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We aimed to study the clinical characteristics and biological indicators of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis with different severity levels to explore factors predicting disease severity at admission. Using the modified Rankin scale (mRS), patients were divided into mild-to-moderate group (mRS ≤ 3) and severe group (mRS > 3) on admission based on severity of illness. General information, previous history, premonitory symptoms, clinical manifestations before admission, imaging findings and biochemical tests were compared to explore the clinical manifestations and biological indicators related to the severity of illness at admission. In the severe group, the incidences of fever, anti-infective therapy, generalized seizures, consciousness disorder, blood white blood cell, neutrophils, and neutrophil–lymphocyte ratio (NLR) were higher than those in mild-to-moderate group (P

Infection and/or drug-mediated acute liver injury, the leading cause of lethal liver failure, is a critical health problem worldwide and lacks effective treatment. Here, we used Lipopolysaccharides (LPS)/D-galactosamine (D-gal)-treated primary hepatocytes to screen a natural library that contains 1130 chemicals. Baicalein in the library showed highest inhibitory effects against LPS/D-Gal-induced liver injury. In-vivo study similarly validated the protection of baicalein against dampened liver function and increased lethality after a challenge of LPS/D-Gal. Using a cytometric bead array, we found that IL-1α and IL-1β, the downstream of NLRP3, had highest reduction among the plasma inflammatory cytokines in LPS/D-Gal-challenged mice after a treatment of baicalein. To determine the target of baicalein and the underlying mechanism, Nlrp3-/-, Gsdmd-/- or WT mice were treated with or without baicalein, IL-1R antibody or recombinant mouse IL-1β (rmIL-1β) prior to a challenge of LPS/D-Gal. Deficiency of Nlrp3 or Gsdmd significantly restored LPS/D-Gal-induced acute liver injury and lethality, and further administration of baicalein did not have additive effects. In addition, the inhibition of the downstream by IL-1R antibody phenocopied the knockout of Nlrp3 or Gsdmd. Moreover, a challenge of rmIL-1β reversed the improvement in Nlrp3-/- mice or the mice treated with baicalein. Taken together, NLRP3 functions as a pivotal promoter in acute liver injury and baicalein attenuates acute liver injury by inhibiting NLRP3 inflammasome.

The application of big data puts forward new requirements for the talent training mode and curriculum reform of big data in higher vocational colleges. Through statistical data, the classroom quality can be measured, evaluated and traced. Under the framework of “Internet plus big data”, taking the cultivation of innovative ability as the core, realizing the multidimensional integration of technology and science, general knowledge and specialty, teaching and research, and teachers and students has become a new concept and Practice for improving the quality of big data talents training in higher vocational colleges. Obstetrics and gynecology nursing is one of the core courses of nursing specialty in higher vocational colleges, which is of great significance to the cultivation of professional talents. The purpose of nursing specialty in higher vocational colleges is to cultivate skilled and technical applied talents to meet the needs of medical and health posts, which requires the combination of theoretical knowledge and practical skills, so as to cultivate students’ clinical thinking and ability. There are some problems in the course design of Obstetrics and gynecology nursing in higher vocational colleges, such as the derailment of theoretical teaching and practical teaching, teaching materials lagging behind the update of clinical skills, students’ low learning initiative, single teaching mode and so on. Based on the OBE teaching concept from the perspective of big data, this paper carries out curriculum design, curriculum implementation and Curriculum Evaluation Guided by students’ learning achievements, and through the reverse design of achievements, highlights the student-centered, quantifies teaching output, and cultivates students’ learning ability and creativity. By reasonably mobilizing students’ learning initiative, students can achieve “self-education, self-management, self-service, and common improvement”, so as to improve the teaching quality of this course, improve students’ clinical skills, promote the self-development of teachers and students, and realize the “winwin” of education.

The structural displacement profile is vital for determining the equivalent single degree-of-freedom system parameters and the distribution of design lateral forces in the Direct Displacement-based Design (DDBD). In this paper, adaptive pushover analyses are conducted for 66 RC frame structures with various configurations and design parameters to calculate the lateral displacement, and the changing law of plastic hinge distribution and deformation mechanism of RC frame structures is investigated. Based on the analysis results, a refined displacement profile expression is proposed where the effect of elastic first order mode, maximum interstory drift, column-to-beam strength ratio, height-width ratio and the drift at first plastic hinge formation are involved. Its accuracy and reliability are validated by compared with the results of nonlinear time history analyses. Finally, an example is provided to illustrate the application of the proposed displacement profile expression in design considering multiple performance objectives.

