A newly synthesized 17-epi-NeuroProtectin D1/17-epi-Protectin D1: Authentication and functional regulation of Inflammation-Resolution.

The production of specialized pro-resolving mediators (SPMs) during the resolution phase in the inflammatory milieu is key to orchestrating the resolution of the acute inflammatory response. 17-epi-neuroprotectin D1/17-epi-protectin D1 (17-epi-NPD1/17-epi-PD1: 10R,17R-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-docosahexaenoic acid) is an SPM of the protectin family, biosynthesized from docosahexaenoic acid (DHA), that exhibits both potent anti-inflammatory and neuroprotective functions. Here, we carried out a new commercial-scale synthesis of 17-epi-NPD1/17-epi-PD1 that enabled the authentication and confirmation of its potent bioactions in vivo and determination of its ability to activate human leukocyte phagocytosis. We provide evidence that this new synthetic 17-epi-NPD1/17-epi-PD1 statistically significantly increases human macrophage uptake of E. coli in vitro and confirm that it limits neutrophilic infiltration in vivo in a murine model of peritonitis. The physical properties of the new synthetic 17-epi-NPD1/17-epi-PD1, namely its ultra-violet absorbance, chromatography, and tandem mass spectrometry fragmentation pattern, matched those of the originally synthesized 17-epi-NPD1/17-epi-PD1. In addition, we verified the structure and complete stereochemical assignment of this new synthetic 17-epi-NPD1/17-epi-PD1 using nuclear magnetic resonance (NMR) spectroscopy. Together, these results authenticate this 17-epi-NPD1/17-epi-PD1 for its structure and potent pro-resolving functions.

A New E-Series Resolvin: RvE4 Stereochemistry and Function in Efferocytosis of Inflammation-Resolution.

The resolution of the acute inflammatory response is governed by phagocytes actively clearing apoptotic cells and pathogens. Biosynthesis of the specialized pro-resolving mediators (SPMs) is pivotal in the resolution of inflammation via their roles in innate immune cells. Resolvin E4 (RvE4: 5S,15S-dihydroxy-eicosapentaenoic acid) is a newly uncovered member of the E-series resolvins biosynthesized from eicosapentaenoic acid (EPA) recently elucidated in physiologic hypoxia. This new resolvin was termed RvE4 given its ability to increase efferocytosis of apoptotic cells by macrophages. Herein, we report on the total organic synthesis of RvE4 confirming its unique structure, complete stereochemistry assignment and function. This synthetic RvE4 matched the physical properties of biogenic RvE4 material, i.e. ultra-violet (UV) absorbance, chromatographic behavior, and tandem mass spectrometry (MS2) fragmentation, as well as bioactivity. We confirmed RvE4 potent responses with human M2 macrophage efferocytosis of human apoptotic neutrophils and senescent red blood cells. Together, these results provide direct evidence for the assignment of the complete stereochemistry of RvE4 as 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid and its bioactions in human phagocyte response.

Pilot study of bevacizumab in combination with docetaxel and cyclophosphamide as adjuvant treatment for patients with early stage HER-2 negative breast cancer, including analysis of candidate circulating markers of cardiac toxicity: ICORG 08-10 trial.

BACKGROUND: Combining bevacizumab and chemotherapy produced superior response rates compared with chemotherapy alone in metastatic breast cancer. As bevacizumab may cause hypertension (HTN) and increase the risk of cardiac failure, we performed a pilot study to evaluate the feasibility and toxicity of a non-anthracycline-containing combination of docetaxel with cyclophosphamide and bevacizumab in early stage breast cancer patients. METHODS: Treatment consisted of four 3-weekly cycles of docetaxel and cyclophosphamide (75/600 mg/m2). Bevacizumab was administered 15 mg/kg intravenously on day 1, and then every 3 weeks to a total of 18 cycles of treatment. Serum biomarker concentrations of vascular endothelial growth factor (VEGF), cardiac troponin-I (cTnI), myeloperoxidase (MPO), and placental growth factor (PlGF) were quantified using enzyme-linked immunosorbent assay (ELISA) in 62 patients at baseline and whilst on treatment to determine their utility as biomarkers of cardiotoxicity, indicated by left ventricular ejection fraction (LVEF). RESULTS: A total of 106 patients were accrued in nine sites. Median follow up was 65 months (1-72 months). Seventeen protocol-defined relapse events were observed, accounting for an overall disease-free survival (DFS) rate of 84%. The DFS rates for hormone receptor positive (HR+) and triple-negative (TN) patients were 95% versus 43%, respectively. The median time to relapse was 25 (12-54) months in TN patients versus 38 (22-71) months in HR+ patients. There have been 13 deaths related to breast cancer . The overall survival (OS) rate was 88%. The 5-year OS rate in HR+ versus TN was 95% versus 57%. None of the measured biomarkers predicted the development of cardiotoxicity. CONCLUSIONS: We observed a low relapse rate in node-positive, HR+ patients; however, results in TN breast cancer were less encouraging. Given the negative results of three large phase III trials, it is unlikely that this approach will be investigated further. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00911716.

