Search

Contains fulltext : 291616.pdf (Publisher’s version ) (Open Access)

BackgroundGroundbreaking studies have linked the gut microbiome with immune homeostasis and antitumor immune responses. Mounting evidence has also demonstrated an intratumoral microbiome, including in soft tissue sarcomas (STS), although detailed characterization of the STS intratumoral microbiome is limited. We sought to characterize the intratumoral microbiome in patients with STS undergoing preoperative radiotherapy and surgery, hypothesizing the presence of a distinct intratumoral microbiome with potentially clinically significant microbial signatures.MethodsWe prospectively obtained tumor and stool samples from adult patients with non-metastatic STS using a strict sterile collection protocol to minimize contamination. Metagenomic classification was used to estimate abundance using genus and species taxonomic levels across all classified organisms, and data were analyzed with respect to clinicopathologic factors.ResultsFifteen patients were enrolled. Most tumors were located at an extremity (67%) and were histologic grade 3 (87%). 40% were well-differentiated/dedifferentiated liposarcoma histology. With a median follow-up of 24 months, 4 (27%) patients developed metastases, and 3 (20%) died. Despite overwhelming human DNA (>99%) intratumorally, we detected a small but consistent proportion of bacterial DNA (0.02-0.03%) in all tumors, including Proteobacteria, Bacteroidetes, and Firmicutes, as well as viral species. In the tumor microenvironment, we observed a strong positive correlation between viral relative abundance and natural killer (NK) infiltration, and higher NK infiltration was associated with superior metastasis-free and overall survival by immunohistochemical, flow cytometry, and multiplex immunofluorescence analyses.ConclusionsWe prospectively demonstrate the presence of a distinct and measurable intratumoral microbiome in patients with STS at multiple time points. Our data suggest that the STS tumor microbiome has prognostic significance with vir

Item does not contain fulltext

Contains fulltext : 294433.pdf (Publisher’s version ) (Open Access), Cells continuously sense external forces from their microenvironment, the extracellular matrix (ECM). In turn, they generate contractile forces, which stiffen and remodel this matrix. Although this bidirectional mechanical exchange is crucial for many cell functions, it remains poorly understood. Key challenges are that the majority of available matrices for such studies, either natural or synthetic, are difficult to control or lack biological relevance. Here, we use a synthetic, yet highly biomimetic hydrogel based on polyisocyanide (PIC) polymers to investigate the effects of the fibrous architecture and the nonlinear mechanics on cell-matrix interactions. Live-cell rheology was combined with advanced microscopy-based approaches to understand the mechanisms behind cell-induced matrix stiffening and plastic remodeling. We demonstrate how cell-mediated fiber remodeling and the propagation of fiber displacements are modulated by adjusting the biological and mechanical properties of this material. Moreover, we validate the biological relevance of our results by demonstrating that cellular tractions in PIC gels develop analogously to those in the natural ECM. This study highlights the potential of PIC gels to disentangle complex bidirectional cell-matrix interactions and to improve the design of materials for mechanobiology studies.

A substantial literature investigates carbon leakage effects for large countries and climate coalitions. However, little is known about leakage effects for a small open economy within a climate coalition. To fill this gap in the literature, we incorporate international climate policies relevant for a small open EU economy into the general equilibrium model GTAP-E. We focus our analysis on Denmark, but we show that our framework can be applied to any EU economy. We find substantial leakage associated with an economy-wide CO2e tax. This result is strongly affected by EU climate policies. We also present sector-specific leakage rates and find large sectoral differences.

A substantial literature investigates carbon leakage effects for large countries and climate coalitions. However, little is known about leakage effects for a small open economy within a climate coalition. To fill this gap in the literature, we incorporate international climate policies relevant for a small open EU economy into the general equilibrium model GTAP-E. We focus our analysis on Denmark, but we show that our framework can be applied to any EU economy. We find substantial leakage associated with an economy-wide CO2e tax. This result is strongly affected by EU climate policies. We also present sector-specific leakage rates and find large sectoral differences.

The carbamate insecticide methomyl is sometimes used to control slugs in field corn and soybean by foliar applications, but control outcomes in research trials and commercial operations have been mixed. In this study, laboratory bioassays were conducted on dusky slug, Arion subfuscus Müller, a common pest of corn and soybean in the Mid-Atlantic United States, to evaluate residual toxicity of Lannate LV (methomyl) at low and high concentrations corresponding to label recommended field rates, and if toxicity may be affected by ambient moisture or repellency to treated plants. Without wetting events, methomyl residues on corn plants caused 90–100% mortality of A. subfuscus for two days and 70–90% mortality for six days. When corn plants were briefly misted with ca. 0.3 cm of water 6 h after methomyl application, mortality was 36% 12 h after treatment, and 0 to 5% 24 h after treatment for both low and high rates. Repellency of A. subfuscus to corn plants treated with the high rate of methomyl was narrowly significant (P = 0.04) and low rate was not significant. These results suggest that high ambient moisture needed to elicit slug activity in the field also abates toxicity of methomyl residues, explaining why field control is usually poor despite high mortality in the lab.

