Self-compression of femtosecond laser pulses in ambient air through conical radiation.

We demonstrate self-compression of 98 fs near-infrared laser pulses down to 8.8 fs in ambient air, utilizing self-phase modulation in air and negative dispersion in the properties of a laser-induced plasma. The blueshifted pulses achieve self-compression through conical radiation, eliminating the need for additional dispersion compensation. The results highlight a simple and compact approach to generate sub-10 fs laser pulses without additional measures for time-resolved applications in ultrafast diagnostics and spectroscopy.

Carrier envelope phase sensitivity of photoelectron circular dichroism.

We report on a combined experimental and numerical study of photoelectron circular dichroism (PECD) induced by intense few-cycle laser pulses, using methyloxirane as the molecular example. Our experiments reveal a remarkably pronounced sensitivity of the PECD strength of double-ionization on the carrier-envelope phase (CEP) of the laser pulses. By comparison to the simulations, which reproduce the measured CEP-dependence for specific orientations of the molecules in the lab frame, we attribute the origin of the observed CEP-dependence of PECD to the CEP-induced modulation of ionization from different areas of the wave functions of three dominant orbitals.

Pseudoangiosarcomatous squamous cell carcinoma: a rare subtype of squamous cell carcinoma that needs to be differentiated from angiosarcoma and has a poor prognosis.

This study aimed to investigate the formation mechanism of  Pseudoangiosarcoma squamous cell carcinoma (PASCC). The researchers reviewed ten cases of PASCC and summarize their clinical outcomes, pathological morphological traits, immunophenotypes, treatment plans and the corresponding follow-up data. Results showed that the pathological morphology revealed complex reticular structures, where numerous tracts of anastomose, and lacunar structures lined with atypical neoplastic cells, which resembles the histopathological appearance of angiosarcoma. Particularly, we observed pathologic patterns that resemble Sclerosing Epithelioid Fibrosarcoma (or Myxoid Fibrosarcoma) in the patients who suffered a relapse. All cases present negative results for vascular markers (CD31, ERG) and positive results for epithelial markers (CK-pan, p40). The average age of the participants is 60 years old (range: 48-79), relative aged, and there is no significant difference between male and female participants (6 men and 4 women). The locations of neoplasms involve face (n=3), upper limbs (n=1), waist(n=1), cervix uteri (n=1), lungs (n=2), thyroid (n=1), and breasts (n=1). All participants had received clinical follow-ups that range from 4 to 47 months, during which the researchers observed Lymph Node Metastases developed in three participants (out of 10; 30%); Distant Metastases in five participants (out of 10; 50%); two local recurrences at the site of surgical resection; and four deaths due to disease (out of 10; 40%), with 9.5 months estimated median survival time and 9 months mean survival time. It was concluded that PASCC presents the tendency for recurrence and metastasis. Accurate pathological diagnosis and standardized medical procedures are crucial to the treatment of PASCC. Epithelial-Mesenchymal Transformation (EMT) and P53 gene mutation are involved in the formation of PASCC.

Ages of weaning influence the gut microbiota diversity and function in Chongming white goats.

