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Starch, lipids, and proteins are key macronutrients in starchy foods. Their interactions during processing can form starch-lipid-protein ternary complexes, significantly affecting food quality. Ultrasonic treatment, as a common processing method, is expected to regulate the quality of starchy foods by influencing the formation of ternary complexes. This study aimed to understand the effect of ultrasonic pretreatment on the formation of starch-lipid-protein ternary complexes using various types of starches. Wheat starch (WS), maize starch (MS), and potato starch (PS) were gelatinized and treated with ultrasound at various power densities (0–40 W/L) to form complexes with lauric acid (LA) and β-lactoglobulin (βLG), respectively. Ultrasound increased the amylose content of gelatinized WS, MS, and PS and shifted their chain length distribution towards the short chains. Results from Fourier transform infrared spectroscopy, laser confocal micro-Raman, X-ray diffraction, and differential scanning calorimetry showed that the largest amount of WS-LA-βLG complexes was formed at the ultrasonic power density of 10 W/L, and MS-LA-βLG and PS-LA-βLG complexes at 20 W/L. Additionally, ultrasound enhanced the content of resistant starch (RS) in the starch-LA-βLG complexes. The RS content increased from 14.12 % to 18.31 % for WS-LA-βLG, and from 19.18 % and 20.69 % to 27.60 % and 28.63 % for MS-LA-βLG and PS-LA-βLG complexes, respectively. This study presents an approach for facilitating the formation of ternary complexes, contributing to the development of low-GI functional foods.

Abstract Quantum-state manipulation through coherent interaction with a radiation field is a fundamental process with broad implications in quantum optics and quantum information processing. However, current quantum control methods are limited by their operation at Rabi frequencies below the gigahertz range, which restricts their applicability to systems with long coherence times. To overcome this limitation, alternative approaches utilizing ultrafast driving lasers have garnered great interest. In this work, we demonstrate two-photon Rabi oscillations in the excited states of argon operating at terahertz frequencies driven by ultrafast laser pulses. Leveraging quantum-path interferometry, we are able to measure and manipulate both the amplitudes and phases of the transition dipoles by exploiting the intensity and polarization state of the driving laser. This precise control enables femtosecond population transfer and coherent accumulation of geometric phase. Our findings provide valuable insights into the all-optical manipulation of extreme-ultraviolet radiations and demonstrate the possibility of ultrafast quantum control through interferometric multiphoton transitions.

Abstract We present a novel approach for Stimulated Raman Scattering (SRS) spectroscopy in which a hyper spectral resolution and high-speed spectral acquisition are achieved by employing amplified offset-phase controlled fs-pulse bursts. We investigate the method by solving the coupled non-linear Schrödinger equations and validate it by numerically characterizing SRS in molecular nitrogen as a model compound. The spectral resolution of the method is found to be determined by the inverse product of the number of pulses in the burst and the intraburst pulse separation. The SRS spectrum is obtained through a motion-free scanning of the offset phase that results in a sweep of the Raman-shift frequency. Due to high spectral resolution and fast motion-free scanning the technique is beneficial for a number SRS-based applications such as gas sensing and chemical analysis.

Purpose: The limited understanding of long-term estradiol (E2) suppression poses challenges to the effectiveness of adjuvant therapy with aromatase inhibitors (AI), necessitating comprehensive serum E2 monitoring to address this issue. Therefore, our objective was to investigate serum E2 levels in women undergoing adjuvant AI treatment and evaluate the significance of such monitoring. Patients and methods: In this prospective cohort study, we recruited women who had received adjuvant AI treatment, including those who underwent ovarian function suppression (OFS). Serum E2 levels were measured using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The primary endpoint was the proportion of women with E2 levels exceeding 2.72 pg/mL, indicating inadequate suppression achieved with AI therapy. Results: A total of 706 patients were enrolled, including 482 women with OFS in combination with AI. Among them, 116 women (16.4 %) exhibited E2 levels exceeding 2.72 pg/mL. The majority of serum E2 elevations (77.6 %) occurred within the first two years of initiating endocrine therapy. Younger age, no prior chemotherapy, shorter duration of the current treatment regimen, and lower follicle stimulating hormone (FSH) levels were associated with inadequate E2 suppression. Serum E2 concentrations demonstrated dynamic variations and occasional rebound following adjuvant AI therapy. Conclusions: Despite receiving adjuvant AI treatment for nearly two years, a certain proportion of patients failed to achieve the adequate threshold of E2 suppression. Our findings emphasize the significance of monitoring serum E2 levels during adjuvant AI therapy, particularly within the first two years. Further research is imperative to facilitate a more comprehensive comprehension of E2 monitoring.

Abstract Breast cancer is the second leading cause of death in women worldwide, with triple-negative breast cancer (TNBC) having the worst prognosis. Although there are numerous studies on TNBC, there is no effective treatment for it, and it is still a major problem today. Studies on PIWI-interacting RNAs (piRNAs) are increasing and investigating the mechanism of piRNAs in the proliferation and metastasis of TNBC may lead to new potential treatment targets. Here, we identified a novel piRNA, piR-YBX1, which was downregulated in TNBC compared to matched normal breast tissue. Overexpression of piR-YBX1 significantly inhibited the proliferation, migration, invasion ability of TNBC cells both in vivo and in vitro. Mechanistically, piR-YBX1 could bind directly to mRNA of Y-box binding protein 1 (YBX1) and overexpression of piR-YBX1 downregulated YBX1 in both mRNA and protein levels, while the function of piR-YBX1 could be partly rescued by overexpression of YBX1. In addition, YBX1 could bind to RAF1 which is the key molecule in the MAPK signaling pathway, and overexpression of piR-YBX1 inhibited the p-MEK and p-ERK1/2, which can be reverted by YBX1. In conclusion, our findings discovered that the piR-YBX1/YBX1/MAPK axis suppresses the proliferation and metastasis of TNBC and therefore piR-YBX1 has the potential to be an effective therapeutic agent for breast cancer.