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Blevins, M. G., Allen, H. L., Colson, B. C., Cook, A.-M., Greenbaum, A. Z., Hemami, S. S., Hollmann, J., Kim, E., LaRocca, A. A., Markoski, K. A., Miraglia, P., Mott, V. L., Robberson, W. M., Santos, J. A., Sprachman, M. M., Swierk, P., Tate, S., Witinski, M. F., Kratchman, L. B., & Michel, A. P. M. Field-portable microplastic sensing in aqueous environments: a perspective on emerging techniques. Sensors, 21(10), (2021): 3532, https://doi.org/10.3390/s21103532., Microplastics (MPs) have been found in aqueous environments ranging from rural ponds and lakes to the deep ocean. Despite the ubiquity of MPs, our ability to characterize MPs in the environment is limited by the lack of technologies for rapidly and accurately identifying and quantifying MPs. Although standards exist for MP sample collection and preparation, methods of MP analysis vary considerably and produce data with a broad range of data content and quality. The need for extensive analysis-specific sample preparation in current technology approaches has hindered the emergence of a single technique which can operate on aqueous samples in the field, rather than on dried laboratory preparations. In this perspective, we consider MP measurement technologies with a focus on both their eventual field-deployability and their respective data products (e.g., MP particle count, size, and/or polymer type). We present preliminary demonstrations of several prospective MP measurement techniques, with an eye towards developing a solution or solutions that can transition from the laboratory to the field. Specifically, experimental results are presented from multiple prototype systems that measure various physical properties of MPs: pyrolysis-differential mobility spectroscopy, short-wave infrared imaging, aqueous Nile Red labeling and counting, acoustophoresis, ultrasound, impedance spectroscopy, and dielectrophoresis., We greatly thank our funding agencies: Gerstner Philanthropies (to A.P.M.M.), the Richard Saltonstall Charitable Foundation (to A.P.M.M.), and the Wallace Research Foundation (to A.P.M.M. and S.S.H.). Funding for M.G.B. was provided by a Draper Fellowship and to B.C.C. by an MIT Martin Fellowship. Draper thanks EPA region 9 for their partnership and support through a Cooperative Research and Development Agreement, an industry/government agreement regarding funding and personnel contributions of time and expertise.

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Blevins, M. G., Allen, H. L., Colson, B. C., Cook, A.-M., Greenbaum, A. Z., Hemami, S. S., Hollmann, J., Kim, E., LaRocca, A. A., Markoski, K. A., Miraglia, P., Mott, V. L., Robberson, W. M., Santos, J. A., Sprachman, M. M., Swierk, P., Tate, S., Witinski, M. F., Kratchman, L. B., & Michel, A. P. M. Field-portable microplastic sensing in aqueous environments: a perspective on emerging techniques. Sensors, 21(10), (2021): 3532, https://doi.org/10.3390/s21103532., Microplastics (MPs) have been found in aqueous environments ranging from rural ponds and lakes to the deep ocean. Despite the ubiquity of MPs, our ability to characterize MPs in the environment is limited by the lack of technologies for rapidly and accurately identifying and quantifying MPs. Although standards exist for MP sample collection and preparation, methods of MP analysis vary considerably and produce data with a broad range of data content and quality. The need for extensive analysis-specific sample preparation in current technology approaches has hindered the emergence of a single technique which can operate on aqueous samples in the field, rather than on dried laboratory preparations. In this perspective, we consider MP measurement technologies with a focus on both their eventual field-deployability and their respective data products (e.g., MP particle count, size, and/or polymer type). We present preliminary demonstrations of several prospective MP measurement techniques, with an eye towards developing a solution or solutions that can transition from the laboratory to the field. Specifically, experimental results are presented from multiple prototype systems that measure various physical properties of MPs: pyrolysis-differential mobility spectroscopy, short-wave infrared imaging, aqueous Nile Red labeling and counting, acoustophoresis, ultrasound, impedance spectroscopy, and dielectrophoresis., We greatly thank our funding agencies: Gerstner Philanthropies (to A.P.M.M.), the Richard Saltonstall Charitable Foundation (to A.P.M.M.), and the Wallace Research Foundation (to A.P.M.M. and S.S.H.). Funding for M.G.B. was provided by a Draper Fellowship and to B.C.C. by an MIT Martin Fellowship. Draper thanks EPA region 9 for their partnership and support through a Cooperative Research and Development Agreement, an industry/government agreement regarding funding and personnel contributions of time and expertise.

Microplastics (MPs) have been found in aqueous environments ranging from rural ponds and lakes to the deep ocean. Despite the ubiquity of MPs, our ability to characterize MPs in the environment is limited by the lack of technologies for rapidly and accurately identifying and quantifying MPs. Although standards exist for MP sample collection and preparation, methods of MP analysis vary considerably and produce data with a broad range of data content and quality. The need for extensive analysis-specific sample preparation in current technology approaches has hindered the emergence of a single technique which can operate on aqueous samples in the field, rather than on dried laboratory preparations. In this perspective, we consider MP measurement technologies with a focus on both their eventual field-deployability and their respective data products (e.g., MP particle count, size, and/or polymer type). We present preliminary demonstrations of several prospective MP measurement techniques, with an eye towards developing a solution or solutions that can transition from the laboratory to the field. Specifically, experimental results are presented from multiple prototype systems that measure various physical properties of MPs: pyrolysis-differential mobility spectroscopy, short-wave infrared imaging, aqueous Nile Red labeling and counting, acoustophoresis, ultrasound, impedance spectroscopy, and dielectrophoresis.

