Search

The fundamental goal of a rare plant translocation is to create self-sustaining populations with the evolutionary resilience to persist in the long term. Yet, most plant translocation syntheses focus on a few factors influencing short-term benchmarks of success (e.g., survival and reproduction). Short-term benchmarks can be misleading when trying to infer future growth and viability because the factors that promote establishment may differ from those required for long-term persistence. We assembled a large (n = 275) and broadly representative data set of well-documented and monitored (7.9 years on average) at-risk plant translocations to identify the most important site attributes, management techniques, and species' traits for six life-cycle benchmarks and population metrics of translocation success. We used the random forest algorithm to quantify the relative importance of 29 predictor variables for each metric of success. Drivers of translocation outcomes varied across time frames and success metrics. Management techniques had the greatest relative influence on the attainment of life-cycle benchmarks and short-term population trends, whereas site attributes and species' traits were more important for population persistence and long-term trends. Specifically, large founder sizes increased the potential for reproduction and recruitment into the next generation, whereas declining habitat quality and the outplanting of species with low seed production led to increased extinction risks and a reduction in potential reproductive output in the long-term, respectively. We also detected novel interactions between some of the most important drivers, such as an increased probability of next-generation recruitment in species with greater seed production rates, but only when coupled with large founder sizes. Because most significant barriers to plant translocation success can be overcome by improving techniques or resolving site-level issues through early intervention and management, we suggest that by combining long-term monitoring with adaptive management, translocation programs can enhance the prospects of achieving long-term success., (© 2023 The Authors. Conservation Biology published by Wiley Periodicals LLC on behalf of Society for Conservation Biology.)

Purpose: New immuno-oncology therapies targeting programmed cell death receptor 1 (PD-1) have improved patient outcomes in a broad range of cancers. The objective of this analysis was to evaluate the PK, pharmacodynamics (PDy), and safety of dostarlimab monotherapy in adult patients with previously-treated advanced solid tumors who participated in parts 1 and 2A of the phase 1 GARNET study., Methods: Part 1 featured a 3 + 3 weight-based dose-escalation study, in which 21 patients received dostarlimab 1, 3, or 10 mg/kg intravenously every 2 weeks. The 2 fixed-dose nonweight-based dosing regimens of dostarlimab 500 mg every 3 weeks (Q3W) and 1000 mg every 6 weeks (Q6W) were evaluated using a modified 6 + 6 design in part 2A (n = 13). In parts 1 and 2A, treatment with dostarlimab could continue for up to 2 years or until progression, unacceptable toxicity, patient withdrawal, investigator's decision, or death., Results: The dostarlimab PK profile was dose proportional, and maximal achievable receptor occupancy (RO) was observed at all dose levels in the weight-based and fixed-dose cohorts. Trough dostarlimab concentration after administration of dostarlimab 500 mg Q3W was similar to that after dostarlimab 1000 mg Q6W, the values of which (≈40 µg/mL) projected well above the lowest dostarlimab concentration required for full peripheral RO. No dose-limiting toxicities were observed., Conclusions: Dostarlimab demonstrated consistent and predictable PK and associated PDy. The observed safety profile was acceptable and characteristic of the anti-PD-1 drug class., Trial Registration: ClinicalTrials.gov, NCT02715284. Registration date: March 9, 2016., (© 2021. The Author(s).)

