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\"Nobody performs better under pressure. Regardless of the task, pressure ruthlessly diminishes our judgment, decision-making, attention, dexterity, and performance in every professional and personal arena. In [this book], we are introduced to the concept of pressure management, offering a score of empirically tested strategies to help us overcome the sabotaging effects of pressure\"-- Provided by publisher.

Key Points Interleukin-7 (IL-7) is required for T cell development in mice and humans and is produced by stromal tissues rather than activated lymphocytes. Under normal conditions, IL-7 is a limiting resource for T cells, but it accumulates during lymphopenic conditions. IL-7 signals through a heterodimeric receptor consisting of the IL-7 receptor α-chain (IL-7Rα) and the common cytokine receptor γ-chain (γc). IL-7 is not required for human B cell development in fetal life, but it affects early B cell progenitors and contributes to B cell development under normal conditions. IL-7 has also been recently demonstrated to regulate lymphoid tissue inducer (LTi) cells, which induce the development of secondary lymphoid organs and can induce tertiary lymphoid tissue postnatally in settings of chronic inflammation. In animals, IL-7 therapy enhances the effectiveness of adoptive immunotherapy for cancer, enhances vaccine responses and enhances viral clearance in the setting of acute and chronic infections. In mature T cells, IL-7Rα is most highly expressed on recent thymic emigrants, maintained on naive T cells, downregulated upon T cell activation, and re-expressed on memory T cell subsets. As a result, treatment with recombinant human IL-7 (rhIL-7) preferentially expands recent thymic emigrants and naive T cells, as well as central memory T cells, but largely spares senescent T cells and regulatory T cells. This results in increased repertoire diversity following rhIL-7 therapy in humans. Clinical results with rhIL-7 thus far have shown it to be well tolerated with dose-dependent increases in T cell numbers that persist long after the cytokine is cleared. Based on the pharmacological and biological properties demonstrated thus far, IL-7 is particularly well-suited as a therapy for conditions associated with lymphocyte immunodeficiency. Multiple trials are ongoing or planned in HIV infection, other chronic infections (including hepatitis B and C), cancer (including as an adjuvant to immune-based therapies), post-haematopoietic stem cell transplantation and ageing. Interleukin-7 (IL-7) induces T cell proliferation and enhances antigen-specific immune responses: attributes that pinpoint its value as a potential therapeutic agent. This Review summarizes preclinical and clinical data on the immunorestorative effects of IL-7 in various pathologies and discusses the conditions for which IL-7 therapy might be of use. Interleukin-7 (IL-7) is required for T cell development and for maintaining and restoring homeostasis of mature T cells. IL-7 is a limiting resource under normal conditions, but it accumulates during lymphopaenia, leading to increased T cell proliferation. The administration of recombinant human IL-7 to normal or lymphopenic mice, non-human primates and humans results in widespread T cell proliferation, increased T cell numbers, modulation of peripheral T cell subsets and increased T cell receptor repertoire diversity. These effects raise the prospect that IL-7 could mediate therapeutic benefits in several clinical settings. This Review summarizes the biology of IL-7 and the results of its clinical use that are available so far to provide a perspective on the opportunities for clinical application of this cytokine.

At the Rocky Mountain Biogenic Aerosol Study (BEACHON-RoMBAS) field campaign in the Colorado front range, July–August 2011, measurements of gas- and aerosol-phase organic nitrates enabled a study of the role of NOx (NOx = NO + NO2) in oxidation of forest-emitted volatile organic compounds (VOCs) and subsequent aerosol formation. Substantial formation of peroxy- and alkyl-nitrates is observed every morning, with an apparent 2.9% yield of alkyl nitrates from daytime RO2 + NO reactions. Aerosol-phase organic nitrates, however, peak in concentration during the night, with concentrations up to 140 ppt as measured by both optical spectroscopic and mass spectrometric instruments. The diurnal cycle in aerosol fraction of organic nitrates shows an equilibrium-like response to the diurnal temperature cycle, suggesting some reversible absorptive partitioning, but the full dynamic range cannot be reproduced by thermodynamic repartitioning alone. Nighttime aerosol organic nitrate is observed to be positively correlated with [NO2] × [O3] but not with [O3]. These observations support the role of nighttime NO3-initiated oxidation of monoterpenes as a significant source of nighttime aerosol. Nighttime production of organic nitrates is comparable in magnitude to daytime photochemical production at this site, which we postulate to be representative of the Colorado front range forests.

Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic leukaemia (ALL). Persisting CAR-T cells generate sustained pressure against CD19 that may drive unique mechanisms of resistance. Pre-B ALL originates from a committed pre-B cell or an earlier progenitor, with potential to reprogram into other hematopoietic lineages. Here we report changes in lineage markers including myeloid conversion in patients following CD19 CAR therapy. Using murine ALL models we study the long-term effects of CD19 CAR-T cells and demonstrate partial or complete lineage switch as a consistent mechanism of CAR resistance depending on the underlying genetic oncogenic driver. Deletion of Pax5 or Ebf1 recapitulates lineage reprogramming occurring during CD19 CAR pressure. Our findings establish lineage switch as a mechanism of CAR resistance exposing inherent plasticity in genetic subtypes of pre-B-cell ALL. CAR-T targeting CD19 have been successfully used in a variety of B-cell malignancies but patients may eventually relapse. Here, the authors show that CD19 CAR-T resistance in pre-B cell ALL can be due to the induction of a myeloid lineage switch through an epigenetic alterations in master regulators of B cell development.

Manufacturing autologous chimeric antigen receptor (CAR) T cell therapeutics is complex, and many patients experience treatment delays or cannot be treated at all. Although current allogeneic CAR products have the potential to overcome manufacturing bottlenecks, they are subject to immune rejection and failure to persist in the host, and thus do not provide the same level of efficacy as their autologous counterparts. Here, we aimed to develop universal allogeneic CAR T cells that evade the immune system and produce a durable response. We generated human hypoimmune (HIP) T cells with disrupted B2M, CIITA , and TRAC genes using CRISPR-Cas9 editing. In addition, CD47 and anti-CD19 CAR were expressed using lentiviral transduction. These allogeneic HIP CD19 CAR T cells were compared to allogeneic CD19 CAR T cells that only expressed the anti-CD19 CAR (allo CAR T). In vitro assays for cancer killing and exhaustion revealed no differences between allo CAR T and HIP CAR T cells, confirming that the HIP edits did not negatively affect T cell performance. Clearance of CD19 + tumors by HIP CAR T cells in immunodeficient NSG mice was comparable to that of allo CAR T cells. In fully immunocompetent humanized mice, HIP CAR T cells significantly outperformed allo CAR T cells, showed improved persistence and expansion, and provided lasting cancer clearance. Furthermore, CD47-targeting safety strategies reliably and specifically eliminated HIP CAR T cells. These findings suggest that universal allogeneic HIP CAR T cell-based therapeutics might overcome the limitations associated with poor persistence of allogeneic CAR T cells and exert durable anti-tumor responses. The development of allogeneic chimaeric antigen receptor (CAR) T cells could overcome manufacturing bottlenecks for immunotherapy. However, immune rejection reduces the persistence and efficacy of these cells. Here, the authors generate allogeneic anti-CD19 CAR T cells that can evade the immune system and provide durable anti-tumour responses.

Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1–30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3 + 3 design to establish the maximum tolerated dose, patients received either 1 × 106 CAR-transduced T cells per kg (dose 1), 3 × 106 CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696. Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1 × 106 CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0–36·3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients). CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. National Institutes of Health Intramural funds and St Baldrick's Foundation.

Immune effector cell (IEC) therapies offer durable and sustained remissions in significant numbers of patients with hematological cancers. While these unique immunotherapies have improved outcomes for pediatric and adult patients in a number of disease states, as ‘living drugs,’ their toxicity profiles, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), differ markedly from conventional cancer therapeutics. At the time of article preparation, the US Food and Drug Administration (FDA) has approved tisagenlecleucel, axicabtagene ciloleucel, and brexucabtagene autoleucel, all of which are IEC therapies based on genetically modified T cells engineered to express chimeric antigen receptors (CARs), and additional products are expected to reach marketing authorization soon and to enter clinical development in due course. As IEC therapies, especially CAR T cell therapies, enter more widespread clinical use, there is a need for clear, cohesive recommendations on toxicity management, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of common toxicities in the context of IEC treatment, including baseline laboratory parameters for monitoring, timing to onset, and pharmacological interventions, ultimately forming evidence- and consensus-based recommendations to assist medical professionals in decision-making and to improve outcomes for patients.

The Late Devonian was a protracted period of low speciation resulting in biodiversity decline, culminating in extinction events near the Devonian–Carboniferous boundary. Recent evidence indicates that the final extinction event may have coincided with a dramatic drop in stratospheric ozone, possibly due to a global temperature rise. Here we study an alternative possible cause for the postulated ozone drop: a nearby supernova explosion that could inflict damage by accelerating cosmic rays that can deliver ionizing radiation for up to ∼ 100 ky. We therefore propose that the end-Devonian extinctions were triggered by supernova explosions at ∼ 20 pc, somewhat beyond the “kill distance” that would have precipitated a full mass extinction. Such nearby supernovae are likely due to core collapses of massive stars; these are concentrated in the thin Galactic disk where the Sun resides. Detecting either of the long-lived radioisotopes 146Sm or 244Pu in one or more end-Devonian extinction strata would confirm a supernova origin, point to the core-collapse explosion of a massive star, and probe supernova nucleosynthesis. Other possible tests of the supernova hypothesis are discussed.