Bayesian Learning and Predictability in a Stochastic Nonlinear Dynamical Model

Bayesian inference methods are applied within a Bayesian hierarchical modelling framework to the problems of joint state and parameter estimation, and of state forecasting. We explore and demonstrate the ideas in the context of a simple nonlinear marine biogeochemical model. A novel approach is proposed to the formulation of the stochastic process model, in which ecophysiological properties of plankton communities are represented by autoregressive stochastic processes. This approach captures the effects of changes in plankton communities over time, and it allows the incorporation of literature metadata on individual species into prior distributions for process model parameters. The approach is applied to a case study at Ocean Station Papa, using Particle Markov chain Monte Carlo computational techniques. The results suggest that, by drawing on objective prior information, it is possible to extract useful information about model state and a subset of parameters, and even to make useful long-term forecasts, based on sparse and noisy observations

Strategic trastuzumab mediated crosslinking driving concomitant HER2 and HER3 endocytosis and degradation in breast cancer

Efficacious anticancer therapies for targeting plasma membrane receptors with antibody based therapeutics are often contingent on sufficient endocytic delivery of receptor and conjugate to lysosomes. This results in downregulation of receptor activity and, in the case of antibody-drug conjugates (ADCs), intracellular release of a drug payload. The oncogenic receptor HER2 is a priority therapeutic target in breast cancer. Known as an “endocytosis resistant” receptor, HER2 thwarts the receptor downregulating efficiency of the frontline treatment trastuzumab and reduces the potential of trastuzumab-based therapies such as trastuzumab-emtansine. We previously demonstrated that strategically inducing trastuzumab and HER2 crosslinking in breast cancer cells promoted endocytosis and lysosomal delivery of the HER2-trastuzumab complex, stimulating downregulation of the receptor. Here we reveal that HER3, but not EGFR, is also concomitantly downregulated with HER2 after crosslinking. This is accompanied by strong activation of MEK/ERK pathway that we show does not directly contribute to HER2/trastuzumab endocytosis. We show that crosslinking induced trastuzumab endocytosis occurs via clathrin-dependent and independent pathways and is an actin-dependent process. Detailed ultrastructural studies of the plasma membrane highlight crosslinking-specific remodelling of microvilli and induction of extensive ruffling. Investigations in a cell model of acquired trastuzumab resistance demonstrate, for the first time, that they are refractory to crosslinking induced HER2 endocytosis and downregulation. This implicates further arrest of HER2 internalisation in developing trastuzumab resistance. Overall our findings highlight the potential of receptor crosslinking as a therapeutic strategy for cancer while exposing the ability of cancer cells to develop resistance via endocytic mechanisms

Glacial and Postglacial Deposits of Northeastern Ohio

Author Institution: Department of Geology, University of AkronRecent high levels of Lake Erie have produced severe erosion and mass wasting along the shore. At the same time they have created excellent exposures of glacial and postglacial deposits east of Cleveland, Ohio. Glacial deposits consist of an older Coastal till and the Late Wisconsinan Ashtabula Till, whereas postglacial deposits generally are gravels, sands and silts. Lithofacies of the Ashtabula Till exposed at Sims Park in Euclid, Ohio, include sheared, massive diamicts and resedimented diamicts. The lowest sheared massive diamict previously identified as the Coastal till possibly represents a lodgement till deposited by Ashtabula ice. Beach deposits at Mentor Headlands resulted from construction of manmade structures. At Camp Isaac Jogues, deltaic sands overlie a sequence of diamicts, which has an unusually high carbonate content when compared to other sections along the shore. The geometry of the overlying sands and the facies sequence strongly suggest a river-dominated deltaic system. Two sand pits in beach ridges (one at the Warren level and the other at the Arkona level) farther inland contain coarse-grained facies that may represent an outwash plain or coastal barrier overlain by dune sand. A log dated at 13-4 ka was found at the Arkona level, 1 km south of the second pit

Stakeholder Theory and Marketing: Moving from a Firm-Centric to a Societal Perspective

This essay is inspired by the ideas and research examined in the special section on “Stakeholder Marketing” of the Journal of Public Policy & Marketing in 2010. The authors argue that stakeholder marketing is slowly coalescing with the broader thinking that has occurred in the stakeholder management and ethics literature streams during the past quarter century. However, the predominant view of stakeholders that many marketers advocate is still primarily pragmatic and company centric. The position advanced herein is that stronger forms of stakeholder marketing that reflect more normative, macro/societal, and network-focused orientations are necessary. The authors briefly explain and justify these characteristics in the context of the growing “prosociety” and “proenvironment” perspectives—orientations that are also in keeping with the public policy focus of this journal. Under the “hard form” of stakeholder theory, which the authors endorse, marketing managers must realize that serving stakeholders sometimes requires sacrificing maximum profits to mitigate outcomes that would inflict major damage on other stakeholders, especially society

Precision medicine to improve use of bleeding avoidance strategies and reduce bleeding in patients undergoing percutaneous coronary intervention: Prospective cohort study before and after implementation of personalized bleeding risks

Objective To examine whether prospective bleeding risk estimates for patients undergoing percutaneous coronary intervention could improve the use of bleeding avoidance strategies and reduce bleeding. Design Prospective cohort study comparing the use of bleeding avoidance strategies and bleeding rates before and after implementation of prospective risk stratification for peri-procedural bleeding. Setting Nine hospitals in the United States. Participants All patients undergoing percutaneous coronary intervention for indications other than primary reperfusion for ST elevation myocardial infarction. Main outcome measures Use of bleeding avoidance strategies, including bivalirudin, radial approach, and vascular closure devices, and peri-procedural bleeding rates, stratified by bleeding risk. Observed changes were adjusted for changes observed in a pool of 1135 hospitals without access to pre-procedural risk stratification. Hospital level and physician level variability in use of bleeding avoidance strategies was examined. Results In a comparison of 7408 pre-intervention procedures with 3529 post-intervention procedures, use of bleeding avoidance strategies within intervention sites increased with pre-procedural risk stratification (odds ratio 1.81, 95% confidence interval 1.44 to 2.27), particularly among higher risk patients (2.03, 1.58 to 2.61; 1.41, 1.09 to 1.83 in low risk patients, after adjustment for control sites; P for interaction=0.05). Bleeding rates within intervention sites were significantly lower after implementation of risk stratification (1.0% v 1.7%; odds ratio 0.56, 0.40 to 0.78; 0.62, 0.44 to 0.87, after adjustment); the reduction in bleeding was greatest in high risk patients. Marked variability in use of bleeding avoidance strategies was observed across sites and physicians, both before and after implementation. Conclusions Prospective provision of individualized bleeding risk estimates was associated with increased use of bleeding avoidance strategies and lower bleeding rates. Marked variability between providers highlights an important opportunity to improve the consistency, safety, and quality of care. Study registration Clinicaltrials.gov NCT01383382