Blockade of the inhibitory receptor TIM-3 shows efficacy in cancer immunotherapy clinical trials. TIM-3 inhibits production of the chemokine CXCL9 by XCR1 + classical dendritic cells (cDC1), thereby limiting antitumor immunity in mammary carcinomas. We found that increased CXCL9 expression by splenic cDC1s upon TIM-3 blockade required type I interferons and extracellular DNA. Chemokine expression as well as combinatorial efficacy of TIM-3 blockade and paclitaxel chemotherapy were impaired by deletion of Cgas and Sting. TIM-3 blockade increased uptake of extracellular DNA by cDC1 through an endocytic process that resulted in cytoplasmic localization. DNA uptake and efficacy of TIM-3 blockade required DNA binding by HMGB1, while galectin-9-induced cell surface clustering of TIM-3 was necessary for its suppressive function. Human peripheral blood cDC1s also took up extracellular DNA upon TIM-3 blockade. Thus, TIM-3 regulates endocytosis of extracellular DNA and activation of the cytoplasmic DNA sensing cGAS-STING pathway in cDC1s, with implications for understanding the mechanisms underlying TIM-3 immunotherapy., Competing Interests: Declaration of interests This work was supported in part by a sponsored research agreement with TESARO. J.K. is an employee of GSK and K.M. was an employee of TESARO. H.S. has received payments from Novartis International AG for consulting and advisory boards. B.R. has received payments from Merck & Co. and Roche Farma S.A. for consulting. H.S., V.C.L., P.C.R., and B.R. have courtesy faculty appointments at the University of South Florida, Tampa., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This study provides the first measurement of microplastic abundance and distribution in surface waters and sediments in Tampa Bay, FL. Microplastic concentrations in discrete water samples ranged from 0.25 to 7.0 particles/L with an average of 0.94 (±0.52) particles/L. Samples taken with a 330 μm plankton net had 1.2-18.1 particles/m 3 with an average of 4.5 (±2.3) particles/m 3 . Discrete samples were 200 times higher than net samples, suggesting substantial losses or undersampling with the net. For both discrete and plankton tow samples, there were no significant differences in concentrations between stations or regions. Intense rainfall events in the summer always preceded samples with substantially higher counts. Most (>75%) microplastics were fibers. Using an average value of 1 particle/L, Tampa Bay contains ~4 billion microplastic particles. Surface sediments had an average of 280 (±290) particles/kg, ranging from 30 to 790 particles/kg. Highest concentrations of microplastics were found in sediments close to industrial sources; lowest values in Middle and Lower Tampa Bay are consistent with shorter residence times., (Copyright © 2019. Published by Elsevier Ltd.)

Purpose: To determine the tumor tissue/cell distribution, functional associations, and clinical significance of PD-1, LAG-3, and TIM-3 protein expression in human non-small cell lung cancer (NSCLC)., Experimental Design: Using multiplexed quantitative immunofluorescence, we performed localized measurements of CD3, PD-1, LAG-3, and TIM-3 protein in >800 clinically annotated NSCLCs from three independent cohorts represented in tissue microarrays. Associations between the marker's expression and major genomic alterations were studied in The Cancer Genome Atlas NSCLC dataset. Using mass cytometry (CyTOF) analysis of leukocytes collected from 20 resected NSCLCs, we determined the levels, coexpression, and functional profile of PD-1, LAG-3, and TIM-3 expressing immune cells. Finally, we measured the markers in baseline samples from 90 patients with advanced NSCLC treated with PD-1 axis blockers and known response to treatment., Results: PD-1, LAG-3, and TIM-3 were detected in tumor-infiltrating lymphocytes (TIL) from 55%, 41.5%, and 25.3% of NSCLC cases, respectively. These markers showed a prominent association with each other and limited association with major clinicopathologic variables and survival in patients not receiving immunotherapy. Expression of the markers was lower in EGFR-mutated adenocarcinomas and displayed limited association with tumor mutational burden. In single-cell CyTOF analysis, PD-1 and LAG-3 were predominantly localized on T-cell subsets/NKT cells, whereas TIM-3 expression was higher in NK cells and macrophages. Coexpression of PD-1, LAG-3, and TIM-3 was associated with prominent T-cell activation (CD69/CD137), effector function (Granzyme-B), and proliferation (Ki-67), but also with elevated levels of proapoptotic markers (FAS/BIM). LAG-3 and TIM-3 were present in TIL subsets lacking PD-1 expression and showed a distinct functional profile. In baseline samples from 90 patients with advanced NSCLC treated with PD-1 axis blockers, elevated LAG-3 was significantly associated with shorter progression-free survival., Conclusions: PD-1, LAG-3, and TIM-3 have distinct tissue/cell distribution, functional implications, and genomic correlates in human NSCLC. Expression of these immune inhibitory receptors in TILs is associated with prominent activation, but also with a proapoptotic T-cell phenotype. Elevated LAG-3 expression is associated with insensitivity to PD-1 axis blockade, suggesting independence of these immune evasion pathways., (©2019 American Association for Cancer Research.)