Abstract Background Genetic testing plays an important role in guiding screening, diagnosis, and precision treatment of breast cancer (BC). However, the appropriate genetic testing criteria remain controversial. The current study aims to facilitate the development of suitable strategies by analyzing the germline mutational profiles and clinicopathological features of large‐scale Chinese BC patients. Methods BC patients who had undergone genetic testing at the Sun Yat‐sen University Cancer Center (SYSUCC) from September 2014 to March 2022 were retrospectively reviewed. Different screening criteria were applied and compared in the population cohort. Results A total of 1035 BC patients were enrolled, 237 pathogenic or likely pathogenic variants (P/LPV) were identified in 235 patients, including 41 out of 203 (19.6%) patients tested only for BRCA1/2 genes, and 194 out of 832 (23.3%) received 21 genes panel testing. Among the 235 P/LPV carriers, 222 (94.5%) met the NCCN high‐risk criteria, and 13 (5.5%) did not. While using Desai's criteria of testing, all females diagnosed with BC by 60 years and NCCN criteria for older patients, 234 (99.6%) met the high‐risk standard, and only one did not. The 21 genes panel testing identified 4.9% of non‐BRCA P/LPVs and a significantly high rate of variants of uncertain significance (VUSs) (33.9%). The most common non‐BRCA P/LPVs were PALB2 (11, 1.3%), TP53 (10, 1.2%), PTEN (3, 0.4%), CHEK2 (3, 0.4%), ATM (3, 0.4%), BARD1 (3, 0.4%), and RAD51C (2, 0.2%). Compared with BRCA1/2 P/LPVs, non‐BRCA P/LPVs showed a significantly low incidence of NCCN criteria listed family history, second primary cancer, and different molecular subtypes. Conclusions Desai's criteria might be a more appropriate genetic testing strategy for Chinese BC patients. Panel testing could identify more non‐BRCA P/LPVs than BRCA1/2 testing alone. Compared with BRCA1/2 P/LPVs, non‐BRCA P/LPVs exhibited different personal and family histories of cancer and molecular subtype distributions. The optimal genetic testing strategy for BC still needs to be investigated with larger continuous population studies.

Abstract Objective Chemokines, which are chemotactic inflammatory mediators involved in controlling the migration and residence of all immune cells, are closely associated with brain inflammation, recognized as one of the potential processes/mechanisms associated with cognitive impairment. We aim to determine the chemokines which are significantly altered in Alzheimer’s disease (AD) and mild cognitive impairment (MCI), as well as the respective effect sizes, by performing a meta-analysis of chemokines in cerebrospinal fluid (CSF) and blood (plasma or serum). Methods We searched three databases (Pubmed, EMBASE and Cochrane library) for studies regarding chemokines. The three pairwise comparisons were as follows: AD vs HC, MCI vs healthy controls (HC), and AD vs MCI. The fold-change was calculated using the ratio of mean (RoM) chemokine concentration for every study. Subgroup analyses were performed for exploring the source of heterogeneity. Results Of 2338 records identified from the databases, 61 articles comprising a total of 3937 patients with AD, 1459 with MCI, and 4434 healthy controls were included. The following chemokines were strongly associated with AD compared with HC: blood CXCL10 (RoM, 1.92, p = 0.039), blood CXCL9 (RoM, 1.78, p

We demonstrate the generation, spectral broadening and post-compression of second harmonic pulses using a thin beta barium borate (BBO) crystal on a fused-silica substrate as the nonlinear interaction medium. By combining second harmonic generation in the BBO crystal with self-phase modulation in the fused-silica substrate, we efficiently generate millijoule-level broadband violet pulses from a single optical component. The second harmonic spectrum covers a range from long wave ultraviolet (down to 310 nm) to visible (up to 550 nm) with a bandwidth of 65 nm. Subsequently, we compress the second harmonic beam to a duration of 4.8 fs with a pulse energy of 0.64 mJ (5 fs with a pulse energy of 1.05 mJ) using chirped mirrors. The all-solid free-space apparatus is compact, robust and pulse energy scalable, making it highly advantageous for generating intense second harmonic pulses from near-infrared femtosecond lasers in the sub-5 fs regime.

Anti-HER2 resistance causes treatment failure in HER2-positive breast cancers. Here the authors identify FGFR4 as one of the vulnerabilities of anti-HER2 resistant breast cancer and show that FGRR4 inhibition enhances sensitivity to anti-HER2 treatment in these resistant cells by triggering ferroptosis.

Strong-field induced valence electron excitation is a common process in strong field interaction with atoms and molecules. In the case of polyatomic molecules, the effects of ionization from low-lying molecular orbitals and nuclear dynamics during the interaction can play critical roles for electron excitation. In this work, we investigate the involved molecular orbitals in the electron excitation of singly ionized acetylene in a strong laser field using alignment dependence and laser intensity dependence. Additionally, the involved nuclear dynamics during the electron excitation are identified from the difference in the kinetic energy release and the angular distribution of laser-induced dissociation with different pulse durations and intensities. The laser intensity dependence clearly shows the relative strength change of two excitation pathways in the measured momentum and angle-resolved distributions.

