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Introduction The incidence of and risk factors for exertional heat illness (EHI) and cold weather injury (CWI) in the U.S. Army have been well documented. The “heat season”, when the risk of EHI is highest and application of risk mitigation procedures is mandatory, has been arbitrarily defined as May 1 through September 30, while the “cold season” is understood to occur from October 1 to April 30 each year. The proportions of EHI and CWI that occur outside of the traditional heat and cold seasons are unknown. Additionally, it is unknown if either of the seasonal definitions are appropriate. The primary purpose of this study was to determine the proportion of EHI and of CWI that occur within the commonly accepted seasonal definitions. We also report the location-specific variability, seasonal definitions, and the demographic characteristics of the populations. Methods The U.S. Army installations with the highest frequency of EHI and of CWI from 2008 to 2013 were identified and used for analysis. In total there were 15 installations included in the study, with five installations used for analysis in both the EHI and CWI projects. In- and out-patient EHI and CWI data (ICD-9-CM codes 992.0 to 992.9 and ICD codes 991.0 to 991.9, respectively) were obtained from the Defense Medical Surveillance System. Installation-specific denominator data were obtained from the Defense Manpower Data Center, and incidence rates were calculated by week, for each installation. Segmental (piecewise) regression analysis was used to determine the start and end of the heat and cold seasons. Results Our analysis indicates that the heat season starts around April 22 and ends around September 9. The cold season starts on October 3 and ends on March 24. The majority (n = 6,445, 82.3%) of EHIs were diagnosed during the “heat season” of May 1 to September 30, while 10.3% occurred before the heat season started (January1 to April 30) and 7.3% occurred after the heat season ended (October 1 to December 31). Similar to EHI, 90.5% of all CWIs occurred within the traditionally defined cold season, while 5.7% occurred before and 3.8% occurred after the cold season. The locations with the greatest EHI frequency were Ft Bragg (n = 2,129), Ft Benning (n = 1,560), and Ft Jackson (n = 1,538). The bases with the largest proportion of CWI in this sample were Ft Bragg (17.8%), Ft Wainwright (17.2%), and Ft Jackson (12.7%). There were considerable inter-installation differences for the start and end dates of the respective seasons. Conclusions The present study indicates that the traditional heat season definition should be revised to begin ∼3 weeks earlier than the current date of May 1; our data indicate that the current cold season definition is appropriate. Inter-installation variability in the start of the cold season was much larger than that for the heat season. Exertional heat illnesses are a year-round problem, with ∼17% of all cases occurring during non-summer months, when environmental heat strain and vigilance are lower. This suggests that EHI mitigation policies and procedures require greater year-round emphasis, particularly at certain locations.

Purpose: This randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer. Patients and Methods: Second-line patients were randomized 2:2:1 to receive durvalumab plus tremelimumab (arm A), or durvalumab (arm B) or tremelimumab monotherapy (arm C), and third-line patients received durvalumab plus tremelimumab (arm D). A tumor-based IFNγ gene signature was prospectively evaluated as a potential predictive biomarker in second- and third-line patients receiving the combination (arm E). The coprimary endpoints were objective response rate and progression-free survival (PFS) rate at 6 months. Results: A total of 113 patients were treated: 6 in phase Ib and 107 (arm A, 27; arm B, 24; arm C, 12; arm D, 25; arm E, 19) in phase II. Overall response rates were 7.4%, 0%, 8.3%, 4.0%, and 15.8% in the five arms, respectively. PFS rates at 6 months were 6.1%, 0%, 20%, 15%, and 0%, and 12-month overall survival rates were 37.0%, 4.6%, 22.9%, 38.8%, and NA, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 4%, 42%, 16%, and 11% of patients, respectively. Conclusions: Response rates were low regardless of monotherapy or combination strategies. No new safety signals were identified. Including use of a tumor-based IFNγ signature and change in baseline and on-treatment circulating tumor DNA are clinically feasible and may be novel strategies to improve treatment response in this difficult-to-treat population.