Stable isotope analyses were performed on gas samples collected within two instrumented biocovers, with the goal of evaluating CH4 oxidation efficiencies (f0). In each of the biocovers, gas probes were installed at four locations and at several depths. One of the biocovers was fed with biogas directly from the waste mass, whereas the other was fed through a gas distribution system that allowed monitoring of biogas fluxes. While the f0 values obtained at a depth of 0.1 m were low (between 0.0 and 25.2%) for profiles with poor aeration, they were high for profiles with better aeration, reaching 89.7%. Several interrelated factors affecting aeration seem to be influencing f0, including the degree of water saturation, the magnitude of the biogas flux, and the temperature within the substrate. Low f0 values do not mean necessarily that little CH4 was oxidized. In fact, in certain cases where the CH4 loading was high, the absolute amount of CH4 oxidized was quite high and comparable to the rate of CH4 oxidation for cases with low CH4 loading and high f0. For the experimental biocover for which the CH4 loading was known, the oxidation efficiency obtained using stable isotopes (f0 = 55.67% for samples taken inside flux chambers) was compared to the value obtained by mass balance (f0 = 70.0%). Several factors can explain this discrepancy, including: the high sensitivity of f0 to slight changes in the isotopic fractionation factor for bacterial oxidation, αox, uncertainties related to mass flow meter readings and to the static chamber method.

ImportanceOne major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders.ObservationsNational Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presen

PurposeRindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma.Patients and methodsIn this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2.ResultsBetween May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (P = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32-0.88; two-sided log-rank P = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; P = 0.38)], median duration of response [7.8 months (95% CI, 3.5-22.2) vs. 5.6 (95% CI, 3.7-7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07-0.45; P < 0.0001).ConclusionsOur randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM.See related commentary by Wick and Wagener, p. 1535.

ImportanceOne major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders.ObservationsNational Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presen

Contains fulltext : 228756.pdf (publisher's version ) (Open Access)

The dynamics and changes in the potential activity and community structure of methanotrophs in landfill covers, as a function of time and depth were investigated. A passive methane oxidation biocover (PMOB-1) was constructed in St-Nicéphore MSW Landfill (Quebec, Canada). The most probable number (MPN) method was used for methanotroph counts, methanotrophic diversity was assessed using denaturing gradient gel electrophoresis (DGGE) fingerprinting of the pmoA gene and the potential CH(4) oxidation rate was determined using soil microcosms. Results of the PMOB-1 were compared with those obtained for the existing landfill cover (silty clay) or a reference soil (RS). During the monitoring period, changes in the number of methanotrophic bacteria in the PMOB-1 exhibited different developmental phases and significant variations with depth. In comparison, no observable changes over time occurred in the number of methanotrophs in the RS. The maximum counts measured in the uppermost layer was 1.5x10(9) cells g dw(-1) for the PMOB-1 and 1.6x10(8) cells g dw(-1) for the RS. No distinct difference was observed in the methanotroph diversity in the PMOB-1 or RS. As expected, the potential methane oxidation rate was higher in the PMOB-1 than in the RS. The maximum potential rates were 441.1 and 76.0 microg CH(4) h(-1) g dw(-1) in the PMOB and RS, respectively. From these results, the PMOB was found to be a good technology to enhance methane oxidation, as its performance was clearly better than the starting soil that was present in the landfill site.

The effects of compost, nitrogen salts, and nitrogen-phosphorous-potassium (NPK) fertilizers on the methane oxidation potential (MOP) of landfill cover soil at various temperatures were assessed. For this, we used batch assays conducted at 5°C, 15°C, and 25°C with microcosms containing landfill cover soil slurries amended with these elements. Results indicated variable impacts dependent on the type of amendment and the incubation temperature. For a given incubation temperature, MOP varied from one compost to another and with the amount of compost added, except for the shrimp/peat compost. With this latter compost, independent of the amount, MOP values remained similar and were significantly higher than those obtained with other composts. Amendment with most of the tested nitrogen salts led to similar improvements in methanotrophic activity, except for urea. MOP with NPK fertilizer addition was amongst the highest in this study; the minimum value obtained with NPK (20-0-20) suggested the importance of P for methanotrophs. MOP generally increased with temperature, and nutrient limitation became less important at higher temperatures. Overall, at each of the three temperatures tested, MOP with NPK fertilizer amendments provided the best results and was comparable to those observed with the addition of the shrimp/peat compost. The results of this study provide the first evidence of the following: (1) compost addition to improve methanotrophic activity in a landfill cover soil should consider the amount and type of compost used and (2) the importance of using NPK fertilizers rather than nitrogen salts, in enhancing this activity, primarily at low temperatures. One can also consider the potential beneficial impact of adding these elements to enhance plant growth, which is an advantage for MOP.