Non-negative matrix factorization (NMF) is an effective technique for feature representation learning and dimensionality reduction. However, there are two critical challenges for improving the performance of NMF-based methods. One is the sparsity of representation, the other is the sensitivity to the initial value of the iteration, which seriously affects the performance of NMF. To solve the problems, L1/2 regularization is skillfully selected to characterize the sparsity of the data. Furthermore, a layer-wise pre-training strategy in deep learning is used to alleviate the effect of the initial value on NMF, whereby complex network structure is avoided. As such, a L1/2 regularization-based deep NMF (L1/2-DNMF) model is proposed in this study, such that a more stable and sparse deep representation is obtained. Moreover, incremental learning is introduced to reduce the high computational complexity of L1/2-DNMF model, called L1/2-DINMF model, which is suitable for online processing. Experiment results on genetic data-based tumor recognition verify that the proposed L1/2-DINMF model outperforms the classic and state-of-the-art methods.

We demonstrate the ultra-stable microwave frequency sources aiming to improve the short time instability of primary frequency standards. These sources are realized by using photonic generation approach, and composed of ultra-stable lasers, optical frequency combs, and optical signal detecting parts. This paper reported a 48th harmonic (9.6 GHz) of optical frequency comb is photodetected by a balanced optical-microwave phase detector with frequency instability of 2.8×10-15 @ 1s. Further improvement is undergoing.

Objectives: Autonomic dysfunction is a common symptom of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis; however, it has been poorly researched. The purpose of this study was to compare the clinical features, tumor occurrence, intensive care unit (ICU) admission, mechanical ventilation, imaging assessment, cerebrospinal fluid examination, disease severity, and immunotherapy in patients with anti-NMDAR encephalitis with or without autonomic dysfunction.Methods: A retrospective study of anti-NMDAR encephalitis patients diagnosed between January 2016 and April 2020 was performed at the First Affiliated Hospital of Zhengzhou University. Patients were divided into two groups according to whether they had autonomic dysfunction, and their clinical features, treatment, and prognosis were compared.Results: A total of 119 patients with anti-NMDAR encephalitis were included in this study. Seventy-three patients (61.3%) had autonomic dysfunction, while the remaining 46 (38.7%) did not. Sinus tachycardia (69.9%) was the autonomic dysfunction with the highest incidence, while the incidences of symptoms including constipation, central hypopnea, and others gradually decreased. Compared to the group without autonomic dysfunction, the prevalence of the main clinical symptoms such as epileptic seizure (P = 0.003), involuntary movement (P = 0.028), and decreased consciousness (P < 0.001) were higher in the group with autonomic dysfunction, which also more frequently presented with complications such as pulmonary infection (P < 0.001) and abnormal liver function (P = 0.001). Moreover, the rates of ICU admission (P < 0.001) and mechanical ventilation (P = 0.001), as well as the modified Rankin scale (mRS) scores at admission (P < 0.001), maximum mRS scores during the course of disease (P < 0.001), and mRS scores at discharge (P < 0.001) were higher in the patients with autonomic dysfunction than in those without. The number of patients in the autonomic dysfunction group who underwent ≥2 immunotherapies was also higher than that in the group without autonomic dysfunction (P < 0.001).Conclusion: Sinus tachycardia is the most common type of autonomic dysfunction in anti-NMDAR encephalitis. Compared to patients without autonomic dysfunction, those with autonomic dysfunction had a higher incidence of epilepsy, involuntary movements, decreased consciousness, pulmonary infections, abnormal liver function, ICU admissions, and mechanical ventilation; moreover, the severity of the disease was greater, and their prognosis worse. Therefore, such patients require intensive immunotherapy.

The assessment of the seismic performance of reinforced concrete (RC) frame structures using the equivalent linearization approach requires comprehensive insight into the nonlinear response of the system, and most previous researches focused on the analysis of a single-degree-of-freedom (SDOF) system. To describe the hysteretic behavior of a multi-degree-of-freedom (MDOF) system accurately, monotonic and cyclic pushover analyses for 88 RC frames structures with various configurations and design parameters are carried out and a unified hysteresis loop expression modeling the cyclic pushover results of RC frame system is developed. Then, a global equivalent damping based on Jacobsen's approach is derived, and comparisons between the displacements obtained by nonlinear static analysis (NSA) utilizing the derived global equivalent damping and those obtained by nonlinear time history analysis (NTHA) are made. Finally, a modified global equivalent damping is presented by calibrating the derived Jacobsen's equivalent damping through NTHA results. Based on the modified equivalent damping, the statistical analysis of the ratios of the results obtained by NTHA to those obtained by NSA is implemented to predicate the probabilistic seismic displacement demands of RC frame structures.