G6b-B is a megakaryocyte lineage-specific immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor, essential for platelet homeostasis. Mice with a genomic deletion of the entire Mpig6b locus develop severe macrothrombocytopenia and myelofibrosis, which is reflected in humans with null-mutations in MPIG6B. The current model proposes that megakaryocytes lacking G6b-B develop normally, while proplatelet release is hampered, but the underlying molecular mechanism remains unclear. Here, we report on a spontaneous recessive single nucleotide mutation in C57BL/6 mice, localized within the intronic region of the Mpig6b locus that abolishes G6b-B expression and reproduces macrothrombocytopenia, myelofibrosis and osteosclerosis. As the mutation is based on a single nucleotide exchange, Mpig6bmut mice represent an ideal model to study the role of G6b-B. Megakaryocytes from these mice were smaller in size, displayed a less developed demarcation membrane system and reduced expression of receptors. RNA sequencing revealed a striking global reduction in the level of megakaryocyte-specific transcripts, in conjunction with decreased protein levels of the transcription factor GATA-1, and impaired thrombopoietin signaling. The reduced number of mature MKs in the bone marrow was corroborated on a newly developed Mpig6b null mouse strain. Our findings highlight an unexpected essential role of G6b-B in the early differentiation within the megakaryocytic lineage.

Objective To examine the persistence of concussion-related symptoms following injury as a function of mechanism of injury (high-level blast [HLB] vs impact) and low-level blast (LLB) exposure among Marines. Setting Upon return from deployment and approximately 6 months later, respectively, Marines completed the Post-Deployment Health Assessment and Post-Deployment Health Re-Assessment in an operational or clinic setting. Participants Data from active duty enlisted Marines who completed both assessments (n = 102 075) and who reported a potentially mild traumatic brain injury (mTBI)-inducing event and completed an mTBI screen (n = 8106) were analyzed. Design This was a retrospective cohort study of Marines deployed between 2008 and 2012. Marines were categorized into groups with relatively high versus low risk for occupational risk of LLB exposure. A mixed model analysis of variance was used to examine the number of symptoms Marines reported experiencing during deployment as a function of probable concussion, HLB exposure, occupational risk, type of symptom, and time of measurement. Main measures Self-reported deployment exposures including HLB, probable mTBIs, and occupational risk of LLB exposure were identified. Outcomes included the proportion of neurological, musculoskeletal, and immunological symptoms for which Marines reported seeking care during and following deployment were analyzed. Results Probable HLB-induced mTBIs (vs impact-induced) were associated with significantly more neurological symptoms at return from deployment and approximately 6 months later. Although symptom reporting decreased at statistically equivalent rates regardless of mechanism of injury, those with a probable HLB-induced concussion continued to report elevated symptomology post-deployment. Additionally, Marines with probable concussion working in occupations with LLB exposure reported elevated levels of persistent neurological symptoms. Both HLB and LLB exposure were associated with neurological symptoms that persisted following deployment. Conclusion These findings suggest that blast-induced brain injuries may be fundamentally different from impact-induced injuries, and that additional screening and symptomatic treatment for blast-exposed patients may be warranted.

Traumatic brain injury (TBI), which can result from either direct impact to the head or blast exposure, has been the leading cause of morbidity and mortality in recent military conflicts. However, little research has compared mTBIs by mechanism of injury. The present research addressed two research questions: (1) Are blast-related mTBIs (mbTBIs) associated with significantly more symptoms than impact-related mTBIs (miTBIs), and (2) are mTBIs associated with more self-reported symptoms among service members with higher (vs. lower) risk of low-level blast (LLB) exposure. We obtained data from 181,423 active duty enlisted United States Marines deployed between 2003 and 2012, who completed the Post-Deployment Health Assessment. We examined the self-reported symptoms of Marines who completed an mTBI screen and could be classified as at high or low risk for LLB exposure, using their military occupation as a proxy (