Cancer-associated fibroblasts (CAFs) are essential for tumor microenvironment remodeling and correlate with tumor progression. However, interactions between CAFs and tumor cells and immune cells in triple-negative breast cancer (TNBC) are still poorly explored. Here, we investigate the role of CAFs in TNBC and potential novel mediators of their functions. The clustering of classic markers was applied to estimate the relative abundance of CAFs in TNBC cohorts. Primary fibroblasts were isolated from normal and tumor samples. The RNA and culture medium of fibroblasts were subjected to RNA sequencing and mass spectrometry to explore the upregulated signatures in CAFs. Microdissection and single-cell RNA sequencing datasets were used to examine the expression profiles. CAFs were associated with hallmark signalings and immune components in TNBC. Clustering based on CAF markers in the literature revealed different CAF infiltration groups in TNBC: low, medium and high. Most of the cancer hallmark signaling pathways were enriched in the high CAF infiltration group. Furthermore, RNA sequencing and mass spectrometry identified biglycan (BGN), a soluble secreted protein, as upregulated in CAFs compared to normal cancer-adjacent fibroblasts (NAFs). The expression of biglycan was negatively correlated with CD8 + T cells. Biglycan indicated poor prognostic outcomes and might be correlated with the immunosuppressive tumor microenvironment (TME). In conclusion, CAFs play an essential role in tumor progression and the TME. We identified an extracellular protein, biglycan, as a prognostic marker and potential therapeutic target in TNBC.

Background: Necroptosis has been an alternatively identified mechanism of programmed cancer cell death, which plays a significant role in cancer. However, research about necroptosis-related long noncoding RNAs (lncRNAs) in cancer are still few. Moreover, the potentially prognostic value of necroptosis-related lncRNAs and their correlation with the immune microenvironment remains unclear. The present study aimed to explore the potential prognostic value of necroptosis-related lncRNAs and their relationship to immune microenvironment in triple-negative breast cancer (TNBC).Methods: The RNA expression matrix of patients with TNBC was obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Finally, 107 patients of GSE58812, 159 patients of TCGA, and 143 patients of GSE96058 were included. Necroptosis-related lncRNAs were screened by Cox regression and Pearson correlation analysis with necroptosis-related genes. By LASSO regression analysis, nine necroptosis-related lncRNAs were employed, and a cell necroptosis index (CNI) was established; then, we evaluated its prognostic value, clinical significance, pathways, immune infiltration, and chemotherapeutics efficacy.Results: Based on the CNI value, the TNBC patients were divided into high- and low-CNI groups, and the patients with high CNI had worse prognosis, more lymph node metastasis, and larger tumor (p < 0.05). The receiver operating characteristic (ROC) analysis showed that the signature performed well. The result of the infiltration proportion of different immune cell infiltration further explained that TNBC patients with high CNI had low immunogenicity, leading to poor therapeutic outcomes. Moreover, we found significant differences of the IC50 values of various chemotherapeutic drugs in the two CNI groups, which might provide a reference to make a personalized chemotherapy for them.Conclusion: The novel prognostic marker CNI could not only precisely predict the survival probability of patients with TNBC but also demonstrate a potential role in antitumor immunity and drug sensitivity.

Two-pore domains potassium channel subunits, encoded by KCNK genes, play vital roles in breast cancer progression. However, the characteristics of most KCNK genes in breast cancer has yet to be clarified. In this study, we comprehensively analyzed the expression, alteration, prognosis, and biological functions of various KCNKs in breast cancer. The expression of KCNK1/4/6/9/10/13 were significantly upregulated, while KCNK2/3/5/7/17 were downregulated in breast cancer tissues compared to normal mammary tissues. Increased expression of KCNK1/3/4/9 was correlated with poor overall survival, while high expression of KCNK2/7/17 predicted better overall survival in breast cancer. Eight KCNK genes were altered in breast cancer patients with a genomic mutation rate ranged from 1.9% to 21%. KCNK1 and KCNK9 were the two most common mutations in breast cancer, occurred in 21% and 18% patients, respectively. Alteration of KCNK genes was associated with the worse clinical characteristics and higher TMB, MSI, and hypoxia score. Using machine learning method, a specific prognostic signature with seven KCNK genes was established, which manifested accuracy in predicting the prognosis of breast cancer in both training and validation cohorts. A nomogram with great predictive performance was afterwards constructed through incorporating KCNK-based risk score with clinical features. Furthermore, KCNKs were correlated with the activation of several tumor microenvironment cells, including T cells, mast cells, macrophages, and platelets. Presentation of antigen, stimulation of G protein signaling and toll-like receptor cascaded were regulated by KCNKs family. Taken together, KCNKs may regulate breast cancer progression via modulating immune response which can serve as ideal prognostic biomarkers for breast cancer patients. Our study provides novel insight for future studies evaluating their usefulness as therapeutic targets.