Background The aim of this study was to explore the prognostic value of copeptin for predicting all-cause mortality in heart failure (HF). Methods PubMed, Embase and Cochrane databases were systematically searched to identify if a 2 × 2 contingency table could be constructed based on both the copeptin level and the all-cause mortality in patients diagnosed with HF. The characteristics of test performance were summarized using forest plots and summary receiver operating characteristic curves (SROC). Q-test and I2 index were used to evaluate heterogeneity. Results Ten prospective cohort studies comprising 4473 patients were eligible in this meta-analysis. An elevated copeptin level was associated with an increased risk of all-cause mortality in HF patients (Relative risk (RR) was 2.64 (95% CI, 2.09–3.32)). The pooled sensitivity (SEN) and specificity (SPE) of copeptin were 0.57 (95% CI, 0.50–0.63) and 0.74 (95% CI, 0.69–0.79), respectively. The positive likelihood ratio was 2.2 (95% CI, 1.90–2.60) and the negative likelihood ratio was 0.58 (95% CI, 0.52–0.66). Furthermore, the summary Diagnostic Odds Ratio (DOR) was 4.00 (95% CI, 3.00–5.00) and the AUC was 0.70 (95% CI, 0.66–0.74) similar to the AUC of NT-proBNP 0.71 (95% CI, 0.67–0.75). Conclusions Elevated levels of copeptin are associated with all-cause mortality in HF patients. The predictive value of copeptin is comparable with NT-proBNP for all-cause mortality in HF patients. Further studies are warranted to explore the prognostic value of copeptin in conjunction with other biomarkers and to determine an optimal cut-off level.

The Kumamoto oyster (Crassostrea sikamea) and the Portuguese oyster (C. angulata) are important aquaculture species which naturally coexist along the southern coast of China. To understand the potential feasibility of hybridization between the two species, we conducted two-by-two factorial cross-experiments in Beihai (Guangxi province), and also compared the survival and growth of the hybrids to that of the two parental progenies during the grow-out period from July 2014 to July 2015. Genetic analysis confirmed that the hybrid spats were true hybrids. Additionally, the biochemical composition of the 1-year-old oyster progenies was determined. In July 2015, the mean shell height of the hybrids was 42.98 ± 6.29 mm, which was higher than that of the Kumamoto oyster progeny. The cumulative survival rate of the hybrids was 26.37 ± 1.32%, which was higher than that of the progeny of the Portuguese oyster. Mean lipid content of the hybrids was 13.65 ± 1.63% of dry weight, which showed obvious heterosis compared to those of the two parental progenies. Observation of gonads revealed that all hybrids were completely fertile. Furthermore, relative expression of the lipid homeostasis genes, SREBP (sterol regulatory element-binding proteins), PPARα (peroxisome proliferator-activated receptor) and INSIG (insulin-induced gene) were found to vary between parental progenies and the hybrids, thus providing a possible reason for difference in the lipid contents of these experimental groups. Overall, the hybrids were viable, rich in lipid and completely fertile and thus could serve as a promising aquaculture stock for oyster breeding in southern China.

An all polarization-maintaining Er:fiber frequency comb based on nonlinear amplifying loop mirror with 136-MHz repetition frequency is demonstrated. The in-loop instabilities of the repetition rate and carrier-envelope-offset frequency are 2.9x10-13 and 1.7x10-18 at 1 s respectively.

International audience; Chinese solar greenhouses (CSGs) play an important role in horticultural development, providing high-efficiency thermal storage performance compared to the other greenhouse styles. CGSs are fully passive solar greenhouses for vegetables without auxiliary heating system during the winter. To improve the thermal environmental conditions of CSGs and produce better crops, some strategies have been investigated to improve the thermal environments. In this study, a comprehensive review is presented focusing on key strategies for improving the thermal environment in CSGs. The technologies considered within the scope of this research are mainly renewable and sustainable solutions such as structures (sunken CSG, variable south roof CSG, air channel heat exchange CSG), options for north wall materials (hollow wall, pebble wall, phase-change materials), and equipment for thermal storage (water circulation thermal storage, energy-efficient heat pump thermal storage, photovoltaic thermal storage). These new findings revealed that through the application of a single strategy or synergistic strategies, we can maximize the utilization of renewable and sustainable energy to provide indoor heating. This review also provides a reference for design, application and research on thermal storage and energy-saving strategies for CSGs.

We report on a demonstration of a long-distance microwave frequency dissemination, in which the so-called Doppler cancellation technique is used to compensate the optical link phase noise. The 10-GHz signal is transferred through a 50km optical fiber spool with fractional frequency instability of $8.1 \times 10^{-15}$ at 1-s integration time and $1.7 \times 10^{18}$ at 8192-s integration time.

We demonstrate 9.192 GHz microwave signals from photonic microwave generation based on Er:fiber-based optical frequency combs and $1.55 \mu \mathrm {m}$ ultra-stable lasers, which used for local oscillators of cesium fountain clock. The frequency instability of the 9.63 GHz/9.54 GHz microwave signals is $3 \times 10^{-15} \text{@}$ 1s, with phase noise is of -94 dB rad2/Hz @ 1 Hz, and the synthesized tunable 9.192 GHz signal exhibits an instability of $6.7 \times 10^{-15}$ @1s. Further improvement of the photonic oscillators is undergoing.

