Older patients hospitalized for heart failure were randomly assigned to a rehabilitation intervention (which included multiple function domains) or control; the intervention began during, or early ...after, hospitalization and continued for 3 months. At 3 months, physical function, as assessed by the Short Physical Performance Battery, was better in the intervention group than in the control group.
Objectives The American College of Surgeons Oncology Group trial Z0060 is a prospective multi-institutional trial with a primary objective to evaluate whether positron emission tomography (PET) with ...F-18 fluorodeoxyglucose (FDG) detects evidence of metastastic disease that precludes esophagectomy in patients with esophageal cancer who are surgical candidates after routine staging. Methods Patients with resectable, biopsy-proven carcinoma were enrolled after computed tomography of chest and abdomen demonstrated no evidence of metastasis. FDG-PET was performed according to specified standards. FDG-PET findings suggesting metastases required confirmation and patients without metastases on PET were expected to proceed to surgery. Results A total of 262 patients were registered. Of these, 199 were deemed eligible and of these, 189 patients were evaluable. Seventy-three patients were ineligible or unevaluable. Reasons for ineligibility included nonresectable disease by routine staging (39), missing or outdated staging procedures (12), PET technical protocol violations (10), no cancer (4), pre-PET induction therapy (3), claustrophobia (1), and other causes (4). There were 145 (78%) patients who went on to have surgery, 42 (22%) who did not, and 2 patients for whom the surgical status was not determined. The reasons for no resection included the following: M1 disease found by PET and confirmed (9), M1 disease found by PET and not confirmed (2), M1 disease at exploration not found by PET (7), decline or death before surgery (10), patient refusal of surgery (7), unresectable local tumor at exploration (5), and extensive N1 disease precluding operation (2). Eight (4.2%) patients undergoing resection had a recurrence in the first 6 months. Conclusions Although 22% of eligible patients did not undergo esophagectomy, FDG-PET after standard clinical staging for esophageal carcinoma identified confirmed M1b disease in at least 4.8% (95% confidence interval: 2.2%-8.9%) of patients before resection. Unconfirmed PET evidence of M1 disease and regional adenopathy (N1 disease) led to definitive nonsurgical or induction therapy in additional patients.
Foundation species define the ecosystems they live in, but ecologists have often characterized dominant plants as foundational without supporting evidence. Giant kelp has long been considered a ...marine foundation species due to its complex structure and high productivity; however, there is little quantitative evidence to evaluate this. Here, we apply structural equation modelling to a 15-year time series of reef community data to evaluate how giant kelp affects the reef community. Although species richness was positively associated with giant kelp biomass, most direct paths did not involve giant kelp. Instead, the foundational qualities of giant kelp were driven mostly by indirect effects attributed to its dominant physical structure and associated engineering influence on the ecosystem, rather than by its use as food by invertebrates and fishes. Giant kelp structure has indirect effects because it shades out understorey algae that compete with sessile invertebrates. When released from competition, sessile species in turn increase the diversity of mobile predators. Sea urchin grazing effects could have been misinterpreted as kelp effects, because sea urchins can overgraze giant kelp, understorey algae and sessile invertebrates alike. Our results confirm the high diversity and biomass associated with kelp forests, but highlight how species interactions and habitat attributes can be misconstrued as direct consequences of a foundation species like giant kelp.
Bitter taste receptors (taste family 2 bitter receptor proteins; T2Rs), discovered in many tissues outside the tongue, have recently become potential therapeutic targets. We have shown previously ...that airway epithelial cells express several T2Rs that activate innate immune responses that may be important for treatment of airway diseases such as chronic rhinosinusitis. It is imperative to more clearly understand what compounds activate airway T2Rs as well as their full range of functions. T2R isoforms in airway motile cilia (T2R4, -14, -16, and -38) produce bactericidal levels of nitric oxide (NO) that also increase ciliary beating, promoting clearance of mucus and trapped pathogens. Bacterial quorum-sensing acyl-homoserine lactones activate T2Rs and stimulate these responses in primary airway cells. Quinolones are another type of quorum-sensing molecule used by Pseudomonas aeruginosa. To elucidate whether bacterial quinolones activate airway T2Rs, we analyzed calcium, cAMP, and NO dynamics using a combination of fluorescent indicator dyes and FRET-based protein biosensors. T2R-transfected HEK293T cells, several lung epithelial cell lines, and primary sinonasal cells grown and differentiated at the air–liquid interface were tested with 2-heptyl-3-hydroxy-4-quinolone (known as Pseudomonas quinolone signal; PQS), 2,4-dihydroxyquinolone, and 4-hydroxy-2-heptylquinolone (HHQ). In HEK293T cells, PQS activated T2R4, -16, and -38, whereas HHQ activated T2R14. 2,4-Dihydroxyquinolone had no effect. PQS and HHQ increased calcium and decreased both baseline and stimulated cAMP levels in cultured and primary airway cells. In primary cells, PQS and HHQ activated levels of NO synthesis previously shown to be bactericidal. This study suggests that airway T2R-mediated immune responses are activated by bacterial quinolones as well as acyl-homoserine lactones.
