The Emergence of Precision Urologic Oncology: A Collaborative Review on Biomarker-driven Therapeutics

CONTEXT: Biomarker-driven cancer therapy, also referred to as precision oncology, has received increasing attention for its promise of improving patient outcomes by defining subsets of patients more likely to respond to various therapies. OBJECTIVES: In this collaborative review article, we examine recent literature regarding biomarker-driven therapeutics in urologic oncology, to better define the state of the field, explore the current evidence supporting utility of this approach, and gauge potential for the future. EVIDENCE ACQUISITION: We reviewed relevant literature, with a particular focus on recent studies about targeted therapy, predictors of response, and biomarker development. EVIDENCE SYNTHESIS: The recent advances in molecular profiling have led to a rapid expansion of potential biomarkers and predictive information for patients with urologic malignancies. Across disease states, distinct molecular subtypes of cancers have been identified, with the potential to inform choices of management strategy. Biomarkers predicting response to standard therapies (such as platinum-based chemotherapy) are emerging. In several malignancies (particularly renal cell carcinoma and castration-resistant prostate cancer), targeted therapy against commonly altered signaling pathways has emerged as standard of care. Finally, targeted therapy against alterations present in rare patients (less than 2%) across diseases has the potential to drastically alter patterns of care and choices of therapeutic options. CONCLUSIONS: Precision medicine has the highest potential to impact the care of patients. Prospective studies in the setting of clinical trials and standard of care therapy will help define reliable predictive biomarkers and new therapeutic targets leading to real improvement in patient outcomes. PATIENT SUMMARY: Precision oncology uses molecular information (DNA and RNA) from the individual and the tumor to match the right patient with the right treatment. Tremendous strides have been made in defining the molecular underpinnings of urologic malignancies and understanding how these predict response to treatment—this represents the future of urologic oncology

Perceiving Others’ Feelings: The Importance of Personality and Social Structure

Recent research has explored the relationship between social hierarchy and empathic accuracy— the ability to accurately infer others’ mental states. In the current research, we tested the hypothesis that, regardless of one’s personal level of status and power, simply believing that social inequality is natural and morally acceptable (e.g., endorsement of social dominance orientation, or SDO), would be negatively associated with empathic accuracy. In a sample of managers, a group for whom empathic accuracy is a valuable skill, empathic accuracy was lower for those who possessed structural power and also for those who endorsed social dominance, regardless of their structural power. Moreover, men were less empathically accurate than women, a relationship statistically mediated by men’s higher SDO and greater structural power. These findings suggest that for empathic abilities, it matters just as much what you think about social hierarchies as it does where you stand within them

Predicting Phenotypic Diversity and the Underlying Quantitative Molecular Transitions

During development, signaling networks control the formation of multicellular patterns. To what extent quantitative fluctuations in these complex networks may affect multicellular phenotype remains unclear. Here, we describe a computational approach to predict and analyze the phenotypic diversity that is accessible to a developmental signaling network. Applying this framework to vulval development in C. elegans, we demonstrate that quantitative changes in the regulatory network can render ~500 multicellular phenotypes. This phenotypic capacity is an order-of-magnitude below the theoretical upper limit for this system but yet is large enough to demonstrate that the system is not restricted to a select few outcomes. Using metrics to gauge the robustness of these phenotypes to parameter perturbations, we identify a select subset of novel phenotypes that are the most promising for experimental validation. In addition, our model calculations provide a layout of these phenotypes in network parameter space. Analyzing this landscape of multicellular phenotypes yielded two significant insights. First, we show that experimentally well-established mutant phenotypes may be rendered using non-canonical network perturbations. Second, we show that the predicted multicellular patterns include not only those observed in C. elegans, but also those occurring exclusively in other species of the Caenorhabditis genus. This result demonstrates that quantitative diversification of a common regulatory network is indeed demonstrably sufficient to generate the phenotypic differences observed across three major species within the Caenorhabditis genus. Using our computational framework, we systematically identify the quantitative changes that may have occurred in the regulatory network during the evolution of these species. Our model predictions show that significant phenotypic diversity may be sampled through quantitative variations in the regulatory network without overhauling the core network architecture. Furthermore, by comparing the predicted landscape of phenotypes to multicellular patterns that have been experimentally observed across multiple species, we systematically trace the quantitative regulatory changes that may have occurred during the evolution of the Caenorhabditis genus

Unifying darko-lepto-genesis with scalar triplet inflation

We present a scalar triplet extension of the standard model to unify the origin of inflation with neutrino mass, asymmetric dark matter and leptogenesis. In presence of non-minimal couplings to gravity the scalar triplet, mixed with the standard model Higgs, plays the role of inflaton in the early Universe, while its decay to SM Higgs, lepton and dark matter simultaneously generate an asymmetry in the visible and dark matter sectors. On the other hand, in the low energy effective theory the induced vacuum expectation value of the triplet gives sub-eV Majorana masses to active neutrinos. We investigate the model parameter space leading to successful inflation as well as the observed dark matter to baryon abundance. Assuming the standard model like Higgs mass to be at 125-126 GeV, we found that the mass scale of the scalar triplet to be ~ O(10^9) GeV and its trilinear coupling to doublet Higgs is ~ 0.09 so that it not only evades the possibility of having a metastable vacuum in the standard model, but also lead to a rich phenomenological consequences as stated above. Moreover, we found that the scalar triplet inflation strongly constrains the quartic couplings, while allowing for a wide range of Yukawa couplings which generate the CP asymmetries in the visible and dark matter sectors.Comment: (v1) 29 pages, 11 figures; (v2) 30 pages, 1 figure added and discussions expanded, to appear in Nuclear Physics