Whither the urban diaspora? The spatial redistribution of Latino origin groups in metropolitan America since 1990.

Our research advances what is known about the urban portion of the Latino diaspora, focusing on the extent to which Hispanic country-of-origin groups have spread throughout metropolitan America. Analyzing 1990-2010 census data for the seven largest origin groups, we find that all seven have become more evenly dispersed across metro areas, with group shares declining in primary gateways and increasing in other types of destinations. At the same time, Dominicans and Cubans remain highly concentrated in New York and Miami, respectively, and certain pairs of groups (e.g., Mexicans and Dominicans) continue to inhabit different metropolises despite a modest trend toward convergent settlement among most pairs. All groups have experienced some growth in exposure to ethnoracial diversity, particularly in primary gateway settings. However, Mexicans are less exposed than any other origin group to African Americans. The variation in our results by group attests to the delicate balance between the forces driving spatial concentration and dispersion. We conclude that multiple diasporas are underway rather than a single, uniform one. This pattern has relevance both for diversity within local Hispanic communities and for relations between Hispanics and other panethnic populations, most notably Whites and Blacks.

Solamente Mexicanos? Patterns and sources of Hispanic diversity in U.S. metropolitan areas.

Rapid Hispanic growth has been a major source of increasing ethnoracial diversity in the United States. However, diversity within the Hispanic population is frequently obscured by the tendency to lump all Latinos together. Our study examines Hispanic diversity at the local level, drawing insights from the Mexican dominance, Caribbean-centric settlement, spatial assimilation, and economic opportunity perspectives. Measures of the magnitude and structure of Hispanic origin-group diversity during the 1990-2010 period are constructed for 363 metropolitan areas based on each area's shares of Mexicans, Puerto Ricans, Cubans, Dominicans, Salvadorans, Guatemalans, Colombians, and 'others'. We find that diversity magnitude varies markedly across metropolitan Hispanic populations. Although the most diverse metro areas lack a majority origin group, Mexicans often constitute a majority or plurality of local Latinos. Diversity levels and structures have remained relatively stable over time. In both 1990 and 2010, metro areas with more diverse, multigroup Hispanic communities are distinguished by their larger size, smaller proportion of Hispanics, location farther from Mexico and closer to the Caribbean, and greater odds of being a military hub. They also exhibit higher rates of housing construction and lower rates of agricultural and manufacturing employment. We use weighted data to show that Dominican metro dwellers experience the highest Hispanic diversity while the average Mexican lives in an area where four-fifths of all Latinos are Mexican. Overall, our results provide primary support for the Mexican dominance perspective but some support for the other three perspectives as well.

The Spatial Diffusion of Racial and Ethnic Diversity Across U.S. Counties.

Although increasing racial and ethnic diversity is a demographic trend with society-wide implications, it has advanced farther in some parts of the United States than others. Our research seeks to understand this unevenness at the local level. Drawing on 1980-2010 census data, we use an innovative spatial analytic approach to examine the spread or diffusion of diversity across counties in the 48 contiguous states. Three perspectives-locational persistence, spatial assimilation, and institutional hub-offer different expectations about the nature of the diffusion process. The perspectives are evaluated by mapping changes in the magnitude and structure of diversity and by tracing county transitions between types of diversity clusters. We document considerable stability in diversity patterns over a 30-year period, consistent with the logic of locational persistence. But support is also found for the spatial assimilation and institutional hub models in the form of cluster-type transitions that reflect contagious diffusion and hierarchical diffusion, respectively.

State-level changes in US racial and ethnic diversity, 1980 to 2015: A universal trend?

Background: Few studies have examined long-term changes in ethnoracial diversity for US states despite the potential social, economic, and political ramifications of such changes at the state level. Objective: We describe shifts in diversity magnitude and structure from 1980 through 2015 to determine if states are following a universal upward path. Methods: Decennial census data for 1980-2010 and American Community Survey data for 2015 are used to compute entropy index (E) and Simpson index (S) measures of diversity magnitude based on five panethnic populations. A typology characterizes the racial-ethnic structure of states. Results: While initial diversity level and subsequent pace of change vary widely, every state has increased in diversity magnitude since 1980. A dramatic decline in the number of predominantly White states has been accompanied by the rise of states with multigroup structures that include Hispanics. These diverse states are concentrated along the coasts and across the southern tier of the nation. Differences in panethnic population growth (especially rapid Hispanic and Asian growth coupled with white stability) drive the diversification trend. Conclusions: The diversity hierarchy among states has remained relatively stable over the past 35 years in the face of universal gains in diversity magnitude and the increasing heterogeneity of racial-ethnic structures. Contribution: We document ethnoracial diversity patterns at an understudied geographic scale where diversity may have important consequences across a range of institutional domains.

