The impacts of pesticides on biodiversity of off-target organisms are neglected, and current conservation strategies pay little attention to these issues. Particularly the sublethal effects of ...chemical compounds used in agriculture and forestry are poorly understood, despite they may have detrimental effects on populations of the affected off-target organisms. Here, we tested the effects of 11 benzimidazole fungicides. Benzimidazole fungicides are still being widely used as broad-spectrum plant fungicides in agriculture since 1960s. We tested their effects on the fecundity and survival of queens of Myrmica rubra, a common farmland ant species, following the oral administration of the fungicides for a period of six weeks. We found that ethanolic solutions, as well as water suspensions of all but one tested benzimidazole fungicides, inhibited significantly the fecundity of M. rubra queens; in addition, the flusilazole was lethal when administered at 1.0 and 0.1 mg ml−1. Combined data suggest that the whole class of benzimidazole fungicides has detrimental sublethal effects on the tested ant species and substantially decrease the fitness of the study species. The fact that common farmland species suffer from the effects the application of any of the whole class of fungicides questions their currently widespread use as agricultural fungicides. These findings bring into question the safety of agricultural benzimidazole fungicides and we recommend that their routine spraying should be re-assessed by regulatory agencies.
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•Conservation implications of pesticides' impacts are insufficiently recognized.•Benzimidazole fungicides are massively used in agriculture for over five decades.•Benzimidazole fungicides are detrimental to common farmland ants.•All but one benzimidazole fungicides inhibited the fecundity of M. rubra queens.•Flusilazole was lethal to M. rubra queens when administered at 100 μg/ml p.o.
Patients with diffuse large B-cell lymphoma or follicular lymphoma that is refractory to or that relapses after immunochemotherapy and transplantation have a poor prognosis. High response rates have ...been reported with the use of T cells modified by chimeric antigen receptor (CAR) that target CD19 in B-cell cancers, although data regarding B-cell lymphomas are limited.
We used autologous T cells that express a CD19-directed CAR (CTL019) to treat patients with diffuse large B-cell lymphoma or follicular lymphoma that had relapsed or was refractory to previous treatments. Patients were monitored for response to treatment, toxic effects, the expansion and persistence of CTL019 cells in vivo, and immune recovery.
A total of 28 adult patients with lymphoma received CTL019 cells, and 18 of 28 had a response (64%; 95% confidence interval CI, 44 to 81). Complete remission occurred in 6 of 14 patients with diffuse large B-cell lymphoma (43%; 95% CI, 18 to 71) and 10 of 14 patients with follicular lymphoma (71%; 95% CI, 42 to 92). CTL019 cells proliferated in vivo and were detectable in the blood and bone marrow of patients who had a response and patients who did not have a response. Sustained remissions were achieved, and at a median follow-up of 28.6 months, 86% of patients with diffuse large B-cell lymphoma who had a response (95% CI, 33 to 98) and 89% of patients with follicular lymphoma who had a response (95% CI, 43 to 98) had maintained the response. Severe cytokine-release syndrome occurred in 5 patients (18%). Serious encephalopathy occurred in 3 patients (11%); 2 cases were self-limiting and 1 case was fatal. All patients in complete remission by 6 months remained in remission at 7.7 to 37.9 months (median, 29.3 months) after induction, with a sustained reappearance of B cells in 8 of 16 patients and with improvement in levels of IgG in 4 of 10 patients and of IgM in 6 of 10 patients at 6 months or later and in levels of IgA in 3 of 10 patients at 18 months or later.
CTL019 cells can be effective in the treatment of relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. High rates of durable remission were observed, with recovery of B cells and immunoglobulins in some patients. Transient encephalopathy developed in approximately one in three patients and severe cytokine-release syndrome developed in one in five patients. (Funded by Novartis and others; ClinicalTrials.gov number, NCT02030834 .).