An experimental landfill cover composed of a mixture of sand and compost was installed at the St-Nicéphore landfill in Québec (Canada). The mixture was evaluated as a potential substrate to promote methane (CH4) oxidation by methanotrophic bacteria. One of the objectives of this field project was to assess the efficiency of the cover in reducing CH4 emissions. For this, both CH4 abatement and the extent to which methanotrophic bacteria developed were followed over time and space in relation to environmental and physico-chemical variables. The results obtained during the first 4 months of monitoring indicated that precipitation and air temperature had a great impact on CH4 oxidation. Over the study period, different patterns in CH4 oxidation through the cover soil were observed; in certain cases, oxidation was observed at various depths, although the zone of optimum oxidation occurred mostly near the surface. However, in the second half of the monitoring period, almost no oxidation was observed at depths greater than 10-cm, presumably because of lack of oxygen at deeper zones within the cover. In the 0–10-cm zone, high numbers and large variability of particulate methane monooxygenase gene (pmoA) copy number were also observed. It is concluded that the adopted substrate has proved to be satisfactory in sustaining and promoting growth of methanotrophic bacteria. However, the water content of the soil seems to be a key factor influencing CH4 oxidation, to an extent that requires further investigation. The uppermost 0–10-cm layer seems to play a critical role in CH4 abatement: a closer examination of this role will take place in the near future, in part by conducting more measurements within this zone.

Three experimental biocovers were installed during the summer of 2006 at the St‐Nicéphore landfill in Québec (Canada). The main objectives of the experimental program were to assess the efficiency of these biocovers in reducing CH4 emissions and to monitor the evolution in space and time of the dynamics and diversity of methanotrophic bacteria that may be responsible for CH4 abatement. Dynamics of methanotroph populations derived from most probable number (MPN) counts exhibited different steps (lag, growth, and collapse phases), with mean abundances decreasing somewhat with depth. Methanotroph diversity, as assessed by denaturing gradient gel electrophoresis showed changes over time in the community structure. These changes were dependent on the sampling depth and only Type I methanotrophs belonging essentially to the genus Methylobacter were retrieved from our samples. Given the youthful character of the system under study, together with the reported behavior of this functional group of methanotrophs, it was concluded that Type I methanotrophs forming the community structure might reflect pioneer species with a potentially high growth rate (r‐strategists) that become numerically dominant reducing the evenness of species distribution. These results contribute to the generally limited body of knowledge on methanotroph diversity in landfill cover soils.

An experimental passive methane oxidation biocover (PMOB) was constructed within the existing final cover of the St-Nicéphore landfill. Its substrate consisted of a 0.80-m-thick mixture of sand and compost. The goal of this experiment was to evaluate the performance of the PMOB in reducing CH 4 CH4 emissions when submitted to an increasing methane load. The CH 4 CH4 load applied started with 9.3 g CH 4 m −2 d −1 9.3 g CH4 m−2 d−1 . When the site had to be closed for the winter, the CH 4 CH4 input was 820 g CH 4 m −2 d −1 820 g CH4 m−2 d−1 . Throughout the study, practically all the CH 4 CH4 input was oxidized; absolute removal rates were linearly correlated to methane loading; and the oxidation zone was established between 0.6–0.8 m. These results seem to indicate that the upper limit potential of this PMOB to oxidize CH 4 CH4 was not necessarily reached during the study period. Surface CH 4 CH4 concentration scans showed no signs of leaks. The substrate offered excellent conditions for the growth of methanotrophs, whose count averaged 3.91×10 8 CFU g dw −1 3.91×108 CFU g dw−1 soil.

PurposeRindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma.Patients and methodsIn this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2.ResultsBetween May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (P = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32-0.88; two-sided log-rank P = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; P = 0.38)], median duration of response [7.8 months (95% CI, 3.5-22.2) vs. 5.6 (95% CI, 3.7-7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07-0.45; P < 0.0001).ConclusionsOur randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM.See related commentary by Wick and Wagener, p. 1535.

ImportanceOne major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders.ObservationsNational Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presen

Contains fulltext : 228756.pdf (publisher's version ) (Open Access)

Three experimental biocovers were installed during the summer of 2006 at the St‐Nicéphore landfill in Québec (Canada). The main objectives of the experimental program were to assess the efficiency of these biocovers in reducing CH4 emissions and to monitor the evolution in space and time of the dynamics and diversity of methanotrophic bacteria that may be responsible for CH4 abatement. Dynamics of methanotroph populations derived from most probable number (MPN) counts exhibited different steps (lag, growth, and collapse phases), with mean abundances decreasing somewhat with depth. Methanotroph diversity, as assessed by denaturing gradient gel electrophoresis showed changes over time in the community structure. These changes were dependent on the sampling depth and only Type I methanotrophs belonging essentially to the genus Methylobacter were retrieved from our samples. Given the youthful character of the system under study, together with the reported behavior of this functional group of methanotrophs, it was concluded that Type I methanotrophs forming the community structure might reflect pioneer species with a potentially high growth rate (r‐strategists) that become numerically dominant reducing the evenness of species distribution. These results contribute to the generally limited body of knowledge on methanotroph diversity in landfill cover soils.