Realizing exactly solvable SU(N) magnets with thermal atoms.

We show that n thermal fermionic alkaline-earth-metal atoms in a flat-bottom trap allow one to robustly implement a spin model displaying two symmetries: the S n symmetry that permutes atoms occupying different vibrational levels of the trap and the SU(N) symmetry associated with N nuclear spin states. The symmetries make the model exactly solvable, which, in turn, enables the analytic study of dynamical processes such as spin diffusion in this SU(N) system. We also show how to use this system to generate entangled states that allow for Heisenberg-limited metrology. This highly symmetric spin model should be experimentally realizable even when the vibrational levels are occupied according to a high-temperature thermal or an arbitrary nonthermal distribution.

Ultrastable laser with average fractional frequency drift rate below 5 × 10⁻¹9/s.

Cryogenic single-crystal optical cavities have the potential to provide high dimensional stability. We have investigated the long-term performance of an ultrastable laser system that is stabilized to a single-crystal silicon cavity operated at 124 K. Utilizing a frequency comb, the laser is compared to a hydrogen maser that is referenced to a primary caesium fountain standard and to the 87Sr optical lattice clock at Physikalisch-Technische Bundesanstalt (PTB). With fractional frequency instabilities of σ(y)(τ)≤2×10(-16) for averaging times of τ=60 s to 1000 s and σ(y)(1 d)≤2×10(-15) the stability of this laser, without any aid from an atomic reference, surpasses the best known microwave standards for short averaging times and is competitive with the best known hydrogen masers for longer times of 1 day. The comparison of modeled thermal response of the cavity with measured data indicates an average fractional frequency drift below 5×10(-19)/s, which we do not expect to be a fundamental limit.

Suppression of collisional shifts in a strongly interacting lattice clock.

Optical lattice clocks with extremely stable frequency are possible when many atoms are interrogated simultaneously, but this precision may come at the cost of systematic inaccuracy resulting from atomic interactions. Density-dependent frequency shifts can occur even in a clock that uses fermionic atoms if they are subject to inhomogeneous optical excitation. However, sufficiently strong interactions can suppress collisional shifts in lattice sites containing more than one atom. We demonstrated the effectiveness of this approach with a strontium lattice clock by reducing both the collisional frequency shift and its uncertainty to the level of 10(-17). This result eliminates the compromise between precision and accuracy in a many-particle system; both will continue to improve as the number of particles increases.

Precision measurement of fermionic collisions using an 87Sr optical lattice clock with 1 x 10(-16) inaccuracy.

We describe recent progress on the JILA Sr optical frequency standard, which has a systematic uncertainty at the 10(¿16) fractional frequency level. The dominant contributions to the systematic error are from blackbody radiation shifts and collisional shifts. We discuss the blackbody radiation shift and propose measurements and experimental protocols that should reduce its systematic contribution. We discuss how collisional frequency shifts can arise in an optical lattice clock employing fermionic atoms, and experimentally demonstrate how the uncertainty in this density-dependent correction to the clock frequency is reduced.

Testing ultrafast mode-locking at microhertz relative optical linewidth.

We report new limits on the phase coherence of the ultrafast mode-locking process in an octave-spanning Ti:sapphire comb.We find that the mode-locking mechanism correlates optical phase across a full optical octave with less than 2.5 microHZ relative linewidth. This result is at least two orders of magnitude below recent predictions for quantum-limited individual comb-mode linewidths, verifying that the mode-locking mechanism strongly correlates quantum noise across the comb spectrum.

Acoustic characterization of panel materials under simulated ocean conditions using a parametric array source.

A technique for evaluating the underwater acoustic performance of panels under simulated ocean conditions in a laboratory test facility is described. The method uses a parametric array as a source of sound within a test vessel capable of simulating ocean depths down to 700 m and water temperatures from 2 to 35 degrees C. The reflection loss and transmission loss of the test panel may be determined at frequencies from a few kilohertz to 50 kHz. The use of the parametric array enables wideband measurements to be undertaken with short-duration pulses and reduces the effects of diffraction from the panel edges. An acoustic filter is used to truncate the array in order to provide a source-free measurement region and to simplify the measurement process. The difficulties of establishing a parametric array in the confined space of the vessel are outlined, and the experimental procedures adopted are described. The techniques were validated by undertaking measurements on two test objects that have predictable behavior. The potential of the technique is also illustrated with experimental results for test panels for hydrostatic pressures up to 2.8 MPa. An extensive discussion of the measurement limitations is included.

