Triple negative breast cancer (TNBC), characterized by lack of estrogen receptors, progesterone hormone receptors, and HER2 overexpression, is a more aggressive high grade tumor and not sensitive to ...current targeted drugs. The clinical prognosis of TNBC is poorer than other types of breast cancer, and there is no effective therapy strategy until now. Thus, it is necessary to determine important factors involved in regulating the progression of TNBC. In this study, we found DEPDC1 was up-regulated in the tissues of TNBC compared with their paired peritumoral tissues. DEPDC1 over-expression facilitated cell proliferation and tumor growth through increasing the expression of FOXM1 in TNBC cells. Conversely, knockdown of DEPDC1 had the opposite effects. Moreover, miR-26b, acting as a tumor suppressor in TNBC, directly repressed the expression of DEPDC1 and mitigated its promotive effects on cell growth and colony formation. These results indicate that DEPDC1, negatively regulated by miR-26b, promotes cell proliferation and tumor growth via up-regulating FOXM1 expression, implying an important underlying mechanism of regulating the progression of TNBC.
•DEPDC1 up-regulated in TNBC tissues facilitates cell proliferation and tumorigenesis.•miR-26b directly represses DEPDC1 expression and mitigates its promotive effects.•Effects of DEPDC1 on cell proliferation are mediated by FOXM1 in TNBC.
•Each increase of 10 μg/m3 in PM2.5 was associated with decreased fecundity by 11%.•It was also associated with an 20% increased likelihood of infertility.•The association might explain the increased ...infertility rates in polluted areas.
Whether exposure to airborne particulate matter less than 2.5 μm (PM2.5) could impact human fecundity is unclear. We aimed to evaluate the potential impact of PM2.5 exposure on time to pregnancy (TTP) and the prevalence of infertility in the general Chinese population.
We collected reproductive information, sociodemographic characteristics, and lifestyle data of 10,211 couples at risk of pregnancy from a large-scale community-based fertility survey in China. Then, we estimated each participant’s 1-year, 3-year, and 5-year average PM2.5 exposure levels based on remote sensing information. After adjusting for demographic, lifestyle, and environmental co-variables, discrete-time Cox regression models were used to estimate the fecundability odds ratio (FOR) per 10 μg/m3 change of PM2.5. We also estimated the odds ratio (OR) of infertility per 10 μg/m3 change of PM2.5, using logistic regression models.
Among the 10,211 couples, 6,875 (67%) had conceived spontaneously, with a median TTP of 5 months (interquartile range: 2–10 months). The median PM2.5 exposure was 56.8 μg/m3, with a wide range of 9.2–93.5 μg/m3. In Cox regression models, each increase of 10 μg/m3 in the 1-year average PM2.5 exposure was associated with a significant decrease in fecundity by 11% (FOR: 0.89; 95% confidence interval CI: 0.86–0.92). In logistic regression models, it was also associated with an 20% increased likelihood of infertility (OR: 1.20; 95% CI: 1.13–1.27).
PM2.5 exposure was associated with reduced human fecundity, presented by a longer TTP and higher odds of infertility, which might explain the increased infertility rates in areas with heavy PM2.5 pollution.
Recent evidence shows that inducing ferroptosis may improve efficacy of tumor therapy. However, ferroptosis-related genes have been little studied in patients with breast cancer especially in the ...neoadjuvant setting. ACSL4 and GPX4 have been well established as the positive and negative regulator of ferroptosis, respectively. This study aimed to explore the predictive value of ACSL4 and GPX4 for patients with breast cancer administered neoadjuvant chemotherapy.
This study included patients treated with paclitaxel-cisplatin-based neoadjuvant chemotherapy. Immunohistochemistry staining of ACSL4 and GPX4 was carried out on the core needle biopsy specimens. Logistic regression was performed to explore the predictive biomarkers of pathological complete response (pCR). Survival analyses were examined by log-rank test and Cox proportional hazard regression.