Introduction Traumatic brain injury (TBI) has been the leading cause of morbidity and mortality in recent military conflicts and deployment-related TBIs are most commonly caused by blast. However, knowledge of risk factors that increase susceptibility to TBI following an acute, high-level blast is limited. We hypothesized that recurrent occupational overpressure exposure (ROPE) may be one factor that increases susceptibility to mild TBI (mTBI) following blast. Materials and Methods Using military occupational specialty as a proxy, we examined the effects of high versus low ROPE on mTBI following blast exposure. Initial analyses included 111,641 active-duty-enlisted U.S. Marines who completed the 2003 or 2008 version of the Post-Deployment Health Assessment. Final analyses examined probable mTBI screens among Marines with at least one qualifying exposure as a function of whether the exposure was a blast and level of ROPE (N = 12,929). This study was approved by the Institutional Review Board at the Naval Health Research Center. Results Blast and ROPE were both independently and jointly associated with a probable mTBI. Marines who experienced a blast (vs other qualifying exposure) and those in high (vs low) risk occupations were 1.07 and 1.23 times more likely to sustain a probable mTBI, respectively. Furthermore, among those who experienced a blast during deployment, those in high-risk occupations were 1.45 times more likely than those in low-risk occupations to sustain a probable mTBI. Conclusions Blast exposure and ROPE were independently associated with mTBIs, and Marines with both blast exposure during deployment and ROPE were especially likely to sustain an mTBI. This suggests that ROPE heightens the risk of mTBI following blast. Ongoing research is examining the severity, symptomology, and sequelae of TBIs as a function of ROPE.

Objective To synthesize the results of a scoping review and analysis of health care use data to identify gaps in knowledge related to the health of women in the U.S. military. Data Sources We searched MEDLINE/PubMed, Web of Science, CINAHL, and PsycINFO for articles published between January 2000 and September 2015. We obtained health care use data from military diagnostic and pharmacy databases. Study Selection All studies pertaining to the health and readiness of U.S. Active Duty service members were retained. Articles that contained mixed samples (i.e., male and female participants) were required to have a gender-stratified analysis of results to be included. Data Extraction We identified a total of 14,999 articles; 979 met inclusion criteria. Articles were categorized across eight major topic areas and 73 subtopic areas. Data Synthesis We synthesized literature results and health care use data to identify gaps in knowledge. We categorized most articles into the readiness (n = 561) and psychological health (n = 429) main topic areas; categorizations were not mutually exclusive. Overall, 89.4% (n = 879) of articles were of good to excellent quality. We identified gaps in seven of eight major topic areas and in 26 of 73 subtopic areas, but most were found in the obstetric-gynecologic health topic area and the psychological health topic areas. Less than 5% (n = 40) of the published research in this analysis included an experimental or quasi-experimental design. Conclusion Although high-quality research on the health of U.S. servicewomen exists on all major topics covered in this review, gaps in the literature exist. Our review provides the first step to map the extant landscape of research on the health of women in the U.S. military and is a guide for future research, policy, and intervention.

The presence of infectious microorganisms in urinary stones is commonly inferred from stone composition, especially by the presence of struvite in a stone. The presence of highly carbonated apatite has also been proposed as a marker of the presence of bacteria within a stone. We retrospectively studied 368 patients who had undergone percutaneous nephrolithotomy, and who also had culture results for both stone and urine. Urine culture showed no association with stone mineral content, but stone culture was more often positive in struvite containing stones (73% positive) and majority apatite stones (65%) than in other stone types (54%, lower than the others, P

Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.

Chemistry meets graphane: a Birch-type reaction using frozen water as a gentle proton source causes the exfoliation of graphite and formation of hydrogenated graphene with electronically decoupled π-nanodomains. This highly functionalized graphene displays pronounced fluorescence.