Polarization of coalitions in an agent-based model of political discourse

Political discourse is the verbal interaction between political actors in a policy domain. This article explains the formation of polarized advocacy or discourse coalitions in this complex phenomenon by presenting a dynamic, stochastic, and discrete agent-based model based on graph theory and local optimization. In a series of thought experiments, actors compute their utility of contributing a specific statement to the discourse by following ideological criteria, preferential attachment, agenda-setting strategies, governmental coherence, or other mechanisms. The evolving macro-level discourse is represented as a dynamic network and evaluated against arguments from the literature on the policy process. A simple combination of four theoretical mechanisms is already able to produce artificial policy debates with theoretically plausible properties. Any sufficiently realistic configuration must entail innovative and path-dependent elements as well as a blend of exogenous preferences and endogenous opinion formation mechanisms

Inefficient NGO labels: strategic proliferation and fragmentation in the market for certification

NGO certication is a prerequisite for corporate engagement in enhanced social behaviors in many settings. Labels with broad scope (like sustainability) coexist with niche competitors much narrower in scope (like bird-friendliness). When NGOs compete for adoptions the wrong suite of schemes emerges, providing a rationale for regulation. An incumbent NGO may strategically narrow the breadth of its label to deter entry of competing schemes, reducing welfare. Even when entry is accommodated, welfare is compromised. Modeling multi-issue competition between NGOs allows us to be the first to analyze label fragmentation and provide a novel perspective on proliferation that has frustrated practitioners

Prostaglandin E2 and T cells: friends or foes?

Our understanding of the key players involved in the differential regulation of T-cell responses during inflammation, infection and auto-immunity is fundamental for designing efficient therapeutic strategies against immune diseases. With respect to this, the inhibitory role of the lipid mediator prostaglandin E2 (PGE2) in T-cell immunity has been documented since the 1970s. Studies that ensued investigating the underlying mechanisms substantiated the suppressive function of micromolar concentrations of PGE2 in T-cell activation, proliferation, differentiation and migration. However, the past decade has seen a revolution in this perspective, since nanomolar concentrations of PGE2 have been shown to potentiate Th1 and Th17 responses and aid in T-cell proliferation. The understanding of concentration-specific effects of PGE2 in other cell types, the development of mice deficient in each subtype of the PGE2 receptors (EP receptors) and the delineation of signalling pathways mediated by the EP receptors have enhanced our understanding of PGE2 as an immune-stimulator. PGE2 regulates a multitude of functions in T-cell activation and differentiation and these effects vary depending on the micro-environment of the cell, maturation and activation state of the cell, type of EP receptor involved, local concentration of PGE2 and whether it is a homeostatic or inflammatory scenario. In this review, we compartmentalize the various aspects of this complex relationship of PGE2 with T lymphocytes. Given the importance of this molecule in T-cell activation, we also address the possibility of using EP receptor antagonism as a potential therapeutic approach for some immune disorders

Microscopic Aspects of Stretched Exponential Relaxation (SER) in Homogeneous Molecular and Network Glasses and Polymers

Because the theory of SER is still a work in progress, the phenomenon itself can be said to be the oldest unsolved problem in science, as it started with Kohlrausch in 1847. Many electrical and optical phenomena exhibit SER with probe relaxation I(t) ~ exp[-(t/{\tau}){\beta}], with 0 < {\beta} < 1. Here {\tau} is a material-sensitive parameter, useful for discussing chemical trends. The "shape" parameter {\beta} is dimensionless and plays the role of a non-equilibrium scaling exponent; its value, especially in glasses, is both practically useful and theoretically significant. The mathematical complexity of SER is such that rigorous derivations of this peculiar function were not achieved until the 1970's. The focus of much of the 1970's pioneering work was spatial relaxation of electronic charge, but SER is a universal phenomenon, and today atomic and molecular relaxation of glasses and deeply supercooled liquids provide the most reliable data. As the data base grew, the need for a quantitative theory increased; this need was finally met by the diffusion-to-traps topological model, which yields a remarkably simple expression for the shape parameter {\beta}, given by d*/(d* + 2). At first sight this expression appears to be identical to d/(d + 2), where d is the actual spatial dimensionality, as originally derived. The original model, however, failed to explain much of the data base. Here the theme of earlier reviews, based on the observation that in the presence of short-range forces only d* = d = 3 is the actual spatial dimensionality, while for mixed short- and long-range forces, d* = fd = d/2, is applied to four new spectacular examples, where it turns out that SER is useful not only for purposes of quality control, but also for defining what is meant by a glass in novel contexts. (Please see full abstract in main text

Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites

Tissue-resident memory T cells (TRMs) in mice mediate optimal protective immunity to infection and vaccination, while in humans, the existence and properties of TRMs remain unclear. Here, we use a unique human tissue resource to determine whether human tissue memory T cells constitute a distinct subset in diverse mucosal and lymphoid tissues. We identify a core transcriptional profile within the CD69+ subset of memory CD4+ and CD8+ T cells in lung and spleen that is distinct from that of CD69− TEM cells in tissues and circulation and defines human TRMs based on homology to the transcriptional profile of mouse CD8+ TRMs. Human TRMs in diverse sites exhibit increased expression of adhesion and inhibitory molecules, produce both pro-inflammatory and regulatory cytokines, and have reduced turnover compared with circulating TEM, suggesting unique adaptations for in situ immunity. Together, our results provide a unifying signature for human TRM and a blueprint for designing tissue-targeted immunotherapies