To study the effect of weaning age on the gut microbiota diversity in the lambs of Chongming white goats, fresh feces from the lambs weaned at 30, 45, and 60 days of age were collected 3 days after weaning at 33, 48, and 63 days of age, for microbial composition analysis by 16S rRNA sequencing. The serum concentrations of lipid metabolites were also investigated at the fecal collection dates. Serum and feces from the ewe-reared groups at 33, 48, and 63 days of age were used as controls. The alpha diversity increased significantly after weaning and with the aging of the lambs. Levels of Ruminococcaceae, Lachnospiraceae, and Ruminococcus varied significantly according to the weaning treatment in lambs (P < 0.05). Butyrate-producing gut bacteria such as Ruminococcaceae_UCG-010, Ruminococcaceae_UCG-013, Ruminococcaceae_UCG-014, Ruminococcaceae_UCG-005, Ruminococcaceae_UCG-002, Lachnospiraceae_AC2044_group, and Lachnospiraceae_NK4B4 were identified as significantly increased genera (P < 0.05) in the feces of weaned Chongming white lambs. Additionally, the abundance of fiber degradation-associated bacteria including Ruminococcaceae_UCG-005, Ruminococcus_1, and Ruminococcus_2 significantly increased with lamb weaning age (P < 0.05). Correlation analysis showed that Lachnospiraceae_AC2044_group, norank_f__Bacteroidales_S24-7_group, and Ruminococcaceae_UCG_005 were negatively correlated, and Lachnoclostridium was positively correlated with levels of cholesterol, while Blautia showed positive correlation with low-density lipoprotein cholesterol in serum samples from weaned lambs. This study helped to understand the maturing development of gut microbiota in Chongming white goats under weaning stress. KEY POINTS: • Effects of weaning age on the gut microbiota diversity in Chongming white goat lambs were studied. • Some butyrate-producing gut bacteria were significantly increased after weaned. • Correlations of gut microbiota and lipid metabolites were analyzed.

Development and validation of a stromal immune phenotype classifier for predicting immune activity and prognosis in triple-negative breast cancer.

Our study aims to construct a prognosis-related immune phenotype classifier for predicting clinical prognosis and immune activity in triple-negative breast cancer (TNBC). A total of 237 patients with TNBC from Sun Yat-sen University Cancer Center (SYSUCC) and 533 patients with TNBC from public datasets were included in our study. A stromal immune quantified index was generated with a LASSO Cox regression model based on five prognosis-related immune cells evaluated by CIBERSORT or IHC and was used to determine immune phenotypes. Immune features were evaluated in the samples before chemotherapy. A total of 119 patients in the SYSUCC training cohort were classified into immune Phenotypes A and B according to the density of stromal CD4+ T cells, γδ T cells, monocytes, M1 macrophages and M2 macrophages. Phenotype A predicted better survival than Phenotype B, and the classification was further validated in the testing cohort of 118 patients and the validation cohort of 533 patients. In the combined cohort, significant differences were found in Phenotype A compared to Phenotype B for the 5-year overall survival (83.5% vs 65.8%, respectively, P < .01) and the 5-year disease-free survival (87.3% vs 76.0%, respectively, P < .01). In Phenotype A, immune-related pathways were significantly enriched, and a higher level of immune checkpoint molecules, including PD-L1, PD-1 and CTLA-4, could be observed. The immune phenotype classification was an independent prognostic indicator for TNBC and might serve as a potential predictor for immune activity within the tumor microenvironment.

Laser-induced inner-shell excitations through direct electron re-collision versus indirect collision.

The dynamics and the decay processes of inner-shell excited atoms are of great interest in physics, chemistry, biology, and technology. The highly excited state decays very quickly through different channels, both radiative and non-radiative. It is therefore a long-standing goal to study such dynamics directly in the time domain. Using few-cycle infrared laser pulses, we investigated the excitation and ionization of inner-shell electrons through laser-induced electron re-collision with the original parent ions and measured the dependence of the emitted x-ray spectra on the intensity and ellipticity of the driving laser. These directly re-colliding electrons can be used as the initiating pump step in pump/probe experiments for studying core-hole dynamics at their natural temporal scale. In our experiment we found that the dependence of the x-ray emission spectrum on the laser intensity and polarization state varies distinctly for the two kinds of atomic systems. Relying on our data and numerical simulations, we explain this behavior by the presence of different excitation mechanisms that are contributing in different ratios to the respective overall x-ray emission yields. Direct re-collision excitation competes with indirect collisions with neighboring atoms by electrons having "drifted away" from the original parent ion.

Optical second harmonic generation in LiB3O5 modulated by intense femtosecond X-ray pulses.