An experimental landfill cover composed of a mixture of sand and compost was installed at the St-Nicéphore landfill in Québec (Canada). The mixture was evaluated as a potential substrate to promote methane (CH4) oxidation by methanotrophic bacteria. One of the objectives of this field project was to assess the efficiency of the cover in reducing CH4 emissions. For this, both CH4 abatement and the extent to which methanotrophic bacteria developed were followed over time and space in relation to environmental and physico-chemical variables. The results obtained during the first 4 months of monitoring indicated that precipitation and air temperature had a great impact on CH4 oxidation. Over the study period, different patterns in CH4 oxidation through the cover soil were observed; in certain cases, oxidation was observed at various depths, although the zone of optimum oxidation occurred mostly near the surface. However, in the second half of the monitoring period, almost no oxidation was observed at depths greater than 10-cm, presumably because of lack of oxygen at deeper zones within the cover. In the 0–10-cm zone, high numbers and large variability of particulate methane monooxygenase gene (pmoA) copy number were also observed. It is concluded that the adopted substrate has proved to be satisfactory in sustaining and promoting growth of methanotrophic bacteria. However, the water content of the soil seems to be a key factor influencing CH4 oxidation, to an extent that requires further investigation. The uppermost 0–10-cm layer seems to play a critical role in CH4 abatement: a closer examination of this role will take place in the near future, in part by conducting more measurements within this zone.

An experimental passive methane oxidation biocover (PMOB) was constructed within the existing final cover of the St-Nicéphore landfill. Its substrate consisted of a 0.80-m-thick mixture of sand and compost. The goal of this experiment was to evaluate the performance of the PMOB in reducing CH 4 CH4 emissions when submitted to an increasing methane load. The CH 4 CH4 load applied started with 9.3 g CH 4 m −2 d −1 9.3 g CH4 m−2 d−1 . When the site had to be closed for the winter, the CH 4 CH4 input was 820 g CH 4 m −2 d −1 820 g CH4 m−2 d−1 . Throughout the study, practically all the CH 4 CH4 input was oxidized; absolute removal rates were linearly correlated to methane loading; and the oxidation zone was established between 0.6–0.8 m. These results seem to indicate that the upper limit potential of this PMOB to oxidize CH 4 CH4 was not necessarily reached during the study period. Surface CH 4 CH4 concentration scans showed no signs of leaks. The substrate offered excellent conditions for the growth of methanotrophs, whose count averaged 3.91×10 8 CFU g dw −1 3.91×108 CFU g dw−1 soil.

The effects of compost, nitrogen salts, and nitrogen-phosphorous-potassium (NPK) fertilizers on the methane oxidation potential (MOP) of landfill cover soil at various temperatures were assessed. For this, we used batch assays conducted at 5°C, 15°C, and 25°C with microcosms containing landfill cover soil slurries amended with these elements. Results indicated variable impacts dependent on the type of amendment and the incubation temperature. For a given incubation temperature, MOP varied from one compost to another and with the amount of compost added, except for the shrimp/peat compost. With this latter compost, independent of the amount, MOP values remained similar and were significantly higher than those obtained with other composts. Amendment with most of the tested nitrogen salts led to similar improvements in methanotrophic activity, except for urea. MOP with NPK fertilizer addition was amongst the highest in this study; the minimum value obtained with NPK (20-0-20) suggested the importance of P for methanotrophs. MOP generally increased with temperature, and nutrient limitation became less important at higher temperatures. Overall, at each of the three temperatures tested, MOP with NPK fertilizer amendments provided the best results and was comparable to those observed with the addition of the shrimp/peat compost. The results of this study provide the first evidence of the following: (1) compost addition to improve methanotrophic activity in a landfill cover soil should consider the amount and type of compost used and (2) the importance of using NPK fertilizers rather than nitrogen salts, in enhancing this activity, primarily at low temperatures. One can also consider the potential beneficial impact of adding these elements to enhance plant growth, which is an advantage for MOP.

The dynamics and changes in the potential activity and community structure of methanotrophs in landfill covers, as a function of time and depth were investigated. A passive methane oxidation biocover (PMOB-1) was constructed in St-Nicéphore MSW Landfill (Quebec, Canada). The most probable number (MPN) method was used for methanotroph counts, methanotrophic diversity was assessed using denaturing gradient gel electrophoresis (DGGE) fingerprinting of the pmoA gene and the potential CH(4) oxidation rate was determined using soil microcosms. Results of the PMOB-1 were compared with those obtained for the existing landfill cover (silty clay) or a reference soil (RS). During the monitoring period, changes in the number of methanotrophic bacteria in the PMOB-1 exhibited different developmental phases and significant variations with depth. In comparison, no observable changes over time occurred in the number of methanotrophs in the RS. The maximum counts measured in the uppermost layer was 1.5x10(9) cells g dw(-1) for the PMOB-1 and 1.6x10(8) cells g dw(-1) for the RS. No distinct difference was observed in the methanotroph diversity in the PMOB-1 or RS. As expected, the potential methane oxidation rate was higher in the PMOB-1 than in the RS. The maximum potential rates were 441.1 and 76.0 microg CH(4) h(-1) g dw(-1) in the PMOB and RS, respectively. From these results, the PMOB was found to be a good technology to enhance methane oxidation, as its performance was clearly better than the starting soil that was present in the landfill site.

