Towards performing high-resolution inelastic X-ray scattering measurements at hard X-ray free-electron lasers coupled with energetic laser drivers.

High-resolution inelastic X-ray scattering is an established technique in the synchrotron community, used to investigate collective low-frequency responses of materials. When fielded at hard X-ray free-electron lasers (XFELs) and combined with high-intensity laser drivers, it becomes a promising technique for investigating matter at high temperatures and high pressures. This technique gives access to important thermodynamic properties of matter at extreme conditions, such as temperature, material sound speed, and viscosity. The successful realization of this method requires the acquisition of many identical laser-pump/X-ray-probe shots, allowing the collection of a sufficient number of photons necessary to perform quantitative analyses. Here, a 2.5-fold improvement in the energy resolution of the instrument relative to previous works at the Matter in Extreme Conditions (MEC) endstation, Linac Coherent Light Source (LCLS), and the High Energy Density (HED) instrument, European XFEL, is presented. Some aspects of the experimental design that are essential for improving the number of photons detected in each X-ray shot, making such measurements feasible, are discussed. A careful choice of the energy resolution, the X-ray beam mode provided by the XFEL, and the position of the analysers used in such experiments can provide a more than ten-fold improvement in the photometrics. The discussion is supported by experimental data on 10 µm-thick iron and 50 nm-thick gold samples collected at the MEC endstation at the LCLS, and by complementary ray-tracing simulations coupled with thermal diffuse scattering calculations.

Imaging the short-lived hydroxyl-hydronium pair in ionized liquid water.

The radiolysis of water is ubiquitous in nature and plays a critical role in numerous biochemical and technological applications. Although the elementary reaction pathways for ionized water have been studied, the short-lived intermediate complex and structural dynamic response after the proton transfer reaction remain poorly understood. Using a liquid-phase ultrafast electron diffraction technique to measure the intermolecular oxygen···oxygen and oxygen···hydrogen bonds, we captured the short-lived radical-cation complex OH(H3O+) that was formed within 140 femtoseconds through a direct oxygen···oxygen bond contraction and proton transfer, followed by the radical-cation pair dissociation and the subsequent structural relaxation of water within 250 femtoseconds. These measurements provide direct evidence of capturing this metastable radical-cation complex before separation, thereby improving our fundamental understanding of elementary reaction dynamics in ionized liquid water.

Electron Kinetics Induced by Ultrafast Photoexcitation of Warm Dense Matter in a 30-nm-Thick Foil.

We report on the study of electron kinetics induced by intense femtosecond (fs) laser excitation of electrons in the 5d band of Au. Changes in the electron system are observed from the temporal evolution of ac conductivity and conduction electron density. The results reveal an increase of electron thermalization time with excitation energy density, contrary to the Fermi-liquid behavior of the decrease of thermalization time associated with the heating of conduction electrons. This is attributed to the severe mitigation of photoexcitation by Auger decay. The study also uncovers the shortening of 5d hole lifetime with the increase of photoexcitation rates. These unique findings provide valuable insights for understanding electron kinetics under extreme nonequilibrium conditions.

Ultrafast multi-cycle terahertz measurements of the electrical conductivity in strongly excited solids.

Key insights in materials at extreme temperatures and pressures can be gained by accurate measurements that determine the electrical conductivity. Free-electron laser pulses can ionize and excite matter out of equilibrium on femtosecond time scales, modifying the electronic and ionic structures and enhancing electronic scattering properties. The transient evolution of the conductivity manifests the energy coupling from high temperature electrons to low temperature ions. Here we combine accelerator-based, high-brightness multi-cycle terahertz radiation with a single-shot electro-optic sampling technique to probe the evolution of DC electrical conductivity using terahertz transmission measurements on sub-picosecond time scales with a multi-undulator free electron laser. Our results allow the direct determination of the electron-electron and electron-ion scattering frequencies that are the major contributors of the electrical resistivity.

