84.1 ± 1.0% at -1.05 V (vs. RHE). The 15N isotopic labelling experiments confirm that the yielded NH3 is indeed from the Au-Cu NWs/CF catalyzed NO3 -RR process. The XPS analysis and in situ infrared spectroscopy (IR) spectroscopy characterization results indicated that the electron transfer between the Cu and Au interface and oxygen vacancy synergistically decreased the reduction reaction barrier and inhibited the generation of hydrogen in the competitive reaction, resulting in a high conversion, selectivity and FE for NO3 -RR. This work not only develops a powerful strategy for the rational design of robust and efficient catalysts by defect engineering, but also provides new insights for selective nitrate electroreduction to NH3.

Characteristics and survival analysis of breast cancer survivors with metachronous double primary cancers: a retrospective cohort study.

Background: Breast cancer (BC) is the most frequently diagnosed malignancies in females, and its incidence has increased dramatically recently. Clinical studies have shown that BC patients are developing double primary cancers more frequently than by chance, and the prognosis has changed greatly. Previous articles rarely mentioned metachronous double primary cancers in BC survivors. Thus, further analysis of the clinical characteristics and survival differences may provide valuable information in BC survivors. Methods: In this study, we retrospectively analyzed 639 cases of double primary cancers in BC patients. Cox univariate and multivariate regression analyses of clinical factors of overall survival (OS) were performed in patients with double primary cancers when breast cancer was the primary tumor to assess the correlation between clinical factors and OS in these patients with double primary cancers. Results: Among the double primary cancer patients, BC was the most frequent first primary cancer. In terms of numbers, thyroid cancer was the most common type of double primary cancer among BC survivors. Patients had a younger median age when BC occurred as the first primary cancer rather than the second primary cancer. The total mean time interval between the onset of double primary tumors was 70.8 months. With the exception of the thyroid and cervical cancer, the incidence of second primary tumors was <60% within 5 years. However, the incidence was >60% within 10 years. The mean OS of double primary cancer patients was 109.8 months. Additionally, patients who had thyroid cancer as their second primary cancer had the highest 5-year survival rate, followed by cervical, colon, and endometrial cancer, while patients who had lung cancer as their second primary cancer had the lowest 5-year survival rate. OS risk of BC survivors with second primary cancers was significantly associated with age, menopause status, family history, tumor size, lymph node metastasis, and human epidermal growth factor receptor 2 (HER2) status. Conclusions: The identification of double primary cancers in earlier stages could play a critical role in guidance and lead to better outcomes. A prolonged follow-up examination period for BC survivors is needed to provide better guidance and treatments.

Single-shot isotropic differential interference contrast microscopy.

Differential interference contrast (DIC) microscopy allows high-contrast, low-phototoxicity, and label-free imaging of transparent biological objects, and has been applied in the field of cellular morphology, cell segmentation, particle tracking, optical measurement and others. Commercial DIC microscopy based on Nomarski or Wollaston prism resorts to the interference of two polarized waves with a lateral differential offset (shear) and axial phase shift (bias). However, the shear generated by these prisms is limited to the rectilinear direction, unfortunately resulting in anisotropic contrast imaging. Here we propose an ultracompact metasurface-assisted isotropic DIC (i-DIC) microscopy based on a grand original pattern of radial shear interferometry, that converts the rectilinear shear into rotationally symmetric along radial direction, enabling single-shot isotropic imaging capabilities. The i-DIC presents a complementary fusion of typical meta-optics, traditional microscopes and integrated optical system, and showcases the promising and synergetic advancements in edge detection, particle motion tracking, and label-free cellular imaging.

Analyzing the multi-target pharmacological mechanism of folium Artemisia argyi acting on breast cancer: a network pharmacology approach.

