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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 triplenegative 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 canceradjacent 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. [ABSTRACT FROM AUTHOR]

We visualize and control molecular dynamics taking place on intermediately populated states during different sequential double ionization pathways of CO2 using a sequence of two delayed laser pulses which exhibit different peak intensities. Measured yields of CO2+2 and of fragment pairs CO+/O+ as a function of delay between the two pulses are weakly modulated by various vibronic dynamics taking place in CO+2. By Fourier analysis of the modulations we identify the dynamics and show that they can be assigned to merely two double ionization pathways. We demonstrate that by reversing the sequence of the two pulses it becomes possible to control the pathway which is taken across CO+2 towards the final state in CO2+2. A comparison between the yields of CO2+2 and CO+/O+ reveals that the modulating vibronic dynamics oscillate out-of-phase with each other, thus opening up opportunities for strong-field fragmentation control on extended time scales. [ABSTRACT FROM AUTHOR]

Purpose Survival of metastatic breast cancer (MBC) patient remains unknown and varies greatly from person to person. Thus, we aimed to construct a nomogram to quantify the survival probability of patients with MBC. Materials and Methods We had included 793 MBC patients and calculated trends of case fatality rate by Kaplan- Meier method and joinpoint regression. Six hundred thirty-four patients with MBC between January 2004 and July 2011 and 159 patients with MBC between August 2011 and July 2013 were assigned to training cohort and internal validation cohort, respectively. We constructed the nomogram based on the results of univariable and multivariable Cox regression analyses in the training cohort and validated the nomogram in the validation cohort. Concordance index and calibration curves were used to assess the effectiveness of nomogram. Results Case fatality rate of MBC was increasing (annual percentage change [APC], 21.6; 95% confidence interval [CI], 1.0 to 46.3; p < 0.05) in the first 18 months and then decreased (APC, -4.5; 95% CI, -8.2 to -0.7; p < 0.05). Metastasis-free interval, age, metastasis location, and hormone receptor status were independent prognostic factors and were included in the nomogram, which had a concordance index of 0.69 in the training cohort and 0.67 in the validation cohort. Calibration curves indicated good consistency between the two cohorts at 1 and 3 years. Conclusion In conclusion, the fatality risk of MBC was increasing and reached the summit between 13th and 18th month after the detection of MBC. We have developed and validated a nomogram to predict the 1- and 3-year survival probability in MBC. [ABSTRACT FROM AUTHOR]

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. Coexpression 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. [ABSTRACT FROM AUTHOR]

Introduction: Specific microRNA (miRNA) expression signatures have been identified in a variety of human cancers. More recently, increasing evidence shows that miRNAs exist in human blood serum and plasma.Materials and Methods: Levels of miR-185 in plasma were measured by quantitative reverse-transcriptase polymerase chain reaction in 66 glioma patients, 11 pituitary adenoma patients, 32 meningioma patients, and 14 acoustic neuroma patients.Results: The plasma levels of miR-185 were significantly altered in glioma patients compared to normal controls. However, its levels were not observably changed in patients with other brain tumors such as meningioma, acoustic neuroma, or pituitary adenoma. Furthermore, the plasma levels of miR-185 in glioblastoma multiforme patients with operation and chemo-radiation almost revived to normal levels. Finally, we also demonstrated that low plasma miR-185 levels are correlated with poor survival in glioma patients.Conclusion: These findings suggest that plasma miR-185 has become potential biomarkers for glioma and may be useful in clinical management for glioma patients. [ABSTRACT FROM AUTHOR]

Background miR-200b has been reported to be a tumor suppressor and a promising therapeutic target in cancer. miR-200b has been associated with epithelial-mesenchymal transition and chemo resistance in cancer. The aim of this study is to investigate the expression of miR-200b, its prognostic roles and its potential targets in breast cancer. Methods qRT-PCR was used to detect miR-200b expression in breast cancer tissues and cell lines. In situ hybridization of miR-200b on tissue microarray including 134 breast cancer samples was used to evaluate its prognostic role. Novel targets of miR-200b in breast cancer were predicted and confirmed by luciferase reporter assay and western bloting. Immunohistochemical staining was used for protein detection. The biological effects of miR- 200b in breast cancer cells were further confirmed by ectopic expression of its mimics followed by MTT assay and invasion test. Results miR-200b was downregulated in breast cancer tissues and cell lines and its low-expression correlated with poor outcome in breast cancer patients. Members of RAB family, RAB21, RAB23, RAB18 and RAB3B were predicted to be the targets of miR-200b. The luciferase reporter assay was performed to certificate this prediction. The expressions of RAB21, RAB23, RAB18 and RAB3B were suppressed by transfection of miR-200b in breast cancer cells. Over-expression of miR-200b or knock-down of RAB21, RAB23, RAB18 and RAB3B inhibited breast cancer cell proliferation and invasion in vitro. Conclusions Our study provides evidence that miR-200b is a prognostic factor in breast cancer targeting multiple members of RAB family. MiR-200b could be a potential therapeutic target in breast cancer. [ABSTRACT FROM AUTHOR]