[Association between obesity and risk for colorectal advanced adenoma].

Objectives: To understand the association between obesity and the risk for colorectal advanced adenoma. Methods: Community residents aged 45 to 74 who had participated in the Shanghai community-based colorectal cancer (CRC) screening project in 2008 were included in our study. Anthropometries information including body weight, height and risk factors for colorectal advanced adenoma were collected. Results on colonoscopic diagnosis and personal health records were used for supplementary outcome information retrieval. Multivariate Cox proportional hazard regression models were used to evaluate the hazard ratio (HR) and 95%CI of obesity on the risk for colorectal advanced adenoma. Results: 20 811 residents were followed up for 122 739.36 person-years, with a median follow-up time of 5.87 years. A total of 657 cases of advanced adenomas were identified. After adjusting for potential confounding risk factors such as age, sex, family history of CRC, level of education, marriage, cigarette smoking, alcohol drinking, foods intake including fat, fried or pickled, vegetables and fruits etc., the HR was 1.25 (95%CI: 1.04-1.51) for obese people when compared with the normal weight persons. Further stratified analysis by age, gender and family history of CRC, results showed that obese people had a much higher risk of colorectal advanced adenoma than those with normal weight (male: HR=1.57, 95%CI: 1.20-2.04; more than 60- year-old: HR=1.63, 95%CI: 1.23-2.16). Conclusion: Data from this large scale population-based study revealed that obesity might be an independent risk factor for colorectal advanced adenoma and the risk increases along with the increase of BMI in China.

[Esculin inhibits proliferation of triple negative breast cancer cells by down-regulating FBI-1].

Objective: To investigate the effect of esculin on the proliferation of triple negative breast cancer cells and its molecular mechanism. Methods: MDA-MB-231 cells were treated with 28, 56, 112, 225, 450 and 900 µmol/L of esculin for 24, 48 and 72 h, respectively, and the cell viability was detected by cell counting kit 8 (CCK-8) assay. In addition, MDA-MB-231 cells were treated with 0, 225, 450 and 900 µmol/L of esculin for 48 h. And then the changes in cell morphology were observed by inverted microscope. The clone-forming ability was detected by colony formation assay. The mRNA expression levels of FBI-1, p53 and p21 were detected using real-time fluorescence quantitative polymerase chain reaction. The protein expression levels of FBI-1, p53, p21 and Ki67 were detected by western blot. Results: Compared with the blank control group, the cell viability of MDA-MB-231 cells that treated with esculin significantly decreased in a dose-dependent and time-dependent manners. After treatment with esculin, MDA-MB-231 cells shrunk, flattened, adhered poorly to the culture dish and the cell spacing became larger. Meanwhile, shedding and incomplete cells appeared, of which 900 µmol/L of esculin treatment group showed the most dramatic changes. In addition, the colony formation ratios were decreased to (77.18±5.13)%, (65.94±4.98)% and (45.92±3.70)% in the 225, 450 and 900 µmol/L of esculin treatment groups compared with blank control, respectively (P<0.01). Furthermore, the mRNA and protein expressions of FBI-1 increased, while the levels of p53 and p21 mRNA and protein, as well as the protein expression of Ki67 decreased in a concentration-dependent manner (P<0.01). Conclusion: Esculin may regulate cell cycle-related p53-p21 pathway via FBI-1 mediated DNA replication, thus inhibit the proliferation of triple negative breast cancer cells.

Liquid-phase mega-electron-volt ultrafast electron diffraction.

The conversion of light into usable chemical and mechanical energy is pivotal to several biological and chemical processes, many of which occur in solution. To understand the structure-function relationships mediating these processes, a technique with high spatial and temporal resolutions is required. Here, we report on the design and commissioning of a liquid-phase mega-electron-volt (MeV) ultrafast electron diffraction instrument for the study of structural dynamics in solution. Limitations posed by the shallow penetration depth of electrons and the resulting information loss due to multiple scattering and the technical challenge of delivering liquids to vacuum were overcome through the use of MeV electrons and a gas-accelerated thin liquid sheet jet. To demonstrate the capabilities of this instrument, the structure of water and its network were resolved up to the 3 rd hydration shell with a spatial resolution of 0.6 Å; preliminary time-resolved experiments demonstrated a temporal resolution of 200 fs.