Obesity has been reported to be a risk factor for breast cancer, but how obesity affects breast cancer (BC) remains unclear. Although body mass index (BMI) is the most commonly used reference for obesity, it is insufficient to evaluate the obesity-related pathophysiological changes in breast tissue. The purpose of this study is to establish a DNA-methylation-based biomarker for BMI (DM-BMI) and explore the connection between obesity and BC. Using DNA methylation data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we developed DM-BMI to evaluate the degree of obesity in breast tissues. In tissues from non-BC and BC population, the DM-BMI model exhibited high accuracy in BMI prediction. In BC tissues, DM-BMI correlated with increased adipose tissue content and BC tissues with increased DM-BMI exhibited higher expression of pro-inflammatory adipokines. Next, we identified the gene expression profile relating to DM-BMI. Using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we observed that the DM-BMI-related genes were mostly involved in the process of cancer immunity. DM-BMI is positively correlated with T cell infiltration in BC tissues. Furthermore, we observed that DM-BMI was positively correlated with immune checkpoint inhibitors (ICI) response markers in BC. Collectively, we developed a new biomarker for obesity and discovered that BC tissues from obese individuals exhibit an increased degree of immune cell infiltration, indicating that obese BC patients might be the potential beneficiaries for ICI treatment.

Abstract Background Mucinous breast carcinoma (MBC) is a relatively rare pathological type of breast cancer. Compared with mastectomy in MBC, the effect and safety of breast‐conserving therapy (BCT) remains unclear. Therefore, we investigated the long‐term prognosis of BCT and mastectomy in T1‐2 stage mucinous breast carcinoma via the Surveillance, Epidemiology, and End Results (SEER) database. Methods Totally, 8830 patients who were diagnosed of mucinous breast carcinoma between 2004 and 2014 from SEER database were reviewed retrospectively. Cox proportional hazards model and Kaplan‐Meier method were performed for evaluating the relationship between surgical method and prognosis. Results One thousand three hundred and twenty (14.9%) patients underwent mastectomy and 7510 (85.1%) underwent BCT. The median follow‐up time was 77 months. There were more non‐Hispanic white, married, and younger ( .05).While for patients who received BCT, the use of radiotherapy showed OS benefit. Conclusions This large population‐based study indicated patients who received BCT had better prognosis than those received mastectomy in T1‐2 stage MBC, especially in patients at the age of 50‐79 years. The use of radiotherapy showed OS benefit in patients receiving BCT. Breast‐conserving therapy might be preferred over mastectomy especially in locoregional treatment of T1‐2 stage MBC.

Background: Invasive micropapillary carcinoma (IMPC) is a rare histological subtype of breast cancer. The outcome of IMPC remains controversial; we conducted a meta-analysis of propensity score matching (PSM) studies to evaluate the prognostic difference between IMPC and invasive ductal carcinoma (IDC). Methods: We searched PubMed, EMBASE and the Cochrane library for PSM studies comparing survival data between IMPC and IDC. The summarized odds ratios (ORs) and 95% confidence interval (95% CI) are calculated by STATA software utilizing fixed-effect or random-effect models, depending on the heterogeneity of the eligible studies. Results: Eight PSM studies including 2102 IMPC patients are included in the meta-analysis. Compared with IDC, IMPC has a similar overall survival (OS) (estimated OR = 0.87, 95% CI: 0.61–1.25), but a shorter relapse free survival (RFS) (estimated OR = 1.31, 95% CI: 1.06–1.61); the shorter RFS might owe to the significantly higher loco-regional recurrence rate of IMPC (estimated OR = 3.60, 95% CI: 1.99–6.52). Funnel plots and Egger’s tests are used to evaluate publication bias and the p value for OS and RFS are 0.036 and 0.564 respectively. Conclusions: Our results demonstrate that compared with IDC, IMPC exhibits a similar, even favorite OS, but a shorter RFS; and the shorter RFS might owe to the significantly higher loco-regional recurrence rate of IMPC. These results could contribute to the individualized therapy and follow-up strategies for IMPC patients.

The prognosis of breast cancer brain metastasis (BCBM) is extremely poor due to its resistance to conventional therapy. Elucidation of the molecular mechanisms of BCBM could contribute to the development of new therapeutic targets. In this study, we isolated RNA samples from primary breast cancer or BCBM, and then performed mRNA profiling. We determined that SOX2 is associated with the occurrence of BCBM and could be a predictor of BCBM. High levels of SOX2 were significantly associated with decreasing BCBM-free survival in patients. Overexpression of SOX2 in breast cancer cells enhanced cancer cell adhesion to brain microvascular endothelial cells, transendothelial migration, and in vitro blood-brain barrier (BBB) migration, whereas silencing SOX2 inhibited these events. SOX2 can increase cancer cell migration and BBB permeability by upregulating FSCN1 and HBEGF, thereby promoting BBB migration of breast cancer cells. Moreover, high levels of FSCN1 and HBEGF were significantly associated with reducing BCBM-free survival in breast cancer patients. Further study indicated that SOX2 mediates the expression of HBEGF and FSCN1 by activating AKT and β-catenin signaling pathways. Additionally, in vivo experiments showed that SOX2 promotes the development of BCBM. This study demonstrated that SOX2 promotes BCBM by upregulating the expression of FSCN1 and HBEGF.

