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Photocatalytic CO2 reduction holds promise as a future technology for the manufacture of fuels and commodity chemicals. However, factors controlling product selectivity remain poorly ...understood. Herein, we compared the performance of a homologous series of Zn-based layered double hydroxide (ZnM-LDH) photocatalysts for CO2 reduction. By varying the trivalent or tetravalent metal cations in the ZnM-LDH photocatalysts (M = Ti4+, Fe3+, Co3+, Ga3+, Al3+), the product selectivity of the reaction could be precisely controlled. ZnTi-LDH afforded CH4 as the main reduction product; ZnFe-LDH and ZnCo-LDH yielded H2 exclusively from water splitting; whilst ZnGa-LDH and ZnAl-LDH generated CO. In-situ diffuse reflectance infrared measurements, valence band XPS and density function theory calculations were applied to rationalize the CO2 reduction selectivities of the different ZnM-LDH photocatalysts. The analyses revealed that the d-band center (εd) position of the M3+ or M4+ cations controlled the adsorption strength of CO2 and thus the selectivity to carbon-containing products or H2. Cations with d-band centers relatively close to the Fermi level (Ti4+, Ga3+ and Al3+) adsorbed CO2 strongly yielding CH4 or CO, whereas metal cations with d-band centers further from the Fermi level (Fe3+ and Co3+) adsorbed CO2 poorly, thereby yielding H2 only (from water splitting). Our findings clarify the role of trivalent and tetravalent metal cations in LDH photocatalysts for the selective CO2 reduction, paving new ways for the development of improved LDH photocatalyst with high selectivities to specific products.
Adjuvant trastuzumab therapy has yielded conflicting results for overall survival, concerns about central nervous system (CNS) metastasis, and questions about optimal schedule. Therefore, we carried ...out a meta-analysis to assess the benefits of concurrent or sequential trastuzumab with adjuvant chemotherapy for early breast cancer patients with HER2-positive tumors.
Computerized and manual searches were performed to identify randomized clinical trials comparing adjuvant chemotherapy with or without trastuzumab in HER2-positive early breast cancer patients. Odds ratios were used to estimate the association between the addition of trastuzumab to adjuvant chemotherapy and various survival outcomes. The fixed-effects or random-effects model was used to combine data.
With six eligible studies identified, this analysis demonstrated that patients with HER2-positive breast cancer derived benefit in disease-free survival, overall survival, locoregional recurrence and distant recurrence (all P<0.001) from the addition of trastuzumab to adjuvant chemotherapy, whereas trastuzumab did worse in CNS recurrence as compared to the control group (P = 0.018). Furthermore, concomitant use of trastuzumab significantly lowered the hazard of death (P<0.001) but bore a higher incidence of CNS recurrence (P = 0.010), while statistical significance failed to be discerned for either overall survival (P = 0.069) or CNS metastasis (P = 0.374) between the sequential and observation arms.
This analysis verifies the efficacy of trastuzumab in the adjuvant setting. Additionally, our findings indirectly corroborate the superiority of concurrent trastuzumab to sequential use and also illuminate that prolonged survival is the possible reason for the higher incidence of CNS with trastuzumab versus observation.
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.
Background MicroRNA-1 (miR-1) is a tumour suppressor that can inhibit cell proliferation and invasion in several cancer types. In addition, miR-1 was found to be associated with drug sensitivity. ...Circulating miRNAs have been proven to be potential biomarkers with predictive and prognostic value. However, studies of miR-1 expression in the serum of breast cancer (BC) patients are relatively scarce, especially in patients receiving neoadjuvant chemotherapy (NAC). Methods Serum samples from 80 patients were collected before chemotherapy, and RT-PCR was performed to detect the serum expression of miR-1. The correlation between miR-1 expression in serum and clinicopathological factors, including pathological complete response (pCR), was analyzed by the chi-squared test and logistic regression. KEGG and GSEA analysis were also performed to determine the biological processes and signalling pathways involved. Results The miR-1 high group included more patients who achieved a pCR than did the miR-1 low group (p < 0.001). Higher serum miR-1 levels showed a strong correlation with decreased ER (R = 0.368, p < 0.001) and PR (R = 0.238, p = 0.033) levels. The univariate model of miR-1 for predicting pCR achieved an AUC of 0.705 according to the ROC curve. According to the interaction analysis, miR-1 interacted with Ki67 to predict the NAC response. According to the Kaplan-Meier plot, a high serum miR-1 level was related to better disease-free survival (DFS) in the NAC cohort. KEGG analysis and GSEA results indicated that miR-1 may be related to the PPAR signalling pathway and glycolysis. Conclusions In summary, our data suggested that miR-1 could be a potential biomarker for pCR and survival outcomes in patients with BC treated with NAC. Keywords: Breast cancer, miRNA-1, Serum biomarker, Neoadjuvant chemotherapy
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.