A total of 199 patients were included for the analyses. Both ACSL4 expression and ACSL4/GPX4 combination status could serve as independent predictive factors for pCR. The interaction for pCR was observed between ACSL4 and clinical tumor stage. Besides, ACSL4 expression, GPX4 expression, and their combination status were independent prognostic factors for disease-free survival. Analyses of the Kaplan-Meier Plotter database suggested that higher ACSL4 expression is related to better overall survival, and higher GPX4 expression is related to better distant metastasis-free survival. Pathway analyses revealed that ACSL4 and GPX4 might function in crucial pathways including apoptosis, autophagy, cell adhesion, lipid metabolism, etc.
This study revealed the critical value of ACSL4 and GPX4 serving as novel predictive and prognostic biomarkers for patients with breast cancer receiving neoadjuvant chemotherapy. It might be a novel strategy to induce ferroptosis to promote chemosensitivity. Future studies are required to elucidate the potential mechanisms.
This work was supported by Shanghai Natural Science Foundation grant number 19ZR1431100, Clinical Research Plan of Shanghai Hospital Development Center grant numbers SHDC2020CR3003A, 16CR3065B, and 12016231, Shanghai “Rising Stars of Medical Talent” Youth Development Program for Youth Medical Talents - Specialist Program grant number 2018-15, Shanghai “Rising Stars of Medical Talent” Youth Development Program for Outstanding Youth Medical Talents grant number 2018-16, Shanghai Collaborative Innovation Center for Translational Medicine grant number TM201908, Multidisciplinary Cross Research Foundation of Shanghai Jiao Tong University grant numbers YG2017QN49, ZH2018QNA42, and YG2019QNA28, Nurturing Fund of Renji Hospital grant numbers PYMDT-002, PY2018-IIC-01, PY2018-III-15, and PYIII20-09, Science and Technology Commission of Shanghai Municipality grant numbers 20DZ2201600 and 15JC1402700, and Shanghai Municipal Key Clinical Specialty.
The production of glucuronic acid (GA) directly from actual biomass via chemocatalysis is of great significance to the effective valorisation of biomass for a sustainable future. Herein, we have ...developed a one-step strategy for the conversion of cellulose in corncob residue into GA with the cooperation of Au/CeO2 and maleic acid, achieving a 60.3% yield. Experimental and density functional theory (DFT) results show that maleic acid is effective in the fractionation of cellulose from corncob residue and the depolymerisation of cellulose fragments to glucose, on account of the good capacity for proton migration. Au/CeO2 is responsible for the selective oxidation of glucose to GA, in which the formation of glucaric acid is restrained, due to the weak capacity of Au/CeO2 on the proton transfer without the occurrence of the ring-opening reaction of glucose. Therefore, the relay catalysis of Au/CeO2 and maleic acid enables the production of GA via the complex cascade reactions. This work may provide insight regarding the conversion of actual biomass to targeted products.
ROS1 rearrangements are validated drivers in lung cancer, which have been identified in a small subset (1-2%) of patients with non-small cell lung cancer (NSCLC). To date, 18 fusion genes of ROS1 ...have been identified in NSCLC. The ALK inhibitor (crizotinib) exhibits therapeutic effect against ROS1-rearranged NSCLC. Next-generation sequencing (NGS) technology represents a novel tool for ROS1 detection that covers many fusion genes.
A 55-year-old female with EGFR mutation (L858R) was diagnosed with lung adenocarcinoma, who was responsive to first-generation EGFR-tyrosine kinase inhibitor (TKI). Afterwards, she developed acquired resistance accompanied with a ROS1 rearrangement. A NGS assay showed that the tumor had a novel ROS1-ADGRG6 rearrangement generated by the fusion of exons of 1-33 of ROS1 on chr6: q22.1 to exons of 2-26 of ADGRG6 on chr6: q24.2. The patient was obviously responsive to crizotinib.
We firstly identified ROS1-ADGRG6 fusion variant in NSCLC by NGS, which should be considered in further ROS1 detecting assays.
Breast cancer is the most common malignancy in women, and neoadjuvant chemotherapy has been recommended to the patients with locally advanced breast cancer as the initial treatments. Long non-coding ...RNA (lncRNA) MEG3, an identified tumor suppressor, has been implicated in the development of various cancers. However, there is no data to evaluate the effect of MEG3 polymorphisms on neoadjuvant treatment in the breast cancer.