Immune system disorder is associated with metastasis of triple-negative breast cancers (TNBCs). A robust, individualized immune-related genes (IRGs)-based classifier was aimed to develop and validate in our study to precisely estimate the axillary lymph node (ALN) status preoperatively in patients with early-stage TNBC. We first analyzed RNA sequencing profiles in TNBC patients from The Cancer Genome Atlas database by using bioinformatics approaches, and screened 23 differentially expressed IRGs. A 9-gene panel was generated with an area under the curve (AUC) of 0.77 [95% confidence interval (95% CI), 0.68–0.87]. We detected the 9 ALN-status-related IRGs in the training set (n = 133) and developed a reduced and optimized five-IRGs signature, which effectively distinguished TNBC patients with ALN metastasis (AUC, 0.80; 95% CI, 0.65–0.86), and was superior to preoperative ultrasound-based ALN status (AUC, 0.73; 95% CI, 0.53–0.93). Predictive efficiency (AUC, 0.77; 95% CI 0.61–0.93) of this five-IRGs signature was validated in the validation set (n = 81). Furthermore, IRGs nomogram incorporated IRGs signature with US-based ALN status showed higher ALN status prediction efficacy than US-based ALN status and five-IRGs signature alone in both training and validation sets. IRGs nomogram may aid in identifying patients who can be exempted from axillary surgery.Novelty and impact: An immune-related genes (IRGs) nomogram was first developed and externally validated in our study, which incorporated the IRGs signature with ultrasound (US)-based axillary lymph nodes (ALN) status. IRGs nomogram is superior to IRGs signature alone for preoperative estimation of ALN metastasis in patients with triple-negative breast cancer (TNBC). It is a favourable biomarker for preoperatively predicting ALN metastasis risk and may aid in clinical decision-making in early-stage TNBCs.

Regarded as the most invasive subtype, triple-negative breast cancer (TNBC) lacks the expression of estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2) proteins. Platelets have recently been shown to be associated with metastasis of malignant tumors. Nevertheless, the status of platelet-related genes in TNBC and their correlation with patient prognosis remain unknown. In this study, the expression and variation levels of platelet-related genes were identified and patients with TNBC were divided into three subtypes. We collected cohorts from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. By applying the least absolute shrinkage and selection operator (LASSO) Cox regression method, we constructed a seven-gene signature which classified the two cohorts of patients with TNBC into low- or high-risk groups. Patients in the high-risk group were more likely to have lower survival rates than those in the low-risk group. The risk score, incorporated with the clinical features, was confirmed as an independent factor for predicting the overall survival (OS) time. Functional enrichment analyses revealed the involvement of a variety of vital biological processes and classical cancer-related pathways that could be important to the ultimate prognosis of TNBC. We then built a nomogram that performed well. Moreover, we tested the model in other cohorts and obtained positive outcomes. In conclusion, platelet-related genes were closely related to TNBC, and this novel signature could serve as a tool for the assessment of clinical prognosis.

Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) is involved in multiple biological functions in cell development, differentiation, and transcriptional regulation. Tet1 deficient mice display the defects of murine glucose metabolism. However, the role of TET1 in metabolic homeostasis keeps unknown. Here, our finding demonstrates that hepatic TET1 physically interacts with silent information regulator T1 (SIRT1) via its C-terminal and activates its deacetylase activity, further regulating the acetylation-dependent cellular translocalization of transcriptional factors PGC-1α and FOXO1, resulting in the activation of hepatic gluconeogenic gene expression that includes PPARGC1A, G6PC, and SLC2A4. Importantly, the hepatic gluconeogenic gene activation program induced by fasting is inhibited in Tet1 heterozygous mice livers. The adenosine 5’-monophosphate-activated protein kinase (AMPK) activators metformin or AICAR—two compounds that mimic fasting—elevate hepatic gluconeogenic gene expression dependent on in turn activation of the AMPK-TET1-SIRT1 axis. Collectively, our study identifies TET1 as a SIRT1 coactivator and demonstrates that the AMPK-TET1-SIRT1 axis represents a potential mechanism or therapeutic target for glucose metabolism or metabolic diseases.

BackgroundResidual cancer cells remaining after chemotherapy may have more aggressive behavior that promotes recurrence or metastasis, and which patients would benefit from subsequent additional treatment is controversial. The purpose of our study was to evaluate the prognostic value of the preoperative radiomics features of computed tomography (CT) imaging in breast cancer (BC) patients with residual tumors after neoadjuvant chemotherapy (NAC).MethodsPost-NAC CT images were reviewed from 114 patients who had received breast surgery and had residual breast tumors. The association of the 110 radiomics features derived from CT images with 5-year disease-free survival (DFS) was assessed by log-rank test in the training cohort, resulting in 13 prognostic radiomics features.ResultsWe constructed a radiomics signature consisting of four selected features by using least absolute shrinkage and selection operator (LASSO) Cox regression analysis, which performed well in the discrimination with an area under the curve (AUC) of 0.78 (95% CI, 0.67–0.89) and 0.73 (95% CI, 0.59–0.87) in the training and validation cohorts, respectively. Radiomics nomogram, incorporating the radiomics signature with the conventional clinical variables, also performed well in the two cohorts (training cohort: AUC, 0.84; validation cohort: AUC, 0.82). Moreover, we found that the high-risk patients determined by our radiomics nomogram could benefit from postoperative adjuvant chemotherapy, while the low-risk and total patient groups could not.ConclusionsOur novel radiomics nomogram is a promising and favorable prognostic biomarker for preoperatively predicting survival outcomes and may aid in clinical decision-making in BC patients with residual tumors after NAC.