Background: Proviral integration Moloney virus (PIM) kinases (PIM1, 2 and 3) are overexpressed in several tumour types and contribute to oncogenesis. AZD1208 is a potent ATP-competitive PIM kinase inhibitor investigated in patients with recurrent or refractory acute myeloid leukaemia (AML) or advanced solid tumours., Methods: Two dose-escalation studies were performed to evaluate the safety and tolerability, and to define the maximum tolerated dose (MTD), of AZD1208 in AML and solid tumours. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics (PD) and preliminary efficacy of AZD1208., Results: Sixty-seven patients received treatment: 32 in the AML study over a 120-900 mg dose range, and 25 in the solid tumour study over a 120-800 mg dose range. Nearly all patients (98.5%) in both studies experienced adverse events, mostly gastrointestinal (92.5%). Dose-limiting toxicities included rash, fatigue and vomiting. AZD1208 was not tolerated at 900 mg, and the protocol-defined MTD was not confirmed. AZD1208 increased CYP3A4 activity after multiple dosing, resulting in increased drug clearance. There were no clinical responses; PD analysis showed biological activity of AZD1208., Conclusions: Despite the lack of single-agent clinical efficacy with AZD1208, PIM kinase inhibition may hold potential as an anticancer treatment, perhaps in combination with other agents.

Background: Healthcare has become increasingly complex and care delivery models have changed dramatically (eg, team-based care, duty-hour restrictions). However, approaches to critical communications among providers have not evolved to meet these new challenges. Evidence from safety culture surveys, academic studies and malpractice claims suggests that healthcare handover quality is problematic, leading to preventable errors and adverse outcomes. To address this concern, from 2013 to 2016 Massachusetts General Hospital completed phase I of a multifaceted programme to implement standardised, structured handovers across all departments, units and direct care providers., Methods: A multidisciplinary Handovers Committee selected the I-PASS handover system. Phase I implementation focused on large-scale training and shift-to-shift handovers. Important features included administrative and clinical leadership support; EHR templates for I-PASS; hospital handover policy revision; varied educational modalities, venues and durations; concomitant TeamSTEPPS training; unit-level I-PASS champions; handover observations; and solicitation of caregiver feedback and suggestions., Results: More than 6000 doctors, nurses and therapists have been trained. Trended observation scores demonstrate progressive but non-uniform adoption of I-PASS, with significant improvements in the correct sequencing and percentage of I-PASS elements included in handovers. Adoption of Synthesis (readback) has been challenging, with lower scores., Conclusions: Comprehensive I-PASS implementation in a large academic medical centre necessitated major cultural change. I-PASS education is straightforward, whereas assuring consistent and sustained adoption across all services is more challenging, requiring adaptation of the basic I-PASS structure to local needs and workflows. EHR I-PASS templates facilitated caregiver acceptance. Initial phase I results are encouraging and the lessons learned should be helpful to other programmes planning handover initiatives. Phase II is ongoing, focusing on more uniform and consistent adoption, spread and sustainability., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Here we identified increased copy number and expression of the PIM1 proto-oncogene in genomic data sets of patients with TNBC. TNBC cells, but not nonmalignant mammary epithelial cells, were dependent on PIM1 for proliferation and protection from apoptosis. PIM1 knockdown reduced expression of the anti-apoptotic factor BCL2, and dynamic BH3 profiling of apoptotic priming revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines. In TNBC tumors and their cellular models, PIM1 expression was associated with several transcriptional signatures involving the transcription factor MYC, and PIM1 depletion in TNBC cell lines decreased, in a MYC-dependent manner, cell population growth and expression of the MYC target gene MCL1. Treatment with the pan-PIM kinase inhibitor AZD1208 impaired the growth of both cell line and patient-derived xenografts and sensitized them to standard-of-care chemotherapy. This work identifies PIM1 as a malignant-cell-selective target in TNBC and the potential use of PIM1 inhibitors for sensitizing TNBC to chemotherapy-induced apoptotic cell death.