We report on a robust mode-locked femtosecond fiber laser based on a nonlinear optical mirror with all polarization-maintaining fibers. Stable and self-starting operation is obtained by exploiting an integrated nonreciprocal device biases $\pi$/2 phase shift. In the single-pulse region, the laser directly generates output power of 3.15 mW at repetition rate of 87.7 MHz, corresponding to the pulse energy of 37 pJ. The center wavelength is 1585 nm with the spectral bandwidth of 25 nm at the maximum output power. We also evaluate the relative intensity noise of the mode-locking laser.

We demonstrate a multi-branch all polarization-maintaining Er:fiber frequency comb with five application ports for precise measurement of atomic/molecular transition frequencies in the near-infrared region. A fully stabilized Er:fiber frequency comb with a nonlinear amplifying loop mirror is achieved. The in-loop relative instability of stabilized carrier-envelope-offset frequency is 5.6 × 10−18 at 1 s integration time, while that of the repetition rate is well below 1.8 × 10−12 limited by the measurement noise floor of the commercial frequency counter. Five application ports are individually optimized for applications with different wavelengths (1064 nm, 1083 nm, 1380 nm, 1637 nm and 1750 nm). The beat note between the optical frequency comb and continuous laser exhibits the signal-to-noise ratio of at least 30 dB at a resolution bandwidth of 100 kHz. The in-loop frequency instability of the comb is evaluated to be good enough for measurement of rotation-resolved transitions of molecules below 1 kHz resolution.

We report on the progress of the thermal noise further reduced method via enlarging the equivalent beam size without increasing the cavity length in cavity-stabilized lasers at 1555 nm, which are built as the frequency source for a photonic microwave generation system. In addition, we perform an experiment to evaluate the effect of thermal noise reduced method via estimating the frequency instability of a synthesized new ultrastable laser. The relative frequency instability reaches 5∗10−16 at 1 s averaging time via reducing the thermal noise of the cavity.

In this paper, we demonstrate two techniques to improve performance of Er:fiber frequency combs at NTSC. the first technique is to obtain a robustness and low noise laser, we combine the nonlinear polarization rotation (NPR) and the nonlinear amplifying loop mirror (NALM) mechanisms to a single system. the laser has a large mode-locking range and can self-starting. It works normally after being unpowered six months, and the noise level is similar to the pure NPR. The second technique is proposed a broad bandwidth and large range frequency control method by tuning the polarization state. A special-designed electro-optic modulator (EOM) is used to rotate the polarization state in the NPR system. Compared with the traditional EOM, the sensitivity offr to the electric field intensity applied to the EOM is about 100 times larger.

Background Pediatric cataract is a clinically and genetically heterogeneous disease which is a significant cause of lifelong visual impairment and treatable blindness. Our study aims to investigate the genotype spectrum in a group of Chinese patients with pediatric cataract. Methods We enrolled 39 families with pediatric cataract from October 2015 to April 2016. DNA samples of the probands were analyzed by target next-generation sequencing. Variants were validated using Sanger sequencing in the probands and available family members. Results In our cohort of 39 cases with different types of pediatric cataract, 23 cases were found to harbor putative pathogenic variants in 15 genes: CRYAA, CRYBA1, CRYBA4, CRYBB1, CRYGC, CRYGD, MIP, GCNT2, IARS2, NHS, BCOR, BFSP2, FYCO1, MAF, and PAX6. The mutation detection rates in the familial and sporadic cases were 75 and 47.8%, respectively. Of the 23 causative variants, over half were novel. Conclusions This is a rare report of systematic mutation screening analysis of pediatric cataract in a comparably large cohort of Chinese patients. Our observations enrich the mutation spectrum of pediatric cataract. Next-generation sequencing provides significant diagnostic information for pediatric cataract cases, especially when considering sporadic and subtle syndromal cases. Electronic supplementary material The online version of this article (10.1186/s13023-018-0828-0) contains supplementary material, which is available to authorized users.

We report on supercontinuum generation in four types of highly-nonlinear-fibers (HNLFs) pumped by 1.56-μm laser solitons. Experimental measurement results provide guidelines for choosing and using HNLFs for erbium-fiber-based optical frequency combs and their applications.

An Er:fiber-based femtosecond laser employing nonlinear amplifier loop mirror (NALM)and nonlinear polarization evolution (NPE)mode-locking mechanisms is demonstrate. The hybrid laser combines advantages of good robustness of NALM and low noise feature of NPE.

We demonstrate a frequency control approach of a nonlinear-polarization-rotation mode-locked Er:fiber laser by rotating polarization state with an intro-cavity electro-optic polarization modulator, enabling a large scale high bandwidth frequency control.