Abstract Background Resection of the primary tumor is recommended for symptom relief in de novo stage IV breast cancer. We explored whether local surgery could provide a survival benefit in these patients and attempted to characterize the population that could benefit from surgery. Methods Metastatic Breast cancer patients (N = 313) with intact primary tumor between January 2006 and April 2013 were separated into two groups according to whether or not they had undergone surgery. The difference in characteristics between the two groups was analyzed using chi-square test, Fisher’s exact test and Mann-Whitney test. Univariable and multivariable Cox regression and stratified survival analysis were used to assess the effect of surgery on survival. Results Of the 313 patients, 188 (60.1%) underwent local surgery. Patients with local surgery had a 47% reduction in mortality risk vs. those with no surgery (median survival 78 months vs. 37 months; HR = 0.53; 95% CI, 0.36–0.78) after adjustment for clinical and tumor characteristics. Stratified survival analysis showed that patients with bone metastasis alone (and primary tumor ≤5 cm), soft tissue metastasis, or ≤ 3 metastasis sites benefit from surgery. Conclusion Surgical resection of the primary tumor can improve survival in selected de novo stage IV breast cancer patients.

Background: Numerous studies have showed that internal mammary lymph node (IMLN) metastasis is an important adverse prognostic factor in patients with breast cancer (BC), however, there are no available prediction model for the preoperative diagnosis of IMLN metastasis.Methods: Data from 102 breast cancer patients treated with IMLN operation were used to establish and calibrate a nomogram for IMLN status based on multivariate logistic regression. Prediction performance of this model was further validated with a second set of 50 patients with BC. Discrimination of the predict model was assessed by the C-index, and calibration assessed by calibration plots. Moreover, we conducted the decision curve analysis (DCA) to evaluate the clinical value of the nomogram. Finally, the survival status of patients in different risk groups based on nomogram were also compared.Results: The final multivariate regression model included tumor location, lymph vascular invasion (LVI), and pathological axillary lymph node stage (pALN stage). A nomogram was developed as a graphical representation of the model and had good calibration and discrimination in both sets (with C-index of 0.86 and 0.83 for the training and validation set, respectively). Moreover, the DCA showed the clinical usefulness of our constructed nomogram. False negative (FN) in low risk group classified by nomogram (FN-LR-nomogram) did not significantly impact adjuvant treatment decision making, and more importantly, patients with FN-LR-nomogram had recurrence-free survival equivalent to patients with pathologically ture negative in low risk group classified by nomogram (TN-LR-nomogram).Conclusions: As a non-invasive prediction tool, our nomogram shows favorable predictive accuracy for IMLN metastasis in patients with BC and can serve as a basis to integrate future molecular markers for its clinical application.

Abstract The risk factors for morbidity and mortality in breast cancer lung metastases (BCLM) patients still remain poorly identified. The aim of this study was to assess the incidence and survival of BCLM and associated risk factors. Patients with BCLM were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariate logistic regression analysis was used to determine the risk factors for BCLM. Predictors of factors associated with death were analyzed in Cox regression and Fine and Gray's test. Of the 11568 patients with stage IV breast cancer, 4213 (36.4%) had BCLM and 1214 (10.5%) had metastases confined to lungs. The median survival time for patients with BCLM was 21 months, and 15.5% of the patients were alive more than 3 years. The tumor subtype distribution was 45.3% HR−/HER2−, 12.2% HR+/HER2+, 7.8% HR−/HER2+, and 15.0% triple‐negative subtype. Compared with patients without BCLM, those with BCLM were more likely to be aged, female, black, higher tumor grade, HR−/HER2+, HR+/HER2+, and triple‐negative subtypes at diagnosis. Survival analysis showed that the aged, black race, HR−/HER2+, triple‐negative subtype, higher grade were the independent risk factor for BCLM patients’ survival, while HR+/HER2+ subtype, insured status, and married status suggested better prognosis. In conclusion, the incidence and prognosis of BCLM varied by tumor subtypes, age, and race. Elderly patients with HER2‐positive or triple‐negative tumors were more likely to have BCLM.

Abstract Backgroud The purpose of this study was to elucidate the regulation of programmed death ligand 1 (PDL1), lactate dehydrogenase A (LDHA) and miR-34a in triple negative breast cancer (TNBC) and to explore the function and mechanism of PDL1 and LDHA as competitive endogenous RNAs (ceRNAs) in TNBC via regulation of miR-34a. Methods Western blotting, quantitative RT-PCR (qRT-PCR) and immunohistochemistry (IHC) assays were conducted to explore the expression of PDL1, LDHA and miR-34a in TNBC and correlations between them. MTS cell viability, Transwell migration, glucose consumption and lactate production assays and flow cytometry were performed and mouse xenograft models were constructed to explore the functions and regulation of the PDL1 3’UTR and LDHA 3’UTR and miR-34a in TNBC. Results We found that PDL1 and LDHA were synchronously upregulated in TNBC cell lines and tissues. Co-expression of PDL1 and LDHA was correlated with poor outcome in TNBC. Both PDL1 and LDHA are targets of miR-34a, and the 3’UTRs of PDL1 and LDHA both have binding sites for miR-34a. The functions of PDL1 and LDHA were inhibited by miR-34a. In addition, PDL1 and LDHA acted as ceRNAs to promote the expression and function of each other through regulation of miR-34a in TNBC. Conclusions This study provides a new theoretical basis for a novel TNBC therapeutic strategy. Simultaneously targeting PDL1 and LDHA, which would combine immunotherapy and metabolically targeted treatments, might shed some light on the treatment of breast cancer, especially TNBC.