MET, the receptor for hepatocyte growth factor (HGF), plays an important role in signaling normal and tumor cell migration and invasion. Here, we describe a previously unrecognized mechanism that promotes MET expression in multiple tumor cell types. The levels of the Pim-1 protein kinase show a positive correlation with the levels of MET protein in human tumor cell lines and patient-derived tumor materials. Using small interfering RNA (siRNA), Pim knockout mice, small-molecule inhibitors, and overexpression of Pim-1, we confirmed this correlation and found that Pim-1 kinase activity regulates HGF-induced tumor cell migration, invasion, and cell scattering. The novel biochemical mechanism for these effects involves the ability of Pim-1 to control the translation of MET by regulating the phosphorylation of eukaryotic initiation factor 4B (eIF4B) on S406. This targeted phosphorylation is required for the binding of eIF4B to the eIF3 translation initiation complex. Importantly, Pim-1 action was validated by the evaluation of patient blood and bone marrow from a phase I clinical trial of a Pim kinase inhibitor, AZD1208. These results suggest that Pim inhibitors may have an important role in the treatment of patients where MET is driving tumor biology., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Upregulation of Pim kinases is observed in several types of leukemias and lymphomas. Pim-1, -2, and -3 promote cell proliferation and survival downstream of cytokine and growth factor signaling pathways. AZD1208 is a potent, highly selective, and orally available Pim kinase inhibitor that effectively inhibits all three isoforms at <5 nM or <150 nM in enzyme and cell assays, respectively. AZD1208 inhibited the growth of 5 of 14 acute myeloid leukemia (AML) cell lines tested, and sensitivity correlates with Pim-1 expression and STAT5 activation. AZD1208 causes cell cycle arrest and apoptosis in MOLM-16 cells, accompanied by a dose-dependent reduction in phosphorylation of Bcl-2 antagonist of cell death, 4EBP1, p70S6K, and S6, as well as increases in cleaved caspase 3 and p27. Inhibition of p4EBP1 and p-p70S6K and suppression of translation are the most representative effects of Pim inhibition in sensitive AML cell lines. AZD1208 inhibits the growth of MOLM-16 and KG-1a xenograft tumors in vivo with a clear pharmacodynamic-pharmacokinetic relationship. AZD1208 also potently inhibits colony growth and Pim signaling substrates in primary AML cells from bone marrow that are Flt3 wild-type or Flt3 internal tandem duplication mutant. These results underscore the therapeutic potential of Pim kinase inhibition for the treatment of AML.

Uncertainty associated with ecological forecasts has long been recognized, but forecast accuracy is rarely quantified. We evaluated how well data on 82 populations of 20 species of plants spanning 3 continents explained and predicted plant population dynamics. We parameterized stage-based matrix models with demographic data from individually marked plants and determined how well these models forecast population sizes observed at least 5 years into the future. Simple demographic models forecasted population dynamics poorly; only 40% of observed population sizes fell within our forecasts' 95% confidence limits. However, these models explained population dynamics during the years in which data were collected; observed changes in population size during the data-collection period were strongly positively correlated with population growth rate. Thus, these models are at least a sound way to quantify population status. Poor forecasts were not associated with the number of individual plants or years of data. We tested whether vital rates were density dependent and found both positive and negative density dependence. However, density dependence was not associated with forecast error. Forecast error was significantly associated with environmental differences between the data collection and forecast periods. To forecast population fates, more detailed models, such as those that project how environments are likely to change and how these changes will affect population dynamics, may be needed. Such detailed models are not always feasible. Thus, it may be wiser to make risk-averse decisions than to expect precise forecasts from models., (© 2013 Society for Conservation Biology.)