The fullerenes, carbon nanotubes, and graphene have enriched the family of carbon allotropes over the last few decades. Synthetic carbon allotropes (SCAs) have attracted chemists, physicists, and materials scientists because of the sheer multitude of their aesthetically pleasing structures and, more so, because of their outstanding and often unprecedented properties. They consist of fully conjugated p-electron systems and are considered topologically confined objects in zero, one, or two dimensions. Among the SCAs, graphene shows the greatest potential for high-performance applications, in the field of nanoelectronics, for example. However, significant fundamental research is still required to develop graphene chemistry. Chemical functionalization of graphene will increase its dispersibility in solvents, improve its processing into new materials, and facilitate the combination of graphene's unprecedented properties with those of other compound classes. On the basis of our experience with fullerenes and carbon nanotubes, we have described a series of covalent and noncovalent approaches to generate graphene derivatives. Using water-soluble perylene surfactants, we could efficiently exfoliate graphite in water and prepare substantial amounts of single-layer-graphene (SLG) and few-layer-graphene (FLG). At the same time, this approach leads to noncovalent graphene derivatives because it establishes efficient π-π-stacking interactions between graphene and the aromatic perylene chromophors supported by hydrophobic interactions. To gain efficient access to covalently functionalized graphene we employed graphite intercalation compounds (GICs), where positively charged metal cations are located between the negatively charged graphene sheets. The balanced combination of intercalation combined with repulsion driven by Coulombic interactions facilitated efficient exfoliation and wet chemical functionalization of the electronically activated graphene sheets via trapping with reactive electrophilic addends. For example, the treatment of reduced graphite with aryl diazonium salts with the elimination of N(2) led to the formation of arylated graphene. We obtained alkylated graphene via related trapping reactions with alkyl iodides. These new developments have opened the door for combining the unprecedented properties of graphene with those of other compound classes. We expect that further studies of the principles of graphene reactivity, improved characterization methods, and better synthetic control over graphene derivatives will lead to a whole series of new materials with highly specific functionalities and enormous potential for attractive applications.

1Graphite crystals are composed of two dimensional sheets of sp2-hybridized, hexagonally arranged carbon atoms— so-called graphene—that are regularly stacked. It has been proposed as early as in ancient Greek literature that graphite, derived from the greek word graphein (to write), consist of such a layered structure. However, it was not until 1779 that graphite was shown to consist of carbon. The common perception was that graphite was a metal owing to its luster and noble appearance. In fact, this insight is reflected in the electronic properties of the graphite-building blocks, i.e., graphene sheets, which are characterized as semi-metallic. In line with theoretical predictions, charge carriers in graphene were found to behave like mass-less Dirac fermions. 2 The latter

[*] Prof. A. Hirsch, J. M. Englert, C. D. Schmidt, Dr. F. Hauke Department of Chemistry and Pharmacy and Institute of Advanced Materials and Processes (ZMP) Friedrich Alexander University Erlangen–Nurnberg Henkestrasse 42, 91054 Erlangen (Germany) E-mail: andreas.hirsch@chemie.uni-erlangen.de J. Rohrl, Dr. R. Graupner, Prof. M. Hundhausen Lehrstuhl fur Technische Physik, Department of Physics Friedrich Alexander University Erlangen–Nurnberg Erwin-Rommel-Strasse 1, 91058 Erlangen (Germany)

