Intrapulmonary Inoculation of Multicellular Tumor Spheroids to Construct an Orthotopic Lung Cancer Xenograft Model that Mimics Four Clinical Stages of Non-small Cell Lung Cancer

Lung cancer leads in mortality among all types of cancer in the US and Non-small cell lung cancer (NSCLC) is the major type of lung cancer. Immuno-compromised mice bearing xenografts of human lung cancer cells represent the most common animal models for studying lung cancer biology and for evaluating potential anticancer agents. However, orthotopic lung cancer models based on intrapulmonary injection of suspended cancer cells feature premature leakage of the cancer cells to both sides of the lung within five days, which generates a quick artifact of metastasis and thus belies the development and progression of lung cancer as seen in the clinic. Based on intrapulmonary inoculation of multicellular spheroids (MCS), we have developed the first orthotopic xenograft model of lung cancer that simulates all four clinical stages of NSCLC progression in mice over one month: Stage 1 localized tumor at the inoculation site; Stage 2 multiple tumor nodules or larger tumor nodule on the same side of the lung; Stage 3 cancer growth on heart surface; and Stage 4 metastatic cancer on both sides of the lung. The cancer development was monitored conveniently by in vivo fluorescent imaging and validated by open-chest anatomy, ex vivo fluorescent imaging, and histological studies. The model enjoys high rates of postoperative survival (100%) and parenchymal tumor establishment (88.9%). The roughness of the inoculated MCS is associated negatively with the time needed to develop metastatic cancer (p=0.0299). In addition, we have constructed a co-culture MCS that consisted of A549-iRFP lung cancer cells and WI38 normal human fibroblast cells. The pro-proliferation effect and the high expression of α-smooth muscle actin (α-SMA) by the co-cultured WI38 cells indicated their transformation from normal fibroblasts to cancer-associated fibroblasts (CAFs). The morphology of the co-culture MCS features a round shape, a tight internal structure, and quicker development of roughness. The large roughness value of co-culture MCS suggests that small co-culture MCS could be inoculated into mice lung with a small needle to reduce the surgical trauma. Taken together, a new orthotopic model of NSCLC has been developed, which would facilitate future development of medications against lung cancer

Unconventional superconducting gap in NaFe0.95_{0.95}Co0.05_{0.05}As observed by angle-resolved photoemission spectroscopy

We have performed high resolution angle-resolved photoemission measurements on superconducting electron-doped NaFe$_{0.95}$Co$_{0.05}$As ($T_{c}\sim$18 K). We observed a hole-like Fermi surface around the zone center and two electron-like Fermi surfaces around the M point which can be connected by the $Q=(\pi, \pi)$ wavevector, suggesting that scattering over the near-nested Fermi surfaces is important to the superconductivity of this "111" pnicitide. Nearly isotropic superconducting gaps with sharp coherent peaks are observed below $T_c$ on all three Fermi surfaces. Upon increasing temperature through $T_c$, the gap size shows little change while the coherence vanishes. Large ratios of $2\Delta/k_{B}T_{c}\sim8$ are observed for all the bands, indicating a strong coupling in this system. These results are not expected from a classical phonon-mediated pairing mechanism.Comment: 4 pages, 4 figure

Small anisotropy of the lower critical field and s±s_\pm-wave two-gap feature in single crystal LiFeAs

The in- and out-of-plane lower critical fields and magnetic penetration depths for LiFeAs were examined. The anisotropy ratio $\gamma_{H_{c1}}(0)$ is smaller than the expected theoretical value, and increased slightly with increasing temperature from 0.6$T_c$ to $T_c$. This small degree of anisotropy was numerically confirmed by considering electron correlation effect. The temperature dependence of the penetration depths followed a power law($\sim$$T^n$) below 0.3$T_c$, with $n$$>$3.5 for both $\lambda_{ab}$ and $\lambda_c$. Based on theoretical studies of iron-based superconductors, these results suggest that the superconductivity of LiFeAs can be represented by an extended $s_\pm$-wave due to weak impurity scattering effect. And the magnitudes of the two gaps were also evaluted by fitting the superfluid density for both the in- and out-of-plane to the two-gap model. The estimated values for the two gaps are consistent with the results of angle resolved photoemission spectroscopy and specific heat experiments.Comment: 10 pages, 5 figure

Prevalence, risk factors, outcomes, and molecular epidemiology of mcr-1 -positive Enterobacteriaceae in patients and healthy adults from China: an epidemiological and clinical study