Genotyping was performed using Nanodispenser Spectro CHIP chip spotting and Mass ARRAY Compact System. Univariate and multivariate logistic regression analyses were used to analyze the associations between the MEG3 polymorphisms and the pathological complete response (pCR). The disease-free survival (DFS) was estimated by the Kaplan-Meier method, and multivariate Cox proportional hazards models were used to calculate the hazard ratios (HRs) with a 95% confidential interval (CI).
A total of 144 patients with available pretreatment blood species were enrolled in the SHPD002 clinic trial of neoadjuvant chemotherapy for breast cancer. MEG3 rs10132552 were significantly associated with good response (Adjusted OR = 2.79, 95% CI 1.096-7.103, p = 0.031) in dominant model. Median follow-up time was 20 months. In multiple regression analysis, rs10132552 TC + CC (adjusted HR = 0.127, 95% CI 0.22-0.728, p = 0.02) and rs941576 AG + GG (adjusted HR = 0.183, 95% CI 0.041-0.807, p = 0.025) were significantly associated with good DFS. MEG3 rs7158663 (OR = 0.377, 95% CI 0.155-0.917, p = 0.032) were associated with a low risk of hemoglobin decrease in dominant models.
LncRNA MEG3 polymorphisms were associated with the chemotherapy response and toxicity of paclitaxel and cisplatin. The result indicates that MEG3 polymorphisms can be considered as the predictive and prognostic markers for the breast cancer patients.
Retrospectively registered (ClinicalTrials. Gov identifier: NCT02221999 ); date of registration: Aug 20th, 2014.
There is currently a lack of effective treatments for non-small cell lung cancer (NSCLC) patients harboring HER2 mutations. We examined the efficacy and safety of, and potential resistance mechanism ...to, pyrotinib, a pan-HER inhibitor, in advanced NSCLC carrying HER2 mutations.
In this multicenter, single-arm, phase II trial, stage IIIB-IV NSCLC patients harboring HER2 mutations, as determined using next-generation sequencing, were enrolled and treated with pyrotinib at a dose of 400 mg/day. The primary endpoint was 6-month progression-free survival (PFS) rate, and secondary endpoints were objective response rate (ORR), PFS, overall survival (OS), disease control rate (DCR), and safety. The impact of different HER2 mutation types on sensitivity to pyrotinib and the potential of utilizing mutational profile derived from circulating tumor DNA (ctDNA) to predict disease progression were also explored.
Seventy-eight patients were enrolled for efficacy and safety analysis. The 6-month PFS rate was 49.5% (95% confidence interval CI, 39.2-60.8). Pyrotinib produced an ORR of 19.2% (95% CI, 11.2-30.0), with median PFS of 5.6 months (95% CI, 2.8-8.4), and median OS of 10.5 months (95% CI, 8.7-12.3). The median duration of response was 9.9 months (95% CI, 6.2-13.6). All treatment-related adverse events (TRAEs) were grade 1-3 (all, 91.0%; grade 3, 20.5%), and the most common TRAE was diarrhea (all, 85.9%; grade 3, 16.7%). Patients with exon 20 and non-exon 20 HER2 mutations had ORRs of 17.7% and 25.0%, respectively. Brain metastases at baseline and prior exposure to afatinib were not associated with ORR, PFS, or OS. Loss of HER2 mutations and appearance of amplification in HER2 and EGFR were detected upon disease progression.
Pyrotinib exhibited promising efficacy and acceptable safety in NSCLC patients carrying exon 20 and non-exon 20 HER2 mutations and is worth further investigation.
Chinese Clinical Trial Registry Identifier: ChiCTR1800020262.