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 strongfield 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 quasiclassical 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. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) have been documented as playing important roles in cancer development. In this study, we investigated the role of miR-124 in breast cancer and clarified the regulation of flotillin-1 (FLOT1) by miR-124. Methods The expression levels of miR-124 were examined in breast cancer cell lines and patient specimens using quantitative reverse transcription-PCR. The clinicopathological significance of the resultant data was later analyzed. Next, we explored the function of miR-124 to determine its potential roles on cancer cell growth and migration in vitro. A luciferase reporter assay was conducted to confirm the target gene of miR-124, and the results were validated in cell lines and patient specimens. Results We found that miR-124 expression was significantly downregulated in breast cancer cell lines and patient specimen compared with normal cell lines and paired adjacent normal tissues (P < 0.0001), respectively. MiR-124 was also associated with tumor node metastasis (TNM) stage (P = 0.0007) and lymph node metastasis (P = 0.0004). In breast cancer cell lines, the ectopic expression of miR-124 inhibited cell growth and migration in vitro. Moreover, we identified the FLOT1 gene as a novel direct target of miR-124, and miR-124 ectopic expression significantly inhibited FLOT1. Luciferase assays confirmed that miR-124 could directly bind to the 3' untranslated region of FLOT1 and suppress translation. Moreover, FLOT1 was widely upregulated, and inversely correlated with miR-124 in breast cancer tissues. Consistent with the effect of miR-124, the knockdown of FLOT1 significantly inhibited breast cancer cell growth and migration. We also observed that the rescue expression of FLOT1 partially restored the effects of miR-124. Conclusions Our study demonstrated that miR-124 might be a tumor suppressor in breast cancer via the regulation of FLOT1. This microRNA could serve as a potential diagnostic marker and therapeutic target for breast cancer. [ABSTRACT FROM AUTHOR]

We experimentally studied proton ejection in the three-body fragmentation of triply charged 1,3-butadiene molecules prepared by intense ultrashort laser pulses using coincidence momentum imaging. The break-up dynamics along the four possible paths that a final set of three fragments can be reached is investigated for the three different fragmentation channels that are analysed. It is found that for each channel the two dominant paths are (i) proton ejection from the triply charged ion and (ii) a sequential path, where the proton is ejected from the doubly charged ion during the second fragmentation step. Based on the measured three-body momentum correlations and accompanying numerical simulations, we discuss whether the fragmentation dynamics, where the proton is ejected from the triply charged ion, proceeds concertedly or sequentially. We also investigate the dependence of the fragmentation dynamics on the intensity and polarization state of the laser pulse. [ABSTRACT FROM AUTHOR]

By tracking the electron wave function of a molecule in a laser field at a distance from the bound system we define rescattering electron momentum distributions within the framework of the time-dependent Schrödinger equation without making the strong field approximation. It is shown that within certain limitations the classical picture of rescattering can be upheld. The dependence of momentum distributions on molecular orientation, orbital symmetry and correlation is investigated. For orbitals with a node, a strong dependence of time and momentum distributions on molecular orientation is found. [ABSTRACT FROM AUTHOR]

We present the results of a combined experimental and numerical study on strong-field ionisation of acetylene performed with the aim of identifying the mechanism behind the previously reported surprisingly large multi-electron ionisation probabilities of polyatomic molecules. Using coincidence momentum imaging techniques and time-dependent density functional simulations, we show that the reported efficient ionisation is due to the combined action of a significant geometrically induced energy upshift of the most relevant valence orbitals as the C–H distance stretches beyond about two times the equilibrium distance, and a strong increase in the coupling between multiple molecular orbitals concomitant with this stretch motion. The identified enhanced ionisation mechanism, which we refer to as EIC-MOUSE, is only effective for molecules aligned close to parallel to the laser polarisation direction, and is inhibited for perpendicularly aligned molecules because of a suppression of the C–H stretch motion during the onset of ionisation. [ABSTRACT FROM AUTHOR]