We demonstrate an optical frequency comb in which an Er:fiber-based femtosecond laser employs nonlinear amplifier loop mirror (NALM) and nonlinear polarization evolution (NPE) mode-locking mechanisms. The laser combines advantages of good robustness of NALM and low noise feature of NPE. Our experimental results show that the hybrid mode-locked laser has high power, low relative intensity noise and self-started property, enabling the construction of a robust optical frequency comb system. In-loop relative instabilities of both stabilized repetition rate and carrier-envelope-offset frequency are well below 1 × 10-17 at 1 second integration time.

Background To determine the factors affecting the in-hospital prognosis of patients with acute ST segment elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI), and to establish its prognostic discriminant model. Methods A total of 701 consecutive STEMI patients undergoing PCI were enrolled in this study. The patients were divided into two groups, good prognosis and poor prognosis, based on whether the patient had adverse outcomes (death or heart function ≥ grade III) at discharge. Demographic and basic clinical characteristics, diagnosis at admission (e.g., ventricular function, complications, or hyperlipidemia), and biomedical indicators (e.g., blood count, basal metabolism and biochemical composition, blood lipid and glucose levels, myocardial biomarkers, and coagulation) were collected and analyzed. Results We determined 22 factors as risk factors for the in-hospital prognosis of STEMI patients after PCI: age, cardiac function during hospitalization, complications, history of diabetes mellitus, et al., among which the history of diabetes, uric acid, urea nitrogen, and activated partial thromboplastin time (APTT) were independent risk factors. Conclusion We identified four independent risk factors for the in-hospital prognosis of STEMI patients after PCI and generated a prognostic model to predict the adverse outcomes of these patients.

We report photonic microwave generation based on Er:fiber-based optical frequency combs and 1.55 μm ultra-stable lasers. The frequency instability of the 9.6 GHz microwave signals is 3 × 10−15@ 1s, and the synthesized tunable 9.192 GHz signal exhibits an instability of 6.7×10−15 @1s. Further improvement of the photonic oscillators is undergoing.

We present the designs and performances of cavity-stabilized lasers at 1555 nm, which are built as the frequency source for a transportable photonic microwave generation system. The frequency instability reaches the thermal noise limit of 10 cm-long vertically held cavity of 7×10−16 at 1 s averaging time, and the beat signal of the two lasers reveals a remarkable linewidth of 185 mHz.

This study was to investigate the utility of platelet-derived microparticles (PMPs) to detect coronary intermediate lesions. Fifty-two patients with coronary intermediate lesions and 24 subjects with normal coronary arteries were enrolled. In the former group, 31 patients accepted both intravenous ultrasound (IVUS) and fractional flow reserve (FFR). Results showed that the level of PMPs was significantly higher in the intermediate lesion group and PMPs titer was positively correlated with thromboxane B2, platelet activating factor, endothelin-1, and neutrophil to lymphocyte ratio. The level of PMPs also increased after IVUS/FFR, suggesting platelet activation and endothelial dysfunction.

Highly nonlinear fibers (HNLFs) are crucial components for supercontinuum (SC) generation with laser solution. However, it is difficult to exactly estimate the structure of produced SC according to material parameters. To give a guideline for choosing and using HNLFs for erbium-fiber-based optical applications, we demonstrate SC generation in five types of HNLFs pumped by 1.57- μ m laser solitons. All five fibers output a SC exceeding 1000 nm. Three different SC formation processes were observed in the experiment. By comparing optical parameters of these fibers, we find the zero dispersion wavelength (ZDW) of fiber has an important influence on the SC structure and energy distribution for a given pump source.

The myelodysplastic syndromes (MDS) are often diagnosed in outpatient clinics and may be under-reported to state cancer registries, which predominantly rely on hospital records and laboratory reports. We used a new method of cancer case capture to determine the rate of missed cases and estimate a more accurate incidence of MDS. Using a unique keyword algorithm, we queried all electronic pathology (E-path) reports sent to the state of Florida cancer registry in 2006 to identify potential MDS cases. A stratified, random sample of E-path reports was then reviewed to confirm diagnosis and assign MDS subtype. Characteristics were compared between captured and uncaptured MDS cases. 7111 E-path reports with MDS keyword hits were identified, of which only 18% linked to a registered MDS case, 47% linked to a different cancer, and 34% did not link with any record. Case review of a stratified, random sampling of 285 individuals led to the discovery that uncaptured cases made up 37.7% of the total true MDS cases in 2006. It is estimated that the true incidence of MDS is 5.3 individuals out of 100,000, compared to previous reports of 3.3 out of 100,000. Uncaptured MDS cases were younger and more likely to have information in the pathology report facilitating MDS subtype assignment. Only two-thirds of true MDS cases are captured in Florida using current case-finding mechanisms. Application of a keyword search strategy to identify cases among E-path reports is a feasible technique to improve MDS case ascertainment.