By analyzing almost 120 000 dinucleotides in over 2000 nonredundant nucleic acid crystal structures, we define 96+1 diNucleotide Conformers, NtCs, which describe the geometry of RNA and DNA ...dinucleotides. NtC classes are grouped into 15 codes of the structural alphabet CANA (Conformational Alphabet of Nucleic Acids) to simplify symbolic annotation of the prominent structural features of NAs and their intuitive graphical display. The search for nontrivial patterns of NtCs resulted in the identification of several types of RNA loops, some of them observed for the first time. Over 30% of the nearly six million dinucleotides in the PDB cannot be assigned to any NtC class but we demonstrate that up to a half of them can be re-refined with the help of proper refinement targets. A statistical analysis of the preferences of NtCs and CANA codes for the 16 dinucleotide sequences showed that neither the NtC class AA00, which forms the scaffold of RNA structures, nor BB00, the DNA most populated class, are sequence neutral but their distributions are significantly biased. The reported automated assignment of the NtC classes and CANA codes available at dnatco.org provides a powerful tool for unbiased analysis of nucleic acid structures by structural and molecular biologists.
Background: Dramaturgy is a specific method of course design and conduct used in experiential education in the Czech Republic. However, little is known about how the application of dramaturgy affects ...participants in experiential education. This paper explores dramaturgy in a winter expeditionary course organized by Vacation School Lipnice and participants' experience. Objective: Firstly, to explicate how the dramaturgy was used to design and conduct a winter expeditionary course by Vacation School Lipnice. Secondly, to explore the participants' experience. Methods: Content analysis was employed, using data from twelve unstructured interviews made with the course participants. Results: Four main themes representing participants' experience emerged from the interviews: a) inner self-experience, reflecting on life; b) relationships with others; c) nature; and d) embodiment and physical demands. These four underlying aspects have turned out to be relevant to the course dramaturgy in a number of ways. Considering the dramaturgy of the course, the main theme of the course was a pilgrimage not only to certain goal, but also to oneself. This theme was transformed into a practical programme of a long winter journey on snowshoes. Conclusions: The dramaturgy approach was found useful in the design of the experiential education course, positively contributing to the participants' experience.
CD19-directed chimeric antigen receptor-modified (CAR T) T cells achieve durable remissions in about 30% to 40% of relapsed/refractory large B-cell lymphomas. T-cell exhaustion and/or an ...immunosuppressive tumor microenvironment may contribute to CAR T-cell failure. Pembrolizumab, an anti-PD1 immune checkpoint inhibitor, may reverse T-cell exhaustion after CAR T-cell therapy. We treated 12 patients with B-cell lymphomas who were either refractory to (n = 9) or relapsed after (n = 3) CD19-directed CAR T-cell (4-1BB-costimulated) therapy with pembrolizumab 200 mg IV every 3 weeks. Median time from CAR T-cell infusion to first pembrolizumab dose was 3.3 months (range, 0.4-42.8 months). Pembrolizumab was well tolerated, and the only grade ≥3 adverse events related to pembrolizumab were neutropenia (n = 3; 25%). Best overall response rate after pembrolizumab was 25% (3 of 12 patients; 1 complete response; 2 partial responses). One (8%) patient had stable disease; thus, 4 of 12 (33%) patients had clinical benefit. After pembrolizumab, 4 patients with clinical benefit had an increase in percentage of CAR T cells by mass cytometry by time of flight (CyTOF); 3 of 4 of these patients also had increases in CAR19 transgene levels by quantitative polymerase chain reaction. Deep immune profiling using CyTOF revealed increased CAR T-cell activation and proliferation and less T-cell exhaustion in clinical responders. Together, PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy appears safe and may achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy. This trial was registered at www.clinicaltrials.gove as #NCT02650999.
Summary
Chimeric antigen receptor (CAR) T cells (CART) therapies have changed and continue to change the treatment paradigms for B‐cell malignancies because they can achieve durable complete ...remission in patients in whom multiple lines of treatment have failed. These unprecedented results have led to the widespread use of anti‐CD19 CART therapy for patients with relapsed and refractory aggressive large B‐cell lymphomas. While long‐term follow‐up data show that about one‐third of patients achieve prolonged complete remission and are potentially cured, the majority of patients either do not respond to CD19 CART therapy or eventually relapse after CD19 CART therapy. These results are, on the one hand, driving intense research into identifying mechanisms of relapse and, on the other hand, inspiring the development of novel strategies to overcome resistance. This review summarizes current clinical outcomes of CART immunotherapy in B‐cell non‐Hodgkin lymphomas, describes the most up‐to‐date understanding of mechanisms of relapse and discusses novel strategies to address resistance to CART therapy. We are indeed at the beginning of a scientific trek to explore the mechanisms of resistance, seek out new, more effective treatment approaches based on these discoveries and to boldly go where no other therapy has gone before!
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