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by severe, progressive fibrosis. Roles for inflammation and oxidative stress have recently been demonstrated, but despite advances in understanding the pathogenesis, there are still no effective therapies for IPF. This study investigates how extracellular superoxide dismutase (EC-SOD), a syndecan-binding antioxidant enzyme, inhibits inflammation and lung fibrosis. We hypothesize that EC-SOD protects the lung from oxidant damage by preventing syndecan fragmentation/shedding. Wild-type or EC-SOD-null mice were exposed to an intratracheal instillation of asbestos or bleomycin. Western blot was used to detect syndecans in the bronchoalveolar lavage fluid and lung. Human lung samples (normal and IPF) were also analyzed. Immunohistochemistry for syndecan-1 and EC-SOD was performed on human and mouse lungs. In vitro, alveolar epithelial cells were exposed to oxidative stress and EC-SOD. Cell supernatants were analyzed for shed syndecan-1 by Western blot. Syndecan-1 ectodomain was assessed in wound healing and neutrophil chemotaxis. Increases in human syndecan-1 are detected in lung homogenates and lavage fluid of IPF lungs. Syndecan-1 is also significantly elevated in the lavage fluid of EC-SOD-null mice after asbestos and bleomycin exposure. On IHC, syndecan-1 staining increases within fibrotic areas of human and mouse lungs. In vitro, EC-SOD inhibits oxidant-induced loss of syndecan-1 from A549 cells. Shed and exogenous syndecan-1 ectodomain induce neutrophil chemotaxis, inhibit alveolar epithelial wound healing, and promote fibrogenesis. Oxidative shedding of syndecan-1 is an underlying cause of neutrophil chemotaxis and aberrant wound healing that may contribute to pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a severely debilitating disease associated with a dismal prognosis. There are currently no effective therapies for IPF, thus the identification of novel therapeutic targets is greatly needed. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface receptors whose activation has been linked to various pathologies. In healthy adult animals, RAGE is expressed at the highest levels in the lung compared to other tissues. To investigate the hypothesis that RAGE is involved in IPF pathogenesis, we have examined its expression in two mouse models of pulmonary fibrosis and in human tissue from IPF patients. In each instance we observed a depletion of membrane RAGE and its soluble (decoy) isoform, sRAGE, in fibrotic lungs. In contrast to other diseases in which RAGE signaling promotes pathology, immunohistochemical and hydroxyproline quantification studies on aged RAGE-null mice indicate that these mice spontaneously develop pulmonary fibrosis-like alterations. Furthermore, when subjected to a model of pulmonary fibrosis, RAGE-null mice developed more severe fibrosis, as measured by hydroxyproline assay and histological scoring, than wild-type controls. Combined with data from other studies on mouse models of pulmonary fibrosis and human IPF tissues indicate that loss of RAGE contributes to IPF pathogenesis.

We have measured the pulmonary capillary blood volume in 28 pneumonectomized patients and in 18 patients with congenital cardiac malformations with left to right shunts. The results are compar

The Belgian law legalizing euthanasia under strict conditions came into effect September 22, 2002. Any physician performing euthanasia has to complete a registration document and to send it within four days to a federal commission whose mission is to verify that the legal conditions were fulfilled. From September 22, 2002 to December 31, 2013, 8.767 documents have been registered and analyzed by this commission. They are described in six reports referred to Parliament. The present paper analyzes the work of this commission and answers the criticisms concerning its quality and its efficiency. The allegations that clandestine euthanasia's escaping any control are performed are also discussed. In conclusion, it appears that the legal obligations concerning the practice of euthanasia in Belgium are fully effective.

This paper describes the first experimental research effort conducted in the United States on Load Distributive Compressive Anchors (LDCA). LDCAs were developed and first used in South Korea. The research effort was aimed at developing design, installation, and testing criteria suitable for U.S. practices. This paper presents a summary of the research findings that will serve as reference for use by practitioners when selecting, designing, installing, and testing LDCAs. The paper describes the process used for removing the anchors after installation, which achieved a 100% success rate during the tests. Since the completion of the research report, LDCAs have been used successfully for several projects in the U.S. Some of these projects include Hudsons Yards in Manhattan and Maryland Public Health Building in Baltimore, where LDCAs were implemented successfully. The authors recommend that similar research efforts be undertaken in other geological formations within the potential geographical market area to obtain average ultimate bond strengths for preliminary design, and to advance the understanding of this innovative technology.

We have isolated mutations in the Drosophila melanogaster homologue of auxilin, a J-domain–containing protein known to cooperate with Hsc70 in the disassembly of clathrin coats from clathrin-coated vesicles in vitro. Consistent with this biochemical role, animals with reduced auxilin function exhibit genetic interactions with Hsc70 and clathrin. Interestingly, the auxilin mutations interact specifically with Notch and disrupt several Notch-mediated processes. Genetic evidence places auxilin function in the signal-sending cells, upstream of Notch receptor activation, suggesting that the relevant cargo for this auxilin-mediated endocytosis is the Notch ligand Delta. Indeed, the localization of Delta protein is disrupted in auxilin mutant tissues. Thus, our data suggest that auxilin is an integral component of the Notch signaling pathway, participating in the ubiquitin-dependent endocytosis of Delta. Furthermore, the fact that auxilin is required for Notch signaling suggests that ligand endocytosis in the signal-sending cells needs to proceed past coat disassembly to activate Notch.