[A single-center retrospective study on axillary evaluation in 1 557 breast ductal carcinoma in situ patients between 2006 and 2016].

Objectives: To examine the influence factors on axillary evaluation in ductal carcinoma in situ (DCIS) patients, and the prognosis of different choices of axillary evaluation in a single-center retrospective study. Methods: Totally 1 557 DCIS patients admitted in Department of Breast Surgery, Fudan University Shanghai Cancer Center from January 2006 to November 2016 were retrospectively enrolled. All patients were female. The median age was 49 years (range: 21 to 85 years). Surgical methods included modified radical mastectomy, simple mastectomy (with or without axillary evaluation) and breast conservation surgery (with or without axillary evaluation). Axillary evaluation included axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB). T tests, χ(2) test and Logistic regression analysis was used to analyze influence factors on axillary evaluation, respectively. Kaplan-Meier curve and Log-rank analysis were used to evaluate recurrence-free survival (RFS) and loco-regional recurrence-free survival (LRRFS) in patients with different surgical methods. Results: Among the 1 557 DCIS patients, there were 1 226 cases received axillary evaluation, while 331 cases not received axillary evaluation. Patients were separated into 3 groups by different axillary evaluation choices: SLNB group (957 cases, 61.46%), ALND group (197 cases, 12.65%) and no evaluation group (403 cases, 25.88%). The patients in SLNB group increased significantly (P=0.000), from 3.85% (60/1 557) in 2006 to 75.19% (1 170/1 557) in 2016. The independent influence factors of receiving axillary evaluation were high nuclear grade (OR=3.191, 95%CI: 1.722 to 5.912, P=0.001) and tumor size>15 mm (OR=1.698, 95%CI: 1.120 to 2.573, P=0.012). Also, patients received breast conservation surgery were more likely to refuse axillary evaluation (OR=0.155, 95%CI: 0.103 to 0.233, P=0.000). There were no significant differences in RFS and LRRFS in patients with different axillary evaluation choices. Conclusions: The investigation in trends and influence factors of different axillary evaluation choices provided basis on surgical precision medicine in DCIS patients. Patients received SLNB increased significantly. The independent influence factors of axillary evaluation were nuclear grade, tumor size and surgical methods. There was no significant differences in prognosis among the groups receiving different axillary evaluations.

[Comparison of modeling effects of two different 7, 12-dimethylbenz[a] anthracene induced breast cancer models in tree shrew].