The aim of the current study was to report the efficacy of topical and systemic treatments for immune-related cutaneous adverse events (ircAEs) attributed to checkpoint inhibitors in an uncontrolled ...cohort of patients referred to oncodermatology clinics.
A retrospective analysis of patients with ircAEs evaluated by dermatologists from January 1, 2014, to December 31, 2017, at three tertiary care hospitals and cancer centers were identified through electronic medical records. Clinicopathologic characteristics, dermatologic therapy outcome, and laboratory data were analyzed.
A total of 285 patients (median age, 65 years range, 17 to 89 years) with 427 ircAEs were included: pruritus (n = 138; 32%), maculopapular rash (n = 120; 28%), psoriasiform rash (n = 22; 5%), and others (n = 147; 34%). Immune checkpoint inhibitor class was associated with ircAE phenotype (
= .007), where maculopapular rash was predominant in patients who received combination therapy. Severity of ircAEs was significantly reduced (mean Common Terminology Criteria for Adverse Events grade: 1.74
0.71;
< .001) with dermatologic interventions, including topical corticosteroids, oral antipruritics, and systemic immunomodulators. A total of 88 ircAEs (20%) were managed with systemic immunomodulators. Of these, 22 (25%) of 88 persisted or worsened. In seven patients with corticosteroid-refractory ircAEs, improvement resulted from targeted biologic immunomodulatory therapies that included rituximab and dupilumab. Serum interleukin-6 (IL-6) was elevated in 34 (52%) of 65 patients; grade 3 or greater ircAEs were associated with increased absolute eosinophils (odds ratio, 4.1; 95% CI, 1.3 to 13.4) and IL-10 (odds ratio, 23.8; 95% CI, 2.1 to 262.5); mean immunoglobulin E serum levels were greater in higher-grade ircAEs: 1,093 kU/L (grade 3), 245 kU/L (grade 2), and 112 kU/L (grade 1;
= .043).
Most ircAEs responded to symptom- and phenotype-directed dermatologic therapies, whereas biologic therapies were effective in patients with corticosteroid-refractory disease. Increased eosinophils, IL-6, IL-10, and immunoglobulin E were associated with ircAEs, and they may represent actionable therapeutic targets for immune-related skin toxicities.
This paper introduces many objective robust decision making (MORDM). MORDM combines concepts and methods from many objective evolutionary optimization and robust decision making (RDM), along with ...extensive use of interactive visual analytics, to facilitate the management of complex environmental systems. Many objective evolutionary search is used to generate alternatives for complex planning problems, enabling the discovery of the key tradeoffs among planning objectives. RDM then determines the robustness of planning alternatives to deeply uncertain future conditions and facilitates decision makers' selection of promising candidate solutions. MORDM tests each solution under the ensemble of future extreme states of the world (SOW). Interactive visual analytics are used to explore whether solutions of interest are robust to a wide range of plausible future conditions (i.e., assessment of their Pareto satisficing behavior in alternative SOW). Scenario discovery methods that use statistical data mining algorithms are then used to identify what assumptions and system conditions strongly influence the cost-effectiveness, efficiency, and reliability of the robust alternatives. The framework is demonstrated using a case study that examines a single city's water supply in the Lower Rio Grande Valley (LRGV) in Texas, USA. Results suggest that including robustness as a decision criterion can dramatically change the formulation of complex environmental management problems as well as the negotiated selection of candidate alternatives to implement. MORDM also allows decision makers to characterize the most important vulnerabilities for their systems, which should be the focus of ex post monitoring and identification of triggers for adaptive management.
► We generate planning alternatives for complex systems and test them for robustness. ► The framework confronts deep uncertainty, where stakeholders cannot agree on risks. ► Visualizations show how solutions' performance changes under uncertain conditions. ► Water portfolio planning with risk-based decisions is used as a demonstration. ► Robustness as a decision criterion transforms selection of candidate alternatives.
The proteasome is the central protease for intracellular protein breakdown. Coordinated binding and hydrolysis of ATP by the six proteasomal ATPase subunits induces conformational changes that drive ...the unfolding and translocation of substrates into the proteolytic 20S core particle for degradation. Here, we combine genetic and biochemical approaches with cryo-electron microscopy and integrative modeling to dissect the relationship between individual nucleotide binding events and proteasome conformational dynamics. We demonstrate unique impacts of ATP binding by individual ATPases on the proteasome conformational distribution and report two conformational states of the proteasome suggestive of a rotary ATP hydrolysis mechanism. These structures, coupled with functional analyses, reveal key roles for the ATPases Rpt1 and Rpt6 in gating substrate entry into the core particle. This deepened knowledge of proteasome conformational dynamics reveals key elements of intersubunit communication within the proteasome and clarifies the regulation of substrate entry into the proteolytic chamber.