The vasculature forms a highly branched network investing every organ of vertebrate organisms. The retinal circulation, in particular, is supported by a central retinal artery branching into superficial arteries, which dive into the retina to form a dense network of capillaries in the deeper retinal layers. The function of the retina is highly dependent on the integrity and proper functioning of its vascular network and numerous ocular diseases including diabetic retinopathy, age-related macular degeneration and retinopathy of prematurity are caused by vascular abnormalities culminating in total and sometimes irreversible loss of vision. CCN1 and CCN2 are inducible extracellular matrix (ECM) proteins which play a major role in normal and aberrant formation of blood vessels as their expression is associated with developmental and pathological angiogenesis. Both CCN1 and CCN2 achieve disparate cell-type and context-dependent activities through modulation of the angiogenic and synthetic phenotype of vascular and mesenchymal cells respectively. At the molecular level, CCN1 and CCN2 may control capillary growth and vascular cell differentiation by altering the composition or function of the constitutive ECM proteins, potentiating or interfering with the activity of various ligands and/or their receptors, physically interfering with the ECM-cell surface interconnections, and/or reprogramming gene expression driving cells toward new phenotypes. As such, these proteins emerged as important prognostic markers and potential therapeutic targets in neovascular and fibrovascular diseases of the eye. The purpose of this review is to highlight our current knowledge and understanding of the most recent data linking CCN1 and CCN2 signaling to ocular neovascularization bolstering the potential value of targeting these proteins in a therapeutic context.

The reduction of the residual amplitude modulation (RAM) induced by electro-optic modulation is essential for many applications of frequency modulation spectroscopy requiring a lower system noise floor. Here, we demonstrate a simple passive approach employing an electro-optic modulator (EOM) cut at Brewster's angle. The proposed EOM exhibits a RAM of a few parts per million, which is comparable with that achieved by a common EOM under critical active temperature and bias voltage controls. The frequency instability of a 10 cm cavity-stabilized laser induced by the RAM effect of the proposed EOM is below 3×10sup-17/supfor integration times from 1 to 1000 s, and below 4×10sup-16/supfor comprehensive noise contributions for integration times from 1 to 100 s.

We report a control method to stabilize frequencies of a nonlinear polarization rotation mode-locked laser by tuning polarization state with a home-made intra-cavity electro-optic modulator (EOM). The EOM rotates polarization state about 1.2 × 10−4 rad/v in ellipticity, and enables wide range frequency control of carrier-envelope-offset frequency (f ceo ) or repetition rate (f r ). By stabilizing the fr, fceo and a comb teeth @ 1550 nm with the EOM respectively, we obtain that frequency control dynamic ranges increase at least one order in comparison with the traditional intra-cavity EOM technique. In additional, this technique exhibits less side-effect than traditional frequency control methods.

Reduction of residual amplitude modulation (RAM) level induced by electro-optic modulation is important for frequency modulation (FM) technique to reach higher sensitivity. Here, we present a passive approach using a well-designed electro-optic modulator (EOM) to reduce the RAM. Although low RAM could be achieved by critical actively controls of temperature and voltage of a common EOM. This passive approach is more simple, reliable and easier to be realized. We evaluate the performance of such an EOM by comparing system noise level of a standard PDH frequency-stabilization system using this EOM with a commercial one with the addition of a good quality polarizer. RAM depth (versus phase modulation (PM) depth) of this EOM is at 10−6 level. Frequency instability induced by this EOM is below 1×10−16 @ 1s for our cavity-based ultra-stable laser, which is more than one order lower than the other.

We report a new method to precisely control carrier-envelope frequency (fceo) of a nonlinear-polarization-rotation mode-locked Er:fiber optical frequency comb. The fceo is phase-locked onto an RF reference frequency by rotating polarization state with a special home-made intra-cavity electro-optic modulator (EOM). The EOM is inserted right after the PBS of a well-known ring mode-locked laser's loop and rotates polarization state with a coefficient of about 1.2 × 10−4 rad/v in ellipticity. The frequency control range of the EOM is two orders of magnitude larger than the traditional ones. Benefiting from fast response of the EOM, in-loop frequency stabilities of the fceo is below 2×10−17 at 1 second, and the corresponding timing jitter is about 0.16 rad.

Reduction of residual amplitude modulation (RAM) level induced by electro-optic modulation is important for frequency modulation (FM) technique to reach higher sensitivity. Here, we present a passive approach to make a well-designed electro-optic modulator (EOM) with ultra-low RAM. Although low RAM could be achieved by critical actively controls of temperature and voltage of a common EOM. This passive approach is more simple, reliable and easier to be realized. We evaluate performance of such an EOM by comparing system noise level of a standard PDH frequency-stabilization system using this EOM with a commercial one with the addition of a good quality polarizer. RAM depth (versus phase modulation (PM) depth) of this EOM is at 10−6 level. Frequency instability induced by this EOM is below 1×10−16 @ 1s, which is more than one order lower than the other.