Many of the scientific applications for X-ray free-electron lasers seek to exploit the ultrashort pulse durations of intense X-rays to obtain femtosecond time resolution of various processes in a "pump-probe" scheme. One of the limiting factors for such experiments is the timing jitter between the X-rays and ultrashort pulses from more conventional lasers operating at near-optical wavelengths. In this work, we investigate the potential of using X-ray-induced changes in the optical second harmonic generation efficiency of a nonlinear crystal to retrieve single-shot arrival times of X-ray pulses with respect to optical laser pulses. Our experimental results and simulations show changes to the efficiency of the second harmonic generation of 12%, approximately three times larger than the measured changes in the transmission of the 800 nm center-wavelength fundamental pulse. Further experiments showing even larger changes in the transmission of 400 nm center-wavelength pulses show that the mechanism of the second harmonic generation efficiency modulation is mainly the result of X-ray-induced changes in the linear absorption coefficients near 400 nm. We demonstrate and characterize a cross-correlation tool based on this effect in reference to a previously demonstrated method of X-ray/optical cross-correlation.

Generalized Phase Sensitivity of Directional Bond Breaking in the Laser-Molecule Interaction.

We establish a generalized picture of the phase sensitivity of laser-induced directional bond breaking using the H_{2} molecule as the example. We show that the well-known proton ejection anisotropy measured with few-cycle pulses as a function of their carrier-envelope phases arises as an amplitude modulation of an intrinsic anisotropy that is sensitive to the laser phase at the ionization time and determined by the molecule's electronic structure. Our work furthermore reveals a strong electron-proton correlation that may open up a new approach to experimentally accessing the laser-sub-cycle intramolecular electron dynamics also in larger molecules.

Experimental Separation of Subcycle Ionization Bursts in Strong-Field Double Ionization of H_{2}.

We report on the unambiguous observation of the subcycle ionization bursts in sequential strong-field double ionization of H_{2} and their disentanglement in molecular frame photoelectron angular distributions. This observation was made possible by the use of few-cycle laser pulses with a known carrier-envelope phase, in combination with multiparticle coincidence momentum imaging. The approach demonstrated here will allow sampling of the intramolecular electron dynamics and the investigation of charge-state-specific Coulomb distortions on emitted electrons in polyatomic molecules.

Laser-Induced Electron Transfer in the Dissociative Multiple Ionization of Argon Dimers.

We report on an experimental and theoretical study of the ionization-fragmentation dynamics of argon dimers in intense few-cycle laser pulses with a tagged carrier-envelope phase. We find that a field-driven electron transfer process from one argon atom across the system boundary to the other argon atom triggers subcycle electron-electron interaction dynamics in the neighboring atom. This attosecond electron-transfer process between distant entities and its implications manifests itself as a distinct phase-shift between the measured asymmetry of electron emission curves of the Ar^{+}+Ar^{2+} and Ar^{2+}+Ar^{2+} fragmentation channels. This letter discloses a strong-field route to controlling the dynamics in molecular compounds through the excitation of electronic dynamics on a distant molecule by driving intermolecular electron-transfer processes.

circRAD18 sponges miR-208a/3164 to promote triple-negative breast cancer progression through regulating IGF1 and FGF2 expression.

As a new rising star of non-coding RNA, circular RNAs (circRNAs) emerged as vital regulators with biological functions in diverse of cancers. However, the function and precise mechanism of the vast majority of circRNAs in triple-negative breast cancer (TNBC) occurrence and progression have not been clearly elucidated. In the current study, we identified and further investigated hsa_circ_0002453 (circRAD18) by analyzing our previous microarray profiling. Expression of circRAD18 was found significantly upregulated in TNBC compared with normal mammary tissues and cell lines. circRAD18 was positively correlated with T stage, clinical stage and pathological grade and was an independent risk factor for TNBC patients. We performed proliferation, colony formation, cell migration, apoptosis and mouse xenograft assays to verify the functions of circRAD18. Knockdown of circRAD18 significantly suppressed cell proliferation and migration, promoted cell apoptosis and inhibited tumor growth in functional and xenograft experiments. Through luciferase reporter assays, we confirmed that circRAD18 acts as a sponge of miR-208a and miR-3164 and promotes TNBC progression through upregulating IGF1 and FGF2 expression. Altogether, our research revealed the pivotal role of circRAD18-miR-208a/3164-IGF1/FGF2 axis in TNBC tumorigenesis and metastasis though the mechanism of competing endogenous RNAs. Thus, circRAD18 may serve as a novel prognostic biomarker and potential target for TNBC treatment in the future.