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•Proteasomal ATPases differently control conformational remodeling and activation•Individual ATP-binding events promote gating of the substrate passageway•Substrate access to the proteolytic sites is controlled by Rpt1 and Rpt6 C termini•Conformational states suggest a sequential rotary ATP hydrolysis mechanism
The proteasome must undergo ATP-dependent conformational reorganizations to be activated for substrate degradation. Eisele et al. uncover the roles of individual ATP-binding events in these reorganizations and reveal the molecular mechanism by which a gated pore into the proteolytic chamber is opened.
Kelp forests (Order Laminariales) form key biogenic habitats in coastal regions of temperate and Arctic seas worldwide, providing ecosystem services valued in the range of billions of dollars ...annually. Although local evidence suggests that kelp forests are increasingly threatened by a variety of stressors, no comprehensive global analysis of change in kelp abundances currently exists. Here, we build and analyze a global database of kelp time series spanning the past half-century to assess regional and global trends in kelp abundances. We detected a high degree of geographic variation in trends, with regional variability in the direction and magnitude of change far exceeding a small global average decline (instantaneous rate of change = −0.018 y−1). Our analysis identified declines in 38% of ecoregions for which there are data (−0.015 to −0.18 y−1), increases in 27% of ecoregions (0.015 to 0.11 y−1), and no detectable change in 35% of ecoregions. These spatially variable trajectories reflected regional differences in the drivers of change, uncertainty in some regions owing to poor spatial and temporal data coverage, and the dynamic nature of kelp populations. We conclude that although global drivers could be affecting kelp forests at multiple scales, local stressors and regional variation in the effects of these drivers dominate kelp dynamics, in contrast to many other marine and terrestrial foundation species.
Background & Aims Hepatocellular carcinoma (HCC) has limited treatment options; long-term outcomes following intra-arterial radiation are unknown. We assessed clinical outcomes of patients treated ...with intra-arterial yttrium-90 microspheres (Y90). Methods Patients with HCC (n = 291) were treated with Y90 as part of a single-center, prospective, longitudinal cohort study. Toxicities were recorded using the Common Terminology Criteria version 3.0. Response rate and time to progression (TTP) were determined using World Health Organization (WHO) and European Association for the Study of the Liver (EASL) guidelines. Survival by stage was assessed. Univariate/multivariate analyses were performed. Results A total of 526 treatments were administered (mean, 1.8; range, 1–5). Toxicities included fatigue (57%), pain (23%), and nausea/vomiting (20%); 19% exhibited grade 3/4 bilirubin toxicity. The 30-day mortality rate was 3%. Response rates were 42% and 57% based on WHO and EASL criteria, respectively. The overall TTP was 7.9 months (95% confidence interval, 6–10.3). Survival times differed between patients with Child–Pugh A and B disease (A, 17.2 months; B, 7.7 months; P = .002). Patients with Child–Pugh B disease who had portal vein thrombosis (PVT) survived 5.6 months (95% confidence interval, 4.5–6.7). Baseline age; sex; performance status; presence of portal hypertension; tumor distribution; levels of bilirubin, albumin, and α-fetoprotein; and WHO/EASL response rate predicted survival. Conclusions Patients with Child–Pugh A disease, with or without PVT, benefited most from treatment. Patients with Child–Pugh B disease who had PVT had poor outcomes. TTP and overall survival varied by patient stage at baseline. These data can be used to design future Y90 trials and to describe Y90 as a potential treatment option for patients with HCC.
Innate and adaptive defense mechanisms protect the respiratory system from attack by microbes. Here, we present evidence that the bitter taste receptor T2R38 regulates the mucosal innate defense of ...the human upper airway. Utilizing immunofluorescent and live cell imaging techniques in polarized primary human sinonasal cells, we demonstrate that T2R38 is expressed in human upper respiratory epithelium and is activated in response to acyl-homoserine lactone quorum-sensing molecules secreted by Pseudomonas aeruginosa and other gram-negative bacteria. Receptor activation regulates calcium-dependent NO production, resulting in stimulation of mucociliary clearance and direct antibacterial effects. Moreover, common polymorphisms of the TAS2R38 gene were linked to significant differences in the ability of upper respiratory cells to clear and kill bacteria. Lastly, TAS2R38 genotype correlated with human sinonasal gram-negative bacterial infection. These data suggest that T2R38 is an upper airway sentinel in innate defense and that genetic variation contributes to individual differences in susceptibility to respiratory infection.
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