Mexican bean beetle, Epilachna varivestis Mulsant, is a pest of snap bean and lima bean in the eastern United States. This pest is susceptible to many insecticides available to conventional growers; however, organic management using parasitoid releases and organic insecticides have inconsistent results. In the interest of developing cultural management techniques such as trap crops or push-pull systems, five bean cultivars were evaluated for preferential host selection by E. varivestis using marked beetles in field cages and open plots. Beetles were marked with a water-based paint pen and their locations on plants monitored over time. In field cages, the purple wax bean, Dragon's Tongue (DT), was preferred over yellow wax, green bean and lima bean; soybean was the least preferred overall. Recaptures of E. varivestis adults in open field plots progressively decreased following beetle release, suggesting the affinity of adults to disperse despite being on or near acceptable hosts. The two wax beans were equally preferred in open field experiments, partially more than the green and lima bean and consistently more than the soybean. These experiments suggest that DT may be a suitable crop for trap cropping or attract and kill strategies for E. varivestis. © The Author(s) 2019. Published by Oxford University Press on behalf of Entomological Society of America.

Background Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM. Methods M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5-1.5 mg/kg) on days 1 and 15, and TMZ (150-200 mg/m 2) on days 1-5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve. Results There were 60 patients, median age 56 years (range, 20-79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%. Conclusions Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).

Mexican bean beetle, Epilachna varivestis Mulsant, is a pest of snap bean and lima bean in the eastern United States. This pest is susceptible to many insecticides available to conventional growers; however, organic management using parasitoid releases and organic insecticides have inconsistent results. In the interest of developing cultural management techniques such as trap crops or push-pull systems, five bean cultivars were evaluated for preferential host selection by E. varivestis using marked beetles in field cages and open plots. Beetles were marked with a water-based paint pen and their locations on plants monitored over time. In field cages, the purple wax bean, Dragon's Tongue (DT), was preferred over yellow wax, green bean and lima bean; soybean was the least preferred overall. Recaptures of E. varivestis adults in open field plots progressively decreased following beetle release, suggesting the affinity of adults to disperse despite being on or near acceptable hosts. The two wax beans were equally preferred in open field experiments, partially more than the green and lima bean and consistently more than the soybean. These experiments suggest that DT may be a suitable crop for trap cropping or attract and kill strategies for E. varivestis. © The Author(s) 2019. Published by Oxford University Press on behalf of Entomological Society of America.

Describes the Mexican bean beetle and presents various methods for control

The susceptibility of western corn rootworm, Diabrotica virgifera virgifera LeConte, larvae to nine insecticides from five different classes and to Bt proteins eCry3.1Ab and mCry3A in the presence or absence of feeding stimulants, was estimated in filter paper and diet toxicity assays, respectively. The use of a synthetic feeding stimulant blend of the sugars glucose, sucrose, and fructose plus linoleic acid at a ratio of 30:4:4:0.3 mg/ml of distilled water was evaluated to determine whether they increase the efficacy of insecticides and Bt proteins. The efficacy of thiamethoxam diluted in solutions with feeding stimulants was significantly increased when compared to thiamethoxam dilutions in water (>60-fold). Differences in the efficacy of the other insecticide classes when diluted in feeding stimulant solutions were no greater than fivefold when compared to the insecticides diluted in water. The presence of corn root juice as a natural feeding stimulant diminished toxicity of the insecticides, except for thiamethoxam, even though larval fresh weight was higher when fed on root juice compared to feeding stimulant or water. The use of feeding stimulants in diet toxicity assays did not enhance efficacy of eCry3.1Ab nor mCry3A proteins. Feeding stimulants can be recommended in combination with thiamethoxam to increase larval mortality. These results are discussed in terms of applicability of feeding stimulants to improve susceptibility of western corn rootworm larvae to pesticides in general.

Feeding behaviour, feeding intensity and staying behaviour of neonate western corn rootworm larvae (Diabrotica virgifera virgifera LeConte) were evaluated in response to synthetic feeding stimulant blends to determine larval preferences among the three maize root sugars (glucose, fructose and sucrose) in the active blend and to determine whether any single sugar can substitute for the 3-sugar combination in a feeding stimulant blend. These experiments demonstrated the strong affinity that western corn rootworm larvae have for the natural sugars found in maize roots and also showed that sucrose is the most preferred of the three primary maize root sugars. The blend containing sucrose at 30 mg/ml elicited feeding that was not significantly different than the natural glucose:fructose:sucrose blend. In subtraction bioassays, removal of sucrose from the blend resulted in significantly fewer larvae feeding. When the three-sugar blend was substituted with one of the number of various mono-, di-or trisaccharides, fewer larvae fed on all of the treatments compared to the blend with sucrose, except for the blend with maltose. In feeding choice tests, larvae preferred a blend containing sucrose over blends with either glucose or fructose, but larvae chose equally between a blend with sucrose and a blend containing the three-sugar mixture found in maize roots. Based on these results, a feeding stimulant blend with glucose (30 mg/ml), fructose (4 mg/ml) and sucrose (4 mg/ml) elicits the strongest feeding response, but sucrose alone, in amounts equivalent to the total maize root sugar concentration (30 mg/ml), could serve as a substitute for the 3-sugar mixture in a synthetic feeding stimulant blend.