Background The mcr-1 gene confers transferable colistin resistance. mcr-1-positive Enterobacteriaceae (MCRPE) have attracted substantial medical, media, and political attention; however, so far studies have not addressed their clinical impact. Herein, we report the prevalence of MCRPE in human infections and carriage, clinical associations of mcr-1-positive Escherichia coli (MCRPEC) infection, and risk factors for MCRPEC carriage. Methods We undertook this study at two hospitals in Zhejiang and Guangdong, China. We did a retrospective cross-sectional assessment of prevalence of MCRPE infection from isolates of Gram-negative bacteria collected at the hospitals from 2007 to 2015 (prevalence study). We did a retrospective case-control study of risk factors for infection and mortality after infection, using all MCRPEC from infection isolates and a random sample of mcr-1-negative E coli infections from the retrospective collection between 2012 and 2015 (infection study). We also did a prospective case-control study to assess risk factors for carriage of MCRPEC in rectal swabs from inpatients with MCRPEC and mcr-1 negative at the hospitals and collected between May and December, 2015, compared with mcr-1-negative isolates from rectal swabs of inpatients (colonisation study). Strains were analysed for antibiotic resistance, plasmid typing, and transfer analysis, and strain relatedness. Findings We identified 21 621 non-duplicate isolates of Enterobacteriaceae, Acinetobacter spp, and Pseudomonas aeruginosa from 18 698 inpatients and 2923 healthy volunteers. Of 17 498 isolates associated with infection, mcr-1 was detected in 76 (1%) of 5332 E coli isolates, 13 (<1%) of 348 Klebsiella pneumoniae, one (<1%) of 890 Enterobacter cloacae, and one (1%) of 162 Enterobacter aerogenes. For the infection study, we included 76 mcr-1-positive clinical E coli isolates and 508 mcr-1-negative isolates. Overall, MCRPEC infection was associated with male sex (209 [41%] vs 47 [63%], adjusted p=0·011), immunosuppression (30 [6%] vs 11 [15%], adjusted p=0·011), and antibiotic use, particularly carbapenems (45 [9%] vs 18 [24%], adjusted p=0·002) and fluoroquinolones (95 [19%] vs 23 [30%], adjusted p=0·017), before hospital admission. For the colonisation study, we screened 2923 rectal swabs from healthy volunteers, of which 19 were MCRPEC, and 1200 rectal swabs from patients, of which 35 were MCRPEC. Antibiotic use before hospital admission (p<0·0001) was associated with MCRPEC carriage in 35 patients compared with 378 patients with mcr-1-negative E coli colonisation, whereas living next to a farm was associated with mcr-1-negative E coli colonisation (p=0·03, univariate test). mcr-1 could be transferred between bacteria at high frequencies (10−1 to 10−3), and plasmid types and MCRPEC multi-locus sequence types (MLSTs) were more variable in Guangdong than in Zhejiang and included the human pathogen ST131. MCRPEC also included 17 unreported ST clades. Interpretation In 2017, colistin will be formally banned from animal feeds in China and switched to human therapy. Infection with MRCPEC is associated with sex, immunosuppression, and previous antibiotic exposure, while colonisation is also associated with antibiotic exposure. MLST and plasmid analysis shows that MCRPEC are diversely spread throughout China and pervasive in Chinese communities

Air-Fuel Ratio Control of Spark Ignition Engines With Unknown System Dynamics Estimator: Theory and Experiments

This brief addresses the emission reduction of spark ignition engines by proposing a new control to regulate the air-fuel ratio (AFR) around the ideal value. After revisiting the engine dynamics, the AFR regulation is represented as a tracking control of the injected fuel amount. This allows to take the fuel film dynamics into consideration and simplify the control design. The lumped unknown engine dynamics in the new formulation are online estimated by suggesting a new effective unknown system dynamics estimator. The estimated variable can be superimposed on a commercially configured, well-calibrated gain scheduling like proportional-integral-differential (PID) control to achieve a better AFR response. The salient feature of this proposed control scheme lies in its simplicity and the small number of required measurements, that is, only the air mass flow rate, the pressure and temperature in the intake manifold, and the measured AFR value are used. Practical experiments on a Tata Motors Limited two-cylinder gasoline engine are carried out under a realistic driving cycle. The comparative results show that the proposed control can achieve an improved AFR control response and reduced emissions

Multi-H∞ controls for unknown input-interference nonlinear system with reinforcement learning

This article studies the multi-H∞ controls for the input-interference nonlinear systems via adaptive dynamic programming (ADP) method, which allows for multiple inputs to have the individual selfish component of the strategy to resist weighted interference. In this line, the ADP scheme is used to learn the Nash-optimization solutions of the input-interference nonlinear system such that multiple H∞ performance indices can reach the defined Nash equilibrium. First, the input-interference nonlinear system is given and the Nash equilibrium is defined. An adaptive neural network (NN) observer is introduced to identify the input-interference nonlinear dynamics. Then, the critic NNs are used to learn the multiple H∞ performance indices. A novel adaptive law is designed to update the critic NN weights by minimizing the Hamiltonian-Jacobi-Isaacs (HJI) equation, which can be used to directly calculate the multi-H∞ controls effectively by using input-output data such that the actor structure is avoided. Moreover, the control system stability and updated parameter convergence are proved. Finally, two numerical examples are simulated to verify the proposed ADP scheme for the input-interference nonlinear system