Background: Folium Artemisia argyi (FAA) is a traditional Chinese herbal medicine that is widely used in the clinic. However, the underlying mechanisms of its anticancer effects have not been fully elucidated. Methods: In this study, we applied a network pharmacology approach to identify the potential mechanisms of FAA against breast cancer. To be specific, we screened the active ingredients and potential targets of the FAA through the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Meanwhile, we employed the oral bioavailability (OB) and drug-likeness (DL) to search for potential bioactive compounds of FAA. Breast cancer-related target genes data were gathered from the GeneCards and Online Mendelian Inheritance in Man (OMIM) databases, and the protein-protein interaction (PPI) data were acquired from the Search Tool for the Retrieval of Interacting Genes (STRING) database. In addition, we constructed the network and performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Enrichment Analysis. Results: We obtained a total of nine active ingredients and 236 potential targets from FAA to construct a network, which showed that quercetin served as the major ingredient in FAA. AKT1 (RAC-alpha serine/threonine-protein kinase), MYC (Myc proto-oncogene protein), CASP3 (Caspase-3), EGFR (Epidermal growth factor receptor), JUN (Transcription factor AP-1), CCND1 (G1/S-specific cyclin-D1), VEGFA (Vascular endothelial growth factor A), ESR1 (Estrogen receptor), MAPK1 (Mitogen-activated protein kinase 1), and EGF (pro-epidermal growth factor) were identified as key targets of FAA in the treatment of breast cancer. The PPI cluster demonstrated that AKT1 was the seed in this cluster, indicating that AKT1 played a crucial role in connecting other nodes in the PPI network. This enrichment demonstrated that FAA was highly related to signal transduction, endocrine system, replication and repair, as well as cell growth and death. The enrichment results also verified that the underlying mechanisms of FAA against breast cancer might be attributed to the coordinated regulation of several cancer-related pathways, such as the MAPK and mammalian target of rapamycin (mTOR) signaling pathways, among others. Conclusions: This study identified the potential targets and pathways of FAA in the treatment of breast cancer using a network pharmacology approach, and systematically elucidated the mechanisms of FAA in the treatment of breast cancer.

LncRNA ST7-AS1 is a Potential Novel Biomarker and Correlated With Immune Infiltrates for Breast Cancer.

Background: Long noncoding RNA (lncRNA) ST7-AS1 can be observed in various cancers, but its role in breast cancer (BRC) remains unclear. Our aim is to, on the basis of The Cancer Genome Atlas (TCGA) database, prove the correlation between lncRNA ST7-AS1 and BRC. Methods: The lncRNA ST7-AS1 expression and its roles in the prognosis of BRC were explored using data from the TCGA database. The expression level of lncRNA ST7-AS1 in BRC samples was detected using RT-PCR. The 1-, 3-, or 5-year survival rate was predicted using a nomogram established through Cox proportional hazard regression. At last, the biological function was explored through gene ontology (GO) analysis and gene set enrichment analysis (GSEA). The hallmark pathways significantly involved in hub genes were described through functional enrichment analysis. The correlation between lncRNA ST7-AS1 expression and immune infiltration was analyzed through single-sample GSEA (ssGSEA). Results: LncRNA ST7-AS1 expression was downregulated in BRC. Decreased lncRNA ST7-AS1 expression in BRC was correlated with advanced clinical pathologic characteristics (high grade, histological type, age, menopause status, and HER2 status), survival time, and poor prognosis. The nomogram was established for using lncRNA ST7-AS1 to predict 1-, 3-, or 5-year survival in patients with BRC. In addition, GO and pathway analyses suggested the involvement of lncRNA ST7-AS1 in cell cycle, DNA repair, and immune cell infiltration in the BRC immune microenvironment. We found the correlation of lncRNA ST7-AS1 with T helper cells and DC cells. Conclusion: Low expression of lncRNA ST7-AS1 indicates poor prognosis and has an impact on cell cycle, DNA repair, and proportion of infiltrating immune cells in the BRC microenvironment. Therefore, lncRNA ST7-AS1 can be used as a protective prognostic marker and a potential treatment target for BRC.

AC Electric-Field Assistant Architecting Ordered Network of Ni@PS Microspheres in Epoxy Resin to Enhance Conductivity.

By using the low loading of the conductor filler to achieve high conductivity is a challenge associated with electrically conductive adhesion. In this study, we show an assembling of nickel-coated polystyrene (Ni@PS) microspheres into 3-dimensional network within the epoxy resin with the assistance of an electric field. The morphology evolution of the microspheres was observed with optical microscopy and scanning electron microscopy (SEM). The response speed of Ni@PS microsphere to the electric field were investigated by measuring the viscosity and shear stress variation of the suspension at a low shear rate with an electrorheological instrument. The SEM results revealed that the Ni@PS microspheres aligned into a pearl-alike structure. The AC impedance spectroscopy confirmed that the conductivity of this pearl-alike alignment was significantly enhanced when compared to the pristine one. The maximum enhancement in conductivity is achieved at 15 wt. % of Ni@PS microspheres with the aligned composites about 3 orders of magnitude as much as unaligned one, typically from ~10-5 S/m to ~10-2 S/m.