SOX8 acts as a prognostic factor and mediator to regulate the progression of triple-negative breast cancer.

The molecular mechanisms underlying triple-negative breast cancer (TNBC) pathology are not fully understood. Here, we reviewed the SOX8 transcript level in 24 types of cancer and normal tissues and the SOX8 expression pattern in breast cancer from the TCGA and METABRIC data sets and found that SOX8 was highly expressed in TNBC. We investigated the effect of SOX8 on tumorigenicity, migration and apoptosis in TNBC cell lines and xenografts models. We identified SOX8 as a functional oncogene that involved in the maintenance of stem-like capacities in TNBC cells. Through a promoter truncation experiment and ChIP experiment, we verified zinc finger E-box binding homeobox 1 (ZEB1) as a transcriptional activator of SOX8 that enhanced SOX8 expression by binding to its promoter. We evaluated the ZEB1 and the SOX8 levels in 240 TNBC patients and high expression of ZEB1 and SOX8 were significantly associated with poor prognosis. We demonstrated the significance of the ZEB1-SOX8 axis in regulating TNBC cancer stem-like cells (CSCs) and its connection with poor prognosis. Due to its vital role in TNBC CSCs, the ZEB1-SOX8 regulatory axis could be a promising therapeutic target for TNBC.

miR-200c suppresses stemness and increases cellular sensitivity to trastuzumab in HER2+ breast cancer.

Resistance to trastuzumab remains a major obstacle in HER2-overexpressing breast cancer treatment. miR-200c is important for many functions in cancer stem cells (CSCs), including tumour recurrence, metastasis and resistance. We hypothesized that miR-200c contributes to trastuzumab resistance and stemness maintenance in HER2-overexpressing breast cancer. In this study, we used HER2-positive SKBR3, HER2-negative MCF-7, and their CD44+ CD24- phenotype mammospheres SKBR3-S and MCF-7-S to verify. Our results demonstrated that miR-200c was weakly expressed in breast cancer cell lines and cell line stem cells. Overexpression of miR-200c resulted in a significant reduction in the number of tumour spheres formed and the population of CD44+ CD24- phenotype mammospheres in SKBR3-S. Combining miR-200c with trastuzumab can significantly reduce proliferation and increase apoptosis of SKBR3 and SKBR3-S. Overexpression of miR-200c also eliminated its downstream target genes. These genes were highly expressed and positively related in breast cancer patients. Overexpression of miR-200c also improved the malignant progression of SKBR3-S and SKBR3 in vivo. miR-200c plays an important role in the maintenance of the CSC-like phenotype and increases drug sensitivity to trastuzumab in HER2+ cells and stem cells.

Identification of a 4-mRNA metastasis-related prognostic signature for patients with breast cancer.