Thiamethoxam is a neonicotinoid insecticide commonly applied directly to the seeds (seed-treatment) of commercial snap beans, Phaseolus vulgaris L. While previous studies have examined target and nontarget effects of thiamethoxam seed-treatments in snap beans and other crops, to our knowledge, none have been conducted in agroecosystems predominated by the pest Mexican bean beetle, Epilachna varivestis Mulsant (Coleoptera: Coccinellidae). This study examined the effects of thiamethoxam-treated snap beans on E. varivestis, other arthropods, and crop performance in southwestern Virginia. Greenhouse experiments were conducted to evaluate residual toxicity of treated snap beans to E. varivestis and a key predator, Podisus maculiventris (Say) (Hemiptera: Pentatomidae). Treated plants were highly toxic to E. varivestis at 13 d, moderately toxic from 16 to 20 d, and minimally toxic at 24 d. P. maculiventris was unaffected by exposure to treated plants or by feeding on E. varivestis that consumed treated plants. Small plot field experiments in 2014 and 2015 showed no significant effects of thiamethoxam seed-treatments on E. varivestis densities, other arthropods, crop injury, or yield. In 2016, planting was delayed by persistent rain, resulting in early E. varivestis colonization. In this year, thiamethoxam-treated plants had significantly lower densities and feeding injury from E. varivestis, followed by significantly higher yields. Natural enemies were unaffected by seed-treatments in all field experiments. These experiments demonstrated that thiamethoxam seed-treatments provide control of E. varivestis when beetles infest fields within 2 to 3 wk after planting; but otherwise provide negligible advantages. Negative effects from thiamethoxam seed-treatments on nontarget arthropods appear minimal for snap beans in this region.

The brownmarmorated stink bug, Halyomorpha halys (Stal), is an invasive species from Asia capable of causing severe agricultural damage. It can also be a nuisance pest when it enters and exits anthropogenic overwintering sites. In recent years, pheromone lures and traps for H. halys have been developed and used to monitor populations in field studies. To date, no study has investigated the applicability of these monitoring tools for use indoors by building residents during the overwintering period. Herein, we 1) assessed when in late winter (diapause) and spring (postdiapause) H. halys begins to respond to its pheromone (10,11-epoxy-1-bisabolen-3-ol), 2) evaluated whether pheromone-based tools can be used reliably for monitoring H. halys adults in unheated and heated buildings, and 3) elucidated the potential for indoor management using pheromone-baited traps. A 2-yr trapping study suggested that H. halys began to respond reliably to pheromone-baited traps after a critical photoperiod of 13.5h in the spring. Captures before that point were not correlated with visual counts of bugs in buildings despite robust populations, suggesting currently available pheromone-baited traps were ineffective for surveillance of diapausing H. halys. Finally, because baited traps captured only 8-20% of the adult H. halys known to be present per location, they were not an effective indoor management tool for overwintering H. halys. Our study contributes important knowledge about the capacity of H. halys to perceive its pheromone during overwintering, and the ramifications thereof for building residents with nuisance problems.

The Mexican bean beetle, Epilachna varivestis Mulsant, is a major pest of snap beans, Phaseolus vulgaris L. in the Central Appalachian region of the United States. To develop pertinent research objectives, background information on this pest was gathered from literature sources and personal communications with growers, extension agents and other agricultural professionals. In objective one, Mexican bean beetle preference, developmental success and plant injury were compared among three snap bean and three lima bean cultivars in field and greenhouse trials. The cultivar 'Dragon's Tongue' was the most preferred, suitable for development, and prone to injury. Growers may benefit from growing less susceptible cultivars, or by using 'Dragon's Tongue' in trap cropping or push-pull strategies. In objective two, Mexican bean beetle densities, feeding injury, and yield were compared among snap beans grown on metallized plastic (highly reflective), white plastic, black plastic, and bare soil. Metallized plastic provided the greatest level of control, and resulted in the highest yields. Managing Mexican bean beetle by growing beans on metallized plastic may be used as a stand-alone method, or in a push-pull strategy. In the final objective, the effects of snap beans grown from thiamethoxam (a neonicotinoid insecticide)-treated seeds on Mexican bean beetle were assessed in greenhouse and field experiments. Thiamethoxam-treated plants killed 40 to 50% of Mexican bean beetle adults and larvae up to 16 days after planting. In the field, thiamethoxam-treated plants mitigated Mexican bean beetle densities and damage in one out of five experiments, resulting in a yield increase. In none of the five field experiments were differences detected in predatory arthropod species between thiamethoxam and non-insecticide treated beans. In summary, the results of this project suggest that non-chemical management methods, such as cultivar selection and planting beans on reflective mulch, can pr