Objective: To explore the feasibility of 7, 12-dimethylbenz[a] anthracene (DMBA) induced tree shrew breast cancer model, and compare the effects of two administration modes by gavage and mammary gland injection. Methods: A total of 40 tree shrews were randomly divided into two groups (20 animals per group): DMBA gavage group and mammary gland injection group. DMBA was dissolved in edible vegetable oil. For gavage group, tree shrews were administered with DMBA solutions (15 mg/kg) by gavage once a day. For mammary gland injection group, DMBA solution (10 mg/kg) was injected into the mammary fat pad of tree shrews, and the injection was performed for a total of 3 times. From the first administration of DMBA, medroxyprogesterone acetate (MPA, 100 mg/kg) was intramuscularly injected into the muscles of the lateral thighs of tree shrews at the same time, for a total of 5 times. The tumorigenesis and survival of tree shrews were monitored. The tumor histological morphology was observed by HE staining. The expression of estrogen receptor (ER), progesterone receptor (PR), cytokeratin5/6 (CK5/6) and human epidermal factor receptor-2 (HER-2) was detected by immunohistochemical staining. Results: In the gavage group, there were 10 deaths, and 4 tree shrews developed mammary tumors with 20.0% (4/20) tumor formation rate. The success rate of mammary cancer modeling was 10.0% (2/20), and the tumor formation time was 197.3±15.1 days. In the mammary gland injection group, there were 8 tree shrews died, and 9 tree shrews formed tumors with 45.0% (9/20) tumor formation rate. The success rate of mammary cancer modeling was 40.0% (8/20), and the tumor formation time was 71.8±19.0 days. There was no significant difference in mortality and tumor formation rate (P>0.05) between the two groups (all P>0.05). However, in the mammary gland injection group, the success rate of mammary cancer modeling was significantly higher than that in the gavage group (P<0.05), whereas the tumor formation time was markedly shorter than that in the gavage group (P<0.01). The pathological types in the gavage group included ductal hyperplasia, intraductal papilloma and ductal carcinoma in situ, while those in the breast injection group included intraductal papilloma and ductal carcinoma in situ. In both groups, immunohistochemical staining showed the negative expression of HER-2 but positive expression of ER, PR and CK5/6 with varying degrees. Conclusion: Both the DMBA gavage and mammary gland injection can successfully establish the tree shrew breast cancer model, and the modeling effect of mammary gland injection is better than gavage.

[Dose-response relationship between maternal hemoglobin concentration and preterm birth, in pregnant women].

Objective: To investigate the dose-response relationship between hemoglobin concentration and preterm birth, during pregnancy. Methods: With Zhuang ethnicity, a total of 12 780 pregnant women and their infants that admitted to Wuming、Pingguo、Jingxi、Debao、Longan and Tiandong hospitals, were recruited, in Guangxi Zhuang Autonomous Region, from January 2015 to December 2017. Non-conditional logistic regression method was used to analyze the effect of anemia on preterm birth during pregnancy. Dose-response relationship between hemoglobin concentration and preterm birth was explored, using the restrictive cubic spline model. Results: After excluding 2 053 pregnant women with hypertension or aged 35 years and over, results from the non-conditional logistic regression analysis showed that the risk of preterm birth in the anemia group was 1.29 times (OR=1.29, 95%CI: 1.04-1.59, P=0.019) of the non-anemia group in the first trimester. Data from the restricted cubic sample showed that there appeared nonlinear "L" dose-response relationship between hemoglobin concentration and preterm birth in the first trimester and "U" shape in the third trimester (non-linearity test P<0.001). Conclusion: There appeared nonlinear dose-response relationship between the hemoglobin concentration and preterm birth, both in the first and third trimesters.

Determination of the electron-lattice coupling strength of copper with ultrafast MeV electron diffraction.

Electron-lattice coupling strength governs the energy transfer between electrons and the lattice and is important for understanding the material behavior under highly non-equilibrium conditions. Here we report the results of employing time-resolved electron diffraction at MeV energies to directly study the electron-lattice coupling strength in 40-nm-thick polycrystalline copper excited by femtosecond optical lasers. The temporal evolution of lattice temperature at various pump fluence conditions were obtained from the measurements of the Debye-Waller decay of multiple diffraction peaks. We observed the temperature dependence of the electron-lattice relaxation time which is a result of the temperature dependence of electron heat capacity. Comparison with two-temperature model simulations reveals an electron-lattice coupling strength of (0.9 ± 0.1) × 1017 W/m3/K for copper.

Interatomic Potential in the Nonequilibrium Warm Dense Matter Regime.

We present a new measurement of lattice disassembly times in femtosecond-laser-heated polycrystalline Au nanofoils. The results are compared with molecular dynamics simulations incorporating a highly optimized, embedded-atom-method interatomic potential. For absorbed energy densities of 0.9-4.3 MJ/kg, the agreement between the experiment and simulation reveals a single-crystal-like behavior of homogeneous melting and corroborates the applicability of the interatomic potential in the nonequilibrium warm dense matter regime. For energy densities below 0.9 MJ/kg, the measurement is consistent with nanocrystal behavior where melting is initiated at the grain boundaries.