The concept that life emerged where alkaline hydrogen-bearing submarine hot springs exhaled into the most ancient acidulous ocean was used as a working hypothesis to investigate the nature of precipitate membranes. Alkaline solutions at 25-70°C and pH between 8 and 12, bearing HS(-)±silicate, were injected slowly into visi-jars containing ferrous chloride to partially simulate the early ocean on this or any other wet and icy, geologically active rocky world. Dependent on pH and sulfide content, fine tubular chimneys and geodal bubbles were generated with semipermeable walls 4-100 μm thick that comprised radial platelets of nanometric mackinawite [FeS]±ferrous hydroxide [∼Fe(OH)(2)], accompanied by silica and, at the higher temperature, greigite [Fe(3)S(4)]. Within the chimney walls, these platelets define a myriad of micropores. The interior walls of the chimneys host iron sulfide framboids, while, in cases where the alkaline solution has a pH>11 or relatively low sulfide content, their exteriors exhibit radial flanges with a spacing of ∼4 μm that comprise microdendrites of ferrous hydroxide. We speculate that this pattern results from outward and inward radial flow through the chimney walls. The outer Fe(OH)(2) flanges perhaps precipitate where the highly alkaline flow meets the ambient ferrous iron-bearing fluid, while the intervening troughs signal where the acidulous iron-bearing solutions could gain access to the sulfidic and alkaline interior of the chimneys, thereby leading to the precipitation of the framboids. Addition of soluble pentameric peptides enhances membrane durability and accentuates the crenulations on the chimney exteriors. These dynamic patterns may have implications for acid-base catalysis and the natural proton motive force acting through the matrix of the porous inorganic membrane. Thus, within such membranes, steep redox and pH gradients would bear across the nanometric platelets and separate the two counter-flowing solutions, a condition that may have led to the onset of an autotrophic metabolism through the reduction of carbon dioxide.

Fabry disease is an X-linked glycosphingolipid storage disorder caused by a deficiency in the activity of the lysosomal hydrolase α-galactosidase A (α-gal). This deficiency results in accumulation of the glycosphingolipid globotriaosylceramide (GL-3) in lysosomes. Endothelial cell storage of GL-3 frequently leads to kidney dysfunction, cardiac and cerebrovascular disease. The current treatment for Fabry disease is through infusions of recombinant α-gal (enzyme-replacement therapy; ERT). Although ERT can markedly reduce the lysosomal burden of GL-3 in endothelial cells, variability is seen in the clearance from several other cell types. This suggests that alternative and adjuvant therapies may be desirable. Use of glucosylceramide synthase inhibitors to abate the biosynthesis of glycosphingolipids (substrate reduction therapy, SRT) has been shown to be effective at reducing substrate levels in the related glycosphingolipidosis, Gaucher disease. Here, we show that such an inhibitor (eliglustat tartrate, Genz-112638) was effective at lowering GL-3 accumulation in a mouse model of Fabry disease. Relative efficacy of SRT and ERT at reducing GL-3 levels in Fabry mouse tissues differed with SRT being more effective in the kidney, and ERT more efficacious in the heart and liver. Combination therapy with ERT and SRT provided the most complete clearance of GL-3 from all the tissues. Furthermore, treatment normalized urine volume and uromodulin levels and significantly delayed the loss of a nociceptive response. The differential efficacies of SRT and ERT in the different tissues indicate that the combination approach is both additive and complementary suggesting the possibility of an improved therapeutic paradigm in the management of Fabry disease.

Persistent activation of Stat3 is oncogenic and is prevalent in a wide variety of human cancers. Chronic cytokine stimulation is associated with Stat3 activation in some tumors, implicating cytokine receptor-associated Jak family kinases. Using Jak2 inhibitors, we demonstrate a central role of Jaks in modulating basal and cytokine-induced Stat3 activation in human solid tumor cell lines. Inhibition of Jak2 activity is associated with abrogation of Stat3 nuclear translocation and tumorigenesis. The Jak2 inhibitor AZD1480 suppresses the growth of human solid tumor xenografts harboring persistent Stat3 activity. We demonstrate the essential role of Stat3 downstream of Jaks by inhibition of tumor growth using short hairpin RNA targeting Stat3. Our data support a key role of Jak kinase activity in Stat3-dependent tumorigenesis.