Upregulation of the PD-L1 (CD274) immune checkpoint ligand on the tumor surface facilitates tumor immune escape and limits the application of immunotherapy in various cancers, including breast ...cancer. However, the mechanisms underlying high PD-L1 levels in cancers are still poorly understood.
Bioinformatics analyses and in vivo and in vitro experiments were carried out to assess the association between CD8
T lymphocytes and TIMELESS (TIM) expression, and to discover the mechanisms of TIM, the transcription factor c-Myc, and PD-L1 in breast cancer cell lines.
The circadian gene TIM enhanced PD-L1 transcription and facilitated the aggressiveness and progression of breast cancer through the intrinsic and extrinsic roles of PD-L1 overexpression. Bioinformatic analyses of our RNA sequencing data in TIM-knockdown breast cancer cells and public transcriptomic datasets showed that TIM might play an immunosuppressive role in breast cancer. We found that TIM expression was inversely associated with CD8
T lymphocyte infiltration in human breast cancer samples and subcutaneous tumor tissues. In vivo and in vitro experiments demonstrated that TIM knockdown increased CD8
T lymphocyte antitumor activity. Furthermore, our results showed that TIM interacts with c-Myc to enhance the transcriptional capability of PD-L1 and facilitates the aggressiveness and progression of breast cancer through the intrinsic and extrinsic roles of PD-L1 overexpression. Moreover, public database analysis suggested that high TIM levels were positively related to PD-L1 inhibitor therapeutic response.
Mechanistically, we first found that TIM could upregulate PD-L1 by interacting with c-Myc to enhance the transcriptional capability of c-Myc to PD-L1. Altogether, our findings not only provide a novel therapeutic strategy to treat breast cancer by targeting the oncogenic effect of TIM but also indicate that TIM is a promising biomarker for predicting the benefit of anti-PD-L1 immunotherapy.
Although the prognosis of patients with small (≤1cm) tumors is generally favorable, emerging data suggests that biological behavior varies between intrinsic subtypes in such patients. Furthermore, it ...still remains unclear whether HER2-positive pT1a-bN0M0 patients could benefit from adjuvant trastuzumab. For further evaluation, we sought to conduct a meta-analysis so as to get a better understanding of the prognosis for HER2-positive pT1a-bN0M0 patients and their survival benefit from adjuvant trastuzumab, accordingly, offering the implications for current practice.
The PubMed database, the online proceedings of the American Society of Clinical Oncology (ASCO) Annual Meetings, the online proceedings of the San Antonio Breast Cancer Symposium, and the CD proceedings of the International St. Gallen Breast Cancer Conference were searched for all relevant studies published before September 2012. Relative risks (RRs) were used to compare the prognosis of different intrinsic subtypes for pT1a-bN0M0 breast cancer. Analyses were also performed to estimate the association between adjuvant trastuzumab and various survival outcomes.
With eight eligible studies identified, this meta-analysis demonstrated a deleterious effect of HER2+ phenotype on disease-free survival (DFS; RR = 3.677, 95% CI 2.606-5.189, p <0.001) and distant disease-free survival (DDFS; RR = 3.824, 95% CI 2.249-6.501, p<0.001) as compared to HR+/HER2- subgroup. However, significant difference failed to be achieved in terms of any endpoint between HER2+ and triple negative breast cancer (TNBC). Besides, a marked improvement in DFS was observed with the addition of trastuzumab for HER2-positive pT1a-bN0M0 patients (RR = 0.323, 95% CI 0.191-0.547, p<0.001).
This meta-analysis clarifies that intrinsic subtypes might be a reliable marker to predict the prognosis in pT1a-bN0M0 breast cancer. Besides, even for such early stage HER2-positive patients, adjuvant trastuzumab might bring significant survival benefit.