Metastasis-related mRNAs have showed great promise as prognostic biomarkers in various types of cancers. Therefore, we attempted to develop a metastasis-associated gene signature to enhance prognostic prediction of breast cancer (BC) based on gene expression profiling. We firstly screened and identified 56 differentially expressed mRNAs by analysing BC tumour tissues with and without metastasis in the discovery cohort (GSE102484, n = 683). We then found 26 of these differentially expressed genes were associated with metastasis-free survival (MFS) in the training set (GSE20685, n = 319). A metastasis-associated gene signature built using a LASSO Cox regression model, which consisted of four mRNAs, can classify patients into high- and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter MFS (hazard ratio [HR] 3.89, 95% CI 2.53-5.98; P < 0.001), disease-free survival (DFS) (HR 4.69, 2.93-7.50; P < 0.001) and overall survival (HR 4.06, 2.56-6.45; P < 0.001) than patients with low-risk scores. The prognostic accuracy of mRNAs signature was validated in the two independent validation cohorts (GSE21653, n = 248; GSE31448, n = 246). We then developed a nomogram based on the mRNAs signature and clinical-related risk factors (T stage and N stage) that predicted an individual's risk of disease, which can be assessed by calibration curves. Our study demonstrated that this 4-mRNA signature might be a reliable and useful prognostic tool for DFS evaluation and will facilitate tailored therapy for BC patients at different risk of disease.

Metformin mediates induction of miR-708 to inhibit self-renewal and chemoresistance of breast cancer stem cells through targeting CD47.

Breast cancer stem cells (BCSCs) have been considered responsible for cancer progression, recurrence, metastasis and drug resistance. However, the mechanisms by which cells acquire self-renewal and chemoresistance properties are remaining largely unclear. Herein, we evaluated the role of miR-708 and metformin in BCSCs, and found that the expression of miR-708 is significantly down-regulated in BCSCs and tumour tissues, and correlates with chemotherapy response and prognosis. Moreover, miR-708 markedly inhibits sphere formation, CD44+ /CD24- ratio, and tumour initiation and increases chemosensitivity of BCSCs. Mechanistically, miR-708 directly binds to cluster of differentiation 47 (CD47), and regulates tumour-associated macrophage-mediated phagocytosis. On the other hand, CD47 is essential for self-renewal, tumour initiation and chemoresistance of BCSCs, and correlates with the prognosis of breast cancer patients. In addition, the anti-type II diabetes drug metformin are found to be involved in the miR-708/CD47 signalling pathway. Therefore, our study demonstrated that miR-708 plays an important tumour suppressor role in BCSCs self-renewal and chemoresistance, and the miR-708/CD47 regulatory axis may represent a novel therapeutic mechanism of metformin in BCSCs.

Incorporating MicroRNA into Molecular Phenotypes of Circulating Tumor Cells Enhances the Prognostic Accuracy for Patients with Metastatic Breast Cancer.

BACKGROUND: The molecular phenotype of circulating tumor cells (CTCs) was associated with clinical outcome of patients with breast cancer. CTCs isolated from patients with metastatic breast cancer (MBC) display a unique microRNA (miRNA) expression profile. The aim of this study was to enhance the prognostic accuracy of the CTC phenotype in patients with MBC, by incorporating miRNA into a combined prediction model. SUBJECTS, MATERIALS, AND METHODS: CTCs were detected by CellSearch and enriched by magnetic cell sorting. miRNA deep sequencing and quantitative polymerase chain reaction were used to screen and verify potentially CTC-specific miRNA candidates. Patients with MBC were enrolled from two independent cohorts, and overall survival (OS) and chemotherapy response were analyzed. RESULTS: We screened and identified that miR-106b was an upregulated molecule in patients with MBC with CTC ≥5/7.5 mL (n = 16) compared with patients with CTC = 0/7.5 mL (n = 16) and healthy donors (n = 8). The expression of CTC-specific miR-106b correlated with vimentin and E-cadherin in CTC and acted as an independent factor for predicting OS (hazard ratio 2.157, 95% confidence interval [CI] 1.098-4.239, p = .026). Although CTC-specific miR-106b, E-cadherin, and vimentin showed a prognostic potential independently, the prognostic performance for OS based on the combination of three markers was significantly enhanced in Cohort 1 (area under the curve [AUC] 0.752, 95% CI 0.658-0.847, n = 128) and further validated in Cohort 2 (AUC 0.726, 95% CI 0.595-0.856, n = 91). Besides, a combined model incorporating miR-106b was associated with therapy response. CONCLUSION: The phenotypic assemblies of CTC incorporating miR-106b show enhanced prognostic accuracy of overall survival in patients with MBC. IMPLICATIONS FOR PRACTICE: In order to enhance the prognostic accuracy of the circulating tumor cell (CTC) phenotype in patients with metastatic breast cancer (MBC), this study screened and identified a CTC-specific microRNA (miRNA), miR-106b, as an upregulated molecule based on the comparison of miRNA profile between CTCs, primary tumors, and healthy blood donors. By incorporating miR-106b into a combined prediction model, the prognostic accuracy of the CTC phenotype for patients with MBC was greatly improved in both the training and validation cohorts. This work provides clinical evidence supporting the prognostic potential of CTC-specific miRNA for patients with MBC. These results indicate that developing CTC-specific miRNAs as new biomarkers will help to further optimize personalized therapy.