Quality of life of lumbar stenosis-treated patients in whom the X STOP interspinous device was implanted.

OBJECT: This study was conducted to compare the quality of life (QOL) in patients with neurogenic intermittent claudication (NIC) secondary to lumbar spinal stenosis (LSS). Using the 36-Item Short Form (SF-36) questionnaire, the authors compared the results obtained in patients treated with the X STOP Interspinous Process Decompression (IPD) System with those obtained in patients who underwent nonoperative therapies. METHODS: Patients with LSS were enrolled in a prospective 2-year multicenter study and randomized either to the X STOP or nonoperative group. The SF-36 survey was used to assess the QOL before treatment and at 6 weeks, 6 months, 1 year, and 2 years posttreatment. An analysis of variance was used to compare individual pre- and posttreatment mean SF-36 domain scores between the two groups and within each treatment group. At all posttreatment time points, the authors observed the following: (1) mean domain scores in X STOP-treated patients were significantly greater than those in patients treated nonoperatively, with the exception of the mean General Health (GH), Role Emotional, and Mental Component Summary scores at 2 years; and (2) mean posttreatment domain scores documented in X STOP-treated patients were significantly greater than mean pretreatment scores, with the exception of mean GH scores at 6, 12, and 24 months. CONCLUSIONS: The results of this study demonstrate that the X STOP device is significantly more effective than nonoperative therapy in improving the QOL in patients with LSS. The results are comparable with those reported in other studies involving traditional decompressive techniques for LSS and suggest that the X STOP implant can provide an effective treatment compared with nonoperative and conventional surgical therapies.

Recent developments in the chemotherapeutic options for nonsmall cell lung cancer.

Lung cancer is one of the leading causes of cancer deaths in the developed world. It is grossly divided into small cell and nonsmall cell types. Depending on the stage at diagnosis, the principal means of treating nonsmall cell lung cancer are surgery, chemotherapy and/or radiotherapy. However, even when it is diagnosed at an early stage, the progression-free and overall survival rates have been disappointing compared with other cancers. In recent years, there have been a number of developments in the chemotherapeutic options for nonsmall cell lung cancer. The aim of this review is to summarize these developments, in a stage-specific manner, with respect to both standard chemotherapy and also the newer targeted therapies.

Current stage-specific chemotherapeutic options in colon cancer.

Colorectal cancer is one of the most common cancers worldwide. Until recently, chemotherapeutic treatment options were limited to various 5-fluorouracil-leucovorin combinations. However, the last 10 years have seen rapid developments in the treatment of colon cancer. These include the introduction of two additional chemotherapeutic agents, irinotecan and oxaliplatin. Additional agents have been developed, namely the targeted therapies in the form of the monoclonal antibodies bevacizumab and cetuximab. The oral forms of chemotherapy (i.e., capecitabine and uracil-tegafur) have been demonstrated to be as efficacious as traditional intravenously administered 5-fluorouracil. As a result, the number of possible treatment options available to patients has increased dramatically. The aim of this review is to report the currently accepted stage-specific chemotherapeutic treatment options for colon cancer, the evidence for these regimens and future developments.

A multicenter, prospective, randomized trial evaluating the X STOP interspinous process decompression system for the treatment of neurogenic intermittent claudication: two-year follow-up results.

STUDY DESIGN: A randomized, controlled, prospective multicenter trial comparing the outcomes of neurogenic intermittent claudication (NIC) patients treated with the interspinous process decompression system (X STOP) with patients treated nonoperatively. OBJECTIVE: To determine the safety and efficacy of the X STOP interspinous implant. SUMMARY OF BACKGROUND DATA: Patients suffering from NIC secondary to lumbar spinal stenosis have been limited to a choice between nonoperative therapies and decompressive surgical procedures, with or without fusion. The X STOP was developed to provide an alternative therapeutic treatment. METHODS.: 191 patients were treated, 100 in the X STOP group and 91 in the control group. The primary outcomes measure was the Zurich Claudication Questionnaire, a patient-completed, validated instrument for NIC. RESULTS: At every follow-up visit, X STOP patients had significantly better outcomes in each domain of the Zurich Claudication Questionnaire. At 2 years, the X STOP patients improved by 45.4% over the mean baseline Symptom Severity score compared with 7.4% in the control group; the mean improvement in the Physical Function domain was 44.3% in the X STOP group and -0.4% in the control group. In the X STOP group, 73.1% patients were satisfied with their treatment compared with 35.9% of control patients. CONCLUSIONS: The X STOP provides a conservative yet effective treatment for patients suffering from lumbar spinal stenosis. In the continuum of treatment options, the X STOP offers an attractive alternative to both conservative care and decompressive surgery.