Purpose: To determine safety and feasibility of adjuvant ipilimumab following resection of high-risk melanoma and to identify surrogate markers for benefit. Experimental Design: In this phase II trial, 75 patients with resected stage IIIc/IV melanoma received the CTLA-4 antibody ipilimumab every 6 to 8 weeks for 1 year. Eligible patients received further maintenance treatments. The first 25 patients received 3 mg/kg of ipilimumab, and an additional 50 patients received 10 mg/kg. HLA-A*0201+ patients received multipeptide immunizations in combination with ipilimumab. Leukapheresis was performed prior to and 6 months after initiation of treatment. Results: Median overall and relapse-free survivals were not reached after a median follow-up of 29.5 months. Significant immune-related adverse events were observed in 28 of 75 patients and were positively associated with longer relapse-free survival. Antigen-specific T cell responses to vaccine were variable, and vaccine combination was not associated with additional benefit. No effects on T regulatory cells were observed. Higher changes in Th-17 inducible frequency were a surrogate marker of freedom from relapse (P = 0.047), and higher baseline C-reactive protein (CRP) levels were associated with freedom from relapse (P = 0.035). Conclusions: Adjuvant ipilimumab following resection of melanoma at high risk for relapse appeared to be associated with improved outcome compared to historical reports. Significant immune-related adverse events were generally reversible and appeared to be associated with improved relapse-free survival. Although vaccination failed to induce a consistent in vitro measurable response, a higher change in Th-17 inducible cells and higher baseline CRP levels were positively associated with freedom from relapse. Clin Cancer Res; 17(4); 896–906. ©2010 AACR.

We demonstrate the ultra-stable frequency sources aiming to improve the short-time instability of primary frequency standards. These sources are realized by using photonic generation approach, and composed of ultra-stable lasers, optical-frequency-combs, optical signal detecting parts, and synthesizers. Preliminary evaluation shows that the sources produce fixed-frequency at 9.54(/9.63) GHz, 10 MHz, and tunable-frequency around 9.192 GHz with relative frequency instability of 10−15 for short terms.

We report an erbium-fiber-based optical frequency comb, whose spectrum is broadened to Strontium clock. Signal-to-noise ration of the beatnote between the comb and Sr clock laser is up to 40 dB under 300 kHz resolution.

We report the research progress of an erbium-fiber-based optical frequency comb with repetition rate 232 MHz. Its repetition rate is stabilized to a continuous wave laser via an intra-cavity electro-optic modulator and a piezo-transducer, yielding an in-loop frequency instability about 2.1×10−16 @ 1s. The carrier envelope offset (CEO) frequency with a signal-to-noise ratio of 45 dB for 300 kHz resolution spectrum is detected by using a common path f−2f interferometer. CEO frequency is locked to a RF reference frequency by controlling the pump current. The frequency instability induced by in-loop CEO frequency is about 2.9×10−16@ 1s. The frequency count in use is a Π-type counter from K&K.

We demonstrate a proposal for making an ultrastable laser referenced to a multi-cavity, enabling a lower thermal noise limit due to the averaging effect. In comparison with a single-cavity system, relative frequency instability of the synthesized laser can be improved by a factor of the square root of the cavity number. We perform an experiment to simulate a two-cavity system with two independent ultrastable lasers. Experimental results show that the relative frequency instability (Allan deviation) of the synthesized laser is 5 × 10−16, improved by a factor of √2 from a single-cavity-stabilized laser.

We demonstrate a new approach to steer the frequencies of a nonlinear polarization-rotation mode-locked laser, where a specially designed intrcavity electro-optic modulator tunes the polarization state of the laser signal. This approach not only results in the broadband associated with high performance, but also results in a large dynamic range associated with good robustness. Our experimental results show that frequency control dynamic ranges are at least one order of magnitude larger than those of the previous ultra-fast frequency control techniques, reaching hundreds of hertz and hundreds of megahertz for repetition rate (fr) and carrier-envelope-offset frequency (fceo), respectively.

We present two cavity-stabilized lasers at 1555 nm, which are built to be the frequency source for a transportable photonic microwave generation system. The frequency instability reaches the thermal noise limit ( of the 10-cm ultra-low expansion glass cavity at 1–10 s averaging time and the beat signal of the two lasers reveals a remarkable linewidth of 185 mHz.

Femtosecond mode-locked lasers are key parts of optical frequency combs which allows a directly link from microwave frequency standards to optical frequencies. In this paper, we report on a 186 MHz mode-locked Erbium-doped fiber femtosecond laser developed for 9.2 GHz ultra-low-noise signal generation. This laser keeps mode-locked states within a large pump power dynamic range (from 300 mW to 1000 mW), and the relative intensity noise of the laser is about -118 dBc/Hz@1 Hz, below -130 dBc/Hz for frequencies higher than 10 Hz.