Role of industry funders in oncology RCTs published in high-impact journals and its association with trial conclusions and time to publication.

Background: Previous studies have shown that industry funded trials are associated with pro-industry conclusions and publication bias. Less is known about the role of industry funders and their influence on trial conclusions and time to publication. Methods: We identified all industry funded RCTs published in six high-impact clinical journals between 2014 and 2016 to estimate the prevalence of the role of industry funders in trial design, data collection, data analyses, data interpretation and manuscript writing. Ordinal logistic regression was used to assess the association between the role of industry funders and trial conclusions, which was classified on a five-point scale. Cox proportional-hazards were used to examine the effect of role of funder on time to publication. Results: Of the 255 eligible RCTs, industry funders had a role in trial design in 179 (70.2%) trials, data collection in 160 (62.7%) trials, data analyses in 173 (67.8%) trials, data interpretation in 135 (52.9%) trials and manuscript writing in 168 (65.9%) trials. Trials with any role of industry funders had 3.6 times (95% CI 2.0-6.6) higher odds of having positive conclusions compared with those without role of industry funders. In trials with any role of industry funders, positive trials were published more rapidly than negative trials (hazard ratio = 4.3; 95% CI 2.7-6.7, P < 0.001), while for trials without role of industry funders, there was no association (hazard ratio = 1.07; 95% CI 0.57-1.99, P = 0.84). Conclusion: The involvement of industry funders is common in all stages of clinical trials and was associated with more positive conclusions and more rapid publication of RCTs with positive results.

Heterogeneous to homogeneous melting transition visualized with ultrafast electron diffraction.

The ultrafast laser excitation of matters leads to nonequilibrium states with complex solid-liquid phase-transition dynamics. We used electron diffraction at mega-electron volt energies to visualize the ultrafast melting of gold on the atomic scale length. For energy densities approaching the irreversible melting regime, we first observed heterogeneous melting on time scales of 100 to 1000 picoseconds, transitioning to homogeneous melting that occurs catastrophically within 10 to 20 picoseconds at higher energy densities. We showed evidence for the heterogeneous coexistence of solid and liquid. We determined the ion and electron temperature evolution and found superheated conditions. Our results constrain the electron-ion coupling rate, determine the Debye temperature, and reveal the melting sensitivity to nucleation seeds.

Nuclear factor erythroid-derived 2-related factor 2 activates glutathione S-transferase expression in the midgut of Spodoptera litura (Lepidoptera: Noctuidae) in response to phytochemicals and insecticides.

Detoxication enzymes play an important role in insect resistance to xenobiotics such as insecticides and phytochemicals. We studied the pathway for activating the expression of glutathione S-transferases (GSTs) in response to selected xenobiotics. An assay of the promoter activity of GST epsilon 1 (Slgste1) of Spodoptera litura led to the discovery of a cis-regulating element. An antioxidant response element was activated in response to indole-3-carbinol (I3C) and chlorpyrifos (CPF) and was able to bind with the xenobiotic sensor protein nuclear factor erythroid-derived 2-related factor 2 (SlNrf2). SlNrf2 and Slgste1 were responsive to reactive oxygen species induced by I3C and CPF in a S. litura cell line, as well as in S. litura midguts. SlNrf2 RNA interference (RNAi) reduced the message RNA levels of Slgste1 and the peroxidase activity of GSTs in response to I3C, xanthotoxin, CPF and deltamethrin. SlNrf2 RNAi and inhibitor treatment of GST activity decreased the viability of I3C-treated cells. These results indicate that SlNrf2 activates the expression of GSTs in response to oxidative stresses caused by exposure to xenobiotics.

Electron-lattice energy relaxation in laser-excited thin-film Au-insulator heterostructures studied by ultrafast MeV electron diffraction.