Sodium/glucose cotransporter 1-dependent metabolic alterations induce tamoxifen resistance in breast cancer by promoting macrophage M2 polarization.

Endocrine therapy is the standard treatment for estrogen receptor (ER)-positive breast cancer, but tumors eventually develop resistance. However, endocrine therapy resistance mechanisms mediated through interactions between breast cancer cells and tumor-associated macrophages (TAMs) are still unclear. Here, we characterized sodium/glucose cotransporter 1 (SGLT1) overexpression drives the highly glycolytic phenotype of tamoxifen-resistant breast cancer cells where enhanced lactic acid secretion promotes M2-like TAM polarization via the hypoxia-inducible factor-1α/signal transducer and activator of transcription-3 pathway. In turn, M2-like TAMs activate breast cancer cells through EGFR/PI3K/Akt signaling, providing feedback to upregulate SGLT1 and promote tamoxifen resistance and accelerate tumor growth in vitro and in vivo. Higher expression of SGLT1 and CD163+ TAMs was associated with endocrine-resistant ER-positive breast cancers. Our study identifies a novel vicious cycle of metabolic reprogramming, M2-like TAM polarization, and endocrine therapy resistance, which involves SGLT1, proposing SGLT1 as a therapeutic target to overcome endocrine therapy resistance in breast cancer.

Sodium-Dependent Glucose Transporter 1 (SGLT1) Stabled by HER2 Promotes Breast Cancer Cell Proliferation by Activation of the PI3K/Akt/mTOR Signaling Pathway in HER2+ Breast Cancer.

Aerobic glycolysis is a hallmark of tumor cells. SGLT1 plays a vital role in glucose metabolism. However, whether SGLT1 could promote cell growth and proliferation in breast cancer remains unclear. Here, we investigated the expression of SGLT1 in breast cancer and examined its role in malignant behavior and prognosis. Further, we examined the SGLT1 expression in breast cancer tissues and its relationship with clinicopathologic characteristics. We clarified that SGLT1 was overexpressed in HER2+ breast cancer cell lines and was affected by HER2 status. We further found that SGLT1 affected breast cancer cell proliferation and patient survival by mediating cell survival pathway activation. SGLT1 was overexpressed in HER2+ breast cancers and associated with lymph node metastasis and HER2+ status. Inhibition of HER2 decreased SGLT1 expression, and the extracellular acidification rate was also reduced in the UACC812 and SKBR3 cell lines. These changes could be reversed by proteasome inhibitor treatment. Knockdown of SGLT1 blocked PI3K/Akt/mTOR signaling, thereby inhibiting cell proliferation. Further, we demonstrated that high SGLT1 was significantly correlated with shorter survival in all breast cancer patients and specifically in HER2+ breast cancer patients. Therefore, we conclude that SGLT1 is overexpressed in HER2+ breast cancer, thereby promoting cell proliferation and shortening survival by activating PI3K/Akt/mTOR signaling. This study submits that SGLT1 is promising not only as a novel biomarker of HER2+ breast cancer subtype but also as a potential drug target.

Lymphocyte-to-monocyte ratio is associated with prognosis of diffuse large B-cell lymphoma: correlation with CD163 positive M2 type tumor-associated macrophages, not PD-1 positive tumor-infiltrating lymphocytes.

The research aims to examine the prognostic value of the lymphocyte-to-monocyte ratio (LMR), neutrophil-to- lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in diffuse large B-cell lymphoma (DLBCL). The relation of these hematologic indicators to poor antitumor immunity and prognosis must be investigated. Clinicopathologic data and survival information of 355 patients with DLBCL was retrospectively analyzed. Univariate analysis revealed that lower LMR (<2.71), higher NLR (≥2.81), CD163+ M2 tumor-associated macrophages (TAM) content ≥9.5% and programmed cell death 1 (PD-1)+ tumor-infiltrating lymphocytes (TILs) content < 4.5 cells per high power field(HPF) were significantly related to unfavorable overall survival (OS) and progression free survival (PFS). When considering the prognostic indexes of IPI, multivariate analysis confirmed that LMR of <2.71 and CD163+ M2 TAM content ≥9.5% significantly affected the prognosis of DLBCL. Spearman correlation test showed LMR was negatively correlated with CD163+ M2 TAM content. However, there were no correlation was found between LMR and PD-1+ TIL as well as between NLR and PD-1+ TIL content. These results indicated that decreased LMR lead to a weak anti-tumor immunity and could be used as a bad prognosis biomarker of DLBCL.