The synthesis of a new hexa-peri-hexabenzocoronene (HBC)–fullerene dyad 1 was accomplished involving a covalent linkage between both the planar and the spherical conjugated π-system of the two chromophores. We also present the first X-ray single crystal structure of a HBC–fullerene conjugate. A very short HBC–fullerene distance of 3.2 A is observed. For the synthesis of this molecule, a new versatile applicable template, namely, a mono-functionalized hexa-peri-hexabenzocoronene 7 was attached to a fullerene. Absorption and fluorescence spectroscopy, as well as quantum yield measurements of 1, indicated close electronic communication between the two subunits, which is promising for possible applications in molecular electronics.

The present study falls within the scope of work on the prevention of slips occurring on industrial workplace floor surfaces. Floor microgeometry is a determining factor in anti-slip flooring. Industrial environment-based quantification of floor microgeometrical properties is more restricting than laboratory quantification. The aim of the present study was to develop a duplication technique allowing reproduction of in situ floor microgeometry so as to be able to quantify this microgeometry in the laboratory. Duplicates were produced from a sample of five industrial floors. Surface microgeometry was characterized for both industrial floors and associated duplicates in order to study their microgeometrical changes following the duplicating operation. The purpose of this process was to reach a conclusion on the “reliability” of the duplication technique, on which the use of such duplicates depends. Parameters established from digitalized surfaces reveal differences of less than 5% between duplicates and original floor and this enables us to conclude that these duplicates offer a high degree of reliability with respect to results dispersion.

Elucidating the sites and mechanisms of sRAGE action in the healthy state is vital to better understand the biological importance of the receptor for advanced glycation end products (RAGE). Previous studies in animal models of disease have demonstrated that exogenous sRAGE has an anti-inflammatory effect, which has been reasoned to arise from sequestration of pro-inflammatory ligands away from membrane-bound RAGE isoforms. We show here that sRAGE exhibits in vitro binding with high affinity and reversibly to extracellular matrix components collagen I, collagen IV, and laminin. Soluble RAGE administered intratracheally, intravenously, or intraperitoneally, does not distribute in a specific fashion to any healthy mouse tissue, suggesting against the existence of accessible sRAGE sinks and receptors in the healthy mouse. Intratracheal administration is the only effective means of delivering exogenous sRAGE to the lung, the organ in which RAGE is most highly expressed; clearance of sRAGE from lung does not differ appreciably from that of albumin.

Udgivelsesdato: 2008-Sep The receptor for advanced glycation end-products (RAGE) has been implicated in numerous disease processes including: atherosclerosis, diabetic nephropathy, impaired wound healing and neuropathy to name a few. Treatment of animals with a soluble isoform of the receptor (sRAGE) has been shown to prevent and even reverse many disease processes. Isolating large quantities of pure sRAGE for in vitro and in vivo studies has hindered its development as a therapeutic strategy in other RAGE mediated diseases that require long-term therapy. This article provides an improvement in both yield and detail of a previously published method to obtain 10mg of pure, endotoxin free sRAGE from 65 g of lung tissue.

Reductive alkylation of three graphite starting materials G(flake), G(powder), and G(spherical) reveals pronounced differences in the obtained covalently functionalized graphene with respect to the degree of functionalization, exfoliation efficiency and product homogeneity, as demonstrated by statistical Raman microscopy (SRM), TGA/MS, IR-spectroscopy and solubility behavior.