We apply time-resolved MeV electron diffraction to study the electron-lattice energy relaxation in thin film Au-insulator heterostructures. Through precise measurements of the transient Debye-Waller-factor, the mean-square atomic displacement is directly determined, which allows to quantitatively follow the temporal evolution of the lattice temperature after short pulse laser excitation. Data obtained over an extended range of laser fluences reveal an increased relaxation rate when the film thickness is reduced or the Au-film is capped with an additional insulator top-layer. This behavior is attributed to a cross-interfacial coupling of excited electrons in the Au film to phonons in the adjacent insulator layer(s). Analysis of the data using the two-temperature-model taking explicitly into account the additional energy loss at the interface(s) allows to deduce the relative strength of the two relaxation channels.

Measurements of ionization states in warm dense aluminum with betatron radiation.

Time-resolved measurements of the ionization states of warm dense aluminum via K-shell absorption spectroscopy are demonstrated using betatron radiation generated from laser wakefield acceleration as a probe. The warm dense aluminum is generated by irradiating a free-standing nanofoil with a femtosecond optical laser pulse and was heated to an electron temperature of ∼20-25 eV at a close-to-solid mass density. Absorption dips in the transmitted x-ray spectrum due to the Al^{4+} and Al^{5+} ions are clearly seen during the experiments. The measured absorption spectra are compared to simulations with various ionization potential depression models, including the commonly used Stewart-Pyatt model and an alternative modified Ecker-Kröll model. The observed absorption spectra are in approximate agreement with these models, though indicating a slightly higher state of ionization and closer agreement for simulations with the modified Ecker-Kröll model.

[Cost-effectiveness of multiple screening modalities on breast cancer in Chinese women from Shanghai].

Objective: To determine the most cost-effective modality for breast cancer screening in women living in Shanghai. Methods: A Markov model for breast cancer was redeveloped based on true effect which was derived from a project for detection of women at high risk of breast cancer and an organized breast cancer screening program conducted simultaneously in Minhang district, Shanghai, during 2008 to 2012. Parameters of the model were derived from literatures. General principles related to cost-effectiveness analysis were used to compare the costs and effects of 12 different screening modalities in a simulated cohort involving 100 000 women aged 45 years. Incremental cost-effectiveness ratio (ICER) was used to determine the most cost-effective modality. Sensitivity analysis was conducted to evaluate how these factors affected the estimated cost-effectiveness. Results: The modality of biennial CBE followed by ultrasonic and mammography among those with positive CBE was observed as the most cost-effective one. The costs appeared as 182 526 Yuan RMB per life year gained and 144 386 Yuan RMB per quality adjusted life-year (QALY) saved, which were within the threshold of 2-3 times of local per capita Gross Domestic Product. Results from sensitivity analysis showed that, due to higher incidence rate of breast cancer in Shanghai, the cost per QALY would be 64 836 Yuan RMB lower in Shanghai than the average level in China. Conclusion: Our research findings showed that the biennial CBE program followed by ultrasonic and mammography for those with positive CBE results might serve as the optimal breast cancer screening modality for Chinese women living in Shanghai, and thus be widely promoted in this population elsewhere.

Relationship between quantum speed limit time and memory time in a photonic-band-gap environment.

Non-Markovian effect is found to be able to decrease the quantum speed limit (QSL) time, and hence to enhance the intrinsic speed of quantum evolution. Although a reservoir with larger degree of non-Markovianity may seem like it should cause smaller QSL times, this seemingly intuitive thinking may not always be true. We illustrate this by investigating the QSL time of a qubit that is coupled to a two-band photonic-band-gap (PBG) environment. We show how the QSL time is influenced by the coherent property of the reservoir and the band-gap width. In particular, we find that the decrease of the QSL time is not attributed to the increasing non-Markovianity, while the memory time of the environment can be seen as an essential reflection to the QSL time. So, the QSL time provides a further insight and sharper identification of memory time in a PBG environment. We also discuss a feasible experimental realization of our prediction.