Highly stable frequency-controlled optical frequency combs are key elements of many applications in time-frequency and optical-metrology domains. In this work, we demonstrate a highly stable frequency-controlled erbium-fiber-based optical frequency comb system. Its repetition rate is phase-stabilized to a continuous-wave laser with both an intra-cavity electro-optic modulator and a piezo-transducer; while the carrier-envelope-offset frequency is phase-locked to a radio-frequency signal generator by controlling the pump power. In-loop relative frequency stabilities of the comb are below 1 × 10−16 at 1 s, and integrate down to low 10−20 level at 104 s. The corresponding timing uncertainties are 100–200 as over the full measurement range.

Abstract 1854 Backgound: Erlotinib is an oral small molecule tyrosine kinase inhibitor that inhibits intracellular EGFR tyrosine kinase. Preclinical data suggest that erlotinib has in vivo and in vitro efficacy in MDS and AML (Boehrer et al., Blood, 2008), inducing apoptosis in MDS and AML cell lines and primary myeoblasts, and promoting myeloid differentiation. The antitumor effect of erlotinib was demonstrated in AML xenograft mouse model. Isolated case reports documented the haematological activity of erlotinib in patients who had lung cancer and concomitant MDS or AML. The precise non-EGFR kinase targets responsible for erlotinib's activity in myeloid malignancies are not clear, but may involve aberrant Lyn, Syk and mTOR-mediated signaling. We report interim analysis results of a phase II trial examining the activity of erlotinib in the treatment of myelodysplastic syndromes. Methods: This is a single-institution two-stage phase 2 study. Eligibility includes confirmed int-2 or high risk MDS, low or int-1 risk patients with symptomatic anemia/transfusion dependent anemia or patients with platelet counts < 50 × 109/L or a significant clinical hemorrhage requiring platelet transfusions, ANC < 1 × 109/L, and RAEB-t by FAB classification are also eligible. All patients signed written infomred consent. Prior intensive induction chemotherapy, malignancy in the past 2 years, known history of HIV infection, ECOG PS 3–4 were exclusions. Erlotinib was given as an oral 150 mg daily dose for 16 weeks. The dose was adjusted for diarrhea, rash and pulmonary toxicty. Study assessments included baseline and weekly complete blood counts and repeat bone marrow aspirate and biopsy at weeks 8 and 16; non-responders were removed from study after 16 weeks. Responding patients (at least hematological response) continued study treatment until evidence of disease progression or relapse. The primary endpoint was the overall response rate ORR (CR, PR, marrow CR, or HI) as defined by the IWG 2006 criteria. ORR in at least two of the first 20 patients (stage 1) was necessary to proceed with expanded accrual of 15 additional patients. The study was approved by scientific review committee and IRB, and monitored by independent internal montioring committee. Results: Between September 2009 and March 2010, 25 patients were enrolled at Moffitt Cancer Center (two patients were found to be ineligible after signing informed consent, the first had myeloblasts >30% and the second patient had low grade MDS progressed to CML, but treated). For the 24 patients treated on protocol, the median age was 71 (range: 64–80) years, 18 patients (75%) were male. Majority were Caucasians (n=23) (96%). According to the WHO classification cases included RCMD 1 (4.2%), RAEB-I 8 (33.3%), RAEB-II 8 (33.3%), CMML 2 (8.3%), AML 4 (16.7%), and MDSU 1 (4.2%). The IPSS risk group was low in 2 (8.3%) patients, int-1 in 7 (29.2%), int-2 in 8 (33.3%) and high risk in 7 (29.2%). The median number of prior treatments was 2 (range: 1–4); all patients (100%) had received a hypomethylating agent (azacitidine or decitabine). The best responses for all 23 eligible subjects treated on study by IWG 2006 criteria were 3 marrow CR (13.0%), one HI (4.4%), and 6 (26.1%) stable disease, for a combined ORR of 4/23 (17.4%, 95% CI: 5%-39%). Four deaths occurred on study (sepsis=1, intracranial hemorrhage=1, sudden death=1, AML=1). The most common observed grade 3/4 toxicity according to CTCAE v3 in 24 treated patients were diarrhea (5, 20.8%), platelets (4, 16.7%), and rash: acne/acneiform (4, 16.7%). Conclusion: Erlotinib has acceptable toxicity profile in MDS patients and anti-leukemia activity in higher risk MDS patients after hypomethylating agents’ failure. The study has proceeded to the stage 2 expansion. Disclosures: Komrokji: Genentech: Research Funding. Off Label Use: Erlotinib use for MDS is investigational.