We report on the introduction of a systematic method for the quantitative and reliable characterization of covalently functionalized graphene based on Scanning-Raman-Microscopy (SRM). This allows for recording and analyzing several thousands of Raman spectra per sample and straightforward display of various Raman properties and their correlations with each other in histograms or coded 2D-plots. In this way, information about the functionalization efficiency of a given reaction, the reproducibility of the statistical analysis, and the sample homogeneity can be easily deduced. Based on geometric considerations, we were also able to provide, for the first time, a correlation between the mean defect distance of densely packed point defects and the Raman ID/IG ratio directly obtained from the statistical analysis. This proved to be the prerequisite for determining the degree of functionalization, termed θ. As model compounds, we have studied a series of arylated graphenes (GPh) for which we have developed new synthetic procedures. Both graphite and graphene grown by chemical vapor deposition (CVD) were used as starting materials. The best route toward GPh consisted of the initial reduction of graphite with a Na/K alloy in 1,2-dimethoxyethane (DME) as it yields the highest overall homogeneity of products reflected in the widths of the Raman ID/IG histograms. The Raman results correlate nicely with parallel thermogravimetric analysis (TGA) coupled with mass spectrometry (MS) studies.

Much of our understanding of the mechanisms by which asbestos injures the lung has been derived from experimental animal studies. Such studies have confirmed the fibrogenic and carcinogenic properties of asbestos fibers that have been surmised from human observations and have provided insights into the ways in which asbestos fibers interact with biological systems. Models commonly used to study asbestos-induced disease involve inhalation exposure to asbestos, intratracheal instillation, and in vitro studies of various cellular systems. Each of these techniques has particular advantages and disadvantages.

Crystal Barrel data on p p → 5π 0 at rest are presented. Mass spectra for 2π0 combinations, 3π0 and 4π0 and decay angular distributions all differ significantly from phase space. We present several ways of fitting the data. All agree on the definite presence of the f0(1500), observed in its 4π0 decay mode. It can decay into ππ(1300) and into σσ where σ stands for the full ππ S-wave amplitude.

Data on\(\bar pp \to \eta \pi ^0 \pi ^0 \pi ^0 \) taken at beam momenta of 1.2 and 1.94 GeV/c reveal evidence for twoI=0JPC=2−+ resonances inηππ. The first, at 1645±14(stat.)±15(syst.) MeV with width 180−21+40±25 MeV, decays toα2(1320)π withL=0. It may be interpreted as the\(q\bar q^1 \)D2 partner ofπ2(1670). A strong signal is also observed just above threshold inf2(1270)η withL=0. It is 11–22 times stronger than is expected for the high mass tail of the 1645 MeV resonance. It can be fitted as a second 2−+ resonance at 1875±20±35 MeV with width 200±25±45 MeV. A third resonance havingJPC=2++ is observed at 2135±20±45 MeV withΛ=250±25±45 MeV, decaying to botha2(1320)π andf2(1270)η withL=1. There is no evidence for resonances with decays toa0(980)π, ση orf0(980)η.

We have observed the ηπ + π − and ηπ 0 π 0 decay modes of the E meson in p p annihilation at rest into π + π − π 0 π 0 η . The mass and width of the E meson are 1409 ± 3 and 86 ± 10 MeV. The production and decay branching ratio is B( p p → Eππ)B(E → ηππ) = (3.3 ± 1.0) × 10 −3 . With a spin-parity analysis we determine that J P = 0 − . The observation of the ηπ 0 π 0 decay mode establishes that E is isoscalar ( C = +1). We find that E decays to η ( ππ ) s (where ( ππ ) s is an S-wave dipion) and πa 0 (980)(→ πη ) with a relative branching ratio of (78 ± 16) %. Using the K K π production and decay branching ratio measured earlier we determine that B[E → K K π] B[E → ηππ] = 0.61 ± 0.19 . A comparison with observations in radiative J Ψ decays suggests that E and ι η (1416) are identical.

We confirm the existence of the two IG(JPC) = 0+(0++) resonances f0(1370) and f0(1500) reported by us in earlier analyses. The analysis presented here couples the final states π0π0π0, π0π0η and π0ηη of pp annihilation at rest. It is based on a 3 × 3 K-matrix. We find masses and widths of M = (1390±30) MeV, Γ = (380±80) MeV; and M = (1500±10) MeV, Γ = (154 ± 30) MeV, respectively. The product branching ratios for the production and decay into π0π0 and ηη of the f0(1500) are (1.27 ± 0.33) · 10−3 and (0.60 ± 0.17) · 10−3, respectively.