With increasing attention given to host-specific lipid metabolism status, it is of urgent need to identify lipid metabolism indices with predictive or prognostic value in locally advanced breast ...cancer patients treated with neoadjuvant chemotherapy (NAC), and to evaluate the performance improvement by incorporating them into the existing Neo-Bioscore staging system.BACKGROUNDWith increasing attention given to host-specific lipid metabolism status, it is of urgent need to identify lipid metabolism indices with predictive or prognostic value in locally advanced breast cancer patients treated with neoadjuvant chemotherapy (NAC), and to evaluate the performance improvement by incorporating them into the existing Neo-Bioscore staging system.Patients from a prospectively maintained database of locally advanced breast cancer patients who received radical surgery after NAC between January 2014 to December 2020 were enrolled in this study. The enrolled patients were randomly divided into a training set and a test set at a ratio of 6:4. The random forest algorithm was applied to rank the importance of prognostic factors, top-ranked lipid metabolism indices of which were then incorporated into Neo-Bioscore to construct an updated prognostic model. The performances of these two models were compared in both training set and test set from multiple perspectives. Study outcomes included disease-free survival (DFS), relapse-free survival (RFS), distance-recurrence-free survival (DRFS), locoregional-recurrence-free survival (LRFS) and overall survival (OS).METHODSPatients from a prospectively maintained database of locally advanced breast cancer patients who received radical surgery after NAC between January 2014 to December 2020 were enrolled in this study. The enrolled patients were randomly divided into a training set and a test set at a ratio of 6:4. The random forest algorithm was applied to rank the importance of prognostic factors, top-ranked lipid metabolism indices of which were then incorporated into Neo-Bioscore to construct an updated prognostic model. The performances of these two models were compared in both training set and test set from multiple perspectives. Study outcomes included disease-free survival (DFS), relapse-free survival (RFS), distance-recurrence-free survival (DRFS), locoregional-recurrence-free survival (LRFS) and overall survival (OS).A total of 200 eligible patients were included in this study. After a median follow-up of 4.73 years, it was demonstrated that the relative increase in total cholesterol (TC; DFS: HR = 4.782, 95%CI 1.410 ~ 16.217, P = 0.012) and low-density lipoprotein (LDL; DFS: HR = 4.622, 95%CI 1.517 ~ 14.088, P = 0.007) during NAC led to poorer survival outcomes. Patients with either a higher body mass index (BMI) or elevated LDL during NAC had a worse prognosis (DFS: HR = 6.351, 95%CI 1.938 ~ 20.809, P = 0.002; OS, HR = 6.919, 95%CI 1.296 ~ 36.932, P = 0.024). Incorporating BMI and LDL fluctuations during NAC into Neo-Bioscore improved the prognostic stratification, especially in terms of LRFS (P = 0.046 vs. P = 0.65) and OS (P = 0.013 vs. P = 0.61). Multidimensional evaluation confirmed the improvement in model fit and clinical use for the updated model in both training set and test set.RESULTSA total of 200 eligible patients were included in this study. After a median follow-up of 4.73 years, it was demonstrated that the relative increase in total cholesterol (TC; DFS: HR = 4.782, 95%CI 1.410 ~ 16.217, P = 0.012) and low-density lipoprotein (LDL; DFS: HR = 4.622, 95%CI 1.517 ~ 14.088, P = 0.007) during NAC led to poorer survival outcomes. Patients with either a higher body mass index (BMI) or elevated LDL during NAC had a worse prognosis (DFS: HR = 6.351, 95%CI 1.938 ~ 20.809, P = 0.002; OS, HR = 6.919, 95%CI 1.296 ~ 36.932, P = 0.024). Incorporating BMI and LDL fluctuations during NAC into Neo-Bioscore improved the prognostic stratification, especially in terms of LRFS (P = 0.046 vs. P = 0.65) and OS (P = 0.013 vs. P = 0.61). Multidimensional evaluation confirmed the improvement in model fit and clinical use for the updated model in both training set and test set.This is the first study to illustrate the relative elevation of LDL and TC levels during NAC as independent prognosticators for locally advanced breast cancer. This is also the first attempt to incorporate lipid metabolism indices into the original Neo-Bioscore staging system, which further improves the prognostic stratification of patients receiving NAC.CONCLUSIONSThis is the first study to illustrate the relative elevation of LDL and TC levels during NAC as independent prognosticators for locally advanced breast cancer. This is also the first attempt to incorporate lipid metabolism indices into the original Neo-Bioscore staging system, which further improves the prognostic stratification of patients receiving NAC.
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
The accurate positioning of sentinel lymph node (SLN) by tracers during surgery is an important prerequisite for SLN biopsy. A major problem of traditional tracers in SLN biopsy is the short surgery ...window due to the fast diffusion of tracers through the lymphatics, resulting in a misjudgment between SLN and second echelon lymph node (2nd LN). Here, a nontoxic Raman nanoparticle tracer, termed gap‐enhanced Raman tags (GERTs), for the accurate intraoperative positioning of SLNs with a sufficient surgical time window is designed. In white New Zealand rabbit models, GERTs enable precise identification of SLNs within 10 min, as well as provide the surgeon with a more than 4 h time window to differentiate SLN and 2nd LN. In addition, the ultrahigh sensitivity of GERTs (detection limit is 0.5 × 10−12 m) allows detection of labeled SLNs before surgery, thereby providing preoperative positioning information for minimally invasive surgery. Comprehensive biosafety evaluations carried out in the context of the Food and Drug Administration and International Standard Organization demonstrate no significant toxicity of GERTs, which supports a promising clinical translation opportunity of GERTs for precise SLN identification in breast cancer.
Nontoxic gap‐enhanced Raman tags (GERTs) are developed for accurate intraoperative identification of sentinel lymph node (SLNs) within 10 min in rabbit models and with a more than 4 h time window to differentiate SLNs and second echelon lymph nodes (2nd LNs). The ultrahigh sensitivity of GERTs allows detection of labeled SLNs before surgery, thereby providing preoperative positioning information for minimally invasive surgery.
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