Purpose: Breast cancer patients with high proportion of cancer stem cells (BCSCs) have unfavorable clinical outcomes. MicroRNAs (miRNAs) regulate key features of BCSCs. We hypothesized that a biology-driven model based on BCSC-associated miRNAs could predict prognosis for the most common subtype, hormone receptor (HR)-positive, HER2-negative breast cancer patients. Patients and Methods: After screening candidate miRNAs based on literature review and a pilot study, we built a miRNA-based classifier using LASSO Cox regression method in the training group (n = 202) and validated its prognostic accuracy in an internal (n = 101) and two external validation groups (n = 308). Results: In this multicenter study, a 10-miRNA classifier incorporating miR-21, miR-30c, miR-181a, miR-181c, miR-125b, miR-7, miR-200a, miR-135b, miR-22 and miR-200c was developed to predict distant relapse free survival (DRFS). With this classifier, HR+HER2− patients were scored and classified into high-risk and low-risk disease recurrence, which was significantly associated with 5-year DRFS of the patients. Moreover, this classifier outperformed traditional clinicopathological risk factors, IHC4 scoring and 21-gene Recurrence Score (RS). The patients with high-risk recurrence determined by this classifier benefit more from chemotherapy. Conclusions: Our 10-miRNA-based classifier provides a reliable prognostic model for disease recurrence in HR+HER2− breast cancer patients. This model may facilitate personalized therapy-decision making for HR+HER2− individuals.

We propose an attosecond time-domain spectroscopy to study laser-induced electron rescattering in atoms by using single photoionization with an attosecond x-ray pulse. From the time-frequency analysis of the time-domain signal, we obtained simultaneously the subcycle time and energy information of the rescattering electron wave packet during the interaction of a helium-like atom with a strong laser field. The obtained time and energy distributions nicely agree with the electron rescattering picture from the analysis based on the high-order harmonic response by the dipole acceleration and classical trajectory calculations. Contributions and interference from multiple rescattering can be unambiguously identified in the time and energy distributions of rescattering electrons. Since the observable of x-ray single photoionization yield is proportional to the electron density near the nucleus, the proposed time-domain spectroscopy can in general be applied to studies of other light-induced linear and nonlinear polarization effects in atoms and molecules.

We demonstrate kinematically complete measurements on frustrated double ionization of argon atoms in strong laser fields with a reaction microscope. We found that the electron trapping probability after strong-field double ionization is much higher than that after strong-field single ionization, especially in the case of high laser intensity. The retrieved electron momentum distributions of frustrated double ionization show a clear transition from the nonsequential to the sequential regime, similar to those of strong-field double ionization. The dependence of electron momentum width on the laser intensity further indicates that the second released electron has a dominant contribution to frustrated double ionization in the sequential regime.

We experimentally investigate laser-induced dissociative recombination of CO_{2} in linearly polarized strong laser fields with coincidence measurements. Our results show laser-induced dissociative processes with electron recombination after laser-induced double ionization. After double ionization, one electron can recombine to one of the two ionic fragments during laser-induced molecular dissociation. Our measurements reveal that the recombination probability of the second ionized electron is three times as high as that of the first ionized electron.

Circular RNA CDR1as/ciRS-7 functions as an oncogenic regulator in various cancers. However, there has been a lack of systematic and comprehensive analysis to further elucidate its underlying role in cancer. In the current study, we firstly performed a bioinformatics analysis of CDR1as among 868 cancer samples by using RNA-seq datasets of the MiOncoCirc database. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), CIBERSORT, Estimating the Proportion of Immune and Cancer cells (EPIC), and the MAlignant Tumors using Expression data (ESTIMATE) algorithm were applied to investigate the underlying functions and pathways. Functional enrichment analysis suggested that CDR1as has roles associated with angiogenesis, extracellular matrix (ECM) organization, integrin binding, and collagen binding. Moreover, pathway analysis indicated that it may regulate the TGF-β signaling pathway and ECM-receptor interaction. Therefore, we used CIBERSORT, EPIC, and the ESTIMATE algorithm to investigate the association between CDR1as expression and the tumor microenvironment. Our data strongly suggest that CDR1as may play a specific role in immune and stromal cell infiltration in tumor tissue, especially those of CD8+ T cells, activated NK cells, M2 macrophages, cancer-associated fibroblasts (CAFs) and endothelial cells. Generally, systematic and comprehensive analyses of CDR1as were conducted to shed light on its underlying pro-cancerous mechanism. CDR1as regulates the TGF-β signaling pathway and ECM-receptor interaction to serve as a mediator in alteration of the tumor microenvironment.

Our previous studies showed that BikDD, a constitutively active mutant form of Bik, exhibited powerful antitumor effects in preclinical pancreatic, lung and breast cancer models. Howerver, the antitumor activity of BikDD in triple-negative breast cancer (TNBC) is unknown. Here we show that aberrant expression of p-ERK1/2 was a meaningful molecular phenotype in TNBC patients, and can be an obstacle for treatment because of the converse correlation with Bik. A novel mutant, BikDDA, in which Ser124 was changed to Alanine to block BikDD phosphorylation by p-ERK1/2 prevented subsequent ubiquitin-proteasome degradation. BikDDA showed a prolonged half-life and enhanced pro-apoptotic ability in TNBC cells compared with BikDD. Moreover, aberrant expression of p-ERK1/2 was associated with 5-fluorouracil resistance in breast cancer patients and BikDDA enhanced the therapeutic effects of 5-fluorouracil in vitro.