Subfemtosecond Tracing of Molecular Dynamics during Strong-Field Interaction.

We introduce and experimentally demonstrate a method where the two intrinsic timescales of a molecule, the slow nuclear motion and the fast electronic motion, are simultaneously measured in a photoelectron photoion coincidence experiment. In our experiment, elliptically polarized, 750 nm, 4.5 fs laser pulses were focused to an intensity of 9×10^{14} W/cm^{2} onto H_{2}. Using coincidence imaging, we directly observe the nuclear wave packet evolving on the 1sσ_{g} state of H_{2}^{+} during its first round-trip with attosecond temporal and picometer spatial resolution. The demonstrated method should enable insight into the first few femtoseconds of the vibronic dynamics of ionization-induced unimolecular reactions of larger molecules.

Preoperative prediction nomogram based on primary tumor miRNAs signature and clinical-related features for axillary lymph node metastasis in early-stage invasive breast cancer.

More than half patients who undergo axillary lymph node (ALN) surgery are ALN negative in early-stage invasive breast cancer (EIBC). Thus, to avoid excessive treatment, we aim to establish and validate a novel nomogram model for the preoperative diagnosis of ALN status in patients with EIBC. In total, 864 patients with EIBC from two independent centers were enrolled in our study. For the discovery set, miRNAs expression profiling with functional roles in ALN metastasis was discovered by microarray analysis and validated by quantitative polymerase chain reaction (PCR). For the training and validation cohorts, we used PCR to quantify miRNAs expression in a model development cohort and assessed miRNAs signature in an internal validation cohort and external independent validation cohort. Multivariable logistic regression analyses were used to establish a nomogram model for the likelihood of ALN metastasis from miRNAs signature and clinical variables. A signature of nine-miRNA was significantly associated with ALN status. The predictive ability of our nomogram that included miRNAs signature and clinical-related variables (age, tumor size, tumor location and axillary ultrasound-reported ALN status) was significantly greater than a model that only considered clinical-related factors (concordance index: 0.856, 0.796) and also performed well in the two validation cohorts (concordance index: 0.841, 0.747). Our nomogram is a reliable prediction method that can be conveniently used to preoperatively predict ALN status in patients with EIBC. Therefore, after further confirmation in prospective and multicenter clinical trial, omission of axillary surgery may be feasible for some patients with EIBC in the future.

Could local surgery improve survival in de novo stage IV breast cancer?

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.

Disentangling Intracycle Interferences in Photoelectron Momentum Distributions Using Orthogonal Two-Color Laser Fields.

We use orthogonally polarized two-color (OTC) laser pulses to separate quantum paths in the multiphoton ionization of Ar atoms. Our OTC pulses consist of 400 and 800 nm light at a relative intensity ratio of 10∶1. We find a hitherto unobserved interference in the photoelectron momentum distribution, which exhibits a strong dependence on the relative phase of the OTC pulse. Analysis of model calculations reveals that the interference is caused by quantum pathways from nonadjacent quarter cycles.