Lignocellulosic biomass as a potential alternative to fossil resource for the production of valuable chemicals and fuels has attracted substantial attention, while reducing the recalcitrance of ...lignocellulosic biomass is still challenging due to the complex and cross-linking structure of biomass. Solvent system plays important roles in the pretreatment of lignocellulose, enabling the transformation of solid biomass to liquid fluid with better mass and heat transfer, as well as in the selective formation of target products. In particular, H2O/tetrahydrofuran (H2O/THF) system has recently been widely applied in lignocellulose valorization, which has been proved to exhibit outstanding efficiency for the conversion of lignocellulose, solubilization of the intermediates and products, and shifting reaction equilibrium, thereby significantly improving the yield and selectivity of target products, as well as the full utilization of lignocellulose. In addition, THF shows low toxicity, and is known as a renewable solvent which can be produced from bio-derived chemicals. Herein, this review concentrates on the advances of H2O/THF system in lignocellulose valorization in recent years. Several aspects relative to the roles of H2O/THF system are discussed as follows: the pretreatment of lignin, conversion of hemicellulose and cellulose components in lignocelluloses, and the promoting formation of valuable chemicals like furfural, 5-hydroxymethyl furfural (HMF), levulinic acid, and so on, as well as the inhibiting role in humins formation. This review might provide useful information for the design of effective solvent system in full utilization of lignocellulosic biomass.
Background
TNBC, whose clinical prognosis is poorer than other subgroups of breast cancer, is a malignant tumor characterized by lack of estrogen receptors, progesterone hormone receptors, and HER2 ...overexpression. Due to the lack of specific targeted drugs, it is crucial to identify critical factors involved in regulating the progression of TNBC.
Methods
We analyzed the expression profiles of TNBC in TCGA and the prognoses values of GLDC. Correlations of GLDC and tumor immune infiltration were also identified. CCK8 and BrdU incorporation assays were utilized to determine cell proliferation. The mRNA and protein levels were examined by using Real-time PCR and Western blot analysis.
Results
In the present study, we analyzed the mRNA expression profiles of TNBC in TCGA and found that GLDC, a key enzyme in glycine cleavage system, was significantly up-regulated in TNBC tissues and higher expression of GLDC was correlated with a worse prognosis in TNBC. Moreover, the expression of GLDC was negatively correlated with macrophage and monocyte and positively correlated with activated CD4 T cell and type 2 T helper cell in TNBC. Overexpression of GLDC facilitated the proliferation of TNBC cells, whereas GLDC knockdown had the opposite effects. Additionally, miR-30e acts as a functional upstream regulator of GLDC and the inhibitory effects of miR-30e on cell proliferation were mitigated by the reintroduction of GLDC.
Conclusions
These results imply that miR-30e-depressed GLDC acts as a tumor suppressive pathway in TNBC and provides potential targets for the treatment of TNBC.
Background Triple negative breast cancer (TNBC) is a subtype of breast cancer with poor prognosis and lack of effective treatment target. Here we screened differentially expressed lncRNAs through ...bioinformatics analysis and identified CARMN as a downregulated lncRNA which is lowest expressed in TNBC. We aimed to identify the potential role and molecular mechanisms of CARMN in TNBC. Methods Predictive value of CARMN was explored in breast cancer cohorts. TNBC cell lines with CARMN overexpression or CARMN silence and were used for in vitro and in vivo experiments. RNA-seq of CARMN overexpressed cells was performed for exploring downstream of CARMN. Results CARMN is downregulated at different phase of malignant transformation of breast tissue. CARMN can predict both better prognosis and higher response rate of cisplatin-based neoadjuvant chemotherapy in breast cancer. A nomogram is built to predict cisplatin-based chemotherapy response in breast cancer. Through in vitro and in vivo studies, we confirmed CARMN can also inhibit tumorigenesis and enhance sensitivity to cisplatin in TNBC cells. RNA-seq and further experiments revealed CARMN can inhibit DNA replication. MCM5, an important DNA replication initiation factor, is the most downregulated gene in DNA replication pathway following CARMN overexpression. We confirmed CARMN can produce miR143-3p from its exon5 which is DROSHA and DICER dependent, resulting binding and decrease of MCM5. Moreover, suppressing miR143-3p can weaken function of CARMN in suppressing tumorigenesis and promoting chemosensitivity. Conclusions Our results indicated lncRNA CARMN is a predictive biomarker of better prognosis and enhanced cisplatin sensitivity in TNBC. CARMN is the host gene of miR143-3p which downregulates MCM5, causing inhibited DNA replication. Keywords: lncRNA, miRNA, Triple negative breast cancer, Neoadjuvant chemotherapy, Predictive and prognostic biomarker, Host gene
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