BackgroundCompared with invasive breast cancer, breast cancer in situ (BCIS) is seldom life threatening. However, an increasing incidence has been observed in recent years over the world. The purpose of our study is to investigate the epidemiological, clinical and pathological profiles of BCIS in Chinese women from 1999-2008.MethodsFour thousand and two hundred-eleven female breast cancer (BC) patients were enrolled in this hospital-based nation-wide and multi-center retrospective study. Patients were randomly selected from seven hospitals in seven representative geographical regions of China between 1999 and 2008. The epidemiological, clinical and pathological data were collected based on the designed case report form (CRF).ResultsThere were one hundred and forty-three BCIS cases in four thousand and two hundred-eleven BC patients (3.4%). The mean age at diagnosis was 48.3 years and BCIS peaked in age group 40-49 yrs (39.9%). The most common subtype was ductal carcinoma in situ (DCIS) (88.0%). 53.8% were positive for estrogen receptor (ER). Human epidermal growth factor receptor 2 (HER2) positive status was observed in 23.8% of patients. All patients underwent surgeries and 14.7% of them had breast conservation therapies (BCT) (21/143), but 41.9% accepted chemotherapy (64/143). Much less patients underwent radiotherapy (16.0%, 23/143) and among patients who had BCT, 67% accepted radiotherapy (14/21). Endocrine therapy was taken in 44.1% patients (63/143).ConclusionsThe younger age of BCIS among Chinese women than Western countries and increasing number of cases pose a great challenge. BCT and endocrine therapy are under great needs.

Breast cancer is the most commonly malignancies in women. MicroRNAs are a family of small non-coding RNAs 18-25 nucleotides in length that post-transcriptionally modulate gene expression. MiR-26a has been reported as a tumor suppressor microRNA in breast cancer, which is attributed mainly to targeting of MTDH and EZH2, however, the expression profile and therapeutic potential of miR-26a is still unclear. Here we demonstrate that miR-26a is down-regulated in breast cancer cells and clinical specimens and its modulation in breast cancer cells regulates cell proliferation, colony formation, migration and apoptosis. MCL-1, an anti-apoptotic member of the Bcl-2 family, as novel targets of miR-26a was found to be in reverse correlation with ectopic expression of miR-26a and knockdown of MCL-1 phenocopied the effect of miR-26a in breast cancer cell lines. It was further explored that miR-26a increased sensitivity of breast cancer cells to paclitaxel in which MCL-1 was involved. Thus, miR-26a impacts on cell proliferation and migration of breast cancer by regulating several carcinogenesis-related processes, including a novel mechanism involving the targeting of MCL-1.

BACKGROUND: Various studies have been searching for new tumor biomarkers for breast cancer for years. However, so far, few markers have been proved clinically useful except CA153. Based on knowledge that most adenocarcinomas including breast carcinoma expressed Cytokeratin19, the authors studied CK19-2G2,a novel fragment of cytokeratin19 shedding into serum in breast cancer patients. PATIENTS AND METHODS: The serum samples of four hundred and seventeen patients including three hundred and three (fifty-four DCIS and two hundred and forty-nine stage I-III) PBC patients and one hundred and fourteen MBC patients, eighty-one healthy controls and twenty-one breast benign disease patients were provided for measurement of CK19-2G2, CEA and CA153.The correlation between clinicopathological characters, prognosis and CK19-2G2 levels was further studied. RESULTS: The serum CK19-2G2 levels in breast cancer patients were significantly higher than that in healthy and benign controls. For breast cancer patients, CK19-2G2 levels in MBC were significantly higher than that in PBC patients. The sensitivities of CK19-2G2 for breast carcinoma are as high as CEA and CA153, and up to 71% in MBC patients. Serum CK19-2G2 levels (≥2 mU/mL) were associated with pathological stages, tumor size (≥2 cm), lymph node involvement, and HER2 status. Multivariate analysis revealed that high serum CK19-2G2 level was an independent factor for relapse (P = 0.029) and death (P = 0.040) in breast cancer patients. CONCLUSION: Serum CK19-2G2 may be an independent indicator for prognosis and a candidate marker for monitoring metastasis in breast cancer.

We experimentally investigate the dependence of the fragmentation behavior of the ethylene dication on the intensity and duration of the laser pulses that initiate the fragmentation dynamics by strong-field double ionization. Using coincidence momentum imaging for the detection of ionic fragments, we disentangle the different contributions of ionization from lower-valence orbitals and field-driven excitation dynamics to the population of certain dissociative excited ionic states that are connected to one of several possible fragmentation pathways towards a given set of fragment ions. We find that the excitation probability to a particular excited state and therewith the outcome of the fragmentation reaction strongly depend on the parameters of the laser pulse. This, in turn, opens up new possibilities for controlling the outcome of fragmentation reactions of polyatomic molecules in that it may allow one to selectively enhance or suppress individual fragmentation channels, which was not possible in previous attempts of controlling fragmentation processes of polyatomic molecules with strong laser fields.

Interpretation of electron or photon spectra obtained with strong laser pulses that may carry attosecond dynamical and Ångström structural information about atoms or molecules usually relies on variants of the strong-field approximation (SFA) within which the influence of the Coulomb potential on the electron trajectory is neglected. We employ two-color sculpted laser fields to experimentally tune and probe the influence of the Coulomb field on the strong-field-driven wavepacket as observed by two-dimensional electron and ion momentum spectra. By comparison of measured spectra with predictions of the three-dimensional time-dependent Schrödinger equation as well as the quasi-classical limit of the SFA, the strong-field classical trajectory model, we are able to trace back the influence of the Coulomb field to the timing of the wavepacket release with sub-cycle precision.