Thiamethoxam is a neonicotinoid insecticide commonly applied directly to the seeds (seed-treatment) of commercial snap beans, Phaseolus vulgaris L. While previous studies have examined target and nontarget effects of thiamethoxam seed-treatments in snap beans and other crops, to our knowledge, none have been conducted in agroecosystems predominated by the pest Mexican bean beetle, Epilachna varivestis Mulsant (Coleoptera: Coccinellidae). This study examined the effects of thiamethoxam-treated snap beans on E. varivestis, other arthropods, and crop performance in southwestern Virginia. Greenhouse experiments were conducted to evaluate residual toxicity of treated snap beans to E. varivestis and a key predator, Podisus maculiventris (Say) (Hemiptera: Pentatomidae). Treated plants were highly toxic to E. varivestis at 13 d, moderately toxic from 16 to 20 d, and minimally toxic at 24 d. P. maculiventris was unaffected by exposure to treated plants or by feeding on E. varivestis that consumed treated plants. Small plot field experiments in 2014 and 2015 showed no significant effects of thiamethoxam seed-treatments on E. varivestis densities, other arthropods, crop injury, or yield. In 2016, planting was delayed by persistent rain, resulting in early E. varivestis colonization. In this year, thiamethoxam-treated plants had significantly lower densities and feeding injury from E. varivestis, followed by significantly higher yields. Natural enemies were unaffected by seed-treatments in all field experiments. These experiments demonstrated that thiamethoxam seed-treatments provide control of E. varivestis when beetles infest fields within 2 to 3 wk after planting; but otherwise provide negligible advantages. Negative effects from thiamethoxam seed-treatments on nontarget arthropods appear minimal for snap beans in this region.

The brownmarmorated stink bug, Halyomorpha halys (Stal), is an invasive species from Asia capable of causing severe agricultural damage. It can also be a nuisance pest when it enters and exits anthropogenic overwintering sites. In recent years, pheromone lures and traps for H. halys have been developed and used to monitor populations in field studies. To date, no study has investigated the applicability of these monitoring tools for use indoors by building residents during the overwintering period. Herein, we 1) assessed when in late winter (diapause) and spring (postdiapause) H. halys begins to respond to its pheromone (10,11-epoxy-1-bisabolen-3-ol), 2) evaluated whether pheromone-based tools can be used reliably for monitoring H. halys adults in unheated and heated buildings, and 3) elucidated the potential for indoor management using pheromone-baited traps. A 2-yr trapping study suggested that H. halys began to respond reliably to pheromone-baited traps after a critical photoperiod of 13.5h in the spring. Captures before that point were not correlated with visual counts of bugs in buildings despite robust populations, suggesting currently available pheromone-baited traps were ineffective for surveillance of diapausing H. halys. Finally, because baited traps captured only 8-20% of the adult H. halys known to be present per location, they were not an effective indoor management tool for overwintering H. halys. Our study contributes important knowledge about the capacity of H. halys to perceive its pheromone during overwintering, and the ramifications thereof for building residents with nuisance problems.

The Medieval Review, (dlps) baj9928.0611.004, (tmr) 06.11.04, http://quod.lib.umich.edu/t/text/accesspolicy.html

The Medieval Review, (dlps) baj9928.0611.004, (tmr) 06.11.04, http://quod.lib.umich.edu/t/text/accesspolicy.html

Mexican bean beetle, Epilachna varivestis Mulsant, is an invasive, phytophagous ladybeetle that has occurred in the United States since the late 1800s. In the 1970s, it was a major defoliating pest of soybeans in the eastern United States, before populations mysteriously crashed. Today, the insect remains a devastating pest of Phaseolus species, such as common bean, P. vulgaris, and lima bean, P. lunatus, in geographic locations with moderate summer temperatures and regular rainfall, such as the Mid-Atlantic and southern Appalachian Mountain regions of the United States. Larvae and adults injure plants by consuming leaf tissue, which promotes desiccation and decreases photosynthetic activity. Beetle damage can be successfully mitigated with various insecticides (both conventional and organic), or via augmentative releases of the biological control agent, Pediobius foveolatus (Crawford). Various cultural and mechanical management tactics also exhibit management potential; however, more research is necessary to determine specific criteria for effective implementation of these strategies. This paper will review the general biology of Mexican bean beetle, management options to mitigate crop damage, and its historical timeline as a pest in the United States.

Mexican bean beetle, Epilachna varivestis Mulsant, is an invasive, phytophagous ladybeetle that has occurred in the United States since the late 1800s. In the 1970s, it was a major defoliating pest of soybeans in the eastern United States, before populations mysteriously crashed. Today, the insect remains a devastating pest of Phaseolus species, such as common bean, P. vulgaris, and lima bean, P. lunatus, in geographic locations with moderate summer temperatures and regular rainfall, such as the Mid-Atlantic and southern Appalachian Mountain regions of the United States. Larvae and adults injure plants by consuming leaf tissue, which promotes desiccation and decreases photosynthetic activity. Beetle damage can be successfully mitigated with various insecticides (both conventional and organic), or via augmentative releases of the biological control agent, Pediobius foveolatus (Crawford). Various cultural and mechanical management tactics also exhibit management potential; however, more research is necessary to determine specific criteria for effective implementation of these strategies. This paper will review the general biology of Mexican bean beetle, management options to mitigate crop damage, and its historical timeline as a pest in the United States.