A partial wave analysis of the reaction p p →π o ηη has been performed, using a high quality, high statistics data set of 198,000 events. In addition to the ƒ 0 (1370), a second scalar resonance decaying into ηη, the ƒ 0 (1500), with mass m = (1505 ± 15) MeV and width Γ = (120 ± 30) MeV has to be introduced to describe the data.

Adenosine signaling through the A2a receptor (A2aR) has pleiotropic immunosuppressive effects on a broad range of immune cells. Extracellular adenosine levels, which are typically very low in normal tissues, are elevated in the tumor microenvironment, allowing increased signaling through the A2aR. Previously, our lab and others have shown increased rejection of tumors in A2aR-null mice, demonstrating that adenosine signaling through A2aR limits immunologic response to tumors. Present work in our lab demonstrates the ability of a potent and specific, orally administered A2aR antagonist, CPI-444, to enhance immunologic response in mice. First, A2aR blockade with CPI-444 (1 mg/kg) in the peri-vaccination period led to significant expansion of antigen-specific T cells over untreated controls. Interestingly, antigen-specific CTLs from CPI-444 treated mice showed significantly lower expression of inhibitory checkpoint receptors, including PD-1 and TIM-3. Second, in an MC38 tumor model, daily treatment with CPI-444 (100 mg/kg) led to tumor growth suppression and survival benefit compared with vehicle-treated controls. Notably, tumor infiltrating regulatory T cells had significantly lower CTLA-4 and FoxP3 expression in CPI-444 treated mice. These initial immunologic findings of enhanced early CTL expansion and suppression of inhibitory co-signaling have important implications for applying A2aR blockade to immunotherapy in cancer. First, given the ability of CPI-444 to augment CTL expansion, we investigated its application to a therapeutic adoptive T cell transfer system using OVA-expressing B16 melanoma cell line. In mice with established tumors, daily CPI-444 (100 mg/kg) treatment initiated on the day of adoptive transfer of activated OVA-specific OT-I T cells led to suppressed tumor growth and increased survival versus vehicle treated controls. Second, in light of our data demonstrating its ability to suppress PD-1 in CTLs, we theorized that CPI-444 may lower the threshold for effective anti-PD-1 therapy and achieve synergistic effects as combination therapy. Indeed, daily CPI-444 (100 mg/kg) treatment combined with anti-PD-1 treatment showed robust antitumor effect in the CT26 tumor model, with complete tumor rejection in 7/9 mice (vs. 2/10 mice in the anti-PD-1 alone group). Survival was markedly improved in mice receiving combination treatment versus either CPI-444 or anti-PD-1 alone. In as much as increased adenosine in the tumor microenvironment is partly a consequence of dysregulated cancer cell metabolism, we hypothesized that targeting tumor metabolism would enhance the efficacy of A2aR antagonism. To this end, inhibition of tumor glutamine metabolism potently augmented the efficacy of CPI-444 in a CT26 model. Overall, our data suggest that A2aR antagonism can enhance the efficacy of immunotherapy in the form of checkpoint blockade and adoptive cellular therapy. Citation Format: Robert D. Leone, Judson M. Englert, Chih-Hsien Cheng, Jiayu Wen, Min-Hee Oh, Im-Hong Sun, Chirag Patel, Ian A. Bettencourt, Jonathan D. Powell. Adenosine A2a receptor blockade as a means of enhancing immune checkpoint inhibition and adoptive T-cell therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4364.

The branching ratios Γ(η → 3π 0 ) Γ(η → π + π − π 0 ) = 1.44 ± 0.09 ± 0.10 and Γ(η → γγ) Γ(η → π + π − π 0 ) = 1.78 ± 0.10 ± 0.13 have been determined using the Crystal Barrel detector at LEAR. The latter ratio yields a partial width of Γ ( η → π + π − π 0 ) = 0.26 ± 0.03 keV using the known value for Γ ( η → γγ ). The η → π + π − π 0 ) Dalitz plot is compared to the predictions of chiral perturbation theory.